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nord_985_5
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Diagnosis of Polymyositis and Necrotizing Myopathy
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The diagnosis of PM is often delayed due to the lack of physical findings before the onset of muscle disease. Both family history and medication history are important in excluding other causes of myopathy. Additionally, various tests may be performed to establish a diagnosis. Tests may include: (a) electromyography done by a specialist in neuromuscular diseases which detects characteristic electrical patterns in muscle tissue and are abnormal in almost all patients with polymyositis; (b) muscle biopsy which reveals inflammation and or necrosis in the muscle tissue; (c) magnetic resonance imaging (MRI) of the affected muscle(s) which demonstrates inflammation and edema within the muscle tissue. Blood tests can be performed to detect elevated levels of muscle enzymes, predominantly creatine kinase (CK) and aldolase among others, which are indicative of muscle damage. Autoantibodies have been identified in many PM and NM patients consistent with an autoimmune cause as discussed earlier.
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Diagnosis of Polymyositis and Necrotizing Myopathy. The diagnosis of PM is often delayed due to the lack of physical findings before the onset of muscle disease. Both family history and medication history are important in excluding other causes of myopathy. Additionally, various tests may be performed to establish a diagnosis. Tests may include: (a) electromyography done by a specialist in neuromuscular diseases which detects characteristic electrical patterns in muscle tissue and are abnormal in almost all patients with polymyositis; (b) muscle biopsy which reveals inflammation and or necrosis in the muscle tissue; (c) magnetic resonance imaging (MRI) of the affected muscle(s) which demonstrates inflammation and edema within the muscle tissue. Blood tests can be performed to detect elevated levels of muscle enzymes, predominantly creatine kinase (CK) and aldolase among others, which are indicative of muscle damage. Autoantibodies have been identified in many PM and NM patients consistent with an autoimmune cause as discussed earlier.
| 985 |
Polymyositis and Necrotizing Myopathy
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nord_985_6
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Therapies of Polymyositis and Necrotizing Myopathy
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TreatmentPolymyositis generally responds well to treatment in most patients, although, residual weakness may occur in approximately 30% of patients. Glucocorticoids (i.e. steroids or prednisone) are widely used as the initial form of treatment in PM. They control the inflammation, lessen pain, and increase muscle strength through their ability to suppress the body’s immune system. The specific dose is individualized; however, the starting dose of prednisone is generally high at about 1mg/kg of body weight (often equating to about 60mg/day). They are then tapered depending on the response of the patient and associated side effects. Measurement of the serum CK is used to gauge the effectiveness of therapy and reduction of the muscle enzymes to normal values is noted in a majority of patients with this disorder within 4 to 8 weeks after treatment is started. This is followed by an improvement in muscle strength. As the steroids are reduced (or often initially when the steroids are started) other medications that also suppress the immune system may be added so that the glucocorticoids can be tapered. This is necessary to reduce the side effects (i.e. osteoporosis, weight gain, change in mental status, increased blood sugar, cataracts, stomach upset, etc.) that the steroids cause. In many cases of adult PM and NM prolonged maintenance therapy with prednisone or other immunosuppressive agents may be necessary indefinitely. A major concern with glucocorticoids is osteoporosis, which may cause significant morbidity. In this instance, additional calcium and vitamin D supplementation may be beneficial.Immunosuppressive drugs such as methotrexate, azathioprine, mycophenolate mofetil, tacrolimus, cyclosporine cyclophosphamide, and others have been beneficial to patients who fail to respond to steroids alone and can be used as second-line therapies or in combination with prednisone. Cyclophosphamide and tacrolimus are used more frequently in patients with interstitial lung disease.Acthar is a synthetic adrenocorticotropic hormone (ACTH) that is FDA-approved for the treatment of polymyositis and dermatomyositis but the exact mechanism of action is unknown and this agent acts through melanocortin receptors. Currently, there is limited data on its effectiveness. Intravenous immunoglobulin (IVIG) is a blood product that enhances the body’s immune system response. IVIG is usually used in patients who do not respond to other therapies but has been noted to be particularly effective in NM. Biologic agents provide a more targeted therapy and are often monoclonal antibodies or proteins targeting various immune system mediators. Anti-tumor necrosis factor (anti-TNF) agents such as etanercept, adalimumab, and infliximab have potential for use in polymyositis as they suppress tumor-necrosis factor proteins that are associated with inflammation but data supporting their effectiveness are limited. Rituximab is another biologic monoclonal antibody that targets B cells which play a role in inflammation. This agent has been studied in treating PM, DM and NM and may provide some benefit to these patients; however, more studies are required.Various vitamins and supplements, although not approved specifically for use in polymyositis, have been useful to patients. Examples include: coenzyme Q10 (CoQ10), creatine, fish oil, and others.Physical therapy and a regular exercise routine are often recommended even when the myositis is active as the beneficial effects of exercise are being increasingly reported. Patients also benefit from heat therapy, passive range-of-motion exercises, and splints to avoid contractures. Speech therapy may be useful if the swallowing muscles become weakened. Additionally, a registered dietitian can be recommended if chewing and swallowing become problematic.
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Therapies of Polymyositis and Necrotizing Myopathy. TreatmentPolymyositis generally responds well to treatment in most patients, although, residual weakness may occur in approximately 30% of patients. Glucocorticoids (i.e. steroids or prednisone) are widely used as the initial form of treatment in PM. They control the inflammation, lessen pain, and increase muscle strength through their ability to suppress the body’s immune system. The specific dose is individualized; however, the starting dose of prednisone is generally high at about 1mg/kg of body weight (often equating to about 60mg/day). They are then tapered depending on the response of the patient and associated side effects. Measurement of the serum CK is used to gauge the effectiveness of therapy and reduction of the muscle enzymes to normal values is noted in a majority of patients with this disorder within 4 to 8 weeks after treatment is started. This is followed by an improvement in muscle strength. As the steroids are reduced (or often initially when the steroids are started) other medications that also suppress the immune system may be added so that the glucocorticoids can be tapered. This is necessary to reduce the side effects (i.e. osteoporosis, weight gain, change in mental status, increased blood sugar, cataracts, stomach upset, etc.) that the steroids cause. In many cases of adult PM and NM prolonged maintenance therapy with prednisone or other immunosuppressive agents may be necessary indefinitely. A major concern with glucocorticoids is osteoporosis, which may cause significant morbidity. In this instance, additional calcium and vitamin D supplementation may be beneficial.Immunosuppressive drugs such as methotrexate, azathioprine, mycophenolate mofetil, tacrolimus, cyclosporine cyclophosphamide, and others have been beneficial to patients who fail to respond to steroids alone and can be used as second-line therapies or in combination with prednisone. Cyclophosphamide and tacrolimus are used more frequently in patients with interstitial lung disease.Acthar is a synthetic adrenocorticotropic hormone (ACTH) that is FDA-approved for the treatment of polymyositis and dermatomyositis but the exact mechanism of action is unknown and this agent acts through melanocortin receptors. Currently, there is limited data on its effectiveness. Intravenous immunoglobulin (IVIG) is a blood product that enhances the body’s immune system response. IVIG is usually used in patients who do not respond to other therapies but has been noted to be particularly effective in NM. Biologic agents provide a more targeted therapy and are often monoclonal antibodies or proteins targeting various immune system mediators. Anti-tumor necrosis factor (anti-TNF) agents such as etanercept, adalimumab, and infliximab have potential for use in polymyositis as they suppress tumor-necrosis factor proteins that are associated with inflammation but data supporting their effectiveness are limited. Rituximab is another biologic monoclonal antibody that targets B cells which play a role in inflammation. This agent has been studied in treating PM, DM and NM and may provide some benefit to these patients; however, more studies are required.Various vitamins and supplements, although not approved specifically for use in polymyositis, have been useful to patients. Examples include: coenzyme Q10 (CoQ10), creatine, fish oil, and others.Physical therapy and a regular exercise routine are often recommended even when the myositis is active as the beneficial effects of exercise are being increasingly reported. Patients also benefit from heat therapy, passive range-of-motion exercises, and splints to avoid contractures. Speech therapy may be useful if the swallowing muscles become weakened. Additionally, a registered dietitian can be recommended if chewing and swallowing become problematic.
| 985 |
Polymyositis and Necrotizing Myopathy
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nord_986_0
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Overview of POMC Deficiency
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SummaryPOMC deficiency affects the way the body stores and uses energy. The main symptoms include constant hunger and excessive feeding, known as hyperphagia. Hyperphagia leads to obesity by one year of age and without treatment people with POMC deficiency remain obese throughout life. Other symptoms include low levels of a hormone called adrenocorticotropic hormone (ACTH) and adrenal insufficiency, which can be fatal if not treated early. Many individuals with POMC deficiency also have pale skin and hair. POMC deficiency is caused by changes (pathogenic variants or mutations) in the POMC gene and is inherited in an autosomal recessive pattern. Diagnosis is based on a clinical examination, symptoms and the results of genetic testing. Treatment is available for people with POMC deficiency over the age of six using a drug called setmelanotide.IntroductionPOMC deficiency was first described in 1998. This condition is rare, making it difficult to predict exactly how it will affect someone with a new diagnosis of this condition. It is one of several conditions that include early-onset obesity, and these conditions can be difficult to distinguish from each other without a careful physical examination and genetic testing.
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Overview of POMC Deficiency. SummaryPOMC deficiency affects the way the body stores and uses energy. The main symptoms include constant hunger and excessive feeding, known as hyperphagia. Hyperphagia leads to obesity by one year of age and without treatment people with POMC deficiency remain obese throughout life. Other symptoms include low levels of a hormone called adrenocorticotropic hormone (ACTH) and adrenal insufficiency, which can be fatal if not treated early. Many individuals with POMC deficiency also have pale skin and hair. POMC deficiency is caused by changes (pathogenic variants or mutations) in the POMC gene and is inherited in an autosomal recessive pattern. Diagnosis is based on a clinical examination, symptoms and the results of genetic testing. Treatment is available for people with POMC deficiency over the age of six using a drug called setmelanotide.IntroductionPOMC deficiency was first described in 1998. This condition is rare, making it difficult to predict exactly how it will affect someone with a new diagnosis of this condition. It is one of several conditions that include early-onset obesity, and these conditions can be difficult to distinguish from each other without a careful physical examination and genetic testing.
| 986 |
POMC Deficiency
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nord_986_1
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Symptoms of POMC Deficiency
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Most individuals diagnosed with POMC deficiency have early-onset obesity and adrenal insufficiency, a condition in which the adrenal glands don’t work correctly. The first symptom of POMC deficiency is often very low blood sugar (hypoglycemia) related to adrenal insufficiency and low levels of ACTH, an important hormone made by the pituitary. ACTH is necessary for the adequate production of cortisol in the adrenal gland. If left untreated, adrenal insufficiency may lead to liver failure and less commonly, death. Infants with POMC deficiency have a normal birth weight but are constantly hungry (hyperphagia) and gain weight very quickly. Obesity is common by age one. Children and adults with this condition have continuous hunger, obesity and behavior problems related to food and eating. Obesity may become severe, leading to other health problems. Some people have a low functioning thyroid gland and are shorter than average. Delayed or absent puberty has also been reported. Many people with POMC deficiency also have pale skin and light or red hair.
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Symptoms of POMC Deficiency. Most individuals diagnosed with POMC deficiency have early-onset obesity and adrenal insufficiency, a condition in which the adrenal glands don’t work correctly. The first symptom of POMC deficiency is often very low blood sugar (hypoglycemia) related to adrenal insufficiency and low levels of ACTH, an important hormone made by the pituitary. ACTH is necessary for the adequate production of cortisol in the adrenal gland. If left untreated, adrenal insufficiency may lead to liver failure and less commonly, death. Infants with POMC deficiency have a normal birth weight but are constantly hungry (hyperphagia) and gain weight very quickly. Obesity is common by age one. Children and adults with this condition have continuous hunger, obesity and behavior problems related to food and eating. Obesity may become severe, leading to other health problems. Some people have a low functioning thyroid gland and are shorter than average. Delayed or absent puberty has also been reported. Many people with POMC deficiency also have pale skin and light or red hair.
| 986 |
POMC Deficiency
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nord_986_2
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Causes of POMC Deficiency
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POMC deficiency is caused by pathogenic variants (mutations) in the POMC gene. The POMC gene works with other genes to help signal the body when it’s time to eat and when it has had enough food. When the POMC gene doesn’t work correctly, these signals don’t exist and a person with POMC deficiency feels hungry all the time. In addition, the protein made by the POMC gene affects other glands in the body, especially the adrenal gland, thyroid and liver.POMC deficiency is inherited in families in a recessive pattern. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
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Causes of POMC Deficiency. POMC deficiency is caused by pathogenic variants (mutations) in the POMC gene. The POMC gene works with other genes to help signal the body when it’s time to eat and when it has had enough food. When the POMC gene doesn’t work correctly, these signals don’t exist and a person with POMC deficiency feels hungry all the time. In addition, the protein made by the POMC gene affects other glands in the body, especially the adrenal gland, thyroid and liver.POMC deficiency is inherited in families in a recessive pattern. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
| 986 |
POMC Deficiency
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nord_986_3
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Affects of POMC Deficiency
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POMC deficiency is very rare, and it is unclear if it is more common in any particular populations. It has been diagnosed more often in populations where marriage between relatives is customary.
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Affects of POMC Deficiency. POMC deficiency is very rare, and it is unclear if it is more common in any particular populations. It has been diagnosed more often in populations where marriage between relatives is customary.
| 986 |
POMC Deficiency
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nord_986_4
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Related disorders of POMC Deficiency
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POMC deficiency is one of several rare inherited conditions that include early-onset obesity with few or no other signs or symptoms. These conditions are due to changes in one of the genes that normally work together to help regulate hunger and energy production. These conditions may be difficult to diagnose based solely on clinical examination. Adrenal insufficiency and pale skin and hair may set POMC deficiency apart from other early-onset obesity conditions, but often genetic testing is the only way to tell the difference between them.Some (but not all) of these conditions include:PCSK1 deficiencyPCSK1 deficiency is a very rare inherited disorder that affects the metabolism and appetite. Severe diarrhea, digestive problems and slow growth are the earliest symptoms which tend to slightly diminish with time, followed by extreme hunger and obesity in early childhood. Excessive thirst and frequent urination (polyuria polydipsia syndrome) are common. Other symptoms related to abnormalities of the endocrine glands include growth hormone deficiency, low thyroid hormone and adrenal gland disorders. PCSK1 deficiency is caused by variants in the PCSK1 gene and is inherited in an autosomal recessive pattern. Diagnosis is based on a clinical examination, symptoms, laboratory testing and the results of genetic testing. Treatment is available for this condition using a drug called setmelanotide. This drug has been approved for treating people age six and over with PCSK1 deficiency and reverses the symptoms including obesity. Less than 50 people have been reported with PCSK1 deficiency.Congenital leptin deficiencyCongenital leptin deficiency (CLD) is a rare, inherited condition that affects how the body processes energy, responds to food and stores fat. Infants with CLD are constantly hungry and quickly gain weight and become obese. Children with CLD have extreme hunger (hyperphagia), low energy and abnormal behaviors related to food. Many people with CLD produce little or no sex hormones (hypogonadotropic hypogonadism) resulting in late or absent puberty and infertility. CLD is caused by variants in the LEP gene, which is responsible for making a protein called leptin. Leptin is important for regulating appetite and growth of body fat. This condition is inherited in an autosomal recessive pattern. Diagnosis is based on a clinical examination, symptoms and the results of genetic testing. Diet, behavior modification, exercise programs and bariatric surgery have been used to help manage the symptoms of CLD. Treatment is available for this condition using a drug called metreleptin, a recombinant form of human leptin, which reverses the symptoms of CLD. With treatment, people with CLD develop a normal appetite, lose weight and fat and regain normal sex hormone levels.Leptin receptor deficiency (LEPR deficiency) Individuals with LEPR deficiency have almost the same symptoms as individuals with congenital leptin deficiency. Early symptoms of both conditions include constant hunger and feeding (hyperphagia) and rapid weight gain leading to obesity in the first few months of life. In addition, endocrine gland abnormalities affecting levels of sex hormones are common, and puberty may be absent or delayed. This condition is caused by variants in the LEPR gene and is inherited in a recessive pattern. Diagnosis is based on a clinical exam, symptoms and the results of genetic testing. Treatment is available for this condition using setmelanotide, which decreases appetite and increases levels of sex hormones.Bardet-Biedl syndrome (BBS)BBS impacts multiple body systems and is classically defined by six features. People with BBS gain excessive weight, especially around the abdomen. They often also have intellectual disabilities. The kidneys, eyes and function of the genitalia may be compromised. People with BBS may also be born with an extra digit on the hands. The severity and symptoms of BBS vary, even among individuals in the same family. For more information on this disorder, choose “Bardet-Biedl syndrome” as your search term in the Rare Disease Database. https://rarediseases.org/rare-diseases/bardet-biedl-syndrome/Alström syndrome Alström syndrome is a rare complex disorder that includes a wide variety of symptoms affecting multiple organ systems of the body. The disorder is characterized by vision and hearing abnormalities, obesity in childhood, insulin resistance and diabetes mellitus. Other symptoms include heart disease (dilated cardiomyopathy) and slowly progressive kidney dysfunction, potentially leading to kidney failure. Additional symptoms include lung, liver, kidney and endocrine dysfunction. Although some children may experience delays in reaching developmental milestones, intelligence is usually unaffected. Alström syndrome is caused by variants in the ALMS1 gene. The protein made by this gene is involved in ciliary function, cell cycle control and intracellular transport. Alström syndrome is inherited in an autosomal recessive pattern. For more information on this disorder, choose “Alstrom syndrome” as your search term in the Rare Disease Database. https://rarediseases.org/rare-diseases/alstrom-syndrome/Prader-Willi syndromePrader-Willi syndrome (PWS) is a multisystem disorder characterized during infancy by lethargy, diminished muscle tone (hypotonia), a weak suck and feeding difficulties with poor weight gain and growth and other hormone deficiencies. In childhood, features of this disorder include short stature, small genitals and an excessive appetite. People with PWS do not feel satisfied after completing a meal (satiety). Without intervention, overeating can lead to life-threatening obesity. The food compulsion requires constant supervision. Individuals with severe obesity may have an increased risk of cardiac insufficiency, sleep apnea, diabetes, respiratory problems and other serious conditions that can cause life-threatening complications. All individuals with PWS have some cognitive impairment that ranges from low normal intelligence with learning disabilities to mild to moderate intellectual disability. Behavioral problems are common and can include temper tantrums, obsessive/compulsive behavior and skin picking. Motor milestones and language development are often delayed. PWS occurs due to changes of specific genes on part of the chromosome 15 inherited from the father. This condition is referred to as a genomic imprinting disorder which depends on which parent passes on the chromosome with the genetic changes to the child. For more information on this disorder, choose “Prader-Willi syndrome” as your search term in the Rare Disease Database. https://rarediseases.org/rare-diseases/prader-willi-syndrome/
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Related disorders of POMC Deficiency. POMC deficiency is one of several rare inherited conditions that include early-onset obesity with few or no other signs or symptoms. These conditions are due to changes in one of the genes that normally work together to help regulate hunger and energy production. These conditions may be difficult to diagnose based solely on clinical examination. Adrenal insufficiency and pale skin and hair may set POMC deficiency apart from other early-onset obesity conditions, but often genetic testing is the only way to tell the difference between them.Some (but not all) of these conditions include:PCSK1 deficiencyPCSK1 deficiency is a very rare inherited disorder that affects the metabolism and appetite. Severe diarrhea, digestive problems and slow growth are the earliest symptoms which tend to slightly diminish with time, followed by extreme hunger and obesity in early childhood. Excessive thirst and frequent urination (polyuria polydipsia syndrome) are common. Other symptoms related to abnormalities of the endocrine glands include growth hormone deficiency, low thyroid hormone and adrenal gland disorders. PCSK1 deficiency is caused by variants in the PCSK1 gene and is inherited in an autosomal recessive pattern. Diagnosis is based on a clinical examination, symptoms, laboratory testing and the results of genetic testing. Treatment is available for this condition using a drug called setmelanotide. This drug has been approved for treating people age six and over with PCSK1 deficiency and reverses the symptoms including obesity. Less than 50 people have been reported with PCSK1 deficiency.Congenital leptin deficiencyCongenital leptin deficiency (CLD) is a rare, inherited condition that affects how the body processes energy, responds to food and stores fat. Infants with CLD are constantly hungry and quickly gain weight and become obese. Children with CLD have extreme hunger (hyperphagia), low energy and abnormal behaviors related to food. Many people with CLD produce little or no sex hormones (hypogonadotropic hypogonadism) resulting in late or absent puberty and infertility. CLD is caused by variants in the LEP gene, which is responsible for making a protein called leptin. Leptin is important for regulating appetite and growth of body fat. This condition is inherited in an autosomal recessive pattern. Diagnosis is based on a clinical examination, symptoms and the results of genetic testing. Diet, behavior modification, exercise programs and bariatric surgery have been used to help manage the symptoms of CLD. Treatment is available for this condition using a drug called metreleptin, a recombinant form of human leptin, which reverses the symptoms of CLD. With treatment, people with CLD develop a normal appetite, lose weight and fat and regain normal sex hormone levels.Leptin receptor deficiency (LEPR deficiency) Individuals with LEPR deficiency have almost the same symptoms as individuals with congenital leptin deficiency. Early symptoms of both conditions include constant hunger and feeding (hyperphagia) and rapid weight gain leading to obesity in the first few months of life. In addition, endocrine gland abnormalities affecting levels of sex hormones are common, and puberty may be absent or delayed. This condition is caused by variants in the LEPR gene and is inherited in a recessive pattern. Diagnosis is based on a clinical exam, symptoms and the results of genetic testing. Treatment is available for this condition using setmelanotide, which decreases appetite and increases levels of sex hormones.Bardet-Biedl syndrome (BBS)BBS impacts multiple body systems and is classically defined by six features. People with BBS gain excessive weight, especially around the abdomen. They often also have intellectual disabilities. The kidneys, eyes and function of the genitalia may be compromised. People with BBS may also be born with an extra digit on the hands. The severity and symptoms of BBS vary, even among individuals in the same family. For more information on this disorder, choose “Bardet-Biedl syndrome” as your search term in the Rare Disease Database. https://rarediseases.org/rare-diseases/bardet-biedl-syndrome/Alström syndrome Alström syndrome is a rare complex disorder that includes a wide variety of symptoms affecting multiple organ systems of the body. The disorder is characterized by vision and hearing abnormalities, obesity in childhood, insulin resistance and diabetes mellitus. Other symptoms include heart disease (dilated cardiomyopathy) and slowly progressive kidney dysfunction, potentially leading to kidney failure. Additional symptoms include lung, liver, kidney and endocrine dysfunction. Although some children may experience delays in reaching developmental milestones, intelligence is usually unaffected. Alström syndrome is caused by variants in the ALMS1 gene. The protein made by this gene is involved in ciliary function, cell cycle control and intracellular transport. Alström syndrome is inherited in an autosomal recessive pattern. For more information on this disorder, choose “Alstrom syndrome” as your search term in the Rare Disease Database. https://rarediseases.org/rare-diseases/alstrom-syndrome/Prader-Willi syndromePrader-Willi syndrome (PWS) is a multisystem disorder characterized during infancy by lethargy, diminished muscle tone (hypotonia), a weak suck and feeding difficulties with poor weight gain and growth and other hormone deficiencies. In childhood, features of this disorder include short stature, small genitals and an excessive appetite. People with PWS do not feel satisfied after completing a meal (satiety). Without intervention, overeating can lead to life-threatening obesity. The food compulsion requires constant supervision. Individuals with severe obesity may have an increased risk of cardiac insufficiency, sleep apnea, diabetes, respiratory problems and other serious conditions that can cause life-threatening complications. All individuals with PWS have some cognitive impairment that ranges from low normal intelligence with learning disabilities to mild to moderate intellectual disability. Behavioral problems are common and can include temper tantrums, obsessive/compulsive behavior and skin picking. Motor milestones and language development are often delayed. PWS occurs due to changes of specific genes on part of the chromosome 15 inherited from the father. This condition is referred to as a genomic imprinting disorder which depends on which parent passes on the chromosome with the genetic changes to the child. For more information on this disorder, choose “Prader-Willi syndrome” as your search term in the Rare Disease Database. https://rarediseases.org/rare-diseases/prader-willi-syndrome/
| 986 |
POMC Deficiency
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nord_986_5
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Diagnosis of POMC Deficiency
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POMC deficiency is diagnosed based on a clinical examination, symptoms and the results of laboratory and genetic testing. POMC deficiency is usually diagnosed after adrenal insufficiency is confirmed and obesity develops. The diagnosis of POMC deficiency is confirmed using genetic testing for variants in the POMC gene.Because there are several inherited conditions that include excessive hunger and early-onset obesity, genetic testing may be done to help make a specific diagnosis. This testing often involves using a gene panel, allowing the lab to look for genetic changes in several different genes at the same time. Genetic testing is usually done with a blood or saliva sample. It is helpful to speak to a genetics professional before having genetic testing to learn more about the risk, benefits and limitations.
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Diagnosis of POMC Deficiency. POMC deficiency is diagnosed based on a clinical examination, symptoms and the results of laboratory and genetic testing. POMC deficiency is usually diagnosed after adrenal insufficiency is confirmed and obesity develops. The diagnosis of POMC deficiency is confirmed using genetic testing for variants in the POMC gene.Because there are several inherited conditions that include excessive hunger and early-onset obesity, genetic testing may be done to help make a specific diagnosis. This testing often involves using a gene panel, allowing the lab to look for genetic changes in several different genes at the same time. Genetic testing is usually done with a blood or saliva sample. It is helpful to speak to a genetics professional before having genetic testing to learn more about the risk, benefits and limitations.
| 986 |
POMC Deficiency
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nord_986_6
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Therapies of POMC Deficiency
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Early treatment options for obesity for people with POMC deficiency include weight management through diet and behavioral counseling, physical training and outpatient obesity programs. However, most of these do not result in permanent weight loss.Setmelanotide has been approved by the U.S. Food and Drug Administration (FDA) for people six years and older with obesity due to POMC deficiency which has been confirmed by genetic testing. This drug is given by daily injection. People taking setmelanotide are able to control their appetite, lose weight and maintain weight loss. Their skin and hair color may also get darker.People with POMC deficiency also receive hydrocortisone to treat adrenal insufficiency and other medications to manage other symptoms of this condition.People with POMC deficiency may be treated by a variety of different medical specialists, including gastroenterologists, nutritionists and endocrinologists. A psychologist or other mental health professional can help people cope with the symptoms of this condition.
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Therapies of POMC Deficiency. Early treatment options for obesity for people with POMC deficiency include weight management through diet and behavioral counseling, physical training and outpatient obesity programs. However, most of these do not result in permanent weight loss.Setmelanotide has been approved by the U.S. Food and Drug Administration (FDA) for people six years and older with obesity due to POMC deficiency which has been confirmed by genetic testing. This drug is given by daily injection. People taking setmelanotide are able to control their appetite, lose weight and maintain weight loss. Their skin and hair color may also get darker.People with POMC deficiency also receive hydrocortisone to treat adrenal insufficiency and other medications to manage other symptoms of this condition.People with POMC deficiency may be treated by a variety of different medical specialists, including gastroenterologists, nutritionists and endocrinologists. A psychologist or other mental health professional can help people cope with the symptoms of this condition.
| 986 |
POMC Deficiency
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nord_987_0
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Overview of Pompe Disease
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SummaryPompe disease is a rare disease continuum with variable rates of disease progression and different ages of onset. First symptoms can occur at any age from birth to late adulthood. Earlier onset compared to later onset is usually associated with faster progression and greater disease severity. At all ages, skeletal muscle weakness characterizes the disease, causing mobility problems and affecting the respiratory system.The most severely affected infants usually present within the first 3 months after birth. They have characteristic heart (cardiac) problems (dysfunction due to heart enlargement) in addition to generalized skeletal muscle weakness and a life expectancy of less than 2 years, if untreated (classic infantile Pompe disease). Less severe forms of Pompe disease with onset during childhood, adolescence, or adulthood, rarely manifest cardiac problems, but gradually lead to walking disability and reduced respiratory function.The scientific literature has different ways of subdividing the clinical spectrum of Pompe disease. Some articles describe ‘classic infantile’, ‘childhood’ and ‘adult’ Pompe disease while others discuss ‘infantile-onset’ (IOPD) and ‘late-onset’ (LOPD) disease.Pompe disease is a rare, multisystemic, hereditary disease, which is caused by ‘pathogenic variations’ (abnormalities / mutations) in the ‘GAA gene’.The GAA gene contains the genetic information for the production and function of a protein called ‘acid alpha-glucosidase’ (GAA). Shortage of this protein hampers the degradation of a complex sugar named ‘glycogen’ into a simple sugar named ‘glucose’. Therefore, glycogen starts to accumulate in all kinds of tissues, but primarily in skeletal muscle, smooth muscle and cardiac muscle, where it causes damage to tissue structure and function.
‘Enzyme replacement therapy’ (ERT), the only treatment presently available, aims to replenishing the shortage of GAA by intravenous administration of industrially made ‘rhGAA’ (recombinant human GAA).Pompe disease is inherited in an autosomal recessive genetic pattern, which implies that healthy parents can have affected children.IntroductionThe human body can be seen as an assembly of interconnecting organs. Organs are composed of organ specific tissues, and tissues are composed of specialized cells like muscle cells, nerve cells, etc. Pompe disease belongs to a group of diseases known as the ‘lysosomal storage disorders’ (LSDs). Lysosomes are small compartments inside the cells wherein all kind of substances are re-cycled. The substances are degraded by the action of digestive enzymes. More than 50 different LSDs are presently known to be caused by the deficiency of one of these enzymes. Acid alpha-glucosidase (GAA) is one such enzyme and is responsible for the lysosomal degradation of glycogen. A shortage or dysfunction of GAA causes glycogen to accumulate within the lysosomes, which subsequently leads to cellular malfunction, cellular damage, tissue damage, and ultimately organ dysfunction. In Pompe disease, the organ dysfunction is mainly manifested by muscle weakness and muscle wasting.Pompe disease is not only listed as an LSD, but also as one of the 15 presently known ‘glycogen storage disorders’ (GSDs), a group of metabolic disorders characterized by abnormalities in glycogen synthesis and breakdown.Pompe disease is known under the alternative names ‘glycogen storage disease type II’ (GSDII), acid alpha-glucosidase (GAA) deficiency, and ‘acid maltase’ deficiency (acid maltase is another name for acid alpha-glucosidase).TerminologyPompe disease is divided into subtypes: ‘Classic infantile’ refers to the form of Pompe disease that was first described in 1932 and characterized by the onset of symptoms shortly after birth, generalized muscle weakness, and ‘cardiomegaly’ (a far too big heart), in combination with excessive glycogen stored in virtually all organs. Terms like ‘childhood’, ‘juvenile’, and ‘adult’ glycogenosis type II / Pompe disease / Acid maltase deficiency were historically introduced as names for the less severe forms of Pompe disease characterized by delayed onset and usually slower progression. Adult-onset was historically synonymous with ‘late-onset’.After the introduction of enzyme replacement therapy, the meaning of ‘late-onset’ was increasingly referred to Pompe disease without hypertrophic cardiomyopathy (HCM) (thickened heart muscle).Currently, the abbreviation IOPD (infantile-onset Pompe disease) refers in most but not all published cases to classic-infantile Pompe disease (some cases of childhood Pompe disease might be included). The abbreviation IPD (infantile Pompe disease) is also used. LOPD (late-onset Pompe disease) refers to all cases in which hypertrophic cardiomyopathy (HCM) did not manifest or was not diagnosed at or under the age of 1 year, as well as to all cases with symptom onset above the age of 1 year.
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Overview of Pompe Disease. SummaryPompe disease is a rare disease continuum with variable rates of disease progression and different ages of onset. First symptoms can occur at any age from birth to late adulthood. Earlier onset compared to later onset is usually associated with faster progression and greater disease severity. At all ages, skeletal muscle weakness characterizes the disease, causing mobility problems and affecting the respiratory system.The most severely affected infants usually present within the first 3 months after birth. They have characteristic heart (cardiac) problems (dysfunction due to heart enlargement) in addition to generalized skeletal muscle weakness and a life expectancy of less than 2 years, if untreated (classic infantile Pompe disease). Less severe forms of Pompe disease with onset during childhood, adolescence, or adulthood, rarely manifest cardiac problems, but gradually lead to walking disability and reduced respiratory function.The scientific literature has different ways of subdividing the clinical spectrum of Pompe disease. Some articles describe ‘classic infantile’, ‘childhood’ and ‘adult’ Pompe disease while others discuss ‘infantile-onset’ (IOPD) and ‘late-onset’ (LOPD) disease.Pompe disease is a rare, multisystemic, hereditary disease, which is caused by ‘pathogenic variations’ (abnormalities / mutations) in the ‘GAA gene’.The GAA gene contains the genetic information for the production and function of a protein called ‘acid alpha-glucosidase’ (GAA). Shortage of this protein hampers the degradation of a complex sugar named ‘glycogen’ into a simple sugar named ‘glucose’. Therefore, glycogen starts to accumulate in all kinds of tissues, but primarily in skeletal muscle, smooth muscle and cardiac muscle, where it causes damage to tissue structure and function.
‘Enzyme replacement therapy’ (ERT), the only treatment presently available, aims to replenishing the shortage of GAA by intravenous administration of industrially made ‘rhGAA’ (recombinant human GAA).Pompe disease is inherited in an autosomal recessive genetic pattern, which implies that healthy parents can have affected children.IntroductionThe human body can be seen as an assembly of interconnecting organs. Organs are composed of organ specific tissues, and tissues are composed of specialized cells like muscle cells, nerve cells, etc. Pompe disease belongs to a group of diseases known as the ‘lysosomal storage disorders’ (LSDs). Lysosomes are small compartments inside the cells wherein all kind of substances are re-cycled. The substances are degraded by the action of digestive enzymes. More than 50 different LSDs are presently known to be caused by the deficiency of one of these enzymes. Acid alpha-glucosidase (GAA) is one such enzyme and is responsible for the lysosomal degradation of glycogen. A shortage or dysfunction of GAA causes glycogen to accumulate within the lysosomes, which subsequently leads to cellular malfunction, cellular damage, tissue damage, and ultimately organ dysfunction. In Pompe disease, the organ dysfunction is mainly manifested by muscle weakness and muscle wasting.Pompe disease is not only listed as an LSD, but also as one of the 15 presently known ‘glycogen storage disorders’ (GSDs), a group of metabolic disorders characterized by abnormalities in glycogen synthesis and breakdown.Pompe disease is known under the alternative names ‘glycogen storage disease type II’ (GSDII), acid alpha-glucosidase (GAA) deficiency, and ‘acid maltase’ deficiency (acid maltase is another name for acid alpha-glucosidase).TerminologyPompe disease is divided into subtypes: ‘Classic infantile’ refers to the form of Pompe disease that was first described in 1932 and characterized by the onset of symptoms shortly after birth, generalized muscle weakness, and ‘cardiomegaly’ (a far too big heart), in combination with excessive glycogen stored in virtually all organs. Terms like ‘childhood’, ‘juvenile’, and ‘adult’ glycogenosis type II / Pompe disease / Acid maltase deficiency were historically introduced as names for the less severe forms of Pompe disease characterized by delayed onset and usually slower progression. Adult-onset was historically synonymous with ‘late-onset’.After the introduction of enzyme replacement therapy, the meaning of ‘late-onset’ was increasingly referred to Pompe disease without hypertrophic cardiomyopathy (HCM) (thickened heart muscle).Currently, the abbreviation IOPD (infantile-onset Pompe disease) refers in most but not all published cases to classic-infantile Pompe disease (some cases of childhood Pompe disease might be included). The abbreviation IPD (infantile Pompe disease) is also used. LOPD (late-onset Pompe disease) refers to all cases in which hypertrophic cardiomyopathy (HCM) did not manifest or was not diagnosed at or under the age of 1 year, as well as to all cases with symptom onset above the age of 1 year.
