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Related disorders of Pallister Killian Mosaic Syndrome
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Symptoms of the following disorders can be similar to those of Pallister Killian mosaic syndrome. Comparisons may be useful for a differential diagnosis:Hypomelanosis of Ito is a rare disorder in which the main characteristic is lesions of the skin. A whorl-like lack of pigmentation of the skin may occur on any part of the body except the soles, palms, and scalp. Over half of the patients with this disorder may have seizures, intellectual disability, crossed eyes, nearsightedness, a cleft along the edge of the eyeball (coloboma), an abnormally small head and/or an abnormal overgrowth of brain tissue (megalencephaly). Autosomal dominant inheritance has been suggested in some cases. For more information on this disorder, choose “Hypomelanosis of Ito” as your search term in the Rare Disease Database.)Chromosome 12, partial trisomy 12P, is a rare genetic disorder in which there is a triplicated section of the short arm of the 12th chromosome. Patients with this disorder have a lack of muscle tone (hypotonia), growth retardation, and distinct facial features such as a flat upturned nose with a wide bridge, shallow eye sockets, a vertical fold of the skin over the inner corner of the eye, an upward slant of the opening between the upper and lower eyelids, a long thick lower lip, a large tongue and short broad hands with the fifth finger bent to the side. Chromosome 12, partial trisomy 12P affects females twice as often as males.
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Related disorders of Pallister Killian Mosaic Syndrome. Symptoms of the following disorders can be similar to those of Pallister Killian mosaic syndrome. Comparisons may be useful for a differential diagnosis:Hypomelanosis of Ito is a rare disorder in which the main characteristic is lesions of the skin. A whorl-like lack of pigmentation of the skin may occur on any part of the body except the soles, palms, and scalp. Over half of the patients with this disorder may have seizures, intellectual disability, crossed eyes, nearsightedness, a cleft along the edge of the eyeball (coloboma), an abnormally small head and/or an abnormal overgrowth of brain tissue (megalencephaly). Autosomal dominant inheritance has been suggested in some cases. For more information on this disorder, choose “Hypomelanosis of Ito” as your search term in the Rare Disease Database.)Chromosome 12, partial trisomy 12P, is a rare genetic disorder in which there is a triplicated section of the short arm of the 12th chromosome. Patients with this disorder have a lack of muscle tone (hypotonia), growth retardation, and distinct facial features such as a flat upturned nose with a wide bridge, shallow eye sockets, a vertical fold of the skin over the inner corner of the eye, an upward slant of the opening between the upper and lower eyelids, a long thick lower lip, a large tongue and short broad hands with the fifth finger bent to the side. Chromosome 12, partial trisomy 12P affects females twice as often as males.
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Pallister Killian Mosaic Syndrome
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nord_928_5
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Diagnosis of Pallister Killian Mosaic Syndrome
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Diagnosis is usually made from a chromosome study of skin cells (fibroblasts) that reveals 47 chromosomes including an extra small chromosome that has two short (p) arms and no long (q) arm (isochromosome). Chromosomal microarray, the first tier analyses in malformation syndromes, can also reveal Pallister Killian syndrome, if the right tissue is selected. Blood chromosome analyses usually shows normal number of chromosomes, but some affected persons have some blood cells (lymphocytes) with an isochromosome 12p. Cells with high cell turnover such as blood may lose the additional chromosomal material over time, and thereby give a false negative result on blood. Therefore, a normal blood chromosomal analysis does not completely rule out Pallister-Killian mosaic syndrome.Two individuals with Pallister-Killian mosaic syndrome have been reported with five copies (hexasomy) for chromosome 12p.Pallister-Killian mosaic syndrome can be diagnosed before birth (prenatally) by removing a small amount of fluid that is in the womb during pregnancy (amniocentesis) or by removing a small number of cells from outside the sac where the fetus develops (chorionic villous sampling). Cell cultures may yield a false negative however, and a normal chromosomal analysis does not completely rule out the condition.
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Diagnosis of Pallister Killian Mosaic Syndrome. Diagnosis is usually made from a chromosome study of skin cells (fibroblasts) that reveals 47 chromosomes including an extra small chromosome that has two short (p) arms and no long (q) arm (isochromosome). Chromosomal microarray, the first tier analyses in malformation syndromes, can also reveal Pallister Killian syndrome, if the right tissue is selected. Blood chromosome analyses usually shows normal number of chromosomes, but some affected persons have some blood cells (lymphocytes) with an isochromosome 12p. Cells with high cell turnover such as blood may lose the additional chromosomal material over time, and thereby give a false negative result on blood. Therefore, a normal blood chromosomal analysis does not completely rule out Pallister-Killian mosaic syndrome.Two individuals with Pallister-Killian mosaic syndrome have been reported with five copies (hexasomy) for chromosome 12p.Pallister-Killian mosaic syndrome can be diagnosed before birth (prenatally) by removing a small amount of fluid that is in the womb during pregnancy (amniocentesis) or by removing a small number of cells from outside the sac where the fetus develops (chorionic villous sampling). Cell cultures may yield a false negative however, and a normal chromosomal analysis does not completely rule out the condition.
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Pallister Killian Mosaic Syndrome
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nord_928_6
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Therapies of Pallister Killian Mosaic Syndrome
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TreatmentThere is no specific therapy for individuals with Pallister-Killian mosaic syndrome. Affected children may benefit from early intervention programs and special education. Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
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Therapies of Pallister Killian Mosaic Syndrome. TreatmentThere is no specific therapy for individuals with Pallister-Killian mosaic syndrome. Affected children may benefit from early intervention programs and special education. Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
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Pallister Killian Mosaic Syndrome
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nord_929_0
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Overview of Pallister W Syndrome
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Pallister W syndrome is a rare genetic disorder characterized by unusual facial features such as clefting of the palate and the upper lip, a broad flat nose, widely spaced slanted eyes, and/or downslanting eyelid folds (palpebral fissures). Other symptoms may include mental retardation, speech problems, bone deformities of the arms and legs, and/or seizures. The exact cause of Pallister W syndrome is not known.
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Overview of Pallister W Syndrome. Pallister W syndrome is a rare genetic disorder characterized by unusual facial features such as clefting of the palate and the upper lip, a broad flat nose, widely spaced slanted eyes, and/or downslanting eyelid folds (palpebral fissures). Other symptoms may include mental retardation, speech problems, bone deformities of the arms and legs, and/or seizures. The exact cause of Pallister W syndrome is not known.
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Pallister W Syndrome
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nord_929_1
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Symptoms of Pallister W Syndrome
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Pallister W syndrome is apparent at birth. It is characterized by widely spaced eyes (hypertelorism) with downward slanting eyelid folds (palpebral fissures), a broad flat nasal bridge, a broad tip of the nose, a broad flat jaw, central clefting of the palate or upper lip, seizures, and mental retardation. There may also be bone abnormalities in the arms and legs such as abnormal deviation of the elbow away from the body when the arm is extended (cubitus valgus). Other symptoms may include hair that does not lie flat on the head (cowlick), missing teeth (partial adontia), broad uvula, and a high broad forehead. Additional findings may include tremor and/or involuntary muscle contractions (i.e., spasticity).
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Symptoms of Pallister W Syndrome. Pallister W syndrome is apparent at birth. It is characterized by widely spaced eyes (hypertelorism) with downward slanting eyelid folds (palpebral fissures), a broad flat nasal bridge, a broad tip of the nose, a broad flat jaw, central clefting of the palate or upper lip, seizures, and mental retardation. There may also be bone abnormalities in the arms and legs such as abnormal deviation of the elbow away from the body when the arm is extended (cubitus valgus). Other symptoms may include hair that does not lie flat on the head (cowlick), missing teeth (partial adontia), broad uvula, and a high broad forehead. Additional findings may include tremor and/or involuntary muscle contractions (i.e., spasticity).
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Pallister W Syndrome
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nord_929_2
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Causes of Pallister W Syndrome
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The exact cause of Pallister W syndrome is not known. The disorder is thought to be inherited as a X-linked genetic trait. Geneticists interested in this disorder cannot agree about whether genetic transmission follows the rules of dominant or recessive inheritance patterns.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.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. X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females have two X chromosomes but one of the X chromosomes is “turned off” and all of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder because it is usually the X chromosome with the abnormal gene that is “turned off”. A male has one X chromosome and if he inherits an X chromosome that contains a disease gene, he will develop the disease. 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. 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. X-linked dominant disorders are also caused by an abnormal gene on the X chromosome, but in these rare conditions, females with an abnormal gene are affected with the disease. Males with an abnormal gene are more severely affected than females, and many of these males do not survive.Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. All individuals carry a few abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. 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.
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Causes of Pallister W Syndrome. The exact cause of Pallister W syndrome is not known. The disorder is thought to be inherited as a X-linked genetic trait. Geneticists interested in this disorder cannot agree about whether genetic transmission follows the rules of dominant or recessive inheritance patterns.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.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. X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females have two X chromosomes but one of the X chromosomes is “turned off” and all of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder because it is usually the X chromosome with the abnormal gene that is “turned off”. A male has one X chromosome and if he inherits an X chromosome that contains a disease gene, he will develop the disease. 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. 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. X-linked dominant disorders are also caused by an abnormal gene on the X chromosome, but in these rare conditions, females with an abnormal gene are affected with the disease. Males with an abnormal gene are more severely affected than females, and many of these males do not survive.Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. All individuals carry a few abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. 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.
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Pallister W Syndrome
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nord_929_3
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Affects of Pallister W Syndrome
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Pallister W syndrome is a very rare disorder. As of the year 2000, only six cases had been reported in the medical literature. More than half involved male infants but the numbers are not large enough to draw any conclusions regarding whether it affects one sex more than the other.
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Affects of Pallister W Syndrome. Pallister W syndrome is a very rare disorder. As of the year 2000, only six cases had been reported in the medical literature. More than half involved male infants but the numbers are not large enough to draw any conclusions regarding whether it affects one sex more than the other.
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Pallister W Syndrome
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nord_929_4
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Related disorders of Pallister W Syndrome
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Symptoms of the following disorders can be similar to those of Pallister-W Syndrome. Comparisons may be useful for a differential diagnosis:Oto-Palato-Digital Syndrome, Types I and II, characteristically affect males more severely than females. Clefting of the palate, slanting of the eyes, abnormalities of the face, fingers and toes, and speech problems occur. (For more information on this disorder, choose “Oto-Palato-Digital” as your search term in the Rare Disease Database.)Frontometaphyseal Dysplasia is a rare genetic disorder characterized by coarse facial features that include a wide nasal bridge, widely spaced eyes, overgrowth of the bone over the eyes, a small jawbone and incomplete development of the sinuses. Multiple deformities of the teeth and bones may also be present. Occasionally mental retardation may occur.Larsen Syndrome is a multi-system genetic disorder that is present at birth. It is characterized by multiple bone dislocations and abnormalities, an extremely high arch of the foot, non-tapering cylindrically shaped fingers, and an unusual facial appearance. In some cases short stature, heart problems, cleft palate or lips, deafness and/or mental retardation may occur. This disorder is inherited through an autosomal dominant or recessive trait. (For more information on this disorder, choose “Larsen” as your search term in the Rare Disease Database.)Oro-Facial-Digital Syndrome is a rare genetic disorder in which there have been four types identified. Symptoms common to all types include episodes of neuromuscular disturbances, split tongue, splits in the jaw, midline cleft lip, overgrowth of the membrane that supports the tongue, a broad based nose, vertical folds of the skin covering the inner angle where the eyelids meet (epicanthic folds), more than the normal number of fingers and/or toes, shorter than normal fingers and/or toes, and more than the normal number of divisions between skull sections. (For more information on this disorder, choose “Oro-Facial-Digital” as your search term in the Rare Disease Database.)
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Related disorders of Pallister W Syndrome. Symptoms of the following disorders can be similar to those of Pallister-W Syndrome. Comparisons may be useful for a differential diagnosis:Oto-Palato-Digital Syndrome, Types I and II, characteristically affect males more severely than females. Clefting of the palate, slanting of the eyes, abnormalities of the face, fingers and toes, and speech problems occur. (For more information on this disorder, choose “Oto-Palato-Digital” as your search term in the Rare Disease Database.)Frontometaphyseal Dysplasia is a rare genetic disorder characterized by coarse facial features that include a wide nasal bridge, widely spaced eyes, overgrowth of the bone over the eyes, a small jawbone and incomplete development of the sinuses. Multiple deformities of the teeth and bones may also be present. Occasionally mental retardation may occur.Larsen Syndrome is a multi-system genetic disorder that is present at birth. It is characterized by multiple bone dislocations and abnormalities, an extremely high arch of the foot, non-tapering cylindrically shaped fingers, and an unusual facial appearance. In some cases short stature, heart problems, cleft palate or lips, deafness and/or mental retardation may occur. This disorder is inherited through an autosomal dominant or recessive trait. (For more information on this disorder, choose “Larsen” as your search term in the Rare Disease Database.)Oro-Facial-Digital Syndrome is a rare genetic disorder in which there have been four types identified. Symptoms common to all types include episodes of neuromuscular disturbances, split tongue, splits in the jaw, midline cleft lip, overgrowth of the membrane that supports the tongue, a broad based nose, vertical folds of the skin covering the inner angle where the eyelids meet (epicanthic folds), more than the normal number of fingers and/or toes, shorter than normal fingers and/or toes, and more than the normal number of divisions between skull sections. (For more information on this disorder, choose “Oro-Facial-Digital” as your search term in the Rare Disease Database.)
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Pallister W Syndrome
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nord_929_5
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Diagnosis of Pallister W Syndrome
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The characteristic facial features assist in the diagnosis.
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Diagnosis of Pallister W Syndrome. The characteristic facial features assist in the diagnosis.
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Pallister W Syndrome
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nord_929_6
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Therapies of Pallister W Syndrome
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TreatmentTreatment of Pallister W syndrome may consist of surgery to repair the clefting of the palate and lip, and to repair deformities of the arms and legs if necessary.. Anti-seizure medication may be prescribed to control seizures. Special education and related services will be helpful in school, and speech therapy may be required after surgical repair of the cleft palate.Genetic counseling may be of benefit for patients and their families. Other treatment is symptomatic and supportive.
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Therapies of Pallister W Syndrome. TreatmentTreatment of Pallister W syndrome may consist of surgery to repair the clefting of the palate and lip, and to repair deformities of the arms and legs if necessary.. Anti-seizure medication may be prescribed to control seizures. Special education and related services will be helpful in school, and speech therapy may be required after surgical repair of the cleft palate.Genetic counseling may be of benefit for patients and their families. Other treatment is symptomatic and supportive.
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Pallister W Syndrome
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nord_930_0
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Overview of Pallister-Hall Syndrome
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SummaryPallister-Hall syndrome (PHS) is an extremely rare genetic disorder that is typically apparent at birth. The symptoms and findings associated with the disorder may vary greatly in range and severity from patient to patient. However, in most individuals with PHS the abnormalities may include the presence of extra fingers and/or toes; an abnormal division of the epiglottis (bifid epiglottis); a malformation of the hypothalamus (hypothalamic hamartoma), a portion of the brain that coordinates the function of the pituitary gland and has several other functions; decreased pituitary function; and/or a condition in which a thin covering blocks the anal opening or the passage that normally connects the anus and the lowest part of the large intestine (rectum) fails to develop (imperforate anus). Additional symptoms and findings may include characteristic malformations of the head and facial area and/or other abnormalities, including genito-urinary malformations. PHS is inherited in an autosomal dominant pattern and is caused by pathogenic variants (gene changes) in the GLI3 gene.IntroductionPallister-Hall syndrome is named for Judith Hall and Philip Pallister who described the condition in 1980.
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Overview of Pallister-Hall Syndrome. SummaryPallister-Hall syndrome (PHS) is an extremely rare genetic disorder that is typically apparent at birth. The symptoms and findings associated with the disorder may vary greatly in range and severity from patient to patient. However, in most individuals with PHS the abnormalities may include the presence of extra fingers and/or toes; an abnormal division of the epiglottis (bifid epiglottis); a malformation of the hypothalamus (hypothalamic hamartoma), a portion of the brain that coordinates the function of the pituitary gland and has several other functions; decreased pituitary function; and/or a condition in which a thin covering blocks the anal opening or the passage that normally connects the anus and the lowest part of the large intestine (rectum) fails to develop (imperforate anus). Additional symptoms and findings may include characteristic malformations of the head and facial area and/or other abnormalities, including genito-urinary malformations. PHS is inherited in an autosomal dominant pattern and is caused by pathogenic variants (gene changes) in the GLI3 gene.IntroductionPallister-Hall syndrome is named for Judith Hall and Philip Pallister who described the condition in 1980.
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Pallister-Hall Syndrome
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nord_930_1
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Symptoms of Pallister-Hall Syndrome
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Symptoms and findings in individuals with PHS may vary greatly in range and severity from patient to patient. Whereas some affected individuals may have only a few characteristic abnormalities, others may have most symptoms and physical features associated with the disorder.The most common characteristic features of PHS include the presence of extra fingers and/or toes (polydactyly); fusion (osseous syndactyly) of certain fingers and/or toes (digits); and improper development (dysplasia) of the nails. In some affected persons, the polydactyly associated with PHS may be characterized by the presence of an extra digit between the third and fourth digits (mesoaxial polydactyly) of the hands and/or feet. Affected individuals may have an extra (supernumerary) digit on the “pinky” (ulnar) side of the hand or the outer (fibular) aspect of the foot (postaxial polydactyly). Many individuals with PHS may also have a condition in which a thin covering blocks the anal opening or the passage that normally connects the anus and the lowest part of the large intestine (rectum) fails to develop (imperforate anus). A few affected individuals also have genito-urinary malformations including hypospadias, bifid or hypoplastic scrotum, hydrometrocolpos and vaginal atresia.According to reports in the medical literature, one of the most significant features of PHS is the presence of a malformation of the hypothalamus (hypothalamic hamartoma), a portion of the brain that coordinates the function of the pituitary gland and that regulates many additional bodily functions. The pituitary gland is the hormone-producing gland at the base of the brain. This is a malformation (and is not a tumor) of the hypothalamus and may cause abnormalities in pituitary function in those who are severely affected. Impaired pituitary function can cause an abnormally small penis (micropenis), low functioning of the thyroid (hypothyroidism), growth hormone deficiency, precious puberty, or more rarely, can cause diabetes or lack of cortisol production. Seizures are also commonly associated with a hypothalamic hamartoma.In some infants affected by severe hypothalamic hamartoma, decreased or absent pituitary function (hypopituitarism) may be present at birth. This may lead to low blood sugar (hypoglycemia), abnormal electrolyte levels, and unusually high acid levels in blood and body tissue (metabolic acidosis). Affected individuals may also experience lethargy and an abnormal yellowish discoloration of the skin, mucous membranes, and whites of the eyes (jaundice). Hypopituitarism may result in severe, life-threatening complications without prompt, appropriate treatment. (For more information on hypopituitarism, see the Related Disorders section of this report.)Infants with PHS may also have distinctive features of the head and facial (craniofacial) area including small ears that are rotated toward the back of the head; a short nose with upturned nostrils (anteverted nares) and a broad or flat nasal bridge; and/or an unusually long vertical groove in the middle of the upper lip (philtrum). Affected individuals may also have a small tongue (microglossia); a cleft or fissure in the larynx, the organ in the throat that is involved in voice production and that prevents food from entering the airway during swallowing; and division of the epiglottis (bifid epiglottis), the flap of cartilage in front of the entrance to the larynx.Some individuals with PHS may have additional abnormalities. These may include the presence of certain teeth at birth (natal teeth), abnormal folds of movement-limiting mucous membrane tissue in the cheek area of the mouth (buccal frenula), abnormally short arms and/or legs (limbs), and/or dislocated hips. In some affected individuals, additional abnormalities may include abnormal development of the lobes of the lungs, absence (agenesis) and/or improper development (dysplasia) of the kidneys, heart defects that are present at birth (congenital heart defects), hypospadias, bifid or hypoplastic scrotum, hydrometrocolpos, and vaginal atresia.Although most individuals with PHS do not have life-threatening malformations, some affected individuals have an early lethality variant of the disorder. This early lethality is most likely attributable to adrenocortical hormone deficiency caused by the hypothalamic hamartoma or severe airway malformations such as laryngotracheal clefts.
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Symptoms of Pallister-Hall Syndrome. Symptoms and findings in individuals with PHS may vary greatly in range and severity from patient to patient. Whereas some affected individuals may have only a few characteristic abnormalities, others may have most symptoms and physical features associated with the disorder.The most common characteristic features of PHS include the presence of extra fingers and/or toes (polydactyly); fusion (osseous syndactyly) of certain fingers and/or toes (digits); and improper development (dysplasia) of the nails. In some affected persons, the polydactyly associated with PHS may be characterized by the presence of an extra digit between the third and fourth digits (mesoaxial polydactyly) of the hands and/or feet. Affected individuals may have an extra (supernumerary) digit on the “pinky” (ulnar) side of the hand or the outer (fibular) aspect of the foot (postaxial polydactyly). Many individuals with PHS may also have a condition in which a thin covering blocks the anal opening or the passage that normally connects the anus and the lowest part of the large intestine (rectum) fails to develop (imperforate anus). A few affected individuals also have genito-urinary malformations including hypospadias, bifid or hypoplastic scrotum, hydrometrocolpos and vaginal atresia.According to reports in the medical literature, one of the most significant features of PHS is the presence of a malformation of the hypothalamus (hypothalamic hamartoma), a portion of the brain that coordinates the function of the pituitary gland and that regulates many additional bodily functions. The pituitary gland is the hormone-producing gland at the base of the brain. This is a malformation (and is not a tumor) of the hypothalamus and may cause abnormalities in pituitary function in those who are severely affected. Impaired pituitary function can cause an abnormally small penis (micropenis), low functioning of the thyroid (hypothyroidism), growth hormone deficiency, precious puberty, or more rarely, can cause diabetes or lack of cortisol production. Seizures are also commonly associated with a hypothalamic hamartoma.In some infants affected by severe hypothalamic hamartoma, decreased or absent pituitary function (hypopituitarism) may be present at birth. This may lead to low blood sugar (hypoglycemia), abnormal electrolyte levels, and unusually high acid levels in blood and body tissue (metabolic acidosis). Affected individuals may also experience lethargy and an abnormal yellowish discoloration of the skin, mucous membranes, and whites of the eyes (jaundice). Hypopituitarism may result in severe, life-threatening complications without prompt, appropriate treatment. (For more information on hypopituitarism, see the Related Disorders section of this report.)Infants with PHS may also have distinctive features of the head and facial (craniofacial) area including small ears that are rotated toward the back of the head; a short nose with upturned nostrils (anteverted nares) and a broad or flat nasal bridge; and/or an unusually long vertical groove in the middle of the upper lip (philtrum). Affected individuals may also have a small tongue (microglossia); a cleft or fissure in the larynx, the organ in the throat that is involved in voice production and that prevents food from entering the airway during swallowing; and division of the epiglottis (bifid epiglottis), the flap of cartilage in front of the entrance to the larynx.Some individuals with PHS may have additional abnormalities. These may include the presence of certain teeth at birth (natal teeth), abnormal folds of movement-limiting mucous membrane tissue in the cheek area of the mouth (buccal frenula), abnormally short arms and/or legs (limbs), and/or dislocated hips. In some affected individuals, additional abnormalities may include abnormal development of the lobes of the lungs, absence (agenesis) and/or improper development (dysplasia) of the kidneys, heart defects that are present at birth (congenital heart defects), hypospadias, bifid or hypoplastic scrotum, hydrometrocolpos, and vaginal atresia.Although most individuals with PHS do not have life-threatening malformations, some affected individuals have an early lethality variant of the disorder. This early lethality is most likely attributable to adrenocortical hormone deficiency caused by the hypothalamic hamartoma or severe airway malformations such as laryngotracheal clefts.
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Pallister-Hall Syndrome
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nord_930_2
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Causes of Pallister-Hall Syndrome
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PHS is typically inherited in an autosomal dominant pattern with wide variability in expression and is caused by pathogenic variants in the GLI3 gene, termed GLI3-related PHS. In affected families, most individuals with the familial GLI3 gene variant will have symptoms and findings associated with the disorder (high penetrance). However, in such instances, the characteristics may vary in range and severity from patient to patient. The variability within a particular family appears to be less than the variability in affected members of different families. GLI3 is the associated gene in 95% of affected individuals with PHS. A few patients have been found to have two variants in the SMO gene, termed SMO-related PHS. This rare form of PHS is inherited in an autosomal recessive 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 changed (mutated) 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. In a number of patients with GLI3-related PHS, the GLI3 variant is not inherited from either parent and is instead caused by a new mutation. In general, these patients are more likely to be severely affected than is a child born to an affected parent.SMO-related PHS is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
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Causes of Pallister-Hall Syndrome. PHS is typically inherited in an autosomal dominant pattern with wide variability in expression and is caused by pathogenic variants in the GLI3 gene, termed GLI3-related PHS. In affected families, most individuals with the familial GLI3 gene variant will have symptoms and findings associated with the disorder (high penetrance). However, in such instances, the characteristics may vary in range and severity from patient to patient. The variability within a particular family appears to be less than the variability in affected members of different families. GLI3 is the associated gene in 95% of affected individuals with PHS. A few patients have been found to have two variants in the SMO gene, termed SMO-related PHS. This rare form of PHS is inherited in an autosomal recessive 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 changed (mutated) 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. In a number of patients with GLI3-related PHS, the GLI3 variant is not inherited from either parent and is instead caused by a new mutation. In general, these patients are more likely to be severely affected than is a child born to an affected parent.SMO-related PHS is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
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Affects of Pallister-Hall Syndrome
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PHS is an extremely rare disorder that is typically apparent at birth (congenital), appears to affect males and females equally. Approximately 100 patients have been reported in the medical literature, including affected individuals from several large families (kindreds) and single occurrences in which a positive family history has not been found. The range and severity of associated symptoms and findings may vary greatly from one affected individual to the next (variable expressivity). Because PHS is extremely variable and therefore may be under- or misdiagnosed, it may be difficult to determine the true frequency of the disorder in the general population.
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Affects of Pallister-Hall Syndrome. PHS is an extremely rare disorder that is typically apparent at birth (congenital), appears to affect males and females equally. Approximately 100 patients have been reported in the medical literature, including affected individuals from several large families (kindreds) and single occurrences in which a positive family history has not been found. The range and severity of associated symptoms and findings may vary greatly from one affected individual to the next (variable expressivity). Because PHS is extremely variable and therefore may be under- or misdiagnosed, it may be difficult to determine the true frequency of the disorder in the general population.
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Related disorders of Pallister-Hall Syndrome
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Symptoms of the following disorders can be similar to those of Pallister-Hall syndrome. Comparisons may be useful for a differential diagnosis:There are several related disorders characterized by pathogenic variants in the GLI3 gene. This group of disorders includes Greig cephalopolysyndactyly syndrome, Pallister-Hall syndrome, postaxial polydactyly type A, preaxial polydactyly type IV, oral-facial-digital syndrome, acrocallosal syndrome, and a novel disorder with polydactyly associated with biallelic variants in GLI3. These disorders occur due to distinct variants of the GLI3 gene (allelic disorders) and share some similar characteristics. Despite similarities, these disorders are considered distinct clinical entities.Greig cephalopolysyndactyly syndrome (GCPS) is a rare inherited disorder characterized by physical abnormalities affecting the fingers and toes (digits) and the head and facial area. Characteristic digital features may include extra fingers and/or toes, webbing and/or fusion of the fingers and/or toes, and/or additional abnormalities. Craniofacial features associated with this disorder may include a large and/or unusually shaped skull; a high, prominent forehead (frontal bossing); an abnormally broad nasal bridge; widely spaced eyes (ocular hypertelorism); and/or other physical findings. The range and severity of symptoms may vary greatly among affected individuals. In most families, GCPS is inherited in an autosomal dominant pattern. For more information on this disorder, choose “Greig Cephalopolysyndactyly Syndrome” as your search term in the Rare Disease Database.Oral-facial-digital syndromes (OFD) are a group of rare inherited disorders categorized into many subtypes. Symptoms common to many types of the syndrome include neuromuscular disturbances, overgrowth of the band of tissue under the tongue (frenulum), extra skin folds at the inner corners of the eyes (epicanthus), broad-based nose, malformations of the hands and feet (i.e., polydactyly or webbing between the fingers and/or toes), extra divisions between the bones of the skull, and/or clefts of the tongue, palate, and/or lip. Other symptoms depend on the form of the syndrome affecting the individual, and may include intellectual disability, extra teeth and/or tooth malformations, and/or eyes that look away from each other (exotropia) or wink involuntarily in an alternating pattern). (For more information on this disorder, choose “Oral- Facial-Digital Syndrome” as your search term in the Rare Disease Database.) Some patients with OFD have GLI3variants.There are several disorders that overlap with PHS but are caused by variants in other genes.Holt-Oram syndrome (HOS) is a rare genetic disorder characterized by distinctive malformations of the bones of the thumbs and forearms and/or abnormalities of the heart. The symptoms and physical findings associated with Holt-Oram syndrome may vary greatly from person to person. In many infants with the disorder, the thumbs may be absent or underdeveloped or have an extra bone (triphalangy). Affected infants may also have additional upper limb malformations such as underdevelopment (hypoplasia) of or extra bones in the wrists (e.g., scaphoid bone); malformations of certain bones of the hands (metacarpals); and/or underdevelopment of the bones of the forearms (radius and ulna) and/or the bones of the upper arms (humerus). The shoulder blades (scapulae), the collarbones (clavicles), and/or other bones may also be abnormal.Holt-Oram syndrome is inherited in an autosomal dominant pattern (For more information on this disorder, choose “Holt-Oram Syndrome” as your search term in the Rare Disease Database.) McKusick-Kaufman syndrome is a very rare genetic disorder characterized by the presence of a cystic abdominal mass caused by dilation of the vagina and uterus and containing cervical secretions (hydrometrocolpos), abnormalities of the heart and extra well-formed digits on the hands and /or feet (mesoaxial or postaxial polydactyly).Hydrolethalus syndrome is a very rare developmental disorder characterized by severe brain and/or spinal (central nervous system) malformations and extra fingers and/or toes. Two great toes on each foot, underdeveloped eyes, a small lower jaw, and/or a poorly formed nose are common. The head may be oversized (macrocephaly) with prominent areas on the forehead (frontal) and at the back of the head (occipital). Lung and heart abnormalities may also occur.Acrocallosal syndrome is a very rare disorder that includes widely spaced eyes, increased head size, polydactyly, seizures, and intellectual disability. A few patients with acrocallosal syndrome have been shown to have GLI3 variants.
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Related disorders of Pallister-Hall Syndrome. Symptoms of the following disorders can be similar to those of Pallister-Hall syndrome. Comparisons may be useful for a differential diagnosis:There are several related disorders characterized by pathogenic variants in the GLI3 gene. This group of disorders includes Greig cephalopolysyndactyly syndrome, Pallister-Hall syndrome, postaxial polydactyly type A, preaxial polydactyly type IV, oral-facial-digital syndrome, acrocallosal syndrome, and a novel disorder with polydactyly associated with biallelic variants in GLI3. These disorders occur due to distinct variants of the GLI3 gene (allelic disorders) and share some similar characteristics. Despite similarities, these disorders are considered distinct clinical entities.Greig cephalopolysyndactyly syndrome (GCPS) is a rare inherited disorder characterized by physical abnormalities affecting the fingers and toes (digits) and the head and facial area. Characteristic digital features may include extra fingers and/or toes, webbing and/or fusion of the fingers and/or toes, and/or additional abnormalities. Craniofacial features associated with this disorder may include a large and/or unusually shaped skull; a high, prominent forehead (frontal bossing); an abnormally broad nasal bridge; widely spaced eyes (ocular hypertelorism); and/or other physical findings. The range and severity of symptoms may vary greatly among affected individuals. In most families, GCPS is inherited in an autosomal dominant pattern. For more information on this disorder, choose “Greig Cephalopolysyndactyly Syndrome” as your search term in the Rare Disease Database.Oral-facial-digital syndromes (OFD) are a group of rare inherited disorders categorized into many subtypes. Symptoms common to many types of the syndrome include neuromuscular disturbances, overgrowth of the band of tissue under the tongue (frenulum), extra skin folds at the inner corners of the eyes (epicanthus), broad-based nose, malformations of the hands and feet (i.e., polydactyly or webbing between the fingers and/or toes), extra divisions between the bones of the skull, and/or clefts of the tongue, palate, and/or lip. Other symptoms depend on the form of the syndrome affecting the individual, and may include intellectual disability, extra teeth and/or tooth malformations, and/or eyes that look away from each other (exotropia) or wink involuntarily in an alternating pattern). (For more information on this disorder, choose “Oral- Facial-Digital Syndrome” as your search term in the Rare Disease Database.) Some patients with OFD have GLI3variants.There are several disorders that overlap with PHS but are caused by variants in other genes.Holt-Oram syndrome (HOS) is a rare genetic disorder characterized by distinctive malformations of the bones of the thumbs and forearms and/or abnormalities of the heart. The symptoms and physical findings associated with Holt-Oram syndrome may vary greatly from person to person. In many infants with the disorder, the thumbs may be absent or underdeveloped or have an extra bone (triphalangy). Affected infants may also have additional upper limb malformations such as underdevelopment (hypoplasia) of or extra bones in the wrists (e.g., scaphoid bone); malformations of certain bones of the hands (metacarpals); and/or underdevelopment of the bones of the forearms (radius and ulna) and/or the bones of the upper arms (humerus). The shoulder blades (scapulae), the collarbones (clavicles), and/or other bones may also be abnormal.Holt-Oram syndrome is inherited in an autosomal dominant pattern (For more information on this disorder, choose “Holt-Oram Syndrome” as your search term in the Rare Disease Database.) McKusick-Kaufman syndrome is a very rare genetic disorder characterized by the presence of a cystic abdominal mass caused by dilation of the vagina and uterus and containing cervical secretions (hydrometrocolpos), abnormalities of the heart and extra well-formed digits on the hands and /or feet (mesoaxial or postaxial polydactyly).Hydrolethalus syndrome is a very rare developmental disorder characterized by severe brain and/or spinal (central nervous system) malformations and extra fingers and/or toes. Two great toes on each foot, underdeveloped eyes, a small lower jaw, and/or a poorly formed nose are common. The head may be oversized (macrocephaly) with prominent areas on the forehead (frontal) and at the back of the head (occipital). Lung and heart abnormalities may also occur.Acrocallosal syndrome is a very rare disorder that includes widely spaced eyes, increased head size, polydactyly, seizures, and intellectual disability. A few patients with acrocallosal syndrome have been shown to have GLI3 variants.
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Pallister-Hall Syndrome
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Diagnosis of Pallister-Hall Syndrome
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The diagnosis of PHS is made based on a thorough clinical evaluation, a detailed family history and a variety of specialized tests such as magnetic resonance imaging (MRI) used to detect the presence and dimensions of a hamartoma. Additional tests that may aid in the diagnosis and evaluating the severity of PHS include renal ultrasonography and fiberoptic laryngoscopy. Molecular genetic testing for variants in the GLI3 gene can confirm the diagnosis and may be especially important in helping to diagnose individuals with more mild presentations of the disorder. If the testing for GLI3 variants is negative, testing for SMO variants should be considered. Clinical Testing and Work-UpThe following evaluations may be done to determine the severity of disease in an individual diagnosed with PHS. Assessment for cortisol deficiency, consultation by an endocrinologist, cranial MRI to establish the location and extent of hamartoma, neurologic examination, limb X-rays, kidney ultrasound, laryngoscopy to view the epiglottis, surgical consultation if imperforate anus or anal stenosis is present and a developmental assessment.
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Diagnosis of Pallister-Hall Syndrome. The diagnosis of PHS is made based on a thorough clinical evaluation, a detailed family history and a variety of specialized tests such as magnetic resonance imaging (MRI) used to detect the presence and dimensions of a hamartoma. Additional tests that may aid in the diagnosis and evaluating the severity of PHS include renal ultrasonography and fiberoptic laryngoscopy. Molecular genetic testing for variants in the GLI3 gene can confirm the diagnosis and may be especially important in helping to diagnose individuals with more mild presentations of the disorder. If the testing for GLI3 variants is negative, testing for SMO variants should be considered. Clinical Testing and Work-UpThe following evaluations may be done to determine the severity of disease in an individual diagnosed with PHS. Assessment for cortisol deficiency, consultation by an endocrinologist, cranial MRI to establish the location and extent of hamartoma, neurologic examination, limb X-rays, kidney ultrasound, laryngoscopy to view the epiglottis, surgical consultation if imperforate anus or anal stenosis is present and a developmental assessment.
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Therapies of Pallister-Hall Syndrome
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Treatment
Infants with PHS who have decreased, or absent pituitary function (hypopituitarism) must be treated immediately with hormonal replacement therapy (i.e., thyroxine, and hydrocortisone). Treatment of hypopituitarism usually resolves the associated symptoms (hypoglycemia, abnormal electrolyte levels, and/or metabolic acidosis). Close monitoring and prompt treatment is imperative to prevent life-threatening complications.Periodic examinations with specialized equipment to monitor the hypothalamic malformation associated with this disorder are essential. An MRI test is often required since computerized tomography (CT scan) may not always detect hypothalamic hamartomas. Surgical removal of a hamartoma is generally not indicated since it is a malformation and is not a tumor. Surgical removal of extra digits is often performed during infancy but is increasingly being done later in life due to concerns about potential cognitive effects of general anesthesia in young children.Seizures may be treated with an anticonvulsant medication such as carbamazepine.Genetic counseling is recommended for affected individuals and their family members.
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Therapies of Pallister-Hall Syndrome. Treatment
Infants with PHS who have decreased, or absent pituitary function (hypopituitarism) must be treated immediately with hormonal replacement therapy (i.e., thyroxine, and hydrocortisone). Treatment of hypopituitarism usually resolves the associated symptoms (hypoglycemia, abnormal electrolyte levels, and/or metabolic acidosis). Close monitoring and prompt treatment is imperative to prevent life-threatening complications.Periodic examinations with specialized equipment to monitor the hypothalamic malformation associated with this disorder are essential. An MRI test is often required since computerized tomography (CT scan) may not always detect hypothalamic hamartomas. Surgical removal of a hamartoma is generally not indicated since it is a malformation and is not a tumor. Surgical removal of extra digits is often performed during infancy but is increasingly being done later in life due to concerns about potential cognitive effects of general anesthesia in young children.Seizures may be treated with an anticonvulsant medication such as carbamazepine.Genetic counseling is recommended for affected individuals and their family members.
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Overview of Palmoplantar Pustulosis
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Palmoplantar pustulosis (PPP) is a rare, recurrent inflammatory disorder. Affected individuals develop small to large sterile blisters filled with a yellow turbid liquid (pustules) on the palms of the hands and/or soles of the feet. The pustules may be painful and cause a burning feeling. The condition primarily affects women between 40 and 69 years of age, and predominantly smokers. The exact cause of PPP is not known. Researchers have determined that possible causes include smoking, bacterial infections (acute or chronic tonsillitis, dental infection, chronic sinusitis), contact allergies (mainly metals) and certain medications. Genetics may play a role for patients who have a family history of the disorder. PPP is strongly related to psoriasis vulgaris, some patients have both PPP and plaque psoriasis or PPP and psoriatic arthritis. Psoriatic nail involvement is frequently seen in PPP and a family history of psoriasis is recorded in 10-42% of patients affected by PPP. Depending on the cause, there are many treatments available including certain moisturizers, medications (topical steroids and/or retinoids), light therapy and systemic therapies for severe cases with retinoids, conventional immunosuppressants (methotrexate, cyclosporine) and/or biological therapies.
