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Related disorders of Pseudoachondroplasia
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Symptoms of the following skeletal dysplasia disorders can be similar to those of pseudoachondroplasia and are considered in the differential diagnosis.Skeletal dysplasia (osteochondrodysplasia) is a general term for a group of disorders characterized by abnormal growth or development of cartilage and bone. Some forms cause life-threatening complications shortly after birth, while many do not. Skeletal dysplasias are generally associated with disproportionate short stature that involves the limbs and/or the trunk. Various other abnormalities may be present depending upon the specific disorder. There are more than 400 types of skeletal dysplasias caused by approximately 360 causative genes, with more being identified.Achondroplasia, the most common skeletal dysplasia, is characterized by distinctive abnormalities of the head and face including macrocephaly, frontal bossing and depressed nasal bridge; short arms and legs with the shortening most obvious in the upper segments and, short hands with fingers that assume a “trident” or three-pronged position during extension. Additional symptoms include limited extension of the elbows and hips, bowing of the legs, and lumbar lordosis, which is an abnormally increased curvature of the bones of the lower spine. Narrowing of the spine (stenosis) is common in achondroplasia. Mutations in the fibroblast growth factor receptor 3 (FGFR3) gene causes all cases of achondroplasia. 80% of cases result from a new mutation and the rest are transmitted in autosomal dominant pattern from an affected parent. Pseudoachondroplasia is sometimes confused with achondroplasia, but these are distinct disorders that occur because of mutations in different genes. (For more information on this disorder, choose “achondroplasia” as your search term in the Rare Disease Database).Multiple epiphyseal dysplasia (MED) is a broad term for a group of disorders characterized by abnormal development of the cartilage and bone of the growth centers (epiphyses). There are at least six disorders that are caused by different genetic mutations. Most subtypes are inherited in an autosomal dominant pattern with only one type inherited in an autosomal recessive pattern. These disorders are characterized by skeletal malformations (dysplasia) affecting bones of the hips, knees, hands and feet. Joint pain, particularly in the hips and/or knees, is common and often develops during early childhood. Initial signs may include pain in the hips and knees. Clubfoot and cleft palate may occur in recessive multiple epiphyseal dysplasia. Multiple epiphyseal dysplasia type 1 is caused by mutations in the same gene (COMP) that causes pseudoachondroplasia (they are allelic disorders). These disorders most likely represent a spectrum with pseudoachondroplasia representing the severe end and MED type 1 representing the milder end. (For more information on this disorder, choose “multiple epiphyseal dysplasia” as your search term in the Rare Disease Database.)
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Related disorders of Pseudoachondroplasia. Symptoms of the following skeletal dysplasia disorders can be similar to those of pseudoachondroplasia and are considered in the differential diagnosis.Skeletal dysplasia (osteochondrodysplasia) is a general term for a group of disorders characterized by abnormal growth or development of cartilage and bone. Some forms cause life-threatening complications shortly after birth, while many do not. Skeletal dysplasias are generally associated with disproportionate short stature that involves the limbs and/or the trunk. Various other abnormalities may be present depending upon the specific disorder. There are more than 400 types of skeletal dysplasias caused by approximately 360 causative genes, with more being identified.Achondroplasia, the most common skeletal dysplasia, is characterized by distinctive abnormalities of the head and face including macrocephaly, frontal bossing and depressed nasal bridge; short arms and legs with the shortening most obvious in the upper segments and, short hands with fingers that assume a “trident” or three-pronged position during extension. Additional symptoms include limited extension of the elbows and hips, bowing of the legs, and lumbar lordosis, which is an abnormally increased curvature of the bones of the lower spine. Narrowing of the spine (stenosis) is common in achondroplasia. Mutations in the fibroblast growth factor receptor 3 (FGFR3) gene causes all cases of achondroplasia. 80% of cases result from a new mutation and the rest are transmitted in autosomal dominant pattern from an affected parent. Pseudoachondroplasia is sometimes confused with achondroplasia, but these are distinct disorders that occur because of mutations in different genes. (For more information on this disorder, choose “achondroplasia” as your search term in the Rare Disease Database).Multiple epiphyseal dysplasia (MED) is a broad term for a group of disorders characterized by abnormal development of the cartilage and bone of the growth centers (epiphyses). There are at least six disorders that are caused by different genetic mutations. Most subtypes are inherited in an autosomal dominant pattern with only one type inherited in an autosomal recessive pattern. These disorders are characterized by skeletal malformations (dysplasia) affecting bones of the hips, knees, hands and feet. Joint pain, particularly in the hips and/or knees, is common and often develops during early childhood. Initial signs may include pain in the hips and knees. Clubfoot and cleft palate may occur in recessive multiple epiphyseal dysplasia. Multiple epiphyseal dysplasia type 1 is caused by mutations in the same gene (COMP) that causes pseudoachondroplasia (they are allelic disorders). These disorders most likely represent a spectrum with pseudoachondroplasia representing the severe end and MED type 1 representing the milder end. (For more information on this disorder, choose “multiple epiphyseal dysplasia” as your search term in the Rare Disease Database.)
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Diagnosis of Pseudoachondroplasia
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The diagnosis of pseudoachondroplasia is based upon identification of characteristic clinical and radiographic findings, detailed patient history and mutational testing. The diagnosis is rarely made at birth because short stature is not present. The distinctive features develop over time, and this sets it apart from other short stature conditions.Clinical Testing and Workup
A complete set of x-rays (radiographs) establishes the diagnosis by revealing abnormal growth centers (epiphyses) and other characteristic skeletal findings. The diagnosis is made clinically and by radiographs. More advanced imaging techniques such as magnetic resonance imaging (MRI) and computed tomography (CT) scans can be used later to assess skeletal health, particular in advance of surgery to correct skeletal malformations. Commercial sequencing of a patient’s COMP gene is available, confirming the diagnosis and identifying he exact mutation. Prenatal diagnosis for pregnancies at increased risk for pseudoachondroplasia is accomplished by chorionic villus sampling or amniocentesis, regardless of whether the COMP mutation has been identified in an affected family member.Genetic counseling is recommended to help families understand the genetics and natural history of pseudoachondroplasia and to provide psychosocial support.
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Diagnosis of Pseudoachondroplasia. The diagnosis of pseudoachondroplasia is based upon identification of characteristic clinical and radiographic findings, detailed patient history and mutational testing. The diagnosis is rarely made at birth because short stature is not present. The distinctive features develop over time, and this sets it apart from other short stature conditions.Clinical Testing and Workup
A complete set of x-rays (radiographs) establishes the diagnosis by revealing abnormal growth centers (epiphyses) and other characteristic skeletal findings. The diagnosis is made clinically and by radiographs. More advanced imaging techniques such as magnetic resonance imaging (MRI) and computed tomography (CT) scans can be used later to assess skeletal health, particular in advance of surgery to correct skeletal malformations. Commercial sequencing of a patient’s COMP gene is available, confirming the diagnosis and identifying he exact mutation. Prenatal diagnosis for pregnancies at increased risk for pseudoachondroplasia is accomplished by chorionic villus sampling or amniocentesis, regardless of whether the COMP mutation has been identified in an affected family member.Genetic counseling is recommended to help families understand the genetics and natural history of pseudoachondroplasia and to provide psychosocial support.
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Therapies of Pseudoachondroplasia
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Treatment
Treatments are directed toward the specific symptoms as they become apparent and usually require the coordinated efforts of a team of specialists. The team includes geneticists, pediatricians, specialists in treating skeletal disorders (orthopedic surgeons), neurologists, physical and occupational therapists and other healthcare professionals who will systematically and comprehensively plan needed treatments.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease severity; the presence or absence of painful symptoms; an individual’s age and general health; and/or other elements. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors. Pain medications may be beneficial in treating pain associated with joint disease. Physical therapy, which can improve joint motion and avoid muscle degeneration (atrophy), is beneficial.Spinal abnormalities, in some children, may require surgical intervention. Abnormal curvature of the spine, e.g. scoliosis, usually does not require surgery, but in severe cases, surgery has been effective. More serious spinal problems such as cervical instability may require spinal fusion. Surgical realignment of the lower extremities, called osteotomy, is often required before adulthood. Total hip replacement surgery (total hip arthroplasty) occurs in more than 50% of individuals.
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Therapies of Pseudoachondroplasia. Treatment
Treatments are directed toward the specific symptoms as they become apparent and usually require the coordinated efforts of a team of specialists. The team includes geneticists, pediatricians, specialists in treating skeletal disorders (orthopedic surgeons), neurologists, physical and occupational therapists and other healthcare professionals who will systematically and comprehensively plan needed treatments.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease severity; the presence or absence of painful symptoms; an individual’s age and general health; and/or other elements. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors. Pain medications may be beneficial in treating pain associated with joint disease. Physical therapy, which can improve joint motion and avoid muscle degeneration (atrophy), is beneficial.Spinal abnormalities, in some children, may require surgical intervention. Abnormal curvature of the spine, e.g. scoliosis, usually does not require surgery, but in severe cases, surgery has been effective. More serious spinal problems such as cervical instability may require spinal fusion. Surgical realignment of the lower extremities, called osteotomy, is often required before adulthood. Total hip replacement surgery (total hip arthroplasty) occurs in more than 50% of individuals.
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Overview of Pseudocholinesterase Deficiency
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Pseudocholinesterase deficiency is an uncommon genetic disorder that makes an affected person very sensitive to any of several anesthetic agents, especially those derived from the drug known as choline. When anesthetic drugs such as succinylcholine or mivacurium are administered to a susceptible person, the muscles that work the lungs may become paralyzed. Mechanical ventilation is essential until the excess anesthetic agent is metabolized and normal breathing is resumed.
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Overview of Pseudocholinesterase Deficiency. Pseudocholinesterase deficiency is an uncommon genetic disorder that makes an affected person very sensitive to any of several anesthetic agents, especially those derived from the drug known as choline. When anesthetic drugs such as succinylcholine or mivacurium are administered to a susceptible person, the muscles that work the lungs may become paralyzed. Mechanical ventilation is essential until the excess anesthetic agent is metabolized and normal breathing is resumed.
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Pseudocholinesterase Deficiency
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Symptoms of Pseudocholinesterase Deficiency
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Individuals with pseudocholinesterase deficiency have a shortage or absence of the enzyme pseudocholinesterase in their blood serum. If the drug succinylcholine (or another anesthetic derivative of choline) is given during surgery, the respiratory muscles become paralyzed and the patient stops breathing (apnea). Artificial respiration (mechanical ventilation) may be necessary until the drug is eliminated from the body and the affected individual is able to resume breathing. If the person with pseudocholinesterase deficiency is not exposed to a choline-derived anesthetic, he or she may never be aware of having a deficiency of the enzyme pseudocholinesterase.
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Symptoms of Pseudocholinesterase Deficiency. Individuals with pseudocholinesterase deficiency have a shortage or absence of the enzyme pseudocholinesterase in their blood serum. If the drug succinylcholine (or another anesthetic derivative of choline) is given during surgery, the respiratory muscles become paralyzed and the patient stops breathing (apnea). Artificial respiration (mechanical ventilation) may be necessary until the drug is eliminated from the body and the affected individual is able to resume breathing. If the person with pseudocholinesterase deficiency is not exposed to a choline-derived anesthetic, he or she may never be aware of having a deficiency of the enzyme pseudocholinesterase.
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Causes of Pseudocholinesterase Deficiency
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Pseudocholinesterase deficiency is inherited as an autosomal recessive trait. The faulty gene is located on chromosome 3 (3q26.1-q26.2).Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome, and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, 3q26.1-q26.2 refers to a region between bands 26.1 and 26.2 on the long arm of chromosome 3. 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. 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.
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Causes of Pseudocholinesterase Deficiency. Pseudocholinesterase deficiency is inherited as an autosomal recessive trait. The faulty gene is located on chromosome 3 (3q26.1-q26.2).Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome, and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, 3q26.1-q26.2 refers to a region between bands 26.1 and 26.2 on the long arm of chromosome 3. 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. 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.
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Pseudocholinesterase Deficiency
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nord_1029_3
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Affects of Pseudocholinesterase Deficiency
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Pseudocholinesterase deficiency is present at birth and occurs in approximately 1 out of every 1,500 to 2,500 people in the United States. Among Caucasian Americans, it seems to affect males almost twice as often as females.
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Affects of Pseudocholinesterase Deficiency. Pseudocholinesterase deficiency is present at birth and occurs in approximately 1 out of every 1,500 to 2,500 people in the United States. Among Caucasian Americans, it seems to affect males almost twice as often as females.
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Related disorders of Pseudocholinesterase Deficiency
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Apnea is the temporary cessation of breathing during sleep. Infantile apnea refers to pauses in breathing during an infant's sleep. Apnea is called central apnea or diaphragmatic apnea when there are no chest movements during the pauses in breathing. When there are chest movements but no passage of air through the mouth or nostrils, the disorder is known as obstructive apnea or upper airway apnea. Central apnea followed by or intermixed with an obstructive apnea is called mixed apnea. (For more information choose “apnea” as your search term in the Rare Disease Database.)
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Related disorders of Pseudocholinesterase Deficiency. Apnea is the temporary cessation of breathing during sleep. Infantile apnea refers to pauses in breathing during an infant's sleep. Apnea is called central apnea or diaphragmatic apnea when there are no chest movements during the pauses in breathing. When there are chest movements but no passage of air through the mouth or nostrils, the disorder is known as obstructive apnea or upper airway apnea. Central apnea followed by or intermixed with an obstructive apnea is called mixed apnea. (For more information choose “apnea” as your search term in the Rare Disease Database.)
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Diagnosis of Pseudocholinesterase Deficiency
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Diagnosis of Pseudocholinesterase Deficiency.
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Therapies of Pseudocholinesterase Deficiency
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Diagnosis and TreatmentTesting can be done to determine the presence of pseudocholinesterase deficiency before surgery is performed. If the patient stops breathing for a prolonged period of time during surgery, artificial respiration (mechanical ventilation) can be administered until the patient is able to resume normal breathing.People with pseudocholinesterase deficiency should warn their relatives to be tested before surgery since this is a genetic disorder. People who have relatives who have died for unknown reasons during surgery should be screened for pseudocholinesterase deficiency prior to undergoing surgery.
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Therapies of Pseudocholinesterase Deficiency. Diagnosis and TreatmentTesting can be done to determine the presence of pseudocholinesterase deficiency before surgery is performed. If the patient stops breathing for a prolonged period of time during surgery, artificial respiration (mechanical ventilation) can be administered until the patient is able to resume normal breathing.People with pseudocholinesterase deficiency should warn their relatives to be tested before surgery since this is a genetic disorder. People who have relatives who have died for unknown reasons during surgery should be screened for pseudocholinesterase deficiency prior to undergoing surgery.
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Overview of Pseudohypoparathyroidism
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Pseudohypoparathyroidism (PHP) is a hereditary disorder characterized by an inadequate response to the parathyroid hormone, although the hormone is present in normal amounts. Parathyroid hormone controls the amounts of calcium, phosphorus and vitamin D in bones and blood. This impacts bone growth and may cause facial and skeletal deformities. Affected individuals may have short stature, a round face and unusually short fourth fingers. They may also experience headaches, unusual sensations, weakness, fatigue, lack of energy, blurred vision, abnormal sensitivity (hypersensitivity) to light, body pains and weakness, muscle twitches and spasms, and intellectual disabilities. There are multiple subtypes of PHP, which are caused by harmful changes (variants) in certain genes, one of which is GNAS1. These subtypes show some variation in symptoms, and other hormones may also be affected (growth hormone, thyroid hormone, etc.). The symptoms of pseudohypoparathyroidism are usually first noticed in childhood. Possible treatments include calcium supplements, vitamin D supplements, low phosphate diets and growth hormone therapy. People with pseudohypoparathyroidism can lead a normal life.
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Overview of Pseudohypoparathyroidism. Pseudohypoparathyroidism (PHP) is a hereditary disorder characterized by an inadequate response to the parathyroid hormone, although the hormone is present in normal amounts. Parathyroid hormone controls the amounts of calcium, phosphorus and vitamin D in bones and blood. This impacts bone growth and may cause facial and skeletal deformities. Affected individuals may have short stature, a round face and unusually short fourth fingers. They may also experience headaches, unusual sensations, weakness, fatigue, lack of energy, blurred vision, abnormal sensitivity (hypersensitivity) to light, body pains and weakness, muscle twitches and spasms, and intellectual disabilities. There are multiple subtypes of PHP, which are caused by harmful changes (variants) in certain genes, one of which is GNAS1. These subtypes show some variation in symptoms, and other hormones may also be affected (growth hormone, thyroid hormone, etc.). The symptoms of pseudohypoparathyroidism are usually first noticed in childhood. Possible treatments include calcium supplements, vitamin D supplements, low phosphate diets and growth hormone therapy. People with pseudohypoparathyroidism can lead a normal life.
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Symptoms of Pseudohypoparathyroidism
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There are two types of PHP, type 1 and type 2. Type 1 is broken into subtypes 1a, 1b, and 1c. Pseudopseudohypoparathyroidism (PPHP) is a limited form of PHP-1a, where an individual has the physical symptoms but not the hormone problems. Type 1a, type 1b, and PPHP are the most common subtypes. Both type 1 and type 2 PHP are characterized by resistance to parathyroid hormone, resulting in elevated phosphate levels and low calcium levels in the blood. The low calcium levels in the blood seen in all types of PHP may lead to childhood seizures in some individuals. Involuntary sudden movements, such as seen with paroxysmal kinesigenic dyskinesia (PKD), have also been reported in affected individuals. Beyond these shared characteristics, type 1 and type 2 differ greatly. Additional symptoms of type 1 are well-characterized while little is known about type 2. PHP type 1 results in resistance to additional endocrine hormones, including thyroid-stimulating hormone (TSH), gonadotropins (LH and FSH) and growth hormone-releasing hormone (GHRH). Resistance to these hormones results in obesity as well as delayed or incomplete development during puberty. In females, this can lead to reduced fertility, menstrual disorders or irregularities and altered levels of LH and FSH. In males, this can lead to failure of the testes to descend (cryptorchidism) and elevated LH and FSH levels. Type 1 is additionally characterized by skeletal abnormalities such as short stature, a round face, short neck and shortened bones in the hands and feet. These abnormalities are collectively referred to as Albright hereditary osteodystrophy (AHO) and vary in severity depending on the type of PHP. People with type 2 lack these physical abnormalities altogether while type 1b has only mild physical abnormalities. In some individuals with type 1, bone formation occurs in soft and connective tissue where bone does not normally exist (heterotopic ossification). This ossification can present as small, raised lesions. In both type 1 and type 2, affected individuals show variable degrees of intellectual disability and developmental delay. Headaches, weakness, tiring easily, lethargy, spinal cord compression, cataracts and blurred vision or hypersensitivity to light may also be present. Teeth tend to erupt later than normal, and enamel is underdeveloped. Affected individuals may also have crooked teeth and a poor bite.
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Symptoms of Pseudohypoparathyroidism. There are two types of PHP, type 1 and type 2. Type 1 is broken into subtypes 1a, 1b, and 1c. Pseudopseudohypoparathyroidism (PPHP) is a limited form of PHP-1a, where an individual has the physical symptoms but not the hormone problems. Type 1a, type 1b, and PPHP are the most common subtypes. Both type 1 and type 2 PHP are characterized by resistance to parathyroid hormone, resulting in elevated phosphate levels and low calcium levels in the blood. The low calcium levels in the blood seen in all types of PHP may lead to childhood seizures in some individuals. Involuntary sudden movements, such as seen with paroxysmal kinesigenic dyskinesia (PKD), have also been reported in affected individuals. Beyond these shared characteristics, type 1 and type 2 differ greatly. Additional symptoms of type 1 are well-characterized while little is known about type 2. PHP type 1 results in resistance to additional endocrine hormones, including thyroid-stimulating hormone (TSH), gonadotropins (LH and FSH) and growth hormone-releasing hormone (GHRH). Resistance to these hormones results in obesity as well as delayed or incomplete development during puberty. In females, this can lead to reduced fertility, menstrual disorders or irregularities and altered levels of LH and FSH. In males, this can lead to failure of the testes to descend (cryptorchidism) and elevated LH and FSH levels. Type 1 is additionally characterized by skeletal abnormalities such as short stature, a round face, short neck and shortened bones in the hands and feet. These abnormalities are collectively referred to as Albright hereditary osteodystrophy (AHO) and vary in severity depending on the type of PHP. People with type 2 lack these physical abnormalities altogether while type 1b has only mild physical abnormalities. In some individuals with type 1, bone formation occurs in soft and connective tissue where bone does not normally exist (heterotopic ossification). This ossification can present as small, raised lesions. In both type 1 and type 2, affected individuals show variable degrees of intellectual disability and developmental delay. Headaches, weakness, tiring easily, lethargy, spinal cord compression, cataracts and blurred vision or hypersensitivity to light may also be present. Teeth tend to erupt later than normal, and enamel is underdeveloped. Affected individuals may also have crooked teeth and a poor bite.
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Causes of Pseudohypoparathyroidism
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Pseudohypoparathyroidism is inherited as an autosomal dominant condition and caused by changes (variants) in the GNAS gene. GNAS variants have been found in about 76% percent of affected individuals, with 38% of those individuals having an affected parent. In the remaining individuals, the cause is unknown.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.PHP is a sex-influenced trait, meaning the symptoms seen in an individual vary depending on whether the affected gene is maternal or paternal. Maternal inheritance often results in PHP while paternal inheritance would lead to the physical symptoms but not the hormonal issues (PPHP).The changes in the GNAS gene seen that cause PHP vary, but overall, these changes have been associated with reduced or absent expression of the alpha subunit of G-proteins. These proteins are involved in cellular messaging in the body. In addition to GNAS, a nearby gene STX16 has been associated with some forms of the disorder. Other genes that may be associated with pseudohypoparathyroidism include PRKAR1A, PDE4D and PDE3A.
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Causes of Pseudohypoparathyroidism. Pseudohypoparathyroidism is inherited as an autosomal dominant condition and caused by changes (variants) in the GNAS gene. GNAS variants have been found in about 76% percent of affected individuals, with 38% of those individuals having an affected parent. In the remaining individuals, the cause is unknown.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.PHP is a sex-influenced trait, meaning the symptoms seen in an individual vary depending on whether the affected gene is maternal or paternal. Maternal inheritance often results in PHP while paternal inheritance would lead to the physical symptoms but not the hormonal issues (PPHP).The changes in the GNAS gene seen that cause PHP vary, but overall, these changes have been associated with reduced or absent expression of the alpha subunit of G-proteins. These proteins are involved in cellular messaging in the body. In addition to GNAS, a nearby gene STX16 has been associated with some forms of the disorder. Other genes that may be associated with pseudohypoparathyroidism include PRKAR1A, PDE4D and PDE3A.
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Affects of Pseudohypoparathyroidism
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PHP is a rare disorder that affects both males and females. The prevalence of PHP and AHO has been estimated to be 0.79 per 100,000 individuals.
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Affects of Pseudohypoparathyroidism. PHP is a rare disorder that affects both males and females. The prevalence of PHP and AHO has been estimated to be 0.79 per 100,000 individuals.
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Related disorders of Pseudohypoparathyroidism
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Symptoms of the following disorders can be similar to those of PHP. Comparisons may be useful for a differential diagnosis:Turner syndrome is a rare chromosomal disorder that affects females. The disorder is characterized by partial or complete loss (monosomy) of one of the second sex chromosomes. Turner syndrome is highly variable and can differ dramatically from one person to another. Affected females can potentially develop a wide variety of symptoms, affecting many different organ systems. Common symptoms include short stature and premature ovarian failure, which can result in the failure to attain puberty. (For more information, choose “Turner” as your search term in the Rare Disease Database.)McCune-Albright syndrome is a genetic disorder that is caused by a harmful variant in the GNAS gene. Affected individuals often display growth of scar-like tissue where bone should be (fibrous dysplasia), colored areas of skin (café au lait macules) with irregular borders, the endocrine system is overactive (autonomous endocrine function), with early puberty, excess thyroid hormone (thyrotoxicosis), growth hormone excess before fusion of growth plates (pituitary gigantism), and Cushing syndrome. (For more information, choose “McCune-Albright syndrome” as your search term in the Rare Disease Database.) 2q37 deletion syndrome is a genetic disorder that results from a missing piece of chromosome 2 that involves the HDAC4 gene. Symptoms of this disorder include mild to moderate developmental delay and/or intellectual disability, short fingers and toes (brachydactyly) in the third to fifth digits, short stature, obesity, decreased muscle tone (hypotonia), round face, behavioral abnormalities, joint hypermobility/dislocation and scoliosis. However, individuals with this disorder have normal endocrine function. Idiopathic or primary hypoparathyroidism is a disorder in which individuals have abnormally low parathyroid functions due to complete (aplasia) or partial (hypoplasia) lack of the parathyroid gland or due to some type of autoimmune damage. Symptoms of this disorder include cramping and twitching of muscles (tetany), abnormal sensations of tingling or pricking (paresthesias), fatigue, abdominal pain, low blood parathyroid hormone and calcium levels and high blood phosphorus levels.Kenny-Caffey syndrome is a genetic disorder that can be inherited in an autosomal dominant or autosomal recessive manner. Harmful changes to the FAM111A gene lead to the autosomal dominant form, and harmful changes to the TBCE gene lead to the autosomal recessive form. Symptoms of this disorder include proportionate short stature, cortical thickening and medullary stenosis of tubule bones, delayed closure of the anterior fontanelle (the space between skull bones on the top/front of an infant’s head), and low blood calcium levels due to hypoparathyroidism. However, afflicted individuals have normal intelligence.Type E brachydactyly is a genetic disorder that is caused by harmful variants in the HOXD13 or PTHLH genes. Symptoms of this disorder include short toes and occasionally finger bones (brachydactyly), moderately short stature, and round faces. However, individuals with this disorder do not display ectopic ossification or intellectual disability. Acrodysostosis is a genetic disorder due to harmful variants in PRKAR1A and PDE4D genes. Symptoms include short stature, short fingers and toes (brachydactyly), round face, abnormally small fetal nose bone (nasal hypoplasia), advanced bone age and obesity. Individuals with this disorder may also show resistance to various hormones such as the parathyroid hormone, thyroid-stimulating hormone, calcitonin, growth hormone-releasing hormone and gonadotropins.
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Related disorders of Pseudohypoparathyroidism. Symptoms of the following disorders can be similar to those of PHP. Comparisons may be useful for a differential diagnosis:Turner syndrome is a rare chromosomal disorder that affects females. The disorder is characterized by partial or complete loss (monosomy) of one of the second sex chromosomes. Turner syndrome is highly variable and can differ dramatically from one person to another. Affected females can potentially develop a wide variety of symptoms, affecting many different organ systems. Common symptoms include short stature and premature ovarian failure, which can result in the failure to attain puberty. (For more information, choose “Turner” as your search term in the Rare Disease Database.)McCune-Albright syndrome is a genetic disorder that is caused by a harmful variant in the GNAS gene. Affected individuals often display growth of scar-like tissue where bone should be (fibrous dysplasia), colored areas of skin (café au lait macules) with irregular borders, the endocrine system is overactive (autonomous endocrine function), with early puberty, excess thyroid hormone (thyrotoxicosis), growth hormone excess before fusion of growth plates (pituitary gigantism), and Cushing syndrome. (For more information, choose “McCune-Albright syndrome” as your search term in the Rare Disease Database.) 2q37 deletion syndrome is a genetic disorder that results from a missing piece of chromosome 2 that involves the HDAC4 gene. Symptoms of this disorder include mild to moderate developmental delay and/or intellectual disability, short fingers and toes (brachydactyly) in the third to fifth digits, short stature, obesity, decreased muscle tone (hypotonia), round face, behavioral abnormalities, joint hypermobility/dislocation and scoliosis. However, individuals with this disorder have normal endocrine function. Idiopathic or primary hypoparathyroidism is a disorder in which individuals have abnormally low parathyroid functions due to complete (aplasia) or partial (hypoplasia) lack of the parathyroid gland or due to some type of autoimmune damage. Symptoms of this disorder include cramping and twitching of muscles (tetany), abnormal sensations of tingling or pricking (paresthesias), fatigue, abdominal pain, low blood parathyroid hormone and calcium levels and high blood phosphorus levels.Kenny-Caffey syndrome is a genetic disorder that can be inherited in an autosomal dominant or autosomal recessive manner. Harmful changes to the FAM111A gene lead to the autosomal dominant form, and harmful changes to the TBCE gene lead to the autosomal recessive form. Symptoms of this disorder include proportionate short stature, cortical thickening and medullary stenosis of tubule bones, delayed closure of the anterior fontanelle (the space between skull bones on the top/front of an infant’s head), and low blood calcium levels due to hypoparathyroidism. However, afflicted individuals have normal intelligence.Type E brachydactyly is a genetic disorder that is caused by harmful variants in the HOXD13 or PTHLH genes. Symptoms of this disorder include short toes and occasionally finger bones (brachydactyly), moderately short stature, and round faces. However, individuals with this disorder do not display ectopic ossification or intellectual disability. Acrodysostosis is a genetic disorder due to harmful variants in PRKAR1A and PDE4D genes. Symptoms include short stature, short fingers and toes (brachydactyly), round face, abnormally small fetal nose bone (nasal hypoplasia), advanced bone age and obesity. Individuals with this disorder may also show resistance to various hormones such as the parathyroid hormone, thyroid-stimulating hormone, calcitonin, growth hormone-releasing hormone and gonadotropins.
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Diagnosis of Pseudohypoparathyroidism
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Blood and urine tests can be used to measure the calcium, phosphorus and parathyroid hormone levels in the body. High levels of parathyroid hormone and phosphorus with low calcium levels suggests that pseudohypoparathyroidism is a possible diagnosis. Subtypes of the disorder that do not involve hormone resistance, like PPHP, cannot be detected using these lab tests. Diagnosis can be confirmed by using genetic testing to look for mutations in the GNAS1 gene.
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Diagnosis of Pseudohypoparathyroidism. Blood and urine tests can be used to measure the calcium, phosphorus and parathyroid hormone levels in the body. High levels of parathyroid hormone and phosphorus with low calcium levels suggests that pseudohypoparathyroidism is a possible diagnosis. Subtypes of the disorder that do not involve hormone resistance, like PPHP, cannot be detected using these lab tests. Diagnosis can be confirmed by using genetic testing to look for mutations in the GNAS1 gene.