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Symptoms of Pompe Disease
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Patients with the ‘classic infantile’ form of Pompe disease are the most severely affected. Although hardly any symptoms may be apparent at birth, the disease usually presents within the first three months of life with rapidly progressive muscle weakness (‘floppy infants’), diminished muscle tone (hypotonia), respiratory deficiency, and a type of heart disease known as hypertrophic cardiomyopathy, a condition characterized by abnormal thickening of the walls of the heart (mainly the left chamber and the wall between the left and right chamber) resulting in diminished cardiac function. These problems together culminate in cardio-respiratory failure within the first 2 years of life.Many infants have a large, protruding, tongue and a moderate enlargement of the liver. The legs often rest in a frog position and feel firm on palpation (pseudo-hypertrophy).
Feeding and swallowing problems as well as respiratory difficulties, which are often combined with respiratory tract infections, are common. Major developmental milestones such as rolling over, sitting up, and standing are delayed or not achieved. Mental development is usually normal. Virtually all infants experience hearing loss. The ‘classic infantile’ form of Pompe disease is caused by a total absence of acid alpha-glucosidase (GAA) activity and by a rapid buildup of glycogen in skeletal muscle and heart.‘Childhood’ Pompe disease typically presents during childhood, and ‘adult’ Pompe disease during adulthood. In the current literature, these two forms of Pompe disease are often grouped together as ‘late-onset’ Pompe disease (abbreviated as LOPD) despite the fact that the time of presentation can vary from the first year of life to the eighth decade. Patients who develop symptoms early in life tend to be more severely affected and to have a faster rate of disease progression than those who develop symptoms later in life. Both children as well as adults usually have more GAA activity (their GAA deficiency is not total) than the most severely affected infants (who do not have any GAA activity), and the glycogen buildup is usually not as rapid. However, symptoms do progress, and can greatly affect the quality of life and diminish the lifespan.Childhood and adult Pompe disease are associated with progressive weakness of mainly the proximal muscles (limb girdle, upper arms and upper legs), and varying degrees of respiratory weakness due to dysfunction of the diaphragm and the intercostal muscles (muscles between the ribs). The lower limbs are more affected than the upper limbs. The extent of muscle involvement is highly variable. Balance can be affected as the major leg muscles lose their strength and spring, forcing core muscles to take up the slack to maintain an upright posture. The muscles adjacent to the spinal column (para-spinal muscles) and neck are usually also involved. Weakness of the para-spinal muscles around puberty can cause abnormal curvature of the spine (scoliosis). Due to the combination of these serious symptoms, affected individuals may become wheelchair and/or ventilator dependent.Other symptoms can include chewing and swallowing difficulties and drooping of the upper eyelids (ptosis). Additionally, blood vessel abnormalities due to smooth muscle weakness and problems of the urinary and digestive systems have been reported.
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Symptoms of Pompe Disease. Patients with the ‘classic infantile’ form of Pompe disease are the most severely affected. Although hardly any symptoms may be apparent at birth, the disease usually presents within the first three months of life with rapidly progressive muscle weakness (‘floppy infants’), diminished muscle tone (hypotonia), respiratory deficiency, and a type of heart disease known as hypertrophic cardiomyopathy, a condition characterized by abnormal thickening of the walls of the heart (mainly the left chamber and the wall between the left and right chamber) resulting in diminished cardiac function. These problems together culminate in cardio-respiratory failure within the first 2 years of life.Many infants have a large, protruding, tongue and a moderate enlargement of the liver. The legs often rest in a frog position and feel firm on palpation (pseudo-hypertrophy).
Feeding and swallowing problems as well as respiratory difficulties, which are often combined with respiratory tract infections, are common. Major developmental milestones such as rolling over, sitting up, and standing are delayed or not achieved. Mental development is usually normal. Virtually all infants experience hearing loss. The ‘classic infantile’ form of Pompe disease is caused by a total absence of acid alpha-glucosidase (GAA) activity and by a rapid buildup of glycogen in skeletal muscle and heart.‘Childhood’ Pompe disease typically presents during childhood, and ‘adult’ Pompe disease during adulthood. In the current literature, these two forms of Pompe disease are often grouped together as ‘late-onset’ Pompe disease (abbreviated as LOPD) despite the fact that the time of presentation can vary from the first year of life to the eighth decade. Patients who develop symptoms early in life tend to be more severely affected and to have a faster rate of disease progression than those who develop symptoms later in life. Both children as well as adults usually have more GAA activity (their GAA deficiency is not total) than the most severely affected infants (who do not have any GAA activity), and the glycogen buildup is usually not as rapid. However, symptoms do progress, and can greatly affect the quality of life and diminish the lifespan.Childhood and adult Pompe disease are associated with progressive weakness of mainly the proximal muscles (limb girdle, upper arms and upper legs), and varying degrees of respiratory weakness due to dysfunction of the diaphragm and the intercostal muscles (muscles between the ribs). The lower limbs are more affected than the upper limbs. The extent of muscle involvement is highly variable. Balance can be affected as the major leg muscles lose their strength and spring, forcing core muscles to take up the slack to maintain an upright posture. The muscles adjacent to the spinal column (para-spinal muscles) and neck are usually also involved. Weakness of the para-spinal muscles around puberty can cause abnormal curvature of the spine (scoliosis). Due to the combination of these serious symptoms, affected individuals may become wheelchair and/or ventilator dependent.Other symptoms can include chewing and swallowing difficulties and drooping of the upper eyelids (ptosis). Additionally, blood vessel abnormalities due to smooth muscle weakness and problems of the urinary and digestive systems have been reported.
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Causes of Pompe Disease
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Pompe disease is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease. Pompe disease carriers 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.Pompe disease is caused by pathogenic variations (mutations) in the acid alpha-glucosidase (GAA) gene. Close to 600 different GAA gene variations have been identified in families with this disorder. All the known variations of the GAA gene are collected and listed in the Pompe variant database at: www.pompevariantdatabase.nl along with a description of how detrimental they are and with which clinical forms of Pompe disease they are associated. The degree of acid alpha-glucosidase (GAA) deficiency is dictated by the nature of the variations in each of the 2 GAA gene copies (1 from the father with variation A and 1 from the mother with variation B) and their combined effect. Generally: the more GAA deficiency these variants are causing, the earlier the onset of symptoms, the faster the disease progression, and the greater the clinical severity. However, the clinical presentation of Pompe disease is not solely dictated by the nature of the inherited pathogenic variations in the 2 GAA gene copies, but additionally influenced by a number of still unknown genetic, epigenetic, and environmental factors. These latter might include diet, lifestyle, exercise, etc.
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Causes of Pompe Disease. Pompe disease is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease. Pompe disease carriers 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.Pompe disease is caused by pathogenic variations (mutations) in the acid alpha-glucosidase (GAA) gene. Close to 600 different GAA gene variations have been identified in families with this disorder. All the known variations of the GAA gene are collected and listed in the Pompe variant database at: www.pompevariantdatabase.nl along with a description of how detrimental they are and with which clinical forms of Pompe disease they are associated. The degree of acid alpha-glucosidase (GAA) deficiency is dictated by the nature of the variations in each of the 2 GAA gene copies (1 from the father with variation A and 1 from the mother with variation B) and their combined effect. Generally: the more GAA deficiency these variants are causing, the earlier the onset of symptoms, the faster the disease progression, and the greater the clinical severity. However, the clinical presentation of Pompe disease is not solely dictated by the nature of the inherited pathogenic variations in the 2 GAA gene copies, but additionally influenced by a number of still unknown genetic, epigenetic, and environmental factors. These latter might include diet, lifestyle, exercise, etc.
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Affects of Pompe Disease
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Pompe disease occurs in various populations and ethnic groups around the world. Estimates vary, but its incidence is generally placed at approximately 1 in 40,000 births in the United States (and in the Netherlands). However, a recent review of birth incidences in Missouri reported a much higher incidence of 1 in 5,463 in that state. A ‘founder effect’ cannot be excluded. The same holds for Pompe disease in the American Black population and for Pompe disease in Taiwan where unique pathogenic variants have been reported.
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Affects of Pompe Disease. Pompe disease occurs in various populations and ethnic groups around the world. Estimates vary, but its incidence is generally placed at approximately 1 in 40,000 births in the United States (and in the Netherlands). However, a recent review of birth incidences in Missouri reported a much higher incidence of 1 in 5,463 in that state. A ‘founder effect’ cannot be excluded. The same holds for Pompe disease in the American Black population and for Pompe disease in Taiwan where unique pathogenic variants have been reported.
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Related disorders of Pompe Disease
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A variety of disorders can cause symptoms or physical findings that are like those seen in individuals with Pompe disease. Several of these disorders are discussed below. For more information on these disorders, choose the specific disorder name as your search term in the NORD Rare Disease Database.Diseases with similarities to classic infantile and childhood Pompe disease:
Werdnig-Hoffman disease, also known as spinal muscular atrophy type 1 (SMA type 1), is a rare genetic disorder characterized by hypotonia and progressive proximal muscle weakness. The disease is caused by pathogenic variations in the SMN gene. Unlike in Pompe disease, the heart is not involved. Infants often experience severe muscle weakness before 6 months of age and often never attain motor milestones such as sitting independently. The specific symptoms and severity of Werdnig-Hoffman disease vary from one infant to another. Werdnig-Hoffman disease is inherited in an autosomal recessive pattern.Danon disease primarily affects males and may be characterized by cardiomyopathy and muscle weakness. Intellectual disability may occur in some cases. Affected males often need a heart transplant at some point during their lives. In females, the disorder is usually mild and may go unrecognized until adulthood. Danon disease is inherited in an X-linked pattern.Other glycogen storage diseases (GSDs) resemble Pompe disease in that there is glycogen storage in one or more organs.Endocardial fibroelastosis affects the heart and is characterized by thickening of the muscular lining of the heart chambers due to an increase in the amount of supporting connective tissue and elastic fibers. This can cause the heart to become enlarged (cardiomegaly). Common symptoms include impaired heart and lung function resulting in breathing difficulties and potentially congestive heart failure. Endocardial fibroelastosis can be genetic or acquired.Diseases with similarities to childhood and adult Pompe disease:
A few muscular dystrophies may have symptoms that are like those seen in childhood and adult Pompe disease including facioscapulohumeral dystrophy (FSHD), Duchenne muscular dystrophy and Becker muscular dystrophy.FSHD is characterized by weakness of facial, shoulder (scapular winging), and upper arm muscles. Associated abnormalities include an impaired ability to completely close the eyes, limited movements of the lips and difficulty raising the arms over the head. Affected individuals may eventually develop weakness and associated wasting (atrophy) of muscles of the hips and thighs and/or involvement of lower leg muscles. FSHD may be inherited in an autosomal dominant pattern or may occur sporadically.Duchenne muscular dystrophy (DMD) is a genetic muscle disorder characterized by weakness and wasting of muscles of the pelvic area followed by the involvement of the shoulder muscles. Onset is in early childhood or infancy. As the disease progresses, muscle weakness and atrophy spread to affect the trunk and forearms and gradually progress to involve additional muscles. The disease is progressive and most affected individuals require a wheelchair by the teenage years. Serious life-threatening complications may develop including cardiomyopathy and respiratory difficulties. Duchenne muscular dystrophy is caused by pathogenic variations in the DMD gene and is inherited in an X-linked pattern.Becker muscular dystrophy is a genetic muscle disorder characterized by muscle weakness that is similar to that seen in Duchenne muscular dystrophy, but with a later age of onset. Individuals with Becker muscular dystrophy remain able to walk independently into their 20s. The disorder is progressive, however, and heart failure may develop. Becker muscular dystrophy, like DMD, is caused by pathogenic variations in the DMD gene and inherited in an X-linked pattern.Polymyositis is a rare inflammatory disorder characterized by degenerative changes in the muscles and supporting connective tissue resulting in muscle weakness and some degree of muscle atrophy. The hip, shoulders, arms, throat, and neck are most often affected. Joint pain, swelling and tenderness may also be present. Muscle weakness is progressive and can interfere with the ability to handle daily tasks. The cause of polymyositis is unknown.McArdle disease (GSD type V) and Hers disease (GSD type VI) are glycogen storage diseases that may resemble Pompe disease.
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Related disorders of Pompe Disease. A variety of disorders can cause symptoms or physical findings that are like those seen in individuals with Pompe disease. Several of these disorders are discussed below. For more information on these disorders, choose the specific disorder name as your search term in the NORD Rare Disease Database.Diseases with similarities to classic infantile and childhood Pompe disease:
Werdnig-Hoffman disease, also known as spinal muscular atrophy type 1 (SMA type 1), is a rare genetic disorder characterized by hypotonia and progressive proximal muscle weakness. The disease is caused by pathogenic variations in the SMN gene. Unlike in Pompe disease, the heart is not involved. Infants often experience severe muscle weakness before 6 months of age and often never attain motor milestones such as sitting independently. The specific symptoms and severity of Werdnig-Hoffman disease vary from one infant to another. Werdnig-Hoffman disease is inherited in an autosomal recessive pattern.Danon disease primarily affects males and may be characterized by cardiomyopathy and muscle weakness. Intellectual disability may occur in some cases. Affected males often need a heart transplant at some point during their lives. In females, the disorder is usually mild and may go unrecognized until adulthood. Danon disease is inherited in an X-linked pattern.Other glycogen storage diseases (GSDs) resemble Pompe disease in that there is glycogen storage in one or more organs.Endocardial fibroelastosis affects the heart and is characterized by thickening of the muscular lining of the heart chambers due to an increase in the amount of supporting connective tissue and elastic fibers. This can cause the heart to become enlarged (cardiomegaly). Common symptoms include impaired heart and lung function resulting in breathing difficulties and potentially congestive heart failure. Endocardial fibroelastosis can be genetic or acquired.Diseases with similarities to childhood and adult Pompe disease:
A few muscular dystrophies may have symptoms that are like those seen in childhood and adult Pompe disease including facioscapulohumeral dystrophy (FSHD), Duchenne muscular dystrophy and Becker muscular dystrophy.FSHD is characterized by weakness of facial, shoulder (scapular winging), and upper arm muscles. Associated abnormalities include an impaired ability to completely close the eyes, limited movements of the lips and difficulty raising the arms over the head. Affected individuals may eventually develop weakness and associated wasting (atrophy) of muscles of the hips and thighs and/or involvement of lower leg muscles. FSHD may be inherited in an autosomal dominant pattern or may occur sporadically.Duchenne muscular dystrophy (DMD) is a genetic muscle disorder characterized by weakness and wasting of muscles of the pelvic area followed by the involvement of the shoulder muscles. Onset is in early childhood or infancy. As the disease progresses, muscle weakness and atrophy spread to affect the trunk and forearms and gradually progress to involve additional muscles. The disease is progressive and most affected individuals require a wheelchair by the teenage years. Serious life-threatening complications may develop including cardiomyopathy and respiratory difficulties. Duchenne muscular dystrophy is caused by pathogenic variations in the DMD gene and is inherited in an X-linked pattern.Becker muscular dystrophy is a genetic muscle disorder characterized by muscle weakness that is similar to that seen in Duchenne muscular dystrophy, but with a later age of onset. Individuals with Becker muscular dystrophy remain able to walk independently into their 20s. The disorder is progressive, however, and heart failure may develop. Becker muscular dystrophy, like DMD, is caused by pathogenic variations in the DMD gene and inherited in an X-linked pattern.Polymyositis is a rare inflammatory disorder characterized by degenerative changes in the muscles and supporting connective tissue resulting in muscle weakness and some degree of muscle atrophy. The hip, shoulders, arms, throat, and neck are most often affected. Joint pain, swelling and tenderness may also be present. Muscle weakness is progressive and can interfere with the ability to handle daily tasks. The cause of polymyositis is unknown.McArdle disease (GSD type V) and Hers disease (GSD type VI) are glycogen storage diseases that may resemble Pompe disease.
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Diagnosis of Pompe Disease
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Most physicians are not familiar with Pompe disease. They may never have had patients with Pompe Disease. They need to know what they are looking for. The diagnosis of Pompe disease is based on a thorough clinical evaluation, a detailed patient and family history, and a variety of biochemical tests with first of all the measuring of GAA activity. Preimplantation testing and prenatal diagnosis are also possible when a pregnancy is known to be at risk for Pompe disease.Clinical Testing and Work Up
In individuals suspected of having Pompe disease, blood can be drawn and the function/activity of GAA (the ‘enzymatic activity’) can be measured in white blood cells (leukocytes), but only if the proper assay conditions are being used and acarbose is added to the reaction mixture to inhibit the activity of glucoamylase. The isolation of lymphocytes to prevent the interference of glucoamylase is not advised, as the successful isolation of lymphocytes is not only time consuming, but also error prone when the blood sample is not sufficiently fresh.Alternatively, the GAA activity/functional assay can also be performed on dried blood spots, but this method is not any quicker, less reliable, and also requires the use of acarbose to inhibit the glucoamylase activity. An important feature of the bloodspot test method is that it allows convenient shipment of samples if a certified diagnostic laboratory test is not locally available. Moreover, the dried blood spot test is unquestionably the most convenient methodology for the screening of large populations of newborns and large numbers of patients with undiagnosed limb-girdle muscular dystrophies and unexplained ‘CK-emias’ (a high level of creatine kinase in the blood pointing to muscle damage).Each diagnosis performed with the dried blood spot test method must be confirmed through molecular genetic testing (GAA gene copy analysis) or by measuring the GAA activity with another method. Leukocytes can be used for this purpose, but cultured skin fibroblasts obtained by a skin biopsy are the very best material. More invasive muscle biopsies are not needed and not optimal either for measuring the GAA activity.
The advantage of measuring the GAA activity/function is that the finding of a clear GAA deficiency testifies of Pompe disease even if the pathogenic variations in the 2 GAA gene copies are not found.The advantage of searching for pathogenic variations in the 2 GAA gene copies (a method called ‘DNA analysis’) is that only this test discriminates unequivocally between carriers and affected children/adults within families (measuring the GAA activity/function may not do so). It is advised to use both test methods if affordable and technically possible.The application of a skin biopsy and the initiation of a culture of skin fibroblasts might not be feasible in every diagnostic setting, but should always be considered as there are important advantages with this procedure. The GAA activity/functional test using skin fibroblasts is superior to all other methods for its high sensitivity and for discriminating between classic-infantile, childhood and adult Pompe disease (IOPD vs LOPD) in almost all cases. Cultured skin fibroblasts can be stored forever and be used as eternal sample source for measuring GAA activity, searching for GAA variations, studying defects in GAA production, and for the development of therapeutic interventions.A variety of other tests can be performed to detect or assess symptoms potentially associated with Pompe disease such as sleep studies, tests that measure lung function, and tests that measure muscle function. Muscle MRI (imaging by magnetic resonance) is used to visualize the degree of muscle damage.Specific tests may also be performed to assess the heart function, including chest x-ray, electrocardiography (ECG), and echocardiography (imaging by ultrasound). Chest x-rays allow physicians to assess the size of the heart, which is enlarged in classic infantile Pompe disease. Electrocardiography (ECG) measures the electric activity of the heart and detects abnormal heart rhythms. Echocardiography uses reflected sound waves to create a picture of the heart and can reveal abnormal thickening of the walls of the heart.When the pathogenic GAA variations of both parents are known, pre-implantation diagnosis and prenatal diagnosis are possible. The latter is preferably performed by chorionic villi sampling (CVS) in early pregnancy. Pre-implantation genetic diagnosis (PGD: testing in a very early embryonic stage to determine whether the embryo has inherited the pathogenic variations from the parents) may also be an option. PGD is performed on embryos created through in vitro fertilization (IVF). Families interested in PGD should seek the counsel of a certified genetic counselor.Not all individuals with Pompe disease are timely diagnosed and too many are, unfortunately, misdiagnosed. Since the introduction of the dried blood spot test method, formerly undiagnosed patients were identified in screening programs among individuals with limb-girdle dystrophies and/or ‘hyper CK-emia’ of unknown cause (a high level of creatine kinase in the blood is indicative of muscle damage).Newborn Screening
The introduction of newborn screening (NBS) in some US states and countries, using dried blood spots for first tier testing, has contributed significantly to the early detection and treatment of Pompe disease patients. But, NBS has the draw back that all clinical forms of Pompe disease are detected at birth while only the most severely affected patients with classic-infantile Pompe disease / IOPD will develop immediate symptoms and are likely to succumb before the age of 1 year, if untreated. Families in which newborns are diagnosed with LOPD, encompassing childhood and adult forms, remain uncertain about their child’s future since symptoms in the newborn may manifest around the age of 1 year or several decades later. The link between GAA variations and clinical phenotypes emerging from the systematic collection of GAA variations and clinical forms in databases such as the Pompevariant database www.pompevariantdatabase.nl and the Pompe Registry is expected to provide future guidance.
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Diagnosis of Pompe Disease. Most physicians are not familiar with Pompe disease. They may never have had patients with Pompe Disease. They need to know what they are looking for. The diagnosis of Pompe disease is based on a thorough clinical evaluation, a detailed patient and family history, and a variety of biochemical tests with first of all the measuring of GAA activity. Preimplantation testing and prenatal diagnosis are also possible when a pregnancy is known to be at risk for Pompe disease.Clinical Testing and Work Up
In individuals suspected of having Pompe disease, blood can be drawn and the function/activity of GAA (the ‘enzymatic activity’) can be measured in white blood cells (leukocytes), but only if the proper assay conditions are being used and acarbose is added to the reaction mixture to inhibit the activity of glucoamylase. The isolation of lymphocytes to prevent the interference of glucoamylase is not advised, as the successful isolation of lymphocytes is not only time consuming, but also error prone when the blood sample is not sufficiently fresh.Alternatively, the GAA activity/functional assay can also be performed on dried blood spots, but this method is not any quicker, less reliable, and also requires the use of acarbose to inhibit the glucoamylase activity. An important feature of the bloodspot test method is that it allows convenient shipment of samples if a certified diagnostic laboratory test is not locally available. Moreover, the dried blood spot test is unquestionably the most convenient methodology for the screening of large populations of newborns and large numbers of patients with undiagnosed limb-girdle muscular dystrophies and unexplained ‘CK-emias’ (a high level of creatine kinase in the blood pointing to muscle damage).Each diagnosis performed with the dried blood spot test method must be confirmed through molecular genetic testing (GAA gene copy analysis) or by measuring the GAA activity with another method. Leukocytes can be used for this purpose, but cultured skin fibroblasts obtained by a skin biopsy are the very best material. More invasive muscle biopsies are not needed and not optimal either for measuring the GAA activity.
The advantage of measuring the GAA activity/function is that the finding of a clear GAA deficiency testifies of Pompe disease even if the pathogenic variations in the 2 GAA gene copies are not found.The advantage of searching for pathogenic variations in the 2 GAA gene copies (a method called ‘DNA analysis’) is that only this test discriminates unequivocally between carriers and affected children/adults within families (measuring the GAA activity/function may not do so). It is advised to use both test methods if affordable and technically possible.The application of a skin biopsy and the initiation of a culture of skin fibroblasts might not be feasible in every diagnostic setting, but should always be considered as there are important advantages with this procedure. The GAA activity/functional test using skin fibroblasts is superior to all other methods for its high sensitivity and for discriminating between classic-infantile, childhood and adult Pompe disease (IOPD vs LOPD) in almost all cases. Cultured skin fibroblasts can be stored forever and be used as eternal sample source for measuring GAA activity, searching for GAA variations, studying defects in GAA production, and for the development of therapeutic interventions.A variety of other tests can be performed to detect or assess symptoms potentially associated with Pompe disease such as sleep studies, tests that measure lung function, and tests that measure muscle function. Muscle MRI (imaging by magnetic resonance) is used to visualize the degree of muscle damage.Specific tests may also be performed to assess the heart function, including chest x-ray, electrocardiography (ECG), and echocardiography (imaging by ultrasound). Chest x-rays allow physicians to assess the size of the heart, which is enlarged in classic infantile Pompe disease. Electrocardiography (ECG) measures the electric activity of the heart and detects abnormal heart rhythms. Echocardiography uses reflected sound waves to create a picture of the heart and can reveal abnormal thickening of the walls of the heart.When the pathogenic GAA variations of both parents are known, pre-implantation diagnosis and prenatal diagnosis are possible. The latter is preferably performed by chorionic villi sampling (CVS) in early pregnancy. Pre-implantation genetic diagnosis (PGD: testing in a very early embryonic stage to determine whether the embryo has inherited the pathogenic variations from the parents) may also be an option. PGD is performed on embryos created through in vitro fertilization (IVF). Families interested in PGD should seek the counsel of a certified genetic counselor.Not all individuals with Pompe disease are timely diagnosed and too many are, unfortunately, misdiagnosed. Since the introduction of the dried blood spot test method, formerly undiagnosed patients were identified in screening programs among individuals with limb-girdle dystrophies and/or ‘hyper CK-emia’ of unknown cause (a high level of creatine kinase in the blood is indicative of muscle damage).Newborn Screening
The introduction of newborn screening (NBS) in some US states and countries, using dried blood spots for first tier testing, has contributed significantly to the early detection and treatment of Pompe disease patients. But, NBS has the draw back that all clinical forms of Pompe disease are detected at birth while only the most severely affected patients with classic-infantile Pompe disease / IOPD will develop immediate symptoms and are likely to succumb before the age of 1 year, if untreated. Families in which newborns are diagnosed with LOPD, encompassing childhood and adult forms, remain uncertain about their child’s future since symptoms in the newborn may manifest around the age of 1 year or several decades later. The link between GAA variations and clinical phenotypes emerging from the systematic collection of GAA variations and clinical forms in databases such as the Pompevariant database www.pompevariantdatabase.nl and the Pompe Registry is expected to provide future guidance.
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Pompe Disease
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nord_987_6
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Therapies of Pompe Disease
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TreatmentThe treatment of Pompe disease is disease-specific, symptomatic and supportive. Treatment requires the coordinated efforts of a team of specialists. The input of pediatricians, internists, neurologists, orthopedists, cardiologists, dieticians, physical therapists and other healthcare professionals may be needed to develop the treatment plan. The treatment plan must be patient centered, including the patient’s self-descriptions or caregiver’s descriptions (patient history), which provide important data for the team of specialists. A patient or caregiver who is fully informed can provide better experiential data. Genetic counseling is of crucial importance for affected individuals and their families.Enzyme Replacement Therapy
Enzyme replacement therapy (ERT) is an approved treatment for all patients with Pompe disease. It involves the intravenous administration of recombinant human acid alpha-glucosidase (rhGAA). This treatment is called Lumizyme (marketed as Myozyme outside the United States) and was first approved by the U.S. Food and Drug Administration (FDA) in 2006. ERT has been shown to extend the life expectancy of patients with infantile-onset Pompe disease, but these patients are not fully cured and residual symptoms remain. There is some evidence that the currently prescribed and approved dosage is not sufficient in all patients.Most patients with childhood and adult forms of Pompe disease also benefit from ERT. In 2021, avalglucosidase alfa-ngpt (Nexviazyme) was approved by the FDA to treat patients one year of age and older with late-onset Pompe disease. This enzyme replacement therapy is an intravenous medication that helps reduce the accumulation of glycogen.Supportive Therapies
Additional treatment of Pompe disease is symptomatic and supportive. Respiratory support may be required, as most patients have some degree of respiratory compromise and/or respiratory failure. Physical therapy may be helpful to strengthen respiratory muscles. Some patients may need respiratory assistance through mechanical ventilation (i.e. Bipap or volume ventilators) during the night and/or periods of the day or during respiratory tract infections. Mechanical ventilation support can be through noninvasive or invasive techniques. Decisions about the duration of respiratory support are best made by the patients themselves or the parents in careful consultation with the patient’s physicians and other members of the healthcare team. Physiotherapy is recommended to improve strength and physical ability. Occupational therapy, including the use of canes or walkers, may be necessary. Eventually, some patients may require the use of a wheelchair. Speech therapy can be beneficial in some patients to improve articulation and speech. Orthopedic devices including braces may be recommended in some patients. Surgery may be required for certain orthopedic symptoms such as contractures or spinal deformity.Since Pompe disease can weaken muscles used for chewing and swallowing, adequate measures may be required to ensure proper nutrition and weight gain. Some patients may need specialized, high-calorie diets and may need to learn techniques to change the size and texture of food to lower the risk of aspiration. Some infants may require the insertion of a feeding tube that is run through the nose, down the esophagus and into the stomach (nasogastric tube). In some children, a feeding tube may need to be inserted directly into the stomach through a small surgical opening in the abdominal wall. Some individuals with childhood or adult Pompe disease / LOPD may require a soft diet, but few require feeding tubes.
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Therapies of Pompe Disease. TreatmentThe treatment of Pompe disease is disease-specific, symptomatic and supportive. Treatment requires the coordinated efforts of a team of specialists. The input of pediatricians, internists, neurologists, orthopedists, cardiologists, dieticians, physical therapists and other healthcare professionals may be needed to develop the treatment plan. The treatment plan must be patient centered, including the patient’s self-descriptions or caregiver’s descriptions (patient history), which provide important data for the team of specialists. A patient or caregiver who is fully informed can provide better experiential data. Genetic counseling is of crucial importance for affected individuals and their families.Enzyme Replacement Therapy
Enzyme replacement therapy (ERT) is an approved treatment for all patients with Pompe disease. It involves the intravenous administration of recombinant human acid alpha-glucosidase (rhGAA). This treatment is called Lumizyme (marketed as Myozyme outside the United States) and was first approved by the U.S. Food and Drug Administration (FDA) in 2006. ERT has been shown to extend the life expectancy of patients with infantile-onset Pompe disease, but these patients are not fully cured and residual symptoms remain. There is some evidence that the currently prescribed and approved dosage is not sufficient in all patients.Most patients with childhood and adult forms of Pompe disease also benefit from ERT. In 2021, avalglucosidase alfa-ngpt (Nexviazyme) was approved by the FDA to treat patients one year of age and older with late-onset Pompe disease. This enzyme replacement therapy is an intravenous medication that helps reduce the accumulation of glycogen.Supportive Therapies
Additional treatment of Pompe disease is symptomatic and supportive. Respiratory support may be required, as most patients have some degree of respiratory compromise and/or respiratory failure. Physical therapy may be helpful to strengthen respiratory muscles. Some patients may need respiratory assistance through mechanical ventilation (i.e. Bipap or volume ventilators) during the night and/or periods of the day or during respiratory tract infections. Mechanical ventilation support can be through noninvasive or invasive techniques. Decisions about the duration of respiratory support are best made by the patients themselves or the parents in careful consultation with the patient’s physicians and other members of the healthcare team. Physiotherapy is recommended to improve strength and physical ability. Occupational therapy, including the use of canes or walkers, may be necessary. Eventually, some patients may require the use of a wheelchair. Speech therapy can be beneficial in some patients to improve articulation and speech. Orthopedic devices including braces may be recommended in some patients. Surgery may be required for certain orthopedic symptoms such as contractures or spinal deformity.Since Pompe disease can weaken muscles used for chewing and swallowing, adequate measures may be required to ensure proper nutrition and weight gain. Some patients may need specialized, high-calorie diets and may need to learn techniques to change the size and texture of food to lower the risk of aspiration. Some infants may require the insertion of a feeding tube that is run through the nose, down the esophagus and into the stomach (nasogastric tube). In some children, a feeding tube may need to be inserted directly into the stomach through a small surgical opening in the abdominal wall. Some individuals with childhood or adult Pompe disease / LOPD may require a soft diet, but few require feeding tubes.
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Pompe Disease
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nord_988_0
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Overview of Pontocerebellar Hypoplasia
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Pontocerebellar hypoplasias (PCH) are a group of rare heterogeneous conditions characterized by prenatal development of an abnormally small cerebellum and brain stem, which is usually associated with profound psychomotor retardation. Although the clinical features vary widely, pontocerebellar hypoplasias are usually associated with profound intellectual disability and delayed or absent psychomotor milestones. In most cases, the disease is uniformly fatal early in life. Life span has ranged from death in the perinatal period to about 20-25 years of age. Only a few individuals-usually patients with PCH type 2-have survived to the second and third decades of life. At least 6 types of PCH have been described and a few rare variants are now being identified.
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Overview of Pontocerebellar Hypoplasia. Pontocerebellar hypoplasias (PCH) are a group of rare heterogeneous conditions characterized by prenatal development of an abnormally small cerebellum and brain stem, which is usually associated with profound psychomotor retardation. Although the clinical features vary widely, pontocerebellar hypoplasias are usually associated with profound intellectual disability and delayed or absent psychomotor milestones. In most cases, the disease is uniformly fatal early in life. Life span has ranged from death in the perinatal period to about 20-25 years of age. Only a few individuals-usually patients with PCH type 2-have survived to the second and third decades of life. At least 6 types of PCH have been described and a few rare variants are now being identified.