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Overview of Palmoplantar Pustulosis. Palmoplantar pustulosis (PPP) is a rare, recurrent inflammatory disorder. Affected individuals develop small to large sterile blisters filled with a yellow turbid liquid (pustules) on the palms of the hands and/or soles of the feet. The pustules may be painful and cause a burning feeling. The condition primarily affects women between 40 and 69 years of age, and predominantly smokers. The exact cause of PPP is not known. Researchers have determined that possible causes include smoking, bacterial infections (acute or chronic tonsillitis, dental infection, chronic sinusitis), contact allergies (mainly metals) and certain medications. Genetics may play a role for patients who have a family history of the disorder. PPP is strongly related to psoriasis vulgaris, some patients have both PPP and plaque psoriasis or PPP and psoriatic arthritis. Psoriatic nail involvement is frequently seen in PPP and a family history of psoriasis is recorded in 10-42% of patients affected by PPP. Depending on the cause, there are many treatments available including certain moisturizers, medications (topical steroids and/or retinoids), light therapy and systemic therapies for severe cases with retinoids, conventional immunosuppressants (methotrexate, cyclosporine) and/or biological therapies.
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Palmoplantar Pustulosis
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Symptoms of Palmoplantar Pustulosis
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PPP causes recurrent crops of sterile pustules to form on the palms of the hands and/or the soles of the feet The pustules often coalesce in an erythematous background where infiltrated and scaly plaques tends to form after several days with the onset of painful fissures. Itching and/or pain are often present. Patients may also feel like their hands and/or feet are burning. Due to these symptoms, patients may have difficulty walking and performing other daily tasks with the hands and feet.
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Symptoms of Palmoplantar Pustulosis. PPP causes recurrent crops of sterile pustules to form on the palms of the hands and/or the soles of the feet The pustules often coalesce in an erythematous background where infiltrated and scaly plaques tends to form after several days with the onset of painful fissures. Itching and/or pain are often present. Patients may also feel like their hands and/or feet are burning. Due to these symptoms, patients may have difficulty walking and performing other daily tasks with the hands and feet.
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Causes of Palmoplantar Pustulosis
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The exact cause of PPP is not known. Researchers have found some possible causes including smoking, infections, certain medications and genetics.
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Causes of Palmoplantar Pustulosis. The exact cause of PPP is not known. Researchers have found some possible causes including smoking, infections, certain medications and genetics.
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Affects of Palmoplantar Pustulosis
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PPP mostly affects women between 40 and 69 years of age and smokers, but this condition may affect people of any age.
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Affects of Palmoplantar Pustulosis. PPP mostly affects women between 40 and 69 years of age and smokers, but this condition may affect people of any age.
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Related disorders of Palmoplantar Pustulosis
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Some researchers suggest that PPP is a type of psoriasis, while others suggest that it is a separate disorder. Psoriasis is a skin condition that causes skin cells to multiply too quickly after inflammation. Symptoms of psoriasis include itchy, scaly skin and dry, red patches which may be painful. Rarely PPP can be part of a syndrome called SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) an autoinflammatory neutrophilic disease most frequently seen in Japan.
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Related disorders of Palmoplantar Pustulosis. Some researchers suggest that PPP is a type of psoriasis, while others suggest that it is a separate disorder. Psoriasis is a skin condition that causes skin cells to multiply too quickly after inflammation. Symptoms of psoriasis include itchy, scaly skin and dry, red patches which may be painful. Rarely PPP can be part of a syndrome called SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) an autoinflammatory neutrophilic disease most frequently seen in Japan.
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Palmoplantar Pustulosis
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Diagnosis of Palmoplantar Pustulosis
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A doctor will look at the affected skin and skin swabs might be indicated to confirm the sterile nature (without bacteria or fungi) inside the pustules. In some patients, a skin biopsy will be needed. If a biopsy is necessary, the doctor will take a piece of skin from the affected area to test it for histopathology.
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Diagnosis of Palmoplantar Pustulosis. A doctor will look at the affected skin and skin swabs might be indicated to confirm the sterile nature (without bacteria or fungi) inside the pustules. In some patients, a skin biopsy will be needed. If a biopsy is necessary, the doctor will take a piece of skin from the affected area to test it for histopathology.
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Palmoplantar Pustulosis
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Therapies of Palmoplantar Pustulosis
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Although there is no definitive cure for PPP but there are different treatment options available.Possible treatment options include:For severe cases, immunosuppressants like methotrexate or cyclosporine may be used. If these medications are not tolerated or inefficient, biologicals like TNF-alpha blockers (etanercept, adalimumab mainly), anti IL-12/23 inhibitor (Ustekinumab), anti IL-23 inhibitors (mainly Guselkumab) and anti IL-17 may be prescribed.Since PPP is common in smokers, quitting smoking may help symptoms improve. Avoidance of contact irritants (avoid wet work, use gloves, avoid using aggressive soaps and detergents) is also recommended. Limiting stress may also help symptoms get better.
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Therapies of Palmoplantar Pustulosis. Although there is no definitive cure for PPP but there are different treatment options available.Possible treatment options include:For severe cases, immunosuppressants like methotrexate or cyclosporine may be used. If these medications are not tolerated or inefficient, biologicals like TNF-alpha blockers (etanercept, adalimumab mainly), anti IL-12/23 inhibitor (Ustekinumab), anti IL-23 inhibitors (mainly Guselkumab) and anti IL-17 may be prescribed.Since PPP is common in smokers, quitting smoking may help symptoms improve. Avoidance of contact irritants (avoid wet work, use gloves, avoid using aggressive soaps and detergents) is also recommended. Limiting stress may also help symptoms get better.
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Palmoplantar Pustulosis
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Overview of Pancreatic Neuroendocrine Neoplasms (pNENs)
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The pancreas is a gland located between the stomach, spleen, duodenum and colon transversum. It contains specialized exocrine cells that secrete enzymes that travel to the intestines and aid in digestion as well as endocrine cells, so called islet cells. Pancreatic neuroendocrine neoplasms (pNENs) are an increasingly common group of malignancies that arise within the endocrine tissue of the pancreas. Endocrine tissue is specialized tissue that contains hormone-secreting cells (e.g. α-cells, ß-cells). These cells secrete several different hormones into the blood (endocrine) or to local cells (paracrine, autocrine). These hormones have a variety of functions within the body (e.g. glucose-metabolism). Neoplasms that arise from endocrine tissue may also secrete hormones, resulting in excessive levels of these hormones in the body and potentially a wide variety of symptoms. There are several different subtypes of functioning pNENs distinguished by the specific type of hormone that they secrete. Insulinomas and gastrinomas are the most common types of hormone secreting pNENs.Although there is no difference in diagnosis and therapy, pNENs can be differentiated as functioning or nonfunctioning. Functioning pNENs secrete hormones into the bloodstream, which cause special symptoms; nonfunctioning neoplasms may produce hormones, but no systemic symptoms. Nonfunctioning neuroendocrine neoplasms can still cause symptoms relating to tumor size and location such as obstruction or internal bleeding. They have some different differentiation (G1-3), but all of them have the potential for malignant transformation. Most pNENs occur sporadically, but in some cases, pNENs may occur as part of a larger genetic syndrome such as multiple endocrine neoplasia type 1 (MEN1) or von Hippel Lindau (VHL) syndrome.Pancreatic cancer as a general term usually refers to pancreatic adenocarcinoma, an aggressive malignant cancer with a poor prognosis. Approximately 95 percent of pancreatic malignancies are adenocarcinomas, for which the prognoses are in general worse than the prognosis of G1- and G2 pNENs. G3 neuroendocrine carcinomas have a similar poor prognosis as pancreatic adenocarinomas.
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Overview of Pancreatic Neuroendocrine Neoplasms (pNENs). The pancreas is a gland located between the stomach, spleen, duodenum and colon transversum. It contains specialized exocrine cells that secrete enzymes that travel to the intestines and aid in digestion as well as endocrine cells, so called islet cells. Pancreatic neuroendocrine neoplasms (pNENs) are an increasingly common group of malignancies that arise within the endocrine tissue of the pancreas. Endocrine tissue is specialized tissue that contains hormone-secreting cells (e.g. α-cells, ß-cells). These cells secrete several different hormones into the blood (endocrine) or to local cells (paracrine, autocrine). These hormones have a variety of functions within the body (e.g. glucose-metabolism). Neoplasms that arise from endocrine tissue may also secrete hormones, resulting in excessive levels of these hormones in the body and potentially a wide variety of symptoms. There are several different subtypes of functioning pNENs distinguished by the specific type of hormone that they secrete. Insulinomas and gastrinomas are the most common types of hormone secreting pNENs.Although there is no difference in diagnosis and therapy, pNENs can be differentiated as functioning or nonfunctioning. Functioning pNENs secrete hormones into the bloodstream, which cause special symptoms; nonfunctioning neoplasms may produce hormones, but no systemic symptoms. Nonfunctioning neuroendocrine neoplasms can still cause symptoms relating to tumor size and location such as obstruction or internal bleeding. They have some different differentiation (G1-3), but all of them have the potential for malignant transformation. Most pNENs occur sporadically, but in some cases, pNENs may occur as part of a larger genetic syndrome such as multiple endocrine neoplasia type 1 (MEN1) or von Hippel Lindau (VHL) syndrome.Pancreatic cancer as a general term usually refers to pancreatic adenocarcinoma, an aggressive malignant cancer with a poor prognosis. Approximately 95 percent of pancreatic malignancies are adenocarcinomas, for which the prognoses are in general worse than the prognosis of G1- and G2 pNENs. G3 neuroendocrine carcinomas have a similar poor prognosis as pancreatic adenocarinomas.
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Symptoms of Pancreatic Neuroendocrine Neoplasms (pNENs)
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The symptoms, severity and rate of progression of pNENs can vary greatly from one person to another, even among individuals with the same type of malignancy.ASYMPTOMATIC NEOPLASMS
The so called nonfunctioning pNENs may not cause any symptoms and will sometimes be diagnosed incidentally. Since nonfunctioning pNENs do not secrete hormones that cause symptoms, they often continue to grow undetected. When nonfunctioning pNENs are eventually detected, they are often quite large. More than half are metastasized upon diagnosis, usually because they remained undetected for so long.As nonfunctioning pNENs grow they may eventually cause symptoms, most often related to their size and specific location. The most common symptom associated with nonfunctioning pNENs is abdominal pain and, in some cases, an abdominal mass may be present. Affected individuals may also have a variety of additional nonspecific symptoms including nausea, diarrhea, indigestion and unintended weight loss. Additional symptoms are caused by the size and bulk of a tumor, which can cause obstruction or compression of nearby structures. Some individuals may have yellowing of the skin (icterus) and whites of the eyes (jaundice). Nonfunctioning pNENs can potentially bleed into the gastrointestinal tract.SYMPTOMATC NEOPLASMS
The symptoms of so called functioning pNENs can vary widely from one person to another, depending upon the specific subtype present and the specific hormone that is overproduced. Some pNENs may secrete more than one hormone, but usually one hormone is produced more than the others. Most individuals usually only have symptoms relating to the hormone that is chiefly produced.Insulinomas
These neoplasms are mostly small and 90 percent of them behave benign. They are the most common form of pancreatic neuroendocrine neoplasms. Insulinomas produce insulin, a hormone that helps to regulate blood sugar levels by promoting the movement of glucose (a simple sugar) into cells for energy production or into the liver and fat cells for storage. The most common symptom of insulinomas is low blood sugar (hypoglycemia) and slow gain of weight, which can be present for years before a diagnosis is made. Untreated hypoglycemia can cause headaches, visual disturbances, personality changes, seizures and, in severe cases, coma and death.Insulinomas can cause additional symptoms including irritability, confusion, weakness, tremors, loss of muscular coordination (ataxia), palpitations, a rapid heartbeat (tachycardia) and excessive sweating (diaphoresis).
Therapy of choice is an enucleation of the insulinoma, which is a small pancreas protective operation.Gastrinomas
These tumors produce the hormone gastrin, which stimulates the stomach to release too much acid. Gastrinomas can cause abdominal pain, diarrhea, excess fat in the feces (steatorrhea), backflow of the contents of the stomach into the esophagus (gastroesophageal reflux) and erosions on the lining of the stomach (peptic ulcers). These lesions may bleed. Peptic ulcers can also cause an intense, burning sensation in the stomach that may last from a few minutes to several hours. In individuals with gastrinomas, peptic ulcers may keep coming back even after treatment. More than 50 percent of gastrinomas are malignant and can potentially spread (metastasize).The symptoms caused by gastrinomas have been classified as a specific syndrome known as Zollinger-Ellison syndrome. (For more information on this disorder, choose “Zollinger Ellison” as your search term in the Rare Disease Database.)Glucagonomas
These tumors produce the hormone glucagon, which increases the amount of glucose in the blood. Glucose is a simple sugar. Too much sugar in the blood is known as hyperglycemia. Glucagonomas can cause a distinct skin rash (dermatitis) usually on the face, stomach or legs. Mild diabetes may also develop. Some affected individuals may develop blood clots, especially in the lungs potentially causing shortness of breath, cough or pain in the chest. Blood clots in extremities may cause deep vein thrombosis, a condition in which blood clots form in the legs causing the legs to become painful and swollen.In addition, anemia, unintended weight loss, and inflammation or sores on the mucous membrane lining the inside of the mouth (stomatitis) have also been associated with glucagonomas. Glucagonomas tend to grow quite large and approximately 70 percent are malignant with the potential to spread (metastasize).VIPomas
These tumors produce the hormone vasoactive intestinal polypeptide, which increases secretions from the intestines and relaxes certain muscles within the gastrointestinal tract. VIPomas can cause large amounts of chronic, watery diarrhea that can eventually result in dehydration, unintended weight loss, and loss of potassium in body (hypokalemia). Additional symptoms may occur including abdominal pain and cramping, lethargy, nausea, and flushing or redness of the face.Many VIPomas are malignant by the time they are first diagnosed and often have already spread (metastasized). VIPomas and their associated symptoms may also be known as Verner-Morrison syndrome or pancreatic cholera.Somatostatinomas
These tumors produce the hormone somatostatin, which inhibits the secretion of other hormones. Somatostatinomas can cause excessive glucose (hyperglycemia) levels in the blood. Additional symptoms that can develop include diabetes mellitus, gallstones (cholelithiasis), diarrhea, unintended weight loss and excess levels of fat in the feces (steatorrhea). Additional symptoms include abdominal pain, nausea, and vomiting. Most somatostatinomas are large and have spread (metastasized) upon diagnosis.ACTHomas
These tumors produce the hormone adrenocorticotropin, which stimulates the adrenal glands to overproduce cortisol. Cortisol is a hormone that is release in response to stressful situations. Cortisol increases blood pressure and blood sugar and inhibits the immune system. ACTHomas can result in Cushing’s syndrome, a disorder characterized by excessive amounts of weight gain (central obesity). Affected individuals may have a round, moon-shaped face, thin, fragile skin that bruises easily, high blood pressure (hypertension), generalized muscle weakness, behavioral changes, facial flushing, and weakened bones that fracture easily (osteoporosis). (For more information, choose “Cushing’s” as your search term in the Rare Disease Database.)GRFomas
These tumors produce the hormone growth hormone release factor, which stimulates the production of growth hormone. GRFomas can result in acromegaly, a disorder characterized by abnormal enlargement of bones of the arms, legs and head. (For more information, choose “acromegaly” as your search term in the Rare Disease Database.)Additional pNENs
Some extremely rare pNENs include PPHrPomas, which secrete parathyroid hormone-related protein and may cause hyperparathyroidism; calcitoninomas, which secrete calcitonin and can cause watery diarrhea and facial flushing; and neurotensinomas, which can cause low blood pressure (hypotension), flushing, diarrhea, unintended weight loss, and diabetes. PPoma secrete pancreatic polypeptide, but usually do not cause any discernable symptoms.
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Symptoms of Pancreatic Neuroendocrine Neoplasms (pNENs). The symptoms, severity and rate of progression of pNENs can vary greatly from one person to another, even among individuals with the same type of malignancy.ASYMPTOMATIC NEOPLASMS
The so called nonfunctioning pNENs may not cause any symptoms and will sometimes be diagnosed incidentally. Since nonfunctioning pNENs do not secrete hormones that cause symptoms, they often continue to grow undetected. When nonfunctioning pNENs are eventually detected, they are often quite large. More than half are metastasized upon diagnosis, usually because they remained undetected for so long.As nonfunctioning pNENs grow they may eventually cause symptoms, most often related to their size and specific location. The most common symptom associated with nonfunctioning pNENs is abdominal pain and, in some cases, an abdominal mass may be present. Affected individuals may also have a variety of additional nonspecific symptoms including nausea, diarrhea, indigestion and unintended weight loss. Additional symptoms are caused by the size and bulk of a tumor, which can cause obstruction or compression of nearby structures. Some individuals may have yellowing of the skin (icterus) and whites of the eyes (jaundice). Nonfunctioning pNENs can potentially bleed into the gastrointestinal tract.SYMPTOMATC NEOPLASMS
The symptoms of so called functioning pNENs can vary widely from one person to another, depending upon the specific subtype present and the specific hormone that is overproduced. Some pNENs may secrete more than one hormone, but usually one hormone is produced more than the others. Most individuals usually only have symptoms relating to the hormone that is chiefly produced.Insulinomas
These neoplasms are mostly small and 90 percent of them behave benign. They are the most common form of pancreatic neuroendocrine neoplasms. Insulinomas produce insulin, a hormone that helps to regulate blood sugar levels by promoting the movement of glucose (a simple sugar) into cells for energy production or into the liver and fat cells for storage. The most common symptom of insulinomas is low blood sugar (hypoglycemia) and slow gain of weight, which can be present for years before a diagnosis is made. Untreated hypoglycemia can cause headaches, visual disturbances, personality changes, seizures and, in severe cases, coma and death.Insulinomas can cause additional symptoms including irritability, confusion, weakness, tremors, loss of muscular coordination (ataxia), palpitations, a rapid heartbeat (tachycardia) and excessive sweating (diaphoresis).
Therapy of choice is an enucleation of the insulinoma, which is a small pancreas protective operation.Gastrinomas
These tumors produce the hormone gastrin, which stimulates the stomach to release too much acid. Gastrinomas can cause abdominal pain, diarrhea, excess fat in the feces (steatorrhea), backflow of the contents of the stomach into the esophagus (gastroesophageal reflux) and erosions on the lining of the stomach (peptic ulcers). These lesions may bleed. Peptic ulcers can also cause an intense, burning sensation in the stomach that may last from a few minutes to several hours. In individuals with gastrinomas, peptic ulcers may keep coming back even after treatment. More than 50 percent of gastrinomas are malignant and can potentially spread (metastasize).The symptoms caused by gastrinomas have been classified as a specific syndrome known as Zollinger-Ellison syndrome. (For more information on this disorder, choose “Zollinger Ellison” as your search term in the Rare Disease Database.)Glucagonomas
These tumors produce the hormone glucagon, which increases the amount of glucose in the blood. Glucose is a simple sugar. Too much sugar in the blood is known as hyperglycemia. Glucagonomas can cause a distinct skin rash (dermatitis) usually on the face, stomach or legs. Mild diabetes may also develop. Some affected individuals may develop blood clots, especially in the lungs potentially causing shortness of breath, cough or pain in the chest. Blood clots in extremities may cause deep vein thrombosis, a condition in which blood clots form in the legs causing the legs to become painful and swollen.In addition, anemia, unintended weight loss, and inflammation or sores on the mucous membrane lining the inside of the mouth (stomatitis) have also been associated with glucagonomas. Glucagonomas tend to grow quite large and approximately 70 percent are malignant with the potential to spread (metastasize).VIPomas
These tumors produce the hormone vasoactive intestinal polypeptide, which increases secretions from the intestines and relaxes certain muscles within the gastrointestinal tract. VIPomas can cause large amounts of chronic, watery diarrhea that can eventually result in dehydration, unintended weight loss, and loss of potassium in body (hypokalemia). Additional symptoms may occur including abdominal pain and cramping, lethargy, nausea, and flushing or redness of the face.Many VIPomas are malignant by the time they are first diagnosed and often have already spread (metastasized). VIPomas and their associated symptoms may also be known as Verner-Morrison syndrome or pancreatic cholera.Somatostatinomas
These tumors produce the hormone somatostatin, which inhibits the secretion of other hormones. Somatostatinomas can cause excessive glucose (hyperglycemia) levels in the blood. Additional symptoms that can develop include diabetes mellitus, gallstones (cholelithiasis), diarrhea, unintended weight loss and excess levels of fat in the feces (steatorrhea). Additional symptoms include abdominal pain, nausea, and vomiting. Most somatostatinomas are large and have spread (metastasized) upon diagnosis.ACTHomas
These tumors produce the hormone adrenocorticotropin, which stimulates the adrenal glands to overproduce cortisol. Cortisol is a hormone that is release in response to stressful situations. Cortisol increases blood pressure and blood sugar and inhibits the immune system. ACTHomas can result in Cushing’s syndrome, a disorder characterized by excessive amounts of weight gain (central obesity). Affected individuals may have a round, moon-shaped face, thin, fragile skin that bruises easily, high blood pressure (hypertension), generalized muscle weakness, behavioral changes, facial flushing, and weakened bones that fracture easily (osteoporosis). (For more information, choose “Cushing’s” as your search term in the Rare Disease Database.)GRFomas
These tumors produce the hormone growth hormone release factor, which stimulates the production of growth hormone. GRFomas can result in acromegaly, a disorder characterized by abnormal enlargement of bones of the arms, legs and head. (For more information, choose “acromegaly” as your search term in the Rare Disease Database.)Additional pNENs
Some extremely rare pNENs include PPHrPomas, which secrete parathyroid hormone-related protein and may cause hyperparathyroidism; calcitoninomas, which secrete calcitonin and can cause watery diarrhea and facial flushing; and neurotensinomas, which can cause low blood pressure (hypotension), flushing, diarrhea, unintended weight loss, and diabetes. PPoma secrete pancreatic polypeptide, but usually do not cause any discernable symptoms.
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Pancreatic Neuroendocrine Neoplasms (pNENs)
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Causes of Pancreatic Neuroendocrine Neoplasms (pNENs)
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The exact cause of pancreatic neuroendocrine neoplasms is unknown. Most pNENs occur randomly for no apparent reason (sporadically). Some individuals may have a genetic predisposition to developing pNENs. A person who is genetically predisposed to a disorder carries a gene (or genes) for the disease, but the disorder may not be expressed unless it is triggered or activated under certain circumstances, such as due to certain environmental factors. The genetic or environmental factors associated with pNENs are unknown. More research is necessary to determine what specific factors may play a role in the development of pNENs.Some individuals develop a pNEN as part of a larger genetic syndrome such as multiple endocrine neoplasia type I (MEN1), von Hippel-Lindau syndrome (VHL) or neurofibromatosis type I (NF-1). These disorders have additional symptoms and physical characteristics. (For more information on these disorders, choose the specific name as your search term in the Rare Disease Database.)
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Causes of Pancreatic Neuroendocrine Neoplasms (pNENs). The exact cause of pancreatic neuroendocrine neoplasms is unknown. Most pNENs occur randomly for no apparent reason (sporadically). Some individuals may have a genetic predisposition to developing pNENs. A person who is genetically predisposed to a disorder carries a gene (or genes) for the disease, but the disorder may not be expressed unless it is triggered or activated under certain circumstances, such as due to certain environmental factors. The genetic or environmental factors associated with pNENs are unknown. More research is necessary to determine what specific factors may play a role in the development of pNENs.Some individuals develop a pNEN as part of a larger genetic syndrome such as multiple endocrine neoplasia type I (MEN1), von Hippel-Lindau syndrome (VHL) or neurofibromatosis type I (NF-1). These disorders have additional symptoms and physical characteristics. (For more information on these disorders, choose the specific name as your search term in the Rare Disease Database.)
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Affects of Pancreatic Neuroendocrine Neoplasms (pNENs)
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PNENs seem to affect women slightly more often than men. Individuals of any ethnic or racial group may develop a pNEN. Affected individuals usually develop sporadic pNENs between the ages of 30-60. When pNENs occur as part of a genetic syndrome, they tend to occur during childhood or young adulthood. PNENs affect approximately ~1 in 100,000 individuals in the general population per year. They account for approximately 2-4 percent of all pancreatic neoplasms.
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Affects of Pancreatic Neuroendocrine Neoplasms (pNENs). PNENs seem to affect women slightly more often than men. Individuals of any ethnic or racial group may develop a pNEN. Affected individuals usually develop sporadic pNENs between the ages of 30-60. When pNENs occur as part of a genetic syndrome, they tend to occur during childhood or young adulthood. PNENs affect approximately ~1 in 100,000 individuals in the general population per year. They account for approximately 2-4 percent of all pancreatic neoplasms.
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Related disorders of Pancreatic Neuroendocrine Neoplasms (pNENs)
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Symptoms of the following disorders can be similar to those of pancreatic neuroendocrine neoplasms. Comparisons may be useful for a differential diagnosis.Carcinoid syndrome is a disease consisting of a combination of symptoms, physical manifestations, and abnormal laboratory chemical findings caused by a carcinoid tumor. A carcinoid tumor is an old word for a neuroendocrine neoplasm that secretes large amounts of the hormone serotonin, along with a number of other active peptides. These tumors usually arise in the gastrointestinal tract and from there may spread (metastasize) to the liver. Carcinoid tumors also sometimes develop in the lung. Only about 10 percent of the people with carcinoid tumors will develop the carcinoid syndrome. Major symptoms of this syndrome include hot, red facial flushing, diarrhea and wheezing. Carcinoid syndrome occurs when the tumor produces excessive amounts of serotonin in an individual with liver metastases. In patients who have no spread to the liver, the serotonin released by an intestinal tumor will be broken down to an inactive substance; thus, carcinoid syndrome does not occur. (For more information on this disorder, choose carcinoid as your search term in the Rare Disease Database.)Pancreatic adenocarcinoma is a type of cancer that forms in the pancreas. This type of cancer often occurs without any early signs or symptoms. When eventually diagnosed, a pancreatic adenocarcinoma may be advanced. Symptoms that can be associated with pancreatic adenocarcinoma include pain or discomfort in the upper portion of the abdomen, fatigue, weakness, nausea, loss of appetite, dark urine, clay-colored stools, and yellowing of the skin and whites of the eyes (jaundice). Additional symptoms that can potentially occur include back pain, difficulty sleeping, blood clots, diarrhea and indigestion. Pancreatic adenocarcinoma is malignant and often spreads (metastasizes) rapidly.
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Related disorders of Pancreatic Neuroendocrine Neoplasms (pNENs). Symptoms of the following disorders can be similar to those of pancreatic neuroendocrine neoplasms. Comparisons may be useful for a differential diagnosis.Carcinoid syndrome is a disease consisting of a combination of symptoms, physical manifestations, and abnormal laboratory chemical findings caused by a carcinoid tumor. A carcinoid tumor is an old word for a neuroendocrine neoplasm that secretes large amounts of the hormone serotonin, along with a number of other active peptides. These tumors usually arise in the gastrointestinal tract and from there may spread (metastasize) to the liver. Carcinoid tumors also sometimes develop in the lung. Only about 10 percent of the people with carcinoid tumors will develop the carcinoid syndrome. Major symptoms of this syndrome include hot, red facial flushing, diarrhea and wheezing. Carcinoid syndrome occurs when the tumor produces excessive amounts of serotonin in an individual with liver metastases. In patients who have no spread to the liver, the serotonin released by an intestinal tumor will be broken down to an inactive substance; thus, carcinoid syndrome does not occur. (For more information on this disorder, choose carcinoid as your search term in the Rare Disease Database.)Pancreatic adenocarcinoma is a type of cancer that forms in the pancreas. This type of cancer often occurs without any early signs or symptoms. When eventually diagnosed, a pancreatic adenocarcinoma may be advanced. Symptoms that can be associated with pancreatic adenocarcinoma include pain or discomfort in the upper portion of the abdomen, fatigue, weakness, nausea, loss of appetite, dark urine, clay-colored stools, and yellowing of the skin and whites of the eyes (jaundice). Additional symptoms that can potentially occur include back pain, difficulty sleeping, blood clots, diarrhea and indigestion. Pancreatic adenocarcinoma is malignant and often spreads (metastasizes) rapidly.
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Diagnosis of Pancreatic Neuroendocrine Neoplasms (pNENs)
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A diagnosis of a pancreatic neuroendocrine neoplasms is made based upon identification of characteristic symptoms (if present), a detailed patient history, a thorough clinical evaluation and a variety of specialized tests including advanced imaging techniques (octrotide-scintigraphy, CT, MRI, PET-CT, PET-MRI), blood tests (Chromogranin A, NETest), biochemical tests, and also biopsies.
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Diagnosis of Pancreatic Neuroendocrine Neoplasms (pNENs). A diagnosis of a pancreatic neuroendocrine neoplasms is made based upon identification of characteristic symptoms (if present), a detailed patient history, a thorough clinical evaluation and a variety of specialized tests including advanced imaging techniques (octrotide-scintigraphy, CT, MRI, PET-CT, PET-MRI), blood tests (Chromogranin A, NETest), biochemical tests, and also biopsies.
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Therapies of Pancreatic Neuroendocrine Neoplasms (pNENs)
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TreatmentThe therapeutic management of individuals with pNENs may require the coordinated efforts of a team of medical professionals, such as physicians who specialize in the diagnosis and treatment of cancer (medical oncologists), specialists in diagnosis and treatment of gastrointestinal disorder (gastroenterologists), specialists in the diagnosis and treatment of hormone-related disorders (endocrinologists), surgeons, oncology nurses, and other healthcare specialists.Specific therapeutic procedures and interventions may vary depending upon numerous factors, such as primary tumor location and extent of the primary tumor (stage); whether the tumor is malignant and whether it has spread to lymph nodes or distant sites; an individual's age and general health; and/or other elements. Decisions concerning the use of particular interventions should be made by physicians and other members of the health care team in careful consultation with the patient, based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks; patient preference; and other appropriate factors.Surgery is the treatment of choice. Other techniques used to pNENs include hormonal and drug therapy, chemotherapy and supportive therapy. In most cases, these therapies are used in conjunction with one another.SURGERY
The only curative therapy for pNENs is surgery. A variety of different surgical techniques may be used based upon the size, location and spread of the tumor. Such techniques include removal of only the tumor (enucleation), removal of as much as the tumor as possible (debulking), and removal of the tumor and nearby tissue and structures (e.g., a portion of the pancreas). If the cancer has spread, surgical removal of affected areas (e.g., affected lymph nodes or liver metastases) may be necessary. In special cases, liver transplantation may be considered for treatment of metastasized pNENs.Two other surgical techniques that may be used to treat individuals with pNENs include radiofrequency ablation or cryosurgery. Radiofrequency ablation uses high energy radio waves to destroy cancer cells. During this procedure, a small, thin tube is run through the skin and into the tumor. The tip of the tube contains tiny electrodes that release the high energy radio waves that destroy the tumor cells.Cryosurgery (also known as cryoablation) is a procedure that uses extreme cold to destroy cancer cells. A metal instrument is passed through the skin and inserted into the tumor where a substance like liquid nitrogen or liquid carbon dioxide is uses to freeze and destroy the tumor cells.HORMONE THERAPY
Some individuals with pNENs may be treated with somatostatin analogue, a drug (such as octreotide) that mimics the effects of somatostatin. Somatostatin is a hormone the blocks the activity of other hormones in the body. Ocetreotide can block the effects of hormones that are released by pNENs. Ocetreotide has improved symptoms in most individuals with pNENs.CHEMOTHERAPY
For some affected individuals, particularly those who have locally advanced, metastatic, or recurrent disease, therapy with certain anticancer drugs (chemotherapy) may also be recommended, possibly in combination with surgical procedures; physicians may recommend combination therapy with multiple chemotherapeutic drugs that have different modes of action in destroying tumor cells and/or preventing them from multiplying.In May of 2011, a specific chemotherapeutic drug known as Afinitor® (everolimus) was approved by the U.S. Food and Drug Administration (FDA) for the treatment of progressive neuroendocrine neoplasms of pancreatic origin in individuals with unresectable (cannot be treated surgically), locally advanced or metastatic disease. Afinitor delays tumor growth and reduces the risk of disease progression. For more information, contact: Novartis Oncology US.Website: http://www.afinitor.com/pnetIn May of 2011, the FDA also approved Sutent® (sunitinib malate) for the treatment of pNENs. In studies, Sutent slowed tumor growth in individuals whose cancer had spread or couldn't be surgically removed. For more information, contact: Pfizer Oncology.Website: http://www.sutent.comLIVER THERAPY
When pNENs become malignant and spread, a frequent site of metastases is the liver. Embolization or chemoembolization are two procedures that may be used to treat pNENs that have metastasized to the liver. Embolization is a non-surgical procedure that hampers blood flow in small blood vessels, thereby decreasing the blood supply to the tumor sites within the liver and can control disease for some time. Chemoembolization used chemotherapy drugs, which are directly injected into small blood vessels that supply tumors with blood. Since tumors need a steady blood supply to grow and spread, these procedures can help to stop tumor growth and reduce symptoms. In individuals with pNENs that have spread to the liver these procedures block the flow of blood through the hepatic artery, which is the main artery that supplies blood to the liver.In some cases, surgical removal of a portion of the liver may be necessary. In very rare cases, individuals with pNENs may ultimately require a liver transplant.SUPPORTIVE CARE
Supportive care is therapy that reduces symptoms of a disease or minimizes side effects of other therapies but does not cure or change the course of a disease.For example, gastrinomas (which cause an increase in stomach acid production) can be treated by drugs that block the production of stomach acid (proton pump inhibitors) such as omeprazole.Individuals with VIPomas who have associated severe diarrhea may be treated by intravenously replacing fluids and electrolytes.Some individuals with glucagonomas may have significant loss of essential nutrients, requiring blood transfusions and/or total parenteral nutrition.Individuals with somatostatinomas may require supplemental nutrition and should have their sugar levels monitored.
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Therapies of Pancreatic Neuroendocrine Neoplasms (pNENs). TreatmentThe therapeutic management of individuals with pNENs may require the coordinated efforts of a team of medical professionals, such as physicians who specialize in the diagnosis and treatment of cancer (medical oncologists), specialists in diagnosis and treatment of gastrointestinal disorder (gastroenterologists), specialists in the diagnosis and treatment of hormone-related disorders (endocrinologists), surgeons, oncology nurses, and other healthcare specialists.Specific therapeutic procedures and interventions may vary depending upon numerous factors, such as primary tumor location and extent of the primary tumor (stage); whether the tumor is malignant and whether it has spread to lymph nodes or distant sites; an individual's age and general health; and/or other elements. Decisions concerning the use of particular interventions should be made by physicians and other members of the health care team in careful consultation with the patient, based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks; patient preference; and other appropriate factors.Surgery is the treatment of choice. Other techniques used to pNENs include hormonal and drug therapy, chemotherapy and supportive therapy. In most cases, these therapies are used in conjunction with one another.SURGERY
The only curative therapy for pNENs is surgery. A variety of different surgical techniques may be used based upon the size, location and spread of the tumor. Such techniques include removal of only the tumor (enucleation), removal of as much as the tumor as possible (debulking), and removal of the tumor and nearby tissue and structures (e.g., a portion of the pancreas). If the cancer has spread, surgical removal of affected areas (e.g., affected lymph nodes or liver metastases) may be necessary. In special cases, liver transplantation may be considered for treatment of metastasized pNENs.Two other surgical techniques that may be used to treat individuals with pNENs include radiofrequency ablation or cryosurgery. Radiofrequency ablation uses high energy radio waves to destroy cancer cells. During this procedure, a small, thin tube is run through the skin and into the tumor. The tip of the tube contains tiny electrodes that release the high energy radio waves that destroy the tumor cells.Cryosurgery (also known as cryoablation) is a procedure that uses extreme cold to destroy cancer cells. A metal instrument is passed through the skin and inserted into the tumor where a substance like liquid nitrogen or liquid carbon dioxide is uses to freeze and destroy the tumor cells.HORMONE THERAPY
Some individuals with pNENs may be treated with somatostatin analogue, a drug (such as octreotide) that mimics the effects of somatostatin. Somatostatin is a hormone the blocks the activity of other hormones in the body. Ocetreotide can block the effects of hormones that are released by pNENs. Ocetreotide has improved symptoms in most individuals with pNENs.CHEMOTHERAPY
For some affected individuals, particularly those who have locally advanced, metastatic, or recurrent disease, therapy with certain anticancer drugs (chemotherapy) may also be recommended, possibly in combination with surgical procedures; physicians may recommend combination therapy with multiple chemotherapeutic drugs that have different modes of action in destroying tumor cells and/or preventing them from multiplying.In May of 2011, a specific chemotherapeutic drug known as Afinitor® (everolimus) was approved by the U.S. Food and Drug Administration (FDA) for the treatment of progressive neuroendocrine neoplasms of pancreatic origin in individuals with unresectable (cannot be treated surgically), locally advanced or metastatic disease. Afinitor delays tumor growth and reduces the risk of disease progression. For more information, contact: Novartis Oncology US.Website: http://www.afinitor.com/pnetIn May of 2011, the FDA also approved Sutent® (sunitinib malate) for the treatment of pNENs. In studies, Sutent slowed tumor growth in individuals whose cancer had spread or couldn't be surgically removed. For more information, contact: Pfizer Oncology.Website: http://www.sutent.comLIVER THERAPY
When pNENs become malignant and spread, a frequent site of metastases is the liver. Embolization or chemoembolization are two procedures that may be used to treat pNENs that have metastasized to the liver. Embolization is a non-surgical procedure that hampers blood flow in small blood vessels, thereby decreasing the blood supply to the tumor sites within the liver and can control disease for some time. Chemoembolization used chemotherapy drugs, which are directly injected into small blood vessels that supply tumors with blood. Since tumors need a steady blood supply to grow and spread, these procedures can help to stop tumor growth and reduce symptoms. In individuals with pNENs that have spread to the liver these procedures block the flow of blood through the hepatic artery, which is the main artery that supplies blood to the liver.In some cases, surgical removal of a portion of the liver may be necessary. In very rare cases, individuals with pNENs may ultimately require a liver transplant.SUPPORTIVE CARE
Supportive care is therapy that reduces symptoms of a disease or minimizes side effects of other therapies but does not cure or change the course of a disease.For example, gastrinomas (which cause an increase in stomach acid production) can be treated by drugs that block the production of stomach acid (proton pump inhibitors) such as omeprazole.Individuals with VIPomas who have associated severe diarrhea may be treated by intravenously replacing fluids and electrolytes.Some individuals with glucagonomas may have significant loss of essential nutrients, requiring blood transfusions and/or total parenteral nutrition.Individuals with somatostatinomas may require supplemental nutrition and should have their sugar levels monitored.
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Pancreatic Neuroendocrine Neoplasms (pNENs)
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Overview of Pantothenate Kinase-Associated Neurodegeneration
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SummaryPantothenate kinase-associated neurodegeneration (PKAN), formerly called Hallervorden-Spatz syndrome, is a rare, inherited neurological movement disorder characterized by the progressive degeneration of specific regions in the central nervous system (neurodegenerative disorder). PKAN is the most common type of neurodegeneration with brain iron accumulation (NBIA), a group of clinical disorders marked by progressive abnormal involuntary movements, alterations in muscle tone, and postural disturbances (extrapyramidal). These disorders show radiographic evidence of iron accumulation in the brain. PKAN is typically diagnosed by molecular genetic testing, most often after a characteristic finding on magnetic resonance imaging (MRI), called the “eye-of-the-tiger” sign, is detected.PKAN is inherited as an autosomal recessive genetic condition and is described as being classical or atypical. Classic PKAN typically appears in early childhood with symptoms that worsen rapidly. Atypical PKAN, which progresses more slowly, appears later in childhood or early adolescence. Some people have been diagnosed in infancy or adulthood, and some of those affected have characteristics that are between the two categories.IntroductionHallervorden-Spatz syndrome was first described in 1922 by Drs. Julius Hallervorden and Hugo Spatz with their study of a family of 12 in which five sisters exhibited progressively increasing dementia and poor articulation and slurred speech (dysarthria). The name Hallervorden-Spatz syndrome became discouraged and was replaced with neurodegeneration with brain iron accumulation because of concerns regarding Dr. Hallervorden’s and Dr. Spatz’s affiliation with the Nazi regime and their unethical activities surrounding how they obtained many autopsy specimens.