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Therapies of Pseudohypoparathyroidism
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Treatment of pseudohypoparathyroidism should aim to bring calcium and phosphorus levels into the normal range. This can be achieved using calcium supplements and vitamin D supplements, which promote reabsorption of calcium in the kidneys. Low-phosphate diets or medications that bind phosphate may be used to reduce the effects of high phosphorus levels. Growth hormone therapy may also be used to improve height. Bone ossifications can be removed surgically, if necessary. In the case of other skeletal abnormalities that cause spinal cord compression, surgical outcomes have been poor. Obesity can be treated with usual methods such as increased exercise and reduced caloric intake. Other symptoms should be treated on a more individualized basis.
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Therapies of Pseudohypoparathyroidism. Treatment of pseudohypoparathyroidism should aim to bring calcium and phosphorus levels into the normal range. This can be achieved using calcium supplements and vitamin D supplements, which promote reabsorption of calcium in the kidneys. Low-phosphate diets or medications that bind phosphate may be used to reduce the effects of high phosphorus levels. Growth hormone therapy may also be used to improve height. Bone ossifications can be removed surgically, if necessary. In the case of other skeletal abnormalities that cause spinal cord compression, surgical outcomes have been poor. Obesity can be treated with usual methods such as increased exercise and reduced caloric intake. Other symptoms should be treated on a more individualized basis.
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Overview of Pseudomyxoma Peritonei
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Pseudomyxoma peritonei is a rare malignant growth characterized by the progressive accumulation of mucus-secreting (mucinous) tumor cells within the abdomen and pelvis. The disorder develops after a small growth (polyp) located within the appendix bursts through the wall of the appendix, and spreads mucus-producing tumor cells throughout the surrounding surfaces (e.g., the membrane that lines the abdominal cavity [peritoneum]). As mucinous tumor cells accumulate, the abdominal area becomes swollen and digestive (gastrointestinal) function becomes impaired. Pseudomyxoma peritonei develops at a variable rate, but may grow at a slower rate (indolent) than other malignancies within the abdomen.
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Overview of Pseudomyxoma Peritonei. Pseudomyxoma peritonei is a rare malignant growth characterized by the progressive accumulation of mucus-secreting (mucinous) tumor cells within the abdomen and pelvis. The disorder develops after a small growth (polyp) located within the appendix bursts through the wall of the appendix, and spreads mucus-producing tumor cells throughout the surrounding surfaces (e.g., the membrane that lines the abdominal cavity [peritoneum]). As mucinous tumor cells accumulate, the abdominal area becomes swollen and digestive (gastrointestinal) function becomes impaired. Pseudomyxoma peritonei develops at a variable rate, but may grow at a slower rate (indolent) than other malignancies within the abdomen.
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Symptoms of Pseudomyxoma Peritonei
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The most common symptoms in individuals with pseudomyxoma peritonei occur due to progressively increasing mucinous tumor within the abdomen and pelvis. Usually, the most common symptom is increasing abdominal size (so called “jelly belly”) and abdominal discomfort from pressure. Although the abdomen may be swollen, it is generally not painful to touch (palpation). In affected males, the second most common finding is protrusion of parts of the intestines through an abnormal opening in the muscular wall of the abdomen near the groin (inguinal hernia). In affected females, the second most common finding is usually an abnormally enlarged ovary. The mucinous tumor seems to grow rapidly within ovarian tissue.The mucinous tumor accumulates within the fatty membrane in front of the intestines (greater omentum), beneath the muscle that separates the chest from the abdomen (diaphragm), and within the pelvis. In most cases, the small bowel is unaffected. Frequently, the primary tumor that ruptured the appendix may be small in comparison to the extensive mucinous tumor that develops within the abdomen and pelvis. Without appropriate treatment intervention, this disorder will result in obstruction of the intestines or the loss of intestinal function. Progressive mucinous tumor accumulation can result in poor food intake, malnutrition, and, eventually, life-threatening complications.
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Symptoms of Pseudomyxoma Peritonei. The most common symptoms in individuals with pseudomyxoma peritonei occur due to progressively increasing mucinous tumor within the abdomen and pelvis. Usually, the most common symptom is increasing abdominal size (so called “jelly belly”) and abdominal discomfort from pressure. Although the abdomen may be swollen, it is generally not painful to touch (palpation). In affected males, the second most common finding is protrusion of parts of the intestines through an abnormal opening in the muscular wall of the abdomen near the groin (inguinal hernia). In affected females, the second most common finding is usually an abnormally enlarged ovary. The mucinous tumor seems to grow rapidly within ovarian tissue.The mucinous tumor accumulates within the fatty membrane in front of the intestines (greater omentum), beneath the muscle that separates the chest from the abdomen (diaphragm), and within the pelvis. In most cases, the small bowel is unaffected. Frequently, the primary tumor that ruptured the appendix may be small in comparison to the extensive mucinous tumor that develops within the abdomen and pelvis. Without appropriate treatment intervention, this disorder will result in obstruction of the intestines or the loss of intestinal function. Progressive mucinous tumor accumulation can result in poor food intake, malnutrition, and, eventually, life-threatening complications.
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Causes of Pseudomyxoma Peritonei
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As with a great majority of tumors the exact cause of pseudomyxoma peritonei is not known. There are no genetic, familial, or environmental factors known to cause this disorder.Pseudomyxoma peritonei develops from a hole (perforation) in the appendix that is caused by the penetration of a small growth (polyp) located within the appendix. The tumor cells from the appendix spread (migrate) within the abdominal and pelvic cavity to characteristic locations. Once they reach these locations, tumor cells continue to grow. Characteristic locations for tumor cell growth are within the fatty membrane in front of the intestines (greater omentum), beneath the muscle that separates the chest from the abdomen (diaphragm), and within the pelvis. In females, there may be excessive growth on both ovaries.
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Causes of Pseudomyxoma Peritonei. As with a great majority of tumors the exact cause of pseudomyxoma peritonei is not known. There are no genetic, familial, or environmental factors known to cause this disorder.Pseudomyxoma peritonei develops from a hole (perforation) in the appendix that is caused by the penetration of a small growth (polyp) located within the appendix. The tumor cells from the appendix spread (migrate) within the abdominal and pelvic cavity to characteristic locations. Once they reach these locations, tumor cells continue to grow. Characteristic locations for tumor cell growth are within the fatty membrane in front of the intestines (greater omentum), beneath the muscle that separates the chest from the abdomen (diaphragm), and within the pelvis. In females, there may be excessive growth on both ovaries.
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Affects of Pseudomyxoma Peritonei
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Pseudomyxoma peritonei is a very rare disorder with approximately 2 cases per million individuals. Males and females are affected in equal numbers. It is a misconception that females develop this disorder more frequently than males. However, this misconception occurs because some ovarian tumors are frequently mistakenly identified as pseudomyxoma ovarii.The average age of onset of pseudomyxoma peritonei is 48 years, which is considerably earlier than other malignancies that occur within the abdomen.
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Affects of Pseudomyxoma Peritonei. Pseudomyxoma peritonei is a very rare disorder with approximately 2 cases per million individuals. Males and females are affected in equal numbers. It is a misconception that females develop this disorder more frequently than males. However, this misconception occurs because some ovarian tumors are frequently mistakenly identified as pseudomyxoma ovarii.The average age of onset of pseudomyxoma peritonei is 48 years, which is considerably earlier than other malignancies that occur within the abdomen.
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Related disorders of Pseudomyxoma Peritonei
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Symptoms of the following disorders can be similar to those of pseudomyxoma peritonei. Comparisons may be useful for a differential diagnosis:An ovarian malignancy known as low malignant potential ovarian tumor may look similar to pseudomyxoma peritonei. However, this tumor remains as a solitary, expanding ovarian mass. It does not distribute itself around the abdomen, and should be distinguishable from pseudomyxoma peritonei. Symptoms may include abdominal or lower back pain. The exact cause of low malignant potential ovarian tumor is not known.Mucinous cancers of the ovary, colon, stomach, and gallbladder may produce an excess of mucous in the abdominal cavity. These cancers are usually much more aggressive than the mucinous tumor from the appendix. They result in rapidly progressing accumulation of mucous in the abdominal region and intestinal obstruction. The exact cause of these tumors is not known.Adenocarcinoid (goblet cell carcinoid) of the appendix is similar to pseudomyxoma peritonei. The mucinous tumor from the adenocarcinoid distributes itself around the abdomen in a very similar fashion to pseudomyxoma peritonei. However, this tumor is much more aggressive than the tumor in pseudomyxoma peritonei. Symptoms of this type of cancer often resemble those of acute appendicitis. The exact cause of adenocarcinoid of the appendix is not known.Mesothelioma is a rare form of cancer that affects the membrane that covers and protects various internal organs of the body (peritoneum). The mesothelium is composed of two layers of specialized cells known as mesothelial cells. One layer directly surrounds all of the intraabdominal organs (visceral peritoneum); the other forms a protective sac surrounding the entire abdomen and pelvis (parietal peritoneum). The most common form of mesothelioma affects the membrane or sac that lines the lungs (pleura). Other common sites include the membrane lining the stomach, small bowel and large bowel (peritoneum) and the membrane lining the heart (pericardium). Mesotheliomas may result in a mucinous tumor accumulation within the abdomen that is very difficult to distinguish from pseudomyxoma peritonei. Symptoms of mesothelioma vary depending upon the location, type and stage of the cancer. Approximately 80 percent of cases of mesothelioma result from exposure to asbestos. Symptoms of mesothelioma may not appear until up to 50 years after initial exposure to asbestos. However, after symptoms become apparent, mesothelioma may rapidly progress to cause life-threatening complications. (For more information on this disorder, choose “mesothelioma” as your search term in the Rare Disease Database.)Appendicitis is an acute inflammation of the appendix. It is characterized by abdominal pain and inflammation of the lining of the abdominal cavity (appendicitis). The first sign of this condition is an unusual slight discomfort around the navel. Pain typically becomes more intense and localize near the lower right-hand side of the abdomen. Other symptoms of appendicitis may include fever, loss of appetite, vomiting, and abdomen tenderness.
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Related disorders of Pseudomyxoma Peritonei. Symptoms of the following disorders can be similar to those of pseudomyxoma peritonei. Comparisons may be useful for a differential diagnosis:An ovarian malignancy known as low malignant potential ovarian tumor may look similar to pseudomyxoma peritonei. However, this tumor remains as a solitary, expanding ovarian mass. It does not distribute itself around the abdomen, and should be distinguishable from pseudomyxoma peritonei. Symptoms may include abdominal or lower back pain. The exact cause of low malignant potential ovarian tumor is not known.Mucinous cancers of the ovary, colon, stomach, and gallbladder may produce an excess of mucous in the abdominal cavity. These cancers are usually much more aggressive than the mucinous tumor from the appendix. They result in rapidly progressing accumulation of mucous in the abdominal region and intestinal obstruction. The exact cause of these tumors is not known.Adenocarcinoid (goblet cell carcinoid) of the appendix is similar to pseudomyxoma peritonei. The mucinous tumor from the adenocarcinoid distributes itself around the abdomen in a very similar fashion to pseudomyxoma peritonei. However, this tumor is much more aggressive than the tumor in pseudomyxoma peritonei. Symptoms of this type of cancer often resemble those of acute appendicitis. The exact cause of adenocarcinoid of the appendix is not known.Mesothelioma is a rare form of cancer that affects the membrane that covers and protects various internal organs of the body (peritoneum). The mesothelium is composed of two layers of specialized cells known as mesothelial cells. One layer directly surrounds all of the intraabdominal organs (visceral peritoneum); the other forms a protective sac surrounding the entire abdomen and pelvis (parietal peritoneum). The most common form of mesothelioma affects the membrane or sac that lines the lungs (pleura). Other common sites include the membrane lining the stomach, small bowel and large bowel (peritoneum) and the membrane lining the heart (pericardium). Mesotheliomas may result in a mucinous tumor accumulation within the abdomen that is very difficult to distinguish from pseudomyxoma peritonei. Symptoms of mesothelioma vary depending upon the location, type and stage of the cancer. Approximately 80 percent of cases of mesothelioma result from exposure to asbestos. Symptoms of mesothelioma may not appear until up to 50 years after initial exposure to asbestos. However, after symptoms become apparent, mesothelioma may rapidly progress to cause life-threatening complications. (For more information on this disorder, choose “mesothelioma” as your search term in the Rare Disease Database.)Appendicitis is an acute inflammation of the appendix. It is characterized by abdominal pain and inflammation of the lining of the abdominal cavity (appendicitis). The first sign of this condition is an unusual slight discomfort around the navel. Pain typically becomes more intense and localize near the lower right-hand side of the abdomen. Other symptoms of appendicitis may include fever, loss of appetite, vomiting, and abdomen tenderness.
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Diagnosis of Pseudomyxoma Peritonei
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The diagnosis of pseudomyxoma peritonei may be confirmed by radiologic technologies such as abdominal CT scan or abdominal MRI (magnetic resonance imaging). These imaging tests may reveal the characteristic distribution of large amounts of mucus to particular locations within the abdomen and pelvis. They may also localize a primary tumor in the area of the appendix referred to as a mucocele.
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Diagnosis of Pseudomyxoma Peritonei. The diagnosis of pseudomyxoma peritonei may be confirmed by radiologic technologies such as abdominal CT scan or abdominal MRI (magnetic resonance imaging). These imaging tests may reveal the characteristic distribution of large amounts of mucus to particular locations within the abdomen and pelvis. They may also localize a primary tumor in the area of the appendix referred to as a mucocele.
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Therapies of Pseudomyxoma Peritonei
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The goal of the treatment of pseudomyxoma peritonei is cure. This is achieved in approximately 65% of patients. The treatments are cytoreductive surgery with peritonectomy in an attempt to remove all visible evidence of the disease from the abdomen and pelvis. Because the mucinous tumor is so widely distributed throughout the abdomen and pelvis, the surgery may take up to 12 hours. Then, to prevent reimplantation of cancer cells, the abdomen is washed with a warm chemotherapy solution. This is commonly referred to hyperthermic intraperitoneal chemotherapy or HIPEC. Sometimes the surgeon must search carefully for the primary appendiceal tumor for it may be very small in comparison to the mucinous tumor and mucinous ascites that can accumulate in kilogram quantities within the abdomen and pelvis. The hyperthermic intraperitoneal drugs which are commonly used to treat this disease include mitomycin C and oxaliplatin. The chemotherapy is heated to 42 degrees in the abdominal cavity to increase penetration of the drugs into the mucinous tumor and to increase the local cytotoxicity.
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Therapies of Pseudomyxoma Peritonei. The goal of the treatment of pseudomyxoma peritonei is cure. This is achieved in approximately 65% of patients. The treatments are cytoreductive surgery with peritonectomy in an attempt to remove all visible evidence of the disease from the abdomen and pelvis. Because the mucinous tumor is so widely distributed throughout the abdomen and pelvis, the surgery may take up to 12 hours. Then, to prevent reimplantation of cancer cells, the abdomen is washed with a warm chemotherapy solution. This is commonly referred to hyperthermic intraperitoneal chemotherapy or HIPEC. Sometimes the surgeon must search carefully for the primary appendiceal tumor for it may be very small in comparison to the mucinous tumor and mucinous ascites that can accumulate in kilogram quantities within the abdomen and pelvis. The hyperthermic intraperitoneal drugs which are commonly used to treat this disease include mitomycin C and oxaliplatin. The chemotherapy is heated to 42 degrees in the abdominal cavity to increase penetration of the drugs into the mucinous tumor and to increase the local cytotoxicity.
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Overview of Pseudoxanthoma Elasticum
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Pseudoxanthoma elasticum (PXE) is an inherited disorder caused by mutations in the ABCC6 transporter gene that affects connective tissue in some parts of the body. Elastic tissue in the body becomes mineralized; that is, calcium is deposited in the tissue. This can result in changes in the skin, eyes, cardiovascular system, and gastrointestinal system. Clinicians first recognized PXE more than 100 years ago. Researchers have made a number of significant advances in the past few years.
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Overview of Pseudoxanthoma Elasticum. Pseudoxanthoma elasticum (PXE) is an inherited disorder caused by mutations in the ABCC6 transporter gene that affects connective tissue in some parts of the body. Elastic tissue in the body becomes mineralized; that is, calcium is deposited in the tissue. This can result in changes in the skin, eyes, cardiovascular system, and gastrointestinal system. Clinicians first recognized PXE more than 100 years ago. Researchers have made a number of significant advances in the past few years.
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Symptoms of Pseudoxanthoma Elasticum
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PXE results in a variety of signs and symptoms that vary in their number, type, and severity from person to person. Certain effects of PXE can cause serious medical problems, while others have less impact. Effects may include: skin changes, changes in the retina of the eye that may result in significant loss of central vision, changes in the cardiovascular system that may involve calcification of arteries and decreased blood flow in the arms and legs, and/or changes in the gastrointestinal system that may lead to bleeding in the stomach or intestines. At present, there is no way to predict the exact progression of the disorder for a particular individual. Some people have no skin lesions; others have no vision loss. Many people do not experience gastrointestinal complications or cardiovascular difficulties. A few have no manifestations of PXE except for a positive skin biopsy or irregular streaks resembling a blood vessel (angioid) in the retina of the eye. The effects of PXE and its rate of progression seem to have no discernible pattern.Skin: PXE often causes visible changes in the skin. These changes vary from person to person. The earliest changes tend to be in the skin on the sides of one’s neck. Small lesions may develop. They may resemble a rash or have a “cobblestone” appearance. These lesions in the skin tend to progress slowly and unpredictably from the neck downward. Skin changes have often been reported in young children. The areas of the body that are most affected are those that bend and flex. The neck, the underarms, the skin on the inside of the elbows, the groin, and the skin behind the knees may be progressively affected, leading to loose folds in these areas. Lesions may appear on the inside of the lower lip or lining of the rectum or vagina. Some of these effects may be alleviated by reconstructive, or plastic, surgery.It is possible to have PXE and not have any apparent skin lesions. In some individuals, careful examination of the skin by a dermatologist does not reveal any visible sign of lesions, but a positive biopsy indicates the diagnosis of PXE. Since the identification of mutations in the ABCC6 transporter gene as the cause of PXE, analysis of blood can be performed in research centers to confirm the presence or absence of mutations.Eyes: PXE affects the retina of the eye. The first changes, visible only during an ophthalmologic examination, are called “peau d’orange” because the retina begins to resemble the skin of an orange. This does not affect vision and neither do characteristic irregular streaks, called angioid streaks that develop later. These streaks occur when mineralization of the highly elastic membrane behind the retina, called Bruch’s membrane, leads to cracking. Small blood vessels beneath this layer take advantage of these breaks in the membrane and grow through the membrane. This is called neovascularization. Sometimes, these blood vessels leak and bleed. This bleeding results in the loss of central vision. While people with PXE may lose so much vision that they become legally blind, almost all people with PXE continue to have peripheral vision.People who have PXE can use a tool called an Amsler grid to monitor their central vision. If there is swelling or bleeding in the center of the retina, this may cause the intersecting lines of the Amsler grid to appear distorted. A retinal specialist can instruct a patient in the use of an Amsler grid.Cardiovascular system: Because PXE can cause mineralization and narrowing of blood vessels, affected individuals may experience cramping in the legs when they are walking, due to decreased blood flow. This decreased flow of blood is called intermittent claudication. Decreased flow of blood to the arms and legs may mean that one’s pulse can no longer be felt in the wrists or feet. Some clinicians believe that high blood pressure (hypertension) and mitral valve prolapse may be more common among people with PXE than in the general population. Individuals with PXE should make periodic visits to their physician for monitoring of blood pressure, cholesterol, and pulses in the arms and legs. A heart-healthy lifestyle is recommended, with low-fat foods and plenty of exercise. Consistent exercise may decrease the effects of PXE on the blood vessels. Maintaining normal weight may also be beneficial. Smoking should be avoided.Gastrointestinal system: Uncommonly, PXE may cause gastrointestinal bleeding. This is sometimes not recognized immediately and can be life-threatening. Little is known about the gastrointestinal effects of PXE, except that the bleeding is usually widespread in the stomach and/or intestines. In a few patients, this bleeding has been mistaken for ulcers. A person with PXE experiencing any gastrointestinal difficulty should be sure to tell the attending physician that he or she has PXE. Some physicians recommend that affected individuals avoid non-steroidal, anti-inflammatory medications, such as aspirin, ibuprofen, and naproxen.Pregnancy: It is thought that most women with PXE have normal pregnancies and that the incidence of pregnancy-related complications is similar to that of the general population. However, for some, gastric or intestinal complications have been reported. In general, complications affecting the fetus have not been reported. There are no prenatal tests to determine whether the fetus has PXE.
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Symptoms of Pseudoxanthoma Elasticum. PXE results in a variety of signs and symptoms that vary in their number, type, and severity from person to person. Certain effects of PXE can cause serious medical problems, while others have less impact. Effects may include: skin changes, changes in the retina of the eye that may result in significant loss of central vision, changes in the cardiovascular system that may involve calcification of arteries and decreased blood flow in the arms and legs, and/or changes in the gastrointestinal system that may lead to bleeding in the stomach or intestines. At present, there is no way to predict the exact progression of the disorder for a particular individual. Some people have no skin lesions; others have no vision loss. Many people do not experience gastrointestinal complications or cardiovascular difficulties. A few have no manifestations of PXE except for a positive skin biopsy or irregular streaks resembling a blood vessel (angioid) in the retina of the eye. The effects of PXE and its rate of progression seem to have no discernible pattern.Skin: PXE often causes visible changes in the skin. These changes vary from person to person. The earliest changes tend to be in the skin on the sides of one’s neck. Small lesions may develop. They may resemble a rash or have a “cobblestone” appearance. These lesions in the skin tend to progress slowly and unpredictably from the neck downward. Skin changes have often been reported in young children. The areas of the body that are most affected are those that bend and flex. The neck, the underarms, the skin on the inside of the elbows, the groin, and the skin behind the knees may be progressively affected, leading to loose folds in these areas. Lesions may appear on the inside of the lower lip or lining of the rectum or vagina. Some of these effects may be alleviated by reconstructive, or plastic, surgery.It is possible to have PXE and not have any apparent skin lesions. In some individuals, careful examination of the skin by a dermatologist does not reveal any visible sign of lesions, but a positive biopsy indicates the diagnosis of PXE. Since the identification of mutations in the ABCC6 transporter gene as the cause of PXE, analysis of blood can be performed in research centers to confirm the presence or absence of mutations.Eyes: PXE affects the retina of the eye. The first changes, visible only during an ophthalmologic examination, are called “peau d’orange” because the retina begins to resemble the skin of an orange. This does not affect vision and neither do characteristic irregular streaks, called angioid streaks that develop later. These streaks occur when mineralization of the highly elastic membrane behind the retina, called Bruch’s membrane, leads to cracking. Small blood vessels beneath this layer take advantage of these breaks in the membrane and grow through the membrane. This is called neovascularization. Sometimes, these blood vessels leak and bleed. This bleeding results in the loss of central vision. While people with PXE may lose so much vision that they become legally blind, almost all people with PXE continue to have peripheral vision.People who have PXE can use a tool called an Amsler grid to monitor their central vision. If there is swelling or bleeding in the center of the retina, this may cause the intersecting lines of the Amsler grid to appear distorted. A retinal specialist can instruct a patient in the use of an Amsler grid.Cardiovascular system: Because PXE can cause mineralization and narrowing of blood vessels, affected individuals may experience cramping in the legs when they are walking, due to decreased blood flow. This decreased flow of blood is called intermittent claudication. Decreased flow of blood to the arms and legs may mean that one’s pulse can no longer be felt in the wrists or feet. Some clinicians believe that high blood pressure (hypertension) and mitral valve prolapse may be more common among people with PXE than in the general population. Individuals with PXE should make periodic visits to their physician for monitoring of blood pressure, cholesterol, and pulses in the arms and legs. A heart-healthy lifestyle is recommended, with low-fat foods and plenty of exercise. Consistent exercise may decrease the effects of PXE on the blood vessels. Maintaining normal weight may also be beneficial. Smoking should be avoided.Gastrointestinal system: Uncommonly, PXE may cause gastrointestinal bleeding. This is sometimes not recognized immediately and can be life-threatening. Little is known about the gastrointestinal effects of PXE, except that the bleeding is usually widespread in the stomach and/or intestines. In a few patients, this bleeding has been mistaken for ulcers. A person with PXE experiencing any gastrointestinal difficulty should be sure to tell the attending physician that he or she has PXE. Some physicians recommend that affected individuals avoid non-steroidal, anti-inflammatory medications, such as aspirin, ibuprofen, and naproxen.Pregnancy: It is thought that most women with PXE have normal pregnancies and that the incidence of pregnancy-related complications is similar to that of the general population. However, for some, gastric or intestinal complications have been reported. In general, complications affecting the fetus have not been reported. There are no prenatal tests to determine whether the fetus has PXE.
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Causes of Pseudoxanthoma Elasticum
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PXE is an inherited disorder caused by changes (mutations) in the ABCC6 transporter gene. ABCC6 is one of a group of genes that transport certain molecules back and forth across cell membranes. It isn’t known at this time what molecules ABCC6 transports, but it is thought that they may play a role in keeping the elastic fibers found in certain body tissues healthy.PXE is inherited in a recessive pattern. Recessive genetic disorders occur when an individual inherits an abnormal gene from each parent. If an individual receives one normal gene and one abnormal gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the abnormal gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. In some instances, autosomal dominant inheritance has been reported in patients with PXE, but it is not clear if the dominant pattern is truly dominant or if it has been reported because, by chance, one parent is an asymptomatic carrier of a mutated ABCC6 gene while the second parent has the disorder.Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.Since PXE may be present but undiagnosed in other family members, it is recommended that all immediate relatives be screened for PXE by both an ophthalmologist and a dermatologist. The ophthalmologist should look for peau d’orange and angioid streaks. If suspicious for PXE, the dermatologist should take biopsies from the neck, under the arm and inside the elbow of a person suspected of having PXE. These biopsies may be necessary even if the skin doesn’t show any visible lesions. Even with a negative biopsy, it is possible that other family members have PXE. PXE affects each individual with great variability. A blood test is available to determine whether a person carries the gene.
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Causes of Pseudoxanthoma Elasticum. PXE is an inherited disorder caused by changes (mutations) in the ABCC6 transporter gene. ABCC6 is one of a group of genes that transport certain molecules back and forth across cell membranes. It isn’t known at this time what molecules ABCC6 transports, but it is thought that they may play a role in keeping the elastic fibers found in certain body tissues healthy.PXE is inherited in a recessive pattern. Recessive genetic disorders occur when an individual inherits an abnormal gene from each parent. If an individual receives one normal gene and one abnormal gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the abnormal gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. In some instances, autosomal dominant inheritance has been reported in patients with PXE, but it is not clear if the dominant pattern is truly dominant or if it has been reported because, by chance, one parent is an asymptomatic carrier of a mutated ABCC6 gene while the second parent has the disorder.Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.Since PXE may be present but undiagnosed in other family members, it is recommended that all immediate relatives be screened for PXE by both an ophthalmologist and a dermatologist. The ophthalmologist should look for peau d’orange and angioid streaks. If suspicious for PXE, the dermatologist should take biopsies from the neck, under the arm and inside the elbow of a person suspected of having PXE. These biopsies may be necessary even if the skin doesn’t show any visible lesions. Even with a negative biopsy, it is possible that other family members have PXE. PXE affects each individual with great variability. A blood test is available to determine whether a person carries the gene.
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Affects of Pseudoxanthoma Elasticum
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Estimates of the incidence of PXE range from 1 in 100,000 people to 1 in 25,000. However, the true incidence of PXE is not known in any population. It is likely that many individuals with PXE have not been diagnosed, particularly people with mild signs of PXE or those whose signs are not typical.
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Affects of Pseudoxanthoma Elasticum. Estimates of the incidence of PXE range from 1 in 100,000 people to 1 in 25,000. However, the true incidence of PXE is not known in any population. It is likely that many individuals with PXE have not been diagnosed, particularly people with mild signs of PXE or those whose signs are not typical.
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Related disorders of Pseudoxanthoma Elasticum
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Symptoms of the following disorders may be similar to those of Pseudoxanthoma Elasticum. Comparisons may be useful for a differential diagnosis:Ehlers-Danlos syndrome is a rare inherited connective tissue disorder. It is characterized by the ability of affected individuals to flex their bodies beyond the normal range (articular hypermobility), to abnormally stretch their skin (hyperelasticity of the skin), and widespread tissue fragility (i.e., skin, blood vessels, and other tissues can rupture from even minor trauma). Many forms of Ehlers-Danlos Syndrome are inherited as an autosomal dominant genetic trait, but some forms of the disorder are inherited as either an autosomal recessive or an X-linked recessive genetic trait. (For more information on this disorder, choose “Ehlers-Danlos” as your search term in the Rare Disease Database).Marfan syndrome is an inherited disorder that affects the connective tissues of the heart and blood vessels (cardiovascular system). The musculoskeletal system (ligaments and muscles) is also affected. Major symptoms also include unusual height, large hands and feet, and involvement of the lungs and the eyes. (For more information on this disorder, choose “Marfan” as your search term in the Rare Disease Database).Other disorders may be characterized by the development of angioid streaks (e.g., sickle cell disease, hemochromatosis, etc.). There are also additional disorders that may have skin changes similar to those associated with PXE (e.g., solar elastosis, etc.). These disorders usually have other physical and microscopic features that may differentiate them from PXE. (For more information on these disorders, choose “sickle cell”, “hemochromatosis”, and/or “connective tissue” as your search term in the Rare Disease Database).