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Pontocerebellar Hypoplasia
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nord_988_1
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Symptoms of Pontocerebellar Hypoplasia
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Pontocerebellar Hypoplasia Type 1 (PCH type 1):In pontocerebellar hypoplasia type 1, there is central and peripheral motor dysfunction from birth leading to early death, mostly before 1 year of age. In addition to an abnormally small cerebellum and brainstem including the pons, there is a degeneration of the anterior horn cells. Because of the anterior horn cell involvement, PCH type 1 has some resemblance to infantile spinal muscular atrophy. The hypoplasia of the pons and cerebellum and spinal anterior horn cell degeneration is also associated with pronounced reactive changes (gliosis). PCH type 1 is associated with reduced fetal movement. The pregnancy sometimes is complicated by polyhydramnios. In most cases, the condition is obvious during the newborn period when the newborn appears floppy and has respiratory insufficiency. At birth, multiple congenital contractures of large joints (arthrogryposis multiplex congenita) may be present. The newborn may show arreflexia, and combined motor signs. PCH type 1 has the hallmark of severe muscle weakness. The associated hypotonia may start prenatally or after birth. Intellectual disability and cerebellar signs of visual impairment, nystagmus and ataxia follow the initial presentation. It has also been found that some patients with PCH type 1 develop the signs of muscle weakness or developmental delay at the age of several months. These late presenting patients have a milder form and may live up to four years. However, the disease is uniformly fatal. Generally, affected babies have a life span not exceeding a few months in most cases. In all patients, postmortem examinations reveal variable spectrum of cerebellar atrophy, neuronal loss in the anterior horns of the spinal cord, basal ganglia and brainstem suggesting a more widespread neuronal degeneration. The inheritance of PCH follows an autosomal recessive pattern. Sequence analysis of the entire coding region, prenatal diagnosis and carrier testing are available for PCH type 1. Pontocerebellar Hypoplasia Type 2 (PCH type 2):In PCH type 2 there is progressive microcephaly from birth combined with extrapyramidal dyskinesia. There is no motor or mental development. Severe chorea occurs, and epilepsy is frequent, while signs of spinal anterior horn involvement are absent in PCH type 2. The main feature distinguishing PCH type 1 from PCH type 2 is that anterior horn cells are spared in PCH type 2. Characteristically, pregnancy is normal. However, at birth, the newborn may show breathing problems or respiratory failure that may require mechanical ventilatory support. Some may have sucking or feeding problems. Most patients with PCH type 2 are born with normal size head. Some already have microcephaly at birth. All affected children have worsening or progression of the microcephaly during infancy. Other features of dysmorphism are absent. They have impaired mental and motor development. They have abnormal movements termed extrapyramidal movement disorder. All affected children develop marked extrapyramidal dyskinetic movement disorder with predominance of dystonia. Jerky movements and almost continuous dystonic choreoathetotic movements may be seen. These movement abnormalities are usually noticed during the neonatal period of these children. Affected children have severe to profound intellectual disability. No patient with the classical PCH type 2 ever achieved the milestones of sitting, crawling, standing, walking, talking, or developed meaningful social contact skills. Visual fixation is persistently poor and only about one third of these patients are able to fixate and follow. Seizure disorder is frequent. Approximately half of these children may have seizures. A minority may also have hypotonia or hypertonia even as early as the newborn period. Minority may show spasticity. They are severely handicapped with no voluntary motor function. The children have severe cognitive and language impairment, and with no verbal or non-verbal communication. There is a near total loss of Purkinje fibers in the cerebellar hemisphere and an undetectable dentate nucleus. Neuronal loss is marked in the basal ganglia and thalamus without any anterior horn cell involvement when autopsy is done. The vermis is also relatively spared. These features are similar to those seen in PCH type 5 and suggest a continuum of pathology between both PCH type 2 and PCH type 5. The clinical findings, the severity of movement disorder and the developmental delay do not correlate with the degree of pontine or cerebellar hypoplasia on MRI. It is possible that there is a continuum of severe neonatal and infantile types rather than clearly defined groups. Death during early childhood has been attributed to respiratory and infectious complications.Mutations in 3 tRNA splicing endonuclease genes (TSEN) have been identified in PCH type 2 and Type 4. This has formed the basis of classifying PCH type 2 into types 2A, 2B, and 2C respectively associated with TSEN54, TSEN2 and TSEN34. Sequence analysis of the entire coding, region, linkage analysis, prenatal diagnosis, and carrier testing are available for TSEN2, TSEN34, and TSEN54 related PCH. In addition, deletion/duplication analysis is available also for TSEN54 related PCH.Pontocerebellar Hypoplasia Type 3 (PCH type 3):PCH type 3 has many features in common with PCH type 2. However, in PCH type 3, extrapyramidal symptoms (dyskinesia) are absent. The children may have seizures and microcephaly, which are the result of poor brain development and small size of the cerebellum and pons that affect the overall size of the brain. PCH Type 3 is a unique form described in three sibs of a consanguineous family from the Sultanate of Oman. Clinical features in these affected children include developmental delay, progressive microcephaly with brachycephaly and seizure in the first year, truncal hypotonia with exaggerated deep tendon reflexes, short stature and optic atrophy. One of the three children had thoracic scoliosis contractures of the elbows and knees, and clubfoot. Visual impairment including optic atrophy may be seen in affected patient. Other features include brachycephaly, prominent eyes, and low-set ears. There was no extrapyramidal involvement or dyskinesia. Imaging studies of the brain showed small brainstem, small cerebellar vermis, and atrophy of the cerebellum and cerebrum. PCH type 3 has been mapped to chromosome 7q11-21 and fine mapping is in progress. Pontocerebellar Hypoplasia Type 4 (PCH type 4):PCH type 4 is associated with severe neonatal encephalopathy, microcephaly, myoclonus, and muscular hypertonia. There is a severe loss of neurons in pontine and olivary nuclei in addition to the hypoplasia of the cerebellum and a diffuse gliosis in white matter of both the cerebellum and all areas of the brain. This is a more severe and fatal variant of PCH type 2, which is associated with death within the first few weeks of life, known as PCH type 4. Pontocerebellar Hypoplasia Type 5 (PCH type 5):PCH type 5 is similar to PCH type 4, but differs in having in-utero fetal seizure-like activity. These patients show evidence of severe olivopontocerebellar hypoplasia and degeneration, dysplastic, c-shaped inferior olivary nuclei, absent or immature dentate nuclei and cell paucity more marked for the cerebellar vermis than the hemispheres. Pontocerebellar Hypoplasia Type 6 (PCH type 6): PCH type 6 manifests as early as the first day of life or within the first month of life as infantile encephalopathy, with generalized hypotonia, lethargic, poor sucking and poor feeding. Recurrent apnea, intractable seizures occur early in the course of this condition. Although head size may be normal at birth, for those infants surviving beyond the newborn period, the growth of the head is arrested and progressive microcephaly is noticed. Like other forms of PCH, no developmental milestone is achieved. The initial hypotonia may progress to hypertonia with spasticity. Fundoscopy is usually unremarkable. In the index family where this condition was described, two of three affected siblings had crib deaths. These three affected children died at ages of 14, 2 and 3 months respectively. Neonatal MRI of the brain reveals cerebellar and vermian hypoplasia but normal brain volume while follow-up studies portray evidence of progressive atrophy of the cerebellum, pons, cerebral cortex, and white matter. Activities of mitochondrial complexes I, III, and IV in muscle from this patient were markedly reduced, but activity of complex II was relatively preserved.Sequence analysis of the entire coding region, deletion/duplication analysis, prenatal diagnosis, and carrier testing are available for PCH type 6. Rare Variants: Severe PCH/atrophy with testicular regression that has onset in the fetal period; possiblly PCH type 7.Deletion in part of chromosome 19 has been identified in a patient with PCH who had multiple congenital anomalies.Symptoms of pontocerebellar hypoplasia vary from case to case and from one PCH type to another. New types of PCH are being added almost every few years. In most infants, there is a small head, (microcephaly) without evidence of other congenital anomalies. Affected infants often experience seizures, postnatal growth retardation, and microcephaly, a term used to describe head circumference that is smaller than would be expected for a child’s age and sex. As affected infants age, they may experience significant delays in speech and in reaching motor milestones such as walking independently. Most of these children will never talk, walk, sit, stand, or even roll over. They may be completely dependent for all activities of daily living. In early life, there may be feeding difficulties warranting feeding by tubes. They may be at risk of aspiration. Usually they are very susceptible to respiratory infections. If not already born with contractures, they may later develop contractures. Seizures are common, and can be fairly controlled with anti-seizure medications. Profound intellectual disability is the norm. Social skills are absent. Patient lacks all ability to develop activities of daily living. Speech is often absent. Patients cannot learn sign language. Motor milestones are always severely delayed. Birth defects (dysmorphism) are rare in pontocerebellar hypoplasia, but deformities such as contractures and clubfoot and short stature have been reported.
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Symptoms of Pontocerebellar Hypoplasia. Pontocerebellar Hypoplasia Type 1 (PCH type 1):In pontocerebellar hypoplasia type 1, there is central and peripheral motor dysfunction from birth leading to early death, mostly before 1 year of age. In addition to an abnormally small cerebellum and brainstem including the pons, there is a degeneration of the anterior horn cells. Because of the anterior horn cell involvement, PCH type 1 has some resemblance to infantile spinal muscular atrophy. The hypoplasia of the pons and cerebellum and spinal anterior horn cell degeneration is also associated with pronounced reactive changes (gliosis). PCH type 1 is associated with reduced fetal movement. The pregnancy sometimes is complicated by polyhydramnios. In most cases, the condition is obvious during the newborn period when the newborn appears floppy and has respiratory insufficiency. At birth, multiple congenital contractures of large joints (arthrogryposis multiplex congenita) may be present. The newborn may show arreflexia, and combined motor signs. PCH type 1 has the hallmark of severe muscle weakness. The associated hypotonia may start prenatally or after birth. Intellectual disability and cerebellar signs of visual impairment, nystagmus and ataxia follow the initial presentation. It has also been found that some patients with PCH type 1 develop the signs of muscle weakness or developmental delay at the age of several months. These late presenting patients have a milder form and may live up to four years. However, the disease is uniformly fatal. Generally, affected babies have a life span not exceeding a few months in most cases. In all patients, postmortem examinations reveal variable spectrum of cerebellar atrophy, neuronal loss in the anterior horns of the spinal cord, basal ganglia and brainstem suggesting a more widespread neuronal degeneration. The inheritance of PCH follows an autosomal recessive pattern. Sequence analysis of the entire coding region, prenatal diagnosis and carrier testing are available for PCH type 1. Pontocerebellar Hypoplasia Type 2 (PCH type 2):In PCH type 2 there is progressive microcephaly from birth combined with extrapyramidal dyskinesia. There is no motor or mental development. Severe chorea occurs, and epilepsy is frequent, while signs of spinal anterior horn involvement are absent in PCH type 2. The main feature distinguishing PCH type 1 from PCH type 2 is that anterior horn cells are spared in PCH type 2. Characteristically, pregnancy is normal. However, at birth, the newborn may show breathing problems or respiratory failure that may require mechanical ventilatory support. Some may have sucking or feeding problems. Most patients with PCH type 2 are born with normal size head. Some already have microcephaly at birth. All affected children have worsening or progression of the microcephaly during infancy. Other features of dysmorphism are absent. They have impaired mental and motor development. They have abnormal movements termed extrapyramidal movement disorder. All affected children develop marked extrapyramidal dyskinetic movement disorder with predominance of dystonia. Jerky movements and almost continuous dystonic choreoathetotic movements may be seen. These movement abnormalities are usually noticed during the neonatal period of these children. Affected children have severe to profound intellectual disability. No patient with the classical PCH type 2 ever achieved the milestones of sitting, crawling, standing, walking, talking, or developed meaningful social contact skills. Visual fixation is persistently poor and only about one third of these patients are able to fixate and follow. Seizure disorder is frequent. Approximately half of these children may have seizures. A minority may also have hypotonia or hypertonia even as early as the newborn period. Minority may show spasticity. They are severely handicapped with no voluntary motor function. The children have severe cognitive and language impairment, and with no verbal or non-verbal communication. There is a near total loss of Purkinje fibers in the cerebellar hemisphere and an undetectable dentate nucleus. Neuronal loss is marked in the basal ganglia and thalamus without any anterior horn cell involvement when autopsy is done. The vermis is also relatively spared. These features are similar to those seen in PCH type 5 and suggest a continuum of pathology between both PCH type 2 and PCH type 5. The clinical findings, the severity of movement disorder and the developmental delay do not correlate with the degree of pontine or cerebellar hypoplasia on MRI. It is possible that there is a continuum of severe neonatal and infantile types rather than clearly defined groups. Death during early childhood has been attributed to respiratory and infectious complications.Mutations in 3 tRNA splicing endonuclease genes (TSEN) have been identified in PCH type 2 and Type 4. This has formed the basis of classifying PCH type 2 into types 2A, 2B, and 2C respectively associated with TSEN54, TSEN2 and TSEN34. Sequence analysis of the entire coding, region, linkage analysis, prenatal diagnosis, and carrier testing are available for TSEN2, TSEN34, and TSEN54 related PCH. In addition, deletion/duplication analysis is available also for TSEN54 related PCH.Pontocerebellar Hypoplasia Type 3 (PCH type 3):PCH type 3 has many features in common with PCH type 2. However, in PCH type 3, extrapyramidal symptoms (dyskinesia) are absent. The children may have seizures and microcephaly, which are the result of poor brain development and small size of the cerebellum and pons that affect the overall size of the brain. PCH Type 3 is a unique form described in three sibs of a consanguineous family from the Sultanate of Oman. Clinical features in these affected children include developmental delay, progressive microcephaly with brachycephaly and seizure in the first year, truncal hypotonia with exaggerated deep tendon reflexes, short stature and optic atrophy. One of the three children had thoracic scoliosis contractures of the elbows and knees, and clubfoot. Visual impairment including optic atrophy may be seen in affected patient. Other features include brachycephaly, prominent eyes, and low-set ears. There was no extrapyramidal involvement or dyskinesia. Imaging studies of the brain showed small brainstem, small cerebellar vermis, and atrophy of the cerebellum and cerebrum. PCH type 3 has been mapped to chromosome 7q11-21 and fine mapping is in progress. Pontocerebellar Hypoplasia Type 4 (PCH type 4):PCH type 4 is associated with severe neonatal encephalopathy, microcephaly, myoclonus, and muscular hypertonia. There is a severe loss of neurons in pontine and olivary nuclei in addition to the hypoplasia of the cerebellum and a diffuse gliosis in white matter of both the cerebellum and all areas of the brain. This is a more severe and fatal variant of PCH type 2, which is associated with death within the first few weeks of life, known as PCH type 4. Pontocerebellar Hypoplasia Type 5 (PCH type 5):PCH type 5 is similar to PCH type 4, but differs in having in-utero fetal seizure-like activity. These patients show evidence of severe olivopontocerebellar hypoplasia and degeneration, dysplastic, c-shaped inferior olivary nuclei, absent or immature dentate nuclei and cell paucity more marked for the cerebellar vermis than the hemispheres. Pontocerebellar Hypoplasia Type 6 (PCH type 6): PCH type 6 manifests as early as the first day of life or within the first month of life as infantile encephalopathy, with generalized hypotonia, lethargic, poor sucking and poor feeding. Recurrent apnea, intractable seizures occur early in the course of this condition. Although head size may be normal at birth, for those infants surviving beyond the newborn period, the growth of the head is arrested and progressive microcephaly is noticed. Like other forms of PCH, no developmental milestone is achieved. The initial hypotonia may progress to hypertonia with spasticity. Fundoscopy is usually unremarkable. In the index family where this condition was described, two of three affected siblings had crib deaths. These three affected children died at ages of 14, 2 and 3 months respectively. Neonatal MRI of the brain reveals cerebellar and vermian hypoplasia but normal brain volume while follow-up studies portray evidence of progressive atrophy of the cerebellum, pons, cerebral cortex, and white matter. Activities of mitochondrial complexes I, III, and IV in muscle from this patient were markedly reduced, but activity of complex II was relatively preserved.Sequence analysis of the entire coding region, deletion/duplication analysis, prenatal diagnosis, and carrier testing are available for PCH type 6. Rare Variants: Severe PCH/atrophy with testicular regression that has onset in the fetal period; possiblly PCH type 7.Deletion in part of chromosome 19 has been identified in a patient with PCH who had multiple congenital anomalies.Symptoms of pontocerebellar hypoplasia vary from case to case and from one PCH type to another. New types of PCH are being added almost every few years. In most infants, there is a small head, (microcephaly) without evidence of other congenital anomalies. Affected infants often experience seizures, postnatal growth retardation, and microcephaly, a term used to describe head circumference that is smaller than would be expected for a child’s age and sex. As affected infants age, they may experience significant delays in speech and in reaching motor milestones such as walking independently. Most of these children will never talk, walk, sit, stand, or even roll over. They may be completely dependent for all activities of daily living. In early life, there may be feeding difficulties warranting feeding by tubes. They may be at risk of aspiration. Usually they are very susceptible to respiratory infections. If not already born with contractures, they may later develop contractures. Seizures are common, and can be fairly controlled with anti-seizure medications. Profound intellectual disability is the norm. Social skills are absent. Patient lacks all ability to develop activities of daily living. Speech is often absent. Patients cannot learn sign language. Motor milestones are always severely delayed. Birth defects (dysmorphism) are rare in pontocerebellar hypoplasia, but deformities such as contractures and clubfoot and short stature have been reported.
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Pontocerebellar Hypoplasia
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nord_988_2
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Causes of Pontocerebellar Hypoplasia
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Pontocerebellar hypoplasia is considered to be inherited as an autosomal recessive disorder because it occurs mostly in consanguineous families (families where both parents are related). Therefore, each offspring of parents carrying the genetic abnormality has a one in four chance of suffering from pontocerebellar hypoplasia. However there is a two out of three chance that a sibling of an affected child may have one of the abnormal genes that on its own will not cause the disease in that sibling. Brain imaging (MRI or CT) shows small cerebellum and pons. There is a one in four chance that an offspring of such parents will not inherit any of the genes. At each conception, there is a three out of four chance that the offspring may not be affected. This is a characteristic of traits that are autosomal recessive in inheritance.
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Causes of Pontocerebellar Hypoplasia. Pontocerebellar hypoplasia is considered to be inherited as an autosomal recessive disorder because it occurs mostly in consanguineous families (families where both parents are related). Therefore, each offspring of parents carrying the genetic abnormality has a one in four chance of suffering from pontocerebellar hypoplasia. However there is a two out of three chance that a sibling of an affected child may have one of the abnormal genes that on its own will not cause the disease in that sibling. Brain imaging (MRI or CT) shows small cerebellum and pons. There is a one in four chance that an offspring of such parents will not inherit any of the genes. At each conception, there is a three out of four chance that the offspring may not be affected. This is a characteristic of traits that are autosomal recessive in inheritance.
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Pontocerebellar Hypoplasia
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nord_988_3
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Affects of Pontocerebellar Hypoplasia
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The disease affects both males and females without a predilection for either sex. More than 100 cases have been reported in the medical literature. The exact incidence of pontocerebellar hypoplasia is unknown.
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Affects of Pontocerebellar Hypoplasia. The disease affects both males and females without a predilection for either sex. More than 100 cases have been reported in the medical literature. The exact incidence of pontocerebellar hypoplasia is unknown.
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Pontocerebellar Hypoplasia
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nord_988_4
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Related disorders of Pontocerebellar Hypoplasia
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Symptoms of the following disorders can be similar to those of PCH. Comparisons may be useful for a differential diagnosis. Congenital disorders of glycosylation (CDG) are a group of disorders and the most common type is CDG1A, caused by mutation in the phosphomannomutase 2 gene and inherited in an autosomal recessive fashion. It has two clinical presentations – solely neurologic form and a neurologic-multivisceral form. It may present prenatally as fetal hydrops and mortality approximately 20% in first 2 years. CDG is characterized by growth failure, failure to thrive and has multisystemic features. Microcephaly with prominent forehead and large ears, abnormal eye movements, internal strabismus retinitis pigmentosa, nystagmus, flat nasal bridge, thin upper lip, pericardial effusion, and cardiomyopathy. Clinical features also include hepatomegaly with hepatic fibrosis, steatosis, feeding problems and diarrhea with vomiting. It may be complicated by nephritic syndrome, osteopenia, kyphosis and abnormal subcutaneous fat distribution. It presents with muscle weakness, hypotonia, psychomotor retardation, ataxia, hyporeflexia, stroke-like episodes, and seizures. Most patients are wheelchair-bound and have olivopontocerebellar hypoplasia, and peripheral neuropathy. Endocrine involvement includes hypothyroidism and decreased thyroxine-binding globulin. Hypergonadotropic hypogonadism may be seen. Laboratory abnormalities in CDG include abnormal isoelectric focusing of serum transferrins (type 1 pattern), abnormal serum glycoproteins, elevated transaminases, Proteinuria, decreased copper, iron, and zinc level, hypocholesterolemia, hypoalbuminemia and phosphomannomutase deficiency in leukocytes, fibroblasts, or liver.
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Related disorders of Pontocerebellar Hypoplasia. Symptoms of the following disorders can be similar to those of PCH. Comparisons may be useful for a differential diagnosis. Congenital disorders of glycosylation (CDG) are a group of disorders and the most common type is CDG1A, caused by mutation in the phosphomannomutase 2 gene and inherited in an autosomal recessive fashion. It has two clinical presentations – solely neurologic form and a neurologic-multivisceral form. It may present prenatally as fetal hydrops and mortality approximately 20% in first 2 years. CDG is characterized by growth failure, failure to thrive and has multisystemic features. Microcephaly with prominent forehead and large ears, abnormal eye movements, internal strabismus retinitis pigmentosa, nystagmus, flat nasal bridge, thin upper lip, pericardial effusion, and cardiomyopathy. Clinical features also include hepatomegaly with hepatic fibrosis, steatosis, feeding problems and diarrhea with vomiting. It may be complicated by nephritic syndrome, osteopenia, kyphosis and abnormal subcutaneous fat distribution. It presents with muscle weakness, hypotonia, psychomotor retardation, ataxia, hyporeflexia, stroke-like episodes, and seizures. Most patients are wheelchair-bound and have olivopontocerebellar hypoplasia, and peripheral neuropathy. Endocrine involvement includes hypothyroidism and decreased thyroxine-binding globulin. Hypergonadotropic hypogonadism may be seen. Laboratory abnormalities in CDG include abnormal isoelectric focusing of serum transferrins (type 1 pattern), abnormal serum glycoproteins, elevated transaminases, Proteinuria, decreased copper, iron, and zinc level, hypocholesterolemia, hypoalbuminemia and phosphomannomutase deficiency in leukocytes, fibroblasts, or liver.
| 988 |
Pontocerebellar Hypoplasia
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nord_988_5
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Diagnosis of Pontocerebellar Hypoplasia
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Molecular genetic diagnosis is available and has been described above with each PCH type for which it is available. Genetic tests are available for PCH types 1, 2A, 2B, 2C, 4 and 6. Prenatal diagnosis is now available for some forms of PCH.Serial ultrasound scans are sometimes used for diagnosis, but can be operator dependent and has very low sensitivity. Radiological diagnosis always lags behind the process of hypoplasia or degeneration of the cerebellum and pons.Most of the tests are done to investigate other known causes of brain abnormalities. These tests include testing for CDG (isoelectric focusing of transferrins), as described above, MRI of the brain and spinal cord, computed axial tomography of the brain and ultrasounds scans.Metabolic evaluation including plasma amino acid profiles, urine organic acids,electromyography, nerve conduction studies, electroencephalography, are sometimes conducted. Invasive studies like muscle, nerve and skin biopsies have been done in some cases. These may only be useful after excluding PCH types with known genetic mutations. Ophthalmological evaluation is needed in most cases.Genetic evaluations for syndromes known to be associated with congenital contractures like karyotype and fluorescent in situ hybridization analysis for Miller Dieker and Prader Willi syndromes may be indicatd. In 2003, Rajab et al mapped genetic locus for PCH type 3 to chromosome 7q11-2111.PCH type 6 results from a mutation in a non-coding region of a gene called RARS2 on chromosome 6 (chromosome 6q16.1). They found a homozygous intronic mutation in RARS2 in all the affected members that was carried by the parents who also had two healthy children. This gene mutation leads to a defect in mitochondrial respiratory chain complexes in affected patients.Recent reports have indicated that mutation in three subunits of the tRNA splicing endonuclease (TSEN) gene is associated with pontocerebellar hypoplasia types 2 and 4. This points to RNA processing as a new basic cellular impairment in neurological disorders.
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Diagnosis of Pontocerebellar Hypoplasia. Molecular genetic diagnosis is available and has been described above with each PCH type for which it is available. Genetic tests are available for PCH types 1, 2A, 2B, 2C, 4 and 6. Prenatal diagnosis is now available for some forms of PCH.Serial ultrasound scans are sometimes used for diagnosis, but can be operator dependent and has very low sensitivity. Radiological diagnosis always lags behind the process of hypoplasia or degeneration of the cerebellum and pons.Most of the tests are done to investigate other known causes of brain abnormalities. These tests include testing for CDG (isoelectric focusing of transferrins), as described above, MRI of the brain and spinal cord, computed axial tomography of the brain and ultrasounds scans.Metabolic evaluation including plasma amino acid profiles, urine organic acids,electromyography, nerve conduction studies, electroencephalography, are sometimes conducted. Invasive studies like muscle, nerve and skin biopsies have been done in some cases. These may only be useful after excluding PCH types with known genetic mutations. Ophthalmological evaluation is needed in most cases.Genetic evaluations for syndromes known to be associated with congenital contractures like karyotype and fluorescent in situ hybridization analysis for Miller Dieker and Prader Willi syndromes may be indicatd. In 2003, Rajab et al mapped genetic locus for PCH type 3 to chromosome 7q11-2111.PCH type 6 results from a mutation in a non-coding region of a gene called RARS2 on chromosome 6 (chromosome 6q16.1). They found a homozygous intronic mutation in RARS2 in all the affected members that was carried by the parents who also had two healthy children. This gene mutation leads to a defect in mitochondrial respiratory chain complexes in affected patients.Recent reports have indicated that mutation in three subunits of the tRNA splicing endonuclease (TSEN) gene is associated with pontocerebellar hypoplasia types 2 and 4. This points to RNA processing as a new basic cellular impairment in neurological disorders.
| 988 |
Pontocerebellar Hypoplasia
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nord_988_6
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Therapies of Pontocerebellar Hypoplasia
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TreatmentThe treatment of PCH is entirely symptomatic and supportive. The primary physician should serve as a medical home coordinating the care of this chronically ill child. The comprehensive care involves the services of a multidisciplinary team that may include the pediatrician, pediatric neurologist, pediatric surgeon, speech pathologist, ophthalmologist, physical therapist, occupational therapist and other specialist as warranted on case-by-case basis. Healthcare professionals may need to collaborate, systematically develop and implement a comprehensive care plan tailored to the need of the child.Gastrostomy tube may be required for feeding; fundoplication may be needed to prevent aspiration. The neurologist needs to be involved in the management of these patients especially for seizure management because their seizures sometimes could be intractable. Surgery may be performed to treat specific contractures, and tendon release. Supportive care may include physical, occupational, speech and therapy.The treatment of PCH is directed toward the specific symptoms that are apparent in each individual. Respiratory management may extend from non invasive ventilation to full mechanical ventilation. Some patient may require the mechanical ventilator for respiratory failure. Parents need to be empowered to make decision for the children.Informed decision making regarding palliative care versus participation in clinical investigatory interventions including the use of heroic and other extraordinary measures to maintain survival of the child will need to be carefully discussed with parents. The primary physician needs to discuss end of life care and issues like "do not resuscitate" and use of heroic treatments well in advance in anticipation of possibilities. Attention should be paid to issues such as day care, respite care, and linking up the patients with available social support services.
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Therapies of Pontocerebellar Hypoplasia. TreatmentThe treatment of PCH is entirely symptomatic and supportive. The primary physician should serve as a medical home coordinating the care of this chronically ill child. The comprehensive care involves the services of a multidisciplinary team that may include the pediatrician, pediatric neurologist, pediatric surgeon, speech pathologist, ophthalmologist, physical therapist, occupational therapist and other specialist as warranted on case-by-case basis. Healthcare professionals may need to collaborate, systematically develop and implement a comprehensive care plan tailored to the need of the child.Gastrostomy tube may be required for feeding; fundoplication may be needed to prevent aspiration. The neurologist needs to be involved in the management of these patients especially for seizure management because their seizures sometimes could be intractable. Surgery may be performed to treat specific contractures, and tendon release. Supportive care may include physical, occupational, speech and therapy.The treatment of PCH is directed toward the specific symptoms that are apparent in each individual. Respiratory management may extend from non invasive ventilation to full mechanical ventilation. Some patient may require the mechanical ventilator for respiratory failure. Parents need to be empowered to make decision for the children.Informed decision making regarding palliative care versus participation in clinical investigatory interventions including the use of heroic and other extraordinary measures to maintain survival of the child will need to be carefully discussed with parents. The primary physician needs to discuss end of life care and issues like "do not resuscitate" and use of heroic treatments well in advance in anticipation of possibilities. Attention should be paid to issues such as day care, respite care, and linking up the patients with available social support services.
| 988 |
Pontocerebellar Hypoplasia
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nord_989_0
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Overview of Porphyria Cutanea Tarda
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SummaryPorphyria cutanea tarda (PCT) is a rare disorder characterized by painful, blistering skin lesions that develop on sun-exposed skin (photosensitivity). Affected skin is fragile and may peel or blister after minor trauma. Liver abnormalities may also occur. PCT is caused by deficient levels of an enzyme known as uroporphyrinogen decarboxylase (UROD). In approximately 75% to 80% of cases this deficiency is acquired (PCT type 1 or sporadic PCT); in the remaining cases, individuals have a genetic predisposition to developing the disorder, specifically a mutation in the UROD gene (PCT type 2 or familial PCT). Most individuals with this genetic mutation do not develop PCT; the mutation is a predisposing factor and additional factors are required for the development of the disorder in these individuals. These factors are called susceptibility factors and are required for the development of both sporadic and familial PCT. Generally, PCT develops in mid to late adulthood. In extremely rare cases, individuals have mutations in both UROD genes. This autosomal recessive form of familial PCT is known as hepatoerythropoietic porphyria (HEP). HEP occurs in childhood and is usually more severe than PCT types 1 or 2. NORD has a separate report on HEP.IntroductionPCT belongs to a group of disorders known as the porphyrias. This group of at least seven disorders is characterized by abnormally high levels of porphyrins and porphyrin precursors due to deficiency of certain enzymes essential to the creation (synthesis) of heme, a part of hemoglobin and other hemoproteins. There are eight enzymes in the pathway for making heme and at least seven major forms of porphyria. The symptoms associated with the various forms of porphyria differ. It is important to note that people who have one type of porphyria do not develop any of the other types. Porphyrias are generally classified into two groups: the “hepatic” and “erythropoietic” types. Porphyrins and porphyrin precursors and related substances originate in excess amounts predominantly from the liver in the hepatic types and mostly from the bone marrow in the erythropoietic types. Porphyrias with skin manifestations are sometimes referred to as “cutaneous porphyrias.” The term “acute porphyria” is used to describe porphyrias that can be associated with sudden attacks of pain and other neurological symptoms. Most forms of porphyria are genetic inborn errors of metabolism. PCT is an acquired liver disease, in which some individuals have a genetic predisposition to developing the disorder.
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Overview of Porphyria Cutanea Tarda. SummaryPorphyria cutanea tarda (PCT) is a rare disorder characterized by painful, blistering skin lesions that develop on sun-exposed skin (photosensitivity). Affected skin is fragile and may peel or blister after minor trauma. Liver abnormalities may also occur. PCT is caused by deficient levels of an enzyme known as uroporphyrinogen decarboxylase (UROD). In approximately 75% to 80% of cases this deficiency is acquired (PCT type 1 or sporadic PCT); in the remaining cases, individuals have a genetic predisposition to developing the disorder, specifically a mutation in the UROD gene (PCT type 2 or familial PCT). Most individuals with this genetic mutation do not develop PCT; the mutation is a predisposing factor and additional factors are required for the development of the disorder in these individuals. These factors are called susceptibility factors and are required for the development of both sporadic and familial PCT. Generally, PCT develops in mid to late adulthood. In extremely rare cases, individuals have mutations in both UROD genes. This autosomal recessive form of familial PCT is known as hepatoerythropoietic porphyria (HEP). HEP occurs in childhood and is usually more severe than PCT types 1 or 2. NORD has a separate report on HEP.IntroductionPCT belongs to a group of disorders known as the porphyrias. This group of at least seven disorders is characterized by abnormally high levels of porphyrins and porphyrin precursors due to deficiency of certain enzymes essential to the creation (synthesis) of heme, a part of hemoglobin and other hemoproteins. There are eight enzymes in the pathway for making heme and at least seven major forms of porphyria. The symptoms associated with the various forms of porphyria differ. It is important to note that people who have one type of porphyria do not develop any of the other types. Porphyrias are generally classified into two groups: the “hepatic” and “erythropoietic” types. Porphyrins and porphyrin precursors and related substances originate in excess amounts predominantly from the liver in the hepatic types and mostly from the bone marrow in the erythropoietic types. Porphyrias with skin manifestations are sometimes referred to as “cutaneous porphyrias.” The term “acute porphyria” is used to describe porphyrias that can be associated with sudden attacks of pain and other neurological symptoms. Most forms of porphyria are genetic inborn errors of metabolism. PCT is an acquired liver disease, in which some individuals have a genetic predisposition to developing the disorder.
| 989 |
Porphyria Cutanea Tarda
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nord_989_1
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Symptoms of Porphyria Cutanea Tarda
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The symptoms of PCT can vary greatly from one individual to another. Skin abnormalities characterize this disorder. Affected individuals are abnormally susceptible to damage of the skin from sunlight (photosensitivity). Extremely fragile skin that can peel or blister on minimal impact is common. Affected individuals may develop blistering skin lesions on areas of the skin that are frequently exposed to the sun such as the hands and face. These lesions may crust over.Eventually, scarring may develop and affected skin may darken (hyperpigmentation) or fade (hypopigmentation) in color. Abnormal, excessive hair growth (hypertrichosis), especially on the face may also occur. The hair may be very fine or coarse and can differ in color. In some patients, their hair may grow, thicken and darken. Small bumps with a distinct white head (milia) may also develop, especially on the backs of the hands.In some cases, the skin in affected areas may thickened and harden, resembling a condition known as sclerosis, this is sometimes known as pseudosclerosis. Pseudosclerosis in individuals with PCT appears as scattered, waxy, harden patches or plaques of skin.Liver abnormalities may develop in some affected individuals including the accumulation of iron in the liver (hepatic siderosis), the accumulation of fat in the liver (steatosis), inflammation of certain parts of the liver (portal triaditis), and thickening and scarring around the portal vein (periportal fibrosis). Affected individuals may be at a greater risk than the general population of developing scarring of the liver (cirrhosis) or liver cancer known as hepatocellular carcinoma. Advanced liver disease is uncommon, except in older individuals with recurrent disease. In some cases, liver disease is due to an associated condition such as hepatitis C infection.