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Overview of Pantothenate Kinase-Associated Neurodegeneration. SummaryPantothenate kinase-associated neurodegeneration (PKAN), formerly called Hallervorden-Spatz syndrome, is a rare, inherited neurological movement disorder characterized by the progressive degeneration of specific regions in the central nervous system (neurodegenerative disorder). PKAN is the most common type of neurodegeneration with brain iron accumulation (NBIA), a group of clinical disorders marked by progressive abnormal involuntary movements, alterations in muscle tone, and postural disturbances (extrapyramidal). These disorders show radiographic evidence of iron accumulation in the brain. PKAN is typically diagnosed by molecular genetic testing, most often after a characteristic finding on magnetic resonance imaging (MRI), called the “eye-of-the-tiger” sign, is detected.PKAN is inherited as an autosomal recessive genetic condition and is described as being classical or atypical. Classic PKAN typically appears in early childhood with symptoms that worsen rapidly. Atypical PKAN, which progresses more slowly, appears later in childhood or early adolescence. Some people have been diagnosed in infancy or adulthood, and some of those affected have characteristics that are between the two categories.IntroductionHallervorden-Spatz syndrome was first described in 1922 by Drs. Julius Hallervorden and Hugo Spatz with their study of a family of 12 in which five sisters exhibited progressively increasing dementia and poor articulation and slurred speech (dysarthria). The name Hallervorden-Spatz syndrome became discouraged and was replaced with neurodegeneration with brain iron accumulation because of concerns regarding Dr. Hallervorden’s and Dr. Spatz’s affiliation with the Nazi regime and their unethical activities surrounding how they obtained many autopsy specimens.
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Symptoms of Pantothenate Kinase-Associated Neurodegeneration
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The common feature among all individuals with PKAN is iron accumulation in the brain, in a pattern called the ‘eye of the tiger sign,’ along with a progressive movement disorder. Symptoms may vary greatly from case to case. In most cases, progression of the disease extends over several years, leading to death in childhood or early adulthood in classic cases. Some patients experience rapid deterioration and die within 1-2 years. Others have a slower progression or can plateau for long periods of time and continue to function into the third decade of life. Atypical individuals often retain a high level of function into later adulthood and some are known to be living in their sixties to seventies.Symptoms include dystonia, (sustained muscle contractions causing repetitive movements), dysarthria (abnormal speech), muscular rigidity, poor balance, and spasticity (sudden involuntary muscle spasms), These features can result in clumsiness, gait (walking) problems, difficulty controlling movement, and speech problems. Another common feature is degeneration of the retina, resulting in progressive night blindness and loss of peripheral (side) vision.Dystonia is characterized by involuntary muscle contractions that may force certain body parts into unusual, and sometimes painful, movements and positions. In addition, there may be stiffness in the arms and legs because of continuous resistance to muscle relaxing (spasticity) and abnormal tightening of the muscles (muscular rigidity). Spasticity and muscle rigidity usually begin in the legs and later develop in the arms. As affected individuals age, they may eventually lose control of voluntary movements. Muscle spasms combined with decreased bone mass can result in bone fractures (not caused by trauma or accident).Dystonia affects the muscles in the mouth and throat, which may cause dysarthria and difficulty swallowing (dysphagia). The progression of dystonia in these muscles can result in loss of speech as well as tongue-biting and difficulty with eating.Specific forms of dystonia that may occur in association with PKAN include blepharospasm and torticollis. Blepharospasm is a condition in which the muscles of the eyelids do not function properly, resulting in excessive blinking and involuntary closing of the eyelids. Torticollis is a condition in which there are involuntary contractions of neck muscles resulting in abnormal movements and positions of the head and neck.Many of the delays in development pertain to motor skills (movement), although a small subgroup may have intellectual delays. Although intellectual impairment has often been described as a part of the condition in the past, it is unclear if this is a true feature. Intellectual testing may be hampered by the movement disorder; therefore, newer methods of studying intelligence are necessary to determine if there are any cognitive features of this condition.The symptoms and physical findings associated with PKAN gene mutations can be distinguished between classical and atypical disease. Individuals with classical disease have a more rapid progression of symptoms. In most cases, atypical disease progresses slowly over several years. The symptoms and physical findings vary from case to case.Classical PKAN develops in the first ten years of life (average age for developing symptoms is three and a half years). These children may initially be perceived as clumsy and later develop more noticeable problems with walking. Speech delay is also common. Eventually, falling becomes a frequent feature. Because of the limited ability to protect themselves during falls, children may have repeated injury to the face and chin. Many individuals with the classic form of PKAN require a wheelchair by their mid-teens (in some cases earlier). Most lose the ability to move/walk independently between 10 and15 years after the beginning of symptoms.Individuals with classical PKAN are more likely to have specific eye problems. Approximately two-thirds of these patients will have retinal degeneration. This is a progressive degeneration of the nerve-rich membrane lining the eyes (retina), resulting in tunnel vision, night blindness, and loss of peripheral vision. Loss of this peripheral vision may contribute to the more frequent falls and gait disturbances in the early stages. [For more information on this retinopathy (retinitis pigmentosa), choose “retinitis pigmentosa” as your search term in the Rare Disease Database]. The atypical form of PKAN usually occurs after the age of ten years and progresses more slowly. The average age for developing symptoms is 13 years. Loss of independent ambulation (walking) often occurs 15 to 40 years after the initial development of symptoms. The initial presenting symptoms usually involve speech. Common speech problems are repetition of words or phrases (palilalia), rapid speech (tachylalia), and dysarthria. Psychiatric symptoms are more commonly observed and include impulsive behavior, violent outbursts, depression, or a tendency to rapid mood swings. While the movement disorder is a very common feature, it usually develops later. In general, atypical disease is less severe and more slowly progressive than early-onset PKAN.In cases of neurodegeneration with brain iron accumulation (NBIA) that are not caused by PKAN, the movement-related symptoms (such as dystonia) may be very similar. Nine additional genes causing various subtypes of NBIA have been identified at this time. For those without a specific diagnosis or known cause of NBIA, symptoms are more varied because there are probably several different causes of neurodegeneration in this group. There is a subgroup of patients with moderate to severe intellectual disability. Also, seizure disorders are more common among non-PKAN individuals.
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Symptoms of Pantothenate Kinase-Associated Neurodegeneration. The common feature among all individuals with PKAN is iron accumulation in the brain, in a pattern called the ‘eye of the tiger sign,’ along with a progressive movement disorder. Symptoms may vary greatly from case to case. In most cases, progression of the disease extends over several years, leading to death in childhood or early adulthood in classic cases. Some patients experience rapid deterioration and die within 1-2 years. Others have a slower progression or can plateau for long periods of time and continue to function into the third decade of life. Atypical individuals often retain a high level of function into later adulthood and some are known to be living in their sixties to seventies.Symptoms include dystonia, (sustained muscle contractions causing repetitive movements), dysarthria (abnormal speech), muscular rigidity, poor balance, and spasticity (sudden involuntary muscle spasms), These features can result in clumsiness, gait (walking) problems, difficulty controlling movement, and speech problems. Another common feature is degeneration of the retina, resulting in progressive night blindness and loss of peripheral (side) vision.Dystonia is characterized by involuntary muscle contractions that may force certain body parts into unusual, and sometimes painful, movements and positions. In addition, there may be stiffness in the arms and legs because of continuous resistance to muscle relaxing (spasticity) and abnormal tightening of the muscles (muscular rigidity). Spasticity and muscle rigidity usually begin in the legs and later develop in the arms. As affected individuals age, they may eventually lose control of voluntary movements. Muscle spasms combined with decreased bone mass can result in bone fractures (not caused by trauma or accident).Dystonia affects the muscles in the mouth and throat, which may cause dysarthria and difficulty swallowing (dysphagia). The progression of dystonia in these muscles can result in loss of speech as well as tongue-biting and difficulty with eating.Specific forms of dystonia that may occur in association with PKAN include blepharospasm and torticollis. Blepharospasm is a condition in which the muscles of the eyelids do not function properly, resulting in excessive blinking and involuntary closing of the eyelids. Torticollis is a condition in which there are involuntary contractions of neck muscles resulting in abnormal movements and positions of the head and neck.Many of the delays in development pertain to motor skills (movement), although a small subgroup may have intellectual delays. Although intellectual impairment has often been described as a part of the condition in the past, it is unclear if this is a true feature. Intellectual testing may be hampered by the movement disorder; therefore, newer methods of studying intelligence are necessary to determine if there are any cognitive features of this condition.The symptoms and physical findings associated with PKAN gene mutations can be distinguished between classical and atypical disease. Individuals with classical disease have a more rapid progression of symptoms. In most cases, atypical disease progresses slowly over several years. The symptoms and physical findings vary from case to case.Classical PKAN develops in the first ten years of life (average age for developing symptoms is three and a half years). These children may initially be perceived as clumsy and later develop more noticeable problems with walking. Speech delay is also common. Eventually, falling becomes a frequent feature. Because of the limited ability to protect themselves during falls, children may have repeated injury to the face and chin. Many individuals with the classic form of PKAN require a wheelchair by their mid-teens (in some cases earlier). Most lose the ability to move/walk independently between 10 and15 years after the beginning of symptoms.Individuals with classical PKAN are more likely to have specific eye problems. Approximately two-thirds of these patients will have retinal degeneration. This is a progressive degeneration of the nerve-rich membrane lining the eyes (retina), resulting in tunnel vision, night blindness, and loss of peripheral vision. Loss of this peripheral vision may contribute to the more frequent falls and gait disturbances in the early stages. [For more information on this retinopathy (retinitis pigmentosa), choose “retinitis pigmentosa” as your search term in the Rare Disease Database]. The atypical form of PKAN usually occurs after the age of ten years and progresses more slowly. The average age for developing symptoms is 13 years. Loss of independent ambulation (walking) often occurs 15 to 40 years after the initial development of symptoms. The initial presenting symptoms usually involve speech. Common speech problems are repetition of words or phrases (palilalia), rapid speech (tachylalia), and dysarthria. Psychiatric symptoms are more commonly observed and include impulsive behavior, violent outbursts, depression, or a tendency to rapid mood swings. While the movement disorder is a very common feature, it usually develops later. In general, atypical disease is less severe and more slowly progressive than early-onset PKAN.In cases of neurodegeneration with brain iron accumulation (NBIA) that are not caused by PKAN, the movement-related symptoms (such as dystonia) may be very similar. Nine additional genes causing various subtypes of NBIA have been identified at this time. For those without a specific diagnosis or known cause of NBIA, symptoms are more varied because there are probably several different causes of neurodegeneration in this group. There is a subgroup of patients with moderate to severe intellectual disability. Also, seizure disorders are more common among non-PKAN individuals.
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Causes of Pantothenate Kinase-Associated Neurodegeneration
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Individuals with PKAN have abnormal accumulation of iron in certain areas of the brain. This is especially seen in regions of the basal ganglia called the globus pallidus and the substantia nigra. The basal ganglia is a collection of structures deep within the base of the brain that assist in regulating movements. The exact relationship between iron accumulation and the symptoms of PKAN is not fully understood.PKAN is an autosomal recessive condition caused by mutations in the PANK2 gene, located on chromosome 20. This gene encodes the enzyme pantothenate kinase, and mutations in the gene lead to an inborn error of vitamin B5 (pantothenate) metabolism. Vitamin B5 is required for the production of coenzyme A in cells. Disruption of this enzyme affects energy and lipid metabolism and may lead to accumulation of potentially harmful compounds in the brain, including iron. Currently, PANK2 is the only gene known to be associated with PKAN.Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females. 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. Consanguinity is thought to be present in approximately 23% of families with PKAN.
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Causes of Pantothenate Kinase-Associated Neurodegeneration. Individuals with PKAN have abnormal accumulation of iron in certain areas of the brain. This is especially seen in regions of the basal ganglia called the globus pallidus and the substantia nigra. The basal ganglia is a collection of structures deep within the base of the brain that assist in regulating movements. The exact relationship between iron accumulation and the symptoms of PKAN is not fully understood.PKAN is an autosomal recessive condition caused by mutations in the PANK2 gene, located on chromosome 20. This gene encodes the enzyme pantothenate kinase, and mutations in the gene lead to an inborn error of vitamin B5 (pantothenate) metabolism. Vitamin B5 is required for the production of coenzyme A in cells. Disruption of this enzyme affects energy and lipid metabolism and may lead to accumulation of potentially harmful compounds in the brain, including iron. Currently, PANK2 is the only gene known to be associated with PKAN.Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females. 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. Consanguinity is thought to be present in approximately 23% of families with PKAN.
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Affects of Pantothenate Kinase-Associated Neurodegeneration
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PKAN affects males and females in equal numbers. The symptoms typically develop during childhood, although occasionally they begin during late adolescence or adulthood. Cases in infancy and of adult onset have also been reported.The frequency of PKAN is estimated to be one to three per million individuals worldwide. Because rare disorders like PKAN often go unrecognized, these disorders may be under-diagnosed or misdiagnosed, making it difficult to determine the accuracy of these estimates.
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Affects of Pantothenate Kinase-Associated Neurodegeneration. PKAN affects males and females in equal numbers. The symptoms typically develop during childhood, although occasionally they begin during late adolescence or adulthood. Cases in infancy and of adult onset have also been reported.The frequency of PKAN is estimated to be one to three per million individuals worldwide. Because rare disorders like PKAN often go unrecognized, these disorders may be under-diagnosed or misdiagnosed, making it difficult to determine the accuracy of these estimates.
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Related disorders of Pantothenate Kinase-Associated Neurodegeneration
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Symptoms of the following disorders can be similar to those of PKAN. Comparisons may be useful for a differential diagnosis.The following three disorders may present with early clinical symptoms that are similar to those seen in classic PKAN:Infantile neuroaxonal dystrophy (INAD), also known as Seitelberger disease, is an extremely rare inherited degenerative disorder of the nervous system characterized by abnormalities of nerve endings (axons) within the brain and spinal cord (central nervous system) and outside the central nervous system (peripheral nerves). In most cases, infants and children with Seitelberger disease appear to develop normally until approximately 14 to 18 months of age, when they may begin to experience progressively increased difficulties in walking. In other cases, symptoms may begin at approximately six to eight months of age, at which time infants may experience delays or an arrest in the acquisition of skills requiring the coordination of mental and physical activities (delayed psychomotor development). Affected infants and children may then begin to lose previously acquired skills (psychomotor regression) including sitting and standing and may demonstrate progressive neuromuscular impairment characterized by generalized muscle weakness, severely diminished muscle tone (hypotonia), abnormally exaggerated reflex responses (hyperreflexia), and/or unusually weak, depressed, or absent reflexes. In some cases, as the disorder progresses, affected children may also experience involuntary movements of the face and hands, sudden involuntary muscle spasms (spasticity) of the lower arms and legs (limbs), and progressive paralysis of the legs and lower part of the body (paraplegia). Progressive cognitive failure occurs in association with gradual motor impairment. In most cases, Seitelberger disease is inherited as an autosomal recessive trait. (For more information on this disorder, choose “Seitelberger” as your search term in the Rare Disease Database.)Familial idiopathic basal ganglia calcification (FIBGC) is a rare neurological disorder characterized by the presence of abnormal calcium deposits (calcifications) of unknown cause. Associated symptoms include progressive deterioration of cognitive abilities (dementia), loss of contact with reality (psychosis), mood swings and loss of acquired motor skills. As the condition progresses, paralysis may develop that is associated with increased muscle stiffness (rigidity) and restricted movements (spastic paralysis). Additional abnormalities may include relatively slow, involuntary, continual writhing movements (athetosis) or chorea, a related condition characterized by irregular, rapid, jerky movements. (For more information on this disorder, choose “familial idiopathic basal ganglia calcification” as your search term in the Rare Disease Database.)Fucosidosis is a rare genetic disorder characterized by deficiency of the enzyme alpha-L-fucosidase, which is required to break down (metabolize) certain complex compounds (e.g., fucose-containing glycolipids or fucose-containing glycoproteins). Fucose is a type of the sugar required by the body to perform certain functions (essential sugar). The inability to breakdown fucose-containing compounds results in their accumulation in various tissues in the body. Fucosidosis results in progressive neurological deterioration, skin abnormalities, growth retardation, skeletal disease and coarsening of facial features. The symptoms and severity of fucosidosis are highly variable and the disorder represents a disease spectrum in which individuals with mild cases have been known to live into the third or fourth decades. Individuals with severe cases of fucosidosis can develop life-threatening complications early in childhood. (For more information on this disorder, choose “fucosidosis” as your search term in the Rare Disease Database.)Other disorders to be considered in a differential diagnosis include:Wilson disease is a rare genetic disorder characterized by excess copper stored in various body tissues, particularly the liver, brain, and corneas of the eyes. The disease is progressive and, if left untreated, it may cause liver (hepatic) disease, central nervous system dysfunction, and death. Early diagnosis and treatment may prevent serious long-term disability and life threatening complications. Treatment is aimed at reducing the amount of copper that has accumulated in the body and maintaining normal copper levels thereafter. (For more information on this disorder, choose “Wilson” as your search term in the Rare Disease Database.)Batten disease, a rare genetic disorder, belongs to a group of progressive degenerative neurometabolic disorders known as the neuronal ceroid lipofuscinoses. These disorders share certain similar symptoms and are distinguished in part by the age at which such symptoms appear. Batten disease is sometimes considered the juvenile form of the neuronal ceroid lipofuscinoses (NCLs). The NCLs are characterized by abnormal accumulation of certain fatty, granular substances (i.e., pigmented lipids [lipopigments] ceroid and lipofuscin) within nerve cells (neurons) of the brain as well as other tissues of the body that may result in progressive deterioration (atrophy) of certain areas of the brain, neurological impairment, and other characteristic symptoms and physical findings. (For more information on this disorder, choose “Batten” as your search term in the Rare Disease Database.)Neuroacanthocytosis is a general term for a group of rare progressive disorders characterized by the association of misshapen, spiny red blood cells (acanthocytosis) and neurological abnormalities, especially movement disorders. Chorea, which is characterized by rapid, involuntary, purposeless movements, especially of the face, feet and hands, is the most common movement disorder associated with neuroacanthocytosis. Additional symptoms often develop including progressive cognitive impairment, muscle weakness, seizures and behavioral or personality changes. The onset, severity and specific physical findings vary depending upon the specific type of neuroacanthocytosis present. Neuroacanthocytosis syndromes typically progress to cause serious, disabling and sometimes life-threatening complications (and are usually fatal). (For more information on this disorder, choose “neuroacanthocytosis” as your search term in the Rare Disease Database.)Parkinson disease is a slowly progressive neurologic condition characterized by involuntary trembling (tremor), muscular stiffness or inflexibility (rigidity), slowness of movement and difficulty carrying out voluntary movements. Degenerative changes occur in areas deep within the brain (substantia nigra and other pigmented regions of the brain), causing a decrease in dopamine levels in the brain. Dopamine is a neurotransmitter, which is a chemical that sends a signal in the brain. Parkinsonian symptoms can also develop secondary to hydrocephalus (a condition in which the head is enlarged and areas of the brain accumulate excessive fluids, resulting in an increase in pressure on the brain), head trauma, inflammation of the brain (encephalitis), obstructions (infarcts) or tumors deep within the cerebral hemispheres and the upper brain stem (basal ganglia), or exposure to certain drugs and toxins. Parkinson disease is slowly progressive and may not become incapacitating for many years.Huntington disease is a genetic, progressive, neurodegenerative disorder characterized by the gradual development of involuntary muscle movements affecting the hands, feet, face, and trunk and progressive deterioration of cognitive processes and memory (dementia). Neurologic movement abnormalities may include uncontrolled, irregular, rapid, jerky movements (chorea) and athetosis, a condition characterized by relatively slow, writhing involuntary movements. Dementia is typically associated with progressive disorientation and confusion, personality disintegration, impairment of memory control, restlessness, agitation, and other symptoms and findings. In individuals with the disorder, disease duration may range from approximately 10 years up to 25 years or more. Life-threatening complications may result from pneumonia or other infections, injuries related to falls, or other associated developments. Huntington’s disease is inherited as an autosomal dominant trait. (For more information on this disorder, choose “Huntington” as your search term in the Rare Disease Database.)Machado-Joseph disease is a rare inherited disorder affecting the central nervous system that is characterized by the slow degeneration of certain areas of the brain. Symptoms typically begin during adulthood and may include an unsteady gait (ataxia), dysarthria, muscle rigidity, impaired muscle tone, slow involuntary movements of the arms and legs (athetosis), and/or irregular eye movements. Mental alertness and intellectual capacities are not affected. This disorder primarily affects people of Portuguese heritage. Joseph’s disease is inherited as an autosomal dominant trait. (For more information on this disorder, choose “Machado-Joseph” as your search term in the Rare Disease Database.)
Certain rare metabolic disorders can also present with symptoms similar to PKAN, including beta-hexosaminidase deficiency disorders such as Tay-Sachs disease and Sandhoff disease. (For more information on these disorders, choose “Tay-Sachs” or “Sandhoff ” as your search term in the Rare Disease Database.)
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Related disorders of Pantothenate Kinase-Associated Neurodegeneration. Symptoms of the following disorders can be similar to those of PKAN. Comparisons may be useful for a differential diagnosis.The following three disorders may present with early clinical symptoms that are similar to those seen in classic PKAN:Infantile neuroaxonal dystrophy (INAD), also known as Seitelberger disease, is an extremely rare inherited degenerative disorder of the nervous system characterized by abnormalities of nerve endings (axons) within the brain and spinal cord (central nervous system) and outside the central nervous system (peripheral nerves). In most cases, infants and children with Seitelberger disease appear to develop normally until approximately 14 to 18 months of age, when they may begin to experience progressively increased difficulties in walking. In other cases, symptoms may begin at approximately six to eight months of age, at which time infants may experience delays or an arrest in the acquisition of skills requiring the coordination of mental and physical activities (delayed psychomotor development). Affected infants and children may then begin to lose previously acquired skills (psychomotor regression) including sitting and standing and may demonstrate progressive neuromuscular impairment characterized by generalized muscle weakness, severely diminished muscle tone (hypotonia), abnormally exaggerated reflex responses (hyperreflexia), and/or unusually weak, depressed, or absent reflexes. In some cases, as the disorder progresses, affected children may also experience involuntary movements of the face and hands, sudden involuntary muscle spasms (spasticity) of the lower arms and legs (limbs), and progressive paralysis of the legs and lower part of the body (paraplegia). Progressive cognitive failure occurs in association with gradual motor impairment. In most cases, Seitelberger disease is inherited as an autosomal recessive trait. (For more information on this disorder, choose “Seitelberger” as your search term in the Rare Disease Database.)Familial idiopathic basal ganglia calcification (FIBGC) is a rare neurological disorder characterized by the presence of abnormal calcium deposits (calcifications) of unknown cause. Associated symptoms include progressive deterioration of cognitive abilities (dementia), loss of contact with reality (psychosis), mood swings and loss of acquired motor skills. As the condition progresses, paralysis may develop that is associated with increased muscle stiffness (rigidity) and restricted movements (spastic paralysis). Additional abnormalities may include relatively slow, involuntary, continual writhing movements (athetosis) or chorea, a related condition characterized by irregular, rapid, jerky movements. (For more information on this disorder, choose “familial idiopathic basal ganglia calcification” as your search term in the Rare Disease Database.)Fucosidosis is a rare genetic disorder characterized by deficiency of the enzyme alpha-L-fucosidase, which is required to break down (metabolize) certain complex compounds (e.g., fucose-containing glycolipids or fucose-containing glycoproteins). Fucose is a type of the sugar required by the body to perform certain functions (essential sugar). The inability to breakdown fucose-containing compounds results in their accumulation in various tissues in the body. Fucosidosis results in progressive neurological deterioration, skin abnormalities, growth retardation, skeletal disease and coarsening of facial features. The symptoms and severity of fucosidosis are highly variable and the disorder represents a disease spectrum in which individuals with mild cases have been known to live into the third or fourth decades. Individuals with severe cases of fucosidosis can develop life-threatening complications early in childhood. (For more information on this disorder, choose “fucosidosis” as your search term in the Rare Disease Database.)Other disorders to be considered in a differential diagnosis include:Wilson disease is a rare genetic disorder characterized by excess copper stored in various body tissues, particularly the liver, brain, and corneas of the eyes. The disease is progressive and, if left untreated, it may cause liver (hepatic) disease, central nervous system dysfunction, and death. Early diagnosis and treatment may prevent serious long-term disability and life threatening complications. Treatment is aimed at reducing the amount of copper that has accumulated in the body and maintaining normal copper levels thereafter. (For more information on this disorder, choose “Wilson” as your search term in the Rare Disease Database.)Batten disease, a rare genetic disorder, belongs to a group of progressive degenerative neurometabolic disorders known as the neuronal ceroid lipofuscinoses. These disorders share certain similar symptoms and are distinguished in part by the age at which such symptoms appear. Batten disease is sometimes considered the juvenile form of the neuronal ceroid lipofuscinoses (NCLs). The NCLs are characterized by abnormal accumulation of certain fatty, granular substances (i.e., pigmented lipids [lipopigments] ceroid and lipofuscin) within nerve cells (neurons) of the brain as well as other tissues of the body that may result in progressive deterioration (atrophy) of certain areas of the brain, neurological impairment, and other characteristic symptoms and physical findings. (For more information on this disorder, choose “Batten” as your search term in the Rare Disease Database.)Neuroacanthocytosis is a general term for a group of rare progressive disorders characterized by the association of misshapen, spiny red blood cells (acanthocytosis) and neurological abnormalities, especially movement disorders. Chorea, which is characterized by rapid, involuntary, purposeless movements, especially of the face, feet and hands, is the most common movement disorder associated with neuroacanthocytosis. Additional symptoms often develop including progressive cognitive impairment, muscle weakness, seizures and behavioral or personality changes. The onset, severity and specific physical findings vary depending upon the specific type of neuroacanthocytosis present. Neuroacanthocytosis syndromes typically progress to cause serious, disabling and sometimes life-threatening complications (and are usually fatal). (For more information on this disorder, choose “neuroacanthocytosis” as your search term in the Rare Disease Database.)Parkinson disease is a slowly progressive neurologic condition characterized by involuntary trembling (tremor), muscular stiffness or inflexibility (rigidity), slowness of movement and difficulty carrying out voluntary movements. Degenerative changes occur in areas deep within the brain (substantia nigra and other pigmented regions of the brain), causing a decrease in dopamine levels in the brain. Dopamine is a neurotransmitter, which is a chemical that sends a signal in the brain. Parkinsonian symptoms can also develop secondary to hydrocephalus (a condition in which the head is enlarged and areas of the brain accumulate excessive fluids, resulting in an increase in pressure on the brain), head trauma, inflammation of the brain (encephalitis), obstructions (infarcts) or tumors deep within the cerebral hemispheres and the upper brain stem (basal ganglia), or exposure to certain drugs and toxins. Parkinson disease is slowly progressive and may not become incapacitating for many years.Huntington disease is a genetic, progressive, neurodegenerative disorder characterized by the gradual development of involuntary muscle movements affecting the hands, feet, face, and trunk and progressive deterioration of cognitive processes and memory (dementia). Neurologic movement abnormalities may include uncontrolled, irregular, rapid, jerky movements (chorea) and athetosis, a condition characterized by relatively slow, writhing involuntary movements. Dementia is typically associated with progressive disorientation and confusion, personality disintegration, impairment of memory control, restlessness, agitation, and other symptoms and findings. In individuals with the disorder, disease duration may range from approximately 10 years up to 25 years or more. Life-threatening complications may result from pneumonia or other infections, injuries related to falls, or other associated developments. Huntington’s disease is inherited as an autosomal dominant trait. (For more information on this disorder, choose “Huntington” as your search term in the Rare Disease Database.)Machado-Joseph disease is a rare inherited disorder affecting the central nervous system that is characterized by the slow degeneration of certain areas of the brain. Symptoms typically begin during adulthood and may include an unsteady gait (ataxia), dysarthria, muscle rigidity, impaired muscle tone, slow involuntary movements of the arms and legs (athetosis), and/or irregular eye movements. Mental alertness and intellectual capacities are not affected. This disorder primarily affects people of Portuguese heritage. Joseph’s disease is inherited as an autosomal dominant trait. (For more information on this disorder, choose “Machado-Joseph” as your search term in the Rare Disease Database.)
Certain rare metabolic disorders can also present with symptoms similar to PKAN, including beta-hexosaminidase deficiency disorders such as Tay-Sachs disease and Sandhoff disease. (For more information on these disorders, choose “Tay-Sachs” or “Sandhoff ” as your search term in the Rare Disease Database.)
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Diagnosis of Pantothenate Kinase-Associated Neurodegeneration
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The diagnosis of PKAN is made based upon a detailed patient history, a thorough clinical evaluation, and a variety of specialized tests. PKAN is typically suspected when the characteristic brain MRI finding called the “eye-of-the-tiger” sign, which is a dark area indicating accumulation of iron with a bright spot in the center, is observed on T2-weighted MRI. This MRI finding is not seen in other forms of NBIA.Molecular genetic testing for the full gene sequence of the PANK2 gene is the gold standard way to make this diagnosis. Approximately 95% of those affected have two identifiable mutations in this gene and approximately 5% have only one identifiable mutation. Some PANK2 gene deletions are not detected by sequencing the gene, so for individuals without a detectable mutation or only one detectable mutation, gene deletion/duplication analysis is also recommended.Clinical Testing and Work-Up
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Diagnosis of Pantothenate Kinase-Associated Neurodegeneration. The diagnosis of PKAN is made based upon a detailed patient history, a thorough clinical evaluation, and a variety of specialized tests. PKAN is typically suspected when the characteristic brain MRI finding called the “eye-of-the-tiger” sign, which is a dark area indicating accumulation of iron with a bright spot in the center, is observed on T2-weighted MRI. This MRI finding is not seen in other forms of NBIA.Molecular genetic testing for the full gene sequence of the PANK2 gene is the gold standard way to make this diagnosis. Approximately 95% of those affected have two identifiable mutations in this gene and approximately 5% have only one identifiable mutation. Some PANK2 gene deletions are not detected by sequencing the gene, so for individuals without a detectable mutation or only one detectable mutation, gene deletion/duplication analysis is also recommended.Clinical Testing and Work-Up
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Therapies of Pantothenate Kinase-Associated Neurodegeneration
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TreatmentThere is no specific treatment for individuals with PKAN. Treatment is directed towards the specific symptoms that appear in each individual. Research is focusing on a better understanding of the underlying cause of this disorder, which may eventually help to find a more comprehensive treatment.Treatment may require the coordinated efforts of a team of specialists. Physicians that the family may work with include the pediatrician or internist, neurologist, ophthalmologist, physiatrist and geneticist. A team approach to supportive therapy may include physical therapy, exercise physiology, occupation therapy, speech pathology and nutrition/feeding. In addition, many families may benefit from genetic counseling.The most consistent forms of relief from disabling dystonia are baclofen, trihexyphenidyl, and clonazepam. These medications can be taken orally. Later in disease, a baclofen pump can be used to administer regular doses automatically into the central nervous system. Intramuscular botulinum toxin may also help treat specific regions where dystonia is problematic.
Levodopa/carbidopa does not generally appear to help patients with PKAN, although there may be exceptions. These treatments may have a role in the treatment of other causes of NBIA; however, their overall effectiveness is unknown and the responsiveness in individual cases is unpredictable.Drugs that reduce the levels of iron in the body (iron chelation) have been attempted to treat individuals with PKAN. These early agents were proven ineffective and can cause anemia. A clinical trial of the drug deferiprone was completed for PKAN and results were published in 2019. The results suggested a possible modest slowing of disease progression, although the statistical analysis of the data was not able to prove this as significant.Pallidotomy and thalamotomy have been investigational attempts at controlling dystonia. These are both surgical techniques which destroy (ablate) very specific regions of the brain, the pallidus and thalamus, respectively. Some families have reported some immediate and temporary relief. However, most patients return to their pre-operative level of dystonia within one year of the operation. Deep brain stimulation of the globus pallidus has been found to have promising results in some patients with PKAN and NBIA and is now favored over ablative procedures. Individuals experiencing seizures usually benefit from standard anti-convulsive drugs. In addition, standard approaches to pain management are generally recommended where there is no identifiable treatment for the underlying cause of pain. Referral to pediatric palliative care specialists can be highly beneficial during later disease stages.The association between pantothenate kinase and PKAN suggests that supplemental pantothenate (pantothenic acid, calcium pantothenate) taken orally could be beneficial. Pantothenate is another name for vitamin B5, a water soluble vitamin. Theoretically, this is most likely to assist individuals with very low levels of pantothenate kinase activity (atypical PKAN). It is hypothesized that classic PKAN results from complete absence of the enzyme pantothenate kinase, whereas atypical PKAN results from a severe deficiency, although the individuals still may have some level of enzyme activity. Clinical trials are needed to investigate the effectiveness of this treatment.The benefits and limitations of any of the above treatments should be discussed in detail with a physician.
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Therapies of Pantothenate Kinase-Associated Neurodegeneration. TreatmentThere is no specific treatment for individuals with PKAN. Treatment is directed towards the specific symptoms that appear in each individual. Research is focusing on a better understanding of the underlying cause of this disorder, which may eventually help to find a more comprehensive treatment.Treatment may require the coordinated efforts of a team of specialists. Physicians that the family may work with include the pediatrician or internist, neurologist, ophthalmologist, physiatrist and geneticist. A team approach to supportive therapy may include physical therapy, exercise physiology, occupation therapy, speech pathology and nutrition/feeding. In addition, many families may benefit from genetic counseling.The most consistent forms of relief from disabling dystonia are baclofen, trihexyphenidyl, and clonazepam. These medications can be taken orally. Later in disease, a baclofen pump can be used to administer regular doses automatically into the central nervous system. Intramuscular botulinum toxin may also help treat specific regions where dystonia is problematic.
Levodopa/carbidopa does not generally appear to help patients with PKAN, although there may be exceptions. These treatments may have a role in the treatment of other causes of NBIA; however, their overall effectiveness is unknown and the responsiveness in individual cases is unpredictable.Drugs that reduce the levels of iron in the body (iron chelation) have been attempted to treat individuals with PKAN. These early agents were proven ineffective and can cause anemia. A clinical trial of the drug deferiprone was completed for PKAN and results were published in 2019. The results suggested a possible modest slowing of disease progression, although the statistical analysis of the data was not able to prove this as significant.Pallidotomy and thalamotomy have been investigational attempts at controlling dystonia. These are both surgical techniques which destroy (ablate) very specific regions of the brain, the pallidus and thalamus, respectively. Some families have reported some immediate and temporary relief. However, most patients return to their pre-operative level of dystonia within one year of the operation. Deep brain stimulation of the globus pallidus has been found to have promising results in some patients with PKAN and NBIA and is now favored over ablative procedures. Individuals experiencing seizures usually benefit from standard anti-convulsive drugs. In addition, standard approaches to pain management are generally recommended where there is no identifiable treatment for the underlying cause of pain. Referral to pediatric palliative care specialists can be highly beneficial during later disease stages.The association between pantothenate kinase and PKAN suggests that supplemental pantothenate (pantothenic acid, calcium pantothenate) taken orally could be beneficial. Pantothenate is another name for vitamin B5, a water soluble vitamin. Theoretically, this is most likely to assist individuals with very low levels of pantothenate kinase activity (atypical PKAN). It is hypothesized that classic PKAN results from complete absence of the enzyme pantothenate kinase, whereas atypical PKAN results from a severe deficiency, although the individuals still may have some level of enzyme activity. Clinical trials are needed to investigate the effectiveness of this treatment.The benefits and limitations of any of the above treatments should be discussed in detail with a physician.
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Overview of Papillitis
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Papillitis, also known as optic neuritis, is characterized by inflammation and deterioration of the portion of the optic nerve known as the optic disk. Also referred to as the “blind spot,” the optic disk (optic papilla) is that portion of the optic nerve that enters the eye and joins with the nerve-rich membrane lining the eye (retina). The optic nerves are the pair of nerves (second cranial nerves) that transmit impulses from the retina to the brain. Individuals with papillitis experience loss of vision in one eye that may occur within several hours of onset. The severity of visual impairment may vary from case to case, ranging from slight visual deficiency to complete loss of light perception. In addition, affected individuals experience a reduction in color perception. In some cases, spontaneous recovery may occur. However, in other cases, permanent visual impairment may result if the underlying cause is not detected or treated. Papillitis may occur for unknown reasons, after a viral illness, or due to or in association with a number of different underlying disorders or other factors.
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Overview of Papillitis. Papillitis, also known as optic neuritis, is characterized by inflammation and deterioration of the portion of the optic nerve known as the optic disk. Also referred to as the “blind spot,” the optic disk (optic papilla) is that portion of the optic nerve that enters the eye and joins with the nerve-rich membrane lining the eye (retina). The optic nerves are the pair of nerves (second cranial nerves) that transmit impulses from the retina to the brain. Individuals with papillitis experience loss of vision in one eye that may occur within several hours of onset. The severity of visual impairment may vary from case to case, ranging from slight visual deficiency to complete loss of light perception. In addition, affected individuals experience a reduction in color perception. In some cases, spontaneous recovery may occur. However, in other cases, permanent visual impairment may result if the underlying cause is not detected or treated. Papillitis may occur for unknown reasons, after a viral illness, or due to or in association with a number of different underlying disorders or other factors.
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Symptoms of Papillitis
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The symptoms of papillitis include loss of vision, pain in the eye, and interference with accurate color vision (dyschromatopsia).Individuals with papillitis usually experience unilateral loss of vision. That is, they lose sight in one eye (about 70% of cases), usually within a short time (a few hours) of having become aware of diminished sight. This condition is usually rapidly progressive.The intensity of vision impairment varies from case to case, ranging from slight visual deficiency to complete loss of light perception. In addition, affected individuals experience a reduction in color perception. In some cases, spontaneous recovery may occur. However, in other cases, permanent visual impairment may result if the underlying cause is not detected or treated. Papillitis may occur for unknown reasons, after a viral illness, or due to or in association with a number of different underlying disorders or other factors.
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Symptoms of Papillitis. The symptoms of papillitis include loss of vision, pain in the eye, and interference with accurate color vision (dyschromatopsia).Individuals with papillitis usually experience unilateral loss of vision. That is, they lose sight in one eye (about 70% of cases), usually within a short time (a few hours) of having become aware of diminished sight. This condition is usually rapidly progressive.The intensity of vision impairment varies from case to case, ranging from slight visual deficiency to complete loss of light perception. In addition, affected individuals experience a reduction in color perception. In some cases, spontaneous recovery may occur. However, in other cases, permanent visual impairment may result if the underlying cause is not detected or treated. Papillitis may occur for unknown reasons, after a viral illness, or due to or in association with a number of different underlying disorders or other factors.
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Causes of Papillitis
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There are many possible causes of papillitis. These include diseases that result in damage to the lining of nerves (demyelinating diseases) such as multiple sclerosis and encephalomyelitis; viral or bacterial infections such as polio, measles, pneumonia, or meningitis; nutritional or metabolic disorders such as diabetes, pernicious anemia, and hyperthyroidism; secondary complications of other diseases; reactions to toxic substances such as methanol, quinine, salicylates, and arsenic; and trauma. In patients over 60 years of age, a common cause of papillitis is temporal arteritis (giant cell arteritis). In such cases, papillitis can spread to the other eye resulting in bilateral blindness.
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Causes of Papillitis. There are many possible causes of papillitis. These include diseases that result in damage to the lining of nerves (demyelinating diseases) such as multiple sclerosis and encephalomyelitis; viral or bacterial infections such as polio, measles, pneumonia, or meningitis; nutritional or metabolic disorders such as diabetes, pernicious anemia, and hyperthyroidism; secondary complications of other diseases; reactions to toxic substances such as methanol, quinine, salicylates, and arsenic; and trauma. In patients over 60 years of age, a common cause of papillitis is temporal arteritis (giant cell arteritis). In such cases, papillitis can spread to the other eye resulting in bilateral blindness.