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Related disorders of Pseudoxanthoma Elasticum. Symptoms of the following disorders may be similar to those of Pseudoxanthoma Elasticum. Comparisons may be useful for a differential diagnosis:Ehlers-Danlos syndrome is a rare inherited connective tissue disorder. It is characterized by the ability of affected individuals to flex their bodies beyond the normal range (articular hypermobility), to abnormally stretch their skin (hyperelasticity of the skin), and widespread tissue fragility (i.e., skin, blood vessels, and other tissues can rupture from even minor trauma). Many forms of Ehlers-Danlos Syndrome are inherited as an autosomal dominant genetic trait, but some forms of the disorder are inherited as either an autosomal recessive or an X-linked recessive genetic trait. (For more information on this disorder, choose “Ehlers-Danlos” as your search term in the Rare Disease Database).Marfan syndrome is an inherited disorder that affects the connective tissues of the heart and blood vessels (cardiovascular system). The musculoskeletal system (ligaments and muscles) is also affected. Major symptoms also include unusual height, large hands and feet, and involvement of the lungs and the eyes. (For more information on this disorder, choose “Marfan” as your search term in the Rare Disease Database).Other disorders may be characterized by the development of angioid streaks (e.g., sickle cell disease, hemochromatosis, etc.). There are also additional disorders that may have skin changes similar to those associated with PXE (e.g., solar elastosis, etc.). These disorders usually have other physical and microscopic features that may differentiate them from PXE. (For more information on these disorders, choose “sickle cell”, “hemochromatosis”, and/or “connective tissue” as your search term in the Rare Disease Database).
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Diagnosis of Pseudoxanthoma Elasticum
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Changes in the skin are usually the earliest sign of PXE and lead to the definitive diagnosis. Although the signs of PXE and the age of onset vary considerably, many people first notice an unusual appearance of their skin, typically on the sides or back of the neck. Small bumps, called lesions, may appear. Some individuals have described these as looking like a rash or an unwashed neck. Usually, a small biopsy of a lesion is done to confirm the diagnosis of PXE. This biopsy requires that a very small piece of skin, the size of a pencil eraser, be taken from the neck, underarm, and/or inside the elbow. The dermatologist sends this sample to a laboratory where a special stain, called a von Kossa stain, is used to detect calcium in the tissue.Sometimes, changes in the eye are the first noticeable sign of PXE. Early changes in the eye are visible only during an ophthalmological examination. Later symptoms can include loss of central vision. Some people are first diagnosed with PXE when they notice distortion of their vision.
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Diagnosis of Pseudoxanthoma Elasticum. Changes in the skin are usually the earliest sign of PXE and lead to the definitive diagnosis. Although the signs of PXE and the age of onset vary considerably, many people first notice an unusual appearance of their skin, typically on the sides or back of the neck. Small bumps, called lesions, may appear. Some individuals have described these as looking like a rash or an unwashed neck. Usually, a small biopsy of a lesion is done to confirm the diagnosis of PXE. This biopsy requires that a very small piece of skin, the size of a pencil eraser, be taken from the neck, underarm, and/or inside the elbow. The dermatologist sends this sample to a laboratory where a special stain, called a von Kossa stain, is used to detect calcium in the tissue.Sometimes, changes in the eye are the first noticeable sign of PXE. Early changes in the eye are visible only during an ophthalmological examination. Later symptoms can include loss of central vision. Some people are first diagnosed with PXE when they notice distortion of their vision.
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Therapies of Pseudoxanthoma Elasticum
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TreatmentA team of medical specialists (for example, an ophthalmologist, dermatologist, gastroenterologist, and primary care physician) may be needed to help manage PXE and its effects. People affected by PXE should be sure that all the health care professionals they visit are well-informed about the possible ramifications of PXE.Regular physician exams by a knowledgeable primary care physician are necessary. A detailed family history should be taken with regard to onset, signs that may be related to PXE and the rest of the family’s medical history. The affected individual’s cholesterol and triglycerides should be checked. Peripheral pulses should be monitored, as well. A dermatologist will most likely be the physician to make the definitive diagnosis and offer advice on reconstructive surgery, if that is of interest to the patient. An ophthalmologist will dilate the eyes to look for peau d’orange and angioid streaks. If angioid streaks are found, it may be wise to consult a retinal specialist. A cardiologist can perform a baseline EKG and sonogram test.In cases that involve retinal hemorrhage, laser treatment or injectable medications have been helpful for some people. However, not everyone can benefit from these treatments. In some cases, laser surgery does not restore vision. In others, scarring from both the bleeding and the laser surgery has made vision worse. A variety of visual aids can be provided to help compensate for loss of vision. A low vision clinic can be helpful in this regard.It is generally thought that people affected by PXE should avoid activities that might cause direct trauma to the eyes. Activities that increase pressure in the eyes, such as weight lifting, should also be avoided.
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Therapies of Pseudoxanthoma Elasticum. TreatmentA team of medical specialists (for example, an ophthalmologist, dermatologist, gastroenterologist, and primary care physician) may be needed to help manage PXE and its effects. People affected by PXE should be sure that all the health care professionals they visit are well-informed about the possible ramifications of PXE.Regular physician exams by a knowledgeable primary care physician are necessary. A detailed family history should be taken with regard to onset, signs that may be related to PXE and the rest of the family’s medical history. The affected individual’s cholesterol and triglycerides should be checked. Peripheral pulses should be monitored, as well. A dermatologist will most likely be the physician to make the definitive diagnosis and offer advice on reconstructive surgery, if that is of interest to the patient. An ophthalmologist will dilate the eyes to look for peau d’orange and angioid streaks. If angioid streaks are found, it may be wise to consult a retinal specialist. A cardiologist can perform a baseline EKG and sonogram test.In cases that involve retinal hemorrhage, laser treatment or injectable medications have been helpful for some people. However, not everyone can benefit from these treatments. In some cases, laser surgery does not restore vision. In others, scarring from both the bleeding and the laser surgery has made vision worse. A variety of visual aids can be provided to help compensate for loss of vision. A low vision clinic can be helpful in this regard.It is generally thought that people affected by PXE should avoid activities that might cause direct trauma to the eyes. Activities that increase pressure in the eyes, such as weight lifting, should also be avoided.
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Overview of Psittacosis
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Psittacosis is an uncommon infectious disease that is most often transmitted to humans through exposure to infected birds, especially parrots, cockatiels, parakeets and similar pet birds. Psittacosis can affect the lungs and may cause inflammatory illness of the lungs (pneumonia). Additional common symptoms include fever, muscle pain (myalgia), headaches, and a dry cough.Psittacosis is caused by infection with the bacterium, Chlamydia psittaci, and may also be known as ornithosis. It is rare among humans. People who own birds as pets are most likely to be affected by psittacosis. In addition, psittacosis may affect people who work in environments with birds that may be carriers of the infection such as pet store workers, farmers, veterinarians and ranchers.
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Overview of Psittacosis. Psittacosis is an uncommon infectious disease that is most often transmitted to humans through exposure to infected birds, especially parrots, cockatiels, parakeets and similar pet birds. Psittacosis can affect the lungs and may cause inflammatory illness of the lungs (pneumonia). Additional common symptoms include fever, muscle pain (myalgia), headaches, and a dry cough.Psittacosis is caused by infection with the bacterium, Chlamydia psittaci, and may also be known as ornithosis. It is rare among humans. People who own birds as pets are most likely to be affected by psittacosis. In addition, psittacosis may affect people who work in environments with birds that may be carriers of the infection such as pet store workers, farmers, veterinarians and ranchers.
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Symptoms of Psittacosis
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The symptoms and severity of psittacosis can vary greatly. Some individuals may not develop any symptoms (asymptomatic) or only have a very mild infection; others can develop serious widespread infection that affects several organ systems of the body. The incubation period, which is the time between exposure to the bacterium to symptom development, is anywhere from five to 15 days. The onset of symptoms may be abrupt or gradual (insidious). The associated symptoms tend to be nonspecific and common to many different conditions. Affected individuals may develop fever, chills, muscle pain (myalgia), headaches, and a general feeling of poor health (malaise). Pneumonia commonly occurs and, in some cases, can be severe. Breathing (respiratory) abnormalities may develop including a dry, nonproductive cough, difficulty breathing (dyspnea), a sore throat, and, in rare cases, chest pain. Frequent nosebleeds (epistaxis) and abnormal enlargement of the liver and spleen (hepatomegaly) are also common findings. Although the lungs is the organ most often affected by psittacosis, the disease can potentially affect many organ systems in the body including the gastrointestinal tract, heart, liver, skin and central nervous system. Associated symptoms may include nausea and vomiting, abdominal pain, an abnormally slow heart rate (bradycardia), inflammation of the thin membrane (pericardium) that surrounds the heart (pericarditis), inflammation of the thin membrane (endocardium) lining the inside of the heart (endocarditis), inflammation of the liver (hepatitis) causing yellowing of the skin and eyes (jaundice), a rash on the face, severe headaches and a sensitivity to light (photophobia).
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Symptoms of Psittacosis. The symptoms and severity of psittacosis can vary greatly. Some individuals may not develop any symptoms (asymptomatic) or only have a very mild infection; others can develop serious widespread infection that affects several organ systems of the body. The incubation period, which is the time between exposure to the bacterium to symptom development, is anywhere from five to 15 days. The onset of symptoms may be abrupt or gradual (insidious). The associated symptoms tend to be nonspecific and common to many different conditions. Affected individuals may develop fever, chills, muscle pain (myalgia), headaches, and a general feeling of poor health (malaise). Pneumonia commonly occurs and, in some cases, can be severe. Breathing (respiratory) abnormalities may develop including a dry, nonproductive cough, difficulty breathing (dyspnea), a sore throat, and, in rare cases, chest pain. Frequent nosebleeds (epistaxis) and abnormal enlargement of the liver and spleen (hepatomegaly) are also common findings. Although the lungs is the organ most often affected by psittacosis, the disease can potentially affect many organ systems in the body including the gastrointestinal tract, heart, liver, skin and central nervous system. Associated symptoms may include nausea and vomiting, abdominal pain, an abnormally slow heart rate (bradycardia), inflammation of the thin membrane (pericardium) that surrounds the heart (pericarditis), inflammation of the thin membrane (endocardium) lining the inside of the heart (endocarditis), inflammation of the liver (hepatitis) causing yellowing of the skin and eyes (jaundice), a rash on the face, severe headaches and a sensitivity to light (photophobia).
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Causes of Psittacosis
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Psittacosis is caused in humans by exposure to the bacterium, Chlamydia psittaci, which is most often transmitted to humans from infected birds, especially parrots and poultry, especially turkeys. Most infections occur from handling of infected birds themselves or by working in areas where such birds are kept or butchered (occupational exposure). Anyone in contact with an infected bird is at risk of psittacosis. However, cases have occurred in pet store workers, veterinarians, ranchers, and breeders of parrots, parakeets, love-birds, and macaws. Poultry workers handling the insides (viscera) of butchered turkeys also run a high risk of contracting the disease from blood and tissue. Another source of infection is the dried feces of birds and poultry and the dust from feathers and cages. Protective gloves and masks can often prevent transmission of the disease to these workers.The respiratory system is the most likely manner through which individuals are affected. Individuals inhale airborne organisms either from dried droppings or respiratory secretions from infected birds. The infected birds may be outwardly ill, or may show no signs of illness. Other animals such as cows, goats and sheep can be infected by the bacterium and can potentially transmit infection to humans. Human-to-human transmission is extremely rare, but has occurred and is usually associated with more severe symptoms than bird (avian)-to-human transmission.
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Causes of Psittacosis. Psittacosis is caused in humans by exposure to the bacterium, Chlamydia psittaci, which is most often transmitted to humans from infected birds, especially parrots and poultry, especially turkeys. Most infections occur from handling of infected birds themselves or by working in areas where such birds are kept or butchered (occupational exposure). Anyone in contact with an infected bird is at risk of psittacosis. However, cases have occurred in pet store workers, veterinarians, ranchers, and breeders of parrots, parakeets, love-birds, and macaws. Poultry workers handling the insides (viscera) of butchered turkeys also run a high risk of contracting the disease from blood and tissue. Another source of infection is the dried feces of birds and poultry and the dust from feathers and cages. Protective gloves and masks can often prevent transmission of the disease to these workers.The respiratory system is the most likely manner through which individuals are affected. Individuals inhale airborne organisms either from dried droppings or respiratory secretions from infected birds. The infected birds may be outwardly ill, or may show no signs of illness. Other animals such as cows, goats and sheep can be infected by the bacterium and can potentially transmit infection to humans. Human-to-human transmission is extremely rare, but has occurred and is usually associated with more severe symptoms than bird (avian)-to-human transmission.
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Affects of Psittacosis
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Psittacosis affects males and females in equal numbers. Anyone who handles an infected bird is at risk of developing psittacosis. Since the disease can become epidemic in animals, discovery of a single case of the disease should be reported to local public health authorities. The number of report cases of psittacosis in the United States has varied, ranging from 50 to 200 per year. Many researchers believe the disorder is under-diagnosed and the true number of cases that occur per year is unknown. The disease was first was first described in the medical literature in 1879. The term, psittacosis, which is derived from the Greek word for parrot, was first used to describe this disease in 1892. Many physicians prefer the term ornithosis, which indicates that the disease can spread by more than just birds of the parrot family.
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Affects of Psittacosis. Psittacosis affects males and females in equal numbers. Anyone who handles an infected bird is at risk of developing psittacosis. Since the disease can become epidemic in animals, discovery of a single case of the disease should be reported to local public health authorities. The number of report cases of psittacosis in the United States has varied, ranging from 50 to 200 per year. Many researchers believe the disorder is under-diagnosed and the true number of cases that occur per year is unknown. The disease was first was first described in the medical literature in 1879. The term, psittacosis, which is derived from the Greek word for parrot, was first used to describe this disease in 1892. Many physicians prefer the term ornithosis, which indicates that the disease can spread by more than just birds of the parrot family.
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Related disorders of Psittacosis
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Symptoms of the following disorders can be similar to those of psittacosis. Comparisons may be useful for a differential diagnosis.Brucellosis is an infectious disease that affects livestock and may be transmitted to humans. It is rare in the United States, but occurs more frequently in other parts of the world. The disorder is caused by one of four different species of bacteria that belong to the genus Brucella. Initial symptoms of infection may be nonspecific including fevers, muscle pain, headache, loss of appetite, profuse sweating, and physical weakness. In some cases, the symptoms occur suddenly (acute), whereas, in others, symptoms may develop over the course of a few months. If brucellosis is not treated, the disease may take months to resolve once appropriate therapy is begun. Brucellosis may be confined to a certain area of the body (local) or have serious widespread complications that affect various organ systems of the body including the central nervous system. Brucellosis may be prevented if people drink only pasteurized cow and goat's milk. Pasteurization kills the bacteria that cause the disease. However, farmers and people exposed to butchered meat may also be affected by brucellosis. (For more information on this disorder, choose “brucellosis” as your search term in the Rare Disease Database.)Tularemia is a rare infectious disease that most often affects small mammals such as rabbits, rodents and hares. It is highly infectious and is most often transmitted to humans by handling an infected animal or being bit by an infected tick or fly. People have not been known to transmit the infection to others. The disease is caused by the bacterium Francisella tularensis. The severity of tularemia varies greatly. Some cases are mild and self-limiting; others may have serious complications, and a small percentage (about 2 percent) may become life-threatening. (For more information on this disorder, choose “tularemia” as your search term in the Rare Disease Database.)Psittacosis must be differentiated from other, more common causes of fever, chronic fatigue, weakness, and other nonspecific flu-like symptoms. These causes include other infectious diseases and various autoimmune diseases. Some specific conditions that may cause symptoms similar to psittacosis include Q fever, influenza, legionellosis, viral pneumonia, bacterial pneumonia, infective endocarditis, and tuberculosis. (For more information, choose the specific disorder name as your search term in the Rare Disease Database.)
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Related disorders of Psittacosis. Symptoms of the following disorders can be similar to those of psittacosis. Comparisons may be useful for a differential diagnosis.Brucellosis is an infectious disease that affects livestock and may be transmitted to humans. It is rare in the United States, but occurs more frequently in other parts of the world. The disorder is caused by one of four different species of bacteria that belong to the genus Brucella. Initial symptoms of infection may be nonspecific including fevers, muscle pain, headache, loss of appetite, profuse sweating, and physical weakness. In some cases, the symptoms occur suddenly (acute), whereas, in others, symptoms may develop over the course of a few months. If brucellosis is not treated, the disease may take months to resolve once appropriate therapy is begun. Brucellosis may be confined to a certain area of the body (local) or have serious widespread complications that affect various organ systems of the body including the central nervous system. Brucellosis may be prevented if people drink only pasteurized cow and goat's milk. Pasteurization kills the bacteria that cause the disease. However, farmers and people exposed to butchered meat may also be affected by brucellosis. (For more information on this disorder, choose “brucellosis” as your search term in the Rare Disease Database.)Tularemia is a rare infectious disease that most often affects small mammals such as rabbits, rodents and hares. It is highly infectious and is most often transmitted to humans by handling an infected animal or being bit by an infected tick or fly. People have not been known to transmit the infection to others. The disease is caused by the bacterium Francisella tularensis. The severity of tularemia varies greatly. Some cases are mild and self-limiting; others may have serious complications, and a small percentage (about 2 percent) may become life-threatening. (For more information on this disorder, choose “tularemia” as your search term in the Rare Disease Database.)Psittacosis must be differentiated from other, more common causes of fever, chronic fatigue, weakness, and other nonspecific flu-like symptoms. These causes include other infectious diseases and various autoimmune diseases. Some specific conditions that may cause symptoms similar to psittacosis include Q fever, influenza, legionellosis, viral pneumonia, bacterial pneumonia, infective endocarditis, and tuberculosis. (For more information, choose the specific disorder name as your search term in the Rare Disease Database.)
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Diagnosis of Psittacosis
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The diagnosis of psittacosis is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic findings and a variety of specialized tests such as specialized blood tests that reveal characteristic antibodies, produced by the body in response to psittacosis infection. Antibodies are specialized proteins produced by the body to fight off foreign material such as bacteria.
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Diagnosis of Psittacosis. The diagnosis of psittacosis is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic findings and a variety of specialized tests such as specialized blood tests that reveal characteristic antibodies, produced by the body in response to psittacosis infection. Antibodies are specialized proteins produced by the body to fight off foreign material such as bacteria.
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Therapies of Psittacosis
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TreatmentAntibiotic therapy is the primary treatment for individuals with psittacosis. Tetracycline and doxycycline are usually the first medications used. Most individuals respond within 24 to 72 hours. Erythromycin may be recommended for children or pregnant women. In rare cases, individuals have been treated with chloramphenicol.Since the disease can become epidemic in animals, discovery of a single case of the disease should be reported to local public health authorities. The treatment of psittacosis in birds is important to avoid further transmission.
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Therapies of Psittacosis. TreatmentAntibiotic therapy is the primary treatment for individuals with psittacosis. Tetracycline and doxycycline are usually the first medications used. Most individuals respond within 24 to 72 hours. Erythromycin may be recommended for children or pregnant women. In rare cases, individuals have been treated with chloramphenicol.Since the disease can become epidemic in animals, discovery of a single case of the disease should be reported to local public health authorities. The treatment of psittacosis in birds is important to avoid further transmission.
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Psittacosis
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nord_1034_0
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Overview of PTEN Hamartoma Tumor Syndrome
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The PTEN hamartoma tumor syndrome (PHTS) is a spectrum of disorders caused by mutations of the PTEN tumor suppressor gene in egg or sperm cells (germline). These disorders are characterized by multiple hamartomas that can affect various areas of the body. Hamartoma is a general term for benign tumor-like malformation composed of mature cells and tissue normally found in the affected area that have grown in a disorganized manner. Individuals with a variety of clinical diagnoses who ultimately have been found to carry a germline PTEN mutation as the underlying cause are said to have PHTS.When the strictest diagnostic criteria are used, patients with a personal and family history of Cowden syndrome (CS) features have up to an 85% chance to have a PTEN mutation. Patients with features of Bannayan-Riley-Ruvalcaba syndrome (BRRS) and with features reminiscent of but not meeting diagnostic criteria for Proteus syndrome (called Proteus-like syndrome) have also been found to have an underlying PHTS diagnosis. Once thought to be completely separate conditions, patients with features of CS or BRRS and an underlying PTEN mutation are unified as all having PHTS, with CS being a diagnosis traditionally given to adults and BRRS being first described in the pediatrics literature. This makes sense given that many of the characteristics first associated with CS tend to not appear until adulthood. PHTS is inherited in an autosomal dominant pattern, which means it can be passed down in a 50-50 fashion. The symptoms vary greatly from patient to patient, even among individuals in the same family.
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Overview of PTEN Hamartoma Tumor Syndrome. The PTEN hamartoma tumor syndrome (PHTS) is a spectrum of disorders caused by mutations of the PTEN tumor suppressor gene in egg or sperm cells (germline). These disorders are characterized by multiple hamartomas that can affect various areas of the body. Hamartoma is a general term for benign tumor-like malformation composed of mature cells and tissue normally found in the affected area that have grown in a disorganized manner. Individuals with a variety of clinical diagnoses who ultimately have been found to carry a germline PTEN mutation as the underlying cause are said to have PHTS.When the strictest diagnostic criteria are used, patients with a personal and family history of Cowden syndrome (CS) features have up to an 85% chance to have a PTEN mutation. Patients with features of Bannayan-Riley-Ruvalcaba syndrome (BRRS) and with features reminiscent of but not meeting diagnostic criteria for Proteus syndrome (called Proteus-like syndrome) have also been found to have an underlying PHTS diagnosis. Once thought to be completely separate conditions, patients with features of CS or BRRS and an underlying PTEN mutation are unified as all having PHTS, with CS being a diagnosis traditionally given to adults and BRRS being first described in the pediatrics literature. This makes sense given that many of the characteristics first associated with CS tend to not appear until adulthood. PHTS is inherited in an autosomal dominant pattern, which means it can be passed down in a 50-50 fashion. The symptoms vary greatly from patient to patient, even among individuals in the same family.
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Symptoms of PTEN Hamartoma Tumor Syndrome
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The primary findings in PHTS include increased risk for certain types of cancer, benign tumors and tumor-like malformations (hamartomas), and neurodevelopmental disorders. The symptoms of PHTS vary greatly from person to person and can develop at any age.Cancer in PHTSPrevious data, which focused only on patients with a clinical diagnosis of Cowden syndrome without understanding whether an underlying PTEN mutation was present, estimated lifetime breast cancer risk to be 25-50% and risk for non-medullary thyroid cancer to be 10%. Risks for endometrial (uterine) and renal cell (kidney) cancer were thought to be increased, but an exact risk level was undetermined.Current data focusing on patients known to have PHTS provide the following lifetime risk estimates, with the majority of diagnoses occurring after age 30:*Earliest age for thyroid cancer in PHTS is as early as 7 years old
Benign tumors in PHTS
Benign skin or oral lesions are very common and tend to appear in early adulthood. The most common types of benign skin lesions seen in PHTS include:·Lipomas – benign fatty tumors which can appear just under the skin or elsewhere (breast area, GI tract)·Acral keratosis – rough patches of skin most often seen on the extremities (arms, hands, legs, feet)·Papillomatous skin papules – wart-like lesions which can appear anywhere, with feet and hands commonly being affected·Mucosal papillomas – Benign overgrowth of tissue affecting the tongue, gums, or inside the nose·Trichilemmomas – Benign tumor of the hair follicle·Fibromas – another kind of overgrowth involving the skin and other connective tissue; may also affect tissue covering organs, such as the ovaries.Gastrointestinal polyps are very common in adults with PHTS. Among patients who had undergone colonoscopy as part of their clinical care, >90% were found to have polyps with a mix of histological subtypes. The most common types of polyps found are hyperplastic or hamartomatous, which rarely develop into malignancy; however, adenomas, which may develop into a cancer, were also identified. Many polyps were very small and did not cause noticeable symptoms such as pain or rectal bleeding. Supported by this evidence, colorectal surveillance should be offered to any PTEN mutation carrier.Benign breast, thyroid, and uterine lesions are also common in persons with PHTS. Some women have severe fibrocystic disease or changes which lead to multiple breast biopsies and complications with imaging. Multinodular goiter and Hashimoto’s thyroiditis may develop in children and adults. Uterine fibroids may appear and cause bleeding or discomfort to the extent that a hysterectomy is indicated without an underlying cancer diagnosis.Vascular tumors, including hemangiomas, arteriovenous malformations, and developmental venous anomalies, have also been observed in patients with PHTS. Treatment of some lesions has been complicated by tendency for regrowth and scarring.A small percentage of adults develop a rare tumor known as a cerebellar dysplastic gangliocytoma (Lhermitte-Duclos syndrome). Symptoms of Lhermitte-Duclos syndrome include increased intracranial pressure, impaired ability to coordinate voluntary movements (ataxia), and seizures. It is rare when a person with adult-onset Lhermitte-Duclos does not have an underlying PTEN mutation, and observing this tumor type is an automatic indicator for PTEN testing.Neurodevelopmental concerns in PHTS
Macrocephaly (large head size) is found in 94% of measured patients with PHTS and can be a helpful screening tool to identify patients for PTEN testing. In most patients, large head size is caused by overgrowth of brain tissue. The head shape also tends to be longer than wide (dolicocephaly).Autism and other developmental disorders, such as intellectual disability and developmental delays, have been observed in patients with PHTS. In previous case series, up to 17% of children presenting with macrocephaly and an autism spectrum disorder alone were found to have an underlying PTEN mutation.
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Symptoms of PTEN Hamartoma Tumor Syndrome. The primary findings in PHTS include increased risk for certain types of cancer, benign tumors and tumor-like malformations (hamartomas), and neurodevelopmental disorders. The symptoms of PHTS vary greatly from person to person and can develop at any age.Cancer in PHTSPrevious data, which focused only on patients with a clinical diagnosis of Cowden syndrome without understanding whether an underlying PTEN mutation was present, estimated lifetime breast cancer risk to be 25-50% and risk for non-medullary thyroid cancer to be 10%. Risks for endometrial (uterine) and renal cell (kidney) cancer were thought to be increased, but an exact risk level was undetermined.Current data focusing on patients known to have PHTS provide the following lifetime risk estimates, with the majority of diagnoses occurring after age 30:*Earliest age for thyroid cancer in PHTS is as early as 7 years old
Benign tumors in PHTS
Benign skin or oral lesions are very common and tend to appear in early adulthood. The most common types of benign skin lesions seen in PHTS include:·Lipomas – benign fatty tumors which can appear just under the skin or elsewhere (breast area, GI tract)·Acral keratosis – rough patches of skin most often seen on the extremities (arms, hands, legs, feet)·Papillomatous skin papules – wart-like lesions which can appear anywhere, with feet and hands commonly being affected·Mucosal papillomas – Benign overgrowth of tissue affecting the tongue, gums, or inside the nose·Trichilemmomas – Benign tumor of the hair follicle·Fibromas – another kind of overgrowth involving the skin and other connective tissue; may also affect tissue covering organs, such as the ovaries.Gastrointestinal polyps are very common in adults with PHTS. Among patients who had undergone colonoscopy as part of their clinical care, >90% were found to have polyps with a mix of histological subtypes. The most common types of polyps found are hyperplastic or hamartomatous, which rarely develop into malignancy; however, adenomas, which may develop into a cancer, were also identified. Many polyps were very small and did not cause noticeable symptoms such as pain or rectal bleeding. Supported by this evidence, colorectal surveillance should be offered to any PTEN mutation carrier.Benign breast, thyroid, and uterine lesions are also common in persons with PHTS. Some women have severe fibrocystic disease or changes which lead to multiple breast biopsies and complications with imaging. Multinodular goiter and Hashimoto’s thyroiditis may develop in children and adults. Uterine fibroids may appear and cause bleeding or discomfort to the extent that a hysterectomy is indicated without an underlying cancer diagnosis.Vascular tumors, including hemangiomas, arteriovenous malformations, and developmental venous anomalies, have also been observed in patients with PHTS. Treatment of some lesions has been complicated by tendency for regrowth and scarring.A small percentage of adults develop a rare tumor known as a cerebellar dysplastic gangliocytoma (Lhermitte-Duclos syndrome). Symptoms of Lhermitte-Duclos syndrome include increased intracranial pressure, impaired ability to coordinate voluntary movements (ataxia), and seizures. It is rare when a person with adult-onset Lhermitte-Duclos does not have an underlying PTEN mutation, and observing this tumor type is an automatic indicator for PTEN testing.Neurodevelopmental concerns in PHTS
Macrocephaly (large head size) is found in 94% of measured patients with PHTS and can be a helpful screening tool to identify patients for PTEN testing. In most patients, large head size is caused by overgrowth of brain tissue. The head shape also tends to be longer than wide (dolicocephaly).Autism and other developmental disorders, such as intellectual disability and developmental delays, have been observed in patients with PHTS. In previous case series, up to 17% of children presenting with macrocephaly and an autism spectrum disorder alone were found to have an underlying PTEN mutation.
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Causes of PTEN Hamartoma Tumor Syndrome
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PHTS is caused by a germline mutation of PTEN, a tumor suppressor gene. PTEN stands for phosphatase tensin homologue. A tumor suppressor is a gene that slows down cell division, repairs damage to the DNA of cells, and tells cells when to die, a normal process called apoptosis. Mutations in a tumor suppressor gene often lead to cancer. The PTEN gene regulates the production of an enzyme (protein tyrosine phosphatase) which is believed to be important in stopping cell growth and starting apoptosis. Researchers believe that the PTEN gene plays a broad role in the development of human malignancies.PHTS is inherited in an autosomal dominant pattern. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
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Causes of PTEN Hamartoma Tumor Syndrome. PHTS is caused by a germline mutation of PTEN, a tumor suppressor gene. PTEN stands for phosphatase tensin homologue. A tumor suppressor is a gene that slows down cell division, repairs damage to the DNA of cells, and tells cells when to die, a normal process called apoptosis. Mutations in a tumor suppressor gene often lead to cancer. The PTEN gene regulates the production of an enzyme (protein tyrosine phosphatase) which is believed to be important in stopping cell growth and starting apoptosis. Researchers believe that the PTEN gene plays a broad role in the development of human malignancies.PHTS is inherited in an autosomal dominant pattern. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
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Affects of PTEN Hamartoma Tumor Syndrome
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Cowden syndrome was estimated to affect 1 in 200,000 individuals; this study was conducted just as PTEN was discovered. However, because the disorder is difficult to recognize, researchers believe it is under-diagnosed, making it difficult to determine its true frequency in the general population. Men and women are affected equally with PHTS. PHTS is not more commonly found in persons of a particular racial or ethnic group.