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Symptoms of Porphyria Cutanea Tarda. The symptoms of PCT can vary greatly from one individual to another. Skin abnormalities characterize this disorder. Affected individuals are abnormally susceptible to damage of the skin from sunlight (photosensitivity). Extremely fragile skin that can peel or blister on minimal impact is common. Affected individuals may develop blistering skin lesions on areas of the skin that are frequently exposed to the sun such as the hands and face. These lesions may crust over.Eventually, scarring may develop and affected skin may darken (hyperpigmentation) or fade (hypopigmentation) in color. Abnormal, excessive hair growth (hypertrichosis), especially on the face may also occur. The hair may be very fine or coarse and can differ in color. In some patients, their hair may grow, thicken and darken. Small bumps with a distinct white head (milia) may also develop, especially on the backs of the hands.In some cases, the skin in affected areas may thickened and harden, resembling a condition known as sclerosis, this is sometimes known as pseudosclerosis. Pseudosclerosis in individuals with PCT appears as scattered, waxy, harden patches or plaques of skin.Liver abnormalities may develop in some affected individuals including the accumulation of iron in the liver (hepatic siderosis), the accumulation of fat in the liver (steatosis), inflammation of certain parts of the liver (portal triaditis), and thickening and scarring around the portal vein (periportal fibrosis). Affected individuals may be at a greater risk than the general population of developing scarring of the liver (cirrhosis) or liver cancer known as hepatocellular carcinoma. Advanced liver disease is uncommon, except in older individuals with recurrent disease. In some cases, liver disease is due to an associated condition such as hepatitis C infection.
| 989 |
Porphyria Cutanea Tarda
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nord_989_2
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Causes of Porphyria Cutanea Tarda
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PCT is a multifactorial disorder, which means that several different factors such as genetic and environmental factors occurring in combination are necessary for the development of the disorder. These factors are not necessarily the same for each individual. These factors contribute either directly or indirectly to decreased levels or ineffectiveness of an enzyme known as uroporphyrinogen decarboxylase (UROD) within the liver. When UROD levels in the liver decrease to approximately 20% of normal levels, the symptoms of PCT may develop.The UROD enzyme is essential for breaking down (metabolizing) certain chemicals in the body known as porphyrins. Low levels of functional UROD result in the abnormal accumulation of specific porphyrins in body, especially within the blood, liver and skin. The symptoms of PCT occur because of this abnormal accumulation of porphyrins and related chemicals. For example when porphyrins accumulate in the skin, they absorb sunlight and enter an excited state (photoactivation). This abnormal activation results in the characteristic damage to the skin found in individuals with PCT. The liver removes porphyrins from the blood plasma and secretes it into the bile. When porphyrins accumulate in the liver, they can cause toxic damage to the liver.The exact, underlying mechanisms that cause PCT are complex and varied. It is determined that iron accumulation within the liver plays a central role in the development of the disorder in most individuals. Recently, researchers have discovered that a substance called uroporphomethene, which is an oxidized form of a specific porphyrin known as uroporphyrinogen, is an inhibitor that reduces the activity of the UROD enzyme in the liver. The oxidation of uroporphyrinogen into uroporphomethene has been shown to be iron dependent, emphasizing the importance or elevated iron levels in the development of PCT.The relationship between iron levels and PCT has long been established and PCT is classified as an iron-dependent disease. Clinical symptoms often correlate with abnormally elevated levels of iron in the liver (iron overloading). Iron overloading in the liver may only be mild or moderate. The exact relationship between iron accumulation and PCT is not fully understood, however, as there is no specific level of iron in the liver that correlates to disease in PCT (e.g. some individuals with symptomatic PCT have normal iron levels).There is an increased prevalence of mutations in the HFE gene in individuals with PCT. Mutations in the HFE gene can cause hemochromatosis, a disorder characterized by the accumulation of iron in the body, especially the liver. Hemochromatosis occurs when a person inherited two mutated HFE genes (one from each parent). Hemochromatosis is associated with low levels of hepcidin, a specialized protein that is the primary regulator of iron absorption in the body, including regulating the uptake of iron by the gastrointestinal tract and liver.Additional risk factors that have been associated with PCT include alcohol, certain infections such as hepatitis C or HIV, and drugs such as estrogens. Some studies have indicated that smoking is a risk factor for PCT in susceptible individuals. Less often, certain chemical exposures (e.g. hexachlorobenzene), kidney dialysis, and lupus appear to be connected to the development of PCT. It is believed that these susceptibility factors reduce hepcidin in the body and consequently lead to iron accumulation in the liver. However, the exact relationship among most susceptibility factors with the development of symptoms in PCT is not fully understood. For example, alcohol clearly contributes to the development of the disorder in some cases, but PCT is not common in alcoholics. Most individuals with PCT have three or more susceptibility factors present.In some cases, individuals develop PCT without a known susceptibility factor, suggesting that additional, as yet unidentified risk factors exist.The underlying cause of UROD deficiency in the acquired form of PCT is unknown. Affected individuals have approximately 50% residual UROD activity and do not develop symptoms unless additional factors are present. The most common factors associated with acquired PCT are hemochromatosis or chronic hepatitis C infection. In individuals with acquired PCT, UROD levels are only deficient in the liver.In the familial form of PCT, individuals have a mutation in the UROD gene. This mutation is inherited as an autosomal dominant trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new (de novo) mutation in the affected individual with no family history. 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.The UROD gene creates (encodes) the UROD enzyme, which is the fifth enzyme in the heme synthesis pathway. A mutation in one of these genes leads to abnormally low levels of this enzyme in all tissues of the body (not just the liver). However, one mutation alone is insufficient to cause familial PCT as residual UROD enzyme levels remain above 20% of normal. In fact, most individuals with a mutation in the UROD gene do not develop the disorder. Additional factors must be present for the disorder to develop.
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Causes of Porphyria Cutanea Tarda. PCT is a multifactorial disorder, which means that several different factors such as genetic and environmental factors occurring in combination are necessary for the development of the disorder. These factors are not necessarily the same for each individual. These factors contribute either directly or indirectly to decreased levels or ineffectiveness of an enzyme known as uroporphyrinogen decarboxylase (UROD) within the liver. When UROD levels in the liver decrease to approximately 20% of normal levels, the symptoms of PCT may develop.The UROD enzyme is essential for breaking down (metabolizing) certain chemicals in the body known as porphyrins. Low levels of functional UROD result in the abnormal accumulation of specific porphyrins in body, especially within the blood, liver and skin. The symptoms of PCT occur because of this abnormal accumulation of porphyrins and related chemicals. For example when porphyrins accumulate in the skin, they absorb sunlight and enter an excited state (photoactivation). This abnormal activation results in the characteristic damage to the skin found in individuals with PCT. The liver removes porphyrins from the blood plasma and secretes it into the bile. When porphyrins accumulate in the liver, they can cause toxic damage to the liver.The exact, underlying mechanisms that cause PCT are complex and varied. It is determined that iron accumulation within the liver plays a central role in the development of the disorder in most individuals. Recently, researchers have discovered that a substance called uroporphomethene, which is an oxidized form of a specific porphyrin known as uroporphyrinogen, is an inhibitor that reduces the activity of the UROD enzyme in the liver. The oxidation of uroporphyrinogen into uroporphomethene has been shown to be iron dependent, emphasizing the importance or elevated iron levels in the development of PCT.The relationship between iron levels and PCT has long been established and PCT is classified as an iron-dependent disease. Clinical symptoms often correlate with abnormally elevated levels of iron in the liver (iron overloading). Iron overloading in the liver may only be mild or moderate. The exact relationship between iron accumulation and PCT is not fully understood, however, as there is no specific level of iron in the liver that correlates to disease in PCT (e.g. some individuals with symptomatic PCT have normal iron levels).There is an increased prevalence of mutations in the HFE gene in individuals with PCT. Mutations in the HFE gene can cause hemochromatosis, a disorder characterized by the accumulation of iron in the body, especially the liver. Hemochromatosis occurs when a person inherited two mutated HFE genes (one from each parent). Hemochromatosis is associated with low levels of hepcidin, a specialized protein that is the primary regulator of iron absorption in the body, including regulating the uptake of iron by the gastrointestinal tract and liver.Additional risk factors that have been associated with PCT include alcohol, certain infections such as hepatitis C or HIV, and drugs such as estrogens. Some studies have indicated that smoking is a risk factor for PCT in susceptible individuals. Less often, certain chemical exposures (e.g. hexachlorobenzene), kidney dialysis, and lupus appear to be connected to the development of PCT. It is believed that these susceptibility factors reduce hepcidin in the body and consequently lead to iron accumulation in the liver. However, the exact relationship among most susceptibility factors with the development of symptoms in PCT is not fully understood. For example, alcohol clearly contributes to the development of the disorder in some cases, but PCT is not common in alcoholics. Most individuals with PCT have three or more susceptibility factors present.In some cases, individuals develop PCT without a known susceptibility factor, suggesting that additional, as yet unidentified risk factors exist.The underlying cause of UROD deficiency in the acquired form of PCT is unknown. Affected individuals have approximately 50% residual UROD activity and do not develop symptoms unless additional factors are present. The most common factors associated with acquired PCT are hemochromatosis or chronic hepatitis C infection. In individuals with acquired PCT, UROD levels are only deficient in the liver.In the familial form of PCT, individuals have a mutation in the UROD gene. This mutation is inherited as an autosomal dominant trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new (de novo) mutation in the affected individual with no family history. 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.The UROD gene creates (encodes) the UROD enzyme, which is the fifth enzyme in the heme synthesis pathway. A mutation in one of these genes leads to abnormally low levels of this enzyme in all tissues of the body (not just the liver). However, one mutation alone is insufficient to cause familial PCT as residual UROD enzyme levels remain above 20% of normal. In fact, most individuals with a mutation in the UROD gene do not develop the disorder. Additional factors must be present for the disorder to develop.
| 989 |
Porphyria Cutanea Tarda
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nord_989_3
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Affects of Porphyria Cutanea Tarda
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PCT is a rare disorder that affects males and females. The disorder usually develops after the age of 30 and its onset in childhood is rare. PCT is found worldwide and in individuals of all races. The prevalence is estimated to be approximately 1 in 10,000 to 25,000 individuals in the general population. PCT is the most common form of porphyria.
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Affects of Porphyria Cutanea Tarda. PCT is a rare disorder that affects males and females. The disorder usually develops after the age of 30 and its onset in childhood is rare. PCT is found worldwide and in individuals of all races. The prevalence is estimated to be approximately 1 in 10,000 to 25,000 individuals in the general population. PCT is the most common form of porphyria.
| 989 |
Porphyria Cutanea Tarda
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nord_989_4
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Related disorders of Porphyria Cutanea Tarda
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Symptoms of the following disorders can be similar to those of PCT. Comparisons may be useful for a differential diagnosis.Variegate porphyria is a rare genetic metabolic disorder characterized by deficient function of the enzyme protoporphyrinogen oxidase (PPO or PPOX). This deficiency is caused by heterozygous mutations in the PPOX gene, and leads to the accumulation of certain chemicals called porphyrins and porphyrin precursors in the body, which, in turn, can potentially result in a variety of symptoms. Specific symptoms can vary greatly from one person to another. Some affected individuals present with skin symptoms, some with neurological symptoms and some with both. Blistering and fragility of sun-exposed skin are the most common skin (cutaneous) symptoms. Common neurological symptoms include abdominal pain, nausea, vomiting, constipation, extremity pain and weakness, anxiety, restlessness and convulsions. Many different PPOX mutations have been identified in different families with variegate porphyria. The genetic mutation in a family is inherited as an autosomal dominant trait, but many individuals who inherit a PPOX mutation do not develop any symptoms (asymptomatic). (For more information on this disorder, choose “variegate porphyria” as your search term in the Rare Disease Database.)Hepatoerythropoietic porphyria (HEP) is an extremely rare genetic disorder characterized severe deficiency of the enzyme, uroporphyrinogen decarboxylase. Onset is usually during infancy or early childhood, although adult onset has been reported. Affected individuals develop painful, blistering skin lesions that develop on sun-exposed skin (photosensitivity). Cutaneous photosensitivity is usually more severe in HEP than in PCT. Affected areas of skin can scar and become discolored. There is a risk of bacterial infection. Hypertrichosis is also common. Mild anemia and enlargement of the liver and/or spleen (hepatomegaly) have also been reported. Adult onset, mild cases of HEP may be clinically indistinguishable from PCT. HEP is caused by mutations of the UROD gene and is inherited as an autosomal recessive trait. (For more information on this disorder, choose “hepatoerythropoietic porphyria” as your search term in the Rare Disease Database.)Pseudoporphyria is a rare skin disease that occurs upon exposure to sunlight. Affected skin may be extremely fragile. In addition, affected individuals can develop large blisters filled with a clear fluid (bullae), small bumps with a distinct white head (milia), and scarring of affected areas. Lesions form in sun-exposed areas of the skin or at the site of trauma on the skin. A sunburn-like rash can develop in some affected individuals. The skin lesions of pseudoporphyria closely resemble those seen in cutaneous forms of porphyria including porphyria cutanea tarda. Pseudoporphyria can occur at any age. Women are affected more often than men. Pseudoporphyria is caused by the use of certain medications. The disorder can also be associated with often chronic kidney failure and hemodialysis. In some cases, tanning beds or ultraviolet light therapy (phototherapy) can worsen symptoms.There are other conditions that may cause signs and symptoms that are similar to those seen in porphyria cutanea tarda. Such conditions include other cutaneous porphyrias, drug-induced photosensitivity, various forms of lupus, and solar urticarial. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Related disorders of Porphyria Cutanea Tarda. Symptoms of the following disorders can be similar to those of PCT. Comparisons may be useful for a differential diagnosis.Variegate porphyria is a rare genetic metabolic disorder characterized by deficient function of the enzyme protoporphyrinogen oxidase (PPO or PPOX). This deficiency is caused by heterozygous mutations in the PPOX gene, and leads to the accumulation of certain chemicals called porphyrins and porphyrin precursors in the body, which, in turn, can potentially result in a variety of symptoms. Specific symptoms can vary greatly from one person to another. Some affected individuals present with skin symptoms, some with neurological symptoms and some with both. Blistering and fragility of sun-exposed skin are the most common skin (cutaneous) symptoms. Common neurological symptoms include abdominal pain, nausea, vomiting, constipation, extremity pain and weakness, anxiety, restlessness and convulsions. Many different PPOX mutations have been identified in different families with variegate porphyria. The genetic mutation in a family is inherited as an autosomal dominant trait, but many individuals who inherit a PPOX mutation do not develop any symptoms (asymptomatic). (For more information on this disorder, choose “variegate porphyria” as your search term in the Rare Disease Database.)Hepatoerythropoietic porphyria (HEP) is an extremely rare genetic disorder characterized severe deficiency of the enzyme, uroporphyrinogen decarboxylase. Onset is usually during infancy or early childhood, although adult onset has been reported. Affected individuals develop painful, blistering skin lesions that develop on sun-exposed skin (photosensitivity). Cutaneous photosensitivity is usually more severe in HEP than in PCT. Affected areas of skin can scar and become discolored. There is a risk of bacterial infection. Hypertrichosis is also common. Mild anemia and enlargement of the liver and/or spleen (hepatomegaly) have also been reported. Adult onset, mild cases of HEP may be clinically indistinguishable from PCT. HEP is caused by mutations of the UROD gene and is inherited as an autosomal recessive trait. (For more information on this disorder, choose “hepatoerythropoietic porphyria” as your search term in the Rare Disease Database.)Pseudoporphyria is a rare skin disease that occurs upon exposure to sunlight. Affected skin may be extremely fragile. In addition, affected individuals can develop large blisters filled with a clear fluid (bullae), small bumps with a distinct white head (milia), and scarring of affected areas. Lesions form in sun-exposed areas of the skin or at the site of trauma on the skin. A sunburn-like rash can develop in some affected individuals. The skin lesions of pseudoporphyria closely resemble those seen in cutaneous forms of porphyria including porphyria cutanea tarda. Pseudoporphyria can occur at any age. Women are affected more often than men. Pseudoporphyria is caused by the use of certain medications. The disorder can also be associated with often chronic kidney failure and hemodialysis. In some cases, tanning beds or ultraviolet light therapy (phototherapy) can worsen symptoms.There are other conditions that may cause signs and symptoms that are similar to those seen in porphyria cutanea tarda. Such conditions include other cutaneous porphyrias, drug-induced photosensitivity, various forms of lupus, and solar urticarial. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Porphyria Cutanea Tarda
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nord_989_5
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Diagnosis of Porphyria Cutanea Tarda
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A diagnosis of PCT is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation, and a variety of specialized tests.Clinical Testing and WorkupScreening tests can help diagnosis PCT by measuring the levels of certain porphyrins in blood plasma. This test can differentiate PCT from variegate porphyria and erythropoietic protoporphyria. Screening tests can also be performed on the urine or feces. The patterns of porphyrins in urine (predominately uroporphyrin and 7-carboxylate porphyrin) and feces (predominately isocoproporphyrin) help to confirm the diagnosis. Familial PCT can be diagnosed by the presence of a reduced amount of the UROD enzyme in red blood cells (erythrocytes). Molecular genetic testing is available for familial PCT if the diagnosis has been confirmed in the patient or a family member by urinary porphyrin analysis and/or enzyme assay of UROD activity.
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Diagnosis of Porphyria Cutanea Tarda. A diagnosis of PCT is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation, and a variety of specialized tests.Clinical Testing and WorkupScreening tests can help diagnosis PCT by measuring the levels of certain porphyrins in blood plasma. This test can differentiate PCT from variegate porphyria and erythropoietic protoporphyria. Screening tests can also be performed on the urine or feces. The patterns of porphyrins in urine (predominately uroporphyrin and 7-carboxylate porphyrin) and feces (predominately isocoproporphyrin) help to confirm the diagnosis. Familial PCT can be diagnosed by the presence of a reduced amount of the UROD enzyme in red blood cells (erythrocytes). Molecular genetic testing is available for familial PCT if the diagnosis has been confirmed in the patient or a family member by urinary porphyrin analysis and/or enzyme assay of UROD activity.
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Porphyria Cutanea Tarda
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nord_989_6
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Therapies of Porphyria Cutanea Tarda
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Treatment
The treatment of PCT is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, general internists, hematologists, dermatologists, hepatologists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment.PCT is the most treatable form of porphyria and treatment appears equally effective for both the sporadic and familial forms. The standard treatment of individuals with PCT is regularly scheduled phlebotomies to reduce iron and porphyrin levels in the liver. This is the preferred treatment of affected individuals at many porphyria centers regardless of whether there is confirmed iron overload. A phlebotomy is a simple and safe procedure that involves removing blood via a vein (bloodletting). Since much of the iron in the body is present in red blood cells, regular phlebotomies can reduce excess iron levels in the body. Regularly scheduled phlebotomies usually results in complete remission in most individuals. A phlebotomy schedule is recommended to achieve a target ferritin level of less than 20 nanograms per milliliter (<20 ng/mL). Ferritin is an iron compound that is used an indicator of the body’s iron stores. Most patients require between five and eight phlebotomies to achieve remission.In some cases, affected individuals may be treated with low doses of chloroquine and hydroxychloroquine, which can also reduce iron levels in the liver. These drugs are often used to treat malaria (antimalarials). This therapy is usually reserved for individuals for whom phlebotomies are not an option (e.g. contraindicated) such as in individuals with anemia, if there is the non-availability of venous access, or because of patient choice. The dosage of these drugs is especially important; dosages approaching those commonly used to treat individuals with other conditions can cause significant adverse effects in individuals with PCT including elevating porphyrin levels and worsening photosensitivity. The recommended dosages are 100 mg twice a week for hydroxychloroquine or 125 mg twice a week for chloroquine. Such a low dose schedule is equally effective as phlebotomy and easier to take with less treatment cost involved. The mechanism of action of these drugs in individuals with PCT is not fully understood, but it is speculated that these drugs bind with porphyrins inside the lysosomes of liver cells, to be eventually excreted in the urine.Hydroxychloroquine and chloroquine are contraindicated in pregnant women or women who are lactating. These drugs are also contraindicated for individuals with advanced liver disease, psoriasis, retinal disease, or glucose-6-phosphate dehydrogenase deficiency or who have recent or continued use of alcohol or drugs that are toxic to the liver (e.g. acetaminophen, isoniazid or valproic acid). Hydroxychloroquine and chloroquine can be associated with side effects including less serious ones (e.g., nausea, vomiting, headaches, etc.), but also more serious ones including seizures, muscle weakness or damage to the retinas of the eyes (retinopathy). Although retinopathy is unlikely with the low dose regimen used for PCT, an eye (ophthalmological) examination is recommended both before and after treatment. Signs of retinopathy can include blurred vision, light sensitivity or seeing halos around lights.Iron chelators are drugs that bind to iron in the body allowing iron to be dissolved in water and excreted from the body through the kidneys. Iron chelators are less effective than phlebotomy or low dose hydroxychloroquine or chloroquine in treating individuals with PCT. However, these drugs may play a role in treating affected individuals in whom the use of the two front-line therapies is not possible, such as individuals with end stage renal disease who are on hemodialysis.Affected individuals are advised to avoid environmental triggering factors of the disorder such as stopping alcohol consumption or smoking. The avoidance of sunlight may be necessary to protect the skin and can include the use of double layers of clothing, long sleeves, wide brimmed hats, gloves, and sunglasses. Pain killers (oral analgesics) can be used to treat painful skin lesion. Care should be taken to avoid infection of skin lesions. Antibiotics can be used to treat skin infections that do develop.The treatment of PCT can achieve complete remission in affected individuals, but relapse is possible. The treatment of relapse is the same as the initial treatment.
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Therapies of Porphyria Cutanea Tarda. Treatment
The treatment of PCT is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, general internists, hematologists, dermatologists, hepatologists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment.PCT is the most treatable form of porphyria and treatment appears equally effective for both the sporadic and familial forms. The standard treatment of individuals with PCT is regularly scheduled phlebotomies to reduce iron and porphyrin levels in the liver. This is the preferred treatment of affected individuals at many porphyria centers regardless of whether there is confirmed iron overload. A phlebotomy is a simple and safe procedure that involves removing blood via a vein (bloodletting). Since much of the iron in the body is present in red blood cells, regular phlebotomies can reduce excess iron levels in the body. Regularly scheduled phlebotomies usually results in complete remission in most individuals. A phlebotomy schedule is recommended to achieve a target ferritin level of less than 20 nanograms per milliliter (<20 ng/mL). Ferritin is an iron compound that is used an indicator of the body’s iron stores. Most patients require between five and eight phlebotomies to achieve remission.In some cases, affected individuals may be treated with low doses of chloroquine and hydroxychloroquine, which can also reduce iron levels in the liver. These drugs are often used to treat malaria (antimalarials). This therapy is usually reserved for individuals for whom phlebotomies are not an option (e.g. contraindicated) such as in individuals with anemia, if there is the non-availability of venous access, or because of patient choice. The dosage of these drugs is especially important; dosages approaching those commonly used to treat individuals with other conditions can cause significant adverse effects in individuals with PCT including elevating porphyrin levels and worsening photosensitivity. The recommended dosages are 100 mg twice a week for hydroxychloroquine or 125 mg twice a week for chloroquine. Such a low dose schedule is equally effective as phlebotomy and easier to take with less treatment cost involved. The mechanism of action of these drugs in individuals with PCT is not fully understood, but it is speculated that these drugs bind with porphyrins inside the lysosomes of liver cells, to be eventually excreted in the urine.Hydroxychloroquine and chloroquine are contraindicated in pregnant women or women who are lactating. These drugs are also contraindicated for individuals with advanced liver disease, psoriasis, retinal disease, or glucose-6-phosphate dehydrogenase deficiency or who have recent or continued use of alcohol or drugs that are toxic to the liver (e.g. acetaminophen, isoniazid or valproic acid). Hydroxychloroquine and chloroquine can be associated with side effects including less serious ones (e.g., nausea, vomiting, headaches, etc.), but also more serious ones including seizures, muscle weakness or damage to the retinas of the eyes (retinopathy). Although retinopathy is unlikely with the low dose regimen used for PCT, an eye (ophthalmological) examination is recommended both before and after treatment. Signs of retinopathy can include blurred vision, light sensitivity or seeing halos around lights.Iron chelators are drugs that bind to iron in the body allowing iron to be dissolved in water and excreted from the body through the kidneys. Iron chelators are less effective than phlebotomy or low dose hydroxychloroquine or chloroquine in treating individuals with PCT. However, these drugs may play a role in treating affected individuals in whom the use of the two front-line therapies is not possible, such as individuals with end stage renal disease who are on hemodialysis.Affected individuals are advised to avoid environmental triggering factors of the disorder such as stopping alcohol consumption or smoking. The avoidance of sunlight may be necessary to protect the skin and can include the use of double layers of clothing, long sleeves, wide brimmed hats, gloves, and sunglasses. Pain killers (oral analgesics) can be used to treat painful skin lesion. Care should be taken to avoid infection of skin lesions. Antibiotics can be used to treat skin infections that do develop.The treatment of PCT can achieve complete remission in affected individuals, but relapse is possible. The treatment of relapse is the same as the initial treatment.
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Porphyria Cutanea Tarda
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nord_990_0
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Overview of Porphyrias
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Summary
Porphyrias are a group of at least eight related disorders that primarily affect the skin or the nervous system, and sometimes the liver and other organs. Porphyrias occur when there is an abnormality in the pathway for making heme, a chemical that is an essential component of many enzymes and other molecules, many of which interact with oxygen. Heme is made in all tissues, but especially the bone marrow and liver. Heme is made in a series of eight steps, with a specific enzyme responsible for each step. Disruption of the pathway to make heme can cause intermediates between these steps to accumulate and cause symptoms of porphyria. Intermediates late in the pathway are porphyrins, whereas those early in the pathway are called porphyrin precursors. Accumulation of porphyrin precursors is associated with effects on the nervous system, whereas excess porphyrins are activated by light and cause skin photosensitivity. Each major type of porphyria is due to an abnormality of a different enzyme in the pathway that produces heme.There are two general categories of porphyria. In hepatic porphyrias, pathway intermediates accumulate initially in the liver, whereas in erythropoietic porphyrias they first originate in the bone marrow, before being transported in blood throughout the body. Erythropoietic porphyrias often begin to cause symptoms early in life, whereas hepatic porphyrias are manifest especially in adults.Three clinical types of porphyria are readily distinguished but are not completely distinct (see table below). The acute porphyrias, also known as the acute hepatic porphyrias, mainly affect the nervous system. Symptoms include periodic attacks of abdominal pain, other gastrointestinal symptoms, mental changes and pain and weakness of the extremities. Blistering cutaneous porphyrias are chronic, with skin blistering, scarring and pigment changes after exposure to sunlight. Non-blistering cutaneous porphyrias cause much more acute, severe and painful reactions after sunlight exposure, which greatly alters behavior but causes few chronic skin changes.All but one of the porphyrias are related to pathogenic variants (mutations) in genes for enzymes in the pathway to make heme and are inherited in families. However, many individuals with a familial mutation may never have symptoms. Other external and genetic factors may be necessary before symptoms occur, especially in hepatic porphyrias. These may include certain medications, alcohol use, changes in diet or exposure to certain hormones or chemicals. External causative factors predominate in the most common porphyria, porphyria cutanea tarda, and most cases occur in the absence of a familial mutation.Diagnosis of porphyrias can be challenging because they are uncommon with symptoms that resemble other more common conditions. Diagnosis is based on clinical suspicion and confirmed by laboratory testing. Further confirmation by genetic testing is now widely available and facilitates screening of relatives. After diagnosis, management focusses on treatment of presenting symptoms and prevention of recurrences and long-term complications.Introduction
This report provides a general overview of the types of porphyria. NORD has individual reports on each type.
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Overview of Porphyrias. Summary
Porphyrias are a group of at least eight related disorders that primarily affect the skin or the nervous system, and sometimes the liver and other organs. Porphyrias occur when there is an abnormality in the pathway for making heme, a chemical that is an essential component of many enzymes and other molecules, many of which interact with oxygen. Heme is made in all tissues, but especially the bone marrow and liver. Heme is made in a series of eight steps, with a specific enzyme responsible for each step. Disruption of the pathway to make heme can cause intermediates between these steps to accumulate and cause symptoms of porphyria. Intermediates late in the pathway are porphyrins, whereas those early in the pathway are called porphyrin precursors. Accumulation of porphyrin precursors is associated with effects on the nervous system, whereas excess porphyrins are activated by light and cause skin photosensitivity. Each major type of porphyria is due to an abnormality of a different enzyme in the pathway that produces heme.There are two general categories of porphyria. In hepatic porphyrias, pathway intermediates accumulate initially in the liver, whereas in erythropoietic porphyrias they first originate in the bone marrow, before being transported in blood throughout the body. Erythropoietic porphyrias often begin to cause symptoms early in life, whereas hepatic porphyrias are manifest especially in adults.Three clinical types of porphyria are readily distinguished but are not completely distinct (see table below). The acute porphyrias, also known as the acute hepatic porphyrias, mainly affect the nervous system. Symptoms include periodic attacks of abdominal pain, other gastrointestinal symptoms, mental changes and pain and weakness of the extremities. Blistering cutaneous porphyrias are chronic, with skin blistering, scarring and pigment changes after exposure to sunlight. Non-blistering cutaneous porphyrias cause much more acute, severe and painful reactions after sunlight exposure, which greatly alters behavior but causes few chronic skin changes.All but one of the porphyrias are related to pathogenic variants (mutations) in genes for enzymes in the pathway to make heme and are inherited in families. However, many individuals with a familial mutation may never have symptoms. Other external and genetic factors may be necessary before symptoms occur, especially in hepatic porphyrias. These may include certain medications, alcohol use, changes in diet or exposure to certain hormones or chemicals. External causative factors predominate in the most common porphyria, porphyria cutanea tarda, and most cases occur in the absence of a familial mutation.Diagnosis of porphyrias can be challenging because they are uncommon with symptoms that resemble other more common conditions. Diagnosis is based on clinical suspicion and confirmed by laboratory testing. Further confirmation by genetic testing is now widely available and facilitates screening of relatives. After diagnosis, management focusses on treatment of presenting symptoms and prevention of recurrences and long-term complications.Introduction
This report provides a general overview of the types of porphyria. NORD has individual reports on each type.
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Porphyrias
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nord_990_1
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Symptoms of Porphyrias
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ACUTE PORPHYRIASThe acute (hepatic) porphyrias are characterized by episodes of abdominal pain (the most common symptom), constipation and other gastrointestinal symptoms, extremity pain and weakness and mental changes such as insomnia, anxiety, agitation, hallucinations, delusions and seizures. Examination often reveals rapid heart rate and hypertension. Attacks may last days or weeks. Other symptoms may include red or dark urine and urinary hesitancy. Weakness can progress to generalized paralysis and need for respiratory support. These severe symptoms can be life threatening especially if diagnosis and treatment are delayed. Effective treatments include intravenous infusion of heme and subcutaneous injection of givosiran, an interfering RNA therapeutic.Acute Intermittent Porphyria (AIP)Acute intermittent porphyria (AIP) is the most common of the acute porphyrias. Symptoms include periodic attacks, as described above. Long-term complications of AIP and other acute porphyrias may include progressive kidney damage, high blood pressure and liver cancer. Symptoms begin during adulthood in almost all patients and are more common in females. Photosensitivity occurs only in some individuals who develop advanced renal failure, which can elevate levels of porphyrins in plasma.AIP patients have a mutation in the gene for porphobilinogen deaminase (PBGD), also known as hydroxymethylbilane synthase (HMBS). Most individuals who inherit a mutation that can cause AIP never have symptoms. Others may have only one or a few attacks in their lifetime, whereas a minority may have attacks that recur frequently. Chronic symptoms may persist between attacks.Variegate Porphyria (VP)Variegate porphyria (VP) is the second most common acute porphyria. Attacks are identical to those seen in AIP. Blistering skin lesions are often misdiagnosed as porphyria cutanea tarda (PCT), which is much more common than VP. Symptoms develop after puberty, as in AIP. VP patients have a mutation in the gene for protoporphyrinogen oxidase (PPOX). Many individuals with a PPOX gene mutation that can cause VP never develop symptoms.Hereditary Coproporphyria (HCP)HCP is less common than VP. Symptoms are like those seen in VP, except that skin manifestations are much less common. HCP patients have a mutation in the gene for coproporphyrinogen oxidase (CPOX). Many individuals with a pathogenic CPOX mutation never develop symptoms.ALAD-Deficiency Porphyria (ADP)ALAD porphyria (ADP) is extremely rare with only eight well documented cases. Why all cases have been males is unexplained. Symptoms occur mostly in attacks, as in AIP. Symptoms usually begin at or near puberty but can begin in childhood. Chronic neurological symptoms are seen in severe cases. In one case, onset in an adult was associated with a bone marrow disorder (polycythemia vera).BLISTERING CUTANEOUS PORPHYRIAS
Porphyria Cutanea Tarda (PCT) This hepatic porphyria is the most common of all porphyrias, and also the most readily treated. It is primarily an acquired, iron related disease in which there is inhibition of uroporphyrinogen decarboxylase (UROD), the fifth enzyme in the heme synthetic pathway, in the liver. A minority or patients have a predisposing UROD gene mutation and are classified as having familial PCT. Symptoms usually occur after age 40. Sun-exposed areas of the skin (most commonly the backs of the hands) can become friable and prone to blistering, scarring and excess hair growth. Other predisposing factors include chronic hepatitis C, HIV infection, alcohol, smoking, estrogens and excess iron. Some of these factors and PCT itself can lead to chronic liver disease and liver cancer. PCT responds well to treatment with phlebotomies (to reduce iron) or a low dose regimen of hydroxychloroquine. Treatment of hepatitis C, if present, is also highly effective.Erythropoietic Protoporphyria (EPP) and X-Linked Protoporphyria (XLP)The symptoms of the protoporphyrias (EEP and XLP) usually begin in infancy or early childhood. Sun exposure causes severe burning pain often within minutes of exposure. Patients learn to avoid sunlight and seldom develop blistering or scarring. Prolonged exposure to sunlight can lead to both cutaneous and systemic symptoms lasting for several days. Protoporphyrin is insoluble in water and is excreted in bile rather than urine. In less than 5% of patients, excess protoporphyrin can cause significant liver damage. Current treatment is sunlight avoidance and agents that increase skin melanin pigmentation.Congenital Erythropoietic Porphyria (CEP)Congenital erythropoietic porphyria (CEP) is very rare, with onset usually in early childhood or even in utero. The blistering skin manifestations are usually severe, but mild cases can resemble PCT. Facial hair growth is often increased. Porphyrins are deposited in bone and teeth. Anemia in severe cases may require red blood cell transfusion. An enlarged spleen is common. Repeated blistering, infection and scarring can lead to loss of fingers and facial features. Rare onset during adulthood is often related to development of a clonal bone marrow disease.Hepatoerythropoietic Porphyria (HEP)Hepatoerythropoietic porphyria (HEP) is caused by two mutations in the UROD gene and resembles CEP clinically. Unusually mild cases can resemble PCT. Symptoms usually begin in infancy or childhood.
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Symptoms of Porphyrias. ACUTE PORPHYRIASThe acute (hepatic) porphyrias are characterized by episodes of abdominal pain (the most common symptom), constipation and other gastrointestinal symptoms, extremity pain and weakness and mental changes such as insomnia, anxiety, agitation, hallucinations, delusions and seizures. Examination often reveals rapid heart rate and hypertension. Attacks may last days or weeks. Other symptoms may include red or dark urine and urinary hesitancy. Weakness can progress to generalized paralysis and need for respiratory support. These severe symptoms can be life threatening especially if diagnosis and treatment are delayed. Effective treatments include intravenous infusion of heme and subcutaneous injection of givosiran, an interfering RNA therapeutic.Acute Intermittent Porphyria (AIP)Acute intermittent porphyria (AIP) is the most common of the acute porphyrias. Symptoms include periodic attacks, as described above. Long-term complications of AIP and other acute porphyrias may include progressive kidney damage, high blood pressure and liver cancer. Symptoms begin during adulthood in almost all patients and are more common in females. Photosensitivity occurs only in some individuals who develop advanced renal failure, which can elevate levels of porphyrins in plasma.AIP patients have a mutation in the gene for porphobilinogen deaminase (PBGD), also known as hydroxymethylbilane synthase (HMBS). Most individuals who inherit a mutation that can cause AIP never have symptoms. Others may have only one or a few attacks in their lifetime, whereas a minority may have attacks that recur frequently. Chronic symptoms may persist between attacks.Variegate Porphyria (VP)Variegate porphyria (VP) is the second most common acute porphyria. Attacks are identical to those seen in AIP. Blistering skin lesions are often misdiagnosed as porphyria cutanea tarda (PCT), which is much more common than VP. Symptoms develop after puberty, as in AIP. VP patients have a mutation in the gene for protoporphyrinogen oxidase (PPOX). Many individuals with a PPOX gene mutation that can cause VP never develop symptoms.Hereditary Coproporphyria (HCP)HCP is less common than VP. Symptoms are like those seen in VP, except that skin manifestations are much less common. HCP patients have a mutation in the gene for coproporphyrinogen oxidase (CPOX). Many individuals with a pathogenic CPOX mutation never develop symptoms.ALAD-Deficiency Porphyria (ADP)ALAD porphyria (ADP) is extremely rare with only eight well documented cases. Why all cases have been males is unexplained. Symptoms occur mostly in attacks, as in AIP. Symptoms usually begin at or near puberty but can begin in childhood. Chronic neurological symptoms are seen in severe cases. In one case, onset in an adult was associated with a bone marrow disorder (polycythemia vera).BLISTERING CUTANEOUS PORPHYRIAS
Porphyria Cutanea Tarda (PCT) This hepatic porphyria is the most common of all porphyrias, and also the most readily treated. It is primarily an acquired, iron related disease in which there is inhibition of uroporphyrinogen decarboxylase (UROD), the fifth enzyme in the heme synthetic pathway, in the liver. A minority or patients have a predisposing UROD gene mutation and are classified as having familial PCT. Symptoms usually occur after age 40. Sun-exposed areas of the skin (most commonly the backs of the hands) can become friable and prone to blistering, scarring and excess hair growth. Other predisposing factors include chronic hepatitis C, HIV infection, alcohol, smoking, estrogens and excess iron. Some of these factors and PCT itself can lead to chronic liver disease and liver cancer. PCT responds well to treatment with phlebotomies (to reduce iron) or a low dose regimen of hydroxychloroquine. Treatment of hepatitis C, if present, is also highly effective.Erythropoietic Protoporphyria (EPP) and X-Linked Protoporphyria (XLP)The symptoms of the protoporphyrias (EEP and XLP) usually begin in infancy or early childhood. Sun exposure causes severe burning pain often within minutes of exposure. Patients learn to avoid sunlight and seldom develop blistering or scarring. Prolonged exposure to sunlight can lead to both cutaneous and systemic symptoms lasting for several days. Protoporphyrin is insoluble in water and is excreted in bile rather than urine. In less than 5% of patients, excess protoporphyrin can cause significant liver damage. Current treatment is sunlight avoidance and agents that increase skin melanin pigmentation.Congenital Erythropoietic Porphyria (CEP)Congenital erythropoietic porphyria (CEP) is very rare, with onset usually in early childhood or even in utero. The blistering skin manifestations are usually severe, but mild cases can resemble PCT. Facial hair growth is often increased. Porphyrins are deposited in bone and teeth. Anemia in severe cases may require red blood cell transfusion. An enlarged spleen is common. Repeated blistering, infection and scarring can lead to loss of fingers and facial features. Rare onset during adulthood is often related to development of a clonal bone marrow disease.Hepatoerythropoietic Porphyria (HEP)Hepatoerythropoietic porphyria (HEP) is caused by two mutations in the UROD gene and resembles CEP clinically. Unusually mild cases can resemble PCT. Symptoms usually begin in infancy or childhood.