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Affects of Papillitis
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Papillitis affects males and females in equal numbers and can occur at any age. A percentage of people with papillitis may eventually be diagnosed with multiple sclerosis. (for more information on this disorder, see the Related Disorders section of this report.)
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Affects of Papillitis. Papillitis affects males and females in equal numbers and can occur at any age. A percentage of people with papillitis may eventually be diagnosed with multiple sclerosis. (for more information on this disorder, see the Related Disorders section of this report.)
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Related disorders of Papillitis
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The following disorders may be associated with papillitis.Giant cell arteritis is a chronic inflammatory disease of the branches of the aortic arch. This disorder is found principally in the temporal and occipital arteries, but may develop in almost any of the large arteries. It rarely involves veins. Papillitis may occur in people with giant cell arteritis. (For more information on this disorder, choose “Arteritis, Giant Cell” as your search term in the Rare Disease Database.)Multiple sclerosis is a chronic disease of the brain and spinal cord (central nervous system) which may be progressive, relapsing and remitting, or stable. People with MS have small nerve lesions called plaques that may form randomly throughout the brain and spinal cord. These patches prevent proper transmission of nerve signals and thus result in a variety of neurological symptoms. (For more information on this disorder, choose “Multiple Sclerosis” as your search term in the Rare Disease Database.)Retrobulbar neuritis is an inflammation of that portion of the optic nerve that lies behind the eyeball. Many cases of this disease are caused by multiple sclerosis while others may be due to viral or infectious disorders. In most cases there may be no apparent cause. This disease usually affects one eye and is characterized by pain associated with movement of the eye, headache and a rapid and progressive loss of vision.
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Related disorders of Papillitis. The following disorders may be associated with papillitis.Giant cell arteritis is a chronic inflammatory disease of the branches of the aortic arch. This disorder is found principally in the temporal and occipital arteries, but may develop in almost any of the large arteries. It rarely involves veins. Papillitis may occur in people with giant cell arteritis. (For more information on this disorder, choose “Arteritis, Giant Cell” as your search term in the Rare Disease Database.)Multiple sclerosis is a chronic disease of the brain and spinal cord (central nervous system) which may be progressive, relapsing and remitting, or stable. People with MS have small nerve lesions called plaques that may form randomly throughout the brain and spinal cord. These patches prevent proper transmission of nerve signals and thus result in a variety of neurological symptoms. (For more information on this disorder, choose “Multiple Sclerosis” as your search term in the Rare Disease Database.)Retrobulbar neuritis is an inflammation of that portion of the optic nerve that lies behind the eyeball. Many cases of this disease are caused by multiple sclerosis while others may be due to viral or infectious disorders. In most cases there may be no apparent cause. This disease usually affects one eye and is characterized by pain associated with movement of the eye, headache and a rapid and progressive loss of vision.
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Diagnosis of Papillitis
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Diagnostic testing may include testing for visual acuity, testing for color vision, examination of the optic disc by means of ophthalmoscopy and magnetic resonance imaging.
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Diagnosis of Papillitis. Diagnostic testing may include testing for visual acuity, testing for color vision, examination of the optic disc by means of ophthalmoscopy and magnetic resonance imaging.
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Therapies of Papillitis
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TreatmentIf spontaneous remission does not occur in people with papillitis it is usually treated with the corticosteroid drugs prednisone or methylprednisolone. Other treatment is symptomatic and supportive.
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Therapies of Papillitis. TreatmentIf spontaneous remission does not occur in people with papillitis it is usually treated with the corticosteroid drugs prednisone or methylprednisolone. Other treatment is symptomatic and supportive.
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Overview of Papillon Lefèvre Syndrome
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Papillon-Lefèvre syndrome (PLS) is an extremely rare genetic disorder that typically becomes apparent from approximately one to five years of age. PLS is characterized by the development of dry scaly patches on the skin of the palms and the soles (palmar-plantar hyperkeratosis) in association with severe inflammation and degeneration of the structures surrounding and supporting the teeth (periodontium). The primary (deciduous) teeth frequently become loose and fall out by about age five. Without treatment, most of the secondary (permanent) teeth may also be lost by approximately age 17. Additional symptoms and findings associated with PLS may include frequent pus-producing (pyogenic) skin infections, abnormalities of the nails (nail dystrophy), and excessive perspiration (hyperhidrosis). Papillon-Lefèvre syndrome is inherited in an autosomal recessive pattern. It results from changes (alterations) of the CTSC gene that regulates production of an enzyme known as cathepsin C.
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Overview of Papillon Lefèvre Syndrome. Papillon-Lefèvre syndrome (PLS) is an extremely rare genetic disorder that typically becomes apparent from approximately one to five years of age. PLS is characterized by the development of dry scaly patches on the skin of the palms and the soles (palmar-plantar hyperkeratosis) in association with severe inflammation and degeneration of the structures surrounding and supporting the teeth (periodontium). The primary (deciduous) teeth frequently become loose and fall out by about age five. Without treatment, most of the secondary (permanent) teeth may also be lost by approximately age 17. Additional symptoms and findings associated with PLS may include frequent pus-producing (pyogenic) skin infections, abnormalities of the nails (nail dystrophy), and excessive perspiration (hyperhidrosis). Papillon-Lefèvre syndrome is inherited in an autosomal recessive pattern. It results from changes (alterations) of the CTSC gene that regulates production of an enzyme known as cathepsin C.
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Symptoms of Papillon Lefèvre Syndrome
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Papillon-Lefèvre syndrome is characterized by the development of dry scaly patches of skin (hyperkeratosis) usually around the age of one to five years. These patches are usually confined to the undersides of the hands and feet, but may spread to the knees and elbows. Rarely, the upper portions of the hands and feet, the eyelids, the lips, the cheeks, and/or other areas of the body may also be affected. Affected skin may be unusually red and thick, but can vary in color and texture. Skin lesions may worsen in the cold and walking may be painful. In rare instances, cysts may form on the eyelids later in life. In affected individuals the teeth usually appear to form and erupt normally. However, most affected individuals exhibit chronic severe inflammation and degeneration of the tissues that surround and support the teeth (gingivitis and periodontitis). The gums and the underlying ligaments and bone that support the teeth are usually involved. When the baby (deciduous or primary) teeth erupt, these areas become red, swell, and bleed (gingivitis). The mouth may become inflamed (stomatitis), lymph nodes may swell (regional adenopathy), and pockets may form in the gums causing susceptibility to infections. Notable bad breath, called halitosis, may develop. Chewing may be very painful. The thickened ridge of bone in which the teeth rest (alveolar process) may break down (alveolar bone lysis). The baby teeth frequently become loose and fall out by the age of four or five. Afterward, the inflammation may be reduced and the gums may appear healthier. However, without treatment, most of the adult (permanent) teeth may be lost in the same manner by the age of 16. Both baby and adult teeth are usually affected in the order of their eruption. Some affected individuals will only have mild periodontal disease, and/or will have later onset of periodontal disease. Affected individuals may have frequently recurring, pus producing (pyogenic) skin infections. Some individuals may be at risk for other infections including liver abscesses, Infection of hair follicles (furunculosis), respiratory tract infections, and hidradenitis supportiva, a condition characterized by swollen, painful lesions occurring in the armpit, groin, anal and breast regions. Most individuals have fragile nails that may easily break off. Hair on the scalp and body may be sparse (hypotrichosis). Some individuals may develop excessive amounts of keratin in hair follicles causing rough, cone-shaped bumps (papules) on the skin. Affected individuals may also exhibit excessive perspiration (hyperhidrosis) associated with an unpleasant (malodorous) odor. Some individuals experience the accumulation of calcium with the skull causing the affected tissue to harden (intracranial calcification).
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Symptoms of Papillon Lefèvre Syndrome. Papillon-Lefèvre syndrome is characterized by the development of dry scaly patches of skin (hyperkeratosis) usually around the age of one to five years. These patches are usually confined to the undersides of the hands and feet, but may spread to the knees and elbows. Rarely, the upper portions of the hands and feet, the eyelids, the lips, the cheeks, and/or other areas of the body may also be affected. Affected skin may be unusually red and thick, but can vary in color and texture. Skin lesions may worsen in the cold and walking may be painful. In rare instances, cysts may form on the eyelids later in life. In affected individuals the teeth usually appear to form and erupt normally. However, most affected individuals exhibit chronic severe inflammation and degeneration of the tissues that surround and support the teeth (gingivitis and periodontitis). The gums and the underlying ligaments and bone that support the teeth are usually involved. When the baby (deciduous or primary) teeth erupt, these areas become red, swell, and bleed (gingivitis). The mouth may become inflamed (stomatitis), lymph nodes may swell (regional adenopathy), and pockets may form in the gums causing susceptibility to infections. Notable bad breath, called halitosis, may develop. Chewing may be very painful. The thickened ridge of bone in which the teeth rest (alveolar process) may break down (alveolar bone lysis). The baby teeth frequently become loose and fall out by the age of four or five. Afterward, the inflammation may be reduced and the gums may appear healthier. However, without treatment, most of the adult (permanent) teeth may be lost in the same manner by the age of 16. Both baby and adult teeth are usually affected in the order of their eruption. Some affected individuals will only have mild periodontal disease, and/or will have later onset of periodontal disease. Affected individuals may have frequently recurring, pus producing (pyogenic) skin infections. Some individuals may be at risk for other infections including liver abscesses, Infection of hair follicles (furunculosis), respiratory tract infections, and hidradenitis supportiva, a condition characterized by swollen, painful lesions occurring in the armpit, groin, anal and breast regions. Most individuals have fragile nails that may easily break off. Hair on the scalp and body may be sparse (hypotrichosis). Some individuals may develop excessive amounts of keratin in hair follicles causing rough, cone-shaped bumps (papules) on the skin. Affected individuals may also exhibit excessive perspiration (hyperhidrosis) associated with an unpleasant (malodorous) odor. Some individuals experience the accumulation of calcium with the skull causing the affected tissue to harden (intracranial calcification).
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Causes of Papillon Lefèvre Syndrome
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Papillon-Lefèvre syndrome is caused by changes (alterations) in CTSC (Cathepsin C) gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a gene is altered, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body. The CTSC gene encodes for the production of a specific type of enzyme (lysosomal protease) known as cathepsin C. The protein is expressed at high levels in various immune cells and certain bodily areas affected by PLS. These include the tightly packed cells, known as epithelial cells, that form the protective outer layer of the skin (epidermis), such as of the palms, soles, and knees, as well as certain cells of the gums (gingiva). Several different alterations of the CTSC gene have been detected in affected kindreds. Certain alterations may result in almost complete loss of cathepsin C enzymatic activity in individuals with the disease-or relatively reduced activity of the enzyme in some family members who carry a single altered copy of the gene (heterozygous carriers).Researchers believe that other factors in addition to alterations in the CTSC gene are necessary for the development of Papillon-Lefèvre syndrome. Most likely, defects in the immune system, specifically white blood called neutrophils or natural killer cells are involved. Neutrophils play a role in helping the body fight off infection, especially bacterial and fungal infections. Natural killer cells help to fight off viruses. However, research into such factors has not led to consistent findings and more research is necessary to understand the underlying mechanisms that lead to the development of clinical manifestation s observed in Papillon-Lefèvre syndrome.Papillon-Lefèvre syndrome inherited in an autosomal recessive manner. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. Parents of several individuals with Papillon-Lefèvre syndrome have been closely related by blood (consanguineous). 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.
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Causes of Papillon Lefèvre Syndrome. Papillon-Lefèvre syndrome is caused by changes (alterations) in CTSC (Cathepsin C) gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a gene is altered, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body. The CTSC gene encodes for the production of a specific type of enzyme (lysosomal protease) known as cathepsin C. The protein is expressed at high levels in various immune cells and certain bodily areas affected by PLS. These include the tightly packed cells, known as epithelial cells, that form the protective outer layer of the skin (epidermis), such as of the palms, soles, and knees, as well as certain cells of the gums (gingiva). Several different alterations of the CTSC gene have been detected in affected kindreds. Certain alterations may result in almost complete loss of cathepsin C enzymatic activity in individuals with the disease-or relatively reduced activity of the enzyme in some family members who carry a single altered copy of the gene (heterozygous carriers).Researchers believe that other factors in addition to alterations in the CTSC gene are necessary for the development of Papillon-Lefèvre syndrome. Most likely, defects in the immune system, specifically white blood called neutrophils or natural killer cells are involved. Neutrophils play a role in helping the body fight off infection, especially bacterial and fungal infections. Natural killer cells help to fight off viruses. However, research into such factors has not led to consistent findings and more research is necessary to understand the underlying mechanisms that lead to the development of clinical manifestation s observed in Papillon-Lefèvre syndrome.Papillon-Lefèvre syndrome inherited in an autosomal recessive manner. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. Parents of several individuals with Papillon-Lefèvre syndrome have been closely related by blood (consanguineous). 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.
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Affects of Papillon Lefèvre Syndrome
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Papillon-Lefèvre syndrome is an extremely rare disorder that affects males and females in equal numbers and is found in all ethnic groups. More than 200 cases have been reported in the medical literature. In the general population, the disorder occurs in approximately one to four individuals per million. However, determining the incidence or prevalence of rare disorder is extremely difficult. Skin abnormalities associated with this disorder may be present at birth (congenital) or by the age of five. Other symptoms usually become apparent between the third and fifth year of life.
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Affects of Papillon Lefèvre Syndrome. Papillon-Lefèvre syndrome is an extremely rare disorder that affects males and females in equal numbers and is found in all ethnic groups. More than 200 cases have been reported in the medical literature. In the general population, the disorder occurs in approximately one to four individuals per million. However, determining the incidence or prevalence of rare disorder is extremely difficult. Skin abnormalities associated with this disorder may be present at birth (congenital) or by the age of five. Other symptoms usually become apparent between the third and fifth year of life.
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Related disorders of Papillon Lefèvre Syndrome
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Symptoms of the following disorders can be similar to those of Papillon-Lefèvre syndrome. Comparisons may be useful for a differential diagnosis:Haim-Munk syndrome, also known as keratosis palmoplantaris with periodontopathia and onychogryphosis is a rare inherited disorder. It is characterized by reddening and overgrowth of skin on the palms of the hands and soles of the feet (palmoplantar hyperkeratosis) and overgrowth of the fingernails and toenails (onychogryphosis). Affected individuals may also have flat feet (pes planus); abnormally long, slender fingers and toes (arachnodactyly); and/or a heightened sensitivity to cold temperatures and loss of bone tissue in the fingers and toes (acroosteolysis). Degeneration of the structures that surround and support the teeth may also be present. Haim-Munk syndrome is inherited as an autosomal recessive genetic trait. Some researchers believe the disorder may be a variant of Papillon-Lefèvre syndrome. (For more information, choose “Haim Munk” as your search term in the Rare Disease Database.)Schopf-Schulz-Passarge syndrome is a rare inherited disorder characterized by the development of dry scaly skin on the palms of the hands and the soles of the feet (palmoplantar keratosis), fragile nails, and/or the development of cysts on the eyelids. Other symptoms may include the early loss of primary (deciduous) teeth, absence of some or all of the permanent teeth (hypodontia), and/or lack of body and/or scalp hair (hypotrichosis). Schopf-Schulz-Passarge syndrome is believed to be inherited as an autosomal dominant genetic trait.Pachyonychia congenita (PC) is a rare keratinizing skin disorder inherited in an autosomal dominant fashion. The predominant characteristics are severe plantar pain, palmoplantar keratoderma (PPK) including calluses with underlying blisters and variable hypertrophic nail dystrophy, often accompanied by oral leukokeratosis, cysts of various types, follicular hyperkeratosis, palmoplantar hyperhydrosis and sometimes natal teeth. PC is caused by a mutation in any one of five keratin genes, KRT6A, KRT6B, KRT6C, KRT16 or KRT17. (For more information, choose “Pachyonychia congenita” as your search term in the Rare Disease Database.)Mal de Meleda is an extremely rare disorder characterized by the slow progressive development of dry scaly skin on the palms of the hands and soles of the feet (palmoplantar hyperkeratosis). Affected skin may be unusually red and become abnormally thick. Affected children may also exhibit abnormalities of the nails, excessive sweating (hyperhidrosis) associated with an unpleasant odor, and/or development of small, firm raised lesions (lichenoid plaques). In addition, some affected children may have heart defects (cardiac abnormalities), such as an abnormally large heart (cardiomegaly). Mal de Meleda is believed to be inherited as an autosomal recessive trait. (For more information, choose “Mal de Meleda” as your search term in the Rare Disease Database.)Sjögren-Larsson syndrome is a rare inherited disorder characterized by the development of dry scaly skin (ichthyosis), hardened reddened skin on the palms of the hands and soles of the feet (palmoplantar hyperkeratosis), and/or discoloration of certain areas of skin (ecchymosis). In addition, affected infants may exhibit intellectual disability, lack of voluntary movements of the arms and legs (spastic tetraplegia), seizures, and/or eye abnormalities. Sjögren-Larsson syndrome is thought to be inherited as an autosomal recessive genetic trait. (For more information on this disorder, choose “Sjögren Larsson” as your search term in the Rare Disease Database.)Fitzsimmons syndrome is an extremely rare inherited disorder characterized by slow progressive development of dry scaly skin on the palms of the hands and soles of the feet (palmoplantar hyperkeratosis), intellectual disability, and lack of control of voluntary movements of the legs (spastic paraplegia). In some cases, children may exhibit an abnormally high arch of the foot (pes cavus). Fitzsimmons syndrome is thought to be inherited as an X-linked genetic trait.There are several additional disorders that are characterized skin abnormalities similar to those seen in Papillon-Lefèvre syndrome. These may include psoriasis, dyskeratosis congenita, epidermolytic hyperkeratosis, and some of the ectodermal dysplasias. (For more information on these disorders, search the Rare Disease Database.)
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Related disorders of Papillon Lefèvre Syndrome. Symptoms of the following disorders can be similar to those of Papillon-Lefèvre syndrome. Comparisons may be useful for a differential diagnosis:Haim-Munk syndrome, also known as keratosis palmoplantaris with periodontopathia and onychogryphosis is a rare inherited disorder. It is characterized by reddening and overgrowth of skin on the palms of the hands and soles of the feet (palmoplantar hyperkeratosis) and overgrowth of the fingernails and toenails (onychogryphosis). Affected individuals may also have flat feet (pes planus); abnormally long, slender fingers and toes (arachnodactyly); and/or a heightened sensitivity to cold temperatures and loss of bone tissue in the fingers and toes (acroosteolysis). Degeneration of the structures that surround and support the teeth may also be present. Haim-Munk syndrome is inherited as an autosomal recessive genetic trait. Some researchers believe the disorder may be a variant of Papillon-Lefèvre syndrome. (For more information, choose “Haim Munk” as your search term in the Rare Disease Database.)Schopf-Schulz-Passarge syndrome is a rare inherited disorder characterized by the development of dry scaly skin on the palms of the hands and the soles of the feet (palmoplantar keratosis), fragile nails, and/or the development of cysts on the eyelids. Other symptoms may include the early loss of primary (deciduous) teeth, absence of some or all of the permanent teeth (hypodontia), and/or lack of body and/or scalp hair (hypotrichosis). Schopf-Schulz-Passarge syndrome is believed to be inherited as an autosomal dominant genetic trait.Pachyonychia congenita (PC) is a rare keratinizing skin disorder inherited in an autosomal dominant fashion. The predominant characteristics are severe plantar pain, palmoplantar keratoderma (PPK) including calluses with underlying blisters and variable hypertrophic nail dystrophy, often accompanied by oral leukokeratosis, cysts of various types, follicular hyperkeratosis, palmoplantar hyperhydrosis and sometimes natal teeth. PC is caused by a mutation in any one of five keratin genes, KRT6A, KRT6B, KRT6C, KRT16 or KRT17. (For more information, choose “Pachyonychia congenita” as your search term in the Rare Disease Database.)Mal de Meleda is an extremely rare disorder characterized by the slow progressive development of dry scaly skin on the palms of the hands and soles of the feet (palmoplantar hyperkeratosis). Affected skin may be unusually red and become abnormally thick. Affected children may also exhibit abnormalities of the nails, excessive sweating (hyperhidrosis) associated with an unpleasant odor, and/or development of small, firm raised lesions (lichenoid plaques). In addition, some affected children may have heart defects (cardiac abnormalities), such as an abnormally large heart (cardiomegaly). Mal de Meleda is believed to be inherited as an autosomal recessive trait. (For more information, choose “Mal de Meleda” as your search term in the Rare Disease Database.)Sjögren-Larsson syndrome is a rare inherited disorder characterized by the development of dry scaly skin (ichthyosis), hardened reddened skin on the palms of the hands and soles of the feet (palmoplantar hyperkeratosis), and/or discoloration of certain areas of skin (ecchymosis). In addition, affected infants may exhibit intellectual disability, lack of voluntary movements of the arms and legs (spastic tetraplegia), seizures, and/or eye abnormalities. Sjögren-Larsson syndrome is thought to be inherited as an autosomal recessive genetic trait. (For more information on this disorder, choose “Sjögren Larsson” as your search term in the Rare Disease Database.)Fitzsimmons syndrome is an extremely rare inherited disorder characterized by slow progressive development of dry scaly skin on the palms of the hands and soles of the feet (palmoplantar hyperkeratosis), intellectual disability, and lack of control of voluntary movements of the legs (spastic paraplegia). In some cases, children may exhibit an abnormally high arch of the foot (pes cavus). Fitzsimmons syndrome is thought to be inherited as an X-linked genetic trait.There are several additional disorders that are characterized skin abnormalities similar to those seen in Papillon-Lefèvre syndrome. These may include psoriasis, dyskeratosis congenita, epidermolytic hyperkeratosis, and some of the ectodermal dysplasias. (For more information on these disorders, search the Rare Disease Database.)
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Papillon Lefèvre Syndrome
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Diagnosis of Papillon Lefèvre Syndrome
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The diagnosis of Papillon-Lefèvre syndrome may be confirmed by a thorough clinical evaluation that includes a detailed patient history and identification of characteristic physical findings. In some instances, skin abnormalities may be apparent at birth (congenital) or during infancy including characteristic skin abnormalities on the palms of the hands and the soles of the feet.In most instances, the diagnosis of the disorder may not be confirmed until inflammation and degeneration of the tissues surrounding and supporting the teeth (periodontium) become apparent. This usually occurs between the third and fifth year of life, when the infant teeth (deciduous) begin to erupt. In many people, abnormalities of the skin occur simultaneously with the loss of teeth. In addition, identification of the abnormal accumulation of calcium with in the skull (intracranial calcification) may assist in confirming a diagnosis.A diagnosis can be made by a simple analysis of an infant’s or child’s urine (urinary analysis). The urine of a child suspected of having Papillon-Lefèvre syndrome is tested to see whether there is any activity of the enzyme cathepsin C. Little or no activity of this enzyme is diagnostic of the disorder. This is extremely important because early diagnosis and prompt treatment can potentially prevent aggressive periodontitis, tooth loss, and improve overall quality of life of people with Papillon-Lefèvre syndrome. Molecular genetic testing can confirm a diagnosis. Molecular genetic testing can detect alterations in the CTSC gene known to cause Papillon-Lefèvre syndrome, but is available only as a diagnostic service at specialized laboratories.
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Diagnosis of Papillon Lefèvre Syndrome. The diagnosis of Papillon-Lefèvre syndrome may be confirmed by a thorough clinical evaluation that includes a detailed patient history and identification of characteristic physical findings. In some instances, skin abnormalities may be apparent at birth (congenital) or during infancy including characteristic skin abnormalities on the palms of the hands and the soles of the feet.In most instances, the diagnosis of the disorder may not be confirmed until inflammation and degeneration of the tissues surrounding and supporting the teeth (periodontium) become apparent. This usually occurs between the third and fifth year of life, when the infant teeth (deciduous) begin to erupt. In many people, abnormalities of the skin occur simultaneously with the loss of teeth. In addition, identification of the abnormal accumulation of calcium with in the skull (intracranial calcification) may assist in confirming a diagnosis.A diagnosis can be made by a simple analysis of an infant’s or child’s urine (urinary analysis). The urine of a child suspected of having Papillon-Lefèvre syndrome is tested to see whether there is any activity of the enzyme cathepsin C. Little or no activity of this enzyme is diagnostic of the disorder. This is extremely important because early diagnosis and prompt treatment can potentially prevent aggressive periodontitis, tooth loss, and improve overall quality of life of people with Papillon-Lefèvre syndrome. Molecular genetic testing can confirm a diagnosis. Molecular genetic testing can detect alterations in the CTSC gene known to cause Papillon-Lefèvre syndrome, but is available only as a diagnostic service at specialized laboratories.
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Papillon Lefèvre Syndrome
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Therapies of Papillon Lefèvre Syndrome
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Treatment is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, physicians who evaluate and treat skin problems (dermatologists), dentist, dental surgical team, which includes a pediatric dentist, a specialist in treating disorders affecting the area supporting and surrounding the teeth (periodontist), and a specialist in the restoration and replacement of teeth (prosthodontist), and other healthcare professionals may need to systematically and comprehensively plan an affected child's treatment. Genetic counseling may be of benefit for affected individuals and their families. Psychosocial support is recommended for the entire family as well. Genetic counseling is recommended for affected individuals and their families. Psychosocial support is recommended for the entire family as well. Physicians may carefully monitor affected individuals to help prevent and ensure early identification of infection. Should gum infection occur antibiotic therapy may be prescribed. Proper oral hygiene and the use of mouth rinses is recommended. If teeth are lost, they may be replaced with dental implants. Limited success has been found in treating associated skin abnormalities with topical lubricants and moisturizers (emollients). Sometimes, medications that break down the outer layer of the skin (keratolytics) or topical steroids, which reduce inflammation of the skin, may also be used. In some cases, surgery and skin grafts may be used to alleviate skin problems. Use of antiperspirants and deodorants may help with excessive perspiration (hyperhidrosis).
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Therapies of Papillon Lefèvre Syndrome. Treatment is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, physicians who evaluate and treat skin problems (dermatologists), dentist, dental surgical team, which includes a pediatric dentist, a specialist in treating disorders affecting the area supporting and surrounding the teeth (periodontist), and a specialist in the restoration and replacement of teeth (prosthodontist), and other healthcare professionals may need to systematically and comprehensively plan an affected child's treatment. Genetic counseling may be of benefit for affected individuals and their families. Psychosocial support is recommended for the entire family as well. Genetic counseling is recommended for affected individuals and their families. Psychosocial support is recommended for the entire family as well. Physicians may carefully monitor affected individuals to help prevent and ensure early identification of infection. Should gum infection occur antibiotic therapy may be prescribed. Proper oral hygiene and the use of mouth rinses is recommended. If teeth are lost, they may be replaced with dental implants. Limited success has been found in treating associated skin abnormalities with topical lubricants and moisturizers (emollients). Sometimes, medications that break down the outer layer of the skin (keratolytics) or topical steroids, which reduce inflammation of the skin, may also be used. In some cases, surgery and skin grafts may be used to alleviate skin problems. Use of antiperspirants and deodorants may help with excessive perspiration (hyperhidrosis).
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Papillon Lefèvre Syndrome
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nord_936_0
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Overview of Paracoccidioidomycosis
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Paracoccidioidomycosis (PCM) is a chronic infectious tropical disease caused by the fungus Paracoccidioides brasiliensis. The initial infection usually occurs in the lungs, but may also spread to the skin, mucous membranes, and other parts of the body. Specialized cells that line the walls of blood and lymphatic vessels and dispose of cellular waste (reticuloendothelial system) may also be affected by paracoccidioidomycosis. If the patient does not receive treatment, life-threatening complications can occur. Most cases of this disease occur in South and Central America.
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Overview of Paracoccidioidomycosis. Paracoccidioidomycosis (PCM) is a chronic infectious tropical disease caused by the fungus Paracoccidioides brasiliensis. The initial infection usually occurs in the lungs, but may also spread to the skin, mucous membranes, and other parts of the body. Specialized cells that line the walls of blood and lymphatic vessels and dispose of cellular waste (reticuloendothelial system) may also be affected by paracoccidioidomycosis. If the patient does not receive treatment, life-threatening complications can occur. Most cases of this disease occur in South and Central America.
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Paracoccidioidomycosis
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Symptoms of Paracoccidioidomycosis
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The symptoms of paracoccidioidomycosis generally occur from several weeks or months to years after the initial exposure to the fungus. The symptoms vary according to which areas of the body are infected. The symptoms of pulmonary paracoccidioidomycosis, in which the lungs are affected, may include cough, difficulty breathing (dyspnea), fatigue, and/or chest pain. Adults with this form of the disorder may also have fibrous and degenerative changes in the lungs that cause the progressive loss of lung function (emphysema). In some people, the symptoms of paracoccidioidomycosis progress to a condition known as cor pulmonale. Heart disease occurs in this condition because of abnormally high blood pressure within the vessels that move blood away from the lungs and toward the heart.In mucocutaneous paracoccidioidomycosis, ulcers (granulomatous lesions) appear on the mucous membranes, especially those of the mouth and nose.When paracoccidioidomycosis affects the lymphatic system, generalized swelling of lymph nodes (lymphadenopathy) may occur in many areas of the body, especially in the neck and the underarm area (axilla). Infected lymph nodes may become painful and produce pus (suppuration).In visceral paracoccidioidomycosis, other organs of the body may also be infected including the liver, spleen, and/or intestines. The adrenal glands may be particularly susceptible to this infection. Chronic adrenal involvement may cause abnormally low levels of adrenal hormones.
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Symptoms of Paracoccidioidomycosis. The symptoms of paracoccidioidomycosis generally occur from several weeks or months to years after the initial exposure to the fungus. The symptoms vary according to which areas of the body are infected. The symptoms of pulmonary paracoccidioidomycosis, in which the lungs are affected, may include cough, difficulty breathing (dyspnea), fatigue, and/or chest pain. Adults with this form of the disorder may also have fibrous and degenerative changes in the lungs that cause the progressive loss of lung function (emphysema). In some people, the symptoms of paracoccidioidomycosis progress to a condition known as cor pulmonale. Heart disease occurs in this condition because of abnormally high blood pressure within the vessels that move blood away from the lungs and toward the heart.In mucocutaneous paracoccidioidomycosis, ulcers (granulomatous lesions) appear on the mucous membranes, especially those of the mouth and nose.When paracoccidioidomycosis affects the lymphatic system, generalized swelling of lymph nodes (lymphadenopathy) may occur in many areas of the body, especially in the neck and the underarm area (axilla). Infected lymph nodes may become painful and produce pus (suppuration).In visceral paracoccidioidomycosis, other organs of the body may also be infected including the liver, spleen, and/or intestines. The adrenal glands may be particularly susceptible to this infection. Chronic adrenal involvement may cause abnormally low levels of adrenal hormones.
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Paracoccidioidomycosis
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Causes of Paracoccidioidomycosis
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Paracoccidioidomycosis is caused by infection with a fungus known as Paracoccidioides brasiliensis. Many cases of this disease occur years after airborne fungal spores are inhaled, although the period of latency is not always this long. The fungus is thought to exist in soil as a mold, and infection occurs following inhalation of spores (conidia). In the lungs, the fungus is converted to yeasts that may spread to other sites. Some of those exposed are able to resist this process and the infection is stopped. However, in others the fungus goes on to cause disease in one or more parts of the body. Paracoccidioidomycosis sometimes occurs in patients whose immune systems have been weakened (immunocompromised), including those with AIDS.
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Causes of Paracoccidioidomycosis. Paracoccidioidomycosis is caused by infection with a fungus known as Paracoccidioides brasiliensis. Many cases of this disease occur years after airborne fungal spores are inhaled, although the period of latency is not always this long. The fungus is thought to exist in soil as a mold, and infection occurs following inhalation of spores (conidia). In the lungs, the fungus is converted to yeasts that may spread to other sites. Some of those exposed are able to resist this process and the infection is stopped. However, in others the fungus goes on to cause disease in one or more parts of the body. Paracoccidioidomycosis sometimes occurs in patients whose immune systems have been weakened (immunocompromised), including those with AIDS.
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Paracoccidioidomycosis
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Affects of Paracoccidioidomycosis
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Paracoccidioidomycosis is a rare fungal disease. For reasons that are not clearly understood, its chronic adult form affects males 15 times more frequently than it does females. Most affected people are between the ages of 20 and 50 years. The subacute juvenile form of the disorder affects males and females equally.Paracoccidioidomycosis is rare in the United States but can occur in people who have visited, or migrated from, South and Central America.
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Affects of Paracoccidioidomycosis. Paracoccidioidomycosis is a rare fungal disease. For reasons that are not clearly understood, its chronic adult form affects males 15 times more frequently than it does females. Most affected people are between the ages of 20 and 50 years. The subacute juvenile form of the disorder affects males and females equally.Paracoccidioidomycosis is rare in the United States but can occur in people who have visited, or migrated from, South and Central America.
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Paracoccidioidomycosis
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Related disorders of Paracoccidioidomycosis
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Symptoms of the following disorders can be similar to those of Paracoccidioidomycosis. Comparisons may be useful for a differential diagnosis:Blastomycosis or North American Blastomycosis is a systemic fungal infection caused by Blastomyces dermatitidis. It occurs primarily in the southeastern and Mississippi valley areas of the United States. Symptoms initially include fever, chills, cough, heavy sweating, and/or difficulty breathing (dyspnea). Other symptoms may develop later and involve the lungs, skin, bones, joints, kidneys, and/or central nervous system. Chronic infection of the lungs may lead to pneumonia. If left untreated, Blastomycosis can have life-threatening complications. (For more information on this disorder, choose “Blastomycosis” as your search term in the Rare Disease Database.)Tuberculosis is a bacterial disease caused by Mycobacterium tuberculosis or Mycobacterium bovis. It is characterized by an initial period without symptoms. Pneumonia may be the first symptom in some people with Tuberculosis. Other symptoms may include coughing, weight loss, night sweats, fever, and/or fatigue. Chest x-rays typically reveal cavities in the lungs caused by chronic infection. The major symptom at this stage is coughing and the production of phlegm. (For more information on this disorder, choose “Tuberculosis” as your search term in the Rare Disease Database.)Nocardiosis is a rare infectious disease caused by the bacteria Nocardia asteroides and is characterized by acute inflammation of the lungs (pneumonia) and abscesses in the lungs. Symptoms include the profound loss of appetite (anorexia), generalized weakness, cough, and/or chest pain. Some affected individuals may also have abscesses in the brain, kidneys, intestines, and/or other organs of the body. Symptoms associated with brain abscesses may include severe headaches and other neurological difficulties. (For more information on this disorder, choose “Nocardiosis” as your search term in the Rare Disease Database.)Toxoplasmosis is an infectious disorder that is caused by a parasite (Toxoplasma gondii) that is found in the feces of cats. This infection is found worldwide and may be either acquired or transmitted to a fetus from an infected mother. When the disorder is acquired, the symptoms are similar to mononucleosis or involve lesions of the lungs, liver, heart, skin, muscle, brain, and spinal cord membranes. Lesions are often accompanied by inflammation and in some cases hepatitis. Acute cases are often characterized by rash, high fever, chills, and fatigue. To avoid this disease, pregnant women and people with an impaired immune system should wear a protective mask when emptying litter boxes containing cat feces. The prognosis for the acquired forms of Toxoplasmosis is usually good with treatment, and complications are uncommon. Without treatment this disorder may persist for many months. (For more information on this disorder, choose “Toxoplasmosis” as your search term in the Rare Disease Database.)
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Related disorders of Paracoccidioidomycosis. Symptoms of the following disorders can be similar to those of Paracoccidioidomycosis. Comparisons may be useful for a differential diagnosis:Blastomycosis or North American Blastomycosis is a systemic fungal infection caused by Blastomyces dermatitidis. It occurs primarily in the southeastern and Mississippi valley areas of the United States. Symptoms initially include fever, chills, cough, heavy sweating, and/or difficulty breathing (dyspnea). Other symptoms may develop later and involve the lungs, skin, bones, joints, kidneys, and/or central nervous system. Chronic infection of the lungs may lead to pneumonia. If left untreated, Blastomycosis can have life-threatening complications. (For more information on this disorder, choose “Blastomycosis” as your search term in the Rare Disease Database.)Tuberculosis is a bacterial disease caused by Mycobacterium tuberculosis or Mycobacterium bovis. It is characterized by an initial period without symptoms. Pneumonia may be the first symptom in some people with Tuberculosis. Other symptoms may include coughing, weight loss, night sweats, fever, and/or fatigue. Chest x-rays typically reveal cavities in the lungs caused by chronic infection. The major symptom at this stage is coughing and the production of phlegm. (For more information on this disorder, choose “Tuberculosis” as your search term in the Rare Disease Database.)Nocardiosis is a rare infectious disease caused by the bacteria Nocardia asteroides and is characterized by acute inflammation of the lungs (pneumonia) and abscesses in the lungs. Symptoms include the profound loss of appetite (anorexia), generalized weakness, cough, and/or chest pain. Some affected individuals may also have abscesses in the brain, kidneys, intestines, and/or other organs of the body. Symptoms associated with brain abscesses may include severe headaches and other neurological difficulties. (For more information on this disorder, choose “Nocardiosis” as your search term in the Rare Disease Database.)Toxoplasmosis is an infectious disorder that is caused by a parasite (Toxoplasma gondii) that is found in the feces of cats. This infection is found worldwide and may be either acquired or transmitted to a fetus from an infected mother. When the disorder is acquired, the symptoms are similar to mononucleosis or involve lesions of the lungs, liver, heart, skin, muscle, brain, and spinal cord membranes. Lesions are often accompanied by inflammation and in some cases hepatitis. Acute cases are often characterized by rash, high fever, chills, and fatigue. To avoid this disease, pregnant women and people with an impaired immune system should wear a protective mask when emptying litter boxes containing cat feces. The prognosis for the acquired forms of Toxoplasmosis is usually good with treatment, and complications are uncommon. Without treatment this disorder may persist for many months. (For more information on this disorder, choose “Toxoplasmosis” as your search term in the Rare Disease Database.)
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Paracoccidioidomycosis
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Diagnosis of Paracoccidioidomycosis
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The diagnosis of paracoccidioidomycosis is usually made by examination of sputum or pus from infected individuals. If positive, microscopic examination will permit the identification of the responsible fungus, Paracoccidioides brasiliensis. Diagnosis may also be made by the examination of tissue samples (biopsy specimens) from the lungs, skin, and/or lymph nodes. The diagnosis is confirmed when samples of infected tissue are grown in the laboratory (cultured) and eventually test positive for the presence of Paracoccidioides brasiliensis.Blood tests may also be useful for the diagnosis of paracoccidioidomycosis, but they cannot distinguish between active and past infection. Skin tests are available but may not be reliable. Chest x-rays of affected individuals may show patchy areas of fungal infection (infiltration).
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Diagnosis of Paracoccidioidomycosis. The diagnosis of paracoccidioidomycosis is usually made by examination of sputum or pus from infected individuals. If positive, microscopic examination will permit the identification of the responsible fungus, Paracoccidioides brasiliensis. Diagnosis may also be made by the examination of tissue samples (biopsy specimens) from the lungs, skin, and/or lymph nodes. The diagnosis is confirmed when samples of infected tissue are grown in the laboratory (cultured) and eventually test positive for the presence of Paracoccidioides brasiliensis.Blood tests may also be useful for the diagnosis of paracoccidioidomycosis, but they cannot distinguish between active and past infection. Skin tests are available but may not be reliable. Chest x-rays of affected individuals may show patchy areas of fungal infection (infiltration).