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Affects of PTEN Hamartoma Tumor Syndrome. Cowden syndrome was estimated to affect 1 in 200,000 individuals; this study was conducted just as PTEN was discovered. However, because the disorder is difficult to recognize, researchers believe it is under-diagnosed, making it difficult to determine its true frequency in the general population. Men and women are affected equally with PHTS. PHTS is not more commonly found in persons of a particular racial or ethnic group.
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Related disorders of PTEN Hamartoma Tumor Syndrome
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Symptoms of the following disorders can be similar to those of PHTS. Comparisons may be useful for purposes of formulating a genetic differential diagnosis.Hereditary breast and ovarian cancer syndrome (HBOC) is similar to PHTS in that patients are at high lifetime risk of developing breast cancer. Ovarian, pancreatic, and prostate cancers as well as melanoma have also been associated. However, patients with HBOC are not at increased risk for the other benign or malignant tumors or neurodevelopmental concerns associated with PHTS. HBOC is inherited in an autosomal dominant manner and is caused by mutation in either the BRCA1 or BRCA2 gene.Lynch syndrome, formerly called hereditary nonpolyposis colorectal cancer syndrome, causes increased risks for primarily colon, uterine, ovarian, and stomach cancers. Debate exists regarding whether risk for breast cancer is increased as well. Lynch syndrome is inherited in an autosomal dominant manner. Like in HBOC, patients with Lynch syndrome are not at increased risk for thyroid cancer or the other benign tumors and neurodevelopmental features seen in PHTS. At present five genes are known to cause Lynch syndrome; these genes are part of the mismatch repair complex.Familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP) are conditions which like PTHS, cause increased risks for polyposis and colorectal cancers. However, patients with FAP/MAP tend to develop adenomatous polyps, whereas patients with PHTS are found to mostly have hyperplastic or hamartomatous polyps. Additionally, the extra-colonic features of PHTS are not identified in patients with FAP/MAP with the exception of papillary thyroid cancer, which has been associated with FAP. FAP is inherited in an autosomal dominant manner and MAP in an autosomal recessive manner. FAP and MAP are caused by mutation of the APC.Familial juvenile polyposis is characterized by small multiple growths (polyps) within the gastrointestinal system. Symptoms may include gastrointestinal bleeding, abdominal pain, diarrhea, rectal prolapse, collapse of a portion of the bowel into itself, and/or gastrointestinal obstruction. Some affected individuals may experience protein loss, malnutrition, and a feeling of general ill health (cachexia). Individuals affected by familial juvenile polyposis may have an increased risk of colon cancer. Other symptoms may include clubbing of the finger and toes, failure to thrive, low levels of circulating red blood cells (anemia). Familial juvenile polyposis is inherited in an autosomal dominant pattern. Familial juvenile polyposis may be caused by mutations in the BMPR1A gene or mutations in the SMAD4 gene also known as the MADH4 or DPC4 gene. A rare subset of juvenile polyposis called juvenile polyposis of infancy can be caused by deletion of a piece of chromosome 10 encompassing both BMPR1A and PTEN.Peutz Jeghers syndrome is a rare, inherited gastrointestinal disorder characterized by the development of polyps on the mucous lining of the intestine and dark discolorations on the skin and mucous membranes. Symptoms include nausea, vomiting, and abdominal pain that occurs because of a form of intestinal obstruction (intussusception). Additional symptoms include bleeding from the rectum and dark skin discolorations around the lips, inside the cheeks, and on the arms. Severe rectal bleeding can cause anemia and episodes of recurring, severe abdominal pain. Peutz-Jeghers syndrome is inherited in an autosomal dominant pattern and occurs due to mutations of a gene located on chromosome 19. (For more information on this disorder, choose “Peutz Jeghers” as your search term in the Rare Disease Database.)Sotos syndrome is a rare genetic disorder characterized by excessive growth that occurs prior to and after birth (prenatally and postnatally). At birth, affected infants have unusually increased body length that is abnormal in proportion to weight, which may also be above average; in addition, newborns typically demonstrate advanced bone growth, abnormally large hands and/or feet, and characteristic facial features. Abnormally rapid growth continues after birth until approximately four or five years of age, at which time growth may slow to a normal rate. An affected individual’s final height often is within normal range. Affected infants and children may demonstrate developmental abnormalities including delays in reaching developmental milestones (e.g., sitting, crawling, walking); delays in the acquisition of skills requiring the coordination of muscular and mental activity (psychomotor retardation); delayed language skills; and mild to severe intellectual disability. Similar to PHTS, characteristic facial abnormalities may include an unusually large head (macrocephaly) that may appear elongated (dolichocephalic). Other facial abnormalities include prominent forehead (frontal bossing); widely-spaced eyes (ocular hypertelorism); downwardly slanting eyelid folds (palpebral fissures); a highly-arched roof of the mouth (palate); protrusion of the lower jaw (prognathism); and/or a pointed chin. Unlike PHTS, most cases of Sotos syndrome occur randomly, for no known reason (sporadically) In rare cases, however, when a positive family history is found, the disorder may be inherited as an autosomal dominant genetic trait. The overlap of neurodevelopmental disabilities and macrocephaly in both PHTS and Sotos syndrome indicates the need for genetic testing to avoid misdiagnosis. (For more information on this disorder, choose “Sotos” as your search term in the Rare Disease Database.)Neurofibromatosis 1 (NF1) can mimic PHTS in that patients with each condition may develop skin lesions and gastrointestinal ganglioneuromatosis (a type of hamartoma) and have macrocephaly and developmental delays. However, the vast majority of patients with NF1 also have multiple café-au-lait macules (light brown birthmarks), freckling in the armpit and groin region, and lisch nodules, benign freckle-like lesions over the colored part of the eye. Additionally, the primary skin lesion which develops is a neurofibroma. NF1 is inherited in an autosomal dominant manner and is caused by mutation of the Neurofibromin gene. (For more information on this disorder, choose “NF1” as your search term in the Rare Disease Database.)Multiple endocrine neoplasia 2B (MEN 2B) overlaps with PHTS in that both conditions cause gastrointestinal ganglioneuromatosis, mucosal lesions, and an increased risk of thyroid cancer. Medullary thyroid cancer is the most common type in MEN 2B, while follicular or papillary thyroid cancers dominate in patients with PHTS, Additionally, patients with MEN 2B do not have the other systemic manifestations of PHTS, and tend towards having a Marfanoid body structure (tall and thin with long arms and legs). Furthermore, in contrast to the MEN 2B-related ganglioneuromatosis, the PHTS-associated lesions are ganglioneuromatous polyps.
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Related disorders of PTEN Hamartoma Tumor Syndrome. Symptoms of the following disorders can be similar to those of PHTS. Comparisons may be useful for purposes of formulating a genetic differential diagnosis.Hereditary breast and ovarian cancer syndrome (HBOC) is similar to PHTS in that patients are at high lifetime risk of developing breast cancer. Ovarian, pancreatic, and prostate cancers as well as melanoma have also been associated. However, patients with HBOC are not at increased risk for the other benign or malignant tumors or neurodevelopmental concerns associated with PHTS. HBOC is inherited in an autosomal dominant manner and is caused by mutation in either the BRCA1 or BRCA2 gene.Lynch syndrome, formerly called hereditary nonpolyposis colorectal cancer syndrome, causes increased risks for primarily colon, uterine, ovarian, and stomach cancers. Debate exists regarding whether risk for breast cancer is increased as well. Lynch syndrome is inherited in an autosomal dominant manner. Like in HBOC, patients with Lynch syndrome are not at increased risk for thyroid cancer or the other benign tumors and neurodevelopmental features seen in PHTS. At present five genes are known to cause Lynch syndrome; these genes are part of the mismatch repair complex.Familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP) are conditions which like PTHS, cause increased risks for polyposis and colorectal cancers. However, patients with FAP/MAP tend to develop adenomatous polyps, whereas patients with PHTS are found to mostly have hyperplastic or hamartomatous polyps. Additionally, the extra-colonic features of PHTS are not identified in patients with FAP/MAP with the exception of papillary thyroid cancer, which has been associated with FAP. FAP is inherited in an autosomal dominant manner and MAP in an autosomal recessive manner. FAP and MAP are caused by mutation of the APC.Familial juvenile polyposis is characterized by small multiple growths (polyps) within the gastrointestinal system. Symptoms may include gastrointestinal bleeding, abdominal pain, diarrhea, rectal prolapse, collapse of a portion of the bowel into itself, and/or gastrointestinal obstruction. Some affected individuals may experience protein loss, malnutrition, and a feeling of general ill health (cachexia). Individuals affected by familial juvenile polyposis may have an increased risk of colon cancer. Other symptoms may include clubbing of the finger and toes, failure to thrive, low levels of circulating red blood cells (anemia). Familial juvenile polyposis is inherited in an autosomal dominant pattern. Familial juvenile polyposis may be caused by mutations in the BMPR1A gene or mutations in the SMAD4 gene also known as the MADH4 or DPC4 gene. A rare subset of juvenile polyposis called juvenile polyposis of infancy can be caused by deletion of a piece of chromosome 10 encompassing both BMPR1A and PTEN.Peutz Jeghers syndrome is a rare, inherited gastrointestinal disorder characterized by the development of polyps on the mucous lining of the intestine and dark discolorations on the skin and mucous membranes. Symptoms include nausea, vomiting, and abdominal pain that occurs because of a form of intestinal obstruction (intussusception). Additional symptoms include bleeding from the rectum and dark skin discolorations around the lips, inside the cheeks, and on the arms. Severe rectal bleeding can cause anemia and episodes of recurring, severe abdominal pain. Peutz-Jeghers syndrome is inherited in an autosomal dominant pattern and occurs due to mutations of a gene located on chromosome 19. (For more information on this disorder, choose “Peutz Jeghers” as your search term in the Rare Disease Database.)Sotos syndrome is a rare genetic disorder characterized by excessive growth that occurs prior to and after birth (prenatally and postnatally). At birth, affected infants have unusually increased body length that is abnormal in proportion to weight, which may also be above average; in addition, newborns typically demonstrate advanced bone growth, abnormally large hands and/or feet, and characteristic facial features. Abnormally rapid growth continues after birth until approximately four or five years of age, at which time growth may slow to a normal rate. An affected individual’s final height often is within normal range. Affected infants and children may demonstrate developmental abnormalities including delays in reaching developmental milestones (e.g., sitting, crawling, walking); delays in the acquisition of skills requiring the coordination of muscular and mental activity (psychomotor retardation); delayed language skills; and mild to severe intellectual disability. Similar to PHTS, characteristic facial abnormalities may include an unusually large head (macrocephaly) that may appear elongated (dolichocephalic). Other facial abnormalities include prominent forehead (frontal bossing); widely-spaced eyes (ocular hypertelorism); downwardly slanting eyelid folds (palpebral fissures); a highly-arched roof of the mouth (palate); protrusion of the lower jaw (prognathism); and/or a pointed chin. Unlike PHTS, most cases of Sotos syndrome occur randomly, for no known reason (sporadically) In rare cases, however, when a positive family history is found, the disorder may be inherited as an autosomal dominant genetic trait. The overlap of neurodevelopmental disabilities and macrocephaly in both PHTS and Sotos syndrome indicates the need for genetic testing to avoid misdiagnosis. (For more information on this disorder, choose “Sotos” as your search term in the Rare Disease Database.)Neurofibromatosis 1 (NF1) can mimic PHTS in that patients with each condition may develop skin lesions and gastrointestinal ganglioneuromatosis (a type of hamartoma) and have macrocephaly and developmental delays. However, the vast majority of patients with NF1 also have multiple café-au-lait macules (light brown birthmarks), freckling in the armpit and groin region, and lisch nodules, benign freckle-like lesions over the colored part of the eye. Additionally, the primary skin lesion which develops is a neurofibroma. NF1 is inherited in an autosomal dominant manner and is caused by mutation of the Neurofibromin gene. (For more information on this disorder, choose “NF1” as your search term in the Rare Disease Database.)Multiple endocrine neoplasia 2B (MEN 2B) overlaps with PHTS in that both conditions cause gastrointestinal ganglioneuromatosis, mucosal lesions, and an increased risk of thyroid cancer. Medullary thyroid cancer is the most common type in MEN 2B, while follicular or papillary thyroid cancers dominate in patients with PHTS, Additionally, patients with MEN 2B do not have the other systemic manifestations of PHTS, and tend towards having a Marfanoid body structure (tall and thin with long arms and legs). Furthermore, in contrast to the MEN 2B-related ganglioneuromatosis, the PHTS-associated lesions are ganglioneuromatous polyps.
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Diagnosis of PTEN Hamartoma Tumor Syndrome
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A diagnosis of PHTS may be suspected based upon a thorough clinical evaluation, a detailed patient history and the presence of characteristic findings. Recently, a mutation risk calculator has been developed which can estimate the risk for adults to have a PTEN mutation based on their personal history characteristics; this tool is available online at http://www.lerner.ccf.org/gmi/ccscore/. The diagnosis can only be confirmed when a mutation of the PTEN gene is identified.
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Diagnosis of PTEN Hamartoma Tumor Syndrome. A diagnosis of PHTS may be suspected based upon a thorough clinical evaluation, a detailed patient history and the presence of characteristic findings. Recently, a mutation risk calculator has been developed which can estimate the risk for adults to have a PTEN mutation based on their personal history characteristics; this tool is available online at http://www.lerner.ccf.org/gmi/ccscore/. The diagnosis can only be confirmed when a mutation of the PTEN gene is identified.
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Therapies of PTEN Hamartoma Tumor Syndrome
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Treatment
Individuals with PTEN mutations should undergo cancer surveillance and screening at the time of diagnosis as follows to enable healthcare providers to detect any tumors at the earliest, most treatable stages. Current suggested screening by age includes:Pediatric (below age 18)·Yearly thyroid ultrasound starting at the time of diagnosis
·Yearly skin check with physical examination
·Consider neurodevelopmental evaluationAdults
·Monthly breast self-examination
·Yearly thyroid ultrasound and dermatologic evaluation
·Women: breast screening (at minimum mammogram) yearly beginning at age 30; MRI may also be incorporated
·Women: annual transvaginal ultrasound and/or endometrial biopsy beginning at age 30
·Colonoscopy beginning at age 35-40; frequency dependent on degree of polyposis identified
·Biannual (every other year) renal imaging (CT or MRI preferred) beginning at age 40For patients with a family history of a particular cancer type, screening may be considered 5-10 years prior to the youngest diagnosis in the family. For example, a patient whose mother developed breast cancer at 30 may begin breast surveillance at age 25-30.Additional treatment for PHTS is symptomatic and supportive. Various techniques may be used to treat the mucocutaneous symptoms of Cowden syndrome including topical agents, the use of extreme cold to destroy affected tissue (cryosurgery), the removal of tissue or growths by through a process called curettage, in which a surgical tool shaped like a spoon (curette) is used to scrape away affect tissue, or destroying affected tissue by exposing it to laser beams (laser ablation). Genetic counseling may be of benefit for affected individuals and their families.
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Therapies of PTEN Hamartoma Tumor Syndrome. Treatment
Individuals with PTEN mutations should undergo cancer surveillance and screening at the time of diagnosis as follows to enable healthcare providers to detect any tumors at the earliest, most treatable stages. Current suggested screening by age includes:Pediatric (below age 18)·Yearly thyroid ultrasound starting at the time of diagnosis
·Yearly skin check with physical examination
·Consider neurodevelopmental evaluationAdults
·Monthly breast self-examination
·Yearly thyroid ultrasound and dermatologic evaluation
·Women: breast screening (at minimum mammogram) yearly beginning at age 30; MRI may also be incorporated
·Women: annual transvaginal ultrasound and/or endometrial biopsy beginning at age 30
·Colonoscopy beginning at age 35-40; frequency dependent on degree of polyposis identified
·Biannual (every other year) renal imaging (CT or MRI preferred) beginning at age 40For patients with a family history of a particular cancer type, screening may be considered 5-10 years prior to the youngest diagnosis in the family. For example, a patient whose mother developed breast cancer at 30 may begin breast surveillance at age 25-30.Additional treatment for PHTS is symptomatic and supportive. Various techniques may be used to treat the mucocutaneous symptoms of Cowden syndrome including topical agents, the use of extreme cold to destroy affected tissue (cryosurgery), the removal of tissue or growths by through a process called curettage, in which a surgical tool shaped like a spoon (curette) is used to scrape away affect tissue, or destroying affected tissue by exposing it to laser beams (laser ablation). Genetic counseling may be of benefit for affected individuals and their families.
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Overview of Pterygium Syndrome, Multiple
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Multiple pterygium syndrome is a very rare genetic disorder characterized by minor facial anomalies, short stature, vertebral defects, multiple joints in a fixed position (contractures) and webbing (pterygia) of the neck, inside bend of the elbows, back of the knees, armpits and fingers. Multiple pterygium syndrome usually follows autosomal recessive inheritance but can also follow autosomal dominant inheritance.
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Overview of Pterygium Syndrome, Multiple. Multiple pterygium syndrome is a very rare genetic disorder characterized by minor facial anomalies, short stature, vertebral defects, multiple joints in a fixed position (contractures) and webbing (pterygia) of the neck, inside bend of the elbows, back of the knees, armpits and fingers. Multiple pterygium syndrome usually follows autosomal recessive inheritance but can also follow autosomal dominant inheritance.
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Symptoms of Pterygium Syndrome, Multiple
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Multiple pterygium syndrome is a very rare disorder characterized by permanently bent fingers (camptodactyly), short stature, rocker-bottom or club feet, joints that are bent in a fixed position (contractures), union or webbing of the skin between the fingers (syndactyly), and/or webbing of the neck, inside bend of the elbows, back of the knees and armpits. The webbing of skin and contractures of the joints that are found in this disorder may restrict movement.Characteristic facial features can include a small jaw (micrognathia), a long vertical groove in the middle of the upper lip (philtrum), down-slanting eyes, a vertical fold of skin over the inner corner of the eye (epicanthal folds), drooping eyelids, low-set ears, cleft palate and down-turned corners of the mouth. Backward and lateral curvature of the spine (kyphoscoliosis) and spinal fusion abnormalities occur often in multiple pterygium syndrome. Other skeletal anomalies include rib fusions, hip dislocation, abnormal ear bones and absent or malformed kneecaps.Males may have undescended testes and an abnormally small penis. Females may have underdeveloped or missing labia majora.
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Symptoms of Pterygium Syndrome, Multiple. Multiple pterygium syndrome is a very rare disorder characterized by permanently bent fingers (camptodactyly), short stature, rocker-bottom or club feet, joints that are bent in a fixed position (contractures), union or webbing of the skin between the fingers (syndactyly), and/or webbing of the neck, inside bend of the elbows, back of the knees and armpits. The webbing of skin and contractures of the joints that are found in this disorder may restrict movement.Characteristic facial features can include a small jaw (micrognathia), a long vertical groove in the middle of the upper lip (philtrum), down-slanting eyes, a vertical fold of skin over the inner corner of the eye (epicanthal folds), drooping eyelids, low-set ears, cleft palate and down-turned corners of the mouth. Backward and lateral curvature of the spine (kyphoscoliosis) and spinal fusion abnormalities occur often in multiple pterygium syndrome. Other skeletal anomalies include rib fusions, hip dislocation, abnormal ear bones and absent or malformed kneecaps.Males may have undescended testes and an abnormally small penis. Females may have underdeveloped or missing labia majora.
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Causes of Pterygium Syndrome, Multiple
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Multiple pterygium syndrome usually follows autosomal recessive inheritance but can also follow autosomal dominant inheritance.Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits 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 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. 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 Pterygium Syndrome, Multiple. Multiple pterygium syndrome usually follows autosomal recessive inheritance but can also follow autosomal dominant inheritance.Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits 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 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. 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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Affects of Pterygium Syndrome, Multiple
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Multiple pterygium syndrome is a very rare genetic disorder that affects males and females equally. There have been approximately fifty cases of this disorder reported in the medical literature. Multiple pterygium syndrome has been found in Germany, France and England.
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Affects of Pterygium Syndrome, Multiple. Multiple pterygium syndrome is a very rare genetic disorder that affects males and females equally. There have been approximately fifty cases of this disorder reported in the medical literature. Multiple pterygium syndrome has been found in Germany, France and England.
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Related disorders of Pterygium Syndrome, Multiple
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Symptoms of the following disorders can be similar to those of multiple pterygium syndrome. Comparisons may be useful for a differential diagnosis:Popliteal pterygium syndrome is a disorder characterized by cleft lip and/or cleft palate, lower lip pits, webbed skin (pterygium) on the backs of both legs (popliteal) and between the legs (intercrural), malformation and/or underdevelopment of the genitals, webbing or fusion of the fingers and/or toes (syndactyly), adhesion of upper and lower jaw and adhesion of upper and lower eyelids. A cone-shaped fold of skin on the nail of the big toe is a very distinctive finding in this condition. Popliteal pterygium syndrome is at the severe end of the spectrum of disorders caused by abnormalities in the interferon regulatory factor (IRF6) gene. (For more information about this disorder, choose “IRF6-related disorders” as your search term in the Rare Disease Database.)Lethal multiple pterygium syndrome is characterized by stillbirth or death of an infant shortly after birth. Affected infants usually have underdeveloped lungs, diaphragmatic hernia and abnormalities of the heart, kidneys and brain in addition to webbed skin in multiple areas and contractures.Arthrogryposis multiplex congenita is a disorder that is apparent at birth and characterized by reduced mobility of multiple joints due to rapid growth of fibrous tissue (fibrous ankylosis). The range of motion of the joints of all limbs is limited or fixed. The shoulders are bent inward and internally rotated. The elbows are extended and the wrists and fingers are bent. The hips may be dislocated and are usually slightly bent. The knees are extended and the heel is bent inward at the ankle (clubfoot). (For more information on this disorder, choose “arthrogryposis multiplex congenita” as your search term in the Rare Disease Database.)Noonan syndrome is a rare genetic disorder characterized by a broad or webbed neck, a low hairline in the back of the head and short stature. Characteristic abnormalities of the head and facial (craniofacial) area may include widely set eyes (ocular hypertelorism), vertical skin folds that may cover the inner corners of the eyes (epicanthal folds), drooping of the upper eyelids (ptosis), a small jaw (micrognathia), a low nasal bridge and low-set, prominent, abnormally rotated ears (pinnae). Distinctive skeletal malformations are abnormalities of the breastbone (sternum), curvature of the spine (kyphosis and/or scoliosis), and outward deviation of the elbows (cubitus valgus). Many infants with Noonan syndrome also have heart defects. In some affected individuals, Noonan syndrome appears to result from spontaneous (sporadic) genetic changes (mutations). In others, the disorder may be transmitted as an autosomal dominant trait. (For more information about this disorder, choose “Noonan” as your search term in the Rare Disease Database).
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Related disorders of Pterygium Syndrome, Multiple. Symptoms of the following disorders can be similar to those of multiple pterygium syndrome. Comparisons may be useful for a differential diagnosis:Popliteal pterygium syndrome is a disorder characterized by cleft lip and/or cleft palate, lower lip pits, webbed skin (pterygium) on the backs of both legs (popliteal) and between the legs (intercrural), malformation and/or underdevelopment of the genitals, webbing or fusion of the fingers and/or toes (syndactyly), adhesion of upper and lower jaw and adhesion of upper and lower eyelids. A cone-shaped fold of skin on the nail of the big toe is a very distinctive finding in this condition. Popliteal pterygium syndrome is at the severe end of the spectrum of disorders caused by abnormalities in the interferon regulatory factor (IRF6) gene. (For more information about this disorder, choose “IRF6-related disorders” as your search term in the Rare Disease Database.)Lethal multiple pterygium syndrome is characterized by stillbirth or death of an infant shortly after birth. Affected infants usually have underdeveloped lungs, diaphragmatic hernia and abnormalities of the heart, kidneys and brain in addition to webbed skin in multiple areas and contractures.Arthrogryposis multiplex congenita is a disorder that is apparent at birth and characterized by reduced mobility of multiple joints due to rapid growth of fibrous tissue (fibrous ankylosis). The range of motion of the joints of all limbs is limited or fixed. The shoulders are bent inward and internally rotated. The elbows are extended and the wrists and fingers are bent. The hips may be dislocated and are usually slightly bent. The knees are extended and the heel is bent inward at the ankle (clubfoot). (For more information on this disorder, choose “arthrogryposis multiplex congenita” as your search term in the Rare Disease Database.)Noonan syndrome is a rare genetic disorder characterized by a broad or webbed neck, a low hairline in the back of the head and short stature. Characteristic abnormalities of the head and facial (craniofacial) area may include widely set eyes (ocular hypertelorism), vertical skin folds that may cover the inner corners of the eyes (epicanthal folds), drooping of the upper eyelids (ptosis), a small jaw (micrognathia), a low nasal bridge and low-set, prominent, abnormally rotated ears (pinnae). Distinctive skeletal malformations are abnormalities of the breastbone (sternum), curvature of the spine (kyphosis and/or scoliosis), and outward deviation of the elbows (cubitus valgus). Many infants with Noonan syndrome also have heart defects. In some affected individuals, Noonan syndrome appears to result from spontaneous (sporadic) genetic changes (mutations). In others, the disorder may be transmitted as an autosomal dominant trait. (For more information about this disorder, choose “Noonan” as your search term in the Rare Disease Database).
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Diagnosis of Pterygium Syndrome, Multiple
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Diagnosis of Pterygium Syndrome, Multiple.
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Therapies of Pterygium Syndrome, Multiple
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Therapy is supportive and depends on the severity of the webbing and spinal abnormalities. Orthopedic specialists should be consulted once a diagnosis is made because scoliosis develops before age five in most patients. Affected individuals have an increased risk for developing pneumonia due to a small rib cage so respiratory infections should be treated promptly. Patients with multiple pterygium syndrome may benefit from plastic surgery in the areas of webbing. This must be done with extreme caution as there may be major nerves and blood vessels in the area that are too short to allow for full extension of the limbs. Plastic surgery may also be performed to improve fused fingers and correct the cleft palate when present. Physical therapy can be of benefit to help in preventing the joints from becoming fixed.Drooping eyelids can interfere with vision so an ophthalmology specialist should be consulted. Hearing testing should be done because of an increased risk for conductive hearing loss.Genetic counseling may be of benefit for patients and their families.
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Therapies of Pterygium Syndrome, Multiple. Therapy is supportive and depends on the severity of the webbing and spinal abnormalities. Orthopedic specialists should be consulted once a diagnosis is made because scoliosis develops before age five in most patients. Affected individuals have an increased risk for developing pneumonia due to a small rib cage so respiratory infections should be treated promptly. Patients with multiple pterygium syndrome may benefit from plastic surgery in the areas of webbing. This must be done with extreme caution as there may be major nerves and blood vessels in the area that are too short to allow for full extension of the limbs. Plastic surgery may also be performed to improve fused fingers and correct the cleft palate when present. Physical therapy can be of benefit to help in preventing the joints from becoming fixed.Drooping eyelids can interfere with vision so an ophthalmology specialist should be consulted. Hearing testing should be done because of an increased risk for conductive hearing loss.Genetic counseling may be of benefit for patients and their families.
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Overview of Pulmonary Alveolar Proteinosis
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The lung is composed of millions of tiny air sacs (alveoli) with very thin walls that allow oxygen in the air we breathe to pass through into the blood. Surfactant is an oily substance comprising phospholipids, lesser amounts of cholesterol and proteins and is made in alveoli. It is present as a thin layer on the surface of alveolar walls and helps them stay open allowing air to come in and out as we breathe. Once used, surfactant is removed (cleared) from alveoli by cells called alveolar macrophages. This helps prevent surfactant from building up too much. Alveolar macrophages require a signaling or ‘messenger’ molecule called granulocyte/macrophage-colony stimulating factor (GM-CSF) to stimulate alveolar macrophages to function properly and maintain a normal surfactant level in alveoli. This process, called surfactant homeostasis, requires GM-CSF to stimulate alveolar macrophages to remove excess surfactant normally.Pulmonary alveolar proteinosis (PAP) is a syndrome, a set of symptoms and signs – not a single disease, in which surfactant in alveoli builds up slowly. This blocks air from entering alveoli and oxygen from passing through into the blood, which results in a feeling of breathlessness (dyspnea). Research has greatly improved our understanding of the diseases that cause PAP and how to diagnose and treat them. Diseases that cause PAP can occur in men, women and children of all ages, ethnic backgrounds, and geographic locations. Disease severity varies from mild to severe and depends on which disease is present. Thus, it is important to know which disease is causing PAP in order to determine the best therapy and expected treatment response. Diseases that cause PAP can be grouped into three categories: primary PAP, secondary PAP and congenital PAP (more accurately called disorders of surfactant production).
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Overview of Pulmonary Alveolar Proteinosis. The lung is composed of millions of tiny air sacs (alveoli) with very thin walls that allow oxygen in the air we breathe to pass through into the blood. Surfactant is an oily substance comprising phospholipids, lesser amounts of cholesterol and proteins and is made in alveoli. It is present as a thin layer on the surface of alveolar walls and helps them stay open allowing air to come in and out as we breathe. Once used, surfactant is removed (cleared) from alveoli by cells called alveolar macrophages. This helps prevent surfactant from building up too much. Alveolar macrophages require a signaling or ‘messenger’ molecule called granulocyte/macrophage-colony stimulating factor (GM-CSF) to stimulate alveolar macrophages to function properly and maintain a normal surfactant level in alveoli. This process, called surfactant homeostasis, requires GM-CSF to stimulate alveolar macrophages to remove excess surfactant normally.Pulmonary alveolar proteinosis (PAP) is a syndrome, a set of symptoms and signs – not a single disease, in which surfactant in alveoli builds up slowly. This blocks air from entering alveoli and oxygen from passing through into the blood, which results in a feeling of breathlessness (dyspnea). Research has greatly improved our understanding of the diseases that cause PAP and how to diagnose and treat them. Diseases that cause PAP can occur in men, women and children of all ages, ethnic backgrounds, and geographic locations. Disease severity varies from mild to severe and depends on which disease is present. Thus, it is important to know which disease is causing PAP in order to determine the best therapy and expected treatment response. Diseases that cause PAP can be grouped into three categories: primary PAP, secondary PAP and congenital PAP (more accurately called disorders of surfactant production).