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Porphyrias
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nord_990_2
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Causes of Porphyrias
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Porphyria occurs when there is an alteration of one of the enzymes used to make the molecule heme. At least eight different enzymes are involved in making heme. A different gene is responsible for making each of these enzymes. Each type of porphyria is related to a different altered (mutated) gene responsible for one of the enzymes involved in the steps making the molecule heme. Most mutations cause decreased function of the affected enzyme, but mutations in one type of porphyria (XLP) cause an increase in enzyme activity.Porphyrias are inherited in families. However, many people who inherit a mutated gene for one of the porphyrias have no symptoms. Especially in hepatic porphyrias, certain medications, chemical exposures or changes in diet may be necessary before someone with a gene mutation for porphyria develops symptoms of the disease. Unknown modifying genes also have effects especially in hepatic porphyrias.The following table summarizes the pattern of inheritance and the enzyme that is altered in each type of porphyria:Autosomal Dominant InheritanceDominant genetic disorders occur when only a single copy of a non-working or partially working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or, rarely, can be the result of a newly 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. Dominant disorders can vary in severity from person to person. Sometimes, someone who inherits a non-working gene for a dominant condition will not have any symptoms of the condition but can still pass it on to a child who may develop symptoms.Autosomal Recessive InheritanceRecessive 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 a 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.X-Linked Recessive InheritanceX-linked genetic disorders are conditions caused by a mutated gene on the X chromosome and manifest mostly in males. Females that have a mutated gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the non-working gene. However, because one X chromosome is variably inactivated, some carrier females may develop symptoms. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a mutated gene, he will develop the disease. X-linked protoporphyria (XLP) results from mutations that increase enzyme activity.Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.If a male with an X-linked disorder can reproduce, he will pass the non-working gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.
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Causes of Porphyrias. Porphyria occurs when there is an alteration of one of the enzymes used to make the molecule heme. At least eight different enzymes are involved in making heme. A different gene is responsible for making each of these enzymes. Each type of porphyria is related to a different altered (mutated) gene responsible for one of the enzymes involved in the steps making the molecule heme. Most mutations cause decreased function of the affected enzyme, but mutations in one type of porphyria (XLP) cause an increase in enzyme activity.Porphyrias are inherited in families. However, many people who inherit a mutated gene for one of the porphyrias have no symptoms. Especially in hepatic porphyrias, certain medications, chemical exposures or changes in diet may be necessary before someone with a gene mutation for porphyria develops symptoms of the disease. Unknown modifying genes also have effects especially in hepatic porphyrias.The following table summarizes the pattern of inheritance and the enzyme that is altered in each type of porphyria:Autosomal Dominant InheritanceDominant genetic disorders occur when only a single copy of a non-working or partially working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or, rarely, can be the result of a newly 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. Dominant disorders can vary in severity from person to person. Sometimes, someone who inherits a non-working gene for a dominant condition will not have any symptoms of the condition but can still pass it on to a child who may develop symptoms.Autosomal Recessive InheritanceRecessive 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 a 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.X-Linked Recessive InheritanceX-linked genetic disorders are conditions caused by a mutated gene on the X chromosome and manifest mostly in males. Females that have a mutated gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the non-working gene. However, because one X chromosome is variably inactivated, some carrier females may develop symptoms. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a mutated gene, he will develop the disease. X-linked protoporphyria (XLP) results from mutations that increase enzyme activity.Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.If a male with an X-linked disorder can reproduce, he will pass the non-working gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.
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Affects of Porphyrias
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The exact number of people who have porphyria is unknown, but it has been estimated that about 1 in 20,000 people may have some type of porphyria. Some forms of porphyria are more common in specific populations. For example, acute intermittent porphyria is more common in Sweden than other parts of the world. Porphyria cutanea tarda may be the most common type of porphyria, occurring in 1 in 25,000 people in the United States. Erythropoietic porphyria is the most common in children, with the highest incidence in the Netherlands of about 1 in 75,000.
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Affects of Porphyrias. The exact number of people who have porphyria is unknown, but it has been estimated that about 1 in 20,000 people may have some type of porphyria. Some forms of porphyria are more common in specific populations. For example, acute intermittent porphyria is more common in Sweden than other parts of the world. Porphyria cutanea tarda may be the most common type of porphyria, occurring in 1 in 25,000 people in the United States. Erythropoietic porphyria is the most common in children, with the highest incidence in the Netherlands of about 1 in 75,000.
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Related disorders of Porphyrias
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Symptoms of the following disorders can be similar to those of the porphyrias. Comparisons may be useful for a differential diagnosis.Guillain-Barré syndrome (GBS) is a rare, rapidly progressive disorder that consists of inflammation of the nerves (polyneuritis) causing muscle weakness, sometimes progressing to complete paralysis. Severe cases of acute porphyrias can be misdiagnosed as having GBS, with consequent delays in starting effective treatment. Although the precise cause of GBS is unknown, a viral or respiratory infection precedes the onset of the syndrome in about half of the patients. This has led to the theory that GBS may be an autoimmune disease (caused by the body’s own immune system). Damage to the covering (myelin) of nerve axons (the extension of the nerve cell that conducts impulses away from the nerve cell body) results in delayed nerve signal transmission. This causes weakness of the muscles that are supplied by the damaged nerves. (For more information on this disorder, choose “Guillain Barre” as your search term in the Rare Disease Database.)Lead poisoning occurs with exposure of children to lead paint and from many occupational exposures. Symptoms can closely resemble those of acute porphyrias. Lead can inhibit the biosynthesis of heme enzymes and elevate porphyrins and the porphyrin precursor delta-aminolevulinic acid dehydratase (ALAD). The definitive test for lead poisoning is blood lead measurement.
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Related disorders of Porphyrias. Symptoms of the following disorders can be similar to those of the porphyrias. Comparisons may be useful for a differential diagnosis.Guillain-Barré syndrome (GBS) is a rare, rapidly progressive disorder that consists of inflammation of the nerves (polyneuritis) causing muscle weakness, sometimes progressing to complete paralysis. Severe cases of acute porphyrias can be misdiagnosed as having GBS, with consequent delays in starting effective treatment. Although the precise cause of GBS is unknown, a viral or respiratory infection precedes the onset of the syndrome in about half of the patients. This has led to the theory that GBS may be an autoimmune disease (caused by the body’s own immune system). Damage to the covering (myelin) of nerve axons (the extension of the nerve cell that conducts impulses away from the nerve cell body) results in delayed nerve signal transmission. This causes weakness of the muscles that are supplied by the damaged nerves. (For more information on this disorder, choose “Guillain Barre” as your search term in the Rare Disease Database.)Lead poisoning occurs with exposure of children to lead paint and from many occupational exposures. Symptoms can closely resemble those of acute porphyrias. Lead can inhibit the biosynthesis of heme enzymes and elevate porphyrins and the porphyrin precursor delta-aminolevulinic acid dehydratase (ALAD). The definitive test for lead poisoning is blood lead measurement.
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Diagnosis of Porphyrias
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Porphyria is diagnosed based on a clinical exam and symptoms, as well as blood, urine and stool tests. Molecular genetic (DNA) testing may be used to help confirm the diagnosis. Once someone in a family has been diagnosed with porphyria, other family members may be tested to see if they have inherited the condition.
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Diagnosis of Porphyrias. Porphyria is diagnosed based on a clinical exam and symptoms, as well as blood, urine and stool tests. Molecular genetic (DNA) testing may be used to help confirm the diagnosis. Once someone in a family has been diagnosed with porphyria, other family members may be tested to see if they have inherited the condition.
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Therapies of Porphyrias
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Treatment
Effective treatment is available for most porphyrias. Porphyria cutanea tarda (PCT) is readily treated by phlebotomies (to reduce iron), low-dose hydroxychloroquine (to remove excess porphyrins from the liver) or by treating hepatitis C (if present). These treatments can normalize porphyrin levels, and most patients do not experience recurrence of PCTExacerbations of the acute porphyrias often require hospitalization for management of severe symptoms. Hemin is approved by the U.S. Food and Drug Administration (FDA) to treat acute attacks. Glucose loading may be helpful but is less effective than hemin. Givosiran, a long-acting interfering RNA drug, is approved by the FDA and is effective for prevention of frequently recurring attacks. GnRH analogues that interrupt ovulation can be used to prevent attacks related to the menstrual cycle in women. Liver transplantation is an effective option for acute porphyria patients who become unresponsive to other treatments.Afamelanotide (a human melanocyte stimulating hormone analogue) is approved by the FDA for treatment of protoporphyrias. It increases skin melanin and can greatly increase sun tolerance in EPP and XLP patients but does not lower circulating levels of protoporphyrin. Patients with protoporphyrias learn to avoid painful reactions by avoiding sunlight. However, patients with blistering cutaneous porphyrias such as CEP have much less pain from sun exposure and are at risk for severe skin damage unless they learn to avoid sunlight. Marrow stem cell transplantation is effective in severe childhood cases of CEP.
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Therapies of Porphyrias. Treatment
Effective treatment is available for most porphyrias. Porphyria cutanea tarda (PCT) is readily treated by phlebotomies (to reduce iron), low-dose hydroxychloroquine (to remove excess porphyrins from the liver) or by treating hepatitis C (if present). These treatments can normalize porphyrin levels, and most patients do not experience recurrence of PCTExacerbations of the acute porphyrias often require hospitalization for management of severe symptoms. Hemin is approved by the U.S. Food and Drug Administration (FDA) to treat acute attacks. Glucose loading may be helpful but is less effective than hemin. Givosiran, a long-acting interfering RNA drug, is approved by the FDA and is effective for prevention of frequently recurring attacks. GnRH analogues that interrupt ovulation can be used to prevent attacks related to the menstrual cycle in women. Liver transplantation is an effective option for acute porphyria patients who become unresponsive to other treatments.Afamelanotide (a human melanocyte stimulating hormone analogue) is approved by the FDA for treatment of protoporphyrias. It increases skin melanin and can greatly increase sun tolerance in EPP and XLP patients but does not lower circulating levels of protoporphyrin. Patients with protoporphyrias learn to avoid painful reactions by avoiding sunlight. However, patients with blistering cutaneous porphyrias such as CEP have much less pain from sun exposure and are at risk for severe skin damage unless they learn to avoid sunlight. Marrow stem cell transplantation is effective in severe childhood cases of CEP.
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Overview of Post Polio Syndrome
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Post-polio syndrome (PPS) is a syndrome that affects some people who have had polio (poliomyelitis) and occurs many years (typically from 10 to 40 years) after recovery from the initial infection. It is characterized by the development of progressive weakness in muscles that were affected by the original polio infection. In addition, those affected may experience extreme fatigue and joint pain. Skeletal deformities, such as scoliosis, may occur as a result of this syndrome. There is variation in the severity of symptoms. In severe cases, symptoms may mimic those of the rare disorder known as Lou Gehrig's disease (amyotrophic lateral sclerosis). The degree of muscle atrophy during the post-polio period appears to reflect the severity of the impact of the initial polio infection. People who were significantly affected by polio are more likely to experience severe symptoms from post-polio syndrome. The cause of this syndrome is not known. Although exact numbers are not available, it has been estimated that there are 300,000 polio survivors in the United States and that from one-fourth to one-half of them may ultimately develop some degree of post-polio syndrome.
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Overview of Post Polio Syndrome. Post-polio syndrome (PPS) is a syndrome that affects some people who have had polio (poliomyelitis) and occurs many years (typically from 10 to 40 years) after recovery from the initial infection. It is characterized by the development of progressive weakness in muscles that were affected by the original polio infection. In addition, those affected may experience extreme fatigue and joint pain. Skeletal deformities, such as scoliosis, may occur as a result of this syndrome. There is variation in the severity of symptoms. In severe cases, symptoms may mimic those of the rare disorder known as Lou Gehrig's disease (amyotrophic lateral sclerosis). The degree of muscle atrophy during the post-polio period appears to reflect the severity of the impact of the initial polio infection. People who were significantly affected by polio are more likely to experience severe symptoms from post-polio syndrome. The cause of this syndrome is not known. Although exact numbers are not available, it has been estimated that there are 300,000 polio survivors in the United States and that from one-fourth to one-half of them may ultimately develop some degree of post-polio syndrome.
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Symptoms of Post Polio Syndrome
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Post-polio syndrome occurs at least 10 years after a person has been stricken by polio. It is characterized by gradual deterioration of muscle function and increased weakness that usually occurs in the limbs that were most severely affected by polio. Sometimes, the disorder involves muscles that appeared to be fully recovered or that were not involved in the original polio attack, including muscles necessary for respiration. Other symptoms may include fatigue, muscle pain and twitching (fasciculations).The fatigue associated with PPS comes on unexpectedly, sometimes as a feeling of total exhaustion throughout the body. Pain in the muscles and joints is not uncommon. Also, the affected person may experience problems related to swallowing, breathing, and sleeping. People with PPS are less able to tolerate the cold, and they are less able to carry on with day-to-day activities such bathing, dressing, and walking.
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Symptoms of Post Polio Syndrome. Post-polio syndrome occurs at least 10 years after a person has been stricken by polio. It is characterized by gradual deterioration of muscle function and increased weakness that usually occurs in the limbs that were most severely affected by polio. Sometimes, the disorder involves muscles that appeared to be fully recovered or that were not involved in the original polio attack, including muscles necessary for respiration. Other symptoms may include fatigue, muscle pain and twitching (fasciculations).The fatigue associated with PPS comes on unexpectedly, sometimes as a feeling of total exhaustion throughout the body. Pain in the muscles and joints is not uncommon. Also, the affected person may experience problems related to swallowing, breathing, and sleeping. People with PPS are less able to tolerate the cold, and they are less able to carry on with day-to-day activities such bathing, dressing, and walking.
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Causes of Post Polio Syndrome
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The cause of post-polio syndrome is not known at this time. One theory is that it may be related to the recovery from the original polio. During recovery from polio, nerve cells in affected muscles may regrow many smaller branches (dendrites) from the message-transmitting large branches (axons) of nerve cells. These sprouts take over the function of neurons killed by the polio virus. It is thought that, after years of functioning beyond capacity, the nerve cells weaken and lose their ability to maintain these tiny dendrites, which then begin to shrink, and the whole muscle becomes weaker. Additional research is needed to determine whether this may, in fact, be the cause of post-polio syndrome. Although this syndrome sometimes resembles amyotrophic lateral sclerosis (ALS), it is not considered to be a form of that disease.
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Causes of Post Polio Syndrome. The cause of post-polio syndrome is not known at this time. One theory is that it may be related to the recovery from the original polio. During recovery from polio, nerve cells in affected muscles may regrow many smaller branches (dendrites) from the message-transmitting large branches (axons) of nerve cells. These sprouts take over the function of neurons killed by the polio virus. It is thought that, after years of functioning beyond capacity, the nerve cells weaken and lose their ability to maintain these tiny dendrites, which then begin to shrink, and the whole muscle becomes weaker. Additional research is needed to determine whether this may, in fact, be the cause of post-polio syndrome. Although this syndrome sometimes resembles amyotrophic lateral sclerosis (ALS), it is not considered to be a form of that disease.
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Post Polio Syndrome
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Affects of Post Polio Syndrome
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Post-polio syndrome affects people who have had acute episodes of poliomyelitis. It occurs 10 years or more after the original illness, and can occur as long as 40 years afterward. According to one estimate, 25% to 50% of the 300,000 polio survivors in the United States may develop the syndrome. At the present time, there is no known way to prevent the syndrome.
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Affects of Post Polio Syndrome. Post-polio syndrome affects people who have had acute episodes of poliomyelitis. It occurs 10 years or more after the original illness, and can occur as long as 40 years afterward. According to one estimate, 25% to 50% of the 300,000 polio survivors in the United States may develop the syndrome. At the present time, there is no known way to prevent the syndrome.
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Related disorders of Post Polio Syndrome
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Symptoms of the following disorders can be similar to those of post-polio syndrome. Comparisons may be useful for differential diagnosis:Amyotrophic lateral sclerosis (ALS) is one of a group of disorders known as motor neuron diseases. It is characterized by the progressive degeneration and eventual death of nerve cells (motor neurons) in the brain, brainstem and spinal cord that facilitate communication between the nervous system and voluntary muscles of the body. Ordinarily, motor neurons in the brain (upper motor neurons) sent messages to motor neurons in the spinal cord (lower motor neurons), and then to various muscles. ALS affects both the upper and lower motor neurons, so that the transmission of messages is interrupted, and muscles gradually weaken and waste away. As a result, the ability to initiate and control voluntary movement is lost. Ultimately, ALS leads to respiratory failure because affected individuals lose the ability to control muscles in the chest and diaphragm. ALS is often called Lou Gehrig's disease. (For more information on this disorder, choose “amyotrophic lateral sclerosis” as your search term in the Rare Disease Database.)Multiple sclerosis is a neuroimmunologic (both the nervous system and immunological system are involved) disorder involving the brain, spinal chord and optic nerves. By means of a mechanism that is not clearly understood, the protective insulating sheath (myelin sheath) that covers the nerve is destroyed. The inflammatory attacks that produce the characteristic scarring (plaques or patches) of the myelin sheath occur randomly, in varying intensity, and at multiple sites. The course of the disease may advance, relapse, remit, or stabilize. The randomness of the location of plaques or patches affects the nerve's ability to transmit information (neurotransmission) and causes a wide range of neurological symptoms, which may vary from person to person. (For more information on this disorder, choose “multiple sclerosis” as your search term in the Rare Disease Database.)
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Related disorders of Post Polio Syndrome. Symptoms of the following disorders can be similar to those of post-polio syndrome. Comparisons may be useful for differential diagnosis:Amyotrophic lateral sclerosis (ALS) is one of a group of disorders known as motor neuron diseases. It is characterized by the progressive degeneration and eventual death of nerve cells (motor neurons) in the brain, brainstem and spinal cord that facilitate communication between the nervous system and voluntary muscles of the body. Ordinarily, motor neurons in the brain (upper motor neurons) sent messages to motor neurons in the spinal cord (lower motor neurons), and then to various muscles. ALS affects both the upper and lower motor neurons, so that the transmission of messages is interrupted, and muscles gradually weaken and waste away. As a result, the ability to initiate and control voluntary movement is lost. Ultimately, ALS leads to respiratory failure because affected individuals lose the ability to control muscles in the chest and diaphragm. ALS is often called Lou Gehrig's disease. (For more information on this disorder, choose “amyotrophic lateral sclerosis” as your search term in the Rare Disease Database.)Multiple sclerosis is a neuroimmunologic (both the nervous system and immunological system are involved) disorder involving the brain, spinal chord and optic nerves. By means of a mechanism that is not clearly understood, the protective insulating sheath (myelin sheath) that covers the nerve is destroyed. The inflammatory attacks that produce the characteristic scarring (plaques or patches) of the myelin sheath occur randomly, in varying intensity, and at multiple sites. The course of the disease may advance, relapse, remit, or stabilize. The randomness of the location of plaques or patches affects the nerve's ability to transmit information (neurotransmission) and causes a wide range of neurological symptoms, which may vary from person to person. (For more information on this disorder, choose “multiple sclerosis” as your search term in the Rare Disease Database.)
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Diagnosis of Post Polio Syndrome
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Diagnosis of post-polio syndrome is made on the basis of a thorough history, a neurological examination, and the process of excluding other possible diseases through various tests. In making the diagnosis, physicians will be aware of three factors. a prior diagnosis of polio, an interval of one or more decades since the original acute episode, and slow, steady, progressive deterioration.
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Diagnosis of Post Polio Syndrome. Diagnosis of post-polio syndrome is made on the basis of a thorough history, a neurological examination, and the process of excluding other possible diseases through various tests. In making the diagnosis, physicians will be aware of three factors. a prior diagnosis of polio, an interval of one or more decades since the original acute episode, and slow, steady, progressive deterioration.
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Therapies of Post Polio Syndrome
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TreatmentThere are no specific treatments for PPS at this time. The goal of management of this disorder is to make the patient as comfortable as possible.Affected individuals are taught to conserve energy by pacing their activities and combining these with periods of rest. Mechanical assists such as canes, walkers, and scooters may be helpful.Moderate exercise is seen by many physicians as beneficial for those affected. Swimming is one type of exercise that is sometimes recommended. Speech therapy may be helpful for individuals whose swallowing has been affected.Also, occupational therapy can lead to adjustments in the home environment that may allow those affected to carry out common activities in ways that are less energy-consuming.
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Therapies of Post Polio Syndrome. TreatmentThere are no specific treatments for PPS at this time. The goal of management of this disorder is to make the patient as comfortable as possible.Affected individuals are taught to conserve energy by pacing their activities and combining these with periods of rest. Mechanical assists such as canes, walkers, and scooters may be helpful.Moderate exercise is seen by many physicians as beneficial for those affected. Swimming is one type of exercise that is sometimes recommended. Speech therapy may be helpful for individuals whose swallowing has been affected.Also, occupational therapy can lead to adjustments in the home environment that may allow those affected to carry out common activities in ways that are less energy-consuming.
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Overview of Post-Transplant Lymphoproliferative Disease
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Post-transplant lymphoproliferative disease (PTLD) is a rare, but well-known complication of solid organ transplants and hematopoietic stem cell transplantation. PTLD is related to the Epstein-Barr virus and immunosuppression therapy. People who receive these transplants are treated with drugs that suppress the activity of the immune system. Doctors must suppress the immune system to help the body accept the transplant and avoid rejection. Individuals receive these drugs at the time of the transplant (induction therapy) and must remain on these drugs for the rest of their lives (maintenance therapy). Immunosuppressive therapy leaves patients at a greater risk of developing infections and, in some people, of developing post-transplant lymphoproliferative disease. Early diagnosis and prompt treatment of these disorders are extremely important.PTLD is characterized by the overproduction and spread of too many white blood cells (lymphocytes). This can cause complications ranging from a benign (noncancerous) enlargement of an organ or tissue because of the overproduction of these cells (hyperplasia) to the development of a malignant (cancerous) form of lymphoma. In most instances, PTLD is associated with the Epstein-Barr virus, a common virus that does not usually cause problems in people with normal-functioning immune systems. The abnormal white blood cells that grow out of control, usually a type of lymphocyte called a B-cell, may be infected by the Epstein-Barr virus. After a transplant, the dormant Epstein-Barr virus is reactivated, or the transplant recipient becomes infected with the virus for the first time.PTLD is classified as a lymphoma, a group of related cancers that affect the lymphatic system. The lymphatic system functions as part of the immune system and helps to protect the body against infection and disease. It consists of a network of tubular channels (lymph vessels) that drain a thin watery fluid known as lymph from different areas of the body into the bloodstream. Lymph accumulates in the tiny spaces between tissue cells and contains proteins, fats, and certain white blood cells known as lymphocytes. As lymph moves through the lymphatic system, it is filtered by a network of small structures known as lymph nodes that help to remove microorganisms (e.g., viruses, bacteria, etc.) and other foreign bodies. Groups of lymph nodes are located throughout the body, including, but not limited to, the neck, under the arms (axillae), at the elbows, and in the chest, abdomen, and groin. Lymphocytes are stored within lymph nodes and may also be found in other lymphatic tissues. In addition to the lymph nodes, the lymphatic system includes the spleen, which filters worn-out red blood cells and produces lymphocytes, and bone marrow, which is the spongy tissue inside the cavities of bones that manufactures blood cells. Lymphatic tissue or circulating lymphocytes may also be located in other regions of the body.There are two main types of lymphocytes: B-lymphocytes (B-cells), which may produce specific antibodies to “neutralize” certain invading microorganisms, and T-lymphocytes (T-cells), which may directly destroy microorganisms or assist in the activities of other lymphocytes. Some T-cells are cytotoxic lymphocytes and they function by eliminating other cells that are damaged, stressed, or infected. In most people with PTLD, there are too many B-cells being produced, but T-cell PTLD is also possible.
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Overview of Post-Transplant Lymphoproliferative Disease. Post-transplant lymphoproliferative disease (PTLD) is a rare, but well-known complication of solid organ transplants and hematopoietic stem cell transplantation. PTLD is related to the Epstein-Barr virus and immunosuppression therapy. People who receive these transplants are treated with drugs that suppress the activity of the immune system. Doctors must suppress the immune system to help the body accept the transplant and avoid rejection. Individuals receive these drugs at the time of the transplant (induction therapy) and must remain on these drugs for the rest of their lives (maintenance therapy). Immunosuppressive therapy leaves patients at a greater risk of developing infections and, in some people, of developing post-transplant lymphoproliferative disease. Early diagnosis and prompt treatment of these disorders are extremely important.PTLD is characterized by the overproduction and spread of too many white blood cells (lymphocytes). This can cause complications ranging from a benign (noncancerous) enlargement of an organ or tissue because of the overproduction of these cells (hyperplasia) to the development of a malignant (cancerous) form of lymphoma. In most instances, PTLD is associated with the Epstein-Barr virus, a common virus that does not usually cause problems in people with normal-functioning immune systems. The abnormal white blood cells that grow out of control, usually a type of lymphocyte called a B-cell, may be infected by the Epstein-Barr virus. After a transplant, the dormant Epstein-Barr virus is reactivated, or the transplant recipient becomes infected with the virus for the first time.PTLD is classified as a lymphoma, a group of related cancers that affect the lymphatic system. The lymphatic system functions as part of the immune system and helps to protect the body against infection and disease. It consists of a network of tubular channels (lymph vessels) that drain a thin watery fluid known as lymph from different areas of the body into the bloodstream. Lymph accumulates in the tiny spaces between tissue cells and contains proteins, fats, and certain white blood cells known as lymphocytes. As lymph moves through the lymphatic system, it is filtered by a network of small structures known as lymph nodes that help to remove microorganisms (e.g., viruses, bacteria, etc.) and other foreign bodies. Groups of lymph nodes are located throughout the body, including, but not limited to, the neck, under the arms (axillae), at the elbows, and in the chest, abdomen, and groin. Lymphocytes are stored within lymph nodes and may also be found in other lymphatic tissues. In addition to the lymph nodes, the lymphatic system includes the spleen, which filters worn-out red blood cells and produces lymphocytes, and bone marrow, which is the spongy tissue inside the cavities of bones that manufactures blood cells. Lymphatic tissue or circulating lymphocytes may also be located in other regions of the body.There are two main types of lymphocytes: B-lymphocytes (B-cells), which may produce specific antibodies to “neutralize” certain invading microorganisms, and T-lymphocytes (T-cells), which may directly destroy microorganisms or assist in the activities of other lymphocytes. Some T-cells are cytotoxic lymphocytes and they function by eliminating other cells that are damaged, stressed, or infected. In most people with PTLD, there are too many B-cells being produced, but T-cell PTLD is also possible.
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Symptoms of Post-Transplant Lymphoproliferative Disease
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The specific symptoms and severity of PTLD can vary greatly from one person to another. Some affected individuals develop a mild, noncancerous overgrowth of affected tissue, while other people can develop a cancerous, life-threatening form of lymphoma. The mild, benign form of PTLD can resemble reactive hyperplasia, the normal process in which lymph nodes become enlarged in response to an infection or inflammation. PTLD can be localized, which means the disease only affects a specific area of the body, or widespread (disseminated), which means it affects several different areas of the body. They can also cause severe, life-threatening complications. In addition, PTLD may affect the transplanted organ, and these disorders commonly involve extranodal tissue.It is important to remember that every person is an individual and how these disorders will affect one person as compared to another person can be very different. This report is a general overview of these disorders and details the most common ways PTLD affects people.The 2017 World Health Organization (WHO) classification breaks down PTLD into six subclasses. Three forms are classified as non-destructive PTLD and are called plasmacytic hyperplasia, infectious mononucleosis-like PTLD, and florid follicular hyperplasia. Three other forms are classified as destructive PTLD and are called polymorphic PTLD, monomorphic PTLD, and classic Hodgkin lymphoma-like PTLD. The three non-destructive forms are almost much more commonly associated with Epstein-Barr virus infection. The symptoms are usually on the milder end of the spectrum, which is sometimes called “early” disease. Early lesions can act similar to how the body reacts to an infection such as infectious mononucleosis, in which there is an increase in B-cell production, but no signs of tumor formation or cancerous cells. This is called reactive hyperplasia and is a noncancerous (benign) condition. In individuals who are taking immunosuppressive drugs, these lesions may go away when the drugs are stopped or reduced. Early lesions can potentially progress to more serious complications, but that does not necessarily occur. Polymorphic PTLD is characterized by the overproduction of both B-cells and T-cells and can have some features of cancer (malignancy), but fail to meet the criteria for lymphoma. The clinical symptoms associated with the polymorphic form are variable. Many cases of polymorphic cases are Epstein-Barr virus positive. Monomorphic PTLD is the most common form and is characterized by the development of malignant lymphoma, usually diffuse large B-cell lymphoma (this is the most common type of non-Hodgkin lymphoma in the United States). The signs and symptoms of the monomorphic form can range from early lesions described above to more severe “late” disease such as organ failure. About 50% of cases are Epstein-Barr virus positive. Classic Hodgkin-like PTLD is when PTLD fulfills the criteria for Hodgkin lymphoma, a form of cancer that arises from white blood cells, and are often are Epstein-Barr virus positive.Specific signs and symptoms depend on several factors including the areas of the body affected and the type of PTLD. Affected individuals often develop symptoms that are vague and can be nonspecific, which means that the symptoms are common to many different disorders or conditions. When dealing with lymphoma, these symptoms may come and go and are sometimes referred to as ‘B symptoms.’ These symptoms can include a persistent, chronic fever; unintended weight loss, and excessive sweating, especially at night (night sweats). Some individuals develop abnormal enlargement of the lymph nodes (lymphadenopathy), fatigue, or a general feeling of poor health (malaise).PTLD can often have a rapid and severe development (fulminant course). Disease may be widespread throughout the body and frequently there is involvement of organs and tissue beyond the lymph nodes (extranodal involvement). The exact organs involved can vary, but often include the gastrointestinal tract, the transplanted organ (allograft), and the central nervous system. Specific signs and symptoms will depend on the organ system(s) involved. For example, central nervous system involvement can be associated with seizures and neuropsychiatric symptoms. Headaches, nausea, vomiting, and vision problems can occur because of an increase in pressure within the skull (intracranial pressure).PTLD may also be referred to as early onset or late onset. Early onset means that a lymphoproliferative disorder develops shortly after the transplant, usually within twelve months. Late onset means that a lymphoproliferative disorder develops after twelve months. In about half the patients, PTLD occurs within the first year following the transplant. Early onset PTLD is more likely to be characterized by the presence of Epstein-Barr virus in affected B-cells, and may include involvement of the donated organ or extranodal sites. Late onset PTLD is more likely to have disease spread outside of the lymphatic system (extranodal), and often results in the development of malignant lymphoma.
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Symptoms of Post-Transplant Lymphoproliferative Disease. The specific symptoms and severity of PTLD can vary greatly from one person to another. Some affected individuals develop a mild, noncancerous overgrowth of affected tissue, while other people can develop a cancerous, life-threatening form of lymphoma. The mild, benign form of PTLD can resemble reactive hyperplasia, the normal process in which lymph nodes become enlarged in response to an infection or inflammation. PTLD can be localized, which means the disease only affects a specific area of the body, or widespread (disseminated), which means it affects several different areas of the body. They can also cause severe, life-threatening complications. In addition, PTLD may affect the transplanted organ, and these disorders commonly involve extranodal tissue.It is important to remember that every person is an individual and how these disorders will affect one person as compared to another person can be very different. This report is a general overview of these disorders and details the most common ways PTLD affects people.The 2017 World Health Organization (WHO) classification breaks down PTLD into six subclasses. Three forms are classified as non-destructive PTLD and are called plasmacytic hyperplasia, infectious mononucleosis-like PTLD, and florid follicular hyperplasia. Three other forms are classified as destructive PTLD and are called polymorphic PTLD, monomorphic PTLD, and classic Hodgkin lymphoma-like PTLD. The three non-destructive forms are almost much more commonly associated with Epstein-Barr virus infection. The symptoms are usually on the milder end of the spectrum, which is sometimes called “early” disease. Early lesions can act similar to how the body reacts to an infection such as infectious mononucleosis, in which there is an increase in B-cell production, but no signs of tumor formation or cancerous cells. This is called reactive hyperplasia and is a noncancerous (benign) condition. In individuals who are taking immunosuppressive drugs, these lesions may go away when the drugs are stopped or reduced. Early lesions can potentially progress to more serious complications, but that does not necessarily occur. Polymorphic PTLD is characterized by the overproduction of both B-cells and T-cells and can have some features of cancer (malignancy), but fail to meet the criteria for lymphoma. The clinical symptoms associated with the polymorphic form are variable. Many cases of polymorphic cases are Epstein-Barr virus positive. Monomorphic PTLD is the most common form and is characterized by the development of malignant lymphoma, usually diffuse large B-cell lymphoma (this is the most common type of non-Hodgkin lymphoma in the United States). The signs and symptoms of the monomorphic form can range from early lesions described above to more severe “late” disease such as organ failure. About 50% of cases are Epstein-Barr virus positive. Classic Hodgkin-like PTLD is when PTLD fulfills the criteria for Hodgkin lymphoma, a form of cancer that arises from white blood cells, and are often are Epstein-Barr virus positive.Specific signs and symptoms depend on several factors including the areas of the body affected and the type of PTLD. Affected individuals often develop symptoms that are vague and can be nonspecific, which means that the symptoms are common to many different disorders or conditions. When dealing with lymphoma, these symptoms may come and go and are sometimes referred to as ‘B symptoms.’ These symptoms can include a persistent, chronic fever; unintended weight loss, and excessive sweating, especially at night (night sweats). Some individuals develop abnormal enlargement of the lymph nodes (lymphadenopathy), fatigue, or a general feeling of poor health (malaise).PTLD can often have a rapid and severe development (fulminant course). Disease may be widespread throughout the body and frequently there is involvement of organs and tissue beyond the lymph nodes (extranodal involvement). The exact organs involved can vary, but often include the gastrointestinal tract, the transplanted organ (allograft), and the central nervous system. Specific signs and symptoms will depend on the organ system(s) involved. For example, central nervous system involvement can be associated with seizures and neuropsychiatric symptoms. Headaches, nausea, vomiting, and vision problems can occur because of an increase in pressure within the skull (intracranial pressure).PTLD may also be referred to as early onset or late onset. Early onset means that a lymphoproliferative disorder develops shortly after the transplant, usually within twelve months. Late onset means that a lymphoproliferative disorder develops after twelve months. In about half the patients, PTLD occurs within the first year following the transplant. Early onset PTLD is more likely to be characterized by the presence of Epstein-Barr virus in affected B-cells, and may include involvement of the donated organ or extranodal sites. Late onset PTLD is more likely to have disease spread outside of the lymphatic system (extranodal), and often results in the development of malignant lymphoma.