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Paracoccidioidomycosis
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Therapies of Paracoccidioidomycosis
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TreatmentAntifungal drugs are the most effective therapeutics for paracoccidio-idomycosis. Among these are itraconazole, ketoconazole and fluconazole. Amphotericin B may be given to patients with severe disease who cannot tolerate other medications. Sulfonamides suppress the symptoms and halt the progress of the disease, but do not eliminate the fungus from the body.
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Therapies of Paracoccidioidomycosis. TreatmentAntifungal drugs are the most effective therapeutics for paracoccidio-idomycosis. Among these are itraconazole, ketoconazole and fluconazole. Amphotericin B may be given to patients with severe disease who cannot tolerate other medications. Sulfonamides suppress the symptoms and halt the progress of the disease, but do not eliminate the fungus from the body.
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Paracoccidioidomycosis
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Overview of Paramyotonia Congenita
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SummaryParamyotonia congenita (PMC) is a rare non-progressive genetic disorder that affects the skeletal muscles. The disorder typically begins in infancy or early childhood. Affected individuals experience spells of muscle stiffness or when the muscles do not relax after contracting (myotonia). Symptoms can be triggered by exposure to the cold or after physical activity. The stiffness most commonly affects the muscles in the neck, face, arms and hands, however it can occur in the lower back and the muscles used for breathing. The stiffness of the muscles can get worse with repeated movements. There are also intermittent periods of a type of muscle weakness in which there is no muscle tone (flaccid paresis). This condition does not necessarily coincide with exposure to cold temperatures or myotonia. There is generally no wasting (atrophy) of muscles; however, there is often increase in bulk (hypertrophy) of muscles with this disorder. There is no cure to PMC; however, with the proper management of diet, lifestyle and medication, patients can lead normal lives. PMC is an autosomal dominant genetic condition caused by a mutation in the muscle sodium channel gene SCN4A.IntroductionPMC is classified as a form of periodic paralyses, a group of muscle disorders characterized by irregular episodes of muscle weakness or stiffness. PMC was first discussed in 1886 by von Eulenburg. It is considered the first recognized temperature-sensitive condition in humans.
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Overview of Paramyotonia Congenita. SummaryParamyotonia congenita (PMC) is a rare non-progressive genetic disorder that affects the skeletal muscles. The disorder typically begins in infancy or early childhood. Affected individuals experience spells of muscle stiffness or when the muscles do not relax after contracting (myotonia). Symptoms can be triggered by exposure to the cold or after physical activity. The stiffness most commonly affects the muscles in the neck, face, arms and hands, however it can occur in the lower back and the muscles used for breathing. The stiffness of the muscles can get worse with repeated movements. There are also intermittent periods of a type of muscle weakness in which there is no muscle tone (flaccid paresis). This condition does not necessarily coincide with exposure to cold temperatures or myotonia. There is generally no wasting (atrophy) of muscles; however, there is often increase in bulk (hypertrophy) of muscles with this disorder. There is no cure to PMC; however, with the proper management of diet, lifestyle and medication, patients can lead normal lives. PMC is an autosomal dominant genetic condition caused by a mutation in the muscle sodium channel gene SCN4A.IntroductionPMC is classified as a form of periodic paralyses, a group of muscle disorders characterized by irregular episodes of muscle weakness or stiffness. PMC was first discussed in 1886 by von Eulenburg. It is considered the first recognized temperature-sensitive condition in humans.
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Paramyotonia Congenita
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Symptoms of Paramyotonia Congenita
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Muscle stiffness in PMC is the inability for the muscles to relax in a timely manner after contracting (myotonia). The muscles most commonly affected are located in the face, neck and upper extremities, although it can affect the muscles used for breathing and swallowing, as well as muscles in the lower back. PMC is usually apparent during infancy and always presents by teenage years. Symptoms do not progress with age. Individuals with this disorder do not have wasting of muscles (atrophy) but often have an increase of muscle bulk (hypertrophy).The severity of the muscle stiffness depends on the individual; some patients experience painful myotonia, while others experience painless myotonia. This condition becomes worse with exposure to cold and alleviated by warm temperatures. In addition, it can become more severe with exercise. Sudden overexertion can trigger muscle stiffness and overall weakness that can take several days to completely resolve. PMC can make small everyday activities difficult, such as letting go of small objects (e.g. pens or door knobs). Some episodes of muscle stiffness can coincide with potassium intake; affected individuals are instructed to avoid certain food products rich in potassium.Some patients with more severe PMC can experience shortness of breath or tightness in their chest muscles.
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Symptoms of Paramyotonia Congenita. Muscle stiffness in PMC is the inability for the muscles to relax in a timely manner after contracting (myotonia). The muscles most commonly affected are located in the face, neck and upper extremities, although it can affect the muscles used for breathing and swallowing, as well as muscles in the lower back. PMC is usually apparent during infancy and always presents by teenage years. Symptoms do not progress with age. Individuals with this disorder do not have wasting of muscles (atrophy) but often have an increase of muscle bulk (hypertrophy).The severity of the muscle stiffness depends on the individual; some patients experience painful myotonia, while others experience painless myotonia. This condition becomes worse with exposure to cold and alleviated by warm temperatures. In addition, it can become more severe with exercise. Sudden overexertion can trigger muscle stiffness and overall weakness that can take several days to completely resolve. PMC can make small everyday activities difficult, such as letting go of small objects (e.g. pens or door knobs). Some episodes of muscle stiffness can coincide with potassium intake; affected individuals are instructed to avoid certain food products rich in potassium.Some patients with more severe PMC can experience shortness of breath or tightness in their chest muscles.
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Causes of Paramyotonia Congenita
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PMC is an autosomal dominant genetic condition caused by a change (mutation) in the SCN4A gene which codes for a sodium channel specific for skeletal muscles. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a mutated 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.In some individuals, the disorder is due to a spontaneous (de novo) genetic mutation that occurs in the egg or sperm cell. In such situations, the disorder is not inherited from the parents. Skeletal muscles move the body; muscle contractions pull on tendons, which are attached to the bones and causes the body to move. Muscle contractions are triggered by the flow of positively charged atoms (e.g. potassium and sodium) through channels into the skeletal muscles. These atoms carry electrical impulses necessary for normal function of the muscle cells. However, a mutation of the SCN4A gene alters the structure of the sodium channels. The sodium channels fail to regulate the flow of atoms into the muscles cells, and the ratio of sodium and potassium becomes unbalanced. The abnormal ratio interferes with normal muscle contraction and relaxation, causing bouts of muscle weakness and stiffness. Most individuals with a SCN4A gene mutation have symptoms; however, there are a few who remain unaffected and are known as “carriers”.
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Causes of Paramyotonia Congenita. PMC is an autosomal dominant genetic condition caused by a change (mutation) in the SCN4A gene which codes for a sodium channel specific for skeletal muscles. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a mutated 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.In some individuals, the disorder is due to a spontaneous (de novo) genetic mutation that occurs in the egg or sperm cell. In such situations, the disorder is not inherited from the parents. Skeletal muscles move the body; muscle contractions pull on tendons, which are attached to the bones and causes the body to move. Muscle contractions are triggered by the flow of positively charged atoms (e.g. potassium and sodium) through channels into the skeletal muscles. These atoms carry electrical impulses necessary for normal function of the muscle cells. However, a mutation of the SCN4A gene alters the structure of the sodium channels. The sodium channels fail to regulate the flow of atoms into the muscles cells, and the ratio of sodium and potassium becomes unbalanced. The abnormal ratio interferes with normal muscle contraction and relaxation, causing bouts of muscle weakness and stiffness. Most individuals with a SCN4A gene mutation have symptoms; however, there are a few who remain unaffected and are known as “carriers”.
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Affects of Paramyotonia Congenita
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PMC is a very rare disorder that affects males and females in equal numbers. The symptoms can begin during infancy, and are always apparent by the teenage years. It is estimated to affect fewer than 1 in 100,000 people.
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Affects of Paramyotonia Congenita. PMC is a very rare disorder that affects males and females in equal numbers. The symptoms can begin during infancy, and are always apparent by the teenage years. It is estimated to affect fewer than 1 in 100,000 people.
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Related disorders of Paramyotonia Congenita
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Symptoms of the following disorders can be similar to those of paramyotonia congenita. Comparisons may be useful for a differential diagnosis.PMC needs to be distinguished from other forms of myotonic disorders such as myotonia congenita and myotonic dystrophy as well as other forms of periodic paralysis including hyperkalemic periodic paralysis, hypokalemic periodic paralysis, and Andersen-Tawil syndrome. Myotonia congenita is a rare genetic disorder in which an abnormality of voluntary (skeletal) muscle fiber membranes causes an unusually exaggerated response to stimulation (hyperexcitability). As a result, affected individuals complain of muscle stiffness due to difficulty relaxing certain muscles after contracting them (myotonia) Such symptoms tend to occur when attempting to move certain muscles after rest and the myotonia improves with repeat use of the muscle. Many individuals with myotonia congenita also have abnormal enlargement of the muscles (hypertrophy), resulting in a “herculean” or “body-builder like” appearance. Two main forms of myotonia congenita have been described: Thomsen disease and Becker disease. Individuals with Thomsen disease may have myotonia, associated muscle rigidity, and abnormal muscle enlargement that becomes apparent from infancy to approximately two to three years of age. In many cases, muscles of the eyelids, hands, and legs may be most affected. Thomsen disease is an autosomal dominant condition. People with Becker disease develop symptoms most commonly between the ages of four and 12 years. As in Thomsen type myotonia congenita, affected individuals develop myotonia, associated muscle rigidity, and abnormal muscle enlargement (hypertrophy). The symptoms tend to remain constant, with little progression. Becker disease is inherited as an autosomal recessive condition. (For more information on this disorder, choose “myotonia congenita” as your search term in the Rare Disease Database.) PMC can be distinguished from myotonia congenita by its exquisite sensitivity to cold.Myotonic dystrophy is a rare disorder inherited as an autosomal dominant trait. This disorder involves the muscles, vision, and endocrine glands. Myotonic dystrophy usually begins during young adulthood and is marked initially by an inability to relax muscles after contraction (myotonia). Loss of muscle strength, mental deficiency, cataracts, reduction of testicular function, and frontal baldness are also symptomatic of this disorder. (For more information on this disorder, choose “myotonic dystrophy” as your search term in the Rare Disease Database.)Hyperkalemic periodic paralysis is an autosomal dominant genetic condition typically detected during infancy. It is caused by my mutations in the same gene that causes PMC. Whereas in PMC the main symptoms is muscle stiffness, the major symptom in hyperkalemic periodic paralysis is periodic muscle weakness with or without muscles that do not relax after contracting (myotonia). Patients may have attacks from once every few months to several times a day. Typically the periods of muscle weakness last from one half an hour to an hour. This weakness may be found in the calves or thighs of the legs, lower back, arms, neck and/or eyelids. Periods of muscle weakness usually follow rest after exercise, hunger, infection, exposure to the cold and/or emotional stress. Permanent weakness and wasting of muscles may develop later on.Hypokalemic periodic paralysis is an autosomal dominant genetic condition typically detected in the first decade of life. The major symptom in hypokalemic periodic paralysis is periodic muscle weakness without muscle stiffness. Patients may have attacks once a week or once a day. Typically the periods of muscle weakness last from hours to a couple days. This weakness may affect muscles of the arms and legs but typically not the speech, swallow or breathing muscles. Periods of muscle weakness are associated with low blood potassium levels and usually follow rest after exercise, large carbohydrate meals, infection, and/or emotional stress. Permanent weakness and wasting of muscles may develop later on.Andersen-Tawil syndrome is a rare disorder that causes muscle weakness and paralysis, as well as affecting the electrical system of the heart causing abnormal rhythms. This disorder is caused by a mutation in the KCNJ2 gene that disrupts the flow of protein to the muscles. (For more information on this disorder, choose “Andersen- Tawil Syndrome” as your search term in the Rare Disease Database.)
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Related disorders of Paramyotonia Congenita. Symptoms of the following disorders can be similar to those of paramyotonia congenita. Comparisons may be useful for a differential diagnosis.PMC needs to be distinguished from other forms of myotonic disorders such as myotonia congenita and myotonic dystrophy as well as other forms of periodic paralysis including hyperkalemic periodic paralysis, hypokalemic periodic paralysis, and Andersen-Tawil syndrome. Myotonia congenita is a rare genetic disorder in which an abnormality of voluntary (skeletal) muscle fiber membranes causes an unusually exaggerated response to stimulation (hyperexcitability). As a result, affected individuals complain of muscle stiffness due to difficulty relaxing certain muscles after contracting them (myotonia) Such symptoms tend to occur when attempting to move certain muscles after rest and the myotonia improves with repeat use of the muscle. Many individuals with myotonia congenita also have abnormal enlargement of the muscles (hypertrophy), resulting in a “herculean” or “body-builder like” appearance. Two main forms of myotonia congenita have been described: Thomsen disease and Becker disease. Individuals with Thomsen disease may have myotonia, associated muscle rigidity, and abnormal muscle enlargement that becomes apparent from infancy to approximately two to three years of age. In many cases, muscles of the eyelids, hands, and legs may be most affected. Thomsen disease is an autosomal dominant condition. People with Becker disease develop symptoms most commonly between the ages of four and 12 years. As in Thomsen type myotonia congenita, affected individuals develop myotonia, associated muscle rigidity, and abnormal muscle enlargement (hypertrophy). The symptoms tend to remain constant, with little progression. Becker disease is inherited as an autosomal recessive condition. (For more information on this disorder, choose “myotonia congenita” as your search term in the Rare Disease Database.) PMC can be distinguished from myotonia congenita by its exquisite sensitivity to cold.Myotonic dystrophy is a rare disorder inherited as an autosomal dominant trait. This disorder involves the muscles, vision, and endocrine glands. Myotonic dystrophy usually begins during young adulthood and is marked initially by an inability to relax muscles after contraction (myotonia). Loss of muscle strength, mental deficiency, cataracts, reduction of testicular function, and frontal baldness are also symptomatic of this disorder. (For more information on this disorder, choose “myotonic dystrophy” as your search term in the Rare Disease Database.)Hyperkalemic periodic paralysis is an autosomal dominant genetic condition typically detected during infancy. It is caused by my mutations in the same gene that causes PMC. Whereas in PMC the main symptoms is muscle stiffness, the major symptom in hyperkalemic periodic paralysis is periodic muscle weakness with or without muscles that do not relax after contracting (myotonia). Patients may have attacks from once every few months to several times a day. Typically the periods of muscle weakness last from one half an hour to an hour. This weakness may be found in the calves or thighs of the legs, lower back, arms, neck and/or eyelids. Periods of muscle weakness usually follow rest after exercise, hunger, infection, exposure to the cold and/or emotional stress. Permanent weakness and wasting of muscles may develop later on.Hypokalemic periodic paralysis is an autosomal dominant genetic condition typically detected in the first decade of life. The major symptom in hypokalemic periodic paralysis is periodic muscle weakness without muscle stiffness. Patients may have attacks once a week or once a day. Typically the periods of muscle weakness last from hours to a couple days. This weakness may affect muscles of the arms and legs but typically not the speech, swallow or breathing muscles. Periods of muscle weakness are associated with low blood potassium levels and usually follow rest after exercise, large carbohydrate meals, infection, and/or emotional stress. Permanent weakness and wasting of muscles may develop later on.Andersen-Tawil syndrome is a rare disorder that causes muscle weakness and paralysis, as well as affecting the electrical system of the heart causing abnormal rhythms. This disorder is caused by a mutation in the KCNJ2 gene that disrupts the flow of protein to the muscles. (For more information on this disorder, choose “Andersen- Tawil Syndrome” as your search term in the Rare Disease Database.)
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Diagnosis of Paramyotonia Congenita
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When PMC is suspected, a test is administered to test the capacity of muscles to conduct electricity (electromyography). During the test, the muscles are chilled and electrical signals are recorded before and after the muscle is cooled. The electromyography (EMG) will show rapid repetitive electrical discharges. EMG cannot always diagnose PMC definitively, and further testing may be necessary. Genetic testing on a blood sample will result in a definitive diagnosis by showing the presence of a characteristic mutation in the SCN4A gene.
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Diagnosis of Paramyotonia Congenita. When PMC is suspected, a test is administered to test the capacity of muscles to conduct electricity (electromyography). During the test, the muscles are chilled and electrical signals are recorded before and after the muscle is cooled. The electromyography (EMG) will show rapid repetitive electrical discharges. EMG cannot always diagnose PMC definitively, and further testing may be necessary. Genetic testing on a blood sample will result in a definitive diagnosis by showing the presence of a characteristic mutation in the SCN4A gene.
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Therapies of Paramyotonia Congenita
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TreatmentThe treatment of PMC is based on the individual’s symptoms; PMC can be handled on a day-to-day basis and many patients can lead normal lives. Individuals must be cautious to sudden exposures to very cold weather, as well as avoiding sudden heavy physical activity. Muscle stiffness could also be triggered or enhanced by potassium-rich foods. Patients will need to learn how to manage their potassium-intake. They should avoid potassium-rich foods, avoid skipping meals and take carbohydrate rich snacks in between meals. The aim of treatment is to reduce the intensity of acute symptoms and to prevent, as far as possible, further attacks. Some attacks are so mild that treatment is not necessary. However, in other instances drug therapy is required.Treatment with medications that block the sodium channels such as mexiletine and lamotrigine may help reduce the stiffness related to myotonia. Some patients with PMC may benefit from acetazolamide or thiazide diuretic drugs to reduce the number of paralytic attacks. Genetic counseling is recommended for patients and their families.
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Therapies of Paramyotonia Congenita. TreatmentThe treatment of PMC is based on the individual’s symptoms; PMC can be handled on a day-to-day basis and many patients can lead normal lives. Individuals must be cautious to sudden exposures to very cold weather, as well as avoiding sudden heavy physical activity. Muscle stiffness could also be triggered or enhanced by potassium-rich foods. Patients will need to learn how to manage their potassium-intake. They should avoid potassium-rich foods, avoid skipping meals and take carbohydrate rich snacks in between meals. The aim of treatment is to reduce the intensity of acute symptoms and to prevent, as far as possible, further attacks. Some attacks are so mild that treatment is not necessary. However, in other instances drug therapy is required.Treatment with medications that block the sodium channels such as mexiletine and lamotrigine may help reduce the stiffness related to myotonia. Some patients with PMC may benefit from acetazolamide or thiazide diuretic drugs to reduce the number of paralytic attacks. Genetic counseling is recommended for patients and their families.
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Overview of Paraneoplastic Neurologic Syndromes
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Paraneoplastic neurologic syndromes (PNS) are a group of conditions that affect the nervous system (brain, spinal cord, nerves and/or muscles) in patients with cancer. The term “paraneoplastic” means that the neurological syndrome is not caused by the tumor itself, but by the immunological reactions that the tumor produces. It is believed that the body’s normal immunological system interprets the tumor as an invasion. When this occurs, the immunological system mounts an immune response, utilizing antibodies and lymphocytes to fight the tumor. The end result is that the patient’s own immune system can cause collateral damage to the nervous system, which can sometimes be severe. In many patients, the immune response can cause nervous system damage that far exceeds the damage done to the tumor. The effects of PNS can remit entirely, although there can also be permanent effects.
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Overview of Paraneoplastic Neurologic Syndromes. Paraneoplastic neurologic syndromes (PNS) are a group of conditions that affect the nervous system (brain, spinal cord, nerves and/or muscles) in patients with cancer. The term “paraneoplastic” means that the neurological syndrome is not caused by the tumor itself, but by the immunological reactions that the tumor produces. It is believed that the body’s normal immunological system interprets the tumor as an invasion. When this occurs, the immunological system mounts an immune response, utilizing antibodies and lymphocytes to fight the tumor. The end result is that the patient’s own immune system can cause collateral damage to the nervous system, which can sometimes be severe. In many patients, the immune response can cause nervous system damage that far exceeds the damage done to the tumor. The effects of PNS can remit entirely, although there can also be permanent effects.
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Symptoms of Paraneoplastic Neurologic Syndromes
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Paraneoplastic neurologic syndromes can manifest themselves in different ways, such as encephalitis (inflammation of the brain), ataxia (loss of balance), neuropathy (progressive numbness/ weakness of feet and hands), myoclonus/opsoclonus (body jerks and irregular rapid eye movements), psychiatric disturbances, or myasthenia gravis (a neuromuscular disorder that causes extreme weakness of several muscle groups, including those that control breathing). It is the presence of specific paraneoplastic antibodies that often leads to the diagnosis of a paraneoplastic neurologic syndrome.Symptoms of PNS can develop rapidly, over the course of a few days or weeks, or they may develop slowly. Often, they seem to follow what may appear to have been a transient viral illness. In about 60% of patients with PNS, the symptoms occur before the diagnosis of cancer is made. For about 40% of patients already known to have cancer, the initial symptoms of PNS may appear to resemble other complications of cancer. In addition, some cancer treatments can also cause neurological symptoms that can be mistaken for PNS.PNS can frequently appear to affect only a single area of the nervous system. In some cases of PNS, only one area of the nervous system is involved initially, but over time, other areas can become affected. Therefore, careful and repeated neurologic examinations are required to follow and monitor the disease process.In the majority of patients with PNS, the tumor is localized to one site without having metastasized (spread) to distant parts of the body. Usually, the size of the tumor at this stage is small. For this reason, it can be very difficult to find the tumor. The combination of symptoms, lab studies, and the paraneoplastic antibodies that may be found in the blood and/or spinal fluid, helps to make the diagnosis of a paraneoplastic neurologic syndrome. The specific antibodies, if detected, can help focus the search for the tumor to one or a few organs.Broadly speaking, paraneoplastic neurologic syndromes (PNS) are categorized by (1) the area of the nervous system that is principally affected; (2) the type of symptoms manifested; or (3) the type of immunological response.Paraneoplastic Limbic EncephalitisThis disorder results from an inflammation of the brain and, in particular, the limbic system, which includes the hippocampus, amygdala, hypothalamus, and several other related areas. This part of the brain is involved in memory, emotion and behavior, and controls reactions of fear and anger. It can also involve the emotions of sexual behavior. The hypothalamus participates in the functioning of the autonomic nervous system, which regulates bodily functions such as blood pressure control, heart rate, pupil reactivity, endocrine/hormone function, body temperature, food and water intake, and sleeping and wakefulness. These functions can each be adversely affected in the setting of any type of encephalitis.A variety of symptoms can result from paraneoplastic limbic encephalitis, such as mood changes, problems sleeping, and severe, short-term memory deficits. In addition, many patients with limbic encephalitis develop seizures or seizure-like spells, or sometimes grand mal seizures resulting in a total loss of consciousness.The combination of clinical symptoms, analysis of blood and spinal fluid, and brain MRI and EEG findings can suggest the diagnosis of limbic encephalitis. However, it is the specific presence of paraneoplastic antibodies (in particular, Hu, Ma2, and CRMP5, NMDA receptor, GABA(B) receptor, AMPA receptor, Caspr2, mGluR5 antibodies) in the blood and/or spinal fluid that usually forms the diagnosis of paraneoplastic limbic encephalitis.The cancers more often associated with paraneoplastic limbic encephalitis are cancers of the lung and testis and tumors of the thymus (thymoma) although other cancers can also be involved.Symptoms identical to paraneoplastic limbic encephalitis may occur without cancer; these patients often have antibodies to LGI1 (previously known as voltage-gated potassium channel antibodies or VGKC).Paraneoplastic Cerebellar DegenerationPatients with this form of PNS develop severe problems in fine motor coordination of the arms, legs, and the muscles that control the eyes, speech and swallowing. In general, all movements will become fragmented and a tremor (shaking of the hands) may develop. Due to problems controlling the movement of the eyes, patients develop double vision or a sensation of “jumpiness” of the visual field (“opscillopsia”). Ordinary activities such as reading or watching TV can become difficult or impossible, and simple chores like writing, feeding oneself or dressing can also become impossible to perform.The brain MRI, at the onset of this type of PNS, can appear normal. However, several months after the presentation of neurological symptoms, the brain MRI will usually show atrophy (shrinkage) of the cerebellum.Several different paraneoplastic antibodies have been associated with paraneoplastic cerebellar degeneration, including among others Yo, Tr, or mGluR1 antibodies. The associated tumors include, but are not limited to, gynecologic cancers (mainly ovarian cancer), breast, lung, and Hodgkin’s lymphoma.Paraneoplastic cerebellar degeneration is one of the most difficult of the PNS to treat. Although there may be some mild improvement after treatment of the primary tumor, the majority of patients do not improve. Treatment may result in stabilization of symptoms. In very rare instances, dramatic improvements can occur.Paraneoplastic EncephalomyelitisThis disorder affects multiple areas of the brain, cerebellum, brainstem and spinal cord.Patients with paraneoplastic encephalomyelitis usually develop symptoms or deficits that combine those found in both “limbic encephalitis” and “cerebellar degeneration” In addition, due to involvement of the brainstem, patients may develop double or blurry vision, slurred speech, vertigo and/or dizziness, changes in heart rhythms, tremor, and slow movements. The symptoms may initially resemble Parkinson’s disease, and can progress to loss of consciousness and coma. There can also be a malfunction of the nerves that carry information and signals to and from the brain/arms/legs.Depending upon which of the paraneoplastic antibodies is present, some patients may develop difficulty in moving the lips. When they try to talk, their voice may be barely audible to the point that they may appear mute. However, they are able to understand other people and answer commands with signals, such as with a thumbs up or down.When the affected patient is a man younger than 50 years, the tumor is often in the testis. If the patient, male or female, is older than 50 years, the associated tumor is likely to be in the lung or other part of the body.Various paraneoplastic antibodies are associated with paraneoplastic encephalomyelitis, including Hu, CRMP5, Ma2, and amphiphysin.Prompt diagnosis of this type paraneoplastic encephalomyelitis is important because some patients improve with treatment.Paraneoplastic Encephalitis associated with anti-NMDAR AntibodiesThis syndrome usually affects teenagers or young women in whom other diseases or problems are frequently suspected. Many of these young patients will at first be thought to be manifesting either an acute psychiatric process or a drug abuse reaction. In general, the progression of severe symptoms leads the practitioner to the suspect the patient has an encephalitis.The symptoms may include anxiety, insomnia, mood changes, bizarre behavior, delusions/hallucinations, episodes of near catatonia (absence of movement), episodes of mumbling or talking gibberish, and/or confusion. Over the course of time, fine muscle twitching can progress to more pronounced abnormal movements and postures of the arms and legs (choreoathetosis). Many patients develop abnormal movements with the face, mouth or tongue (orofacial dyskinesias). Autonomic nervous system dysfunction becomes apparent, and a high temperature (as a result of autonomic dysfunction) can occur, leading to suspect an infection.This type of encephalitis can be paraneoplastic or not. When paraneoplastic the most common tumor found is a teratoma. The presence of a tumor varies according to the age of the patient, sex, and ethnicity. For example, about 50% of young women (between 18 years and 45 years) have an ovarian teratoma. Older women and men may have other types of tumors or cancer. In contrast, most children (younger than 12 years) male or female, do not have a tumor. Removal of the tumor (when identified) and immunotherapy result in decreased levels of NMDAR antibodies, and improvement or full neurological recovery.In summary, the encephalitis associated with anti-NMDAR antibodies is one of the most commonly identified autoimmune encephalitis and can occur as a paraneoplastic or non-paraneoplastic disorder. Both forms of encephalitis are highly responsive to immunotherapy and tumor removal (if present).Paraneoplastic Stiff-Person SyndromeThis type of PNS presents as muscle stiffness and rigidity, along with painful spasms. The symptoms usually present in the muscles of the lower back and legs, but may also affect the arms and legs, and then progress to affect other parts of the body. The spasms can be enhanced or triggered by anxiety, loud noises, or simply by touch or trying to move.Paraneoplastic stiff-person syndrome should not be confused with the non-paraneoplastic form of stiff-person syndrome. When the disorder is the paraneoplastic type, a specific antibody called anti-amphiphysin is usually found in the blood and spinal fluid of the patient. The tumors usually associated with this PNS are cancer of the breast or lung.Patients with non-paraneoplastic stiff-person syndrome more often develop other type of antibodies, such as GAD or Glycine receptor (GlyR) antibodies. In rare instances, these antibodies can also occur in patients with paraneoplastic stiff-person syndrome.Paraneoplastic Opsoclonus-Myoclonus or Opsoclonus-AtaxiaOpsoclonus is a neurological symptom in which the patient’s eyes move rapidly from one direction to another in an uncontrolled fashion. Myoclonus is a neurological symptom of uncontrolled muscle body jerks that can affect the face, arms or legs. Ataxia is a neurological symptom of difficulty controlling the muscles of the trunk and or arms or legs, leading to an uncoordinated, swerving gait. These symptoms can affect children or adults.In children, opsoclonus is the most common paraneoplastic syndrome. It usually affects patients younger than four years of age, and presents with sudden development of staggering and falling (ataxia) often followed by body jerks, drooling, refusal to walk or sit, opsoclonus, irritability and sleep disburbances. The associated tumor is neuroblastoma (about 50% of children with similar symptoms do not have a tumor). Although symptoms may resolve or improve after treatment of the tumor and immunotherapy, many children are left with behavioral abnormalities and other developmental abnormalities.While no specific antibody has been identified for pediatric paraneoplastic opsoclonus-myoclonus, there is a large amount of evidence that as-of-yet unidentified antibodies are involved.In adults with opsoclonus-myoclonus, there are usually fewer behavioral abnormalities, but ataxia is often prominent. The cancers most often associated with these symptoms in adults are usually located in the lung, breast, and ovary. Sometimes, in approximately 20% of adults with this disorder, well-known paraneoplastic antibodies are discovered. The best known of these antibodies is called “anti-Ri”.Treatment of the tumor and immunotherapy usually results in improvement or stabilization of the neurologic symptoms.Sensory NeuronopathyThis term refers to the neurons from which the sensory nerves originate. These neurons are clustered in the “dorsal root ganglia” which are located along the sensory nerve roots close to the spinal cord.Symptoms of sensory neuronopathy usually start in an asymmetric fashion. That is, they will begin on one side, and in a matter of days and weeks progress to involve the other side, eventually becoming symmetric. The symptoms most frequently described by patients include lancinating pain (short-lasting, electric shock type pain), a sensation of walking on sand, cold, numbness, or a feeling of burning in hands and feet. Sensations in the face, as well as the taste and hearing, can be affected. In the advanced stage of sensory neuronopathy, all sensations can be severely diminished or lost. Sensory ataxia can occur, which diminishes the ability to know where the limbs are when the eyes are closed, making it difficult to reach out for something or to walk.The antibodies most often associated with paraneoplastic sensory neuronopathy are the “anti-Hu” antibodies. There is often an association with small-cell lung cancer, although other cancers can be associated.Paraneoplastic Neuropathies
There are two main types of peripheral nerves: motor and sensory. Motor nerves make the muscles move and are important in muscle strength. Sensory nerves allow for the feeling of different sensations, such as touch, pain, heat, cold and vibration. Most neuropathies affect both sides of the body equally, with the worse symptoms in the hands and feet, rather than in the hip or shoulders.It is important to note that patients with cancer can develop peripheral neuropathy as a result of other complications of cancer, or from side-effects of the cancer treatments. The cancers most often associated with paraneoplastic neuropathies are lung cancer, myeloma, B-cell lymphoma, and Waldenstrom’s macroglobulinemia. Only a small number of patients have paraneoplastic neuropathies with associated antibodies. The two antibodies that are associated with this PNS are “anti-Hu” and “anti-CV2/CRMP5;” patients with these antibodies often have lung cancer.Vasculitis of the Nerve and Muscle
This is a very rare disorder that consists of inflammation of the small blood vessels of the peripheral nerves and muscles. Patients often develop symptoms of peripheral neuropathy that may initially affect only one arm or leg before involving both sides. Pain often occurs.Several types of tumors have been associated with this type of paraneoplastic neurologic syndrome, including cancers of the lung, kidney, prostate and lymphomas. There are no specific paraneoplastic antibodies associated with this disorder.Lambert Eaton Myasthenic Syndrome (LEMS)This disorder results from impaired release of the neurotransmitter acetylcholine. Because of this deficit, the muscles do not contract well, causing weakness that usually presents in the hips and shoulders. A transient drooping of the eyelids (ptosis) and double vision (diplopia) can occur. The muscles of the neck, and sometimes, the respiratory muscles that control breathing, can be affected.LEMS is also associated with symptoms of autonomic nervous system dysfunction, including dry mouth, rapid decrease of blood pressure on standing up (orthostatic hypotension), constipation, difficulty controlling bladder dysfunction, and erectile dysfunction.Patients with LEMS have antibodies called voltage-gated calcium channel (VGCC) antibodies. However, it should be noted that the VGCC antibodies do not indicate that the specific cause of LEMS is paraneoplastic, as the disorder can occur in the absence of cancer. Approximately 60% of all patients with LEMS have small-cell lung cancer.Myasthenia Gravis (MG)This is a well-known disorder of the neuromuscular junction. The symptoms of MG may resemble those of patients with LEMS, but the muscles of the eyes, eyelids, face, swallowing, speech and respiratory muscles are more frequently and severely involved.In contrast to LEMS, in which many patients have cancer, only 10-15% of patients with myasthenia gravis have a tumor, in which case it is in the thymus gland (thymoma). While there is an antibody associated with myasthenia gravis (AChR antibodies), this is not a paraneoplastic antibody.Polymyositis/DermatomyositisThese are two different disorders of the muscle. The term “myositis” means inflammation in the muscle. “Polymyositis” means that multiple muscles are affected by the inflammation. “Dermatomyositis” means that in addition to the muscles, there is also involvement of the skin.Both disorders cause similar muscle symptoms, including pain or soreness of the shoulders and thighs, along with weakness. The weakness predominantly affects the hips and shoulders, and can also affect the neck, causing difficulty in holding the head up, and muscles of the throat and esophagus causing difficulty swallowing. Inflammation of the heart (myocarditis), joints (arthralgias), and lungs (interstitial lung disease) can occur.Patients with dermatomyositis develop skin changes usually characterized by a purplish discoloration of the eyelids (heliotrope rash) with swelling. In addition, a crusty red rash can occur over the knuckles. Some patients develop itchiness and ulcerations in the skin.Most patients with polymyositis do not have an associated cancer, so this disorder is rarely paraneoplastic. However, dermatomyositis is more likely to be associated with a malignant tumor. There are several tumors that can be involved, including but not limited to lung, breast, ovary, and gastrointestinal tract tumors. It has been shown that patients with dermatomyositis positive for either anti-transcriptional intermediary factor 1-gamma or anti-nuclear matrix protein 2 antibodies have increased risk of having cancer. Necrotizing Autoimmune Myopathy This is a disease that associates with prominent muscle weakness at the level of the shoulders and hips. The muscle destruction (necrosis) is more prominent than the presence of inflammation. There are several antibodies that have been reported in patients with this disease including anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) and anti-signal recognition particle (SRP). Studies have shown that patients without antibodies or with antibodies against HMGCR are more likely to have an associated cancer than patients with antibodies against SRP. No specific type of cancer was found to predominate.