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Symptoms of Pulmonary Alveolar Proteinosis
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In autoimmune PAP, a feeling of breathlessness (dyspnea) is the most common symptom. Most patients develop dyspnea very slowly over time typically noticing it only with activity at first and eventually also at rest. As the disease gets worse from the buildup of surfactant, the fingertips can become bluish in color (cyanosis) due to a low level of oxygen in the blood. Cough is the next most common symptom. This can be a dry cough or a productive cough that produces whitish phlegm (sputum). Coughing up phlegm with streaks of blood (hemoptysis), with or without fever, usually indicates that infection is also present. Rounding of the fingernails and swelling of the fingertips (clubbing) is not a sign of autoimmune PAP. Fatigue, weight loss, chest pain or a general feeling of ill health (malaise) can also occur. Less commonly, secondary infections can occur in or outside the lungs. The disease activity over time (natural history) varies among patients with some experiencing life-threatening respiratory failure while others having a ‘smoldering’ or slowly progressing course and others (about 5-7 percent) may undergo spontaneous improvement. At any given time, about thirty percent of patients may not have any symptoms and the disease is discovered accidentally (incidental).Hereditary PAP is caused by harmful gene variants (mutations) that disrupt the structure of GM-CSF receptors (proteins) on alveolar macrophages, which normally bind GM-CSF and function in an ‘ignition switch’ and ‘car key’ allowing GM-CSF to stimulate these cells. The gene mutations prevent GM-CSF receptors from functioning normally and thus block the effects of GM-CSF on surfactant removal by alveolar macrophages. The clinical presentation of hereditary PAP is similar to that of autoimmune PAP except that it usually develops in children between the ages of 1 and 10 years of age but occasionally occurs in adolescents and older adults. The natural history is also similar to that of autoimmune PAP except that spontaneous improvement has not been reported.In secondary PAP, the presentation is similar to that of primary PAP but occurs in individuals with another underlying disease (or toxic exposure) known to cause PAP. The natural history typically follows the clinical course of the underlying disease.In congenital PAP, the clinical presentation depends on which genetic mutation is present. It can vary from respiratory failure at birth to slow development of lung scaring (fibrosis) in children, adolescents or adults. Symptoms can include rapid breathing (tachypnea), difficulty gaining weight and fever. Fever is usually an indication that infection is present. The natural history may involve worsening of disease over time and progression to respiratory failure at various ages, depending on the specific gene involved and which mutations are present.
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Symptoms of Pulmonary Alveolar Proteinosis. In autoimmune PAP, a feeling of breathlessness (dyspnea) is the most common symptom. Most patients develop dyspnea very slowly over time typically noticing it only with activity at first and eventually also at rest. As the disease gets worse from the buildup of surfactant, the fingertips can become bluish in color (cyanosis) due to a low level of oxygen in the blood. Cough is the next most common symptom. This can be a dry cough or a productive cough that produces whitish phlegm (sputum). Coughing up phlegm with streaks of blood (hemoptysis), with or without fever, usually indicates that infection is also present. Rounding of the fingernails and swelling of the fingertips (clubbing) is not a sign of autoimmune PAP. Fatigue, weight loss, chest pain or a general feeling of ill health (malaise) can also occur. Less commonly, secondary infections can occur in or outside the lungs. The disease activity over time (natural history) varies among patients with some experiencing life-threatening respiratory failure while others having a ‘smoldering’ or slowly progressing course and others (about 5-7 percent) may undergo spontaneous improvement. At any given time, about thirty percent of patients may not have any symptoms and the disease is discovered accidentally (incidental).Hereditary PAP is caused by harmful gene variants (mutations) that disrupt the structure of GM-CSF receptors (proteins) on alveolar macrophages, which normally bind GM-CSF and function in an ‘ignition switch’ and ‘car key’ allowing GM-CSF to stimulate these cells. The gene mutations prevent GM-CSF receptors from functioning normally and thus block the effects of GM-CSF on surfactant removal by alveolar macrophages. The clinical presentation of hereditary PAP is similar to that of autoimmune PAP except that it usually develops in children between the ages of 1 and 10 years of age but occasionally occurs in adolescents and older adults. The natural history is also similar to that of autoimmune PAP except that spontaneous improvement has not been reported.In secondary PAP, the presentation is similar to that of primary PAP but occurs in individuals with another underlying disease (or toxic exposure) known to cause PAP. The natural history typically follows the clinical course of the underlying disease.In congenital PAP, the clinical presentation depends on which genetic mutation is present. It can vary from respiratory failure at birth to slow development of lung scaring (fibrosis) in children, adolescents or adults. Symptoms can include rapid breathing (tachypnea), difficulty gaining weight and fever. Fever is usually an indication that infection is present. The natural history may involve worsening of disease over time and progression to respiratory failure at various ages, depending on the specific gene involved and which mutations are present.
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Causes of Pulmonary Alveolar Proteinosis
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Primary PAP is caused by reduced GM-CSF stimulation of alveolar macrophages, which reduces their ability to remove surfactant from alveoli and results in surfactant build up and breathlessness. Since GM-CSF is also necessary to help alveolar macrophages (and white blood cells) kill and remove bacteria and viruses, loss of GM-CSF stimulation can also result in secondary infections. Primary PAP includes two diseases: autoimmune PAP and hereditary PAP.In autoimmune PAP, the body’s immune cells (B cells) begin making a protein (GM-CSF autoantibody) that attacks GM-CSF and blocks its ability to stimulate alveolar macrophages. While it is known how GM-CSF autoantibodies cause disease (pathogenesis), it is not known what causes the disease to start (etiology). However, PAP occurs more commonly in smokers suggesting cigarette smoke is a ‘trigger’ for the disease.In hereditary PAP, individuals are born with harmful gene variants (mutations) that destroy the function of proteins (receptors) on alveolar macrophage that interact with GM-CSF. The loss of GM-CSF receptor function blocks the ability of GM-CSF to stimulate alveolar macrophages. Hereditary PAP is a recessive genetic disorder. The abnormal GM-CSF receptor function is caused by the presence of two harmful gene variants.Recessive genetic disorders occur when an individual inherits a harmful gene variant from each parent. If an individual inherits one normal gene and one harmful gene variant 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 harmful gene variant 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.In secondary PAP, an underlying disease or clinical condition causes a reduction in the number (or function) of alveolar macrophages, which in turn results in the buildup of surfactant in alveoli and breathlessness. Many diseases, medications or toxic substance exposures are associated with secondary PAP. Examples include, but are not limited to, myelodysplasia (most common), HIV infection, systemic juvenile idiopathic arthritis, chemotherapy, immune suppression medications such as sirolimus, and inhalation of dusts (silica, titanium, aluminum, others).In congenital PAP, individuals are born with harmful gene variants that disrupt the production of normal surfactant. These include variants in genes coding for surfactant protein B (SFTPB), surfactant protein C (SFTPC), a protein involved in lung development (NKX2.1), a protein needed for inclusion of surfactant lipids (ABCA3), and most likely other undiscovered genes. These harmful gene variants lead to production of abnormal surfactant. This buildup in the alveoli results in PAP, but also has more important harmful effects including alveolar collapse, alveolar scarring, and alveolar distortion (interstitial fibrosis) that can result in reduced lung function or respiratory failure. Some forms of congenital PAP are inherited in a recessive pattern (see above) while others follow a dominant pattern where only one of the genes is harmful and the other is normal.
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Causes of Pulmonary Alveolar Proteinosis. Primary PAP is caused by reduced GM-CSF stimulation of alveolar macrophages, which reduces their ability to remove surfactant from alveoli and results in surfactant build up and breathlessness. Since GM-CSF is also necessary to help alveolar macrophages (and white blood cells) kill and remove bacteria and viruses, loss of GM-CSF stimulation can also result in secondary infections. Primary PAP includes two diseases: autoimmune PAP and hereditary PAP.In autoimmune PAP, the body’s immune cells (B cells) begin making a protein (GM-CSF autoantibody) that attacks GM-CSF and blocks its ability to stimulate alveolar macrophages. While it is known how GM-CSF autoantibodies cause disease (pathogenesis), it is not known what causes the disease to start (etiology). However, PAP occurs more commonly in smokers suggesting cigarette smoke is a ‘trigger’ for the disease.In hereditary PAP, individuals are born with harmful gene variants (mutations) that destroy the function of proteins (receptors) on alveolar macrophage that interact with GM-CSF. The loss of GM-CSF receptor function blocks the ability of GM-CSF to stimulate alveolar macrophages. Hereditary PAP is a recessive genetic disorder. The abnormal GM-CSF receptor function is caused by the presence of two harmful gene variants.Recessive genetic disorders occur when an individual inherits a harmful gene variant from each parent. If an individual inherits one normal gene and one harmful gene variant 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 harmful gene variant 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.In secondary PAP, an underlying disease or clinical condition causes a reduction in the number (or function) of alveolar macrophages, which in turn results in the buildup of surfactant in alveoli and breathlessness. Many diseases, medications or toxic substance exposures are associated with secondary PAP. Examples include, but are not limited to, myelodysplasia (most common), HIV infection, systemic juvenile idiopathic arthritis, chemotherapy, immune suppression medications such as sirolimus, and inhalation of dusts (silica, titanium, aluminum, others).In congenital PAP, individuals are born with harmful gene variants that disrupt the production of normal surfactant. These include variants in genes coding for surfactant protein B (SFTPB), surfactant protein C (SFTPC), a protein involved in lung development (NKX2.1), a protein needed for inclusion of surfactant lipids (ABCA3), and most likely other undiscovered genes. These harmful gene variants lead to production of abnormal surfactant. This buildup in the alveoli results in PAP, but also has more important harmful effects including alveolar collapse, alveolar scarring, and alveolar distortion (interstitial fibrosis) that can result in reduced lung function or respiratory failure. Some forms of congenital PAP are inherited in a recessive pattern (see above) while others follow a dominant pattern where only one of the genes is harmful and the other is normal.
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Pulmonary Alveolar Proteinosis
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Affects of Pulmonary Alveolar Proteinosis
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While the frequency of diseases causing PAP in the general population (prevalence) is not well studied, it is thought that autoimmune PAP accounts for 85 – 90 % of all cases. Hereditary PAP, secondary PAP and congenital PAP each account for roughly 5%. Autoimmune PAP occurs in 6-7 people per million individuals in the general population. It most commonly presents in adults of 30 – 40 years of age but can occur in children as young as three years old. It is more common in men, presumably because more men smoke. Hereditary PAP usually presents in children less than ten years old but can present in adults as old as 35 years. The presentation of secondary PAP is linked to the development of another disease capable of causing PAP. The presentation of congenital PAP is variable, ranging from respiratory failure at the time of birth (associated with harmful variants in SFTPB, ABCA3 or NKX2.1 genes) or slow development of interstitial lung disease in children, adolescents or adults (associated with harmful variants in SFTPC or ABCA3 genes).
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Affects of Pulmonary Alveolar Proteinosis. While the frequency of diseases causing PAP in the general population (prevalence) is not well studied, it is thought that autoimmune PAP accounts for 85 – 90 % of all cases. Hereditary PAP, secondary PAP and congenital PAP each account for roughly 5%. Autoimmune PAP occurs in 6-7 people per million individuals in the general population. It most commonly presents in adults of 30 – 40 years of age but can occur in children as young as three years old. It is more common in men, presumably because more men smoke. Hereditary PAP usually presents in children less than ten years old but can present in adults as old as 35 years. The presentation of secondary PAP is linked to the development of another disease capable of causing PAP. The presentation of congenital PAP is variable, ranging from respiratory failure at the time of birth (associated with harmful variants in SFTPB, ABCA3 or NKX2.1 genes) or slow development of interstitial lung disease in children, adolescents or adults (associated with harmful variants in SFTPC or ABCA3 genes).
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Related disorders of Pulmonary Alveolar Proteinosis
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Symptoms of the following disorders can be similar to those of PAP. Comparisons may be useful for a differential diagnosis.Sarcoidosis is a multisystem disorder characterized by the abnormal formation of inflammatory masses or nodules (granulomas) consisting of certain granular white blood cells (modified macrophages or epithelioid cells) in certain organs of the body. The granulomas formed are thought to alter the normal structure of, and potentially the normal functions of, the affected organ(s). This causes symptoms associated with the particular body system(s) in question. Such granuloma formation most commonly affects the lungs in individuals with sarcoidosis. However, in many patients the upper respiratory system, lymph nodes, skin and/or eyes may be involved. The range and severity of symptoms associated with sarcoidosis vary greatly, depending upon the specific organ(s) involved and the degree of the involvement. In some patients, the symptoms may begin suddenly (acute), can be severe and subside in a relatively short period of time (self-limited). Acute sarcoidosis is often characterized by fatigue, fever, generalized muscle aches, difficulty breathing (dyspnea), joint pain, swollen glands, skin eruptions, eye irregularities and/or other symptoms. In the sub-acute form, affected individuals may experience no symptoms (asymptomatic) even with organ involvement. In the chronic form of sarcoidosis, symptoms may appear slowly and subtly and may persist or reoccur over a long time span. Initial symptoms of the chronic form of the disorder may include difficulty breathing (dyspnea), dry cough, limited airflow and other respiratory abnormalities. Symptoms associated with other organ involvement may develop later.Pneumonia is an acute infection of the alveolar spaces and/or the interstitial tissue of the lung. A whole lobe or only a part of a lobe can be involved. The pneumonia may be caused by different bacteria, viruses, fungi or protozoa. Pneumonia is often preceded by an upper respiratory infection. Symptoms usually start suddenly, with a shaking chill, sharp pain in the affected side of the chest, a cough, a high fever and/or a headache. Breathing is difficult and painful.Idiopathic pulmonary fibrosis is an inflammatory lung disorder characterized by abnormal formation of fibrous tissue (fibrosis) between tiny air sacs (alveoli) or ducts in the lungs. Coughing and rapid, shallow breathing occur with moderate exercise. The skin may appear slightly bluish in color (cyanotic) due to lack of circulating oxygen. Complications such as infection, emphysema or heart problems may develop. The exact cause of idiopathic pulmonary fibrosis is unknown. (For more information on this disorder, choose “idiopathic pulmonary fibrosis” as your search term in the Rare Disease Database.)Acute respiratory distress syndrome (ARDS) is a type of severe, acute lung dysfunction affecting all or most of both lungs. It occurs as a result of illness or injury. Although it is sometimes called adult respiratory distress syndrome, it can also affect children. Major symptoms may include breathing difficulties (dyspnea), rapid breathing (tachypnea), excessively deep and rapid breathing (hyperventilation) and insufficient levels of oxygen in the circulating blood (hypoxemia). ARDS may develop in conjunction with widespread infection in the body (sepsis). It can also result from pneumonia, trauma, shock, severe burns, aspiration of food into the lung, multiple blood transfusions and inhalation of toxic fumes. It usually develops within 24 to 48 hours after the original illness or injury and is considered a medical emergency. ARDS may progress to involvement of other organs. (For more information on this disorder, choose “acute respiratory distress” as your search term in the Rare Disease Database.)
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Related disorders of Pulmonary Alveolar Proteinosis. Symptoms of the following disorders can be similar to those of PAP. Comparisons may be useful for a differential diagnosis.Sarcoidosis is a multisystem disorder characterized by the abnormal formation of inflammatory masses or nodules (granulomas) consisting of certain granular white blood cells (modified macrophages or epithelioid cells) in certain organs of the body. The granulomas formed are thought to alter the normal structure of, and potentially the normal functions of, the affected organ(s). This causes symptoms associated with the particular body system(s) in question. Such granuloma formation most commonly affects the lungs in individuals with sarcoidosis. However, in many patients the upper respiratory system, lymph nodes, skin and/or eyes may be involved. The range and severity of symptoms associated with sarcoidosis vary greatly, depending upon the specific organ(s) involved and the degree of the involvement. In some patients, the symptoms may begin suddenly (acute), can be severe and subside in a relatively short period of time (self-limited). Acute sarcoidosis is often characterized by fatigue, fever, generalized muscle aches, difficulty breathing (dyspnea), joint pain, swollen glands, skin eruptions, eye irregularities and/or other symptoms. In the sub-acute form, affected individuals may experience no symptoms (asymptomatic) even with organ involvement. In the chronic form of sarcoidosis, symptoms may appear slowly and subtly and may persist or reoccur over a long time span. Initial symptoms of the chronic form of the disorder may include difficulty breathing (dyspnea), dry cough, limited airflow and other respiratory abnormalities. Symptoms associated with other organ involvement may develop later.Pneumonia is an acute infection of the alveolar spaces and/or the interstitial tissue of the lung. A whole lobe or only a part of a lobe can be involved. The pneumonia may be caused by different bacteria, viruses, fungi or protozoa. Pneumonia is often preceded by an upper respiratory infection. Symptoms usually start suddenly, with a shaking chill, sharp pain in the affected side of the chest, a cough, a high fever and/or a headache. Breathing is difficult and painful.Idiopathic pulmonary fibrosis is an inflammatory lung disorder characterized by abnormal formation of fibrous tissue (fibrosis) between tiny air sacs (alveoli) or ducts in the lungs. Coughing and rapid, shallow breathing occur with moderate exercise. The skin may appear slightly bluish in color (cyanotic) due to lack of circulating oxygen. Complications such as infection, emphysema or heart problems may develop. The exact cause of idiopathic pulmonary fibrosis is unknown. (For more information on this disorder, choose “idiopathic pulmonary fibrosis” as your search term in the Rare Disease Database.)Acute respiratory distress syndrome (ARDS) is a type of severe, acute lung dysfunction affecting all or most of both lungs. It occurs as a result of illness or injury. Although it is sometimes called adult respiratory distress syndrome, it can also affect children. Major symptoms may include breathing difficulties (dyspnea), rapid breathing (tachypnea), excessively deep and rapid breathing (hyperventilation) and insufficient levels of oxygen in the circulating blood (hypoxemia). ARDS may develop in conjunction with widespread infection in the body (sepsis). It can also result from pneumonia, trauma, shock, severe burns, aspiration of food into the lung, multiple blood transfusions and inhalation of toxic fumes. It usually develops within 24 to 48 hours after the original illness or injury and is considered a medical emergency. ARDS may progress to involvement of other organs. (For more information on this disorder, choose “acute respiratory distress” as your search term in the Rare Disease Database.)
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Diagnosis of Pulmonary Alveolar Proteinosis
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PAP may be suspected based upon the history (breathlessness of very slow onset) and physical examination (occasionally, crackles heard by listening with a stethoscope and rarely, cyanosis). Routine blood tests are usually normal. A diagnosis of PAP is typically supported by results from a chest X-ray or computed tomography (CT scan), which typically reveal extensive white patches within the lungs (ground glass opacity) with superimposed angular lines (reticular densities). This pattern is known as ‘crazy paving’ and is characteristic, but not diagnostic, of PAP.Specialized procedures such as bronchoscopy or surgery can be used to obtain lung washings (bronchoalveolar lavage fluid (BAL)) or lung tissue (biopsy) that can be examined to demonstrate PAP is present. Importantly, however, neither of these approaches can determine which disease is present and the cause of PAP.Autoimmune PAP can be identified by very sensitive and specific blood tests that identify the presence or absence of an increased level of GM-CSF autoantibody. Hereditary PAP can be identified by a series of blood tests that are similarly being developed for introduction into routine clinical practice. Finally, the genetic risk factors for hereditary PAP and congenital PAP can be identified by genetic testing.
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Diagnosis of Pulmonary Alveolar Proteinosis. PAP may be suspected based upon the history (breathlessness of very slow onset) and physical examination (occasionally, crackles heard by listening with a stethoscope and rarely, cyanosis). Routine blood tests are usually normal. A diagnosis of PAP is typically supported by results from a chest X-ray or computed tomography (CT scan), which typically reveal extensive white patches within the lungs (ground glass opacity) with superimposed angular lines (reticular densities). This pattern is known as ‘crazy paving’ and is characteristic, but not diagnostic, of PAP.Specialized procedures such as bronchoscopy or surgery can be used to obtain lung washings (bronchoalveolar lavage fluid (BAL)) or lung tissue (biopsy) that can be examined to demonstrate PAP is present. Importantly, however, neither of these approaches can determine which disease is present and the cause of PAP.Autoimmune PAP can be identified by very sensitive and specific blood tests that identify the presence or absence of an increased level of GM-CSF autoantibody. Hereditary PAP can be identified by a series of blood tests that are similarly being developed for introduction into routine clinical practice. Finally, the genetic risk factors for hereditary PAP and congenital PAP can be identified by genetic testing.
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Therapies of Pulmonary Alveolar Proteinosis
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Treatment
Therapy for PAP varies depending upon what disease is present, disease severity and the age of the patient. In autoimmune PAP, about one third of patients do not have symptoms and 5 – 7 percent improve spontaneously. Of those needing therapy, whole lung lavage (WLL) is the current standard therapy. WLL is a procedure done with the patient asleep in which excess surfactant is ‘washed’ out of one lung with salt water (saline) while the other is hooked to a breathing machine supplying pure oxygen. In some patients, WLL is needed only once, while in others it is needed repeatedly on average every year or so. For some, it can be required as frequently as every month. Most patients with autoimmune PAP respond very well to WLL. Hereditary PAP is also treated by WLL, and most patients respond well to therapy. In secondary PAP, removal and avoidance of the causative agent (e.g., silica dust exposure) or successful treatment of the underlying disorder may improve symptoms. Treatment of congenital PAP is generally supportive. However, lung transplantation has been successfully used in infants and children with congenital PAP caused by genetic mutations that disrupt the production of normal surfactant.Genetic counseling is recommended for families of individuals with the hereditary or congenital forms of PAP.
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Therapies of Pulmonary Alveolar Proteinosis. Treatment
Therapy for PAP varies depending upon what disease is present, disease severity and the age of the patient. In autoimmune PAP, about one third of patients do not have symptoms and 5 – 7 percent improve spontaneously. Of those needing therapy, whole lung lavage (WLL) is the current standard therapy. WLL is a procedure done with the patient asleep in which excess surfactant is ‘washed’ out of one lung with salt water (saline) while the other is hooked to a breathing machine supplying pure oxygen. In some patients, WLL is needed only once, while in others it is needed repeatedly on average every year or so. For some, it can be required as frequently as every month. Most patients with autoimmune PAP respond very well to WLL. Hereditary PAP is also treated by WLL, and most patients respond well to therapy. In secondary PAP, removal and avoidance of the causative agent (e.g., silica dust exposure) or successful treatment of the underlying disorder may improve symptoms. Treatment of congenital PAP is generally supportive. However, lung transplantation has been successfully used in infants and children with congenital PAP caused by genetic mutations that disrupt the production of normal surfactant.Genetic counseling is recommended for families of individuals with the hereditary or congenital forms of PAP.
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Overview of Pulmonary Arterial Hypertension
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SummaryPulmonary arterial hypertension (PAH) is a rare, progressive disorder characterized by high blood pressure (hypertension) in the arteries of the lungs (pulmonary artery) for no apparent reason. The pulmonary arteries are the blood vessels that carry blood from the right side of the heart through the lungs. Symptoms of PAH include shortness of breath (dyspnea) especially during exercise, chest pain, and fainting episodes. The exact cause of PAH is unknown and although treatable, there is no known cure for the disease. PAH usually affects women between the ages of 30-60. Individuals with PAH may go years without a diagnosis, either because their symptoms are mild, nonspecific, or only present during demanding exercise. However, it is important to treat PAH because without treatment, high blood pressure in the lungs causes the right heart to work much harder, and over time, this heart muscle may weaken or fail. The progressive nature of this disease means that an individual may experience only mild symptoms at first, but will eventually require treatment and medical care to maintain a reasonable quality of life.Approximately 15-20% of patients with PAH have heritable forms of PAH. People with heritable PAH have either: (1) an autosomal dominant genetic condition associated with mutations in the BMPR2 gene or other recently identified genes now associated with HPAH or other forms of PAH or associated conditions such as pulmonary capillary hemangiomatosis or pulmonary veno-occlusive disease, or (2) are members of a family in which PAH is known to occur as primary disease.IntroductionThe first reported case of PAH occurred in 1891, when the German doctor E. Romberg published a description of a patient who, at autopsy, showed thickening of the pulmonary artery but no heart or lung disease that might have caused the condition. In 1951, 3 cases were reported by Dr. D.T. Dresdale in the U.S. and the illness was originally called primary pulmonary hypertension, which is a term no longer used but broadly refers to a form of pulmonary arterial hypertension (PAH). PAH has been linked to diet drugs such as Fen-Phen, Pondimin and Redux. These drugs were taken off the market in 1997, although cases related to drugs and toxins, such as methamphetamines do still appear. PAH is also associated with a number of other medical diseases such as cirrhosis, congenital heart disease and connective tissue diseases like scleroderma. About 30% of patients with PAH have an associated connective tissue disease.
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Overview of Pulmonary Arterial Hypertension. SummaryPulmonary arterial hypertension (PAH) is a rare, progressive disorder characterized by high blood pressure (hypertension) in the arteries of the lungs (pulmonary artery) for no apparent reason. The pulmonary arteries are the blood vessels that carry blood from the right side of the heart through the lungs. Symptoms of PAH include shortness of breath (dyspnea) especially during exercise, chest pain, and fainting episodes. The exact cause of PAH is unknown and although treatable, there is no known cure for the disease. PAH usually affects women between the ages of 30-60. Individuals with PAH may go years without a diagnosis, either because their symptoms are mild, nonspecific, or only present during demanding exercise. However, it is important to treat PAH because without treatment, high blood pressure in the lungs causes the right heart to work much harder, and over time, this heart muscle may weaken or fail. The progressive nature of this disease means that an individual may experience only mild symptoms at first, but will eventually require treatment and medical care to maintain a reasonable quality of life.Approximately 15-20% of patients with PAH have heritable forms of PAH. People with heritable PAH have either: (1) an autosomal dominant genetic condition associated with mutations in the BMPR2 gene or other recently identified genes now associated with HPAH or other forms of PAH or associated conditions such as pulmonary capillary hemangiomatosis or pulmonary veno-occlusive disease, or (2) are members of a family in which PAH is known to occur as primary disease.IntroductionThe first reported case of PAH occurred in 1891, when the German doctor E. Romberg published a description of a patient who, at autopsy, showed thickening of the pulmonary artery but no heart or lung disease that might have caused the condition. In 1951, 3 cases were reported by Dr. D.T. Dresdale in the U.S. and the illness was originally called primary pulmonary hypertension, which is a term no longer used but broadly refers to a form of pulmonary arterial hypertension (PAH). PAH has been linked to diet drugs such as Fen-Phen, Pondimin and Redux. These drugs were taken off the market in 1997, although cases related to drugs and toxins, such as methamphetamines do still appear. PAH is also associated with a number of other medical diseases such as cirrhosis, congenital heart disease and connective tissue diseases like scleroderma. About 30% of patients with PAH have an associated connective tissue disease.
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Symptoms of Pulmonary Arterial Hypertension
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PAH symptoms are those that are usually due to not having enough oxygen in the blood or inability of the heart to pump enough blood to meet the demands of the body. In most cases, the initial symptom is severe shortness of breath following exertion. Additional symptoms include excessive fatigue, weakness, chest pain, dizzy spells, and fainting episodes.Affected individuals may also have a cough, sometimes with blood (hemoptysis), an enlarged heart and liver, low blood pressure (hypotension), and hoarseness due to compression of a nerve in the chest by an enlarged pulmonary artery.Some affected individuals may experience puffiness or swelling of the face, ankles, abdomen and feet due to abnormal accumulation of fluid (edema) within fascial tissues.Individuals with advanced stages of PAH may have abnormal bluish discoloration of the skin due to low levels of circulating oxygen in the blood (cyanosis). In addition, in severe cases of PAH, the right chamber (ventricle) of the heart is abnormally enlarged (hypertrophy), resulting in diminished functioning of the right portion of the heart and, potentially, right heart failure. Some patients with PAH are diagnosed with more advanced disease when they are no longer able to continue with their normal activities. At this time, the disease may have progressed to a point where the patient is completely bedridden from shortness of breath or other symptoms.
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Symptoms of Pulmonary Arterial Hypertension. PAH symptoms are those that are usually due to not having enough oxygen in the blood or inability of the heart to pump enough blood to meet the demands of the body. In most cases, the initial symptom is severe shortness of breath following exertion. Additional symptoms include excessive fatigue, weakness, chest pain, dizzy spells, and fainting episodes.Affected individuals may also have a cough, sometimes with blood (hemoptysis), an enlarged heart and liver, low blood pressure (hypotension), and hoarseness due to compression of a nerve in the chest by an enlarged pulmonary artery.Some affected individuals may experience puffiness or swelling of the face, ankles, abdomen and feet due to abnormal accumulation of fluid (edema) within fascial tissues.Individuals with advanced stages of PAH may have abnormal bluish discoloration of the skin due to low levels of circulating oxygen in the blood (cyanosis). In addition, in severe cases of PAH, the right chamber (ventricle) of the heart is abnormally enlarged (hypertrophy), resulting in diminished functioning of the right portion of the heart and, potentially, right heart failure. Some patients with PAH are diagnosed with more advanced disease when they are no longer able to continue with their normal activities. At this time, the disease may have progressed to a point where the patient is completely bedridden from shortness of breath or other symptoms.