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Post-Transplant Lymphoproliferative Disease
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Causes of Post-Transplant Lymphoproliferative Disease
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Post-transplant lymphoproliferative disease may be associated with infection with the Epstein-Barr virus (EBV). This is a common virus that, generally, does not cause any problems in people after an active phase. This virus infects B-cells. After the active phase, the virus remains in the body, where it lies dormant or “silent” in these cells (latent phase). Most people are first infected with the Epstein-Barr virus in childhood and only develop mild symptoms or no symptoms. If infection first occurs in the teen-aged years or adulthood, affected individuals may develop fever, sore throat, and enlarged lymph nodes. The Epstein-Barr virus is one of the most common causes of infectious mononucleosis or “mono.” As many as 90-95% of people will be infected with the Epstein-Barr virus at some point during their lives. EBV negative recipients are at higher risk of PTLD.When patients who have undergone a solid organ or hematopoietic stem cell transplant receive drugs to suppress their immune systems, this can lead to reactivation of Epstein-Barr-infected B-cells, which demonstrate uncontrolled growth and accumulation. This most likely occurs because of a lack of T-cells due to immunosuppression. Some T-cells called cytotoxic T-cells function by eliminating other cells that are damaged, stressed, or infected. Because cytotoxic T-cells levels are low, Epstein-Barr-infected B-cells are allowed to grow and spread.Sometimes, PTLD occurs because of reactivation and uncontrolled growth of Epstein-Barr-infected B-cells that come from the donor organ. This is most common in people who receive a hematopoietic stem cell transplant. When an organ or stem cells are donated, other cells are also donated, including B-cells. If the person who donates the organ or stem cells has had Epstein-Barr infection in the past, these dormant, infected cells will be passed onto the recipient. This is most common with solid organ transplants. PTLD can also occur if a person who received a transplant becomes infected with the Epstein-Barr virus for the first time.PTLD only occurs in a small percentage of people who receive a transplant, regardless if they have had Epstein-Barr infection. As an example, the long-term risk in renal transplantation is 2%, but it is higher in other solid organ transplant patients. Because of this, researchers believe that there are additional factors necessary for the development of these disorders. Although the Epstein-Barr virus is associated with the majority of affected individuals, some people do not have any evidence of this infection. Researchers are not sure what causes PTLD in people with the Epstein-Barr-negative version of PTLD.There are several risk factors that have been identified for PTLD. These risk factors can differ based on the type of transplant. For solid organ transplants, risk factors include EBV serostatus of the donor and recipient and what organ is being transplanted (see Affected Populations below). For hematopoietic stem cell transplants, the source of the stem cells affects the degree of risk. Stem cells donated from unrelated individuals or that are mismatched based on tissue type increase the risk. The use of antibodies preparations containing antithymocyte globulin or anti-CD3 antibodies also increases the risk. Being over the age of 50 is also a risk factor for PTLD following a hematopoietic stem cell transplant. Chronic graft-versus-host disease, in which immune system cells from the donated stem cells attack healthy cells in the recipient, is a major risk factor for the development of late onset PTLD.Risk factors for both types of transplants include the degree of immunosuppression and types of drugs used, specifically in how low the levels of cytotoxic T-cells drop (T-cell depletion); the serostatus of the Epstein-Barr virus in the transplant recipient, which determines whether antibodies against the Epstein-Barr virus are detectable in the blood; fewer human leukocyte antigen matches between the cells of the donor and recipient (HLAs are used by the immune system to recognize cells of the body so they are not destroyed); a history of cancer (malignancy) before the transplant in the recipient; and younger age.PTLD occurs in solid organ transplants and hematopoietic stem cell transplants. Solid organ transplants are when surgeons remove a solid organ like the heart, lungs, liver or kidneys because the organs are no longer functioning sufficiently and cannot be improved. The organ is replaced by a healthy, functioning organ from a donor.A hematopoietic stem cell transplant is a type of bone marrow transplant. Hematopoietic stem cells are special cells found in bone marrow that manufacture different types of blood cells (e.g., red blood cells, white blood cells, platelets). In allogeneic stem cell transplantation, stem cells are donated from another person, usually from a closely matched family member. Allogeneic stem cell transplants can be used for different conditions but often are used to treat blood cancers. Generally, this therapy is reserved for people who do not respond to other treatment options and younger patients who meet specific criteria.
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Causes of Post-Transplant Lymphoproliferative Disease. Post-transplant lymphoproliferative disease may be associated with infection with the Epstein-Barr virus (EBV). This is a common virus that, generally, does not cause any problems in people after an active phase. This virus infects B-cells. After the active phase, the virus remains in the body, where it lies dormant or “silent” in these cells (latent phase). Most people are first infected with the Epstein-Barr virus in childhood and only develop mild symptoms or no symptoms. If infection first occurs in the teen-aged years or adulthood, affected individuals may develop fever, sore throat, and enlarged lymph nodes. The Epstein-Barr virus is one of the most common causes of infectious mononucleosis or “mono.” As many as 90-95% of people will be infected with the Epstein-Barr virus at some point during their lives. EBV negative recipients are at higher risk of PTLD.When patients who have undergone a solid organ or hematopoietic stem cell transplant receive drugs to suppress their immune systems, this can lead to reactivation of Epstein-Barr-infected B-cells, which demonstrate uncontrolled growth and accumulation. This most likely occurs because of a lack of T-cells due to immunosuppression. Some T-cells called cytotoxic T-cells function by eliminating other cells that are damaged, stressed, or infected. Because cytotoxic T-cells levels are low, Epstein-Barr-infected B-cells are allowed to grow and spread.Sometimes, PTLD occurs because of reactivation and uncontrolled growth of Epstein-Barr-infected B-cells that come from the donor organ. This is most common in people who receive a hematopoietic stem cell transplant. When an organ or stem cells are donated, other cells are also donated, including B-cells. If the person who donates the organ or stem cells has had Epstein-Barr infection in the past, these dormant, infected cells will be passed onto the recipient. This is most common with solid organ transplants. PTLD can also occur if a person who received a transplant becomes infected with the Epstein-Barr virus for the first time.PTLD only occurs in a small percentage of people who receive a transplant, regardless if they have had Epstein-Barr infection. As an example, the long-term risk in renal transplantation is 2%, but it is higher in other solid organ transplant patients. Because of this, researchers believe that there are additional factors necessary for the development of these disorders. Although the Epstein-Barr virus is associated with the majority of affected individuals, some people do not have any evidence of this infection. Researchers are not sure what causes PTLD in people with the Epstein-Barr-negative version of PTLD.There are several risk factors that have been identified for PTLD. These risk factors can differ based on the type of transplant. For solid organ transplants, risk factors include EBV serostatus of the donor and recipient and what organ is being transplanted (see Affected Populations below). For hematopoietic stem cell transplants, the source of the stem cells affects the degree of risk. Stem cells donated from unrelated individuals or that are mismatched based on tissue type increase the risk. The use of antibodies preparations containing antithymocyte globulin or anti-CD3 antibodies also increases the risk. Being over the age of 50 is also a risk factor for PTLD following a hematopoietic stem cell transplant. Chronic graft-versus-host disease, in which immune system cells from the donated stem cells attack healthy cells in the recipient, is a major risk factor for the development of late onset PTLD.Risk factors for both types of transplants include the degree of immunosuppression and types of drugs used, specifically in how low the levels of cytotoxic T-cells drop (T-cell depletion); the serostatus of the Epstein-Barr virus in the transplant recipient, which determines whether antibodies against the Epstein-Barr virus are detectable in the blood; fewer human leukocyte antigen matches between the cells of the donor and recipient (HLAs are used by the immune system to recognize cells of the body so they are not destroyed); a history of cancer (malignancy) before the transplant in the recipient; and younger age.PTLD occurs in solid organ transplants and hematopoietic stem cell transplants. Solid organ transplants are when surgeons remove a solid organ like the heart, lungs, liver or kidneys because the organs are no longer functioning sufficiently and cannot be improved. The organ is replaced by a healthy, functioning organ from a donor.A hematopoietic stem cell transplant is a type of bone marrow transplant. Hematopoietic stem cells are special cells found in bone marrow that manufacture different types of blood cells (e.g., red blood cells, white blood cells, platelets). In allogeneic stem cell transplantation, stem cells are donated from another person, usually from a closely matched family member. Allogeneic stem cell transplants can be used for different conditions but often are used to treat blood cancers. Generally, this therapy is reserved for people who do not respond to other treatment options and younger patients who meet specific criteria.
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Post-Transplant Lymphoproliferative Disease
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Affects of Post-Transplant Lymphoproliferative Disease
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The incidence and prevalence of post-transplant lymphoproliferative disease varies based on the type of transplant and affects about 1%-2% of people who have received a kidney (renal) transplant. Rates are higher in heart and lung transplants. PTLD occurs most often with gastrointestinal and multiorgan transplants. PTLD is the most common cancer affecting people who receive solid organ transplants after squamous cell carcinoma of the skin. In a retrospective multicenter study, the overall incidence of PTLD in people who had hematopoietic stem-cell transplants was reported to be 3.2%
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Affects of Post-Transplant Lymphoproliferative Disease. The incidence and prevalence of post-transplant lymphoproliferative disease varies based on the type of transplant and affects about 1%-2% of people who have received a kidney (renal) transplant. Rates are higher in heart and lung transplants. PTLD occurs most often with gastrointestinal and multiorgan transplants. PTLD is the most common cancer affecting people who receive solid organ transplants after squamous cell carcinoma of the skin. In a retrospective multicenter study, the overall incidence of PTLD in people who had hematopoietic stem-cell transplants was reported to be 3.2%
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Post-Transplant Lymphoproliferative Disease
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Related disorders of Post-Transplant Lymphoproliferative Disease
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Symptoms of the following disorders can be similar to those of post-transplant lymphoproliferative disease. Comparisons may be useful for a differential diagnosis.The signs and symptoms of PTLD can vary greatly and these disorders can produce symptoms that resemble those of many other conditions including various bacterial, mycobacterial and fungal infections; a life-threatening, widespread infection of the blood (sepsis); and lymphomas that are not associated with immunosuppression. In people who have received a solid organ transplant, symptoms of PTLD can resemble those seen when the body rejects the donated organ.
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Related disorders of Post-Transplant Lymphoproliferative Disease. Symptoms of the following disorders can be similar to those of post-transplant lymphoproliferative disease. Comparisons may be useful for a differential diagnosis.The signs and symptoms of PTLD can vary greatly and these disorders can produce symptoms that resemble those of many other conditions including various bacterial, mycobacterial and fungal infections; a life-threatening, widespread infection of the blood (sepsis); and lymphomas that are not associated with immunosuppression. In people who have received a solid organ transplant, symptoms of PTLD can resemble those seen when the body rejects the donated organ.
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Post-Transplant Lymphoproliferative Disease
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Diagnosis of Post-Transplant Lymphoproliferative Disease
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A diagnosis of a post-transplant lymphoproliferative disease is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests, including a complete blood count (CBC), chemical panel, specialized imaging (x-ray) techniques, an evaluation for the Epstein-Barr virus, and a tissue biopsy.Clinical Testing and Workup
A doctor may remove a small sample of an area identified on scans or physical examination that will be studied under a microscope (biopsy). The sample is studied by a pathologist, who is a specialist trained in examining tissues and cells to find disease and determine what disease is present. Immunohistochemistry is routinely performed.This examination involves using antibodies to diagnosis and differentiate cancer. Antibodies are specialized proteins of the immune system that work to help protect the body from foreign substances. Different antibodies react to specific substances, which are collectively called antigens. When doing immunohistochemistry, antibodies are linked to an enzyme or fluorescent dye and exposed to the tissue sample. Specific antibodies will bind to specific antigens and the enzyme or dye will allow physicians to see this under a microscope. Immunohistochemistry can diagnose cancer as well as differentiate different types of cancer.Tissue samples may also be studied for the presence of genomic changes that can indicate PTLD. These are changes in the DNA within the cells that are often associated with the development of cancer. At this time, genomic studies are not routinely performed.Additional tests can be done to support a diagnosis of PTLD or can help determine the extent and spread of the disease. A complete blood count will measure the levels of the three main blood cells: red cells, white cells and platelets, which can be low in people with PTLD. A chemical (metabolic) panel is a group of blood tests that measure the levels of certain substances in the body. A chemical panel can help to assess how well certain organs are functioning. Some affected individuals will undergo a blood test to assess the levels of lactate dehydrogenase (LDH). LDH is a chemical that is released from cells that are damaged. High levels of LDH in the blood indicate that cell damage is present. This can occur in cancer, and is a sign of tumor lysis.A test called an Epstein-Barr virus viral load will be conducted to determine the status of Epstein-Barr infection in both the transplant recipient and the donor. Most people scheduled to receive a transplant have this test done before the transplant is to take place, but not all donors do. During a viral load test, a sample of blood is studied to detect the DNA of the Epstein-Barr virus. A test called polymerase chain reaction (PCR) is usually used. PCR, which has been described as a form of “photocopying,” enables doctors to enlarge, analyze, and copy sequences of DNA and can be used to identify the DNA of the Epstein-Barr virus. A positive result on Epstein-Barr virus viral load test is not necessary for a diagnosis of PTLD as there are people who develop this condition without evidence of EBV infection.Specialized imaging techniques may include computerized tomography (CT) scanning, PET scanning, and magnetic resonance imaging (MRI) can be used to determine the extent of the disease. During CT and PET scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. Imaging scans of the neck, chest, abdomen, pelvis, and head are commonly conducted to look for signs of cancer spread such as enlarged lymph nodes or the presence of a tumor.A highly sensitive imaging test called combined positron emission tomography (PET) and computerized tomography (CT) scan known as a PET/CT scan can also be recommended. During a PET scan, three-dimensional images are produced to evaluate how healthy and functional certain tissues and organs are. This exam involves the use of a radioactive drug called a tracer that is combined with sugar (glucose). This radioactive sugar is injected into the body. This sugar will collect in areas of the body where there is a higher demand for energy. Cancer requires a lot of energy to keep growing and spreading, and will soak up the radioactive sugar. These areas will show up on the PET scan as brighter than the surrounding areas. A CT scan can show enlarged organs or lymph nodes. A PET/CT allows physicians to assess the metabolic and structural (anatomic) in one session and can return a more accurate image or picture of cancer than either test can by itself.If doctors suspect that the central nervous system is involved, they may order a lumbar puncture, which is also called a spinal tap. During a lumbar puncture, a needle is inserted into the spinal canal in the lower back to retrieve a sample of cerebrospinal fluid (CSF). CSF is the fluid that surrounds the brain and spinal cord. The fluid is examined to detect malignant cells.
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Diagnosis of Post-Transplant Lymphoproliferative Disease. A diagnosis of a post-transplant lymphoproliferative disease is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests, including a complete blood count (CBC), chemical panel, specialized imaging (x-ray) techniques, an evaluation for the Epstein-Barr virus, and a tissue biopsy.Clinical Testing and Workup
A doctor may remove a small sample of an area identified on scans or physical examination that will be studied under a microscope (biopsy). The sample is studied by a pathologist, who is a specialist trained in examining tissues and cells to find disease and determine what disease is present. Immunohistochemistry is routinely performed.This examination involves using antibodies to diagnosis and differentiate cancer. Antibodies are specialized proteins of the immune system that work to help protect the body from foreign substances. Different antibodies react to specific substances, which are collectively called antigens. When doing immunohistochemistry, antibodies are linked to an enzyme or fluorescent dye and exposed to the tissue sample. Specific antibodies will bind to specific antigens and the enzyme or dye will allow physicians to see this under a microscope. Immunohistochemistry can diagnose cancer as well as differentiate different types of cancer.Tissue samples may also be studied for the presence of genomic changes that can indicate PTLD. These are changes in the DNA within the cells that are often associated with the development of cancer. At this time, genomic studies are not routinely performed.Additional tests can be done to support a diagnosis of PTLD or can help determine the extent and spread of the disease. A complete blood count will measure the levels of the three main blood cells: red cells, white cells and platelets, which can be low in people with PTLD. A chemical (metabolic) panel is a group of blood tests that measure the levels of certain substances in the body. A chemical panel can help to assess how well certain organs are functioning. Some affected individuals will undergo a blood test to assess the levels of lactate dehydrogenase (LDH). LDH is a chemical that is released from cells that are damaged. High levels of LDH in the blood indicate that cell damage is present. This can occur in cancer, and is a sign of tumor lysis.A test called an Epstein-Barr virus viral load will be conducted to determine the status of Epstein-Barr infection in both the transplant recipient and the donor. Most people scheduled to receive a transplant have this test done before the transplant is to take place, but not all donors do. During a viral load test, a sample of blood is studied to detect the DNA of the Epstein-Barr virus. A test called polymerase chain reaction (PCR) is usually used. PCR, which has been described as a form of “photocopying,” enables doctors to enlarge, analyze, and copy sequences of DNA and can be used to identify the DNA of the Epstein-Barr virus. A positive result on Epstein-Barr virus viral load test is not necessary for a diagnosis of PTLD as there are people who develop this condition without evidence of EBV infection.Specialized imaging techniques may include computerized tomography (CT) scanning, PET scanning, and magnetic resonance imaging (MRI) can be used to determine the extent of the disease. During CT and PET scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. Imaging scans of the neck, chest, abdomen, pelvis, and head are commonly conducted to look for signs of cancer spread such as enlarged lymph nodes or the presence of a tumor.A highly sensitive imaging test called combined positron emission tomography (PET) and computerized tomography (CT) scan known as a PET/CT scan can also be recommended. During a PET scan, three-dimensional images are produced to evaluate how healthy and functional certain tissues and organs are. This exam involves the use of a radioactive drug called a tracer that is combined with sugar (glucose). This radioactive sugar is injected into the body. This sugar will collect in areas of the body where there is a higher demand for energy. Cancer requires a lot of energy to keep growing and spreading, and will soak up the radioactive sugar. These areas will show up on the PET scan as brighter than the surrounding areas. A CT scan can show enlarged organs or lymph nodes. A PET/CT allows physicians to assess the metabolic and structural (anatomic) in one session and can return a more accurate image or picture of cancer than either test can by itself.If doctors suspect that the central nervous system is involved, they may order a lumbar puncture, which is also called a spinal tap. During a lumbar puncture, a needle is inserted into the spinal canal in the lower back to retrieve a sample of cerebrospinal fluid (CSF). CSF is the fluid that surrounds the brain and spinal cord. The fluid is examined to detect malignant cells.
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Post-Transplant Lymphoproliferative Disease
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Therapies of Post-Transplant Lymphoproliferative Disease
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Treatment
The treatment of post-transplant lymphoproliferative disease is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists, including physicians who specialize in the diagnosis and treatment of cancer (medical oncologists), disorders of the blood and blood-forming tissues (hematologists), the use of radiation to treat cancers (radiation oncologists); transplant specialists; surgeons; oncology nurses; dietitians; and other healthcare professionals may need to systematically and comprehensively plan treatment. Psychosocial support for the entire family is essential as well.The primary goal of treatment is to cure the PTLD, while preserving the function and health of the transplant. Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as transplant type; disease stage; specific lymphoma subtype; tumor size; the organ systems involved; the presence or absence of certain 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.The reduction (tapering) of immunosuppressive drugs may be recommended and may be sufficient for people with early PTLD. Such reduction can allow the immune system to recover and fight off the Epstein-Barr infection. However, sufficiently reducing the dosage of immunosuppression is not always possible because tapering these drugs can increase the risk of post-transplant complications including graft-versus-host disease or organ rejection.If PTLD is localized to one specific area of the body, surgery may be recommended to remove the tumor and/or surrounding lymph nodes.Sometimes, a drug called rituximab (Rituxan®) may be recommended. This drug can destroy Epstein-Barr-infected B-cells and can be used alone as a single agent (monotherapy) or as part of a drug regimen (immunochemotherapy) that includes other drugs. Rituximab is classified as a monoclonal antibody or biologic therapy – medications that act like antibodies, but are artificially created in a lab. Rituximab is recommended for CD20+ PTLD. CD20 is a substance found on the surface of B-cells that can be targeted by rituximab. PTLD can recur after successful treatment with this drug. Rituximab is also a type of immunotherapy because it aims to enhance the body’s innate ability to fight cancer cells using the immune system.Sometimes, doctors may recommend anti-cancer drugs (chemotherapy). Chemotherapy is often given along with rituximab in patients with CD20+ disease (immunochemotherapy). In patients without CD20+ disease, different combinations of chemotherapy drugs, called regimens, will be recommended. When chemotherapy is given, the specific chemotherapy regimen used can vary. There are no standard regimens identified for PTLD. Different medical centers may have their own preferences as to the best way to approach treatment and what chemotherapeutic regimen is best for each individual.Sometimes, the use of radiation to kill cancer cells (radiation therapy) is recommended. This is usually recommended for individuals whose disease is localized to one area of the body, or in individuals with involvement of the central nervous system.Antiviral therapy, which is the use of drugs that are effective against viruses, has been tried in people with PTLD. These drugs, which include acyclovir, ganciclovir, and foscarnet, are usually used in conjunction with reducing the dosage of immunosuppression. These drugs have not been effective in treating PTLD when used by themselves, and the overall effectiveness as a treatment for PTLD remains unproven.
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Therapies of Post-Transplant Lymphoproliferative Disease. Treatment
The treatment of post-transplant lymphoproliferative disease is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists, including physicians who specialize in the diagnosis and treatment of cancer (medical oncologists), disorders of the blood and blood-forming tissues (hematologists), the use of radiation to treat cancers (radiation oncologists); transplant specialists; surgeons; oncology nurses; dietitians; and other healthcare professionals may need to systematically and comprehensively plan treatment. Psychosocial support for the entire family is essential as well.The primary goal of treatment is to cure the PTLD, while preserving the function and health of the transplant. Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as transplant type; disease stage; specific lymphoma subtype; tumor size; the organ systems involved; the presence or absence of certain 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.The reduction (tapering) of immunosuppressive drugs may be recommended and may be sufficient for people with early PTLD. Such reduction can allow the immune system to recover and fight off the Epstein-Barr infection. However, sufficiently reducing the dosage of immunosuppression is not always possible because tapering these drugs can increase the risk of post-transplant complications including graft-versus-host disease or organ rejection.If PTLD is localized to one specific area of the body, surgery may be recommended to remove the tumor and/or surrounding lymph nodes.Sometimes, a drug called rituximab (Rituxan®) may be recommended. This drug can destroy Epstein-Barr-infected B-cells and can be used alone as a single agent (monotherapy) or as part of a drug regimen (immunochemotherapy) that includes other drugs. Rituximab is classified as a monoclonal antibody or biologic therapy – medications that act like antibodies, but are artificially created in a lab. Rituximab is recommended for CD20+ PTLD. CD20 is a substance found on the surface of B-cells that can be targeted by rituximab. PTLD can recur after successful treatment with this drug. Rituximab is also a type of immunotherapy because it aims to enhance the body’s innate ability to fight cancer cells using the immune system.Sometimes, doctors may recommend anti-cancer drugs (chemotherapy). Chemotherapy is often given along with rituximab in patients with CD20+ disease (immunochemotherapy). In patients without CD20+ disease, different combinations of chemotherapy drugs, called regimens, will be recommended. When chemotherapy is given, the specific chemotherapy regimen used can vary. There are no standard regimens identified for PTLD. Different medical centers may have their own preferences as to the best way to approach treatment and what chemotherapeutic regimen is best for each individual.Sometimes, the use of radiation to kill cancer cells (radiation therapy) is recommended. This is usually recommended for individuals whose disease is localized to one area of the body, or in individuals with involvement of the central nervous system.Antiviral therapy, which is the use of drugs that are effective against viruses, has been tried in people with PTLD. These drugs, which include acyclovir, ganciclovir, and foscarnet, are usually used in conjunction with reducing the dosage of immunosuppression. These drugs have not been effective in treating PTLD when used by themselves, and the overall effectiveness as a treatment for PTLD remains unproven.
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Overview of Posterior Urethral Valves
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Summary
Posterior urethral valves (PUV) are a rare condition found only in boys where obstructing membranous tissue is present within the lumen of the posterior urethra. It is the most common cause of urinary tract obstruction in newborn males, occurring in 1 in 5,000 to 8,000 pregnancies or roughly 500 babies per year in the U.S. PUV is also the most common cause of chronic kidney disease (CKD) due to urinary tract obstruction in children. PUV can be suspected on prenatal imaging during the pregnancy, but it is only diagnosed after birth when imaging can be done on the child, including a bladder x-ray. PUV requires surgical treatment. There can be some residual bladder dysfunction that might require medical management. Introduction
Posterior urethral valves are blockages in the lower urinary tract of males. They are folds of residual tissue in the tube that carries urine out of the body (the urethra) and only occur in boys. These valves were first described by doctors in the 1800s. They can also cause problems in the upper urinary system as well as other parts of the body such as the lungs. It is important to realize that there can be ongoing changes to the urinary bladder even after the PUV have been surgically treated. It is important to diagnose and treat the condition as soon as possible to prevent long-term complications, such as kidney damage, urinary tract infections and poor growth and development.
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Overview of Posterior Urethral Valves. Summary
Posterior urethral valves (PUV) are a rare condition found only in boys where obstructing membranous tissue is present within the lumen of the posterior urethra. It is the most common cause of urinary tract obstruction in newborn males, occurring in 1 in 5,000 to 8,000 pregnancies or roughly 500 babies per year in the U.S. PUV is also the most common cause of chronic kidney disease (CKD) due to urinary tract obstruction in children. PUV can be suspected on prenatal imaging during the pregnancy, but it is only diagnosed after birth when imaging can be done on the child, including a bladder x-ray. PUV requires surgical treatment. There can be some residual bladder dysfunction that might require medical management. Introduction
Posterior urethral valves are blockages in the lower urinary tract of males. They are folds of residual tissue in the tube that carries urine out of the body (the urethra) and only occur in boys. These valves were first described by doctors in the 1800s. They can also cause problems in the upper urinary system as well as other parts of the body such as the lungs. It is important to realize that there can be ongoing changes to the urinary bladder even after the PUV have been surgically treated. It is important to diagnose and treat the condition as soon as possible to prevent long-term complications, such as kidney damage, urinary tract infections and poor growth and development.
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Symptoms of Posterior Urethral Valves
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Most cases of posterior urethral valves are found before birth during an ultrasound. Doctors look for things like swelling in the tubes that carry urine from the kidneys to the bladder (the ureters) and for a swollen thick-walled bladder that may not empty well. A low level of fluid around the baby or swelling in the baby’s belly may also be seen.After birth, symptoms of PUV can vary. Affected boys may have trouble urinating or need to urinate often, get infections or have a swollen bladder. They may also be very tired, not want to eat or not grow well. In severe cases, they may have trouble breathing because their lungs didn’t develop properly. Older boys may present with slightly different symptoms such as urinary tract infections, bedwetting after being potty trained or other problems like high levels of waste in their blood.Doctors can look for signs of PUV in babies by checking their belly for any swelling of the kidneys and/or the bladder.The most common symptoms in a child with PUV include:● Difficulty urinating (i.e., weak urine stream or dribbling of urine) or inability to urinate
● Frequent urinary tract infections
● Abdominal or lower back pain
● Blood in the urine
● Enlarged bladder or kidneys
● Swelling in the abdomen or genital area
● Frequent urination
● Poor weight gain or failure to thrive in infants and young children
● Urinary incontinence or leakage of urine
● Delayed development of physical and cognitive abilities in infants and children.
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Symptoms of Posterior Urethral Valves. Most cases of posterior urethral valves are found before birth during an ultrasound. Doctors look for things like swelling in the tubes that carry urine from the kidneys to the bladder (the ureters) and for a swollen thick-walled bladder that may not empty well. A low level of fluid around the baby or swelling in the baby’s belly may also be seen.After birth, symptoms of PUV can vary. Affected boys may have trouble urinating or need to urinate often, get infections or have a swollen bladder. They may also be very tired, not want to eat or not grow well. In severe cases, they may have trouble breathing because their lungs didn’t develop properly. Older boys may present with slightly different symptoms such as urinary tract infections, bedwetting after being potty trained or other problems like high levels of waste in their blood.Doctors can look for signs of PUV in babies by checking their belly for any swelling of the kidneys and/or the bladder.The most common symptoms in a child with PUV include:● Difficulty urinating (i.e., weak urine stream or dribbling of urine) or inability to urinate
● Frequent urinary tract infections
● Abdominal or lower back pain
● Blood in the urine
● Enlarged bladder or kidneys
● Swelling in the abdomen or genital area
● Frequent urination
● Poor weight gain or failure to thrive in infants and young children
● Urinary incontinence or leakage of urine
● Delayed development of physical and cognitive abilities in infants and children.
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Causes of Posterior Urethral Valves
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Posterior urethral valves form when a baby is still developing inside its mother, but the cause is not known. Some theories suggest it’s due to problems with the formation of the urinary system. More research is needed to pinpoint the exact cause.PUV results from the formation of valve-like membranes from a tissue in the beginning of the urethra, near the base of the bladder. The valves can block the outflow of urine through the urethra, leading to damage in the bladder, ureters and kidneys. However, it is important to note that PUV occurs randomly by chance and is not caused by anything a mother did or did not do during pregnancy.In the womb, if the baby is unable to urinate due to PUV, there might be a deficiency in amniotic fluid, known as oligohydramnios. A major concern for oligohydramnios is the lack of proper lung development, called lung hypoplasia. Therefore, management of a baby boy born with PUV may involve more than urinary support but also respiratory support.
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Causes of Posterior Urethral Valves. Posterior urethral valves form when a baby is still developing inside its mother, but the cause is not known. Some theories suggest it’s due to problems with the formation of the urinary system. More research is needed to pinpoint the exact cause.PUV results from the formation of valve-like membranes from a tissue in the beginning of the urethra, near the base of the bladder. The valves can block the outflow of urine through the urethra, leading to damage in the bladder, ureters and kidneys. However, it is important to note that PUV occurs randomly by chance and is not caused by anything a mother did or did not do during pregnancy.In the womb, if the baby is unable to urinate due to PUV, there might be a deficiency in amniotic fluid, known as oligohydramnios. A major concern for oligohydramnios is the lack of proper lung development, called lung hypoplasia. Therefore, management of a baby boy born with PUV may involve more than urinary support but also respiratory support.
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Affects of Posterior Urethral Valves
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PUV is rare, occurring in about 1 in 5,000 to 1 in 8,000 male infants. It is the most common cause of urinary tract obstruction in newborn males, occurring in roughly 500 babies per year in the U.S.
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Affects of Posterior Urethral Valves. PUV is rare, occurring in about 1 in 5,000 to 1 in 8,000 male infants. It is the most common cause of urinary tract obstruction in newborn males, occurring in roughly 500 babies per year in the U.S.
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Related disorders of Posterior Urethral Valves
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The following disorders sometimes occur along with PUV: Bladder outlet obstruction – a condition in which the bladder cannot empty properly due to a blockage in the urethra or bladder neck.Oligohydramnios – a condition characterized by a deficiency of amniotic fluid, the protective liquid that surrounds the baby in the womb, which can result in complications during pregnancy and delivery.Congenital urethral obstruction – a condition in which the urethra is abnormally narrow or blocked, hindering the flow of urine.Urethral stenosis – a narrowing of the urethra, which can cause difficulty urinating or urinary retention.Lung hypoplasia – a condition that occurs when a baby’s lungs do not fully develop during pregnancy, leading to breathing difficulties after birth.Posterior urethral diverticulum – a pouch or sac that forms in the urethra, which can cause urinary obstruction or infection.Vesicoureteral reflux (VUR) – a condition in which urine flows back into the kidneys, increasing the risk of urinary tract infections. VUR is found in about half of boys with PUV.Urethral duplication – a condition in which the urethra is divided into two separate tubes.Hypospadias – a birth defect in which the urethra is not fully developed, causing the urinary opening to be located on the underside of the penis.Megaureter – this is when one or both tubes that carry urine from the kidneys to the bladder (ureters) are wider than normal. It can be caused by problems with the ureter itself, rather than problems with other parts of the urinary system.
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Related disorders of Posterior Urethral Valves. The following disorders sometimes occur along with PUV: Bladder outlet obstruction – a condition in which the bladder cannot empty properly due to a blockage in the urethra or bladder neck.Oligohydramnios – a condition characterized by a deficiency of amniotic fluid, the protective liquid that surrounds the baby in the womb, which can result in complications during pregnancy and delivery.Congenital urethral obstruction – a condition in which the urethra is abnormally narrow or blocked, hindering the flow of urine.Urethral stenosis – a narrowing of the urethra, which can cause difficulty urinating or urinary retention.Lung hypoplasia – a condition that occurs when a baby’s lungs do not fully develop during pregnancy, leading to breathing difficulties after birth.Posterior urethral diverticulum – a pouch or sac that forms in the urethra, which can cause urinary obstruction or infection.Vesicoureteral reflux (VUR) – a condition in which urine flows back into the kidneys, increasing the risk of urinary tract infections. VUR is found in about half of boys with PUV.Urethral duplication – a condition in which the urethra is divided into two separate tubes.Hypospadias – a birth defect in which the urethra is not fully developed, causing the urinary opening to be located on the underside of the penis.Megaureter – this is when one or both tubes that carry urine from the kidneys to the bladder (ureters) are wider than normal. It can be caused by problems with the ureter itself, rather than problems with other parts of the urinary system.