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Symptoms of Paraneoplastic Neurologic Syndromes. Paraneoplastic neurologic syndromes can manifest themselves in different ways, such as encephalitis (inflammation of the brain), ataxia (loss of balance), neuropathy (progressive numbness/ weakness of feet and hands), myoclonus/opsoclonus (body jerks and irregular rapid eye movements), psychiatric disturbances, or myasthenia gravis (a neuromuscular disorder that causes extreme weakness of several muscle groups, including those that control breathing). It is the presence of specific paraneoplastic antibodies that often leads to the diagnosis of a paraneoplastic neurologic syndrome.Symptoms of PNS can develop rapidly, over the course of a few days or weeks, or they may develop slowly. Often, they seem to follow what may appear to have been a transient viral illness. In about 60% of patients with PNS, the symptoms occur before the diagnosis of cancer is made. For about 40% of patients already known to have cancer, the initial symptoms of PNS may appear to resemble other complications of cancer. In addition, some cancer treatments can also cause neurological symptoms that can be mistaken for PNS.PNS can frequently appear to affect only a single area of the nervous system. In some cases of PNS, only one area of the nervous system is involved initially, but over time, other areas can become affected. Therefore, careful and repeated neurologic examinations are required to follow and monitor the disease process.In the majority of patients with PNS, the tumor is localized to one site without having metastasized (spread) to distant parts of the body. Usually, the size of the tumor at this stage is small. For this reason, it can be very difficult to find the tumor. The combination of symptoms, lab studies, and the paraneoplastic antibodies that may be found in the blood and/or spinal fluid, helps to make the diagnosis of a paraneoplastic neurologic syndrome. The specific antibodies, if detected, can help focus the search for the tumor to one or a few organs.Broadly speaking, paraneoplastic neurologic syndromes (PNS) are categorized by (1) the area of the nervous system that is principally affected; (2) the type of symptoms manifested; or (3) the type of immunological response.Paraneoplastic Limbic EncephalitisThis disorder results from an inflammation of the brain and, in particular, the limbic system, which includes the hippocampus, amygdala, hypothalamus, and several other related areas. This part of the brain is involved in memory, emotion and behavior, and controls reactions of fear and anger. It can also involve the emotions of sexual behavior. The hypothalamus participates in the functioning of the autonomic nervous system, which regulates bodily functions such as blood pressure control, heart rate, pupil reactivity, endocrine/hormone function, body temperature, food and water intake, and sleeping and wakefulness. These functions can each be adversely affected in the setting of any type of encephalitis.A variety of symptoms can result from paraneoplastic limbic encephalitis, such as mood changes, problems sleeping, and severe, short-term memory deficits. In addition, many patients with limbic encephalitis develop seizures or seizure-like spells, or sometimes grand mal seizures resulting in a total loss of consciousness.The combination of clinical symptoms, analysis of blood and spinal fluid, and brain MRI and EEG findings can suggest the diagnosis of limbic encephalitis. However, it is the specific presence of paraneoplastic antibodies (in particular, Hu, Ma2, and CRMP5, NMDA receptor, GABA(B) receptor, AMPA receptor, Caspr2, mGluR5 antibodies) in the blood and/or spinal fluid that usually forms the diagnosis of paraneoplastic limbic encephalitis.The cancers more often associated with paraneoplastic limbic encephalitis are cancers of the lung and testis and tumors of the thymus (thymoma) although other cancers can also be involved.Symptoms identical to paraneoplastic limbic encephalitis may occur without cancer; these patients often have antibodies to LGI1 (previously known as voltage-gated potassium channel antibodies or VGKC).Paraneoplastic Cerebellar DegenerationPatients with this form of PNS develop severe problems in fine motor coordination of the arms, legs, and the muscles that control the eyes, speech and swallowing. In general, all movements will become fragmented and a tremor (shaking of the hands) may develop. Due to problems controlling the movement of the eyes, patients develop double vision or a sensation of “jumpiness” of the visual field (“opscillopsia”). Ordinary activities such as reading or watching TV can become difficult or impossible, and simple chores like writing, feeding oneself or dressing can also become impossible to perform.The brain MRI, at the onset of this type of PNS, can appear normal. However, several months after the presentation of neurological symptoms, the brain MRI will usually show atrophy (shrinkage) of the cerebellum.Several different paraneoplastic antibodies have been associated with paraneoplastic cerebellar degeneration, including among others Yo, Tr, or mGluR1 antibodies. The associated tumors include, but are not limited to, gynecologic cancers (mainly ovarian cancer), breast, lung, and Hodgkin’s lymphoma.Paraneoplastic cerebellar degeneration is one of the most difficult of the PNS to treat. Although there may be some mild improvement after treatment of the primary tumor, the majority of patients do not improve. Treatment may result in stabilization of symptoms. In very rare instances, dramatic improvements can occur.Paraneoplastic EncephalomyelitisThis disorder affects multiple areas of the brain, cerebellum, brainstem and spinal cord.Patients with paraneoplastic encephalomyelitis usually develop symptoms or deficits that combine those found in both “limbic encephalitis” and “cerebellar degeneration” In addition, due to involvement of the brainstem, patients may develop double or blurry vision, slurred speech, vertigo and/or dizziness, changes in heart rhythms, tremor, and slow movements. The symptoms may initially resemble Parkinson’s disease, and can progress to loss of consciousness and coma. There can also be a malfunction of the nerves that carry information and signals to and from the brain/arms/legs.Depending upon which of the paraneoplastic antibodies is present, some patients may develop difficulty in moving the lips. When they try to talk, their voice may be barely audible to the point that they may appear mute. However, they are able to understand other people and answer commands with signals, such as with a thumbs up or down.When the affected patient is a man younger than 50 years, the tumor is often in the testis. If the patient, male or female, is older than 50 years, the associated tumor is likely to be in the lung or other part of the body.Various paraneoplastic antibodies are associated with paraneoplastic encephalomyelitis, including Hu, CRMP5, Ma2, and amphiphysin.Prompt diagnosis of this type paraneoplastic encephalomyelitis is important because some patients improve with treatment.Paraneoplastic Encephalitis associated with anti-NMDAR AntibodiesThis syndrome usually affects teenagers or young women in whom other diseases or problems are frequently suspected. Many of these young patients will at first be thought to be manifesting either an acute psychiatric process or a drug abuse reaction. In general, the progression of severe symptoms leads the practitioner to the suspect the patient has an encephalitis.The symptoms may include anxiety, insomnia, mood changes, bizarre behavior, delusions/hallucinations, episodes of near catatonia (absence of movement), episodes of mumbling or talking gibberish, and/or confusion. Over the course of time, fine muscle twitching can progress to more pronounced abnormal movements and postures of the arms and legs (choreoathetosis). Many patients develop abnormal movements with the face, mouth or tongue (orofacial dyskinesias). Autonomic nervous system dysfunction becomes apparent, and a high temperature (as a result of autonomic dysfunction) can occur, leading to suspect an infection.This type of encephalitis can be paraneoplastic or not. When paraneoplastic the most common tumor found is a teratoma. The presence of a tumor varies according to the age of the patient, sex, and ethnicity. For example, about 50% of young women (between 18 years and 45 years) have an ovarian teratoma. Older women and men may have other types of tumors or cancer. In contrast, most children (younger than 12 years) male or female, do not have a tumor. Removal of the tumor (when identified) and immunotherapy result in decreased levels of NMDAR antibodies, and improvement or full neurological recovery.In summary, the encephalitis associated with anti-NMDAR antibodies is one of the most commonly identified autoimmune encephalitis and can occur as a paraneoplastic or non-paraneoplastic disorder. Both forms of encephalitis are highly responsive to immunotherapy and tumor removal (if present).Paraneoplastic Stiff-Person SyndromeThis type of PNS presents as muscle stiffness and rigidity, along with painful spasms. The symptoms usually present in the muscles of the lower back and legs, but may also affect the arms and legs, and then progress to affect other parts of the body. The spasms can be enhanced or triggered by anxiety, loud noises, or simply by touch or trying to move.Paraneoplastic stiff-person syndrome should not be confused with the non-paraneoplastic form of stiff-person syndrome. When the disorder is the paraneoplastic type, a specific antibody called anti-amphiphysin is usually found in the blood and spinal fluid of the patient. The tumors usually associated with this PNS are cancer of the breast or lung.Patients with non-paraneoplastic stiff-person syndrome more often develop other type of antibodies, such as GAD or Glycine receptor (GlyR) antibodies. In rare instances, these antibodies can also occur in patients with paraneoplastic stiff-person syndrome.Paraneoplastic Opsoclonus-Myoclonus or Opsoclonus-AtaxiaOpsoclonus is a neurological symptom in which the patient’s eyes move rapidly from one direction to another in an uncontrolled fashion. Myoclonus is a neurological symptom of uncontrolled muscle body jerks that can affect the face, arms or legs. Ataxia is a neurological symptom of difficulty controlling the muscles of the trunk and or arms or legs, leading to an uncoordinated, swerving gait. These symptoms can affect children or adults.In children, opsoclonus is the most common paraneoplastic syndrome. It usually affects patients younger than four years of age, and presents with sudden development of staggering and falling (ataxia) often followed by body jerks, drooling, refusal to walk or sit, opsoclonus, irritability and sleep disburbances. The associated tumor is neuroblastoma (about 50% of children with similar symptoms do not have a tumor). Although symptoms may resolve or improve after treatment of the tumor and immunotherapy, many children are left with behavioral abnormalities and other developmental abnormalities.While no specific antibody has been identified for pediatric paraneoplastic opsoclonus-myoclonus, there is a large amount of evidence that as-of-yet unidentified antibodies are involved.In adults with opsoclonus-myoclonus, there are usually fewer behavioral abnormalities, but ataxia is often prominent. The cancers most often associated with these symptoms in adults are usually located in the lung, breast, and ovary. Sometimes, in approximately 20% of adults with this disorder, well-known paraneoplastic antibodies are discovered. The best known of these antibodies is called “anti-Ri”.Treatment of the tumor and immunotherapy usually results in improvement or stabilization of the neurologic symptoms.Sensory NeuronopathyThis term refers to the neurons from which the sensory nerves originate. These neurons are clustered in the “dorsal root ganglia” which are located along the sensory nerve roots close to the spinal cord.Symptoms of sensory neuronopathy usually start in an asymmetric fashion. That is, they will begin on one side, and in a matter of days and weeks progress to involve the other side, eventually becoming symmetric. The symptoms most frequently described by patients include lancinating pain (short-lasting, electric shock type pain), a sensation of walking on sand, cold, numbness, or a feeling of burning in hands and feet. Sensations in the face, as well as the taste and hearing, can be affected. In the advanced stage of sensory neuronopathy, all sensations can be severely diminished or lost. Sensory ataxia can occur, which diminishes the ability to know where the limbs are when the eyes are closed, making it difficult to reach out for something or to walk.The antibodies most often associated with paraneoplastic sensory neuronopathy are the “anti-Hu” antibodies. There is often an association with small-cell lung cancer, although other cancers can be associated.Paraneoplastic Neuropathies
There are two main types of peripheral nerves: motor and sensory. Motor nerves make the muscles move and are important in muscle strength. Sensory nerves allow for the feeling of different sensations, such as touch, pain, heat, cold and vibration. Most neuropathies affect both sides of the body equally, with the worse symptoms in the hands and feet, rather than in the hip or shoulders.It is important to note that patients with cancer can develop peripheral neuropathy as a result of other complications of cancer, or from side-effects of the cancer treatments. The cancers most often associated with paraneoplastic neuropathies are lung cancer, myeloma, B-cell lymphoma, and Waldenstrom’s macroglobulinemia. Only a small number of patients have paraneoplastic neuropathies with associated antibodies. The two antibodies that are associated with this PNS are “anti-Hu” and “anti-CV2/CRMP5;” patients with these antibodies often have lung cancer.Vasculitis of the Nerve and Muscle
This is a very rare disorder that consists of inflammation of the small blood vessels of the peripheral nerves and muscles. Patients often develop symptoms of peripheral neuropathy that may initially affect only one arm or leg before involving both sides. Pain often occurs.Several types of tumors have been associated with this type of paraneoplastic neurologic syndrome, including cancers of the lung, kidney, prostate and lymphomas. There are no specific paraneoplastic antibodies associated with this disorder.Lambert Eaton Myasthenic Syndrome (LEMS)This disorder results from impaired release of the neurotransmitter acetylcholine. Because of this deficit, the muscles do not contract well, causing weakness that usually presents in the hips and shoulders. A transient drooping of the eyelids (ptosis) and double vision (diplopia) can occur. The muscles of the neck, and sometimes, the respiratory muscles that control breathing, can be affected.LEMS is also associated with symptoms of autonomic nervous system dysfunction, including dry mouth, rapid decrease of blood pressure on standing up (orthostatic hypotension), constipation, difficulty controlling bladder dysfunction, and erectile dysfunction.Patients with LEMS have antibodies called voltage-gated calcium channel (VGCC) antibodies. However, it should be noted that the VGCC antibodies do not indicate that the specific cause of LEMS is paraneoplastic, as the disorder can occur in the absence of cancer. Approximately 60% of all patients with LEMS have small-cell lung cancer.Myasthenia Gravis (MG)This is a well-known disorder of the neuromuscular junction. The symptoms of MG may resemble those of patients with LEMS, but the muscles of the eyes, eyelids, face, swallowing, speech and respiratory muscles are more frequently and severely involved.In contrast to LEMS, in which many patients have cancer, only 10-15% of patients with myasthenia gravis have a tumor, in which case it is in the thymus gland (thymoma). While there is an antibody associated with myasthenia gravis (AChR antibodies), this is not a paraneoplastic antibody.Polymyositis/DermatomyositisThese are two different disorders of the muscle. The term “myositis” means inflammation in the muscle. “Polymyositis” means that multiple muscles are affected by the inflammation. “Dermatomyositis” means that in addition to the muscles, there is also involvement of the skin.Both disorders cause similar muscle symptoms, including pain or soreness of the shoulders and thighs, along with weakness. The weakness predominantly affects the hips and shoulders, and can also affect the neck, causing difficulty in holding the head up, and muscles of the throat and esophagus causing difficulty swallowing. Inflammation of the heart (myocarditis), joints (arthralgias), and lungs (interstitial lung disease) can occur.Patients with dermatomyositis develop skin changes usually characterized by a purplish discoloration of the eyelids (heliotrope rash) with swelling. In addition, a crusty red rash can occur over the knuckles. Some patients develop itchiness and ulcerations in the skin.Most patients with polymyositis do not have an associated cancer, so this disorder is rarely paraneoplastic. However, dermatomyositis is more likely to be associated with a malignant tumor. There are several tumors that can be involved, including but not limited to lung, breast, ovary, and gastrointestinal tract tumors. It has been shown that patients with dermatomyositis positive for either anti-transcriptional intermediary factor 1-gamma or anti-nuclear matrix protein 2 antibodies have increased risk of having cancer. Necrotizing Autoimmune Myopathy This is a disease that associates with prominent muscle weakness at the level of the shoulders and hips. The muscle destruction (necrosis) is more prominent than the presence of inflammation. There are several antibodies that have been reported in patients with this disease including anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) and anti-signal recognition particle (SRP). Studies have shown that patients without antibodies or with antibodies against HMGCR are more likely to have an associated cancer than patients with antibodies against SRP. No specific type of cancer was found to predominate.
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Causes of Paraneoplastic Neurologic Syndromes
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The specific cause of PNS is unknown. The findings in the serum or cerebrospinal fluid (CSF) of antibodies (onconeural antibodies) to specific malignant tumors suggest that the cause of some PNS is the immune response against the tumor being misdirected against the nervous system.
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Causes of Paraneoplastic Neurologic Syndromes. The specific cause of PNS is unknown. The findings in the serum or cerebrospinal fluid (CSF) of antibodies (onconeural antibodies) to specific malignant tumors suggest that the cause of some PNS is the immune response against the tumor being misdirected against the nervous system.
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Affects of Paraneoplastic Neurologic Syndromes
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In general, PNS are considered rare disorders. However, some PNS such as the paraneoplastic neuropathies are relatively frequent, affecting approximately 10% of patients with some cancers of the immunological system. In many instances, PNS are not recognized and the patients’ complaints attributed to other more common problems.PNS affect males and females in equal numbers. In general PNS are more common in older patients as they more frequently develop those cancers associated with PNS. However, PNS can occur in children and teenagers and as noted above there are some PNS (e.g., paraneoplastic anti-NMDAR encephalitis) that more commonly affect younger patients.
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Affects of Paraneoplastic Neurologic Syndromes. In general, PNS are considered rare disorders. However, some PNS such as the paraneoplastic neuropathies are relatively frequent, affecting approximately 10% of patients with some cancers of the immunological system. In many instances, PNS are not recognized and the patients’ complaints attributed to other more common problems.PNS affect males and females in equal numbers. In general PNS are more common in older patients as they more frequently develop those cancers associated with PNS. However, PNS can occur in children and teenagers and as noted above there are some PNS (e.g., paraneoplastic anti-NMDAR encephalitis) that more commonly affect younger patients.
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Related disorders of Paraneoplastic Neurologic Syndromes
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Related disorders of Paraneoplastic Neurologic Syndromes.
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Diagnosis of Paraneoplastic Neurologic Syndromes
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Patients with a suspected paraneoplastic syndrome should receive a complete panel of laboratory studies, including blood, urine, and CSF. In addition, the use of an MRI, EEG (electroencephalogram), and EMG (electromyogram) can further display abnormalities that help to diagnose PNS.Many (but not all) patients with PNS have paraneoplastic antibodies in their blood and/or CSF. If any of these antibodies are identified, then the diagnosis of PNS is strongly supported or definite (depending on the type of antibody).It should be understood that there are three types of antibodies that associate with neurological syndromes. There is one type that associates with specific neurological syndromes but not with cancer. Another type includes antibodies that almost always associate with the presence of cancer. The third type of antibodies includes those that may occur with or without cancer. Therefore, it is important to understand the relative value of each category of antibodies in suggesting that the neurological syndrome is paraneoplastic or not.Once a diagnosis of or a suspicion of a paraneoplastic syndrome is apparent, other tests are used to identify the location and type of tumor. These include CT scanning (usually of the chest, abdomen, and pelvis), mammography, ultrasound, PET scan, and blood tests for specific tumor markers (such as the CA125, for ovarian cancer). The type of paraneoplastic antibody often helps to direct the search of the tumor to a specific organ (for example, most patients with Hu antibodies have lung cancer).
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Diagnosis of Paraneoplastic Neurologic Syndromes. Patients with a suspected paraneoplastic syndrome should receive a complete panel of laboratory studies, including blood, urine, and CSF. In addition, the use of an MRI, EEG (electroencephalogram), and EMG (electromyogram) can further display abnormalities that help to diagnose PNS.Many (but not all) patients with PNS have paraneoplastic antibodies in their blood and/or CSF. If any of these antibodies are identified, then the diagnosis of PNS is strongly supported or definite (depending on the type of antibody).It should be understood that there are three types of antibodies that associate with neurological syndromes. There is one type that associates with specific neurological syndromes but not with cancer. Another type includes antibodies that almost always associate with the presence of cancer. The third type of antibodies includes those that may occur with or without cancer. Therefore, it is important to understand the relative value of each category of antibodies in suggesting that the neurological syndrome is paraneoplastic or not.Once a diagnosis of or a suspicion of a paraneoplastic syndrome is apparent, other tests are used to identify the location and type of tumor. These include CT scanning (usually of the chest, abdomen, and pelvis), mammography, ultrasound, PET scan, and blood tests for specific tumor markers (such as the CA125, for ovarian cancer). The type of paraneoplastic antibody often helps to direct the search of the tumor to a specific organ (for example, most patients with Hu antibodies have lung cancer).
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Therapies of Paraneoplastic Neurologic Syndromes
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TreatmentExcept for a few PNS of the peripheral nerves and neuromuscular junction, there is no general consensus yet for treating many of these syndromes. However, there are several principles in which most investigators agree upon:The tumor is the main trigger for all PNS. Therefore, in general, prompt identification and treatment of the tumor is essential. Thus, the first therapeutic option is usually surgery, radiation, or chemotherapy (singly or in combination).Because many PNS are immune-mediated, immunotherapy should be considered based on the type of antibody involved. PNS in which the antibody attacks the cell-surface of neurons respond better to immunotherapies than PNS in which the antibodies react with proteins that are inside the neurons (or intracellular antigens).The usage, timing, and type of immunotherapy will vary depending on the specific type of PNS and/or whether the tumor is being treated at the same time.In a patient who has been in remission from a cancer treated within the prior five years, symptoms that appear to be a PNS imply a high likelihood of tumor recurrence. Repeat cancer screening should be undertaken.Similarly, a relapse or sudden worsening of neurological symptoms in a patient known to have a PNS, but whose cancer was thought to be in remission, should raise a high index of suspicion for cancer recurrence.
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Therapies of Paraneoplastic Neurologic Syndromes. TreatmentExcept for a few PNS of the peripheral nerves and neuromuscular junction, there is no general consensus yet for treating many of these syndromes. However, there are several principles in which most investigators agree upon:The tumor is the main trigger for all PNS. Therefore, in general, prompt identification and treatment of the tumor is essential. Thus, the first therapeutic option is usually surgery, radiation, or chemotherapy (singly or in combination).Because many PNS are immune-mediated, immunotherapy should be considered based on the type of antibody involved. PNS in which the antibody attacks the cell-surface of neurons respond better to immunotherapies than PNS in which the antibodies react with proteins that are inside the neurons (or intracellular antigens).The usage, timing, and type of immunotherapy will vary depending on the specific type of PNS and/or whether the tumor is being treated at the same time.In a patient who has been in remission from a cancer treated within the prior five years, symptoms that appear to be a PNS imply a high likelihood of tumor recurrence. Repeat cancer screening should be undertaken.Similarly, a relapse or sudden worsening of neurological symptoms in a patient known to have a PNS, but whose cancer was thought to be in remission, should raise a high index of suspicion for cancer recurrence.
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Overview of Paroxysmal Cold Hemoglobinuria
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Paroxysmal cold hemoglobinuria (PCH) is a rare type of anemia characterized by the premature destruction of healthy red blood cells by autoantibodies. The disorder is classified as an autoimmune hemolytic anemia (AIHA), an uncommon group of disorders in which the immune system mistakenly attacks healthy red blood cells. Autoimmune diseases occur when the body’s natural defenses against foreign organisms destroy healthy tissue for unknown reasons. Normally, red blood cells have a life span of approximately 120 days before they get removed by the spleen. In individuals with PCH, red blood cells are destroyed prematurely and sometimes suddenly (paroxysmally). Many reports emphasize that PCH is an unusual disease. However, in recent years, PCH has become recognized as one of the most common causes of acute AIHA in young children. The reason why acute transient PCH appears to be a more common type of childhood AIHA than it was thought to be several decades ago is uncertain, but probably relates to greater awareness of the disorder and more frequent use of the Donath-Landsteiner test (see Diagnosis section ), especially in children with acute AIHA with hemoglobinuria.PCH was first described as a distinct disorder in the medical literature in 1872. The specific antibody associated with the disorder (Donath-Landsteiner autoantibody) was first described by Drs. Donath and Landsteiner in 1904.A majority of cases of PCH recorded in the early medical literature were associated with late syphilis or congenital syphilis. In the early 1900s over 90 percent of patients with chronic PCH had a positive test for syphilis and approximately 30 percent showed clinical evidence of the disease. With the effective treatment of syphilis and the virtual elimination of the congenital form, “classical” syphilitic PCH is now an extremely rare disorder, as is chronic PCH. It was in patients with the chronic form of PCH that exposure to cold resulted in a paroxysm of hemoglobinuria.In modern times, PCH is almost always encountered as an acute transient syndrome in young children with a recent history of a viral illness, so that paroxysms resulting from cold exposure are rarely encountered. Thus, although this type of AIHA is known as PCH, the words paroxysmal and cold are generally not relevant to the disorder as it is manifest in the modern era. As children with PCH do not usually have hemolysis directly related to exposure to the cold (e.g., they continue hemolysis when in a warm hospital environment), it has been suggested that a better term might be Donath-Landsteiner test positive hemolytic anemia.
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Overview of Paroxysmal Cold Hemoglobinuria. Paroxysmal cold hemoglobinuria (PCH) is a rare type of anemia characterized by the premature destruction of healthy red blood cells by autoantibodies. The disorder is classified as an autoimmune hemolytic anemia (AIHA), an uncommon group of disorders in which the immune system mistakenly attacks healthy red blood cells. Autoimmune diseases occur when the body’s natural defenses against foreign organisms destroy healthy tissue for unknown reasons. Normally, red blood cells have a life span of approximately 120 days before they get removed by the spleen. In individuals with PCH, red blood cells are destroyed prematurely and sometimes suddenly (paroxysmally). Many reports emphasize that PCH is an unusual disease. However, in recent years, PCH has become recognized as one of the most common causes of acute AIHA in young children. The reason why acute transient PCH appears to be a more common type of childhood AIHA than it was thought to be several decades ago is uncertain, but probably relates to greater awareness of the disorder and more frequent use of the Donath-Landsteiner test (see Diagnosis section ), especially in children with acute AIHA with hemoglobinuria.PCH was first described as a distinct disorder in the medical literature in 1872. The specific antibody associated with the disorder (Donath-Landsteiner autoantibody) was first described by Drs. Donath and Landsteiner in 1904.A majority of cases of PCH recorded in the early medical literature were associated with late syphilis or congenital syphilis. In the early 1900s over 90 percent of patients with chronic PCH had a positive test for syphilis and approximately 30 percent showed clinical evidence of the disease. With the effective treatment of syphilis and the virtual elimination of the congenital form, “classical” syphilitic PCH is now an extremely rare disorder, as is chronic PCH. It was in patients with the chronic form of PCH that exposure to cold resulted in a paroxysm of hemoglobinuria.In modern times, PCH is almost always encountered as an acute transient syndrome in young children with a recent history of a viral illness, so that paroxysms resulting from cold exposure are rarely encountered. Thus, although this type of AIHA is known as PCH, the words paroxysmal and cold are generally not relevant to the disorder as it is manifest in the modern era. As children with PCH do not usually have hemolysis directly related to exposure to the cold (e.g., they continue hemolysis when in a warm hospital environment), it has been suggested that a better term might be Donath-Landsteiner test positive hemolytic anemia.
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Symptoms of Paroxysmal Cold Hemoglobinuria
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The typical presentation is that of a child who during the preceding 1-2 weeks had suffered from what appeared to be an undefined or “flu-like” illness. Usually the onset of hemolysis is signaled by a recurrence of fever and then the passage of red-brown urine. This urine contains the iron bearing, oxygen transporting, protein pigment of blood called hemoglobin, which is released when red blood cells are prematurely destroyed. The presence of hemoglobin in the urine (hemoglobinuria) causes the dark brown color of the urine. Hemoglobinuria, hemoglobinemia (hemoglobin in the plasma), jaundice and pallor are common clinical findings in acute PCH and, of particular significance is that hemoglobinuria is found in almost all acute cases in childhood. Abdominal pain and fever are also common findings. Approximately 25 percent of cases have palpable liver and spleen. Although hemoglobinuria may be induced by exposure to cold, such an occurrence is rare in acute PCH. In acute PCH, hemolysis typically lasts for a few days only and recovery is usually uninterrupted.The older medical literature describes chronic syphilitic PCH as a rather benign disease that rarely caused severe chronic anemia. However, acute attacks of hemolysis and hemoglobinuria were well known and were characterized by the sudden onset of shaking chills, fever, malaise, abdominal distress, aching pains in the back or legs, arid nausea. Usually, hemoglobin was present in the first specimen of urine passed after the onset of symptoms, and the interval between chilling and the development of symptoms ranged from a few minutes to eight hours. The extent of cold exposure could be surprisingly slight and, in some cases, a history of undue exposure to cold was not elicited.Individuals with PCH often develop the classic symptoms of anemia- the medical term for low levels of circulating red blood cells. These symptoms may include fatigue, difficulty breathing upon exertion (dyspnea) and abnormal or extreme paleness of the skin (pallor). In addition, affected individuals may develop chills, fever, abdominal pain, and pain or aching in the legs or lower back. Less common findings associated with PCH include headaches, vomiting and diarrhea. Following an episode, affected individuals usually develop the signs of hemolysis including yellowing of the skin, whites of the eyes and mucous membranes (jaundice). In some cases additional symptoms may occur including tingling in the hands and feet, a condition marked by a feeling of coldness or numbness of the hands, nose and ears in response to cold temperatures (Raynaud’s phenomenon), or a skin condition marked by reddening and itching of the skin in response to cold temperatures (cold urticaria). In extremely rare cases, the kidney may become involved and kidney (renal) failure has been reported in a few cases.
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Symptoms of Paroxysmal Cold Hemoglobinuria. The typical presentation is that of a child who during the preceding 1-2 weeks had suffered from what appeared to be an undefined or “flu-like” illness. Usually the onset of hemolysis is signaled by a recurrence of fever and then the passage of red-brown urine. This urine contains the iron bearing, oxygen transporting, protein pigment of blood called hemoglobin, which is released when red blood cells are prematurely destroyed. The presence of hemoglobin in the urine (hemoglobinuria) causes the dark brown color of the urine. Hemoglobinuria, hemoglobinemia (hemoglobin in the plasma), jaundice and pallor are common clinical findings in acute PCH and, of particular significance is that hemoglobinuria is found in almost all acute cases in childhood. Abdominal pain and fever are also common findings. Approximately 25 percent of cases have palpable liver and spleen. Although hemoglobinuria may be induced by exposure to cold, such an occurrence is rare in acute PCH. In acute PCH, hemolysis typically lasts for a few days only and recovery is usually uninterrupted.The older medical literature describes chronic syphilitic PCH as a rather benign disease that rarely caused severe chronic anemia. However, acute attacks of hemolysis and hemoglobinuria were well known and were characterized by the sudden onset of shaking chills, fever, malaise, abdominal distress, aching pains in the back or legs, arid nausea. Usually, hemoglobin was present in the first specimen of urine passed after the onset of symptoms, and the interval between chilling and the development of symptoms ranged from a few minutes to eight hours. The extent of cold exposure could be surprisingly slight and, in some cases, a history of undue exposure to cold was not elicited.Individuals with PCH often develop the classic symptoms of anemia- the medical term for low levels of circulating red blood cells. These symptoms may include fatigue, difficulty breathing upon exertion (dyspnea) and abnormal or extreme paleness of the skin (pallor). In addition, affected individuals may develop chills, fever, abdominal pain, and pain or aching in the legs or lower back. Less common findings associated with PCH include headaches, vomiting and diarrhea. Following an episode, affected individuals usually develop the signs of hemolysis including yellowing of the skin, whites of the eyes and mucous membranes (jaundice). In some cases additional symptoms may occur including tingling in the hands and feet, a condition marked by a feeling of coldness or numbness of the hands, nose and ears in response to cold temperatures (Raynaud’s phenomenon), or a skin condition marked by reddening and itching of the skin in response to cold temperatures (cold urticaria). In extremely rare cases, the kidney may become involved and kidney (renal) failure has been reported in a few cases.
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Causes of Paroxysmal Cold Hemoglobinuria
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In most affected children, PCH occurs as an acute hemolytic anemia, following an infection and spontaneously resolves once the infection subsides. Usually, PCH does not recur (self-limited) in children, but recurrent cases have been reported in the medical literature. In most adults the cause of PCH is unknown (idiopathic) and is usually a chronic disease. With the dramatic decline in the prevalence of syphilis, PCH in adults has declined, and the current understanding of the adult form of the disease is less clear. PCH is an autoimmune disorder, a disorder in which the body’s natural defenses against invading organisms destroy healthy tissue for unknown reasons. In PCH, antibodies mistakenly attack red blood cells causing the cells to breakdown prematurely, a condition called (hemolysis). When antibodies attack healthy tissue, they are referred to as autoantibodies.Antibodies (which are also known as immunoglobulins) are specialized proteins that bind to invading organisms and bring about their destruction. There are five main classes of antibodies – IgA, IgD, IgE, IgG, and IgM. In PCH, a specific autoantibody known as the Donath-Landsteiner autoantibody is produced often in response to a viral infection. This autoantibody binds to red blood cells during exposure to cold temperatures. The Donath-Landsteiner autoantibody is a type of IgG antibody; its target is the P blood group antigen, present on the red cells of almost all individuals.
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Causes of Paroxysmal Cold Hemoglobinuria. In most affected children, PCH occurs as an acute hemolytic anemia, following an infection and spontaneously resolves once the infection subsides. Usually, PCH does not recur (self-limited) in children, but recurrent cases have been reported in the medical literature. In most adults the cause of PCH is unknown (idiopathic) and is usually a chronic disease. With the dramatic decline in the prevalence of syphilis, PCH in adults has declined, and the current understanding of the adult form of the disease is less clear. PCH is an autoimmune disorder, a disorder in which the body’s natural defenses against invading organisms destroy healthy tissue for unknown reasons. In PCH, antibodies mistakenly attack red blood cells causing the cells to breakdown prematurely, a condition called (hemolysis). When antibodies attack healthy tissue, they are referred to as autoantibodies.Antibodies (which are also known as immunoglobulins) are specialized proteins that bind to invading organisms and bring about their destruction. There are five main classes of antibodies – IgA, IgD, IgE, IgG, and IgM. In PCH, a specific autoantibody known as the Donath-Landsteiner autoantibody is produced often in response to a viral infection. This autoantibody binds to red blood cells during exposure to cold temperatures. The Donath-Landsteiner autoantibody is a type of IgG antibody; its target is the P blood group antigen, present on the red cells of almost all individuals.
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Affects of Paroxysmal Cold Hemoglobinuria
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Autoimmune hemolytic anemias as a group are estimated to affect 1-3 people per 100,000 in the general population. Both the syphilitic and non-syphilitic forms of chronic PCH are exceedingly rare. The prevalence and incidence rates are unknown. Anyone may acquire PCH, but it is more common among children than among adults. An individual with a viral infection is at higher risk of contracting the disorder. No known genetic, sex, or racial risk factors exist, although the disease has been reported in families.
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Affects of Paroxysmal Cold Hemoglobinuria. Autoimmune hemolytic anemias as a group are estimated to affect 1-3 people per 100,000 in the general population. Both the syphilitic and non-syphilitic forms of chronic PCH are exceedingly rare. The prevalence and incidence rates are unknown. Anyone may acquire PCH, but it is more common among children than among adults. An individual with a viral infection is at higher risk of contracting the disorder. No known genetic, sex, or racial risk factors exist, although the disease has been reported in families.
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Related disorders of Paroxysmal Cold Hemoglobinuria
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Symptoms of the following disorders can be similar to those of PCH. Comparisons may be useful for a differential diagnosis.Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired stem cell disorder. The classic finding is the premature destruction of red blood cells (hemolysis), resulting in repeated episodes of hemoglobin in the urine (hemoglobinuria). Hemoglobin is the red, iron-rich pigment of blood. Individuals with hemoglobinuria may exhibit dark-colored or bloody urine. This finding is most prominent in the morning, after the urine has concentrated overnight during sleep. In addition to hemolysis, individuals with PNH are also susceptible to developing repeated, potentially life-threatening blood clots (thromboses). Affected individuals also have some degree of underlying bone marrow dysfunction. Severe bone marrow dysfunction potentially results in low levels of red and white blood cells and platelets (pancytopenia). The specific symptoms of PNH vary great and affected individuals usually do not exhibit all of the symptoms potentially associated with the disorder. Two factors are necessary for the development of PNH: an acquired somatic (not passed on to children) mutation of the PIG-A gene, which affects hematopoietic stem cells creating defective “PNH” blood cells, and a predisposition to the multiplication and expansion of these defective stem cells. Most likely, PNH arises in the setting of autoimmune bone marrow failure, as occurs in most cases of acquired aplastic anemia. Researchers believe that defective PNH stem cells survive the misguided attack by the immune system and multiply, while the healthy stem cells are destroyed, resulting in the development of PNH. PCH is easy to differentiate from PNH by laboratory tests. PNH is not caused by an autoantibody to red cells in contrast to PCH, which is caused by an autoantibody (detectable by the Donath-Landsteiner test). (For more information on this disorder, choose “paroxysmal nocturnal hemoglobinuria” as your search term in the Rare Disease Database.) Acquired hemolytic anemias are non-genetic in origin. Idiopathic acquired autoimmune diseases occur when the body's natural defenses against invading organisms destroy its own healthy tissues for no known reason. Normally, the red blood cells (erythrocytes) have a life span of approximately 120 days before being removed by the spleen. The severity of this type of anemia is determined by the life span of the red blood cell and by the rate at which these cells are replaced by the bone marrow. Acquired autoimmune hemolytic anemia is a disorder that occurs in individuals who previously had a normal red blood cell system. The disorder may occur as the result of, or in conjunction with, some other medical condition, in which case it is “secondary” to another disorder. Less commonly, it occurs alone without a precipitating factor. Acquired autoimmune hemolytic anemia occurs in different forms, including warm antibody hemolytic anemia and cold antibody hemolytic anemia. In warm antibody hemolytic anemia, the self-generated antibodies (autoantibodies) attach themselves and cause the destruction of the red blood cells at body temperature. In contrast, the cases of cold antibody hemolytic anemia (cold agglutinin disease and PCH have antibodies that react optimally at cold temperatures), the self-generated antibodies (autoantibodies) attach themselves and cause the destruction of the red blood cells at temperatures below normal body temperature. (For more information on this disorder, choose “Warm Antibody Hemolytic Anemia” and/or “Cold Antibody Hemolytic Anemia” as your search term in the Rare Disease Database.)
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Related disorders of Paroxysmal Cold Hemoglobinuria. Symptoms of the following disorders can be similar to those of PCH. Comparisons may be useful for a differential diagnosis.Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired stem cell disorder. The classic finding is the premature destruction of red blood cells (hemolysis), resulting in repeated episodes of hemoglobin in the urine (hemoglobinuria). Hemoglobin is the red, iron-rich pigment of blood. Individuals with hemoglobinuria may exhibit dark-colored or bloody urine. This finding is most prominent in the morning, after the urine has concentrated overnight during sleep. In addition to hemolysis, individuals with PNH are also susceptible to developing repeated, potentially life-threatening blood clots (thromboses). Affected individuals also have some degree of underlying bone marrow dysfunction. Severe bone marrow dysfunction potentially results in low levels of red and white blood cells and platelets (pancytopenia). The specific symptoms of PNH vary great and affected individuals usually do not exhibit all of the symptoms potentially associated with the disorder. Two factors are necessary for the development of PNH: an acquired somatic (not passed on to children) mutation of the PIG-A gene, which affects hematopoietic stem cells creating defective “PNH” blood cells, and a predisposition to the multiplication and expansion of these defective stem cells. Most likely, PNH arises in the setting of autoimmune bone marrow failure, as occurs in most cases of acquired aplastic anemia. Researchers believe that defective PNH stem cells survive the misguided attack by the immune system and multiply, while the healthy stem cells are destroyed, resulting in the development of PNH. PCH is easy to differentiate from PNH by laboratory tests. PNH is not caused by an autoantibody to red cells in contrast to PCH, which is caused by an autoantibody (detectable by the Donath-Landsteiner test). (For more information on this disorder, choose “paroxysmal nocturnal hemoglobinuria” as your search term in the Rare Disease Database.) Acquired hemolytic anemias are non-genetic in origin. Idiopathic acquired autoimmune diseases occur when the body's natural defenses against invading organisms destroy its own healthy tissues for no known reason. Normally, the red blood cells (erythrocytes) have a life span of approximately 120 days before being removed by the spleen. The severity of this type of anemia is determined by the life span of the red blood cell and by the rate at which these cells are replaced by the bone marrow. Acquired autoimmune hemolytic anemia is a disorder that occurs in individuals who previously had a normal red blood cell system. The disorder may occur as the result of, or in conjunction with, some other medical condition, in which case it is “secondary” to another disorder. Less commonly, it occurs alone without a precipitating factor. Acquired autoimmune hemolytic anemia occurs in different forms, including warm antibody hemolytic anemia and cold antibody hemolytic anemia. In warm antibody hemolytic anemia, the self-generated antibodies (autoantibodies) attach themselves and cause the destruction of the red blood cells at body temperature. In contrast, the cases of cold antibody hemolytic anemia (cold agglutinin disease and PCH have antibodies that react optimally at cold temperatures), the self-generated antibodies (autoantibodies) attach themselves and cause the destruction of the red blood cells at temperatures below normal body temperature. (For more information on this disorder, choose “Warm Antibody Hemolytic Anemia” and/or “Cold Antibody Hemolytic Anemia” as your search term in the Rare Disease Database.)
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Paroxysmal Cold Hemoglobinuria
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Diagnosis of Paroxysmal Cold Hemoglobinuria
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A diagnosis of PCH may be suspected in some individuals with anemia. In particular, the diagnosis should be suspected in any acutely ill child with hemoglobinuria. A diagnosis is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic symptoms and a variety of specialized tests such as a direct antiglobulin test (Coombs) test, which is used to detect certain antibodies that act against red blood cells. A diagnosis of PCH is confirmed by the results of a Donath-Landsteiner test, which can distinguish PCH from other forms of hemolytic anemia. The test consists of incubating a sample of the patient’s serum with normal red blood cells (RBCs) in the cold for 30 minutes and then warming the mixture to body temperature (37C). Hemolysis of the RBCs in this "bi-phasic" test indicates a diagnosis of PCH.
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Diagnosis of Paroxysmal Cold Hemoglobinuria. A diagnosis of PCH may be suspected in some individuals with anemia. In particular, the diagnosis should be suspected in any acutely ill child with hemoglobinuria. A diagnosis is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic symptoms and a variety of specialized tests such as a direct antiglobulin test (Coombs) test, which is used to detect certain antibodies that act against red blood cells. A diagnosis of PCH is confirmed by the results of a Donath-Landsteiner test, which can distinguish PCH from other forms of hemolytic anemia. The test consists of incubating a sample of the patient’s serum with normal red blood cells (RBCs) in the cold for 30 minutes and then warming the mixture to body temperature (37C). Hemolysis of the RBCs in this "bi-phasic" test indicates a diagnosis of PCH.
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Therapies of Paroxysmal Cold Hemoglobinuria
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TreatmentMost cases of PCH resolve without treatment (spontaneously) and only require supportive therapy for a few days to weeks after onset. Strict avoidance of cold temperatures is recommended to protect against the premature breakdown of red blood cells and loss of hemoglobin (hemolysis).In some cases, severe anemia may require a red blood cell transfusion. In such cases, a transfusion should not be delayed. Use of a blood warmer during transfusion is sometimes recommended.Due to the temporary (transient) nature of the disease in children in most cases, affected children are often in the recovery phase of the illness at the time symptoms become apparent. Most cases that involve children and are linked to a viral infection require only supportive therapy, bed rest, and protection of the affected individual from cold temperatures.
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Therapies of Paroxysmal Cold Hemoglobinuria. TreatmentMost cases of PCH resolve without treatment (spontaneously) and only require supportive therapy for a few days to weeks after onset. Strict avoidance of cold temperatures is recommended to protect against the premature breakdown of red blood cells and loss of hemoglobin (hemolysis).In some cases, severe anemia may require a red blood cell transfusion. In such cases, a transfusion should not be delayed. Use of a blood warmer during transfusion is sometimes recommended.Due to the temporary (transient) nature of the disease in children in most cases, affected children are often in the recovery phase of the illness at the time symptoms become apparent. Most cases that involve children and are linked to a viral infection require only supportive therapy, bed rest, and protection of the affected individual from cold temperatures.
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Overview of Paroxysmal Nocturnal Hemoglobinuria
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Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disorder in which red blood cells break apart prematurely. It is an acquired hematopoietic stem cell disorder. Hematopoietic stem cells are created in the bone marrow, the spongy center of the long bones of the body. These cells grow and eventually develop into red blood cells, white blood cells and platelets. Some hematopoietic stem cells in individuals with PNH are defective and consequently produce defective blood cells. These defective red blood cells of PNH are extremely susceptible to premature destruction by a particular part of a person’s own immune system called the complement system. The destruction of red blood cells (hemolysis) by complement leads to episodes of hemoglobin in the urine (hemoglobinuria). Hemoglobin is the red, iron-rich, oxygen-containing pigment of the blood. Individuals with hemoglobinuria may exhibit dark-colored or blood colored urine. This finding is most prominent in the morning, after the urine has concentrated overnight during sleep. However, hemolysis in individuals with PNH is a constant process (i.e., it does not occur only at night). Hemoglobin in the urine may not always be visible. In addition to hemolysis, individuals with PNH are also susceptible to developing repeated, potentially life-threatening blood clots (thromboses). Affected individuals also have some degree of underlying bone marrow dysfunction. Severe bone marrow dysfunction results in low levels of red and white blood cells and platelets (pancytopenia). The specific symptoms of PNH vary greatly from one person to another and affected individuals usually do not exhibit all the symptoms associated with the disorder.