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Causes of Pulmonary Arterial Hypertension
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The exact cause of PAH is unknown. Researchers believe that injury to the layer of cells that line the small blood vessels of the lung, perhaps then causing or in concert with changes in the smooth muscle cells in the vessel wall, initiates blood vessel disease. This injury, which occurs for unknown reasons, results in the contraction of smooth muscle and therefore narrows the vessel. Researchers also think that some people who develop PAH have blood vessels that are particularly sensitive to certain internal or external factors and constrict, or narrow, when exposed to these factors.Approximately 15-20% of patients with PAH have heritable PAH. Heritable PAH is an autosomal dominant genetic condition caused by changes (mutations) in the BMPR2 gene most commonly, though recently other genes and pathways have been identified. In approximately 20% of families with PAH, we do not yet know the underlying gene mutations.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 in the affected individual. Approximately 80% of individuals who have a mutated (abnormal) BMPR2 gene will not develop PAH, so other genes or environmental triggers must be necessary for PAH to develop. The risk of passing the abnormal gene from parent to child is 50% for each pregnancy and the risk is the same for males and females.Of note, there now exist several publications associating PAH with mutations in other genes in a small number of patients (e.g. CAV1, KCNK3, etc), although many of these genes are closely linked to BMPR2 in terms of biologic signaling (SMAD9, ALK1, endoglin). Recently, pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis have been linked to mutations in the gene EIF2AK4. The function of this gene is still being studied.In August 1996, the Food and Drug Administration (FDA) evaluated data from a report of the International Primary Pulmonary Hypertension Study (IPPHS). The study examined the relationship between appetite-suppressant drugs (dexfenfluramine [Redux] and fenfluramine [Pondimin] and what was then called primary pulmonary hypertension. Findings indicated that the risk of primary pulmonary hypertension (now called a type of PAH) in individuals using appetite-suppressant drugs for three months or longer is about nine times higher than the risk for non-users. The final IPPHS report estimated that the risk of this disorder is about 23 times higher in individuals who use appetite-suppressants for three months or longer. These drugs were taken off the market in 1997, though other diet drugs have been associated with PAH such as benfluorex that was used in Europe until 2009.Along with the increased risk of diet pills, other exposures have been associated with the development of PAH. These include methamphetamines and dasatanib. In addition, a very small percentage of people with HIV develop PAH. In terms of other exposures which may contribute to the development of PAH, few are validated in rigorous studies. However, female sex hormones are an area of great interest for several reasons, including: (1) the higher risk of PAH among females and (2) the association of pregnancy with the development of PAH (may be more common in the peripartum period). Several conditions have been associated with PAH such as liver disease (cirrhosis), congenital heart disease and connective tissue diseases such as scleroderma. The mechanisms through which these conditions might cause PAH are presently being studied and are unknown.Scleroderma is a chronic systemic autoimmune disease (primarily of the skin) characterized by fibrosis (or hardening), vascular alterations, and auto-antibodies. One of the serious complications of this rare disease is PAH, which can occur in up to a third of scleroderma patients. Almost everyone with scleroderma experiences Raynaud’s phenomenon, or cold sensitivity in the fingers and toes, as well, however it is important to note that many patients with PAH have Raynaud’s phenomenon and do not have scleroderma. (For more information on this disorder, choose “scleroderma” as your search term in the Rare Disease Database.)Persistent pulmonary hypertension of the newborn (PPHN) is a kind of PAH that occurs when a newborn’s circulatory system does not adapt to breathing outside the womb. It occurs most often in full-term or post-term babies who had a difficult birth. Newborns that have PPHN have rapid respiration (tachypnea) and abnormal bluish discoloration of the skin due to low levels of circulating oxygen in the blood (cyanosis). The disorder is believed to be caused by insufficient oxygen in the blood flowing to the lungs just before, during or after birth (perinatal hypoxemia), although its precise cause is unknown.
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Causes of Pulmonary Arterial Hypertension. The exact cause of PAH is unknown. Researchers believe that injury to the layer of cells that line the small blood vessels of the lung, perhaps then causing or in concert with changes in the smooth muscle cells in the vessel wall, initiates blood vessel disease. This injury, which occurs for unknown reasons, results in the contraction of smooth muscle and therefore narrows the vessel. Researchers also think that some people who develop PAH have blood vessels that are particularly sensitive to certain internal or external factors and constrict, or narrow, when exposed to these factors.Approximately 15-20% of patients with PAH have heritable PAH. Heritable PAH is an autosomal dominant genetic condition caused by changes (mutations) in the BMPR2 gene most commonly, though recently other genes and pathways have been identified. In approximately 20% of families with PAH, we do not yet know the underlying gene mutations.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 in the affected individual. Approximately 80% of individuals who have a mutated (abnormal) BMPR2 gene will not develop PAH, so other genes or environmental triggers must be necessary for PAH to develop. The risk of passing the abnormal gene from parent to child is 50% for each pregnancy and the risk is the same for males and females.Of note, there now exist several publications associating PAH with mutations in other genes in a small number of patients (e.g. CAV1, KCNK3, etc), although many of these genes are closely linked to BMPR2 in terms of biologic signaling (SMAD9, ALK1, endoglin). Recently, pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis have been linked to mutations in the gene EIF2AK4. The function of this gene is still being studied.In August 1996, the Food and Drug Administration (FDA) evaluated data from a report of the International Primary Pulmonary Hypertension Study (IPPHS). The study examined the relationship between appetite-suppressant drugs (dexfenfluramine [Redux] and fenfluramine [Pondimin] and what was then called primary pulmonary hypertension. Findings indicated that the risk of primary pulmonary hypertension (now called a type of PAH) in individuals using appetite-suppressant drugs for three months or longer is about nine times higher than the risk for non-users. The final IPPHS report estimated that the risk of this disorder is about 23 times higher in individuals who use appetite-suppressants for three months or longer. These drugs were taken off the market in 1997, though other diet drugs have been associated with PAH such as benfluorex that was used in Europe until 2009.Along with the increased risk of diet pills, other exposures have been associated with the development of PAH. These include methamphetamines and dasatanib. In addition, a very small percentage of people with HIV develop PAH. In terms of other exposures which may contribute to the development of PAH, few are validated in rigorous studies. However, female sex hormones are an area of great interest for several reasons, including: (1) the higher risk of PAH among females and (2) the association of pregnancy with the development of PAH (may be more common in the peripartum period). Several conditions have been associated with PAH such as liver disease (cirrhosis), congenital heart disease and connective tissue diseases such as scleroderma. The mechanisms through which these conditions might cause PAH are presently being studied and are unknown.Scleroderma is a chronic systemic autoimmune disease (primarily of the skin) characterized by fibrosis (or hardening), vascular alterations, and auto-antibodies. One of the serious complications of this rare disease is PAH, which can occur in up to a third of scleroderma patients. Almost everyone with scleroderma experiences Raynaud’s phenomenon, or cold sensitivity in the fingers and toes, as well, however it is important to note that many patients with PAH have Raynaud’s phenomenon and do not have scleroderma. (For more information on this disorder, choose “scleroderma” as your search term in the Rare Disease Database.)Persistent pulmonary hypertension of the newborn (PPHN) is a kind of PAH that occurs when a newborn’s circulatory system does not adapt to breathing outside the womb. It occurs most often in full-term or post-term babies who had a difficult birth. Newborns that have PPHN have rapid respiration (tachypnea) and abnormal bluish discoloration of the skin due to low levels of circulating oxygen in the blood (cyanosis). The disorder is believed to be caused by insufficient oxygen in the blood flowing to the lungs just before, during or after birth (perinatal hypoxemia), although its precise cause is unknown.
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Affects of Pulmonary Arterial Hypertension
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PAH occurs 3-5 times more frequently in females than in males. It tends to affect females between the ages of 30 and 60. New cases are estimated to occur in one to two individuals per million each year in the U.S. The incidence is estimated to be similar in Europe. Approximately 500-1000 new cases of PAH are diagnosed each year in the U.S. There is no ethnic or racial group that is known to have a higher frequency of patients with PAH. An exception to this is an apparent paucity of cases of HPAH among subjects of African ancestry, although this may relate to reporting bias and has not been rigorously studied.A rare form of pulmonary hypertension affects individuals who are at high altitude levels (e.g., mountain climbing). It is not recommended for people with PAH or a family history of PAH to live at high altitudes.
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Affects of Pulmonary Arterial Hypertension. PAH occurs 3-5 times more frequently in females than in males. It tends to affect females between the ages of 30 and 60. New cases are estimated to occur in one to two individuals per million each year in the U.S. The incidence is estimated to be similar in Europe. Approximately 500-1000 new cases of PAH are diagnosed each year in the U.S. There is no ethnic or racial group that is known to have a higher frequency of patients with PAH. An exception to this is an apparent paucity of cases of HPAH among subjects of African ancestry, although this may relate to reporting bias and has not been rigorously studied.A rare form of pulmonary hypertension affects individuals who are at high altitude levels (e.g., mountain climbing). It is not recommended for people with PAH or a family history of PAH to live at high altitudes.
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Related disorders of Pulmonary Arterial Hypertension
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Pulmonary hypertension is a general term that means high blood pressure that occurs only in the arteries in the lungs may affect the right side of the heart. The term PAH refers to a specific cause of pulmonary hypertension, but there are other causes of pulmonary hypertension as well. There are four other main causes of pulmonary hypertension:Comparisons may be useful for a differential diagnosis:Most advanced stages of cardiac conditions affecting the left heart can cause pulmonary hypertension through back up of fluid into the lung blood vessels. These cardiac diseases include ischemic heart disease, valvular disease, and cardiomyopathy. They can be ruled out as the cause of pulmonary hypertension by careful history, and using electrocardiography, echocardiography, and cardiac catheterization. This kind of pulmonary hypertension is sometimes called pulmonary venous hypertension. Pulmonary venous hypertension can lead to accumulation of blood in the lung which puts the affected individual at a higher risk for developing pleural effusions and pulmonary edema. Like PAH, pulmonary venous hypertension can cause high blood pressure in the pulmonary artery, difficulty breathing, fatigue, and cough.Lung disease is a leading cause of secondary pulmonary hypertension. Most lung diseases that lead to pulmonary hypertension are detected by abnormal lung sounds on physical examination, pulmonary function testing, and/or high resolution computed tomographic lung imaging. Interstitial pneumonia is a type of chronic lung disease that is associated with pulmonary hypertension. It involves the spaces and tissues in the lining of the lungs with abnormal increases in these tissues. Major symptoms may include shortness of breath on exertion, coughing and loss of appetite. The symptoms may vary from mild to severe according to the extent of involvement. An affected individual usually has no fever, and there is usually no overproduction of mucous.Blood clots may obstruct blood flow into the pulmonary arteries and can cause pulmonary hypertension, so called chronic thromboembolic pulmonary hypertension. These are usually detected by history and specialized lung imaging. This cause of pulmonary hypertension is important to test for because it can be cured in some patients with surgery.Cor pulmonale is a term that denotes enlargement of the right ventricle of the heart that occurs as a result of severe lung disease and associated pulmonary hypertension. It is used as a term for pulmonary heart disease that affects both the heart and lungs. A common cause of cor pulmonale is massive lung clotting from chronic thromboembolic pulmonary hypertension that results in increased pressure in the right ventricle of the heart, usually resulting in heart failure. Additional causes include severe forms of chronic bronchitis and emphysema, as well as extensive loss of lung tissue from surgery or injury. Symptoms usually include difficulty breathing, fainting spells upon exertion, and substernal angina pain in the chest.
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Related disorders of Pulmonary Arterial Hypertension. Pulmonary hypertension is a general term that means high blood pressure that occurs only in the arteries in the lungs may affect the right side of the heart. The term PAH refers to a specific cause of pulmonary hypertension, but there are other causes of pulmonary hypertension as well. There are four other main causes of pulmonary hypertension:Comparisons may be useful for a differential diagnosis:Most advanced stages of cardiac conditions affecting the left heart can cause pulmonary hypertension through back up of fluid into the lung blood vessels. These cardiac diseases include ischemic heart disease, valvular disease, and cardiomyopathy. They can be ruled out as the cause of pulmonary hypertension by careful history, and using electrocardiography, echocardiography, and cardiac catheterization. This kind of pulmonary hypertension is sometimes called pulmonary venous hypertension. Pulmonary venous hypertension can lead to accumulation of blood in the lung which puts the affected individual at a higher risk for developing pleural effusions and pulmonary edema. Like PAH, pulmonary venous hypertension can cause high blood pressure in the pulmonary artery, difficulty breathing, fatigue, and cough.Lung disease is a leading cause of secondary pulmonary hypertension. Most lung diseases that lead to pulmonary hypertension are detected by abnormal lung sounds on physical examination, pulmonary function testing, and/or high resolution computed tomographic lung imaging. Interstitial pneumonia is a type of chronic lung disease that is associated with pulmonary hypertension. It involves the spaces and tissues in the lining of the lungs with abnormal increases in these tissues. Major symptoms may include shortness of breath on exertion, coughing and loss of appetite. The symptoms may vary from mild to severe according to the extent of involvement. An affected individual usually has no fever, and there is usually no overproduction of mucous.Blood clots may obstruct blood flow into the pulmonary arteries and can cause pulmonary hypertension, so called chronic thromboembolic pulmonary hypertension. These are usually detected by history and specialized lung imaging. This cause of pulmonary hypertension is important to test for because it can be cured in some patients with surgery.Cor pulmonale is a term that denotes enlargement of the right ventricle of the heart that occurs as a result of severe lung disease and associated pulmonary hypertension. It is used as a term for pulmonary heart disease that affects both the heart and lungs. A common cause of cor pulmonale is massive lung clotting from chronic thromboembolic pulmonary hypertension that results in increased pressure in the right ventricle of the heart, usually resulting in heart failure. Additional causes include severe forms of chronic bronchitis and emphysema, as well as extensive loss of lung tissue from surgery or injury. Symptoms usually include difficulty breathing, fainting spells upon exertion, and substernal angina pain in the chest.
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Pulmonary Arterial Hypertension
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Diagnosis of Pulmonary Arterial Hypertension
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It can often be hard to detect PAH in a routine clinical examination, even if the disease has progressed. Symptoms of PAH are not unique and may be confused with many other diseases that cause a lack of oxygen in the blood. The diagnosis of PAH is also one of exclusion, meaning that PAH is only diagnosed when other causes of pulmonary hypertension have been ruled out and there seems to be no known cause of the hypertension. The tests that are commonly performed to diagnose PAH and rule out other diseases are echocardiography, blood tests, pulmonary function tests, X-rays of the chest, lung blood flow scans, electrocardiography (ECG), and the “6-minute walk test”, which measures how far an individual can walk in that time period. Ultimately, the majority of subjects undergo confirmation by cardiac catheterization with and without vasodilator testing.Heritable PAH is confirmed if two or more family members have PAH or if a BMPR2 gene mutation or mutation in another gene known to cause PAH is identified in the affected person. Molecular genetic testing for mutations in the BMPR2 gene is available, but should only be performed in concert with genetic counseling.Clinical Testing and Work-UpPatients suspected to have PAH should be referred to a referral center specializing in PAH diagnosis and treatment. The Pulmonary Hypertension Association website can provide contact information for these centers.Genetic counseling is recommended for affected individuals and their families.
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Diagnosis of Pulmonary Arterial Hypertension. It can often be hard to detect PAH in a routine clinical examination, even if the disease has progressed. Symptoms of PAH are not unique and may be confused with many other diseases that cause a lack of oxygen in the blood. The diagnosis of PAH is also one of exclusion, meaning that PAH is only diagnosed when other causes of pulmonary hypertension have been ruled out and there seems to be no known cause of the hypertension. The tests that are commonly performed to diagnose PAH and rule out other diseases are echocardiography, blood tests, pulmonary function tests, X-rays of the chest, lung blood flow scans, electrocardiography (ECG), and the “6-minute walk test”, which measures how far an individual can walk in that time period. Ultimately, the majority of subjects undergo confirmation by cardiac catheterization with and without vasodilator testing.Heritable PAH is confirmed if two or more family members have PAH or if a BMPR2 gene mutation or mutation in another gene known to cause PAH is identified in the affected person. Molecular genetic testing for mutations in the BMPR2 gene is available, but should only be performed in concert with genetic counseling.Clinical Testing and Work-UpPatients suspected to have PAH should be referred to a referral center specializing in PAH diagnosis and treatment. The Pulmonary Hypertension Association website can provide contact information for these centers.Genetic counseling is recommended for affected individuals and their families.
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Therapies of Pulmonary Arterial Hypertension
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TreatmentSeveral medications have been approved by the US Food and Drug Administration (FDA) for the treatment of PAH. These medications can be broadly broken down into four categories described below.ProstaglandinsThe orphan drug Flolan (epoprostenol sodium for injection or prostacycline) has been approved as a standard long-term treatment of individuals with severe PAH. It was the first drug approved specifically for patients with pulmonary hypertension. This drug is used in individuals who do not respond to other types of therapy and in patients with very severe disease. This drug is administered by intravenous infusion through a permanent ambulatory in-dwelling central venous catheter. Since this drug requires continuous infusion, it must not be withdrawn suddenly (including sudden reduction of dosage). Flolan, which is a version of a natural hormone called prostacyclin that dilates constricted blood vessels, is manufactured by GlaxoSmithKline.Recently, a room temperature stable form of epoprostenol had been developed. This is known and Veletri and is made by Actelion Pharmaceuticals US, Inc.The FDA has approved the orphan drug treprostinil (Remodulin) in subcutaneous and intravenous forms and Tyvaso, an inhaled form of treprostinil, and oral form (Orenitram) for the treatment of PAH. The drug is made by United Therapeutics Corp.In 2004, the FDA approved iloprost (Ventavis) for the treatment of PAH. The treatment is inhaled through the mouth with the assistance of a special nebulizer, dilating the arteries and preventing the formation of blood clots. Ventavis is marketed in the U.S. by Actelion Pharmaceuticals US, Inc.Endothelin Receptor AntagonistsThe orphan drug bosentan (Tracleer) has been approved by the FDA for treatment of PAH. The drug allows affected individuals to exert themselves physically with less shortness of breath. It should be carefully monitored while in use. Tracleer is manufactured by Actelion Pharmaceuticals US, Inc.The FDA approved the orphan drug Ambrisentan (Letairis) for treatment of PAH in June 2007. It is used primarily to make exercise and breathing easier. The FDA approved the orphan drug Macitentan (Opsumit) for treatment of PAH in October 2013. In clinical trials this drug was shown to delay disease progression. It works through similar mechanisms as bosentan and ambrisentan. Macitentan is manufactured by Actelion Pharmaceuticals US, Inc.Because of the risk of birth defects with this entire class of medication, these drugs are available only through a special restricted distribution program and require monthly pregnancy testing for women capable of becoming pregnant. Phosphodiesterase Type 5 InhibitorsRevatio (sildenafil), a phosphodiesterase type 5 (PDE5) inhibitor is also used to treat PAH. In clinical studies it increased the distance people walked and decreased pressure in the pulmonary artery. It contains the same ingredient as Viagra (sildenafil citrate). This medication is manufactured by Pfizer Pharmaceuticals.Tadalafil (Adcirca) is a once-daily phosphodiesterase type 5 (PDE-5) inhibitor, shown to improve the patient’s ability to exercise. Adcirca contains the same ingredient (tadalafil) as Cialis.This medication is from United Therapeutics.Other MechanismsThe FDA has approved the drug riociguat (Adempas) for the treatment of PAH. Riociguat works on the same pathway as the phosphodiesterase type 5 inhibitors. This medication is made by Bayer.In 2016, selexipag(Uptravi) was approved for adults and acts by relaxing muscles in the walls of blood vessels. Uptravi is manufactured by Actelion Pharmaceuticals US, Inc.Supportive TherapiesDrugs that cause widening of blood vessels (vasodilators) and lessen blood pressure may also be used to treat PAH. In some PAH cases, calcium channel blockers (e,g, nifedipine and diltiazem) are used as vasodilators. Unfortunately, only a small minority of patients appear to respond with improvement to the use of calcium channel blockers. Other vasodilator drugs have been used including phentolamine, phenoxybenzamine and prazosin. The effectiveness of vasodilator therapy varies from case to case.Other treatments such as anticoagulants, diuretics, and oxygen may be used to treat PAH as supportive therapies. Anticoagulants, such as warfarin, are drugs that prevent blood clots from forming. There are equivocal data on whether these drugs are useful in PAH patients and there are significant bleeding risks associated with them. Diuretics are used to treat fluid retention and swelling (edema) often associated with the condition.To continue with daily activities some individuals may need to carry portable oxygen when they go out. Often light exercise such as walking is still possible for PAH patients and can be useful to maintain muscle strength and conditioning.In severe cases of PAH, a heart-lung, single lung or double lung transplant may be recommended. In patients with lung transplants, both the structure and function of the right ventricle markedly improve. Lung transplant is itself a difficult process and results in new challenges for patients who undergo this procedure. Complications of transplantation include rejection of the transplanted organ and infection. Patients take medications for life to reduce their immune system’s ability to reject their transplanted organ.Pregnancy is not advised for patients with PAH because it puts an extra load on the heart. Estrogen-containing oral contraceptives are generally not recommended, but other types of birth control may be used.
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Therapies of Pulmonary Arterial Hypertension. TreatmentSeveral medications have been approved by the US Food and Drug Administration (FDA) for the treatment of PAH. These medications can be broadly broken down into four categories described below.ProstaglandinsThe orphan drug Flolan (epoprostenol sodium for injection or prostacycline) has been approved as a standard long-term treatment of individuals with severe PAH. It was the first drug approved specifically for patients with pulmonary hypertension. This drug is used in individuals who do not respond to other types of therapy and in patients with very severe disease. This drug is administered by intravenous infusion through a permanent ambulatory in-dwelling central venous catheter. Since this drug requires continuous infusion, it must not be withdrawn suddenly (including sudden reduction of dosage). Flolan, which is a version of a natural hormone called prostacyclin that dilates constricted blood vessels, is manufactured by GlaxoSmithKline.Recently, a room temperature stable form of epoprostenol had been developed. This is known and Veletri and is made by Actelion Pharmaceuticals US, Inc.The FDA has approved the orphan drug treprostinil (Remodulin) in subcutaneous and intravenous forms and Tyvaso, an inhaled form of treprostinil, and oral form (Orenitram) for the treatment of PAH. The drug is made by United Therapeutics Corp.In 2004, the FDA approved iloprost (Ventavis) for the treatment of PAH. The treatment is inhaled through the mouth with the assistance of a special nebulizer, dilating the arteries and preventing the formation of blood clots. Ventavis is marketed in the U.S. by Actelion Pharmaceuticals US, Inc.Endothelin Receptor AntagonistsThe orphan drug bosentan (Tracleer) has been approved by the FDA for treatment of PAH. The drug allows affected individuals to exert themselves physically with less shortness of breath. It should be carefully monitored while in use. Tracleer is manufactured by Actelion Pharmaceuticals US, Inc.The FDA approved the orphan drug Ambrisentan (Letairis) for treatment of PAH in June 2007. It is used primarily to make exercise and breathing easier. The FDA approved the orphan drug Macitentan (Opsumit) for treatment of PAH in October 2013. In clinical trials this drug was shown to delay disease progression. It works through similar mechanisms as bosentan and ambrisentan. Macitentan is manufactured by Actelion Pharmaceuticals US, Inc.Because of the risk of birth defects with this entire class of medication, these drugs are available only through a special restricted distribution program and require monthly pregnancy testing for women capable of becoming pregnant. Phosphodiesterase Type 5 InhibitorsRevatio (sildenafil), a phosphodiesterase type 5 (PDE5) inhibitor is also used to treat PAH. In clinical studies it increased the distance people walked and decreased pressure in the pulmonary artery. It contains the same ingredient as Viagra (sildenafil citrate). This medication is manufactured by Pfizer Pharmaceuticals.Tadalafil (Adcirca) is a once-daily phosphodiesterase type 5 (PDE-5) inhibitor, shown to improve the patient’s ability to exercise. Adcirca contains the same ingredient (tadalafil) as Cialis.This medication is from United Therapeutics.Other MechanismsThe FDA has approved the drug riociguat (Adempas) for the treatment of PAH. Riociguat works on the same pathway as the phosphodiesterase type 5 inhibitors. This medication is made by Bayer.In 2016, selexipag(Uptravi) was approved for adults and acts by relaxing muscles in the walls of blood vessels. Uptravi is manufactured by Actelion Pharmaceuticals US, Inc.Supportive TherapiesDrugs that cause widening of blood vessels (vasodilators) and lessen blood pressure may also be used to treat PAH. In some PAH cases, calcium channel blockers (e,g, nifedipine and diltiazem) are used as vasodilators. Unfortunately, only a small minority of patients appear to respond with improvement to the use of calcium channel blockers. Other vasodilator drugs have been used including phentolamine, phenoxybenzamine and prazosin. The effectiveness of vasodilator therapy varies from case to case.Other treatments such as anticoagulants, diuretics, and oxygen may be used to treat PAH as supportive therapies. Anticoagulants, such as warfarin, are drugs that prevent blood clots from forming. There are equivocal data on whether these drugs are useful in PAH patients and there are significant bleeding risks associated with them. Diuretics are used to treat fluid retention and swelling (edema) often associated with the condition.To continue with daily activities some individuals may need to carry portable oxygen when they go out. Often light exercise such as walking is still possible for PAH patients and can be useful to maintain muscle strength and conditioning.In severe cases of PAH, a heart-lung, single lung or double lung transplant may be recommended. In patients with lung transplants, both the structure and function of the right ventricle markedly improve. Lung transplant is itself a difficult process and results in new challenges for patients who undergo this procedure. Complications of transplantation include rejection of the transplanted organ and infection. Patients take medications for life to reduce their immune system’s ability to reject their transplanted organ.Pregnancy is not advised for patients with PAH because it puts an extra load on the heart. Estrogen-containing oral contraceptives are generally not recommended, but other types of birth control may be used.
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Overview of Pure Autonomic Failure
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The autonomic nervous system controls involuntary actions such as widening or narrowing of our blood vessels. Failure in this system can lead to orthostatic hypotension, which means a sudden drastic drop in blood pressure especially from a lying or sitting down position. The exact cause of pure autonomic failure (PAF) is not known, but is defined as autonomic failure without central nervous system (brain or spinal cord) involvement.
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Overview of Pure Autonomic Failure. The autonomic nervous system controls involuntary actions such as widening or narrowing of our blood vessels. Failure in this system can lead to orthostatic hypotension, which means a sudden drastic drop in blood pressure especially from a lying or sitting down position. The exact cause of pure autonomic failure (PAF) is not known, but is defined as autonomic failure without central nervous system (brain or spinal cord) involvement.
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Pure Autonomic Failure
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Symptoms of Pure Autonomic Failure
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The main symptom of PAF is orthostatic hypotension. Due to the drop in blood pressure, people can have dizziness or faintness including syncope (loss of consciousness) in severe cases. Other related symptoms include visual disturbances, neck pain, breathing difficulty, and decrease in sweating which can lead to heat intolerance. Constipation and urinary problems such as frequent urination and frequent urinary infections may also occur as well as tiredness. A first sign in men can be impotence. The symptoms of orthostatic hypotension are more common in the morning, after eating, after exercise, in hot weather, and at high altitudes. Symptoms worsen when walking, standing or after eating. Symptoms should be relieved by lying down. Signs of PAF include a fall in blood pressure by more than 20 mm systolic or 10 mm diastolic after at least 1 minute of standing.
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Symptoms of Pure Autonomic Failure. The main symptom of PAF is orthostatic hypotension. Due to the drop in blood pressure, people can have dizziness or faintness including syncope (loss of consciousness) in severe cases. Other related symptoms include visual disturbances, neck pain, breathing difficulty, and decrease in sweating which can lead to heat intolerance. Constipation and urinary problems such as frequent urination and frequent urinary infections may also occur as well as tiredness. A first sign in men can be impotence. The symptoms of orthostatic hypotension are more common in the morning, after eating, after exercise, in hot weather, and at high altitudes. Symptoms worsen when walking, standing or after eating. Symptoms should be relieved by lying down. Signs of PAF include a fall in blood pressure by more than 20 mm systolic or 10 mm diastolic after at least 1 minute of standing.
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Pure Autonomic Failure
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Causes of Pure Autonomic Failure
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PAF is caused by abnormal accumulation of a protein called alpha-synuclein in autonomic nerves. This protein helps nerve cells communicate, but its function is not fully understood. Patients with PAF have a loss of nerve cells (neurons) in the intermediolateral column of the spinal cord.
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Causes of Pure Autonomic Failure. PAF is caused by abnormal accumulation of a protein called alpha-synuclein in autonomic nerves. This protein helps nerve cells communicate, but its function is not fully understood. Patients with PAF have a loss of nerve cells (neurons) in the intermediolateral column of the spinal cord.
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Pure Autonomic Failure
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Affects of Pure Autonomic Failure
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The worldwide prevalence of PAF is not known. The age of onset is during adulthood usually in individuals over 60 years. It is more common in males than in females.
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Affects of Pure Autonomic Failure. The worldwide prevalence of PAF is not known. The age of onset is during adulthood usually in individuals over 60 years. It is more common in males than in females.
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Pure Autonomic Failure
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Related disorders of Pure Autonomic Failure
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Symptoms of the following disorders can be similar to those of PAF. Comparisons may be useful for a differential diagnosis.Multiple system atrophy and Parkinson disease are types of primary autonomic failure, which are different from pure autonomic failure and are usually more severe than PAF. Multiple system atrophy is a rare sporadic progressive neurological disorder that causes symptoms of muscle stiffness and weakness, blurred vision, and difficulty with bladder control. Other symptoms can include hoarseness, sleep apnea. Some patients have balance problems instead of stiffness (For more information on this disorder, choose “multiple system atrophy” as your search term in the Rare Disease Database.) Parkinson disease is a neurological disease that affects movement. Symptoms include tremors of the hands, arms, legs, jaw, or head; stiffness; slow movement; and balance problems. The symptoms progress over time and affect activities such as walking and talking. Other symptoms may include trouble swallowing; urinary problems or constipation; skin problems; sleep problems and orthostatic hypotension. Familial dysautonomia is a rare genetic disorder of the autonomic nervous system. The symptoms include poor control of muscle reflexes, abnormal low body temperature, unstable blood pressure, and uncontrollable sweating. A classic symptom in infants is crying without any tears. (For more information on this disorder, choose “familial dysautonomia” as your search term in the Rare Disease Database.)
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Related disorders of Pure Autonomic Failure. Symptoms of the following disorders can be similar to those of PAF. Comparisons may be useful for a differential diagnosis.Multiple system atrophy and Parkinson disease are types of primary autonomic failure, which are different from pure autonomic failure and are usually more severe than PAF. Multiple system atrophy is a rare sporadic progressive neurological disorder that causes symptoms of muscle stiffness and weakness, blurred vision, and difficulty with bladder control. Other symptoms can include hoarseness, sleep apnea. Some patients have balance problems instead of stiffness (For more information on this disorder, choose “multiple system atrophy” as your search term in the Rare Disease Database.) Parkinson disease is a neurological disease that affects movement. Symptoms include tremors of the hands, arms, legs, jaw, or head; stiffness; slow movement; and balance problems. The symptoms progress over time and affect activities such as walking and talking. Other symptoms may include trouble swallowing; urinary problems or constipation; skin problems; sleep problems and orthostatic hypotension. Familial dysautonomia is a rare genetic disorder of the autonomic nervous system. The symptoms include poor control of muscle reflexes, abnormal low body temperature, unstable blood pressure, and uncontrollable sweating. A classic symptom in infants is crying without any tears. (For more information on this disorder, choose “familial dysautonomia” as your search term in the Rare Disease Database.)