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Diagnosis of Posterior Urethral Valves
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Posterior urethral valves are typically suspected during prenatal ultrasound and diagnosed with imaging after birth. Doctors look for signs like a swollen bladder, but it’s not always clear. If undetected during pregnancy, symptoms such as difficulty urinating, urinary retention and/or urinary tract infections in infants and young children may raise suspicion.After birth, doctors can do blood tests to check for kidney problems. A urine sample may also be collected to test for infection or abnormalities.To confirm PUV diagnosis, a healthcare provider assesses the child’s medical history and then performs a physical examination and imaging tests like bladder ultrasound or voiding cystourethrogram (VCUG). VCUG uses special dye and x-rays to identify the structure of the bladder and detect if an obstruction is present while the baby urinates. They may also order another type of scan known as renal scintigraphy, which uses a tracer to examine kidney function. Further workup using urodynamic studies can also be done to see how well the bladder stores and empties urine. These tests help determine more definitively if a baby has PUV and its severity.Based on test results, the healthcare provider can address the urethral/bladder obstruction and prevent any ongoing complications. Regular follow-up care with a urologist (surgical doctor of the urinary tract) and a nephrologist (medical doctor of the kidneys) is crucial to monitor the condition, ensure proper urinary tract functioning and prevent ongoing injury to the kidneys and/or bladder.
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Diagnosis of Posterior Urethral Valves. Posterior urethral valves are typically suspected during prenatal ultrasound and diagnosed with imaging after birth. Doctors look for signs like a swollen bladder, but it’s not always clear. If undetected during pregnancy, symptoms such as difficulty urinating, urinary retention and/or urinary tract infections in infants and young children may raise suspicion.After birth, doctors can do blood tests to check for kidney problems. A urine sample may also be collected to test for infection or abnormalities.To confirm PUV diagnosis, a healthcare provider assesses the child’s medical history and then performs a physical examination and imaging tests like bladder ultrasound or voiding cystourethrogram (VCUG). VCUG uses special dye and x-rays to identify the structure of the bladder and detect if an obstruction is present while the baby urinates. They may also order another type of scan known as renal scintigraphy, which uses a tracer to examine kidney function. Further workup using urodynamic studies can also be done to see how well the bladder stores and empties urine. These tests help determine more definitively if a baby has PUV and its severity.Based on test results, the healthcare provider can address the urethral/bladder obstruction and prevent any ongoing complications. Regular follow-up care with a urologist (surgical doctor of the urinary tract) and a nephrologist (medical doctor of the kidneys) is crucial to monitor the condition, ensure proper urinary tract functioning and prevent ongoing injury to the kidneys and/or bladder.
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Therapies of Posterior Urethral Valves
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Treatment
Treatment for PUV involves surgical and medical management. The goal is to remove obstruction and prevent complications like chronic kidney disease and bladder damage. If the baby is very sick, they may need breathing assistance. A swollen bladder may also need draining with a catheter. Medications can prevent urinary tract infections and manage symptoms.Before birth, doctors may consider surgery inside the womb to treat PUV if certain conditions are met. There’s no clear agreement on whether this earlier intervention outweighs the risk to both the pregnant mother and the unborn baby.After birth, urethral valve ablation is the most common surgical treatment for PUV. The abnormal tissue blocking the urethra is cut using a surgical scope, inserted through the urethra. This surgery is usually performed before the baby leaves the hospital.Alternative, less common surgeries include making temporary openings in either the bladder (vesicostomy) or the ureter(s) (ureterostomy). Vesicostomy can help when there’s a severe blockage or when a baby is too small for valve ablation. It creates an opening from the bladder to the belly so urine can drain outside the body all the time. This takes pressure off the bladder and kidneys. Vesicostomies are temporary and can be closed later. Ureterostomies are less common but have similar goals. The ureter is disconnected from the bladder and connected to an opening on the belly for drainage. It is also intended to relieve pressure and decrease the risk of infections.Long-term outcomes for PUV vary greatly depending on the severity of obstruction. Many boys with PUV (~15-40%) will have permanent kidney damage or chronic kidney disease (CKD). Almost all these children will have bladder issues that can be mild or very serious. When children lose kidney function, they can’t make normal urine. They make three to four times more urine than normal each day since the injured kidneys cannot retain it in the body. Children with CKD are then at risk for dehydration if they can’t drink enough fluids.Regular follow-up care is crucial after treatment to monitor urinary function and prevent complications. This may include check-ups and imaging tests to assess urinary tract functioning. Ongoing medical management may also be necessary to ensure proper urinary function and prevent long-term complications. The treatment team may involve specialties like neonatology, pediatric surgery/urology, nephrology, pediatrics, transplant surgery, psychology, social work and nutrition.
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Therapies of Posterior Urethral Valves. Treatment
Treatment for PUV involves surgical and medical management. The goal is to remove obstruction and prevent complications like chronic kidney disease and bladder damage. If the baby is very sick, they may need breathing assistance. A swollen bladder may also need draining with a catheter. Medications can prevent urinary tract infections and manage symptoms.Before birth, doctors may consider surgery inside the womb to treat PUV if certain conditions are met. There’s no clear agreement on whether this earlier intervention outweighs the risk to both the pregnant mother and the unborn baby.After birth, urethral valve ablation is the most common surgical treatment for PUV. The abnormal tissue blocking the urethra is cut using a surgical scope, inserted through the urethra. This surgery is usually performed before the baby leaves the hospital.Alternative, less common surgeries include making temporary openings in either the bladder (vesicostomy) or the ureter(s) (ureterostomy). Vesicostomy can help when there’s a severe blockage or when a baby is too small for valve ablation. It creates an opening from the bladder to the belly so urine can drain outside the body all the time. This takes pressure off the bladder and kidneys. Vesicostomies are temporary and can be closed later. Ureterostomies are less common but have similar goals. The ureter is disconnected from the bladder and connected to an opening on the belly for drainage. It is also intended to relieve pressure and decrease the risk of infections.Long-term outcomes for PUV vary greatly depending on the severity of obstruction. Many boys with PUV (~15-40%) will have permanent kidney damage or chronic kidney disease (CKD). Almost all these children will have bladder issues that can be mild or very serious. When children lose kidney function, they can’t make normal urine. They make three to four times more urine than normal each day since the injured kidneys cannot retain it in the body. Children with CKD are then at risk for dehydration if they can’t drink enough fluids.Regular follow-up care is crucial after treatment to monitor urinary function and prevent complications. This may include check-ups and imaging tests to assess urinary tract functioning. Ongoing medical management may also be necessary to ensure proper urinary function and prevent long-term complications. The treatment team may involve specialties like neonatology, pediatric surgery/urology, nephrology, pediatrics, transplant surgery, psychology, social work and nutrition.
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Overview of Posterior Uveitis
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Uveitis is a general term that refers to inflammation of the part of the eye known as the uvea. The uvea is a relatively thick, strong layer of fibrous tissue that encloses and protects the eyeball. It contains many blood vessels and can cause inflammation in neighboring structures of the eye such as the retina, vitreous, optic nerve head and retinal vessels. The uvea consists of three parts: the iris, ciliary body and choroid.There are four types of uveitis, classified according to the part of the uvea that is affected. Anterior uveitis, which affects the front part of the eye, is also sometimes called iritis since the iris is part of the front of the eye. Almost 80% of cases of uveitis affect the anterior portion of the eye. Intermediate uveitis, also known as pars planitis or cyclitis, refers to inflammation of tissues in the area just behind the iris and lens of the eye. Posterior uveitis, also known as choroiditis, refers to inflammation of the choroid, the back part of the uvea. Posterior uveitis may affect the retina and/or the optic nerve and may lead to permanent loss of vision. Panuveitis refers to inflammation throughout the eye and does not refer to a specific area.Posterior uveitis is the rare form of the disorder and is the type of uveitis most associated with loss of vision. Uveitis can affect one or both eyes and it affects people of all ages, including children. Posterior uveitis can cause further complications if it is not treated, such as blindness.People with certain genes may be more likely to develop posterior uveitis. Patients who have a weakened or impaired immune system (immunocompromised) such as those with HIV or AIDS are at higher risk for viral posterior uveitis. People with a normally functioning immune system may also develop viral posterior uveitis. Cigarette smoking has been associated with a harder to manage disease.
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Overview of Posterior Uveitis. Uveitis is a general term that refers to inflammation of the part of the eye known as the uvea. The uvea is a relatively thick, strong layer of fibrous tissue that encloses and protects the eyeball. It contains many blood vessels and can cause inflammation in neighboring structures of the eye such as the retina, vitreous, optic nerve head and retinal vessels. The uvea consists of three parts: the iris, ciliary body and choroid.There are four types of uveitis, classified according to the part of the uvea that is affected. Anterior uveitis, which affects the front part of the eye, is also sometimes called iritis since the iris is part of the front of the eye. Almost 80% of cases of uveitis affect the anterior portion of the eye. Intermediate uveitis, also known as pars planitis or cyclitis, refers to inflammation of tissues in the area just behind the iris and lens of the eye. Posterior uveitis, also known as choroiditis, refers to inflammation of the choroid, the back part of the uvea. Posterior uveitis may affect the retina and/or the optic nerve and may lead to permanent loss of vision. Panuveitis refers to inflammation throughout the eye and does not refer to a specific area.Posterior uveitis is the rare form of the disorder and is the type of uveitis most associated with loss of vision. Uveitis can affect one or both eyes and it affects people of all ages, including children. Posterior uveitis can cause further complications if it is not treated, such as blindness.People with certain genes may be more likely to develop posterior uveitis. Patients who have a weakened or impaired immune system (immunocompromised) such as those with HIV or AIDS are at higher risk for viral posterior uveitis. People with a normally functioning immune system may also develop viral posterior uveitis. Cigarette smoking has been associated with a harder to manage disease.
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Symptoms of Posterior Uveitis
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Some people do not experience symptoms; however, some who experience them may have a sudden onset and get worse quickly.Symptoms that people may experience if they have posterior uveitis include:Floaters are small specks, flakes or clouds that move through the field of vision and decrease vision. While anterior uveitis often causes eye pain and redness, light sensitivity and blurred vision, the symptoms of posterior uveitis are more subtle. Uveitis can lead to other complications including glaucoma, cataracts or retinal detachment. Of note, 50% of patients have reduced vision and 10-15% have complete vision loss. Early detection and treatment is important to reduce the risk of permanent vision loss.
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Symptoms of Posterior Uveitis. Some people do not experience symptoms; however, some who experience them may have a sudden onset and get worse quickly.Symptoms that people may experience if they have posterior uveitis include:Floaters are small specks, flakes or clouds that move through the field of vision and decrease vision. While anterior uveitis often causes eye pain and redness, light sensitivity and blurred vision, the symptoms of posterior uveitis are more subtle. Uveitis can lead to other complications including glaucoma, cataracts or retinal detachment. Of note, 50% of patients have reduced vision and 10-15% have complete vision loss. Early detection and treatment is important to reduce the risk of permanent vision loss.
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Causes of Posterior Uveitis
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Uveitis can be caused by a person’s immune system, infections, tumors, bruising, eye injury or exposure to toxins. Posterior uveitis is inflammation of the uvea due to the body’s response to various factors such as microorganisms, toxins and damaged tissue. Inflammation may cause redness, swelling and heat in a particular area of the eye. This reaction can trigger an immune response and lead to the destruction of certain tissues and cause white blood cells to collect in that area of the eye. Posterior uveitis can have infectious or noninfectious causes. Infectious causes include bacterial, fungal, parasitic and viral infections. Noninfectious causes include immunologic problems, allergies, malignancies and unknown causes. Infectious causes include herpesviruses, measles, rubella and arboviruses such as dengue, West Nile and chikungunya virus. Oftentimes, viruses can remain latent in the body and can lead to serious complications and vision loss over time. The most important risk factor for viral posterior uveitis is being in an immunocompromised state, such as with HIV and AIDS.Posterior uveitis can be a result of associated autoimmune disorders, infections and/or trauma. Some of the disorders that can be associated with posterior uveitis are Behcet’s syndrome, ankylosing spondylitis, Lyme disease, sarcoidosis and psoriasis. The more common causes include sarcoidosis, syphilis and tuberculosis. Among children, the disorder is frequently associated with juvenile rheumatoid arthritis.
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Causes of Posterior Uveitis. Uveitis can be caused by a person’s immune system, infections, tumors, bruising, eye injury or exposure to toxins. Posterior uveitis is inflammation of the uvea due to the body’s response to various factors such as microorganisms, toxins and damaged tissue. Inflammation may cause redness, swelling and heat in a particular area of the eye. This reaction can trigger an immune response and lead to the destruction of certain tissues and cause white blood cells to collect in that area of the eye. Posterior uveitis can have infectious or noninfectious causes. Infectious causes include bacterial, fungal, parasitic and viral infections. Noninfectious causes include immunologic problems, allergies, malignancies and unknown causes. Infectious causes include herpesviruses, measles, rubella and arboviruses such as dengue, West Nile and chikungunya virus. Oftentimes, viruses can remain latent in the body and can lead to serious complications and vision loss over time. The most important risk factor for viral posterior uveitis is being in an immunocompromised state, such as with HIV and AIDS.Posterior uveitis can be a result of associated autoimmune disorders, infections and/or trauma. Some of the disorders that can be associated with posterior uveitis are Behcet’s syndrome, ankylosing spondylitis, Lyme disease, sarcoidosis and psoriasis. The more common causes include sarcoidosis, syphilis and tuberculosis. Among children, the disorder is frequently associated with juvenile rheumatoid arthritis.
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Affects of Posterior Uveitis
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Posterior uveitis occurs as an isolated condition or as part of other diseases that affect multiple body systems. This condition affects males and females in equal numbers. It can strike at almost any age, but usually begins between the ages of 30 and 40. According to one estimate, posterior uveitis occurs in 18/100,000 people (2020).
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Affects of Posterior Uveitis. Posterior uveitis occurs as an isolated condition or as part of other diseases that affect multiple body systems. This condition affects males and females in equal numbers. It can strike at almost any age, but usually begins between the ages of 30 and 40. According to one estimate, posterior uveitis occurs in 18/100,000 people (2020).
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Related disorders of Posterior Uveitis
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Symptoms of the following disorders can be similar to those of posterior uveitis. Comparisons may be useful for a differential diagnosis:Anterior uveitis is characterized by inflammation of the front (anterior) part of the eye. It is more common than posterior uveitis and its symptoms, which frequently include pain and redness of the eye, are not as subtle as those of posterior uveitis.Intermediate uveitis, also known as pars planitis, is a vision disorder characterized by inflammation of the peripheral retina and pars plana (a section of the ciliary body connected to the retina) sections of the eye. Fluid and foreign cells can infiltrate the clear gelatin-like substance (vitreous humor) near the retina and/or pars plana. Swelling inside the eye can also occur. These abnormalities may appear in one or both eyes. (For more information on this disorder, choose “pars planitis” as your search term in the Rare Disease Database.)
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Related disorders of Posterior Uveitis. Symptoms of the following disorders can be similar to those of posterior uveitis. Comparisons may be useful for a differential diagnosis:Anterior uveitis is characterized by inflammation of the front (anterior) part of the eye. It is more common than posterior uveitis and its symptoms, which frequently include pain and redness of the eye, are not as subtle as those of posterior uveitis.Intermediate uveitis, also known as pars planitis, is a vision disorder characterized by inflammation of the peripheral retina and pars plana (a section of the ciliary body connected to the retina) sections of the eye. Fluid and foreign cells can infiltrate the clear gelatin-like substance (vitreous humor) near the retina and/or pars plana. Swelling inside the eye can also occur. These abnormalities may appear in one or both eyes. (For more information on this disorder, choose “pars planitis” as your search term in the Rare Disease Database.)
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Diagnosis of Posterior Uveitis
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An ophthalmic exam using direct visualization of the inflammation and or white blood cells (leukocytes) can show the vitreous humor, which is a clear jelly-like substance behind the lens. Patients should be asked about their medication history and additional laboratory tests may be performed. Lab tests are done to check if the symptoms are caused by immunological or infectious conditions. Blood studies for infectious agents such as herpes virus, toxoplasmosis, toxocariasis and spirochetes are helpful. Chest x-rays may detect sarcoidosis or tuberculosis. If systemic or central nervous system involvement is present or large cell lymphoma is suspected, neuroimaging studies and lumbar puncture may be used.Eye exams that may be performed include:Classification systems in uveitis are based on:Eye doctors may use the Standardization of Uveitis Nomenclature (SUN) guidelines to diagnose this condition.
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Diagnosis of Posterior Uveitis. An ophthalmic exam using direct visualization of the inflammation and or white blood cells (leukocytes) can show the vitreous humor, which is a clear jelly-like substance behind the lens. Patients should be asked about their medication history and additional laboratory tests may be performed. Lab tests are done to check if the symptoms are caused by immunological or infectious conditions. Blood studies for infectious agents such as herpes virus, toxoplasmosis, toxocariasis and spirochetes are helpful. Chest x-rays may detect sarcoidosis or tuberculosis. If systemic or central nervous system involvement is present or large cell lymphoma is suspected, neuroimaging studies and lumbar puncture may be used.Eye exams that may be performed include:Classification systems in uveitis are based on:Eye doctors may use the Standardization of Uveitis Nomenclature (SUN) guidelines to diagnose this condition.
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Therapies of Posterior Uveitis
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Treatment
It is important to identify and treat an underlying infection or immunological disorder before initiating other treatment.Corticosteroids
Corticosteroids, also abbreviated as “steroids,” are considered the gold standard for treatment. Corticosteroids resemble cortisol (stress hormone) which work by reducing the activity of the immune system by decreasing inflammatory chemicals and migration of the white blood cells to the inflamed area. Thus, steroids are able to lower the amount of inflammation, redness and itching. Giving steroids on a long-term basis can cause changes in the blood cell counts and hormone levels. For example, corticosteroids can reduce the amount of white blood cells that generally stick to the blood vessels or are in the circulation, which can lead to greater infection risk. In addition, fluctuations in hormone levels upon long-term use of systemic corticosteroids can increase the risk of increased pressure in the eye (glaucoma) and cataracts, so the patient must be followed closely.There are three different classes of steroids that can be given.Periocular steroidsIntravitreal steroidsSystemic steroidsLong term safety concerns of taking steroids have led to the development of other therapies.Immunomodulator Therapy
Overtime, if a patient stops responding to systemic steroids and needs to continue therapy, off-label medications may be prescribed. Immunomodulator therapies can help lower inflammation in the body and help suppress the immune system.Immunomodulatory medications used for posterior uveitis:Biologic Response Modifiers (BRM)
These medications are bioengineered molecules that inhibit the activity of the immune response. They target specific cytokines, interleukins, proteins and analogues. BRM are also used if the patient is unable to take other treatments.Biologic response modifiers used for certain posterior uveitis conditions include:Ocular Gene Therapy
Ocular gene therapy works by injecting small amounts of adeno-associated virus (AAV) and lentivirus which act as vectors. These vectors have either direct or indirect anti-inflammatory properties.
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Therapies of Posterior Uveitis. Treatment
It is important to identify and treat an underlying infection or immunological disorder before initiating other treatment.Corticosteroids
Corticosteroids, also abbreviated as “steroids,” are considered the gold standard for treatment. Corticosteroids resemble cortisol (stress hormone) which work by reducing the activity of the immune system by decreasing inflammatory chemicals and migration of the white blood cells to the inflamed area. Thus, steroids are able to lower the amount of inflammation, redness and itching. Giving steroids on a long-term basis can cause changes in the blood cell counts and hormone levels. For example, corticosteroids can reduce the amount of white blood cells that generally stick to the blood vessels or are in the circulation, which can lead to greater infection risk. In addition, fluctuations in hormone levels upon long-term use of systemic corticosteroids can increase the risk of increased pressure in the eye (glaucoma) and cataracts, so the patient must be followed closely.There are three different classes of steroids that can be given.Periocular steroidsIntravitreal steroidsSystemic steroidsLong term safety concerns of taking steroids have led to the development of other therapies.Immunomodulator Therapy
Overtime, if a patient stops responding to systemic steroids and needs to continue therapy, off-label medications may be prescribed. Immunomodulator therapies can help lower inflammation in the body and help suppress the immune system.Immunomodulatory medications used for posterior uveitis:Biologic Response Modifiers (BRM)
These medications are bioengineered molecules that inhibit the activity of the immune response. They target specific cytokines, interleukins, proteins and analogues. BRM are also used if the patient is unable to take other treatments.Biologic response modifiers used for certain posterior uveitis conditions include:Ocular Gene Therapy
Ocular gene therapy works by injecting small amounts of adeno-associated virus (AAV) and lentivirus which act as vectors. These vectors have either direct or indirect anti-inflammatory properties.
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Overview of Potter Syndrome
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SummaryPotter syndrome is a rare condition characterized by the physical characteristics of a fetus that develop when there is too little amniotic fluid in the uterus (in utero) during pregnancy. Insufficient amounts of amniotic fluid during pregnancy is called oligohydramnios; the absence of amniotic fluid is called anhydramnios. Amniotic fluid supports, cushions, and protects a developing fetus. When there is too little amniotic fluid normal pressure that is exerted on the fetus during pregnancy can cause certain physical features such as distinctive facial features or skeletal abnormalities. When oligo-anhydramnios is present from early in pregnancy, the lungs are also underdeveloped (pulmonary hypoplasia), which can lead to severe breathing difficulties. Most often, this condition is caused by absence of both kidneys (bilateral renal agenesis). This is sometimes referred to as classic Potter syndrome. Potter syndrome can also result from other conditions including polycystic kidney disease, malformed (dysplastic) or underdeveloped (hypoplastic) kidneys, and obstructive uropathy, in which urine cannot be voided from the bladder and builds up within the kidneys. Sometimes, later during gestation, there may be amniotic fluid leakage; this will not lead to Potter syndrome. Potter syndrome is an extremely serious condition and is often fatal at or shortly after birth, mainly due to the pulmonary hypoplasia. IntroductionSome physicians believe that Potter sequence is a more appropriate name than Potter syndrome because while the signs and symptoms can vary among affected newborns, the sequence of events that leads to the development of this condition is the same. Some physicians use Potter sequence to denote a less severe form of Potter syndrome, but, generally, the three terms – Potter syndrome, Potter sequence, and oligohydramnios sequence – are used interchangeably in the medical literature. The condition was first described in the medical literature in 1946 by Edith Potter, a pathologist working in Chicago, Illinois.
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Overview of Potter Syndrome. SummaryPotter syndrome is a rare condition characterized by the physical characteristics of a fetus that develop when there is too little amniotic fluid in the uterus (in utero) during pregnancy. Insufficient amounts of amniotic fluid during pregnancy is called oligohydramnios; the absence of amniotic fluid is called anhydramnios. Amniotic fluid supports, cushions, and protects a developing fetus. When there is too little amniotic fluid normal pressure that is exerted on the fetus during pregnancy can cause certain physical features such as distinctive facial features or skeletal abnormalities. When oligo-anhydramnios is present from early in pregnancy, the lungs are also underdeveloped (pulmonary hypoplasia), which can lead to severe breathing difficulties. Most often, this condition is caused by absence of both kidneys (bilateral renal agenesis). This is sometimes referred to as classic Potter syndrome. Potter syndrome can also result from other conditions including polycystic kidney disease, malformed (dysplastic) or underdeveloped (hypoplastic) kidneys, and obstructive uropathy, in which urine cannot be voided from the bladder and builds up within the kidneys. Sometimes, later during gestation, there may be amniotic fluid leakage; this will not lead to Potter syndrome. Potter syndrome is an extremely serious condition and is often fatal at or shortly after birth, mainly due to the pulmonary hypoplasia. IntroductionSome physicians believe that Potter sequence is a more appropriate name than Potter syndrome because while the signs and symptoms can vary among affected newborns, the sequence of events that leads to the development of this condition is the same. Some physicians use Potter sequence to denote a less severe form of Potter syndrome, but, generally, the three terms – Potter syndrome, Potter sequence, and oligohydramnios sequence – are used interchangeably in the medical literature. The condition was first described in the medical literature in 1946 by Edith Potter, a pathologist working in Chicago, Illinois.
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Symptoms of Potter Syndrome
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The signs and symptoms of Potter syndrome can vary from one newborn to another. However, the condition is associated with severe complications affecting the developing fetus and is often fatal at or shortly after birth. When caused by bilateral agenesis of the kidneys, Potter syndrome is not compatible with life. Potter syndrome due to other causes is also often fatal at or shortly after birth, but there is an increased chance for survival. Infants who do survive the newborn period generally experience chronic lung disease and chronic kidney failure. Because of the lack of amniotic fluid to protect the developing fetus, normal pressure from the uterine walls can affect the growth and development of the fetus. Such pressure may cause distinctive facial features including a recessed chin; a flattened, depressed bridge of the nose; eyes that are spaced further apart than normal (hypertelorism); low-set ears that lack cartilage (Potter ears); abnormally prominent skins folds in the inner corners of the eyes (prominent epicanthal folds); and a crease beneath the lower lips. This collection of facial features is sometimes referred to as “Potter facies.”There is usually a lack of urine creation and output because of kidney abnormalities. Absence (agenesis) of both kidneys is the most common defect associated with Potter syndrome. The kidneys can also be malformed (dysplastic), or damaged because of a larger syndrome affecting the kidneys such as polycystic kidney disease, a group of rare disorders characterized by the development of numerous cysts within the kidneys. The lungs may be underdeveloped (hypoplastic) and most newborns experience severe breathing complications after birth (respiratory distress).Sometimes there are abnormalities in the development of the arms and legs, lack of formation of half of the spine (hemivertebrae), absence of the lower portion of the spine (sacral agenesis), congenital heart defects, or abnormalities of the eyes such as cataracts, or displacement or dislocation (prolapse) of the lenses of the eyes. Infants with Potter syndrome are often born prematurely and are small for their gestational age, which means they are smaller than would normally be expected for how far along the pregnancy is.
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Symptoms of Potter Syndrome. The signs and symptoms of Potter syndrome can vary from one newborn to another. However, the condition is associated with severe complications affecting the developing fetus and is often fatal at or shortly after birth. When caused by bilateral agenesis of the kidneys, Potter syndrome is not compatible with life. Potter syndrome due to other causes is also often fatal at or shortly after birth, but there is an increased chance for survival. Infants who do survive the newborn period generally experience chronic lung disease and chronic kidney failure. Because of the lack of amniotic fluid to protect the developing fetus, normal pressure from the uterine walls can affect the growth and development of the fetus. Such pressure may cause distinctive facial features including a recessed chin; a flattened, depressed bridge of the nose; eyes that are spaced further apart than normal (hypertelorism); low-set ears that lack cartilage (Potter ears); abnormally prominent skins folds in the inner corners of the eyes (prominent epicanthal folds); and a crease beneath the lower lips. This collection of facial features is sometimes referred to as “Potter facies.”There is usually a lack of urine creation and output because of kidney abnormalities. Absence (agenesis) of both kidneys is the most common defect associated with Potter syndrome. The kidneys can also be malformed (dysplastic), or damaged because of a larger syndrome affecting the kidneys such as polycystic kidney disease, a group of rare disorders characterized by the development of numerous cysts within the kidneys. The lungs may be underdeveloped (hypoplastic) and most newborns experience severe breathing complications after birth (respiratory distress).Sometimes there are abnormalities in the development of the arms and legs, lack of formation of half of the spine (hemivertebrae), absence of the lower portion of the spine (sacral agenesis), congenital heart defects, or abnormalities of the eyes such as cataracts, or displacement or dislocation (prolapse) of the lenses of the eyes. Infants with Potter syndrome are often born prematurely and are small for their gestational age, which means they are smaller than would normally be expected for how far along the pregnancy is.
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Causes of Potter Syndrome
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The most common underlying cause of Potter syndrome is absence, underdevelopment or malformation of the kidneys. Absence of both kidneys (bilateral renal agenesis) is the most common condition associated with Potter syndrome. The kidneys produce urine, which makes up the major part of the amniotic fluid, which supports, cushions and protects a developing fetus. Because there is not enough amniotic fluid to protect the fetus, the pressure a fetus undergoes while developing within the uterus that normally does not cause any problems can cause a variety of physical features including distinctive facial features, skeletal abnormalities, and other complications. Amniotic fluid is also essential for the proper development of the lungs. Absence of amniotic fluid, especially in the first half of gestation, will result in underdevelopment of the lungs (pulmonary hypoplasia) as well. Potter syndrome can also result from autosomal recessive polycystic kidney disease, malformation of the kidneys, a rare disorder characterized by absence of the abdominal muscles (prune belly syndrome), certain chromosomal disorders, and obstructive uropathy, in which urine cannot be voided from the body and builds up into the kidneys. Sometimes, Potter syndrome results from prolonged rupture of the amniotic membranes, which allows amniotic fluid to leak out. This usually seen when the rupture occurs early in a pregnancy and goes undetected for a long period of time. In most instances, Potter syndrome occurs sporadically for no known reason. However, sometimes the underlying cause, such as certain kidney abnormalities, may be genetic. If related to a genetic condition, this can occur spontaneously without a family history of the condition, or the genetic condition could have been inherited and genetic counseling is recommended.
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Causes of Potter Syndrome. The most common underlying cause of Potter syndrome is absence, underdevelopment or malformation of the kidneys. Absence of both kidneys (bilateral renal agenesis) is the most common condition associated with Potter syndrome. The kidneys produce urine, which makes up the major part of the amniotic fluid, which supports, cushions and protects a developing fetus. Because there is not enough amniotic fluid to protect the fetus, the pressure a fetus undergoes while developing within the uterus that normally does not cause any problems can cause a variety of physical features including distinctive facial features, skeletal abnormalities, and other complications. Amniotic fluid is also essential for the proper development of the lungs. Absence of amniotic fluid, especially in the first half of gestation, will result in underdevelopment of the lungs (pulmonary hypoplasia) as well. Potter syndrome can also result from autosomal recessive polycystic kidney disease, malformation of the kidneys, a rare disorder characterized by absence of the abdominal muscles (prune belly syndrome), certain chromosomal disorders, and obstructive uropathy, in which urine cannot be voided from the body and builds up into the kidneys. Sometimes, Potter syndrome results from prolonged rupture of the amniotic membranes, which allows amniotic fluid to leak out. This usually seen when the rupture occurs early in a pregnancy and goes undetected for a long period of time. In most instances, Potter syndrome occurs sporadically for no known reason. However, sometimes the underlying cause, such as certain kidney abnormalities, may be genetic. If related to a genetic condition, this can occur spontaneously without a family history of the condition, or the genetic condition could have been inherited and genetic counseling is recommended.
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Potter Syndrome
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Affects of Potter Syndrome
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Potter syndrome is a rare disorder, and the exact incidence or prevalence is unknown. The main cause of this condition, bilateral renal agenesis, occurs in approximately 1 in 5,000 fetuses and accounts for about 20% of Potter syndrome cases. The incidence or prevalence of other causes are unknown. Overall, estimates for the incidence or prevalence of Potter syndrome range from 1 in 4,000 to 10,000 births. A couple studies have shown that male newborns are affected more often than female newborns, probably due to the obstructive uropathy that is seen more often in males.
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Affects of Potter Syndrome. Potter syndrome is a rare disorder, and the exact incidence or prevalence is unknown. The main cause of this condition, bilateral renal agenesis, occurs in approximately 1 in 5,000 fetuses and accounts for about 20% of Potter syndrome cases. The incidence or prevalence of other causes are unknown. Overall, estimates for the incidence or prevalence of Potter syndrome range from 1 in 4,000 to 10,000 births. A couple studies have shown that male newborns are affected more often than female newborns, probably due to the obstructive uropathy that is seen more often in males.
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Related disorders of Potter Syndrome
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Related disorders of Potter Syndrome.
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Diagnosis of Potter Syndrome
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A diagnosis of Potter syndrome is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and certain specialized tests. If not detected before birth (prenatally), then lack of urine production, specific (facial) features or difficulty breathing may be signs of Potter syndrome. Clinical Testing and Workup
A routine specialized imaging technique called a fetal ultrasound may detect Potter syndrome before birth. A fetal ultrasound uses reflected sound waves to create an image of the developing fetus and can reveal a lack of amniotic fluid. An ultrasound can also show abnormalities or absence of the kidneys. Swelling of the kidneys due to a buildup of urine (hydronephrosis), which can occur when there is an obstruction of the urinary tract, can also be seen on an ultrasound. X-ray examination of the lungs after birth may show underdevelopment of the lungs. Physicians may run blood and urine tests to determine the levels of electrolytes, enzymes and other substances that may be elevated or decreased in Potter syndrome. These tests can aid in obtaining a diagnosis of the condition. An echocardiogram, which is a test that uses sound waves to create a picture of the heart, may be conducted to detect congenital heart defects potentially associated with this condition.
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Diagnosis of Potter Syndrome. A diagnosis of Potter syndrome is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and certain specialized tests. If not detected before birth (prenatally), then lack of urine production, specific (facial) features or difficulty breathing may be signs of Potter syndrome. Clinical Testing and Workup
A routine specialized imaging technique called a fetal ultrasound may detect Potter syndrome before birth. A fetal ultrasound uses reflected sound waves to create an image of the developing fetus and can reveal a lack of amniotic fluid. An ultrasound can also show abnormalities or absence of the kidneys. Swelling of the kidneys due to a buildup of urine (hydronephrosis), which can occur when there is an obstruction of the urinary tract, can also be seen on an ultrasound. X-ray examination of the lungs after birth may show underdevelopment of the lungs. Physicians may run blood and urine tests to determine the levels of electrolytes, enzymes and other substances that may be elevated or decreased in Potter syndrome. These tests can aid in obtaining a diagnosis of the condition. An echocardiogram, which is a test that uses sound waves to create a picture of the heart, may be conducted to detect congenital heart defects potentially associated with this condition.
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Potter Syndrome
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Therapies of Potter Syndrome
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There is no treatment for Potter syndrome due to bilateral absence of the kidneys, which is not compatible with life. Efforts should be made to ensure the entire family receives coping support and grief counseling. Genetic counseling is recommended. Psychosocial support for the entire family is essential as well. Newborns with Potter syndrome due to other causes will usually need assistance to breath (mechanical ventilation). Resuscitation may also be necessary. Decisions whether to resuscitate are made in close consultation with the parents, physicians and entire medical team. In some newborns who have partially functioning kidneys and sufficient lung function, dialysis may be needed, which is an intensive and troublesome therapy in newborns.
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Therapies of Potter Syndrome. There is no treatment for Potter syndrome due to bilateral absence of the kidneys, which is not compatible with life. Efforts should be made to ensure the entire family receives coping support and grief counseling. Genetic counseling is recommended. Psychosocial support for the entire family is essential as well. Newborns with Potter syndrome due to other causes will usually need assistance to breath (mechanical ventilation). Resuscitation may also be necessary. Decisions whether to resuscitate are made in close consultation with the parents, physicians and entire medical team. In some newborns who have partially functioning kidneys and sufficient lung function, dialysis may be needed, which is an intensive and troublesome therapy in newborns.
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Potter Syndrome
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Overview of Prader-Willi Syndrome
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Summary
Prader-Willi syndrome (PWS) is a genetic multisystem disorder characterized during infancy by lethargy, diminished muscle tone (hypotonia), a weak suck and feeding difficulties with poor weight gain and growth and other hormone deficiency. In childhood, features of this disorder include short stature, small genitals and an excessive appetite. Affected individuals do not feel satisfied after completing a meal (satiety). Without intervention, overeating can lead to onset of life-threatening obesity. The food compulsion requires constant supervision. Individuals with severe obesity may have an increased risk of cardiac insufficiency, sleep apnea, diabetes, respiratory problems and other serious conditions that can cause life-threatening complications. All individuals with PWS have some cognitive impairment that ranges from low normal intelligence with learning disabilities to mild to moderate intellectual disability. Behavioral problems are common and can include temper tantrums, obsessive/compulsive behavior and skin picking. Motor milestones and language development are often delayed. PWS occurs due to abnormalities affecting certain genes in the proximal long arm of chromosome 15 when deleted from the father’s chromosome 15 and hence referred to as a genomic imprinting disorder which depends on the sex of the parent donating the chromosome leading to the chromosome defect in the child. These abnormalities usually result from random (sporadic) errors in egg or sperm development but are sometimes inherited.Introduction
Originally described in the medical literature in 1956, PWS is the first disorder confirmed to be due to imprinting errors (see Causes section). It is the most common genetic cause of life-threatening childhood obesity. The disorder was once known as hypogonadism, hypotonia, hypomentia, obesity (HHHO).