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Overview of Paroxysmal Nocturnal Hemoglobinuria. Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disorder in which red blood cells break apart prematurely. It is an acquired hematopoietic stem cell disorder. Hematopoietic stem cells are created in the bone marrow, the spongy center of the long bones of the body. These cells grow and eventually develop into red blood cells, white blood cells and platelets. Some hematopoietic stem cells in individuals with PNH are defective and consequently produce defective blood cells. These defective red blood cells of PNH are extremely susceptible to premature destruction by a particular part of a person’s own immune system called the complement system. The destruction of red blood cells (hemolysis) by complement leads to episodes of hemoglobin in the urine (hemoglobinuria). Hemoglobin is the red, iron-rich, oxygen-containing pigment of the blood. Individuals with hemoglobinuria may exhibit dark-colored or blood colored urine. This finding is most prominent in the morning, after the urine has concentrated overnight during sleep. However, hemolysis in individuals with PNH is a constant process (i.e., it does not occur only at night). Hemoglobin in the urine may not always be visible. In addition to hemolysis, individuals with PNH are also susceptible to developing repeated, potentially life-threatening blood clots (thromboses). Affected individuals also have some degree of underlying bone marrow dysfunction. Severe bone marrow dysfunction results in low levels of red and white blood cells and platelets (pancytopenia). The specific symptoms of PNH vary greatly from one person to another and affected individuals usually do not exhibit all the symptoms associated with the disorder.
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Symptoms of Paroxysmal Nocturnal Hemoglobinuria
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The symptoms of PNH occur because of the production of defective blood cells and because the bone marrow does not produce enough blood cells. The specific symptoms and progression of the disorder vary greatly from one person to another. Some individuals may have mild symptoms that remain stable for many years; others may have serious symptoms that can progress to cause life-threatening complications.It is important to note that affected individuals may not have all the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.The premature destruction of red blood cells (hemolysis) is the primary clinical finding associated with PNH. Hemolysis may result in hemoglobin in the urine, although many individuals with hemolysis do not have visible hemoglobin in the urine. When hemolysis occurs, a red blood cell’s outer wall (membrane) breaks down (lysis) releasing hemoglobin. Hemoglobin is excreted from the body in the urine, resulting in the dark-colored or blood colored urine (hemoglobinuria) that is characteristic of this disorder. Hemolysis is ongoing, but may worsen (i.e., a person may have a hemolytic episode) during periods of infection, trauma or stress. The premature destruction of red blood cells may result in low levels of circulating red blood cells (hemolytic anemia) that is made worse by the underlying bone marrow dysfunction.Chronic hemolysis is central to all the symptoms and physical findings associated with PNH. Mild hemolysis can cause fatigue, rapid heartbeat, headaches, chest pain and difficulty breathing when exercising. If hemolysis is severe, additional symptoms can develop, including disabling fatigue, difficulty swallowing (dysphagia) and painful contractions that affect the abdomen, the esophagus (esophageal spasms) and, in men, can cause erectile dysfunction and impotence. Chronic hemolysis can also lead to the development of blood clots and some affected individuals may develop acute and chronic kidney (renal) disease.Approximately 15-30 percent of individuals with PNH develop blood clots, especially in the veins (venous thrombosis). The exact reason individuals with PNH develop blood clots is not fully understood. In addition to red blood cells, defective hematopoietic stem cells may also produce defective platelets. Some researchers believe that these defective platelets are abnormally prone to forming blood clots. Chronic hemolysis may also contribute to the development of blood clots. Blood clots can be carried via the bloodstream to various areas of the body, potentially resulting in life-threatening complications. Blood clots may reduce or cut off blood flow to various organs, especially the stomach, liver, and brain. The specific symptoms associated with venous thrombosis depend upon the specific area of the body affected. For example, blood clots affecting the liver may result in jaundice, abdominal pain, or, potentially, a condition known as Budd-Chiari syndrome (for more information, see the Related Disorders section below). Blood clots affecting the stomach and bowels may result in a sharp pain in the abdomen or a bloated or full feeling. Blood clots affecting cerebral veins may cause symptoms such as headaches or problems with cognition (thinking). Blood clots in the lungs can result in shortness of breath, difficulty breathing and heart palpitations. In rare cases, blood clots may form in the arteries. Blood clots can potentially cause life-threatening complications by cutting off blood flow to vital organs.All patients with PNH have some degree of bone marrow dysfunction. Individuals with mild bone marrow dysfunction may not have any symptoms or only mild symptoms. Individuals with severe bone marrow dysfunction may have low levels of red and white blood cells and platelets (pancytopenia). Red blood cells deliver oxygen to the body, white blood cells help in fighting off infections and platelets allow the body to form clots to stop bleeding. A low level of circulating red blood cells is known as anemia. A low level of white blood cells is known as leukopenia. A low level of platelets is known as thrombocytopenia.Individuals with anemia may experience tiredness, increased need for sleep, weakness, lightheadedness, dizziness, irritability, headaches, pale skin color, difficulty breathing (dyspnea) and cardiac symptoms, including chest pain. Individuals with leukopenia have an increased risk of contracting bacterial and fungal infections. Individuals with thrombocytopenia are more susceptible to excessive bruising following minimal injury and spontaneous bleeding from the mucous membranes, especially those of the gums and nose. Women may develop increased menstrual blood loss (menorrhagia).Many individuals with PNH may simultaneously have another, closely related disorder known as acquired aplastic anemia. To a lesser extent, some individuals may have myelodysplasia. Although the exact relationship among these disorders is unknown, researchers now believe that PNH arises from autoimmune bone marrow failure, which is the cause of most cases of acquired aplastic anemia and some cases of myelodysplasia. In rare cases, PNH may eventually develop into acute leukemia. The reason for this transformation is unknown. (For more information on these disorders, see the Related Disorders section below.)
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Symptoms of Paroxysmal Nocturnal Hemoglobinuria. The symptoms of PNH occur because of the production of defective blood cells and because the bone marrow does not produce enough blood cells. The specific symptoms and progression of the disorder vary greatly from one person to another. Some individuals may have mild symptoms that remain stable for many years; others may have serious symptoms that can progress to cause life-threatening complications.It is important to note that affected individuals may not have all the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.The premature destruction of red blood cells (hemolysis) is the primary clinical finding associated with PNH. Hemolysis may result in hemoglobin in the urine, although many individuals with hemolysis do not have visible hemoglobin in the urine. When hemolysis occurs, a red blood cell’s outer wall (membrane) breaks down (lysis) releasing hemoglobin. Hemoglobin is excreted from the body in the urine, resulting in the dark-colored or blood colored urine (hemoglobinuria) that is characteristic of this disorder. Hemolysis is ongoing, but may worsen (i.e., a person may have a hemolytic episode) during periods of infection, trauma or stress. The premature destruction of red blood cells may result in low levels of circulating red blood cells (hemolytic anemia) that is made worse by the underlying bone marrow dysfunction.Chronic hemolysis is central to all the symptoms and physical findings associated with PNH. Mild hemolysis can cause fatigue, rapid heartbeat, headaches, chest pain and difficulty breathing when exercising. If hemolysis is severe, additional symptoms can develop, including disabling fatigue, difficulty swallowing (dysphagia) and painful contractions that affect the abdomen, the esophagus (esophageal spasms) and, in men, can cause erectile dysfunction and impotence. Chronic hemolysis can also lead to the development of blood clots and some affected individuals may develop acute and chronic kidney (renal) disease.Approximately 15-30 percent of individuals with PNH develop blood clots, especially in the veins (venous thrombosis). The exact reason individuals with PNH develop blood clots is not fully understood. In addition to red blood cells, defective hematopoietic stem cells may also produce defective platelets. Some researchers believe that these defective platelets are abnormally prone to forming blood clots. Chronic hemolysis may also contribute to the development of blood clots. Blood clots can be carried via the bloodstream to various areas of the body, potentially resulting in life-threatening complications. Blood clots may reduce or cut off blood flow to various organs, especially the stomach, liver, and brain. The specific symptoms associated with venous thrombosis depend upon the specific area of the body affected. For example, blood clots affecting the liver may result in jaundice, abdominal pain, or, potentially, a condition known as Budd-Chiari syndrome (for more information, see the Related Disorders section below). Blood clots affecting the stomach and bowels may result in a sharp pain in the abdomen or a bloated or full feeling. Blood clots affecting cerebral veins may cause symptoms such as headaches or problems with cognition (thinking). Blood clots in the lungs can result in shortness of breath, difficulty breathing and heart palpitations. In rare cases, blood clots may form in the arteries. Blood clots can potentially cause life-threatening complications by cutting off blood flow to vital organs.All patients with PNH have some degree of bone marrow dysfunction. Individuals with mild bone marrow dysfunction may not have any symptoms or only mild symptoms. Individuals with severe bone marrow dysfunction may have low levels of red and white blood cells and platelets (pancytopenia). Red blood cells deliver oxygen to the body, white blood cells help in fighting off infections and platelets allow the body to form clots to stop bleeding. A low level of circulating red blood cells is known as anemia. A low level of white blood cells is known as leukopenia. A low level of platelets is known as thrombocytopenia.Individuals with anemia may experience tiredness, increased need for sleep, weakness, lightheadedness, dizziness, irritability, headaches, pale skin color, difficulty breathing (dyspnea) and cardiac symptoms, including chest pain. Individuals with leukopenia have an increased risk of contracting bacterial and fungal infections. Individuals with thrombocytopenia are more susceptible to excessive bruising following minimal injury and spontaneous bleeding from the mucous membranes, especially those of the gums and nose. Women may develop increased menstrual blood loss (menorrhagia).Many individuals with PNH may simultaneously have another, closely related disorder known as acquired aplastic anemia. To a lesser extent, some individuals may have myelodysplasia. Although the exact relationship among these disorders is unknown, researchers now believe that PNH arises from autoimmune bone marrow failure, which is the cause of most cases of acquired aplastic anemia and some cases of myelodysplasia. In rare cases, PNH may eventually develop into acute leukemia. The reason for this transformation is unknown. (For more information on these disorders, see the Related Disorders section below.)
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Causes of Paroxysmal Nocturnal Hemoglobinuria
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Two factors are necessary for the development of PNH: an acquired somatic mutation of the PIGA gene, which affects one or more hematopoietic stem cells creating defective “PNH” blood cells, and a process that leads to the multiplication and expansion of these defective stem cells. Most likely, PNH arises in the setting of autoimmune bone marrow failure, as occurs in most cases of acquired aplastic anemia. Researchers believe that defective PNH stem cells survive the misguided attack by the immune system and multiply, while healthy stem cells are destroyed, resulting in the development of PNH. The reason that defective cells survive while healthy cells are destroyed is incompletely understood but appears to be due to properties of the PNH cell that provide a survival advantage in the setting of immune-mediated attack on the bone marrow. The mutation in the PIGA gene is a somatic mutation, which means that it occurs after conception; it is not inherited and is not passed on to children. This mutation occurs randomly, for no apparent reason (sporadically). In PNH, this mutation occurs in a single hematopoietic stem cell (clonal disorder), which then multiplies and expands. The reason why PNH cells expand and multiply is not fully understood. Researchers believe that other factors such as secondary gene mutations or immune factors may be necessary for PNH cells to expand and multiply. Therefore, although the PIGA mutation is necessary for the development of PNH, its presence alone is not sufficient to cause the disorder. In a few cases, this additional factor has been shown to be a second somatic mutation (other than PIGA) that gives the mutant cell a growth advantage.The PIGA gene produces a protein that is essential to the creation (biosynthesis) of glycosyl phosphatidylinositol (GPI) anchors. These anchors allow some proteins to attach to a cell’s membrane. These proteins are called GPI-anchored proteins. In cells with a PIGA gene mutation, the GPI anchors are not formed, and, consequently, GPI-anchored proteins cannot attach to the cells’ membranes. Some of these GPI-anchored proteins serve to protect cells from the immune system. Consequently, a lack of these surface proteins renders “PNH” blood cells extremely susceptible to destruction by a part of the immune system known as the complement system. The complement system is a complex group of proteins that work together to fight infection in the body. These proteins respond to bacteria, viruses or other foreign substances in the body. They work with white blood cells to destroy foreign material in the body. In individuals with PNH, the complement system mistakenly destroys “PNH” blood cells due to the lack of GPI-anchored proteins that normally protect blood cells from the activity of the complement system.
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Causes of Paroxysmal Nocturnal Hemoglobinuria. Two factors are necessary for the development of PNH: an acquired somatic mutation of the PIGA gene, which affects one or more hematopoietic stem cells creating defective “PNH” blood cells, and a process that leads to the multiplication and expansion of these defective stem cells. Most likely, PNH arises in the setting of autoimmune bone marrow failure, as occurs in most cases of acquired aplastic anemia. Researchers believe that defective PNH stem cells survive the misguided attack by the immune system and multiply, while healthy stem cells are destroyed, resulting in the development of PNH. The reason that defective cells survive while healthy cells are destroyed is incompletely understood but appears to be due to properties of the PNH cell that provide a survival advantage in the setting of immune-mediated attack on the bone marrow. The mutation in the PIGA gene is a somatic mutation, which means that it occurs after conception; it is not inherited and is not passed on to children. This mutation occurs randomly, for no apparent reason (sporadically). In PNH, this mutation occurs in a single hematopoietic stem cell (clonal disorder), which then multiplies and expands. The reason why PNH cells expand and multiply is not fully understood. Researchers believe that other factors such as secondary gene mutations or immune factors may be necessary for PNH cells to expand and multiply. Therefore, although the PIGA mutation is necessary for the development of PNH, its presence alone is not sufficient to cause the disorder. In a few cases, this additional factor has been shown to be a second somatic mutation (other than PIGA) that gives the mutant cell a growth advantage.The PIGA gene produces a protein that is essential to the creation (biosynthesis) of glycosyl phosphatidylinositol (GPI) anchors. These anchors allow some proteins to attach to a cell’s membrane. These proteins are called GPI-anchored proteins. In cells with a PIGA gene mutation, the GPI anchors are not formed, and, consequently, GPI-anchored proteins cannot attach to the cells’ membranes. Some of these GPI-anchored proteins serve to protect cells from the immune system. Consequently, a lack of these surface proteins renders “PNH” blood cells extremely susceptible to destruction by a part of the immune system known as the complement system. The complement system is a complex group of proteins that work together to fight infection in the body. These proteins respond to bacteria, viruses or other foreign substances in the body. They work with white blood cells to destroy foreign material in the body. In individuals with PNH, the complement system mistakenly destroys “PNH” blood cells due to the lack of GPI-anchored proteins that normally protect blood cells from the activity of the complement system.
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Paroxysmal Nocturnal Hemoglobinuria
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Affects of Paroxysmal Nocturnal Hemoglobinuria
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PNH is believed to affect males and females in equal numbers, although some studies show a slightly more females affected. The prevalence is estimated to be between 0.5-1.5 per million people in the general population. The disorder has been described in people of many ethnic backgrounds and has been identified in all areas of the world. The disorder may occur with greater frequency in individuals from Southeast Asia or the Far East who experience greater rates of aplastic anemia. The disorder can affect any age group. The median age at diagnosis is during the 30s.PNH was first reported in the medical literature in the latter half of the 19th century. The disorder was termed paroxysmal nocturnal hemoglobinuria because of the mistaken belief that hemolysis and subsequent hemoglobinuria occurred only in intermittent episodes (paroxysmally) and with greater frequency during the night (nocturnal). However, while hemoglobinuria may appear paroxysmally, hemolysis is ongoing both during the day and at night.
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Affects of Paroxysmal Nocturnal Hemoglobinuria. PNH is believed to affect males and females in equal numbers, although some studies show a slightly more females affected. The prevalence is estimated to be between 0.5-1.5 per million people in the general population. The disorder has been described in people of many ethnic backgrounds and has been identified in all areas of the world. The disorder may occur with greater frequency in individuals from Southeast Asia or the Far East who experience greater rates of aplastic anemia. The disorder can affect any age group. The median age at diagnosis is during the 30s.PNH was first reported in the medical literature in the latter half of the 19th century. The disorder was termed paroxysmal nocturnal hemoglobinuria because of the mistaken belief that hemolysis and subsequent hemoglobinuria occurred only in intermittent episodes (paroxysmally) and with greater frequency during the night (nocturnal). However, while hemoglobinuria may appear paroxysmally, hemolysis is ongoing both during the day and at night.
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Paroxysmal Nocturnal Hemoglobinuria
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Related disorders of Paroxysmal Nocturnal Hemoglobinuria
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Symptoms of the following disorders can be similar to those of PNH. Comparisons may be useful for a differential diagnosis.PNH and acquired aplastic anemia are closely related disorders, while PNH can also occur in association with low grade forms of myelodysplasia such as refractory anemia. Individuals with PNH may have acquired aplastic anemia or myelodysplasia at the same time. Researchers believe that PNH may arise out of autoimmune bone marrow failure, which causes most cases of acquired aplastic anemia and some cases of myelodysplasia.Acquired aplastic anemia is a rare disorder caused by profound, almost complete bone marrow failure. Bone marrow is the spongy substance found in the center of the long bones of the body. The bone marrow produces specialized cells (hematopoietic stem cells) that grow and eventually develop into red blood cells (erythrocytes), white blood cells (leukocytes) and platelets. In acquired aplastic anemia, an almost complete absence of hematopoietic stem cells eventually results in low levels of red and white blood cells and platelets (pancytopenia). Specific symptoms associated with acquired aplastic anemia may vary, but include fatigue, recurrent infections, dizziness, weakness, headaches and episodes of excessive bleeding. Most cases of acquired aplastic anemia occur for unknown reasons (idiopathic), although researchers now believe that most of these cases result from the immune system mistakenly targeting the bone marrow (autoimmunity). (For more information on this disorder, choose “acquired aplastic anemia” as your search term in the Rare Disease Database.)Myelodysplastic syndrome (myelodysplasia) is a rare group of blood disorders that occur because of improper development of blood cells within the bone marrow. The three main types of blood cells (i.e., red blood cells, white blood cells and platelets) are affected. Red blood cells deliver oxygen to the body, white blood cells help fight infections, and platelets assist in clotting to stop blood loss. These improperly developed blood cells fail to develop normally and enter the bloodstream. As a result, individuals with MDS have abnormally low blood cell levels (low blood counts). General symptoms associated with MDS include fatigue, dizziness, weakness, bruising and bleeding, frequent infections, and headaches. In some cases, MDS may progress to life-threatening failure of the bone marrow or develop into an acute leukemia. The exact cause of MDS is unknown, but in approximately 90 percent of patients, acquired (somatic) genetic abnormalities can be identified in the bone marrow cells. No specific environmental risk factors have been identified. (For more information on this disorder, choose “myelodysplastic syndromes” as your search term in the Rare Disease Database.)Rarely, individuals with PNH may develop leukemia, which is a form of cancer affecting the bone marrow and blood. It is characterized by the uncontrolled accumulation of immature blood cells. Acute forms of leukemia may result in low levels of red and white blood cells and platelets (pancytopenia) or in a high white blood cell count (leukocytosis) with low levels of red cells and platelets.Paroxysmal cold hemoglobinuria is a rare autoimmune hemolytic disorder characterized by the premature destruction of healthy red blood cells (hemolysis) minutes to hours after exposure to cold. Autoimmune diseases occur when the body’s natural defenses against invading organisms mistakenly destroy healthy tissue for unknown reasons. Normally, red blood cells have a life span of approximately 120 days. In an individual affected with paroxysmal cold hemoglobinuria, the red blood cells are destroyed prematurely and suddenly by an antibody mediated process upon exposure to temperatures of 10 to 15 degrees Centigrade and below. (For more information on this disorder, choose “paroxysmal cold hemoglobinuria” as your search term in the Rare Disease Database.)The following disorders may be associated with PNH as secondary characteristics. They are not necessary for a differential diagnosis:Budd-Chiari syndrome is a rare disorder characterized by narrowing and obstruction (occlusion) of the veins of the liver (hepatic veins). In individuals with PNH, blood clots (thromboses) block the hepatic veins. Symptoms associated with Budd Chiari syndrome include pain in the upper right part of the abdomen, an abnormally large liver (hepatomegaly) and/or accumulation of fluid (ascites) in the space between the two layers of the membrane that lines the stomach (peritoneal cavity). Additional findings that may be associated with the disorder include nausea, vomiting and/or an abnormally large spleen (splenomegaly). The severity of the disorder varies from person to person, depending upon the site and number of affected veins. In some cases, if the major hepatic veins are involved, high blood pressure in the veins carrying blood from the gastrointestinal (GI) tract back to the heart through the liver (portal hypertension) may be present. (For more information on this disorder, choose “Budd-Chiari” as your search term in the Rare Disease Database.)
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Related disorders of Paroxysmal Nocturnal Hemoglobinuria. Symptoms of the following disorders can be similar to those of PNH. Comparisons may be useful for a differential diagnosis.PNH and acquired aplastic anemia are closely related disorders, while PNH can also occur in association with low grade forms of myelodysplasia such as refractory anemia. Individuals with PNH may have acquired aplastic anemia or myelodysplasia at the same time. Researchers believe that PNH may arise out of autoimmune bone marrow failure, which causes most cases of acquired aplastic anemia and some cases of myelodysplasia.Acquired aplastic anemia is a rare disorder caused by profound, almost complete bone marrow failure. Bone marrow is the spongy substance found in the center of the long bones of the body. The bone marrow produces specialized cells (hematopoietic stem cells) that grow and eventually develop into red blood cells (erythrocytes), white blood cells (leukocytes) and platelets. In acquired aplastic anemia, an almost complete absence of hematopoietic stem cells eventually results in low levels of red and white blood cells and platelets (pancytopenia). Specific symptoms associated with acquired aplastic anemia may vary, but include fatigue, recurrent infections, dizziness, weakness, headaches and episodes of excessive bleeding. Most cases of acquired aplastic anemia occur for unknown reasons (idiopathic), although researchers now believe that most of these cases result from the immune system mistakenly targeting the bone marrow (autoimmunity). (For more information on this disorder, choose “acquired aplastic anemia” as your search term in the Rare Disease Database.)Myelodysplastic syndrome (myelodysplasia) is a rare group of blood disorders that occur because of improper development of blood cells within the bone marrow. The three main types of blood cells (i.e., red blood cells, white blood cells and platelets) are affected. Red blood cells deliver oxygen to the body, white blood cells help fight infections, and platelets assist in clotting to stop blood loss. These improperly developed blood cells fail to develop normally and enter the bloodstream. As a result, individuals with MDS have abnormally low blood cell levels (low blood counts). General symptoms associated with MDS include fatigue, dizziness, weakness, bruising and bleeding, frequent infections, and headaches. In some cases, MDS may progress to life-threatening failure of the bone marrow or develop into an acute leukemia. The exact cause of MDS is unknown, but in approximately 90 percent of patients, acquired (somatic) genetic abnormalities can be identified in the bone marrow cells. No specific environmental risk factors have been identified. (For more information on this disorder, choose “myelodysplastic syndromes” as your search term in the Rare Disease Database.)Rarely, individuals with PNH may develop leukemia, which is a form of cancer affecting the bone marrow and blood. It is characterized by the uncontrolled accumulation of immature blood cells. Acute forms of leukemia may result in low levels of red and white blood cells and platelets (pancytopenia) or in a high white blood cell count (leukocytosis) with low levels of red cells and platelets.Paroxysmal cold hemoglobinuria is a rare autoimmune hemolytic disorder characterized by the premature destruction of healthy red blood cells (hemolysis) minutes to hours after exposure to cold. Autoimmune diseases occur when the body’s natural defenses against invading organisms mistakenly destroy healthy tissue for unknown reasons. Normally, red blood cells have a life span of approximately 120 days. In an individual affected with paroxysmal cold hemoglobinuria, the red blood cells are destroyed prematurely and suddenly by an antibody mediated process upon exposure to temperatures of 10 to 15 degrees Centigrade and below. (For more information on this disorder, choose “paroxysmal cold hemoglobinuria” as your search term in the Rare Disease Database.)The following disorders may be associated with PNH as secondary characteristics. They are not necessary for a differential diagnosis:Budd-Chiari syndrome is a rare disorder characterized by narrowing and obstruction (occlusion) of the veins of the liver (hepatic veins). In individuals with PNH, blood clots (thromboses) block the hepatic veins. Symptoms associated with Budd Chiari syndrome include pain in the upper right part of the abdomen, an abnormally large liver (hepatomegaly) and/or accumulation of fluid (ascites) in the space between the two layers of the membrane that lines the stomach (peritoneal cavity). Additional findings that may be associated with the disorder include nausea, vomiting and/or an abnormally large spleen (splenomegaly). The severity of the disorder varies from person to person, depending upon the site and number of affected veins. In some cases, if the major hepatic veins are involved, high blood pressure in the veins carrying blood from the gastrointestinal (GI) tract back to the heart through the liver (portal hypertension) may be present. (For more information on this disorder, choose “Budd-Chiari” as your search term in the Rare Disease Database.)
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Paroxysmal Nocturnal Hemoglobinuria
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Diagnosis of Paroxysmal Nocturnal Hemoglobinuria
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A diagnosis of PNH may be suspected in individuals who have symptoms of intravascular hemolysis (e.g., hemoglobinuria, abnormally high serum LDH concentration) with no known cause. A diagnosis may be made based upon a thorough clinical evaluation, a detailed patient history and a variety of specialized tests. The main diagnostic test for individuals with suspected PNH is flow cytometry, a blood test that can identify PNH cells (blood cells that are missing GPI-anchored proteins).
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Diagnosis of Paroxysmal Nocturnal Hemoglobinuria. A diagnosis of PNH may be suspected in individuals who have symptoms of intravascular hemolysis (e.g., hemoglobinuria, abnormally high serum LDH concentration) with no known cause. A diagnosis may be made based upon a thorough clinical evaluation, a detailed patient history and a variety of specialized tests. The main diagnostic test for individuals with suspected PNH is flow cytometry, a blood test that can identify PNH cells (blood cells that are missing GPI-anchored proteins).
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Paroxysmal Nocturnal Hemoglobinuria
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Therapies of Paroxysmal Nocturnal Hemoglobinuria
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TreatmentThe treatment of PNH is directed at the specific symptoms that are present in each individual and includes a variety of different therapeutic options.In 2007, the U.S. Food and Drug Administration (FDA) approved eculizumab (Soliris) as a treatment for PNH. This is the first drug to be approved for this disorder. Eculizumab does not cure PNH but halts the breakdown of red blood cells and can reduce the risk of thrombosis and improve overall quality of life. Eculizumab works by blocking the complement system of the body that inadvertently destroys PNH red blood cells. Because it blocks part of the body’s natural immune system, eculizumab increases the risk of meningococcal infections. Therefore, patients must be vaccinated with a meningococcal vaccine at least two weeks prior to receiving the first dose of eculizumab. In 2009, Canada’s national healthcare regulatory agency, Health Canada, approved eculizumab (Soliris) for the treatment of patients in Canada with PNH.In 2018, the FDA approved ravulizumab (Ultomiris) for treatment of the hemolysis of PNH. Ravulizumab works in a manner identical to eculizumab and was shown to be clinically non-inferior to eculizumab. Ravulizumab is given every eight weeks, whereas eculizumab is given every two weeks.In 2021, the FDA approved pegcetacoplan (Empaveli) to treat adults with PNH. Compared to eculizumab and ravulizumab that block the fifth component of complement (C5), pegcetacoplan blocks the third component of complement (C3). Consequently, pegcetacoplan blocks both extravascular hemolysis and intravascular hemolysis, whereas eculizumab and ravulizumab block intravascular hemolysis but not extravascular hemolysis. Patients who remain anemic (particularly if transfusions are required) due to extravascular hemolysis despite treatment with eculizumab or ravulizumab may benefit from treatment with pegcetacoplan. Pegcetacoplan is given as a self-administered subcutaneous infusion two or in some cases, three times per week. Additional treatment for PNH is symptomatic and supportive and varies depending upon the individual’s age, general health, presence of associated disorders, severity of PNH and degree of underlying bone marrow failure.Some individuals with PNH receive folic acid (folate) supplements to ensure that the supply of folate is adequate as demand increases when the bone marrow attempts to compensate for the hemolytic anemia of PNH by augmenting red blood cell production (erythropoiesis) in the bone marrow. Supplemental iron should be given to individuals with iron deficiency, which can occur because of red blood cell destruction and the consequent loss of iron in the urine.Some physicians suggest that individuals exhibiting symptoms of hemolysis should receive treatment with steroids such as prednisone because it is believed that such treatment slows the rate of destruction of red blood cells. However, treatment with steroids such as prednisone is controversial because steroid therapy is not beneficial to everyone and carries the potential for serious side effects, especially if the therapy is continued for a long duration.The administration of drugs that block the formation of blood clots (anticoagulation therapy) may be prescribed. Some individuals may be placed on long-term anticoagulant therapy. Use of blood thinners must be strictly managed because of the risk of excessive bleeding due to low platelet numbers in some individuals.Individuals with Budd-Chiari syndrome may be treated by thrombolytic therapy, in which certain drugs are used to breakdown or dissolve blood clots. Such treatment requires experience in managing the potential side-effects these drugs as the risk of adverse events (particularly bleeding) is substantial.The only curative therapy for individuals with PNH is bone marrow transplantation. However, because of the risk of morbidity and mortality, it is reserved for individuals with serious complications such as severe bone marrow failure or repeated, life-threatening blood clot formation. The specific form of bone marrow transplantation used most often in treating PNH is an allogeneic bone marrow transplant. During an allogeneic bone marrow transplant, an affected individual’s bone marrow is destroyed usually by chemotherapy, immunotherapy, radiation or some combination and replaced with healthy marrow obtained from a donor. The donor marrow is transplanted intravenously into the body where it travels to the bone marrow and eventually begins producing new blood cells. The best match for a bone marrow transplant is a sibling with an identical HLA type. However, in some individuals, a search for an unrelated, matched donor is necessary. Bone marrow transplantation can cure underlying bone marrow dysfunction and can eliminate the defective PNH stem cells.Drug treatments for the hemolysis of PNH have no effect on the underlying bone marrow dysfunction that affects many people with PNH. Individuals who have severe bone marrow failure may be treated with immunosuppressive therapy. Individuals with acquired aplastic anemia have responded favorably to this form of treatment, in which certain drugs are used to suppress the activity of the immune system. This form of treatment may be beneficial in cases of PNH that are dominated by bone marrow failure. While the immunosuppressive therapy can restore bone marrow function, it does not eradicate the PNH clone. The two most commonly used immunosuppressive agents, given alone or in combination, are antithymocyte globulin (ATG), cyclosporin and eltrombopag.Some individuals with PNH with low blood cell counts may receive treatment with blood transfusions. This treatment consists of giving red blood cell transfusions to correct anemia, platelet transfusions to treat or prevent serious bleeding and antibiotics to treat or prevent infections. Affected individuals who are eligible for a bone marrow transplant should not, if possible, receive blood transfusions because blood transfusions reduce the chances of a successful transplant.Some individuals with PNH may receive treatment with manmade (synthetic) growth factors. Growth factors are proteins normally found in the body that stimulate the bone marrow to produce blood cells. Erythropoietin (EPO) is a growth factor produced by the kidneys that stimulates the bone marrow to create red blood cells. Epogen, Procrit and Aranesp are forms of erythropoietin. Therapy with red blood cell growth factors may lessen the need for blood transfusions.Individuals with PNH who have low levels of white blood cells may receive growth factors such as granulocyte-colony stimulating factor (G-CSF) that stimulate the bone marrow to make granulocytes (a type of white blood cell that fights bacterial infections).Some individuals with PNH may receive treatment with androgens, which are male hormones that stimulate the bone marrow to produce red blood cells. Androgen therapy, such as danazol, may help to improve the symptoms of anemia.
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Therapies of Paroxysmal Nocturnal Hemoglobinuria. TreatmentThe treatment of PNH is directed at the specific symptoms that are present in each individual and includes a variety of different therapeutic options.In 2007, the U.S. Food and Drug Administration (FDA) approved eculizumab (Soliris) as a treatment for PNH. This is the first drug to be approved for this disorder. Eculizumab does not cure PNH but halts the breakdown of red blood cells and can reduce the risk of thrombosis and improve overall quality of life. Eculizumab works by blocking the complement system of the body that inadvertently destroys PNH red blood cells. Because it blocks part of the body’s natural immune system, eculizumab increases the risk of meningococcal infections. Therefore, patients must be vaccinated with a meningococcal vaccine at least two weeks prior to receiving the first dose of eculizumab. In 2009, Canada’s national healthcare regulatory agency, Health Canada, approved eculizumab (Soliris) for the treatment of patients in Canada with PNH.In 2018, the FDA approved ravulizumab (Ultomiris) for treatment of the hemolysis of PNH. Ravulizumab works in a manner identical to eculizumab and was shown to be clinically non-inferior to eculizumab. Ravulizumab is given every eight weeks, whereas eculizumab is given every two weeks.In 2021, the FDA approved pegcetacoplan (Empaveli) to treat adults with PNH. Compared to eculizumab and ravulizumab that block the fifth component of complement (C5), pegcetacoplan blocks the third component of complement (C3). Consequently, pegcetacoplan blocks both extravascular hemolysis and intravascular hemolysis, whereas eculizumab and ravulizumab block intravascular hemolysis but not extravascular hemolysis. Patients who remain anemic (particularly if transfusions are required) due to extravascular hemolysis despite treatment with eculizumab or ravulizumab may benefit from treatment with pegcetacoplan. Pegcetacoplan is given as a self-administered subcutaneous infusion two or in some cases, three times per week. Additional treatment for PNH is symptomatic and supportive and varies depending upon the individual’s age, general health, presence of associated disorders, severity of PNH and degree of underlying bone marrow failure.Some individuals with PNH receive folic acid (folate) supplements to ensure that the supply of folate is adequate as demand increases when the bone marrow attempts to compensate for the hemolytic anemia of PNH by augmenting red blood cell production (erythropoiesis) in the bone marrow. Supplemental iron should be given to individuals with iron deficiency, which can occur because of red blood cell destruction and the consequent loss of iron in the urine.Some physicians suggest that individuals exhibiting symptoms of hemolysis should receive treatment with steroids such as prednisone because it is believed that such treatment slows the rate of destruction of red blood cells. However, treatment with steroids such as prednisone is controversial because steroid therapy is not beneficial to everyone and carries the potential for serious side effects, especially if the therapy is continued for a long duration.The administration of drugs that block the formation of blood clots (anticoagulation therapy) may be prescribed. Some individuals may be placed on long-term anticoagulant therapy. Use of blood thinners must be strictly managed because of the risk of excessive bleeding due to low platelet numbers in some individuals.Individuals with Budd-Chiari syndrome may be treated by thrombolytic therapy, in which certain drugs are used to breakdown or dissolve blood clots. Such treatment requires experience in managing the potential side-effects these drugs as the risk of adverse events (particularly bleeding) is substantial.The only curative therapy for individuals with PNH is bone marrow transplantation. However, because of the risk of morbidity and mortality, it is reserved for individuals with serious complications such as severe bone marrow failure or repeated, life-threatening blood clot formation. The specific form of bone marrow transplantation used most often in treating PNH is an allogeneic bone marrow transplant. During an allogeneic bone marrow transplant, an affected individual’s bone marrow is destroyed usually by chemotherapy, immunotherapy, radiation or some combination and replaced with healthy marrow obtained from a donor. The donor marrow is transplanted intravenously into the body where it travels to the bone marrow and eventually begins producing new blood cells. The best match for a bone marrow transplant is a sibling with an identical HLA type. However, in some individuals, a search for an unrelated, matched donor is necessary. Bone marrow transplantation can cure underlying bone marrow dysfunction and can eliminate the defective PNH stem cells.Drug treatments for the hemolysis of PNH have no effect on the underlying bone marrow dysfunction that affects many people with PNH. Individuals who have severe bone marrow failure may be treated with immunosuppressive therapy. Individuals with acquired aplastic anemia have responded favorably to this form of treatment, in which certain drugs are used to suppress the activity of the immune system. This form of treatment may be beneficial in cases of PNH that are dominated by bone marrow failure. While the immunosuppressive therapy can restore bone marrow function, it does not eradicate the PNH clone. The two most commonly used immunosuppressive agents, given alone or in combination, are antithymocyte globulin (ATG), cyclosporin and eltrombopag.Some individuals with PNH with low blood cell counts may receive treatment with blood transfusions. This treatment consists of giving red blood cell transfusions to correct anemia, platelet transfusions to treat or prevent serious bleeding and antibiotics to treat or prevent infections. Affected individuals who are eligible for a bone marrow transplant should not, if possible, receive blood transfusions because blood transfusions reduce the chances of a successful transplant.Some individuals with PNH may receive treatment with manmade (synthetic) growth factors. Growth factors are proteins normally found in the body that stimulate the bone marrow to produce blood cells. Erythropoietin (EPO) is a growth factor produced by the kidneys that stimulates the bone marrow to create red blood cells. Epogen, Procrit and Aranesp are forms of erythropoietin. Therapy with red blood cell growth factors may lessen the need for blood transfusions.Individuals with PNH who have low levels of white blood cells may receive growth factors such as granulocyte-colony stimulating factor (G-CSF) that stimulate the bone marrow to make granulocytes (a type of white blood cell that fights bacterial infections).Some individuals with PNH may receive treatment with androgens, which are male hormones that stimulate the bone marrow to produce red blood cells. Androgen therapy, such as danazol, may help to improve the symptoms of anemia.
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Paroxysmal Nocturnal Hemoglobinuria
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Overview of Parry Romberg Syndrome
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Parry-Romberg syndrome is a rare, acquired disorder characterized by slowly progressive shrinkage (atrophy) of the skin and soft tissues of half of the face (hemifacial atrophy). In rare cases, both sides of the face are affected. In some people, atrophy may also affect the limbs, usually on the same side of the body as the facial atrophy. The severity and specific symptoms of Parry-Romberg syndrome are highly variable from one person to another. Additional symptoms can potentially develop in some people including neurological abnormalities or abnormalities affecting the eyes or teeth. Parry-Romberg syndrome usually becomes apparent during the first decade of life or early during the second decade but does occur in adulthood. Most individuals with Parry-Romberg syndrome experience symptoms before the age of 20 years.The exact cause of Parry-Romberg syndrome is unknown and appears to occur randomly for unknown reasons (sporadically).
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Overview of Parry Romberg Syndrome. Parry-Romberg syndrome is a rare, acquired disorder characterized by slowly progressive shrinkage (atrophy) of the skin and soft tissues of half of the face (hemifacial atrophy). In rare cases, both sides of the face are affected. In some people, atrophy may also affect the limbs, usually on the same side of the body as the facial atrophy. The severity and specific symptoms of Parry-Romberg syndrome are highly variable from one person to another. Additional symptoms can potentially develop in some people including neurological abnormalities or abnormalities affecting the eyes or teeth. Parry-Romberg syndrome usually becomes apparent during the first decade of life or early during the second decade but does occur in adulthood. Most individuals with Parry-Romberg syndrome experience symptoms before the age of 20 years.The exact cause of Parry-Romberg syndrome is unknown and appears to occur randomly for unknown reasons (sporadically).