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Pure Autonomic Failure
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Diagnosis of Pure Autonomic Failure
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PAF is diagnosed by exclusion of other disorders. Multiple blood pressure measurements that show a fall in blood pressure by more than 20 mm systolic or 10 mm diastolic after at least 1 minute of standing is typical.Norepinephrine levels in the blood and urine are usually greatly reduced and do not increase in an upright position. The neurological exam of a patient with PAF will show no signs of movement disorders.
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Diagnosis of Pure Autonomic Failure. PAF is diagnosed by exclusion of other disorders. Multiple blood pressure measurements that show a fall in blood pressure by more than 20 mm systolic or 10 mm diastolic after at least 1 minute of standing is typical.Norepinephrine levels in the blood and urine are usually greatly reduced and do not increase in an upright position. The neurological exam of a patient with PAF will show no signs of movement disorders.
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Pure Autonomic Failure
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Therapies of Pure Autonomic Failure
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Treatment
There is currently no specific treatment for PAF and treatment for focuses on decreasing the effects of the symptoms. Non-medical measures for sudden changes in blood pressure include tight compression stockings, standing up slowly, increase in salt and water intake, and abdominal binders. These measures are taken to stabilize the sudden changes in blood pressure. Consuming more salt and water may increase the volume of blood and thus help increase blood pressure. Standing up slowly may prevent blood pressure from decreasing too much or too fast. Wearing compression stockings or abdominal binders helps maintain blood pressure by promoting blood flow from the legs to the heart and prevents too much blood from staying in the low parts of the body. Raising the head of the bed by about 4 inches can help prevent blood pressure from increasing too much when lying down. Symptoms of constipation can be managed with high-fiber diet and stool softeners. Problems with urination can be resolved by insertion of a thin rubber tube (catheter) into the bladder. Drug treatments for symptomatic relief include fludrocortisone, midodrine, droxidopa (Northera), and other vasopressors to manage the water and blood pressure balance of the body.
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Therapies of Pure Autonomic Failure. Treatment
There is currently no specific treatment for PAF and treatment for focuses on decreasing the effects of the symptoms. Non-medical measures for sudden changes in blood pressure include tight compression stockings, standing up slowly, increase in salt and water intake, and abdominal binders. These measures are taken to stabilize the sudden changes in blood pressure. Consuming more salt and water may increase the volume of blood and thus help increase blood pressure. Standing up slowly may prevent blood pressure from decreasing too much or too fast. Wearing compression stockings or abdominal binders helps maintain blood pressure by promoting blood flow from the legs to the heart and prevents too much blood from staying in the low parts of the body. Raising the head of the bed by about 4 inches can help prevent blood pressure from increasing too much when lying down. Symptoms of constipation can be managed with high-fiber diet and stool softeners. Problems with urination can be resolved by insertion of a thin rubber tube (catheter) into the bladder. Drug treatments for symptomatic relief include fludrocortisone, midodrine, droxidopa (Northera), and other vasopressors to manage the water and blood pressure balance of the body.
| 1,038 |
Pure Autonomic Failure
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nord_1039_0
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Overview of Pure Red Cell Aplasia, Acquired
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Acquired Pure Red Cell Aplasia is a rare bone marrow disorder characterized by an isolated decline of red blood cells (erythrocytes) produced by the bone marrow. Affected individuals may experience fatigue, lethargy, and/or abnormal paleness of the skin (pallor). Acquired Pure Red Cell Aplasia may occur for unknown reasons (idiopathic) or as a primary autoimmune disorder. It is also believed that Acquired Pure Red Cell Aplasia may occur secondary to a tumor of the thymus gland (thyoma), viral infections, or certain drugs.
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Overview of Pure Red Cell Aplasia, Acquired. Acquired Pure Red Cell Aplasia is a rare bone marrow disorder characterized by an isolated decline of red blood cells (erythrocytes) produced by the bone marrow. Affected individuals may experience fatigue, lethargy, and/or abnormal paleness of the skin (pallor). Acquired Pure Red Cell Aplasia may occur for unknown reasons (idiopathic) or as a primary autoimmune disorder. It is also believed that Acquired Pure Red Cell Aplasia may occur secondary to a tumor of the thymus gland (thyoma), viral infections, or certain drugs.
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Pure Red Cell Aplasia, Acquired
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nord_1039_1
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Symptoms of Pure Red Cell Aplasia, Acquired
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Acquired Pure Red Cell Aplasia is characterized by a decrease in the number of red blood cells produced in the bone marrow. Individuals with this disorder are deficient in the number of precursors of red blood cells (erythroblasts). Levels of the hormone erythropoietin that stimulates the bone marrow to produce red blood cells are usually elevated.Affected individuals may experience fatigue, lethargy, and/or abnormal paleness of the skin (pallor).
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Symptoms of Pure Red Cell Aplasia, Acquired. Acquired Pure Red Cell Aplasia is characterized by a decrease in the number of red blood cells produced in the bone marrow. Individuals with this disorder are deficient in the number of precursors of red blood cells (erythroblasts). Levels of the hormone erythropoietin that stimulates the bone marrow to produce red blood cells are usually elevated.Affected individuals may experience fatigue, lethargy, and/or abnormal paleness of the skin (pallor).
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Pure Red Cell Aplasia, Acquired
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nord_1039_2
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Causes of Pure Red Cell Aplasia, Acquired
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Acquired Pure Red Cell Aplasia is thought to be an autoimmune disorder possibly caused either by a tumor of the thymus gland, certain drugs or a viral infection. It is one of a group of bone marrow failure syndromes.
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Causes of Pure Red Cell Aplasia, Acquired. Acquired Pure Red Cell Aplasia is thought to be an autoimmune disorder possibly caused either by a tumor of the thymus gland, certain drugs or a viral infection. It is one of a group of bone marrow failure syndromes.
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Pure Red Cell Aplasia, Acquired
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nord_1039_3
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Affects of Pure Red Cell Aplasia, Acquired
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Acquired Pure Red Cell Aplasia is a rare disorder affecting males and females in equal numbers.
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Affects of Pure Red Cell Aplasia, Acquired. Acquired Pure Red Cell Aplasia is a rare disorder affecting males and females in equal numbers.
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Pure Red Cell Aplasia, Acquired
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Related disorders of Pure Red Cell Aplasia, Acquired
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Symptoms of the following disorders are similar to those of Acquired Pure Red Cell Aplasia. Comparisons may be useful for a differential diagnosis:Aplastic Anemia is characterized by failure of the bone marrow to produce red blood cells, white blood cells and platelets. Certain other anemias are due either to excessive red cell destruction or a limited production of red blood cells. Aplastic Anemia may occur for unknown reasons, or it may be the result of a toxic reaction to radiation, certain drugs or chemicals. In rare cases, the disorder may be caused by a tumor in the thymus gland. (For more information on this disorder, choose “Aplastic Anemia” as your search term in the Rare Disease Database.)Blackfan-Diamond Anemia is a very rare genetic blood disorder which is present at birth. Blood cell abnormalities accompany an unusual physical appearance, paleness, weakness, and lethargy. (For more information on this disorder, choose “Blackfan” as your search term in the Rare Disease Database.)Fanconi's Anemia is a rare form of familial aplastic anemia. It is characterized by bone abnormalities, an abnormally small head (microcephaly), decreased functioning of the sex organs (hypogenitalism) and brown pigmentation of the skin. Complications may include infections such as pneumonia, meningitis, excessive bleeding (hemorrhages), and leukemia. Other malignancies may also occur. (For more information on this disorder, choose “Fanconi” as your search term in the Rare Disease Database.)
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Related disorders of Pure Red Cell Aplasia, Acquired. Symptoms of the following disorders are similar to those of Acquired Pure Red Cell Aplasia. Comparisons may be useful for a differential diagnosis:Aplastic Anemia is characterized by failure of the bone marrow to produce red blood cells, white blood cells and platelets. Certain other anemias are due either to excessive red cell destruction or a limited production of red blood cells. Aplastic Anemia may occur for unknown reasons, or it may be the result of a toxic reaction to radiation, certain drugs or chemicals. In rare cases, the disorder may be caused by a tumor in the thymus gland. (For more information on this disorder, choose “Aplastic Anemia” as your search term in the Rare Disease Database.)Blackfan-Diamond Anemia is a very rare genetic blood disorder which is present at birth. Blood cell abnormalities accompany an unusual physical appearance, paleness, weakness, and lethargy. (For more information on this disorder, choose “Blackfan” as your search term in the Rare Disease Database.)Fanconi's Anemia is a rare form of familial aplastic anemia. It is characterized by bone abnormalities, an abnormally small head (microcephaly), decreased functioning of the sex organs (hypogenitalism) and brown pigmentation of the skin. Complications may include infections such as pneumonia, meningitis, excessive bleeding (hemorrhages), and leukemia. Other malignancies may also occur. (For more information on this disorder, choose “Fanconi” as your search term in the Rare Disease Database.)
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Pure Red Cell Aplasia, Acquired
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nord_1039_5
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Diagnosis of Pure Red Cell Aplasia, Acquired
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Diagnosis of Pure Red Cell Aplasia, Acquired.
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Pure Red Cell Aplasia, Acquired
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Therapies of Pure Red Cell Aplasia, Acquired
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Acquired Pure Red Cell Aplasia usually goes into remission when certain drugs such as sulfonylureas (used for treating diabetes), gold for treatment of arthritis, penicillin, phenytoin and phenobarbitol used for treating epilepsy, or the anesthetic halothane which can cause this disorder are discontinued. In affected individuals under 30 years of age, the disorder may initially be treated with the immune suppressant drug prednisone and/or antithymocyte globulin. The drugs cyclophosphamide, azathioprine, or 6-mercaptopurine which also suppress the immune system may be used for treating older individuals with Acquired Pure Red Cell Aplasia or those who fail to respond to steroids or antithymocyte globulin. Patients in both age groups may require periodic blood transfusions until the drugs take effect. The drug treatment is slowly decreased when remission of the disorder is acheived.If an individual with Acquired Pure Red Cell Aplasia has a tumor of the thymus gland, surgical removal of this gland often causes remission of this disorder.
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Therapies of Pure Red Cell Aplasia, Acquired. Acquired Pure Red Cell Aplasia usually goes into remission when certain drugs such as sulfonylureas (used for treating diabetes), gold for treatment of arthritis, penicillin, phenytoin and phenobarbitol used for treating epilepsy, or the anesthetic halothane which can cause this disorder are discontinued. In affected individuals under 30 years of age, the disorder may initially be treated with the immune suppressant drug prednisone and/or antithymocyte globulin. The drugs cyclophosphamide, azathioprine, or 6-mercaptopurine which also suppress the immune system may be used for treating older individuals with Acquired Pure Red Cell Aplasia or those who fail to respond to steroids or antithymocyte globulin. Patients in both age groups may require periodic blood transfusions until the drugs take effect. The drug treatment is slowly decreased when remission of the disorder is acheived.If an individual with Acquired Pure Red Cell Aplasia has a tumor of the thymus gland, surgical removal of this gland often causes remission of this disorder.
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Pure Red Cell Aplasia, Acquired
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nord_1040_0
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Overview of Pycnodysostosis
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SummaryPycnodysostosis is a rare genetic disorder characterized by distinctive facial features and skeletal malformations. Affected individuals may have osteosclerosis, a condition characterized by abnormal hardening and increased density of bone. The abnormality of the bones of affected individuals cause the bones to be fragile and brittle. Affected individuals are prone to repeated fractures. Affected individuals may fail to grow and can be shorter than would otherwise be expected (short stature). Intelligence is not affected and the disorder is not believed to be life-threatening. The severity of the disorder including the frequency of fractures, final adult height, and specific symptoms can vary greatly among affected individuals. Pycnodysostosis is caused by changes (mutations) in the cathepsin K (CTSK) gene and is inherited in an autosomal recessive trait.IntroductionPycnodysostosis belongs to a larger group of diseases known as lysosomal storage disorders. Lysosomes are membrane-bound compartments within cells. They contain enzymes that break down large molecules such as proteins, carbohydrates and fats into their building blocks. Low levels or inactivity of an enzyme called cathepsin K results in the abnormal accumulation (storage) of toxic materials in lysosomes. Pycnodysostosis is similar to osteopetrosis and they are sometimes discussed in the medical literature together. Osteopetrosis is a disorder characterized by abnormally dense bones that are brittle and prone to fracture. Osteopetrosis is sometimes associated with skeletal malformations.
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Overview of Pycnodysostosis. SummaryPycnodysostosis is a rare genetic disorder characterized by distinctive facial features and skeletal malformations. Affected individuals may have osteosclerosis, a condition characterized by abnormal hardening and increased density of bone. The abnormality of the bones of affected individuals cause the bones to be fragile and brittle. Affected individuals are prone to repeated fractures. Affected individuals may fail to grow and can be shorter than would otherwise be expected (short stature). Intelligence is not affected and the disorder is not believed to be life-threatening. The severity of the disorder including the frequency of fractures, final adult height, and specific symptoms can vary greatly among affected individuals. Pycnodysostosis is caused by changes (mutations) in the cathepsin K (CTSK) gene and is inherited in an autosomal recessive trait.IntroductionPycnodysostosis belongs to a larger group of diseases known as lysosomal storage disorders. Lysosomes are membrane-bound compartments within cells. They contain enzymes that break down large molecules such as proteins, carbohydrates and fats into their building blocks. Low levels or inactivity of an enzyme called cathepsin K results in the abnormal accumulation (storage) of toxic materials in lysosomes. Pycnodysostosis is similar to osteopetrosis and they are sometimes discussed in the medical literature together. Osteopetrosis is a disorder characterized by abnormally dense bones that are brittle and prone to fracture. Osteopetrosis is sometimes associated with skeletal malformations.
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Symptoms of Pycnodysostosis
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Although researchers have been able to establish a clear syndrome with characteristic or “core” symptoms, much about the disorder is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of other genes influencing the disorder prevent physicians from developing a complete picture of the potential associated symptoms and prognosis. Therefore, it is important to note that affected individuals may not have all the symptoms discussed below. Parents should talk to their children’s physician and medical team about their specific case, associated symptoms and overall prognosis.Infants with pycnodysostosis may experience delayed closure of the sutures of the skull. An infant’s skull has seven bones and several joints called sutures. Sutures are made of tough, elastic fibrous tissue and separate the bones from one another. Sutures meet up (intersect) at two spots on the skull called fontanelles, which are better known as an infant’s “soft spots”. The seven bones of an infant’s skull usually fuse together until around age two or later. In infants with pycnodysostosis, the sutures take longer to fuse together, which can affect the proper development of the skull. The skull is often larger than normal.Distinctive facial features are common and include an abnormally prominent forehead (frontal bossing), a pointed nose, a highly-arched roof of the mouth (palate), prominent eyes with blue discoloration to the whites of the eyes (bluish sclerae), and a small jaw due to underdevelopment of the bones of the jaw (hypoplasia of the maxilla and mandible). Affected individuals may have several dental problems including delayed eruption of baby (deciduous) teeth, and then persistence of these teeth after they come in. They also experience delayed eruption of the permanent teeth. Some individuals may be missing teeth because the teeth fail to develop (hypodontia). Individuals with pycnodysostosis may also have malformation of the collarbone (clavicular dysplasia) and breakdown of bone (osteolysis), particularly the outermost bones of the fingers and toes (acroosteolysis). The fingers may be small and stubby, and the fingernails may be absent or abnormally small. People with pycnodysostosis experience abnormal hardening and density of bone (osteosclerosis). Osteosclerosis causes bone to be fragile and affected individuals are prone to repeated fractures with minimal trauma or without trauma (spontaneously). The legs are most commonly affected by fracturing. Some people may have abnormal curvature of the spine such as having an s-shaped spine (scoliosis). Lower back pain due to stress fractures of the lower spinal bones (vertebrae) can occur. There may be deformities of chest development, which can cause breathing (respiratory) issues. Some individuals may snore, while others may have sleep apnea. Sleep apnea is a condition where a person will momentarily stop breathing during sleep. Sometimes, sleep apnea can be severe. Some individuals with pycnodysostosis have growth hormone deficiency and deficiency of another hormone called insulin-like growth factor 1 (IGF-1), which also plays a role in growth during childhood. Affected individuals reach an adult height that is shorter than would otherwise be expected (short stature). The arms and legs of affected individuals are usually abnormally short. Less often, pycnodysostosis may occur with other symptoms such as loose (lax) joints, underdevelopment (hypoplasia) of the sinuses, enlargement of the liver and spleen (hepatosplenomegaly), and underdevelopment of the pituitary gland.
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Symptoms of Pycnodysostosis. Although researchers have been able to establish a clear syndrome with characteristic or “core” symptoms, much about the disorder is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of other genes influencing the disorder prevent physicians from developing a complete picture of the potential associated symptoms and prognosis. Therefore, it is important to note that affected individuals may not have all the symptoms discussed below. Parents should talk to their children’s physician and medical team about their specific case, associated symptoms and overall prognosis.Infants with pycnodysostosis may experience delayed closure of the sutures of the skull. An infant’s skull has seven bones and several joints called sutures. Sutures are made of tough, elastic fibrous tissue and separate the bones from one another. Sutures meet up (intersect) at two spots on the skull called fontanelles, which are better known as an infant’s “soft spots”. The seven bones of an infant’s skull usually fuse together until around age two or later. In infants with pycnodysostosis, the sutures take longer to fuse together, which can affect the proper development of the skull. The skull is often larger than normal.Distinctive facial features are common and include an abnormally prominent forehead (frontal bossing), a pointed nose, a highly-arched roof of the mouth (palate), prominent eyes with blue discoloration to the whites of the eyes (bluish sclerae), and a small jaw due to underdevelopment of the bones of the jaw (hypoplasia of the maxilla and mandible). Affected individuals may have several dental problems including delayed eruption of baby (deciduous) teeth, and then persistence of these teeth after they come in. They also experience delayed eruption of the permanent teeth. Some individuals may be missing teeth because the teeth fail to develop (hypodontia). Individuals with pycnodysostosis may also have malformation of the collarbone (clavicular dysplasia) and breakdown of bone (osteolysis), particularly the outermost bones of the fingers and toes (acroosteolysis). The fingers may be small and stubby, and the fingernails may be absent or abnormally small. People with pycnodysostosis experience abnormal hardening and density of bone (osteosclerosis). Osteosclerosis causes bone to be fragile and affected individuals are prone to repeated fractures with minimal trauma or without trauma (spontaneously). The legs are most commonly affected by fracturing. Some people may have abnormal curvature of the spine such as having an s-shaped spine (scoliosis). Lower back pain due to stress fractures of the lower spinal bones (vertebrae) can occur. There may be deformities of chest development, which can cause breathing (respiratory) issues. Some individuals may snore, while others may have sleep apnea. Sleep apnea is a condition where a person will momentarily stop breathing during sleep. Sometimes, sleep apnea can be severe. Some individuals with pycnodysostosis have growth hormone deficiency and deficiency of another hormone called insulin-like growth factor 1 (IGF-1), which also plays a role in growth during childhood. Affected individuals reach an adult height that is shorter than would otherwise be expected (short stature). The arms and legs of affected individuals are usually abnormally short. Less often, pycnodysostosis may occur with other symptoms such as loose (lax) joints, underdevelopment (hypoplasia) of the sinuses, enlargement of the liver and spleen (hepatosplenomegaly), and underdevelopment of the pituitary gland.
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Causes of Pycnodysostosis
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Pycnodysostosis is caused by a change (mutation) in the cathepsin K (CTSK) gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body. Pycnodysostosis is 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. In certain populations, pycnodysostosis has occurred in families where the parents are closely related. 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. The CTSK gene produces an enzyme called cathepsin K. This enzyme is a lysosomal enzyme and its job is to break down certain substances in the body include bone matrix proteins, certain types of collagen and other substances. This enzyme is predominantly found in osteoclasts, which are bone cells that absorb bone tissue during growth and healing. Basically, osteoclasts break down bone, a normal process called resorption. Bone is a dynamic system continuously engaged in a remodeling process of resorption and formation. Bone resorption refers to the breakdown of bone followed by the formation of new bone. In pycnodysostosis, some of these materials are not completely broken down and build up in lysosomes of cell. When enough of these materials build up, they become toxic to the affected cells and tissues of the body.
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Causes of Pycnodysostosis. Pycnodysostosis is caused by a change (mutation) in the cathepsin K (CTSK) gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body. Pycnodysostosis is 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. In certain populations, pycnodysostosis has occurred in families where the parents are closely related. 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. The CTSK gene produces an enzyme called cathepsin K. This enzyme is a lysosomal enzyme and its job is to break down certain substances in the body include bone matrix proteins, certain types of collagen and other substances. This enzyme is predominantly found in osteoclasts, which are bone cells that absorb bone tissue during growth and healing. Basically, osteoclasts break down bone, a normal process called resorption. Bone is a dynamic system continuously engaged in a remodeling process of resorption and formation. Bone resorption refers to the breakdown of bone followed by the formation of new bone. In pycnodysostosis, some of these materials are not completely broken down and build up in lysosomes of cell. When enough of these materials build up, they become toxic to the affected cells and tissues of the body.
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Affects of Pycnodysostosis
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Pycnodysostosis is an extremely rare disorder that affects both males and females. About 200 people have been reported in the medical literature with this disorder. It is estimated to affect about 1 in 1.7 million people in the general discussion. Pycnodysostosis may go undiagnosed or misdiagnosed, making it difficult to determine the true frequency in the general population.
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Affects of Pycnodysostosis. Pycnodysostosis is an extremely rare disorder that affects both males and females. About 200 people have been reported in the medical literature with this disorder. It is estimated to affect about 1 in 1.7 million people in the general discussion. Pycnodysostosis may go undiagnosed or misdiagnosed, making it difficult to determine the true frequency in the general population.
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Related disorders of Pycnodysostosis
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Symptoms of the following disorders can be similar to those of pycnodysostosis. Comparisons may be useful for a differential diagnosis.Osteopetrosis may be inherited as either a dominant or recessive trait and is marked by increased bone density, brittle bones, and, in some people, skeletal abnormalities. Although symptoms may not initially be apparent in people with mild forms of this disorder, trivial injuries may cause bone fractures due to abnormalities of the bone. There are three major types of osteopetrosis: the malignant infantile form, the intermediate form, and the adult form. The adult form is milder than the other forms, and may not be diagnosed until adolescence or adulthood when symptoms first appear. The intermediate form, found in children younger than ten years old, is more severe than the adult form but less severe than the malignant infantile form. The malignant infantile form is apparent from birth and frequently shortens life expectancy. The specific forms of osteopetrosis are caused by mutations in specific genes. (For more information on this disorder, choose “osteopetrosis” as your search term in the Rare Disease Database.)Cleidocranial dysplasia is a rare skeletal dysplasia characterized by short stature, distinctive facial features and narrow, sloping shoulders caused by defective or absent collarbones (clavicles). Major symptoms may include premature closing of the soft spot on the head (coronal), delayed closure of the space between the bones of the skull (fontanels), narrow and abnormally shaped pelvic and pubic bones and deformations in the chest (thoracic region). Delayed eruption of teeth, moderately short stature, a high arched palate, a wide pelvic joint, failure of the lower jaw joints to unite, and fingers that are irregular in length may also be present. Cleidocranial dysplasia is inherited as an autosomal dominant genetic trait. (For more information on this disorder, choose “cleidocranial dysplasia” as your search term in the Rare Disease Database.)Osteogenesis imperfecta (OI) is a group of rare disorders affecting the connective tissue and characterized by extremely fragile bones that break or fracture easily (brittle bones), often without apparent cause. The specific symptoms and physical findings associated with OI vary greatly from case to case. The severity of OI also varies greatly, even among individuals of the same family. OI may be a mild disorder or may result in severe complications. Four main types of OI have been identified. OI type I is the most common and the mildest form of the disorder. OI type II is the most severe. In most cases, the various forms of osteogenesis imperfecta are inherited as autosomal dominant traits.Hajdu-Cheney syndrome (HCS) is a rare, genetic disorder of connective tissue; only about 50 cases have been reported in the medical literature. The breakdown of bone (osteolysis), especially the outermost bones of the fingers and toes (acroosteolysis), is a major characteristic of HCS. In addition, affected individuals frequently have skull deformities, short stature, abnormally loose joints (joint laxity), reduction of bone mass (osteoporosis) and other signs or symptoms. Most affected individuals have normal mental development but a small proportion show mild intellectual disability. Hajdu-Cheney syndrome is caused by mutations in the NOTCH2 gene. These mutations are inherited in an autosomal dominant manner. (For more information on this disorder, choose “Hajdu-Cheney” as your search term in the Rare Disease Database.)
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Related disorders of Pycnodysostosis. Symptoms of the following disorders can be similar to those of pycnodysostosis. Comparisons may be useful for a differential diagnosis.Osteopetrosis may be inherited as either a dominant or recessive trait and is marked by increased bone density, brittle bones, and, in some people, skeletal abnormalities. Although symptoms may not initially be apparent in people with mild forms of this disorder, trivial injuries may cause bone fractures due to abnormalities of the bone. There are three major types of osteopetrosis: the malignant infantile form, the intermediate form, and the adult form. The adult form is milder than the other forms, and may not be diagnosed until adolescence or adulthood when symptoms first appear. The intermediate form, found in children younger than ten years old, is more severe than the adult form but less severe than the malignant infantile form. The malignant infantile form is apparent from birth and frequently shortens life expectancy. The specific forms of osteopetrosis are caused by mutations in specific genes. (For more information on this disorder, choose “osteopetrosis” as your search term in the Rare Disease Database.)Cleidocranial dysplasia is a rare skeletal dysplasia characterized by short stature, distinctive facial features and narrow, sloping shoulders caused by defective or absent collarbones (clavicles). Major symptoms may include premature closing of the soft spot on the head (coronal), delayed closure of the space between the bones of the skull (fontanels), narrow and abnormally shaped pelvic and pubic bones and deformations in the chest (thoracic region). Delayed eruption of teeth, moderately short stature, a high arched palate, a wide pelvic joint, failure of the lower jaw joints to unite, and fingers that are irregular in length may also be present. Cleidocranial dysplasia is inherited as an autosomal dominant genetic trait. (For more information on this disorder, choose “cleidocranial dysplasia” as your search term in the Rare Disease Database.)Osteogenesis imperfecta (OI) is a group of rare disorders affecting the connective tissue and characterized by extremely fragile bones that break or fracture easily (brittle bones), often without apparent cause. The specific symptoms and physical findings associated with OI vary greatly from case to case. The severity of OI also varies greatly, even among individuals of the same family. OI may be a mild disorder or may result in severe complications. Four main types of OI have been identified. OI type I is the most common and the mildest form of the disorder. OI type II is the most severe. In most cases, the various forms of osteogenesis imperfecta are inherited as autosomal dominant traits.Hajdu-Cheney syndrome (HCS) is a rare, genetic disorder of connective tissue; only about 50 cases have been reported in the medical literature. The breakdown of bone (osteolysis), especially the outermost bones of the fingers and toes (acroosteolysis), is a major characteristic of HCS. In addition, affected individuals frequently have skull deformities, short stature, abnormally loose joints (joint laxity), reduction of bone mass (osteoporosis) and other signs or symptoms. Most affected individuals have normal mental development but a small proportion show mild intellectual disability. Hajdu-Cheney syndrome is caused by mutations in the NOTCH2 gene. These mutations are inherited in an autosomal dominant manner. (For more information on this disorder, choose “Hajdu-Cheney” as your search term in the Rare Disease Database.)
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Diagnosis of Pycnodysostosis
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A diagnosis of pycnodysostosis is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and x-ray studies. X-ray studies can show many of the characteristic bone changes that are associated with this disorder. Molecular genetic testing can confirm a diagnosis of pycnodysostosis. Molecular genetic testing can detect mutations in the CTSK gene that causes the disorder, but is available only on as a diagnostic service at specialized laboratories.
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Diagnosis of Pycnodysostosis. A diagnosis of pycnodysostosis is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and x-ray studies. X-ray studies can show many of the characteristic bone changes that are associated with this disorder. Molecular genetic testing can confirm a diagnosis of pycnodysostosis. Molecular genetic testing can detect mutations in the CTSK gene that causes the disorder, but is available only on as a diagnostic service at specialized laboratories.
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Therapies of Pycnodysostosis
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TreatmentThe treatment of pycnodysostosis is directed toward the specific symptoms that are apparent in an individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, specialists who diagnose and treat bone disorder (orthopedists), orthopedic surgeons, specialists who diagnose and treat hormonal disorders (endocrinologists), dental specialists, 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 for the entire family is essential as well. There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with pycnodysostosis.Individuals with pycnodysostosis will need orthopedic care when fractures occur. There are no standard guidelines on the best method or surgical intervention for fracture treatment in pycnodysostosis. Specialized dental care should be provided and craniofacial surgery may be warranted.Pycnodysostosis can potentially complicate the use of anesthesia in some people because of abnormalities affecting the jaw and the roof of the mouth (palate). Affected individuals should be evaluated before undergoing procedures that require anesthesia.
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Therapies of Pycnodysostosis. TreatmentThe treatment of pycnodysostosis is directed toward the specific symptoms that are apparent in an individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, specialists who diagnose and treat bone disorder (orthopedists), orthopedic surgeons, specialists who diagnose and treat hormonal disorders (endocrinologists), dental specialists, 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 for the entire family is essential as well. There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with pycnodysostosis.Individuals with pycnodysostosis will need orthopedic care when fractures occur. There are no standard guidelines on the best method or surgical intervention for fracture treatment in pycnodysostosis. Specialized dental care should be provided and craniofacial surgery may be warranted.Pycnodysostosis can potentially complicate the use of anesthesia in some people because of abnormalities affecting the jaw and the roof of the mouth (palate). Affected individuals should be evaluated before undergoing procedures that require anesthesia.
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nord_1041_0
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Overview of Pyoderma Gangrenosum
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Pyoderma gangrenosum (PG) is an inflammatory skin disorder that is characterized by small, red bumps (papules or nodules) or pustules that eventually erode to form swollen open sores (ulcerations). The size and depth of the ulcerations vary greatly, and they are often extremely painful. In approximately 50 percent of cases, PG occurs secondary to another disorder such as inflammatory bowel disease. The exact cause of PG is unknown (idiopathic). Some researchers believe it may be an autoimmune disorder.
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Overview of Pyoderma Gangrenosum. Pyoderma gangrenosum (PG) is an inflammatory skin disorder that is characterized by small, red bumps (papules or nodules) or pustules that eventually erode to form swollen open sores (ulcerations). The size and depth of the ulcerations vary greatly, and they are often extremely painful. In approximately 50 percent of cases, PG occurs secondary to another disorder such as inflammatory bowel disease. The exact cause of PG is unknown (idiopathic). Some researchers believe it may be an autoimmune disorder.
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Symptoms of Pyoderma Gangrenosum
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Pyoderma gangrenosum often begins as small, quick-spreading reddish- or purple-colored bumps or pustules. These small growths eventually develop into swollen, open sores (ulcerations) with a well-defined blue or violet-colored border. The size and depth of ulcerations vary. Ulcerations may spread, widen and deepen and may become extremely painful. In individual cases, ulcerations may continue to spread, remain unchanged, or heal without treatment.Ulcerations can affect any part of the body and have been classified into four variants: classic, atypical/bullous, pustular and vegetative.Classic pyoderma gangrenosum most often occurs on the legs and is characterized by deep ulcerations. These lesions often begin as small pus-filled bumps (pustules) that enlarge and spread rapidly. This form of the disease is often very painful and may also affect the trunk, penis, head and neck areas.Classic PG also occurs near surgical openings (stoma sites) in the body. This condition is referred to as peristomal pyoderma gangrenosum.Atypical or bullous pyoderma gangrenosum is characterized by superficial blisters (bullae). This form of the disease most often affects the hands and is often associated with an underlying disorder, especially hematological malignancy such as leukemia. Some cases that have been called atypical pyoderma gangrenosum actually represent Sweet syndrome.Classic pyoderma gangrenosum is often characterized by the presence of pus and can begin with pustules. Pustular pyoderma gangrenosum is characterized by painful bumps (pustules) most often found on the arms and legs. These lesions eventually develop into ulcerations. This form is often associated with inflammatory bowel disease.Vegetative pyoderma gangrenosum is characterized by chronic ulcerations that are not usually painful.Additional findings sometimes associated with PG include fever, localized tenderness, joint pain (arthralgia), and a general feeling of ill health (malaise). PG may occur as a secondary characteristic of another disorder, most often ulcerative colitis or Crohn’s disease.
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Symptoms of Pyoderma Gangrenosum. Pyoderma gangrenosum often begins as small, quick-spreading reddish- or purple-colored bumps or pustules. These small growths eventually develop into swollen, open sores (ulcerations) with a well-defined blue or violet-colored border. The size and depth of ulcerations vary. Ulcerations may spread, widen and deepen and may become extremely painful. In individual cases, ulcerations may continue to spread, remain unchanged, or heal without treatment.Ulcerations can affect any part of the body and have been classified into four variants: classic, atypical/bullous, pustular and vegetative.Classic pyoderma gangrenosum most often occurs on the legs and is characterized by deep ulcerations. These lesions often begin as small pus-filled bumps (pustules) that enlarge and spread rapidly. This form of the disease is often very painful and may also affect the trunk, penis, head and neck areas.Classic PG also occurs near surgical openings (stoma sites) in the body. This condition is referred to as peristomal pyoderma gangrenosum.Atypical or bullous pyoderma gangrenosum is characterized by superficial blisters (bullae). This form of the disease most often affects the hands and is often associated with an underlying disorder, especially hematological malignancy such as leukemia. Some cases that have been called atypical pyoderma gangrenosum actually represent Sweet syndrome.Classic pyoderma gangrenosum is often characterized by the presence of pus and can begin with pustules. Pustular pyoderma gangrenosum is characterized by painful bumps (pustules) most often found on the arms and legs. These lesions eventually develop into ulcerations. This form is often associated with inflammatory bowel disease.Vegetative pyoderma gangrenosum is characterized by chronic ulcerations that are not usually painful.Additional findings sometimes associated with PG include fever, localized tenderness, joint pain (arthralgia), and a general feeling of ill health (malaise). PG may occur as a secondary characteristic of another disorder, most often ulcerative colitis or Crohn’s disease.
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Causes of Pyoderma Gangrenosum
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The exact cause of pyoderma gangrenosum is unknown (idiopathic) although it is suspected to be an autoimmune disease. Autoimmune disorders are caused when the body’s natural defenses (e.g., antibodies) against foreign or invading organisms begin to attack healthy tissue for unknown reasons.Approximately 50 percent of cases of pyoderma gangrenosum are associated with other disorders, especially the inflammatory bowel diseases ulcerative colitis or Crohn’s disease. Additional disorders associated with pyoderma gangrenosum include rheumatoid arthritis, acute and chronic myelogenous leukemia, myeloid metaplasia, and paraproteinemia.In some people, the development of pyoderma gangrenosum follows surgery or trauma. This condition is known as pathergy.
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Causes of Pyoderma Gangrenosum. The exact cause of pyoderma gangrenosum is unknown (idiopathic) although it is suspected to be an autoimmune disease. Autoimmune disorders are caused when the body’s natural defenses (e.g., antibodies) against foreign or invading organisms begin to attack healthy tissue for unknown reasons.Approximately 50 percent of cases of pyoderma gangrenosum are associated with other disorders, especially the inflammatory bowel diseases ulcerative colitis or Crohn’s disease. Additional disorders associated with pyoderma gangrenosum include rheumatoid arthritis, acute and chronic myelogenous leukemia, myeloid metaplasia, and paraproteinemia.In some people, the development of pyoderma gangrenosum follows surgery or trauma. This condition is known as pathergy.
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Affects of Pyoderma Gangrenosum
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Pyoderma gangrenosum affects women slightly more often than men. It occurs most often between the ages of 20 to 50 years. Infants or adolescents account for fewer than 4 percent of cases. One estimate places the incidence of PG at 1 in every 100,000 people in the United States.
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Affects of Pyoderma Gangrenosum. Pyoderma gangrenosum affects women slightly more often than men. It occurs most often between the ages of 20 to 50 years. Infants or adolescents account for fewer than 4 percent of cases. One estimate places the incidence of PG at 1 in every 100,000 people in the United States.
| 1,041 |
Pyoderma Gangrenosum
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nord_1041_4
|
Related disorders of Pyoderma Gangrenosum
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Symptoms of the following disorders resemble pyoderma gangrenosum clinically or histologically. Comparisons may be useful for a differential diagnosis:Sweet syndrome is a rare skin disorder characterized by fever, inflammation of the joints (arthritis) and the sudden onset of a rash. The rash consists of bluish-red, tender papules that usually occur on the arms, legs, face or neck, most often on one side of the body (asymmetric). In many cases, Sweet syndrome occurs by itself for no known reason (idiopathic). In some cases, the disorder is associated with an underlying malignancy, usually a hematologic malignancy such as certain types of leukemia. The exact cause of Sweet syndrome is unknown. (For more information on this disorder, choose “Sweet” as your search term in the Rare Disease Database).Cutaneous sporotrichosis is a chronic fungal infection under the skin (subcutaneous) spread by way of the lymph glands and caused by the fungus known as Sporothrix schenckii. The disease may remain localized or may become generalized, involving bones, joints, lungs and the central nervous system. Lesions may be grainy, full of pus, ulcerative or draining.The following disorders may precede the development of pyoderma gangrenosum. They can be useful in identifying an underlying cause of some forms of this disorder:Ulcerative colitis is a non-specific inflammatory disease of the bowel characterized by chronic ulceration. The chief characteristic of this disorder is bloody diarrhea. This disease is of unknown cause. It generally begins in the area of the rectum but may involve the entire large bowel. Ulcerative colitis is usually chronic, with acute inflammation of the colon. It is characterized by multiple, irregular superficial ulcerations, thickening of the wall of the colon with scar tissue and pseudopolyps. (For more information on this disorder, choose “Ulcerative Colitis” as your search term in the Rare Disease Database.)Crohn’s disease is a form of inflammatory bowel disease, characterized by severe chronic inflammation of the wall of the small intestine, but it can involve any part of the gastrointestinal tract. The symptoms include fatigue, anorexia, weight loss, abdominal pain and chronic diarrhea. Less commonly, there is inflammation of the mucosa of the mouth, esophagus or stomach. Regional lymph nodes can become involved. A solid mass may be felt in the abdomen during acute stages of the disease.
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Related disorders of Pyoderma Gangrenosum. Symptoms of the following disorders resemble pyoderma gangrenosum clinically or histologically. Comparisons may be useful for a differential diagnosis:Sweet syndrome is a rare skin disorder characterized by fever, inflammation of the joints (arthritis) and the sudden onset of a rash. The rash consists of bluish-red, tender papules that usually occur on the arms, legs, face or neck, most often on one side of the body (asymmetric). In many cases, Sweet syndrome occurs by itself for no known reason (idiopathic). In some cases, the disorder is associated with an underlying malignancy, usually a hematologic malignancy such as certain types of leukemia. The exact cause of Sweet syndrome is unknown. (For more information on this disorder, choose “Sweet” as your search term in the Rare Disease Database).Cutaneous sporotrichosis is a chronic fungal infection under the skin (subcutaneous) spread by way of the lymph glands and caused by the fungus known as Sporothrix schenckii. The disease may remain localized or may become generalized, involving bones, joints, lungs and the central nervous system. Lesions may be grainy, full of pus, ulcerative or draining.The following disorders may precede the development of pyoderma gangrenosum. They can be useful in identifying an underlying cause of some forms of this disorder:Ulcerative colitis is a non-specific inflammatory disease of the bowel characterized by chronic ulceration. The chief characteristic of this disorder is bloody diarrhea. This disease is of unknown cause. It generally begins in the area of the rectum but may involve the entire large bowel. Ulcerative colitis is usually chronic, with acute inflammation of the colon. It is characterized by multiple, irregular superficial ulcerations, thickening of the wall of the colon with scar tissue and pseudopolyps. (For more information on this disorder, choose “Ulcerative Colitis” as your search term in the Rare Disease Database.)Crohn’s disease is a form of inflammatory bowel disease, characterized by severe chronic inflammation of the wall of the small intestine, but it can involve any part of the gastrointestinal tract. The symptoms include fatigue, anorexia, weight loss, abdominal pain and chronic diarrhea. Less commonly, there is inflammation of the mucosa of the mouth, esophagus or stomach. Regional lymph nodes can become involved. A solid mass may be felt in the abdomen during acute stages of the disease.
| 1,041 |
Pyoderma Gangrenosum
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nord_1041_5
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Diagnosis of Pyoderma Gangrenosum
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No specific diagnostic tests exist for pyoderma gangrenosum. Diagnosis is made by excluding similar disorders based upon a thorough clinical evaluation, a detailed patient history and a variety of tests such as surgical removal and microscopic evaluation of affected tissue (biopsy).
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Diagnosis of Pyoderma Gangrenosum. No specific diagnostic tests exist for pyoderma gangrenosum. Diagnosis is made by excluding similar disorders based upon a thorough clinical evaluation, a detailed patient history and a variety of tests such as surgical removal and microscopic evaluation of affected tissue (biopsy).
| 1,041 |
Pyoderma Gangrenosum
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nord_1041_6
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Therapies of Pyoderma Gangrenosum
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Treatment
Treatment of PG consists of open wet dressings on the ulcers and topical application of anti-inflammatory creams and ointments such as corticosteroids. The skin must be protected from any other injury that could result in the development of additional ulcers. In some cases, the grafting of new skin to the wound may be recommended once the inflammation is controlled.Additional treatment of PG includes the administration of corticosteroid drugs such as methylprednisolone and prednisone. Corticosteroids may be administered by intramuscular injection or orally or by intralesional injection directly into the pyoderma gangrenosum.
According to some researchers, individuals with a history of PG should receive preventive (prophylactic) treatment with corticosteroids before undergoing surgery because surgery may cause a recurrence of the disorder.Immunosuppressive therapies (drugs that suppress the immune system) are sometimes used to treat people with pyoderma gangrenosum. Cyclosporine is effective for many patients. Azathioprine and cyclophosphamide are also immunosuppressive drugs that have been used to treat PG. In recent years drugs known as tumor necrosis factor inhibitors have been used very successfully to treat pyoderma gangrenosum. Infliximab and adalimumab have been most successful. Antibacterial agents such as Dapsone may also be administered. In some people, surgical treatment of the underlying disorder such as ulcerative colitis has alleviated symptoms of pyoderma gangrenosum.Additional treatment is symptomatic and supportive.
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Therapies of Pyoderma Gangrenosum. Treatment
Treatment of PG consists of open wet dressings on the ulcers and topical application of anti-inflammatory creams and ointments such as corticosteroids. The skin must be protected from any other injury that could result in the development of additional ulcers. In some cases, the grafting of new skin to the wound may be recommended once the inflammation is controlled.Additional treatment of PG includes the administration of corticosteroid drugs such as methylprednisolone and prednisone. Corticosteroids may be administered by intramuscular injection or orally or by intralesional injection directly into the pyoderma gangrenosum.
According to some researchers, individuals with a history of PG should receive preventive (prophylactic) treatment with corticosteroids before undergoing surgery because surgery may cause a recurrence of the disorder.Immunosuppressive therapies (drugs that suppress the immune system) are sometimes used to treat people with pyoderma gangrenosum. Cyclosporine is effective for many patients. Azathioprine and cyclophosphamide are also immunosuppressive drugs that have been used to treat PG. In recent years drugs known as tumor necrosis factor inhibitors have been used very successfully to treat pyoderma gangrenosum. Infliximab and adalimumab have been most successful. Antibacterial agents such as Dapsone may also be administered. In some people, surgical treatment of the underlying disorder such as ulcerative colitis has alleviated symptoms of pyoderma gangrenosum.Additional treatment is symptomatic and supportive.
| 1,041 |
Pyoderma Gangrenosum
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nord_1042_0
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Overview of Pyridoxine-Dependent Epilepsy
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Pyridoxine-dependent epilepsy (PDE) is a rare cause of stubborn, difficult to control, (intractable) seizures appearing in newborns, infants and occasionally older children. More than 200 patients have now been reported in the medical literature. PDE presents in a variety of forms with variable signs and symptoms (phenotypically heterogeneous). The one clinical feature characteristic of all patients with PDE is intractable seizures that are not controlled with anticonvulsant drugs but which do respond both clinically and usually on EEG (electroencephalographically) to large daily supplements of pyridoxine. These patients are not pyridoxine-deficient. They are metabolically dependent on the vitamin. In other words, even though they get the recommended daily allowance (RDA) of pyridoxine from their normal diet, they require substantially more of the vitamin than an otherwise normal individual. Patients with PDE require pyridoxine therapy for life.
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Overview of Pyridoxine-Dependent Epilepsy. Pyridoxine-dependent epilepsy (PDE) is a rare cause of stubborn, difficult to control, (intractable) seizures appearing in newborns, infants and occasionally older children. More than 200 patients have now been reported in the medical literature. PDE presents in a variety of forms with variable signs and symptoms (phenotypically heterogeneous). The one clinical feature characteristic of all patients with PDE is intractable seizures that are not controlled with anticonvulsant drugs but which do respond both clinically and usually on EEG (electroencephalographically) to large daily supplements of pyridoxine. These patients are not pyridoxine-deficient. They are metabolically dependent on the vitamin. In other words, even though they get the recommended daily allowance (RDA) of pyridoxine from their normal diet, they require substantially more of the vitamin than an otherwise normal individual. Patients with PDE require pyridoxine therapy for life.
| 1,042 |
Pyridoxine-Dependent Epilepsy
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nord_1042_1
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Symptoms of Pyridoxine-Dependent Epilepsy
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Patients with the classic neonatal PDE experience seizures soon after birth. In retrospect, many mothers describe rhythmic movements in the uterus (womb) that may start in the late second trimester and which likely represent fetal seizures. Affected neonates frequently have periods of irritability, unusual eye and facial movements, fluctuating tone, and poor feeding (encephalopathy) that precede the onset of clinical seizures. Abnormal Apgar scores (which measure heart rate, respiration, muscle tone, reflex irritability and color at birth plus one minute and at birth plus five minutes) and cord blood gases may also be seen. Under such conditions, it is not uncommon for these infants to be diagnosed initially as laboring under insufficient oxygen with consequent damage to the nervous system. Similar periods of encephalopathy may be seen in older infants with PDE, particularly prior to the onset of a recurrence of clinical seizures. Pyridoxine-treated patients who have been lax in taking their medicine (non-compliant) or those patients whose daily vitamin requirement may have increased due to growth or an intercurrent infection (particularly fever or gastroenteritis) may also experience recurrent seizures.Many atypical presentations of PDE have been described. These include late onset seizures (up to two years of age, and in very rare instances into adolescence), seizures which initially respond to anticonvulsant drugs and then become intractable, seizures during early life which do not respond to pyridoxine but which then come under control with pyridoxine several months later, and patients with prolonged seizure-free intervals (up to 5.5 months) which occur after discontinuing pyridoxine.Patients with PDE may have various types of clinical seizures. While dramatic presentations consisting of prolonged seizures and/or recurrent episodes of shorter seizures associated with a long-lasting loss of consciousness (status epilepticus) are considered to be the typical feature of affected individuals, PDE patients may also have recurrent self-limited events including partial seizures, generalized seizures, atonic seizures, myoclonic events and infantile spasms. On EEG, patients with PDE may also have electrographic seizures without clinical correlates.A variable degree of intellectual disability is common in these patients. Patients whose seizures appear earlier in life are more likely to show diminished cognitive function. Some clinical reports conclude that the length of the delay in diagnosis and initiation of effective pyridoxine treatment may be related to increased handicaps. Future cognitive function is also likely related to the type of genetic mutation underlying PDE in a particular patient, as well as any associated abnormalities in brain development. Few formal psychometric assessments in patients with PDE have been performed. The limited studies performed to date indicate that in these patients verbal intellectual function is more impaired than non-verbal skills. While significant neurodevelopmental disabilities and psychiatric disorders may be present in some PDE patients, it is important that parents know that patients with PDE may have normal intellectual function.
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Symptoms of Pyridoxine-Dependent Epilepsy. Patients with the classic neonatal PDE experience seizures soon after birth. In retrospect, many mothers describe rhythmic movements in the uterus (womb) that may start in the late second trimester and which likely represent fetal seizures. Affected neonates frequently have periods of irritability, unusual eye and facial movements, fluctuating tone, and poor feeding (encephalopathy) that precede the onset of clinical seizures. Abnormal Apgar scores (which measure heart rate, respiration, muscle tone, reflex irritability and color at birth plus one minute and at birth plus five minutes) and cord blood gases may also be seen. Under such conditions, it is not uncommon for these infants to be diagnosed initially as laboring under insufficient oxygen with consequent damage to the nervous system. Similar periods of encephalopathy may be seen in older infants with PDE, particularly prior to the onset of a recurrence of clinical seizures. Pyridoxine-treated patients who have been lax in taking their medicine (non-compliant) or those patients whose daily vitamin requirement may have increased due to growth or an intercurrent infection (particularly fever or gastroenteritis) may also experience recurrent seizures.Many atypical presentations of PDE have been described. These include late onset seizures (up to two years of age, and in very rare instances into adolescence), seizures which initially respond to anticonvulsant drugs and then become intractable, seizures during early life which do not respond to pyridoxine but which then come under control with pyridoxine several months later, and patients with prolonged seizure-free intervals (up to 5.5 months) which occur after discontinuing pyridoxine.Patients with PDE may have various types of clinical seizures. While dramatic presentations consisting of prolonged seizures and/or recurrent episodes of shorter seizures associated with a long-lasting loss of consciousness (status epilepticus) are considered to be the typical feature of affected individuals, PDE patients may also have recurrent self-limited events including partial seizures, generalized seizures, atonic seizures, myoclonic events and infantile spasms. On EEG, patients with PDE may also have electrographic seizures without clinical correlates.A variable degree of intellectual disability is common in these patients. Patients whose seizures appear earlier in life are more likely to show diminished cognitive function. Some clinical reports conclude that the length of the delay in diagnosis and initiation of effective pyridoxine treatment may be related to increased handicaps. Future cognitive function is also likely related to the type of genetic mutation underlying PDE in a particular patient, as well as any associated abnormalities in brain development. Few formal psychometric assessments in patients with PDE have been performed. The limited studies performed to date indicate that in these patients verbal intellectual function is more impaired than non-verbal skills. While significant neurodevelopmental disabilities and psychiatric disorders may be present in some PDE patients, it is important that parents know that patients with PDE may have normal intellectual function.
| 1,042 |
Pyridoxine-Dependent Epilepsy
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nord_1042_2
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Causes of Pyridoxine-Dependent Epilepsy
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Mutations in the antiquitin gene (ALDH7A1) were identified in 2006 as the cause of PDE. Antiquitin is an enzyme that plays a role in the metabolism of lysine, an amino acid. Abnormal function of antiquitin secondarily results in elevations of the chemical alpha-aminoadipic semialdehyde (α-AASA) which leads to reduced activity of several enzymes in the brain that regulate the transmission of signals between neurons as well as brain development. PDE is a familial (genetic) disorder that follows autosomal recessive inheritance. 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.
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Causes of Pyridoxine-Dependent Epilepsy. Mutations in the antiquitin gene (ALDH7A1) were identified in 2006 as the cause of PDE. Antiquitin is an enzyme that plays a role in the metabolism of lysine, an amino acid. Abnormal function of antiquitin secondarily results in elevations of the chemical alpha-aminoadipic semialdehyde (α-AASA) which leads to reduced activity of several enzymes in the brain that regulate the transmission of signals between neurons as well as brain development. PDE is a familial (genetic) disorder that follows autosomal recessive inheritance. 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.
| 1,042 |
Pyridoxine-Dependent Epilepsy
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nord_1042_3
|
Affects of Pyridoxine-Dependent Epilepsy
|
PDE is considered to be a rare disease, and only a few epidemiologic studies have been published. For example, a study from the United Kingdom and the Republic of Ireland reported a point prevalence of 1:687,000 for definite and probable cases of PDE, while a survey conducted in the Netherlands reported an estimated birth incidence of 1:396,000. PDE is quite likely under-diagnosed and a higher birth incidence is suspected. This notion is supported by a study from a German center where pyridoxine administration is part of a standard treatment protocol for neonatal seizures and a birth incidence of probable cases of 1:20,000 was reported. Recently, an international genetics study of 185 PDE subjects together with the analysis of population-based genomic databases concluded that the birth incidence of PDE is approximately 1:64,000 live births.
|
Affects of Pyridoxine-Dependent Epilepsy. PDE is considered to be a rare disease, and only a few epidemiologic studies have been published. For example, a study from the United Kingdom and the Republic of Ireland reported a point prevalence of 1:687,000 for definite and probable cases of PDE, while a survey conducted in the Netherlands reported an estimated birth incidence of 1:396,000. PDE is quite likely under-diagnosed and a higher birth incidence is suspected. This notion is supported by a study from a German center where pyridoxine administration is part of a standard treatment protocol for neonatal seizures and a birth incidence of probable cases of 1:20,000 was reported. Recently, an international genetics study of 185 PDE subjects together with the analysis of population-based genomic databases concluded that the birth incidence of PDE is approximately 1:64,000 live births.
| 1,042 |
Pyridoxine-Dependent Epilepsy
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nord_1042_4
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Related disorders of Pyridoxine-Dependent Epilepsy
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While PDE due to antiquitin deficiency should be considered when evaluating possible causes of intractable seizures in young patients, other more common causes must be ruled out, including a variety of brain malformation syndromes, serious acquired disorders of the central nervous system (such as hemorrhagic conditions and infections), and other inborn errors of metabolism. There are two additional neonatal metabolic disorders that have similarities to form of PDE that is due to mutations in ALDH7A1. One of these is a rare form of pyridoxine-dependent neonatal seizures due to abnormalities in the PLPBP gene which encodes the pyridoxal phosphate homeostasis protein. Infants with this disorder have a similar clinical presentation but do not have an abnormality in lysine metabolism with elevations in α-AASA. In this disorder, seizures do respond to pyridoxine. Another closely related neonatal metabolic epilepsy is pyridoxamine-5′-phosphate oxidase deficiency (PNPO deficiency). Babies with this genetic disorder also have intractable seizures, but the seizures in these patients respond to pyridoxal-5’-phosphate (P5P, the biologically active form of pyridoxine) but in most instances do not respond to pyridoxine. Other genetic pyridoxine-dependency states have been described (e.g. pyridoxine-dependent anemia and pyridoxine-dependent forms of homocystinuria, xanthurenic aciduria and cystathioninuria), but these conditions are not genetically related to PDE, and intractable seizures are not a feature of these other disorders.
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Related disorders of Pyridoxine-Dependent Epilepsy. While PDE due to antiquitin deficiency should be considered when evaluating possible causes of intractable seizures in young patients, other more common causes must be ruled out, including a variety of brain malformation syndromes, serious acquired disorders of the central nervous system (such as hemorrhagic conditions and infections), and other inborn errors of metabolism. There are two additional neonatal metabolic disorders that have similarities to form of PDE that is due to mutations in ALDH7A1. One of these is a rare form of pyridoxine-dependent neonatal seizures due to abnormalities in the PLPBP gene which encodes the pyridoxal phosphate homeostasis protein. Infants with this disorder have a similar clinical presentation but do not have an abnormality in lysine metabolism with elevations in α-AASA. In this disorder, seizures do respond to pyridoxine. Another closely related neonatal metabolic epilepsy is pyridoxamine-5′-phosphate oxidase deficiency (PNPO deficiency). Babies with this genetic disorder also have intractable seizures, but the seizures in these patients respond to pyridoxal-5’-phosphate (P5P, the biologically active form of pyridoxine) but in most instances do not respond to pyridoxine. Other genetic pyridoxine-dependency states have been described (e.g. pyridoxine-dependent anemia and pyridoxine-dependent forms of homocystinuria, xanthurenic aciduria and cystathioninuria), but these conditions are not genetically related to PDE, and intractable seizures are not a feature of these other disorders.
| 1,042 |
Pyridoxine-Dependent Epilepsy
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nord_1042_5
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Diagnosis of Pyridoxine-Dependent Epilepsy
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Until the third year of life, PDE must be considered as a possible cause of intractable seizures in any patient. In particular, this diagnosis needs to be investigated in any newborn (neonate) with encephalopathy and seizures when there is no convincing evidence of oxygen deprivation, brain hemorrhage, other identifiable underlying metabolic disturbance or brain malformation. PDE must also be suspected in all young patients with intractable seizures with a history of a similar disorder in a sibling. Prior to the discovery of the abnormal gene and biochemical markers, the diagnosis could only be made on a clinical basis by observing over the course of days to weeks a patient’s response to pyridoxine therapy. Importantly, there are no definitive EEG or imaging features that will confirm a diagnosis of PDE. A clinical diagnosis may be made on an acute basis in patients experiencing prolonged or very frequent seizures by administering 100 mg of pyridoxine intravenously while monitoring the EEG, oxygen saturation and vital signs. In most patients with PDE, clinical seizures will cease and a corresponding change in the EEG will be noted. If a response is not demonstrated, the dose should be repeated up to a maximum of 500 mg. In some patients with PDE, significant neurologic and cardiorespiratory adverse effects followed this trial; therefore, close systemic monitoring is essential. For patients who are experiencing shorter seizures which occur at least daily, the diagnosis can be made by administering 30 mg/kg/day of pyridoxine orally. Patients with PDE who are treated in this fashion should stop having clinical seizures within a week. In either case, to confirm the diagnosis of PDE, a patient whose seizures stop after the use of pyridoxine should have blood or urine tested for α-AASA, or a test of the ALDH7A1 gene. With the development of multi-gene “epilepsy panels” and whole exome sequencing, PDE may be an unanticipated diagnosis in patients with intractable epilepsy and its discovery should lead to an immediate change in management.
|
Diagnosis of Pyridoxine-Dependent Epilepsy. Until the third year of life, PDE must be considered as a possible cause of intractable seizures in any patient. In particular, this diagnosis needs to be investigated in any newborn (neonate) with encephalopathy and seizures when there is no convincing evidence of oxygen deprivation, brain hemorrhage, other identifiable underlying metabolic disturbance or brain malformation. PDE must also be suspected in all young patients with intractable seizures with a history of a similar disorder in a sibling. Prior to the discovery of the abnormal gene and biochemical markers, the diagnosis could only be made on a clinical basis by observing over the course of days to weeks a patient’s response to pyridoxine therapy. Importantly, there are no definitive EEG or imaging features that will confirm a diagnosis of PDE. A clinical diagnosis may be made on an acute basis in patients experiencing prolonged or very frequent seizures by administering 100 mg of pyridoxine intravenously while monitoring the EEG, oxygen saturation and vital signs. In most patients with PDE, clinical seizures will cease and a corresponding change in the EEG will be noted. If a response is not demonstrated, the dose should be repeated up to a maximum of 500 mg. In some patients with PDE, significant neurologic and cardiorespiratory adverse effects followed this trial; therefore, close systemic monitoring is essential. For patients who are experiencing shorter seizures which occur at least daily, the diagnosis can be made by administering 30 mg/kg/day of pyridoxine orally. Patients with PDE who are treated in this fashion should stop having clinical seizures within a week. In either case, to confirm the diagnosis of PDE, a patient whose seizures stop after the use of pyridoxine should have blood or urine tested for α-AASA, or a test of the ALDH7A1 gene. With the development of multi-gene “epilepsy panels” and whole exome sequencing, PDE may be an unanticipated diagnosis in patients with intractable epilepsy and its discovery should lead to an immediate change in management.
| 1,042 |
Pyridoxine-Dependent Epilepsy
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