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Parry Romberg Syndrome
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Symptoms of Parry Romberg Syndrome
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The symptoms, progression and severity of Parry-Romberg syndrome are highly variable from one person to another and range from mild to severe. It is important to note that affected individuals will not have all the symptoms discussed below. It seems likely that individuals with milder symptoms are much more common than severely affected individuals. Affected individuals should talk to their physician and medical team about their specific case and associated symptoms.The characteristic symptom of Parry-Romberg syndrome is thinning or shrinkage (atrophy) of various tissues of the face including fat, skin, connective tissues, muscle, and, in some people, bone. The degree of atrophy can vary widely, ranging from mild, barely perceptible changes to significant asymmetry in which one side of the face appears “sunken in”. The progression of atrophic changes can vary as well. Facial atrophy may progress slowly over many years, or more frequently progresses slowly for several years before stopping. If the atrophy stops progressing, it may occasionally reactivate later in life, but this is rare. In other people, the atrophy may progress indefinitely. In some people, when Parry-Romberg syndrome starts at an early age, the progression seems to accelerate more quickly than when it starts later in life.The initial facial changes associated with Parry-Romberg syndrome usually occur near the middle portion of the face such as the cheek area above the upper jaw bone (maxilla) or between the nose and the upper corner of the lip. As the disease process continues, the upper face (e.g., the areas around the eye, the eyebrow, and the ear) as well as the angle of the mouth and the lower jaw bone (mandible) usually are affected. In some patients, one half of the chin may also be involved. Affected areas undergo shrinkage (atrophy) of tissues beneath the skin (subcutaneous tissue), the layer of fat under the skin (subcutaneous fat), and sometimes underlying cartilage, muscle, and bone. Areas affected by such changes may develop an abnormally sunken appearance. Many individuals may exhibit an unusual bony depression or hollow in the forehead or upper domed portion of the skull, the bony cavity that accommodates the eye (orbit), and/or the lower jawbone (mandible).In some people, a “line” may form in the area where the atrophic changes on one side of the face meet the normal, unaffected skin on the other side of the face. In some patients, this “line” may be very distinct and runs either vertically or diagonally down the forehead. The abnormal skin is thickened and hardened (sclerosis). This condition may be referred to as linear scleroderma “en coup de sabre” (LSCS–this comes from the French for ‘sabre cut’). LSCS can occur by itself as an isolated finding. According to the medical literature, LSCS is either a separate disorder that overlaps to a large degree with Parry-Romberg syndrome or essentially the same disorder (i.e., different expressions of one disease process or spectrum of disease). The exact relationship of LCSC and Parry-Romberg syndrome is not fully understood but it’s clear that the two commonly co-exist. About one third of people with linear scleroderma on the head or neck have Parry-Romberg syndromeProgressive atrophic changes associated with the Parry-Romberg syndrome may rarely also cause abnormalities of an ear. In individuals with the disorder, the ear on the affected side may become misshapen and unusually small and may appear to abnormally protrude from the head due to loss of supporting tissue.In some people, perhaps one in five, the atrophic skin and soft tissue changes associated with Parry-Romberg syndrome may progress to involve the arm, trunk and legs on one side of the body, either the same side (ipsilateral) as the atrophic changes to the face or the opposite side (contralateral). In addition, many affected individuals also experience abnormal changes affecting the hair on the affected side including the development of abnormal bald patches on the scalp (alopecia), absence of eyelashes, and absence of the middle portion of the eyebrow and/or whitening (blanching) of the hair. In some people, such hair changes may occur before other abnormalities associated with the disorder.Some individuals with Parry-Romberg syndrome may develop abnormalities affecting the mouth and teeth. Some individuals develop atrophy of half (hemiatrophy) of the upper lip and/or one side of the tongue. In addition, due to progressive atrophic changes associated with the disorder, portions of the lower jaw bone (mandible) may be unusually short on the affected side and the jaw may rarely be prone to spontaneous fracture. The unaffected side of the mouth and nose may sometimes point (deviate) towards the affected side. Some affected individuals may have difficulty opening or closing the jaws. Involuntary contractions of muscles used in chewing (hemi-masticatory spasm or trismus) may occur. One side of the upper lip may have an unusually twisted or raised appearance and certain teeth may be abnormally exposed, erupt unusually late, and/or have atrophic roots. In addition, the upper and lower teeth may meet inappropriately (malocclusion).Some affected individuals may also experience various neurological symptoms. Migraine headaches (severe headaches accompanied by visual symptoms, light sensitivity, nausea and vomiting) are common in the general population but may be even more common in individuals with Parry Romberg syndrome. Individuals with Parry Romberg syndrome may have more prolonged migraines with associated pupillary abnormalities (the black part of the eye). Less often, perhaps one in ten individuals with Parry-Romberg syndrome can experience episodes of uncontrolled electrical disturbances in the brain (epileptic seizures). In these people, seizure episodes are usually characterized by jerky movements of muscles on the side of the body not affected by hemifacial atrophy. Such seizures, called contralateral focal seizures, are characterized by rapid jerky movements of muscles that may spread up or down a limb. Additional neurological symptoms that may occur include abnormal sensations (e.g., prickling or burning sensations called paresthesia) in the facial area and/or episodes of severe pain in the facial areas supplied by the fifth cranial nerve (trigeminal nerve) including the mouth, cheek, nose, and/or other areas (trigeminal neuralgia). Spasm of the jaw (trismus) sometimes occurs in Parry-Romberg syndrome, typically on the same side as the hemiatrophy. Some patients with neurological involvement may experience weakness of the opposite side of the body. Individuals with Parry-Romberg syndrome may also experience certain additional skin (dermatological) abnormalities including abnormal darkening or fading of the skin overlying the affected areas (hyper- and hypopigmentation). These skin pigment changes may precede the atrophic symptoms in some people. Rarely, patches of skin on the arms, legs, and/or trunk may have similar pigmentation abnormalities. Some affected individuals have a condition called vitiligo, a skin condition in which loss of color (pigmentation) of areas of skin results in the development of abnormal white patches.Affected individuals may also develop several eye (ocular) abnormalities. Loss of fat lining the cavity that accommodates the eye (orbit) and loss of bone from the orbit may cause the eye to have an abnormally sunken appearance (enophthalmos). Additional ocular symptoms include displacement of the eyeball farther back in the eye socket than normal (globe retraction), drooping of the upper eyelid (ptosis), different colored eyes (heterochromia), and difficulty closing the eye (lagophthalamos). Some people may have inflammation of the retina (retinitis) or uvea (uveitis) – the iris and middle part of the eye. If the nerves that control eye muscles are involved, then affected individuals may have double vision (diplopia). Anxiety and depression may accompany Parry Romberg syndrome because of the effect on facial appearance. Although it may be an autoimmune disorder it is not clear whether individuals with the disorder are more likely to have other autoimmune conditions.
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Symptoms of Parry Romberg Syndrome. The symptoms, progression and severity of Parry-Romberg syndrome are highly variable from one person to another and range from mild to severe. It is important to note that affected individuals will not have all the symptoms discussed below. It seems likely that individuals with milder symptoms are much more common than severely affected individuals. Affected individuals should talk to their physician and medical team about their specific case and associated symptoms.The characteristic symptom of Parry-Romberg syndrome is thinning or shrinkage (atrophy) of various tissues of the face including fat, skin, connective tissues, muscle, and, in some people, bone. The degree of atrophy can vary widely, ranging from mild, barely perceptible changes to significant asymmetry in which one side of the face appears “sunken in”. The progression of atrophic changes can vary as well. Facial atrophy may progress slowly over many years, or more frequently progresses slowly for several years before stopping. If the atrophy stops progressing, it may occasionally reactivate later in life, but this is rare. In other people, the atrophy may progress indefinitely. In some people, when Parry-Romberg syndrome starts at an early age, the progression seems to accelerate more quickly than when it starts later in life.The initial facial changes associated with Parry-Romberg syndrome usually occur near the middle portion of the face such as the cheek area above the upper jaw bone (maxilla) or between the nose and the upper corner of the lip. As the disease process continues, the upper face (e.g., the areas around the eye, the eyebrow, and the ear) as well as the angle of the mouth and the lower jaw bone (mandible) usually are affected. In some patients, one half of the chin may also be involved. Affected areas undergo shrinkage (atrophy) of tissues beneath the skin (subcutaneous tissue), the layer of fat under the skin (subcutaneous fat), and sometimes underlying cartilage, muscle, and bone. Areas affected by such changes may develop an abnormally sunken appearance. Many individuals may exhibit an unusual bony depression or hollow in the forehead or upper domed portion of the skull, the bony cavity that accommodates the eye (orbit), and/or the lower jawbone (mandible).In some people, a “line” may form in the area where the atrophic changes on one side of the face meet the normal, unaffected skin on the other side of the face. In some patients, this “line” may be very distinct and runs either vertically or diagonally down the forehead. The abnormal skin is thickened and hardened (sclerosis). This condition may be referred to as linear scleroderma “en coup de sabre” (LSCS–this comes from the French for ‘sabre cut’). LSCS can occur by itself as an isolated finding. According to the medical literature, LSCS is either a separate disorder that overlaps to a large degree with Parry-Romberg syndrome or essentially the same disorder (i.e., different expressions of one disease process or spectrum of disease). The exact relationship of LCSC and Parry-Romberg syndrome is not fully understood but it’s clear that the two commonly co-exist. About one third of people with linear scleroderma on the head or neck have Parry-Romberg syndromeProgressive atrophic changes associated with the Parry-Romberg syndrome may rarely also cause abnormalities of an ear. In individuals with the disorder, the ear on the affected side may become misshapen and unusually small and may appear to abnormally protrude from the head due to loss of supporting tissue.In some people, perhaps one in five, the atrophic skin and soft tissue changes associated with Parry-Romberg syndrome may progress to involve the arm, trunk and legs on one side of the body, either the same side (ipsilateral) as the atrophic changes to the face or the opposite side (contralateral). In addition, many affected individuals also experience abnormal changes affecting the hair on the affected side including the development of abnormal bald patches on the scalp (alopecia), absence of eyelashes, and absence of the middle portion of the eyebrow and/or whitening (blanching) of the hair. In some people, such hair changes may occur before other abnormalities associated with the disorder.Some individuals with Parry-Romberg syndrome may develop abnormalities affecting the mouth and teeth. Some individuals develop atrophy of half (hemiatrophy) of the upper lip and/or one side of the tongue. In addition, due to progressive atrophic changes associated with the disorder, portions of the lower jaw bone (mandible) may be unusually short on the affected side and the jaw may rarely be prone to spontaneous fracture. The unaffected side of the mouth and nose may sometimes point (deviate) towards the affected side. Some affected individuals may have difficulty opening or closing the jaws. Involuntary contractions of muscles used in chewing (hemi-masticatory spasm or trismus) may occur. One side of the upper lip may have an unusually twisted or raised appearance and certain teeth may be abnormally exposed, erupt unusually late, and/or have atrophic roots. In addition, the upper and lower teeth may meet inappropriately (malocclusion).Some affected individuals may also experience various neurological symptoms. Migraine headaches (severe headaches accompanied by visual symptoms, light sensitivity, nausea and vomiting) are common in the general population but may be even more common in individuals with Parry Romberg syndrome. Individuals with Parry Romberg syndrome may have more prolonged migraines with associated pupillary abnormalities (the black part of the eye). Less often, perhaps one in ten individuals with Parry-Romberg syndrome can experience episodes of uncontrolled electrical disturbances in the brain (epileptic seizures). In these people, seizure episodes are usually characterized by jerky movements of muscles on the side of the body not affected by hemifacial atrophy. Such seizures, called contralateral focal seizures, are characterized by rapid jerky movements of muscles that may spread up or down a limb. Additional neurological symptoms that may occur include abnormal sensations (e.g., prickling or burning sensations called paresthesia) in the facial area and/or episodes of severe pain in the facial areas supplied by the fifth cranial nerve (trigeminal nerve) including the mouth, cheek, nose, and/or other areas (trigeminal neuralgia). Spasm of the jaw (trismus) sometimes occurs in Parry-Romberg syndrome, typically on the same side as the hemiatrophy. Some patients with neurological involvement may experience weakness of the opposite side of the body. Individuals with Parry-Romberg syndrome may also experience certain additional skin (dermatological) abnormalities including abnormal darkening or fading of the skin overlying the affected areas (hyper- and hypopigmentation). These skin pigment changes may precede the atrophic symptoms in some people. Rarely, patches of skin on the arms, legs, and/or trunk may have similar pigmentation abnormalities. Some affected individuals have a condition called vitiligo, a skin condition in which loss of color (pigmentation) of areas of skin results in the development of abnormal white patches.Affected individuals may also develop several eye (ocular) abnormalities. Loss of fat lining the cavity that accommodates the eye (orbit) and loss of bone from the orbit may cause the eye to have an abnormally sunken appearance (enophthalmos). Additional ocular symptoms include displacement of the eyeball farther back in the eye socket than normal (globe retraction), drooping of the upper eyelid (ptosis), different colored eyes (heterochromia), and difficulty closing the eye (lagophthalamos). Some people may have inflammation of the retina (retinitis) or uvea (uveitis) – the iris and middle part of the eye. If the nerves that control eye muscles are involved, then affected individuals may have double vision (diplopia). Anxiety and depression may accompany Parry Romberg syndrome because of the effect on facial appearance. Although it may be an autoimmune disorder it is not clear whether individuals with the disorder are more likely to have other autoimmune conditions.
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Causes of Parry Romberg Syndrome
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The cause of Parry-Romberg syndrome is unknown and appears to occur randomly for unknown reasons (sporadically). Different theories have been proposed to explain the development of the disorder including abnormal development or inflammation of the sympathetic nervous system; viral infections; inflammation of the brain and membranes (meninges) covering the brain (meningoencephalitis); trauma; abnormalities of blood vessel formation (angiogenesis); or autoimmunity.One specific theory is that inflammation in the nerves that supply skin and fat causes an autoimmune reaction. Autoimmune disorders occur when the body’s immune system mistakenly attacks healthy tissue. The immune system produces specialized proteins called antibodies that destroy foreign materials (e.g., bacteria, viruses, toxins). When antibodies react against healthy tissue, they are known as autoantibodies. There is some evidence from a variety of sources that autoimmune inflammation occurs in Parry-Romberg syndrome, but it is not known if this is the main cause.Some individuals with Parry-Romberg syndrome have a history of trauma to face or head. Because many individuals with Parry-Romberg syndrome do not have a history of trauma this may be a coincidental finding. More research is necessary to determine what role, if any, that trauma plays in the development of Parry-Romberg syndrome.Rarely, some individuals with Parry-Romberg syndrome have had relatives with facial asymmetry. However, there is no specific evidence suggesting that a genetic component plays a role in the development of Parry-Romberg syndrome There is also no evidence that it can be passed on to children.In other types of disorders which affect the soft tissues and sometimes the nervous system, studies in recent years have highlighted the role of ‘somatic mutation’ of genes in causing disease. An example of this is Sturge-Weber syndrome. Somatic mutations are genetic problems that occur during very early development after the sperm has fertilized the egg but when the developing human being is still a ‘ball of cells’. At this very early stage one of these cells can develop a spontaneous genetic mutation which then leads to problems later in cells that derive from this ‘problem’ cell. It is not known whether Parry Romberg syndrome is caused by a somatic mutation, but it is another hypothesis. Disorders caused by somatic mutations will not be passed on to children unless the somatic mutation is also in the sperm or egg which would not be expected in Parry Romberg syndrome.More research is necessary to determine the specific, underlying cause(s) of Parry-Romberg syndrome. It is possible that the cause may be different in one person than in another and the development of the disorder may require multiple different factors occurring together.
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Causes of Parry Romberg Syndrome. The cause of Parry-Romberg syndrome is unknown and appears to occur randomly for unknown reasons (sporadically). Different theories have been proposed to explain the development of the disorder including abnormal development or inflammation of the sympathetic nervous system; viral infections; inflammation of the brain and membranes (meninges) covering the brain (meningoencephalitis); trauma; abnormalities of blood vessel formation (angiogenesis); or autoimmunity.One specific theory is that inflammation in the nerves that supply skin and fat causes an autoimmune reaction. Autoimmune disorders occur when the body’s immune system mistakenly attacks healthy tissue. The immune system produces specialized proteins called antibodies that destroy foreign materials (e.g., bacteria, viruses, toxins). When antibodies react against healthy tissue, they are known as autoantibodies. There is some evidence from a variety of sources that autoimmune inflammation occurs in Parry-Romberg syndrome, but it is not known if this is the main cause.Some individuals with Parry-Romberg syndrome have a history of trauma to face or head. Because many individuals with Parry-Romberg syndrome do not have a history of trauma this may be a coincidental finding. More research is necessary to determine what role, if any, that trauma plays in the development of Parry-Romberg syndrome.Rarely, some individuals with Parry-Romberg syndrome have had relatives with facial asymmetry. However, there is no specific evidence suggesting that a genetic component plays a role in the development of Parry-Romberg syndrome There is also no evidence that it can be passed on to children.In other types of disorders which affect the soft tissues and sometimes the nervous system, studies in recent years have highlighted the role of ‘somatic mutation’ of genes in causing disease. An example of this is Sturge-Weber syndrome. Somatic mutations are genetic problems that occur during very early development after the sperm has fertilized the egg but when the developing human being is still a ‘ball of cells’. At this very early stage one of these cells can develop a spontaneous genetic mutation which then leads to problems later in cells that derive from this ‘problem’ cell. It is not known whether Parry Romberg syndrome is caused by a somatic mutation, but it is another hypothesis. Disorders caused by somatic mutations will not be passed on to children unless the somatic mutation is also in the sperm or egg which would not be expected in Parry Romberg syndrome.More research is necessary to determine the specific, underlying cause(s) of Parry-Romberg syndrome. It is possible that the cause may be different in one person than in another and the development of the disorder may require multiple different factors occurring together.
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Affects of Parry Romberg Syndrome
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Parry-Romberg syndrome is a rare disorder. The true incidence is unknown. Because the disorder often goes undiagnosed or misdiagnosed determining the true frequency of Parry-Romberg syndrome in the general population is difficult. Physicians studying the disorder have estimated that Parry-Romberg may affect as many as 1 in 250,000 people in the general population. Parry-Romberg syndrome appears to affect women slightly more often than men, but proper studies of the population are lacking. Parry-Romberg syndrome typically becomes apparent during the first or early during the second decade of life, with most affected individuals experiencing symptoms before the age of 20 years. However, the disorder has been described in infants and individuals more than 50 years of age. Parry-Romberg syndrome was originally described in the medical literature in 1825 (C.H. Parry) and 1846 (E. Henoch and H.M. Romberg). There are anecdotal reports of Parry-Romberg syndrome worsening in some pregnant women, either during pregnancy or shortly after childbirth.
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Affects of Parry Romberg Syndrome. Parry-Romberg syndrome is a rare disorder. The true incidence is unknown. Because the disorder often goes undiagnosed or misdiagnosed determining the true frequency of Parry-Romberg syndrome in the general population is difficult. Physicians studying the disorder have estimated that Parry-Romberg may affect as many as 1 in 250,000 people in the general population. Parry-Romberg syndrome appears to affect women slightly more often than men, but proper studies of the population are lacking. Parry-Romberg syndrome typically becomes apparent during the first or early during the second decade of life, with most affected individuals experiencing symptoms before the age of 20 years. However, the disorder has been described in infants and individuals more than 50 years of age. Parry-Romberg syndrome was originally described in the medical literature in 1825 (C.H. Parry) and 1846 (E. Henoch and H.M. Romberg). There are anecdotal reports of Parry-Romberg syndrome worsening in some pregnant women, either during pregnancy or shortly after childbirth.
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Related disorders of Parry Romberg Syndrome
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Symptoms of the following disorders can be similar to those of Parry-Romberg syndrome. Comparisons may be useful for a differential diagnosis although in practice the clinical features of Parry Romberg syndrome are quite distinct to a doctor familiar with the condition.Hemifacial microsomia is a rare disorder characterized by craniofacial abnormalities involving the jaws, mouth, and ears in addition to extra cranial anomalies of the cardiac, skeletal, renal systems, and extremities (HFM with expanded spectrum). Many researchers consider Goldenhar syndrome a variant and subgroup of hemifacial microsomia. In the medical literature, hemifacial microsomia and Goldenhar syndrome are often grouped together under the term “oculoauriculovertebral (OAV) spectrum”. For most affected people, no apparent cause has been identified. In other people, there has been a positive family history that, according to some researchers, appears to suggest autosomal dominant inheritance. The physical features associated with hemifacial microsomia OAV spectrum vary dramatically from person to person. Such features tend to involve one side of the body (unilateral) and may represent varying combinations of certain abnormalities. These include underdevelopment of the cheekbones, the upper jaw, and the lower jaw (malar, maxillary, and mandibular hypoplasia); underdevelopment of certain muscles in the face; abnormalities of the tongue, incomplete closure of the roof of the mouth (cleft palate), and/or an abnormal groove in the lip (cleft lip); malformed external ears (pinnae) with blind ending or absent external ear canals (microtia), resulting in hearing impairment (conductive hearing loss); abnormal outgrowths of skin on the ears (skin tags); and/or incomplete development of certain bones in the spinal column (vertebral hypoplasia). Additional abnormalities include partial or total absence of tissue (coloboma) from the upper eyelids, crossed eyes (strabismus), and/or abnormally small eyes (microphthalmia); heart (cardiac) defects; kidney (renal) abnormalities; and/or additional physical abnormalities. (For more information on this disorder, choose “OAV Spectrum” as your search term in the Rare Disease Database.)Bell’s palsy is a nonprogressive neurological disorder of one of the facial nerves (7th cranial nerve). This disorder is characterized by the sudden onset of facial paralysis that may be preceded by a slight fever, pain behind the ear on the affected side, a stiff neck, and weakness and/or stiffness on one side of the face. Paralysis results from inflammation of the 7th cranial nerve. The exact cause of Bell’s palsy is not known. Viral (e.g., herpes zoster virus) and immune disorders are frequently implicated as a cause for this disorder. There may also be an inherited tendency toward developing Bell’s palsy. (For more information on this disorder, choose “Bell’s palsy” as your search term in the Rare Disease Database.)Many neurological disorders including Bell’s palsy may cause weakness of the face on one side. However, in Parry Romberg syndrome the facial muscles are thin but not weak.Lipodystrophies are a group of rare inherited or acquired disorders of fat metabolism characterized by almost complete (generalized) or partial loss of body fat (adipose tissue) and certain abnormalities of the body’s chemical processes (metabolism) including resistance to insulin, increased levels of glucose in the blood (hyperglycemia), and/or other findings. The lipodystrophies are differentiated by degrees of severity and the specific areas of the body affected. Generalized or total lipodystrophy, which usually is apparent at birth or during the first decade of life, is characterized by generalized wasting (atrophy) of the layer of fat under the skin (subcutaneous fat) and other fatty tissue (extracutaneous adipose tissue) occurring in association with a variety of metabolic abnormalities (e.g., diabetes, hyperglycemia), abnormally increased growth, advanced bone age, abnormal darkening and thickening of patches of skin in certain areas of the body (acanthosis nigricans), excessive hair growth (hirsutism or hypertrichosis), and/or other findings. Generalized lipodystrophy may occur in inherited or acquired forms. Acquired partial lipodystrophy, which is usually apparent in the first decade of life, is characterized by atrophy of subcutaneous fat beginning in the facial area and gradually affecting the neck, chest, back, and arms. In most patients with acquired partial lipodystrophy, both sides of the body (bilateral) are affected, although, in rare cases, just one side may be involved (unilateral). A form of acquired partial lipodystrophy that affects the face first is called Barraquer-Simons syndrome. (For more information, choose “lipodystrophy” or the exact name of the disease in question as your search term in the Rare Disease Database.)Individuals who have sustained injuries or burns to their face may develop an appearance similar to Parry Romberg syndrome.
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Related disorders of Parry Romberg Syndrome. Symptoms of the following disorders can be similar to those of Parry-Romberg syndrome. Comparisons may be useful for a differential diagnosis although in practice the clinical features of Parry Romberg syndrome are quite distinct to a doctor familiar with the condition.Hemifacial microsomia is a rare disorder characterized by craniofacial abnormalities involving the jaws, mouth, and ears in addition to extra cranial anomalies of the cardiac, skeletal, renal systems, and extremities (HFM with expanded spectrum). Many researchers consider Goldenhar syndrome a variant and subgroup of hemifacial microsomia. In the medical literature, hemifacial microsomia and Goldenhar syndrome are often grouped together under the term “oculoauriculovertebral (OAV) spectrum”. For most affected people, no apparent cause has been identified. In other people, there has been a positive family history that, according to some researchers, appears to suggest autosomal dominant inheritance. The physical features associated with hemifacial microsomia OAV spectrum vary dramatically from person to person. Such features tend to involve one side of the body (unilateral) and may represent varying combinations of certain abnormalities. These include underdevelopment of the cheekbones, the upper jaw, and the lower jaw (malar, maxillary, and mandibular hypoplasia); underdevelopment of certain muscles in the face; abnormalities of the tongue, incomplete closure of the roof of the mouth (cleft palate), and/or an abnormal groove in the lip (cleft lip); malformed external ears (pinnae) with blind ending or absent external ear canals (microtia), resulting in hearing impairment (conductive hearing loss); abnormal outgrowths of skin on the ears (skin tags); and/or incomplete development of certain bones in the spinal column (vertebral hypoplasia). Additional abnormalities include partial or total absence of tissue (coloboma) from the upper eyelids, crossed eyes (strabismus), and/or abnormally small eyes (microphthalmia); heart (cardiac) defects; kidney (renal) abnormalities; and/or additional physical abnormalities. (For more information on this disorder, choose “OAV Spectrum” as your search term in the Rare Disease Database.)Bell’s palsy is a nonprogressive neurological disorder of one of the facial nerves (7th cranial nerve). This disorder is characterized by the sudden onset of facial paralysis that may be preceded by a slight fever, pain behind the ear on the affected side, a stiff neck, and weakness and/or stiffness on one side of the face. Paralysis results from inflammation of the 7th cranial nerve. The exact cause of Bell’s palsy is not known. Viral (e.g., herpes zoster virus) and immune disorders are frequently implicated as a cause for this disorder. There may also be an inherited tendency toward developing Bell’s palsy. (For more information on this disorder, choose “Bell’s palsy” as your search term in the Rare Disease Database.)Many neurological disorders including Bell’s palsy may cause weakness of the face on one side. However, in Parry Romberg syndrome the facial muscles are thin but not weak.Lipodystrophies are a group of rare inherited or acquired disorders of fat metabolism characterized by almost complete (generalized) or partial loss of body fat (adipose tissue) and certain abnormalities of the body’s chemical processes (metabolism) including resistance to insulin, increased levels of glucose in the blood (hyperglycemia), and/or other findings. The lipodystrophies are differentiated by degrees of severity and the specific areas of the body affected. Generalized or total lipodystrophy, which usually is apparent at birth or during the first decade of life, is characterized by generalized wasting (atrophy) of the layer of fat under the skin (subcutaneous fat) and other fatty tissue (extracutaneous adipose tissue) occurring in association with a variety of metabolic abnormalities (e.g., diabetes, hyperglycemia), abnormally increased growth, advanced bone age, abnormal darkening and thickening of patches of skin in certain areas of the body (acanthosis nigricans), excessive hair growth (hirsutism or hypertrichosis), and/or other findings. Generalized lipodystrophy may occur in inherited or acquired forms. Acquired partial lipodystrophy, which is usually apparent in the first decade of life, is characterized by atrophy of subcutaneous fat beginning in the facial area and gradually affecting the neck, chest, back, and arms. In most patients with acquired partial lipodystrophy, both sides of the body (bilateral) are affected, although, in rare cases, just one side may be involved (unilateral). A form of acquired partial lipodystrophy that affects the face first is called Barraquer-Simons syndrome. (For more information, choose “lipodystrophy” or the exact name of the disease in question as your search term in the Rare Disease Database.)Individuals who have sustained injuries or burns to their face may develop an appearance similar to Parry Romberg syndrome.
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Diagnosis of Parry Romberg Syndrome
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A diagnosis of Parry-Romberg syndrome is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. The specific tests that are used depend on which symptoms are present and which symptoms occur first. For example, magnetic resonance imaging (MRI) may be used in individuals with neurological symptoms. An MRI uses a magnetic field and radio waves to produce cross-sectional images of organs and bodily tissues. MRI allows better characterization of the soft tissue and bony changes when present. Between 10-20% of individuals with Parry-Romberg syndrome may have changes on brain MRI scans. These changes can include atrophy of the brain on the same side as the facial changes, and sometimes inflammation within the brain itself. Surgical removal and microscopic examination (biopsy) of affected skin tissue may be used in individuals with linear scleroderma en coup sabre.
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Diagnosis of Parry Romberg Syndrome. A diagnosis of Parry-Romberg syndrome is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. The specific tests that are used depend on which symptoms are present and which symptoms occur first. For example, magnetic resonance imaging (MRI) may be used in individuals with neurological symptoms. An MRI uses a magnetic field and radio waves to produce cross-sectional images of organs and bodily tissues. MRI allows better characterization of the soft tissue and bony changes when present. Between 10-20% of individuals with Parry-Romberg syndrome may have changes on brain MRI scans. These changes can include atrophy of the brain on the same side as the facial changes, and sometimes inflammation within the brain itself. Surgical removal and microscopic examination (biopsy) of affected skin tissue may be used in individuals with linear scleroderma en coup sabre.
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Therapies of Parry Romberg Syndrome
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Treatment
The treatment of Parry-Romberg syndrome is directed toward the specific symptoms that are apparent in each. Treatment may require the coordinated efforts of a team of specialists. Pediatricians or internists, surgeons (especially plastic surgeons), dentists, ophthalmologists, dermatologists, neurologists, and/or other health care professionals may need to systematically and comprehensively plan an affected individual's treatment. For example, migraine, epilepsy or uveitis can be treated as they would in any other situation.A variety of surgical techniques have been used to improve cosmetic appearance in affected individuals. The success rates of these surgical options are highly variable. Surgical treatment is usually not advised until the atrophic changes have ceased and the extent of resulting facial deformity is known. Some doctors advise those with Parry-Romberg syndrome to postpone any surgical procedures until the skull and face are fully developed and the symptoms have subsided for at least a year. Monitoring can be done by having medical photographs taken over a period of time, to be used for comparison. Surgery may leave scar tissue. The effects of this scar tissue on subsequent surgeries should be considered for the final outcome.Surgical techniques used to treat individuals with Parry-Romberg syndrome include fat or silicone injections, flap/pedicle grafts, or bone implants. These procedures may be effective in achieving cosmetic improvement. It should be noted, however, that fat injections may be reabsorbed when given during the active disease phase. A flap/pedicle procedure is a skin and tissue graft that is left temporarily attached to its original site in order to maintain a constant blood supply while it heals into place.In some patients, additional measures may help treat certain abnormalities resulting from the disease process. Associated dental abnormalities may be treated with additional surgical and/or other corrective techniques. Additional surgical, corrective, and/or supportive measures may help improve visual problems resulting from hemifacial atrophy. Treatment with anticonvulsant drug therapy may help prevent, reduce, or control seizures potentially occurring in association with the disorder. In addition, in affected individuals with trigeminal neuralgia, certain medications and/or surgical treatments may be beneficial in some cases. (For more information on this disorder, please choose “trigeminal neuralgia” as your search term in the Rare Disease Database.)
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Therapies of Parry Romberg Syndrome. Treatment
The treatment of Parry-Romberg syndrome is directed toward the specific symptoms that are apparent in each. Treatment may require the coordinated efforts of a team of specialists. Pediatricians or internists, surgeons (especially plastic surgeons), dentists, ophthalmologists, dermatologists, neurologists, and/or other health care professionals may need to systematically and comprehensively plan an affected individual's treatment. For example, migraine, epilepsy or uveitis can be treated as they would in any other situation.A variety of surgical techniques have been used to improve cosmetic appearance in affected individuals. The success rates of these surgical options are highly variable. Surgical treatment is usually not advised until the atrophic changes have ceased and the extent of resulting facial deformity is known. Some doctors advise those with Parry-Romberg syndrome to postpone any surgical procedures until the skull and face are fully developed and the symptoms have subsided for at least a year. Monitoring can be done by having medical photographs taken over a period of time, to be used for comparison. Surgery may leave scar tissue. The effects of this scar tissue on subsequent surgeries should be considered for the final outcome.Surgical techniques used to treat individuals with Parry-Romberg syndrome include fat or silicone injections, flap/pedicle grafts, or bone implants. These procedures may be effective in achieving cosmetic improvement. It should be noted, however, that fat injections may be reabsorbed when given during the active disease phase. A flap/pedicle procedure is a skin and tissue graft that is left temporarily attached to its original site in order to maintain a constant blood supply while it heals into place.In some patients, additional measures may help treat certain abnormalities resulting from the disease process. Associated dental abnormalities may be treated with additional surgical and/or other corrective techniques. Additional surgical, corrective, and/or supportive measures may help improve visual problems resulting from hemifacial atrophy. Treatment with anticonvulsant drug therapy may help prevent, reduce, or control seizures potentially occurring in association with the disorder. In addition, in affected individuals with trigeminal neuralgia, certain medications and/or surgical treatments may be beneficial in some cases. (For more information on this disorder, please choose “trigeminal neuralgia” as your search term in the Rare Disease Database.)
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Parry Romberg Syndrome
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Overview of Pars Planitis
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Although pars planitis is generally benign, there can be significant vision loss in extreme cases. It is an immunological disorder of the eye characterized by inflammation of a part of the uvea, the layer of tissue between the sclera and the retina, the membranes protecting the eyeball. The uvea, in turn, is made up of three portions: the iris, the ciliary body, and the choroid. In addition, the uvea contains many of the blood vessels that supply the eye.The pars plana is a narrow section of the ciliary body, inflammation of which is known as pars planitis. In association with the inflammation or immunological response, fluid and cells infiltrate the clear gelatin-like substance (vitreous humor) of the eyeball, near the retina and/or pars plana. As a result, swelling of the eye or eyes can also occur, but more importantly blurred vision and progressive increase in the vision of floaters is reported as main symptoms by patients suffering this condition as a result of the infiltration of the vitreous humor.The inflammation occurs in the intermediate zone of the eye; that is, between the anterior part(s) of the eye (iris) and the posterior part(s), the retina and/or choroid. It has therefore been designated as one of the diseases of a family of intermediate uveitis.In some cases, the disturbance of vision may be slightly progressive.
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Overview of Pars Planitis. Although pars planitis is generally benign, there can be significant vision loss in extreme cases. It is an immunological disorder of the eye characterized by inflammation of a part of the uvea, the layer of tissue between the sclera and the retina, the membranes protecting the eyeball. The uvea, in turn, is made up of three portions: the iris, the ciliary body, and the choroid. In addition, the uvea contains many of the blood vessels that supply the eye.The pars plana is a narrow section of the ciliary body, inflammation of which is known as pars planitis. In association with the inflammation or immunological response, fluid and cells infiltrate the clear gelatin-like substance (vitreous humor) of the eyeball, near the retina and/or pars plana. As a result, swelling of the eye or eyes can also occur, but more importantly blurred vision and progressive increase in the vision of floaters is reported as main symptoms by patients suffering this condition as a result of the infiltration of the vitreous humor.The inflammation occurs in the intermediate zone of the eye; that is, between the anterior part(s) of the eye (iris) and the posterior part(s), the retina and/or choroid. It has therefore been designated as one of the diseases of a family of intermediate uveitis.In some cases, the disturbance of vision may be slightly progressive.
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Pars Planitis
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Symptoms of Pars Planitis
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The symptoms of pars planitis include blurred vision and dark floating spots that intrude upon clarity of eyesight. Swelling can occur inside the eye, particularly on the peripheral retina or macula that may lead to decreased vision. Glaucoma may occur as well.The clinical picture may be complicated by cataracts, retinal detachment, or fluid within the retina (macular edema) More often the examining ophthalmologist (specialist in diseases of the eye) will see clusters of white blood cells trapped within the eyeball that are called snowballs. The term physicians may use for these is inflammatory exudate. These are clusters of white blood cells trapped within the eyeball. If these clusters are located on the pars plana, they are known as snowbanks.
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Symptoms of Pars Planitis. The symptoms of pars planitis include blurred vision and dark floating spots that intrude upon clarity of eyesight. Swelling can occur inside the eye, particularly on the peripheral retina or macula that may lead to decreased vision. Glaucoma may occur as well.The clinical picture may be complicated by cataracts, retinal detachment, or fluid within the retina (macular edema) More often the examining ophthalmologist (specialist in diseases of the eye) will see clusters of white blood cells trapped within the eyeball that are called snowballs. The term physicians may use for these is inflammatory exudate. These are clusters of white blood cells trapped within the eyeball. If these clusters are located on the pars plana, they are known as snowbanks.
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Pars Planitis
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Causes of Pars Planitis
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Pars planitis is thought to be an autoimmune disorder. An autoimmune reaction causes the inflammation that is thought to cause symptoms of this disorder. Autoimmune disorders are caused when the body's natural defenses against foreign or invading organisms (e.g., antibodies) begin to attack healthy tissue for unknown reasons. In rare cases, pars planitis has occurred within families; however, as yet, no genetic inheritance pattern has been identified.Some clinicians have put forward the idea that the immunological response may be the result of one of two possible causes: (1) an isolated set of events internal to the patient (endogenous), or (2) an association with some other disorder (exogenous). Among the disorders with which pars planitis has been associated are: multiple sclerosis, Lyme disease, Behcet disease, sarcoidosis, and tuberculosis, among others.
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Causes of Pars Planitis. Pars planitis is thought to be an autoimmune disorder. An autoimmune reaction causes the inflammation that is thought to cause symptoms of this disorder. Autoimmune disorders are caused when the body's natural defenses against foreign or invading organisms (e.g., antibodies) begin to attack healthy tissue for unknown reasons. In rare cases, pars planitis has occurred within families; however, as yet, no genetic inheritance pattern has been identified.Some clinicians have put forward the idea that the immunological response may be the result of one of two possible causes: (1) an isolated set of events internal to the patient (endogenous), or (2) an association with some other disorder (exogenous). Among the disorders with which pars planitis has been associated are: multiple sclerosis, Lyme disease, Behcet disease, sarcoidosis, and tuberculosis, among others.
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Affects of Pars Planitis
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Pars planitis is an uncommon ocular disorder of children and young adults that affects males slightly more frequently than females.
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Affects of Pars Planitis. Pars planitis is an uncommon ocular disorder of children and young adults that affects males slightly more frequently than females.
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Related disorders of Pars Planitis
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The following disorders may be associated with pars planitis as secondary characteristics. They are not necessary for a differential diagnosis: Cystoid macular edema is characterized by swelling (edema) of the central part of the retina as a result of abnormal leakage of fluid from capillaries. In pars planitis, swelling or leakage of fluid due to inflammation can affect the peripheral retina. Cystoid macular edema can often be a complication of pars planitis.Ocular hypotension is a condition defined as lowered intraocular pressure as a result of decreased production of aqueous humor secondary to decreased blood pressure in the veins or capillaries inside the eye tissue. When this happens, vision disturbances similar to those of pars planitis may occur. This condition may in some cases be a complication of pars planitis.Autoimmune endotheliopathy (endothelitis/ vasculitis) is an attack by the immune system on the layer of flat cells lining blood vessels (endothelium). This condition can occur in the blood vessels of the eyes as a complication of pars planitis, but can also occur alone in any part of the body. A more common name for this is: autoimmune vasculitis
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Related disorders of Pars Planitis. The following disorders may be associated with pars planitis as secondary characteristics. They are not necessary for a differential diagnosis: Cystoid macular edema is characterized by swelling (edema) of the central part of the retina as a result of abnormal leakage of fluid from capillaries. In pars planitis, swelling or leakage of fluid due to inflammation can affect the peripheral retina. Cystoid macular edema can often be a complication of pars planitis.Ocular hypotension is a condition defined as lowered intraocular pressure as a result of decreased production of aqueous humor secondary to decreased blood pressure in the veins or capillaries inside the eye tissue. When this happens, vision disturbances similar to those of pars planitis may occur. This condition may in some cases be a complication of pars planitis.Autoimmune endotheliopathy (endothelitis/ vasculitis) is an attack by the immune system on the layer of flat cells lining blood vessels (endothelium). This condition can occur in the blood vessels of the eyes as a complication of pars planitis, but can also occur alone in any part of the body. A more common name for this is: autoimmune vasculitis
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Diagnosis of Pars Planitis
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Pars planitis is usually diagnosed by means of a thorough physical evaluation, detailed patient history, and specialized eye examination.
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Diagnosis of Pars Planitis. Pars planitis is usually diagnosed by means of a thorough physical evaluation, detailed patient history, and specialized eye examination.
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Pars Planitis
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