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Overview of Prader-Willi Syndrome. Summary
Prader-Willi syndrome (PWS) is a genetic multisystem disorder characterized during infancy by lethargy, diminished muscle tone (hypotonia), a weak suck and feeding difficulties with poor weight gain and growth and other hormone deficiency. In childhood, features of this disorder include short stature, small genitals and an excessive appetite. Affected individuals do not feel satisfied after completing a meal (satiety). Without intervention, overeating can lead to onset of life-threatening obesity. The food compulsion requires constant supervision. Individuals with severe obesity may have an increased risk of cardiac insufficiency, sleep apnea, diabetes, respiratory problems and other serious conditions that can cause life-threatening complications. All individuals with PWS have some cognitive impairment that ranges from low normal intelligence with learning disabilities to mild to moderate intellectual disability. Behavioral problems are common and can include temper tantrums, obsessive/compulsive behavior and skin picking. Motor milestones and language development are often delayed. PWS occurs due to abnormalities affecting certain genes in the proximal long arm of chromosome 15 when deleted from the father’s chromosome 15 and hence referred to as a genomic imprinting disorder which depends on the sex of the parent donating the chromosome leading to the chromosome defect in the child. These abnormalities usually result from random (sporadic) errors in egg or sperm development but are sometimes inherited.Introduction
Originally described in the medical literature in 1956, PWS is the first disorder confirmed to be due to imprinting errors (see Causes section). It is the most common genetic cause of life-threatening childhood obesity. The disorder was once known as hypogonadism, hypotonia, hypomentia, obesity (HHHO).
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Symptoms of Prader-Willi Syndrome
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The symptoms and severity of PWS can vary from one person to another. Many features of the disorder are nonspecific, and others may develop slowly over time or can be subtle. It is important to note that affected individuals may not have all the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis. Often this requires input from a clinical geneticist or genetic counselor with experience in this genetic disorder to supply the most recent and accurate information about the disorder and discuss genetic testing options or treatment plans.Initially, infants will exhibit diminished muscle tone (hypotonia), which can cause a baby to feel “floppy” when held. Infantile hypotonia, which is often severe, is a near universal feature of the disorder. Hypotonia can be present before birth (prenatally) potentially causing decreased fetal movements and abnormal positioning of the fetus (e.g., breech position). Prenatal hypotonia is associated with an increased risk of requiring an assisted delivery. After birth, hypotonia is associated with lethargy, a weak cry, poor responsiveness to stimuli and poor reflexes including poor sucking ability, which result in feeding difficulties and failure to thrive. Infants are usually unable to breastfeed and may require tube feeding. Hypotonia slowly improves over time, but some adults with PWS may continue to have some degree of hypotonia.Affected infants may also have distinctive facial features including almond-shaped eyes, a thin upper lip, a downturned mouth, a narrow bridge of the nose, a narrow forehead, and a disproportionately long, narrow head (dolichocephaly). Distinctive facial features can be noticeable shortly after birth or may develop slowly over time.As affected infants grow older, their feeding and appetite will improve, and they will grow appropriately. Typically, between 2-4.5 years of age, their weight increases although there may not be a noticeable change in appetite or caloric intake. Between 4.5-8 years old, appetite and caloric intake usually increases, often thereafter developing a need to eat an extraordinarily large amount of food (hyperphagia) usually because they do not feel satisfied after completing a meal (satiety). In addition, there is a decreased calorie requirement in people with PWS due to low muscle, decreased metabolism and decreased physical activity if not treated with growth hormone replacement. Consequently, overeating, rapid weight gain, and morbid obesity occur if not controlled by others. Not all affected children will go through these stages.If left uncontrolled and untreated, morbid obesity can develop, potentially leading to life-threatening heart and lung complications, diabetes, high blood pressure (hypertension), and to other serious complications. The compulsion to eat is so overwhelming that people with this disorder, if left unsupervised, may endanger themselves by eating harmful food such as spoiled food or garbage and excessive quantities, harmful to the stomach. Affected children may also exhibit unusual behaviors regarding food including hoarding and/or foraging for food, stealing food and stealing money to buy food.Some affected individuals have developed serious, life-threatening gastrointestinal complications due to episodes of binge eating. Such complications can include severe bloating (gastric dilatation) with the development of a hole or tear in the intestinal wall (perforation) and tissue loss (necrosis). They are noted to have decreased gastric emptying and swallowing difficulties.Children with PWS also have varying levels of cognitive impairment, ranging from borderline or low normal intelligence with learning disabilities to mild to moderate intellectual disability. The attainment of motor milestones (e.g., walking or sitting up) and language development are often delayed.Affected children generally have sweet and loving personalities, but often develop distinct behavioral issues. Such issues can include temper tantrums, stubbornness, obsessive/compulsive behavior, manipulative behavior and skin picking, which can cause chronic open wounds, scarring and infection. In some patients, the behavior profile may be suggestive of autism. Psychosis occurs in approximately 10-20% of late adolescents and young adults. Evidence shows that the type of chromosome 15 abnormality may relate to certain learning and behavioral problems.Hypogonadism is a common finding in PWS. Hypogonadism refers to inadequate function of the sex organs, the testes in males and the ovaries in females. The sex organs in affected individuals fail to produce sufficient sex hormones, which can result in underdeveloped sex organs, incomplete development at puberty, delayed onset of puberty, and infertility. Genital underdevelopment is evident at birth. Affected males may have a small penis, underdeveloped scrotum, and small testes. Failure of one or both testes to descend (cryptorchidism) is a common finding, as well. Affected females may have an abnormally small clitoris or labia minor. Absence of a menstrual cycle (primary amenorrhea) is common and in some females the initial menstrual period (menarche) may not occur until 30 years of age or older.Individuals with PWS have growth hormone (GH) insufficiency, a condition characterized by the inadequate secretion of growth hormone from the anterior pituitary gland, a small gland located at the base of the brain that is responsible for the production of several hormones. Children may be significantly below average height based upon sex and age (short stature). GH deficiency affects both children and adults and the final adult height of affected individuals is shorter than unaffected family members. If GH treatment is prescribed at the time of diagnosis, often now during early infancy, then the results are positive with a decrease in the amount of fat seen in PWS patients, an increase in muscle mass and altered body composition. In addition, there is reported evidence of an earlier diagnosis in PWS which reduces the other medical problems (comorbidities) seen in people with this disorder. Hence, GH treatment beginning at an early age in PWS can improve stature and body composition including weight with near normalization of growth by 18 years of age based on PWS specific growth charts in comparison with normal growth charts.Affected individuals may also have abnormally small hands and feet, side-to-side curvature of the spine (scoliosis) and, in approximately 10% of individuals, a malformed hip (hip dysplasia). Scoliosis can occur at any age including infancy, varies in severity and should be monitored. Sleep problems are common, including excessive daytime sleepiness, reduced rapid eye movement (REM) latency, disruption of the normal sleep cycle, and central and/or obstructive sleep apnea.Some individuals may have lack of color (pigment) known as hypopigmentation affecting the hair, eyes and skin particularly in those with the chromosome 15q deletion seen in about 60% of those with PWS (discussed in Causes). They may appear fair-skinned compared to other family members. Nearsightedness (myopia) and misaligned eyes (strabismus) may also occur.Affected individuals may also experience recurrent respiratory infections. Up to 25% of affected individuals may have an underactive thyroid gland (hypothyroidism). In addition, the rates of certain conditions are increased in individuals with PWS including fractures due to decreased bone density (osteopenia), altered temperature sensation, a high vomiting threshold and swelling (edema) and ulcerations of the legs, especially in obese adults. Some individuals may have reduced flow of saliva with abnormally thick, sticky saliva. Additional symptoms that can occur in affected individuals include a high pain threshold, a tendency to bruise easily without known cause and seizures.Some individuals with PWS may develop central adrenal insufficiency (CAI), a condition characterized by deficiency of adrenocorticotropic hormone (ACTH). This hormone is produced by the pituitary gland. One of the main functions of ACTH is to stimulate the adrenal glands to produce cortisol, which helps to regulate blood sugar and the body to deal with stress. In some patients, CAI may only be detectable during periods of stress (e.g., during illness or injury). The exact percentage of affected individuals with CAI and its overall implications to individuals with PWS are not yet fully understood. Natural history causes of death and survival trends in PWS have recently been published and useful to gain knowledge and current understanding and diagnosis with comorbidities in order to better monitor the health status and prognosis of someone with PWS.
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Symptoms of Prader-Willi Syndrome. The symptoms and severity of PWS can vary from one person to another. Many features of the disorder are nonspecific, and others may develop slowly over time or can be subtle. It is important to note that affected individuals may not have all the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis. Often this requires input from a clinical geneticist or genetic counselor with experience in this genetic disorder to supply the most recent and accurate information about the disorder and discuss genetic testing options or treatment plans.Initially, infants will exhibit diminished muscle tone (hypotonia), which can cause a baby to feel “floppy” when held. Infantile hypotonia, which is often severe, is a near universal feature of the disorder. Hypotonia can be present before birth (prenatally) potentially causing decreased fetal movements and abnormal positioning of the fetus (e.g., breech position). Prenatal hypotonia is associated with an increased risk of requiring an assisted delivery. After birth, hypotonia is associated with lethargy, a weak cry, poor responsiveness to stimuli and poor reflexes including poor sucking ability, which result in feeding difficulties and failure to thrive. Infants are usually unable to breastfeed and may require tube feeding. Hypotonia slowly improves over time, but some adults with PWS may continue to have some degree of hypotonia.Affected infants may also have distinctive facial features including almond-shaped eyes, a thin upper lip, a downturned mouth, a narrow bridge of the nose, a narrow forehead, and a disproportionately long, narrow head (dolichocephaly). Distinctive facial features can be noticeable shortly after birth or may develop slowly over time.As affected infants grow older, their feeding and appetite will improve, and they will grow appropriately. Typically, between 2-4.5 years of age, their weight increases although there may not be a noticeable change in appetite or caloric intake. Between 4.5-8 years old, appetite and caloric intake usually increases, often thereafter developing a need to eat an extraordinarily large amount of food (hyperphagia) usually because they do not feel satisfied after completing a meal (satiety). In addition, there is a decreased calorie requirement in people with PWS due to low muscle, decreased metabolism and decreased physical activity if not treated with growth hormone replacement. Consequently, overeating, rapid weight gain, and morbid obesity occur if not controlled by others. Not all affected children will go through these stages.If left uncontrolled and untreated, morbid obesity can develop, potentially leading to life-threatening heart and lung complications, diabetes, high blood pressure (hypertension), and to other serious complications. The compulsion to eat is so overwhelming that people with this disorder, if left unsupervised, may endanger themselves by eating harmful food such as spoiled food or garbage and excessive quantities, harmful to the stomach. Affected children may also exhibit unusual behaviors regarding food including hoarding and/or foraging for food, stealing food and stealing money to buy food.Some affected individuals have developed serious, life-threatening gastrointestinal complications due to episodes of binge eating. Such complications can include severe bloating (gastric dilatation) with the development of a hole or tear in the intestinal wall (perforation) and tissue loss (necrosis). They are noted to have decreased gastric emptying and swallowing difficulties.Children with PWS also have varying levels of cognitive impairment, ranging from borderline or low normal intelligence with learning disabilities to mild to moderate intellectual disability. The attainment of motor milestones (e.g., walking or sitting up) and language development are often delayed.Affected children generally have sweet and loving personalities, but often develop distinct behavioral issues. Such issues can include temper tantrums, stubbornness, obsessive/compulsive behavior, manipulative behavior and skin picking, which can cause chronic open wounds, scarring and infection. In some patients, the behavior profile may be suggestive of autism. Psychosis occurs in approximately 10-20% of late adolescents and young adults. Evidence shows that the type of chromosome 15 abnormality may relate to certain learning and behavioral problems.Hypogonadism is a common finding in PWS. Hypogonadism refers to inadequate function of the sex organs, the testes in males and the ovaries in females. The sex organs in affected individuals fail to produce sufficient sex hormones, which can result in underdeveloped sex organs, incomplete development at puberty, delayed onset of puberty, and infertility. Genital underdevelopment is evident at birth. Affected males may have a small penis, underdeveloped scrotum, and small testes. Failure of one or both testes to descend (cryptorchidism) is a common finding, as well. Affected females may have an abnormally small clitoris or labia minor. Absence of a menstrual cycle (primary amenorrhea) is common and in some females the initial menstrual period (menarche) may not occur until 30 years of age or older.Individuals with PWS have growth hormone (GH) insufficiency, a condition characterized by the inadequate secretion of growth hormone from the anterior pituitary gland, a small gland located at the base of the brain that is responsible for the production of several hormones. Children may be significantly below average height based upon sex and age (short stature). GH deficiency affects both children and adults and the final adult height of affected individuals is shorter than unaffected family members. If GH treatment is prescribed at the time of diagnosis, often now during early infancy, then the results are positive with a decrease in the amount of fat seen in PWS patients, an increase in muscle mass and altered body composition. In addition, there is reported evidence of an earlier diagnosis in PWS which reduces the other medical problems (comorbidities) seen in people with this disorder. Hence, GH treatment beginning at an early age in PWS can improve stature and body composition including weight with near normalization of growth by 18 years of age based on PWS specific growth charts in comparison with normal growth charts.Affected individuals may also have abnormally small hands and feet, side-to-side curvature of the spine (scoliosis) and, in approximately 10% of individuals, a malformed hip (hip dysplasia). Scoliosis can occur at any age including infancy, varies in severity and should be monitored. Sleep problems are common, including excessive daytime sleepiness, reduced rapid eye movement (REM) latency, disruption of the normal sleep cycle, and central and/or obstructive sleep apnea.Some individuals may have lack of color (pigment) known as hypopigmentation affecting the hair, eyes and skin particularly in those with the chromosome 15q deletion seen in about 60% of those with PWS (discussed in Causes). They may appear fair-skinned compared to other family members. Nearsightedness (myopia) and misaligned eyes (strabismus) may also occur.Affected individuals may also experience recurrent respiratory infections. Up to 25% of affected individuals may have an underactive thyroid gland (hypothyroidism). In addition, the rates of certain conditions are increased in individuals with PWS including fractures due to decreased bone density (osteopenia), altered temperature sensation, a high vomiting threshold and swelling (edema) and ulcerations of the legs, especially in obese adults. Some individuals may have reduced flow of saliva with abnormally thick, sticky saliva. Additional symptoms that can occur in affected individuals include a high pain threshold, a tendency to bruise easily without known cause and seizures.Some individuals with PWS may develop central adrenal insufficiency (CAI), a condition characterized by deficiency of adrenocorticotropic hormone (ACTH). This hormone is produced by the pituitary gland. One of the main functions of ACTH is to stimulate the adrenal glands to produce cortisol, which helps to regulate blood sugar and the body to deal with stress. In some patients, CAI may only be detectable during periods of stress (e.g., during illness or injury). The exact percentage of affected individuals with CAI and its overall implications to individuals with PWS are not yet fully understood. Natural history causes of death and survival trends in PWS have recently been published and useful to gain knowledge and current understanding and diagnosis with comorbidities in order to better monitor the health status and prognosis of someone with PWS.
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Prader-Willi Syndrome
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nord_996_2
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Causes of Prader-Willi Syndrome
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PWS occurs when the genes in a specific region of chromosome 15 are not present or do not function. This region of chromosome 15 is located at 15q11.2-q13 and has been designated the Prader-Will syndrome/Angelman syndrome region (PWS/AS). In individuals with PWS, the nonfunctioning PWS/AS region is always located on the number 15 chromosome inherited from the father.Chromosomes, which are present in the nucleus of human cells, carry 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 as X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 15q11.2-q13” refers to bands 11.2-13 on the long arm of chromosome 15. The numbered bands specify the location of the thousands of genes that are present on each chromosome.The changes affecting the genes associated with PWS may involve changes in the structure of a gene (genetic factors) or changes in the function or expression of a gene (epigenetics). Three specific abnormalities are primarily associated with PWS – chromosomal 15q11-q13 deletion, maternal uniparental disomy 15 or both chromosome 15s from the mother and genetic imprinting errors in the region controlling gene activity on chromosome 15.PWS is associated with a specific process known as genetic imprinting. Normally, everyone has two copies of every gene – one received from the father, and one received from the mother. In most people, both genes are “turned on” or active. However, some genes are preferentially silenced or “turned off” based upon which parent gave the gene to the child (genetic imprinting). Genetic imprinting is controlled by chemical switches through a process called methylation and other chemical changes at the DNA level. Proper genetic imprinting is necessary for normal development. Defective imprinting has been associated with several disorders including PWS.Imprinted genes tend to cluster or group together on chromosomes. Several imprinted genes are found in a cluster on the long arm (q) of chromosome 15. The cluster contains a functional region known as an imprinting center that regulates activity of the imprinted genes in this region.In most people with PWS (about 60%), the PWS/AS region of the father’s chromosome 15 is missing or deleted. This chromosomal deletion results from a random error in development and is not inherited (de novo deletion) and is not inherited. Thus, most cases of PWS occur sporadically and the risk of recurrence in another pregnancy is less than 1%.Recent data shows that in about 35% of people with PWS, the affected person inherits two copies of chromosome 15 from the mother and no copy of the father’s chromosome 15 (referred to as maternal uniparental disomy). This type of genetic change also occurs because of a random error in development. In most cases, the risk of recurrence of uniparental disomy is estimated to be less than 1%.In less than 5% of people with PWS, the PWS/AS region of the father’s chromosome 15 is present, but the genes do not work properly. This form of PWS is due to an abnormality in genes called the imprinting center and is sometimes due to a genetic change (e.g., microdeletion) that can be passed from one generation to the next at a high risk (up to 50%).In a very small proportion of affected people, PWS has occurred due to a balanced translocation of chromosome 15. Translocations occur when portions of certain chromosomes break off and are rearranged, resulting in shifting of genetic (e.g., genes of the imprinting center) material and an altered set of chromosomes. If a chromosomal translocation is balanced (meaning that it consists of rearranged chromosomes without anything missing or extra), then it is usually harmless to the carrier. However, such a chromosomal rearrangement may be associated with an increased risk of abnormal chromosomal development in the carrier’s children depending on events that occur in the egg or sperm production.Several imprinted genes have been mapped to the PWS/AS region of chromosome 15. However, the specific genes involved and their role in the development of the various symptoms of PWS are being characterized but not yet known. Many symptoms associated with PWS are believed to be due to malfunction of the hypothalamus, a gland in the brain that regulates hormone secretions and under genetic control. Hormones produced by the hypothalamus affect body temperature, hunger, moods, sex drive, sleep and thirst. The hypothalamus also influences the release of hormones from other glands, especially the pituitary gland, which regulates the release of certain hormones including growth and sex hormones.
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Causes of Prader-Willi Syndrome. PWS occurs when the genes in a specific region of chromosome 15 are not present or do not function. This region of chromosome 15 is located at 15q11.2-q13 and has been designated the Prader-Will syndrome/Angelman syndrome region (PWS/AS). In individuals with PWS, the nonfunctioning PWS/AS region is always located on the number 15 chromosome inherited from the father.Chromosomes, which are present in the nucleus of human cells, carry 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 as X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 15q11.2-q13” refers to bands 11.2-13 on the long arm of chromosome 15. The numbered bands specify the location of the thousands of genes that are present on each chromosome.The changes affecting the genes associated with PWS may involve changes in the structure of a gene (genetic factors) or changes in the function or expression of a gene (epigenetics). Three specific abnormalities are primarily associated with PWS – chromosomal 15q11-q13 deletion, maternal uniparental disomy 15 or both chromosome 15s from the mother and genetic imprinting errors in the region controlling gene activity on chromosome 15.PWS is associated with a specific process known as genetic imprinting. Normally, everyone has two copies of every gene – one received from the father, and one received from the mother. In most people, both genes are “turned on” or active. However, some genes are preferentially silenced or “turned off” based upon which parent gave the gene to the child (genetic imprinting). Genetic imprinting is controlled by chemical switches through a process called methylation and other chemical changes at the DNA level. Proper genetic imprinting is necessary for normal development. Defective imprinting has been associated with several disorders including PWS.Imprinted genes tend to cluster or group together on chromosomes. Several imprinted genes are found in a cluster on the long arm (q) of chromosome 15. The cluster contains a functional region known as an imprinting center that regulates activity of the imprinted genes in this region.In most people with PWS (about 60%), the PWS/AS region of the father’s chromosome 15 is missing or deleted. This chromosomal deletion results from a random error in development and is not inherited (de novo deletion) and is not inherited. Thus, most cases of PWS occur sporadically and the risk of recurrence in another pregnancy is less than 1%.Recent data shows that in about 35% of people with PWS, the affected person inherits two copies of chromosome 15 from the mother and no copy of the father’s chromosome 15 (referred to as maternal uniparental disomy). This type of genetic change also occurs because of a random error in development. In most cases, the risk of recurrence of uniparental disomy is estimated to be less than 1%.In less than 5% of people with PWS, the PWS/AS region of the father’s chromosome 15 is present, but the genes do not work properly. This form of PWS is due to an abnormality in genes called the imprinting center and is sometimes due to a genetic change (e.g., microdeletion) that can be passed from one generation to the next at a high risk (up to 50%).In a very small proportion of affected people, PWS has occurred due to a balanced translocation of chromosome 15. Translocations occur when portions of certain chromosomes break off and are rearranged, resulting in shifting of genetic (e.g., genes of the imprinting center) material and an altered set of chromosomes. If a chromosomal translocation is balanced (meaning that it consists of rearranged chromosomes without anything missing or extra), then it is usually harmless to the carrier. However, such a chromosomal rearrangement may be associated with an increased risk of abnormal chromosomal development in the carrier’s children depending on events that occur in the egg or sperm production.Several imprinted genes have been mapped to the PWS/AS region of chromosome 15. However, the specific genes involved and their role in the development of the various symptoms of PWS are being characterized but not yet known. Many symptoms associated with PWS are believed to be due to malfunction of the hypothalamus, a gland in the brain that regulates hormone secretions and under genetic control. Hormones produced by the hypothalamus affect body temperature, hunger, moods, sex drive, sleep and thirst. The hypothalamus also influences the release of hormones from other glands, especially the pituitary gland, which regulates the release of certain hormones including growth and sex hormones.
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Prader-Willi Syndrome
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Affects of Prader-Willi Syndrome
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PWS affects males and females in equal numbers and occurs in all ethnic groups and geographic regions in the world. Most estimates place the incidence between 1 in 10,000-30,000 individuals in the general population and about 350,000-400,000 individuals worldwide.
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Affects of Prader-Willi Syndrome. PWS affects males and females in equal numbers and occurs in all ethnic groups and geographic regions in the world. Most estimates place the incidence between 1 in 10,000-30,000 individuals in the general population and about 350,000-400,000 individuals worldwide.
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Prader-Willi Syndrome
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Related disorders of Prader-Willi Syndrome
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Symptoms of the following disorders can be similar to those seen in PWS including fragile X, Bardet-Biedl Cohen, Borjesson-Forssman-Lehmann, and Alstrom syndromes, uniparental disomy 14 and several other different chromosomal alterations besides chromosome 15, Albright hereditary osteodystrophy, congenital muscular dystrophy and spinal muscular atrophy. For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.Angelman syndrome (AS) is another rare genetic neurological disorder characterized by severe developmental delays and learning disabilities; the absence or near absence of speech; an inability to coordinate voluntary movements (ataxia) and tremulous, jerky movements of the arms and legs; and a distinct behavioral pattern characterized by a happy disposition and unprovoked episodes of laughter and smiling, often at inappropriate times. Although affected individuals may be unable to speak, many gradually learn to communicate through other means such as gesturing. In addition, children may have enough receptive language ability to understand language to understand simple commands. Additional symptoms may occur including seizures, sleep disorders and feeding difficulties. They may also have distinctive facial features. Angelman syndrome is often discussed in the medical field alongside PWS despite the different clinical presentation because Angelman syndrome is caused by a deletion or abnormal expression of the UBE3A gene which is located on the long arm (q) of chromosome 15 (15q11-q13) and referred to as the PWS/AS region. In contrast to PWS, the abnormalities that cause Angelman syndrome always affect the number chromosome 15 inherited from the mother. PWS and Angelman syndrome became recognized as the first examples in humans of genetic imprinting. For more information on this disorder, choose “Angelman” as your search term in the Rare Disease Database.
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Related disorders of Prader-Willi Syndrome. Symptoms of the following disorders can be similar to those seen in PWS including fragile X, Bardet-Biedl Cohen, Borjesson-Forssman-Lehmann, and Alstrom syndromes, uniparental disomy 14 and several other different chromosomal alterations besides chromosome 15, Albright hereditary osteodystrophy, congenital muscular dystrophy and spinal muscular atrophy. For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.Angelman syndrome (AS) is another rare genetic neurological disorder characterized by severe developmental delays and learning disabilities; the absence or near absence of speech; an inability to coordinate voluntary movements (ataxia) and tremulous, jerky movements of the arms and legs; and a distinct behavioral pattern characterized by a happy disposition and unprovoked episodes of laughter and smiling, often at inappropriate times. Although affected individuals may be unable to speak, many gradually learn to communicate through other means such as gesturing. In addition, children may have enough receptive language ability to understand language to understand simple commands. Additional symptoms may occur including seizures, sleep disorders and feeding difficulties. They may also have distinctive facial features. Angelman syndrome is often discussed in the medical field alongside PWS despite the different clinical presentation because Angelman syndrome is caused by a deletion or abnormal expression of the UBE3A gene which is located on the long arm (q) of chromosome 15 (15q11-q13) and referred to as the PWS/AS region. In contrast to PWS, the abnormalities that cause Angelman syndrome always affect the number chromosome 15 inherited from the mother. PWS and Angelman syndrome became recognized as the first examples in humans of genetic imprinting. For more information on this disorder, choose “Angelman” as your search term in the Rare Disease Database.
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Prader-Willi Syndrome
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nord_996_5
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Diagnosis of Prader-Willi Syndrome
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A diagnosis of PWS is based upon a detailed patient history, thorough clinical evaluation and identification of characteristic symptoms. Consensus diagnostic criteria for PWS have been established and are effective for identifying potential cases of PWS but genetic testing is required to confirm the diagnosis and to identify the specific genetic subtype (15q11-q13 deletion, maternal disomy 15, imprinting defect). Hence, all infants and newborns with unexplained hypotonia and poor suck should be tested for PWS. To confirm a diagnosis of PWS, certain specialized tests are required including DNA methylation tests and fluorescent in situ hybridization (FISH). More recently, high resolution chromosomal microarray studies with several hundred thousand DNA probes (e.g., 2.8 million probes) from throughout the genome representing all chromosomes can be utilized to identify small deletions or duplications of the chromosomes that cannot be seen with routine chromosome studies. High resolution chromosome microarrays are most useful in identifying the typical chromosome 15q11-q13 deletions in which there are two types (larger type I and smaller type II), other rearrangements of this chromosome region, imprinting defects and specific maternal disomy 15 subclasses seen in PWS. Genetic laboratory testing algorithms and advances in genetic technology have allowed more precise testing results and PWS molecular genetic class identified which is important as the severity of clinical findings, disease surveillance and recurrence risks can depend on the specific genetic abnormality.Clinical Testing and Workup
Approximately 99% of people with PWS can be diagnosed by DNA methylation study. This test allows for the examination of gene activity status in the PWS/AS critical region of chromosome 15. If the methylation pattern is consistent with maternal inheritance, then this indicates that the paternal chromosome 15 is not present or not active. This finding is diagnostic of PWS, but methylation tests alone cannot distinguish among the different underlying causes of PWS (i.e., deletions, imprinting defects or maternal disomy 15).If DNA methylation tests indicate PWS, then additional tests are necessary to determine the underlying cause of the disorder. This is important for determining whether there is an increased risk for the parents or other family members to have an affected child. High resolution microarrays have replaced the FISH test as microarrays can detect the size of the 15q11-q13 deletion, the most common genetic cause of PWS. High resolution microarrays can also detect maternal disomy 15 if present in the majority of those with PWS having no recognized deletion but both chromosome 15s come from the mother. There are two typical chromosomal 15q11-q13 deletion subtypes (larger type I and smaller type II) and three subclasses of maternal disomy 15 (heterodisomy, segmental isodisomy, total isodisomy) in PWS. Clinical and behavioral differences are reported in those with the PWS deletion subtypes or those with maternal disomy 15 subclasses. Those with the larger 15q11-q13 Type I deletion have more learning and behavioral problems and those with maternal disomy 15 are more prone to autistic findings and psychosis in young adulthood. If no deletion is present on chromosome 15, then additional testing is performed to distinguish between maternal disomy 15 or a defect of the imprinting center.Prenatal diagnosis is possible in families with a previous history of PWS. Prior identification of a disease-causing abnormality can facilitate prenatal testing, but it is available by methylation analysis or high-resolution microarrays following amniocentesis regardless of cause.
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Diagnosis of Prader-Willi Syndrome. A diagnosis of PWS is based upon a detailed patient history, thorough clinical evaluation and identification of characteristic symptoms. Consensus diagnostic criteria for PWS have been established and are effective for identifying potential cases of PWS but genetic testing is required to confirm the diagnosis and to identify the specific genetic subtype (15q11-q13 deletion, maternal disomy 15, imprinting defect). Hence, all infants and newborns with unexplained hypotonia and poor suck should be tested for PWS. To confirm a diagnosis of PWS, certain specialized tests are required including DNA methylation tests and fluorescent in situ hybridization (FISH). More recently, high resolution chromosomal microarray studies with several hundred thousand DNA probes (e.g., 2.8 million probes) from throughout the genome representing all chromosomes can be utilized to identify small deletions or duplications of the chromosomes that cannot be seen with routine chromosome studies. High resolution chromosome microarrays are most useful in identifying the typical chromosome 15q11-q13 deletions in which there are two types (larger type I and smaller type II), other rearrangements of this chromosome region, imprinting defects and specific maternal disomy 15 subclasses seen in PWS. Genetic laboratory testing algorithms and advances in genetic technology have allowed more precise testing results and PWS molecular genetic class identified which is important as the severity of clinical findings, disease surveillance and recurrence risks can depend on the specific genetic abnormality.Clinical Testing and Workup
Approximately 99% of people with PWS can be diagnosed by DNA methylation study. This test allows for the examination of gene activity status in the PWS/AS critical region of chromosome 15. If the methylation pattern is consistent with maternal inheritance, then this indicates that the paternal chromosome 15 is not present or not active. This finding is diagnostic of PWS, but methylation tests alone cannot distinguish among the different underlying causes of PWS (i.e., deletions, imprinting defects or maternal disomy 15).If DNA methylation tests indicate PWS, then additional tests are necessary to determine the underlying cause of the disorder. This is important for determining whether there is an increased risk for the parents or other family members to have an affected child. High resolution microarrays have replaced the FISH test as microarrays can detect the size of the 15q11-q13 deletion, the most common genetic cause of PWS. High resolution microarrays can also detect maternal disomy 15 if present in the majority of those with PWS having no recognized deletion but both chromosome 15s come from the mother. There are two typical chromosomal 15q11-q13 deletion subtypes (larger type I and smaller type II) and three subclasses of maternal disomy 15 (heterodisomy, segmental isodisomy, total isodisomy) in PWS. Clinical and behavioral differences are reported in those with the PWS deletion subtypes or those with maternal disomy 15 subclasses. Those with the larger 15q11-q13 Type I deletion have more learning and behavioral problems and those with maternal disomy 15 are more prone to autistic findings and psychosis in young adulthood. If no deletion is present on chromosome 15, then additional testing is performed to distinguish between maternal disomy 15 or a defect of the imprinting center.Prenatal diagnosis is possible in families with a previous history of PWS. Prior identification of a disease-causing abnormality can facilitate prenatal testing, but it is available by methylation analysis or high-resolution microarrays following amniocentesis regardless of cause.
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Prader-Willi Syndrome
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nord_996_6
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Therapies of Prader-Willi Syndrome
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Treatment
The treatment of PWS is directed toward the specific symptoms that are apparent in each individual. Early intervention and strict maintenance to treatment can greatly improve the overall health and quality of life for affected individuals and their families. Treatment may require the coordinated efforts of a team of specialists. Clinical geneticists, pediatricians, orthopedists, endocrinologists, speech therapists, psychologists, dieticians, nutritionists and other healthcare professionals may need to systematically and comprehensively plan an effective program for the child’s treatment. Genetic counseling is recommended for affected individuals and their families to further discuss the condition and to provide information and recurrence risks once genetic testing is completed for identification of specific PWS molecular classes. Parents are strongly recommended to learn appropriate parenting techniques for the behavioral and eating issues associated with PWS; such education correlates with better prognosis.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease severity; the presence or absence of certain symptoms; an individual’s age and general health; and/or other elements. Decisions concerning the use of drug regimens and/or other treatments should be made by physicians and other members of the health care team following pharmacogenetics or a personalized medicine approach to test for and identify DNA patterns of genes involved with coding proteins (e.g., liver enzymes) that breakdown or metabolism drugs or medications prescribed to treat a patient with PWS. 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.In infants, special nipples or gavage feeding may be used to ensure adequate nutrition. Gavage feeding is a procedure in which a small, thin tube is passed through the nose and mouth to the stomach to directly feed a newborn who has feeding difficulties.In males, the treatment of hypogonadism with either testosterone or human chorionic gonadotropin may be beneficial during infancy, potentially increasing the size of the genitalia or prompting testicular descent into the scrotum when cryptorchidism is present. Although cryptorchidism may occasionally resolve spontaneously or with hormone therapy, most males require surgical treatment.Individuals with PWS also benefit from growth hormone (GH) therapy, which can help to increase height, improve lean body mass, mobility and respiratory function, decrease body fat and ultimately improve the quality of life. Some studies have shown that GH therapy may improve development and behavior. In 2000, the U.S. Food and Drug Administration (FDA) approved the use of human growth hormone for the treatment of children with genetically confirmed PWS and evidence of growth failure. Studies have shown that the earlier GH therapy is started the more beneficial it is, and that therapy can begin as early as two to three months of age. GH therapy has been shown to improve facial appearance and overall body build (body habitus). Development of standardized growth charts for PWS with and without growth hormone treatment have been generated and can be used to monitor the growth parameters at specific ages in PWS. It is recommended that affected individuals undergo a sleep study to detect and treat obstructive sleep apnea before initiating GH therapy because some reports suggest a link between premature death and GH therapy in certain individuals with PWS (e.g., those with profound hypotonia or obesity and pre-existing respiratory or cardiac problems). However, other researchers have expressed doubt as to whether GH therapy had a direct role in these cases but decisions regarding GH therapy in individuals with PWS are best made after consultation with a pediatric endocrinologist after a sleep study and assessments for adrenal gland insufficiency.Children with PWS require early intervention to assess and treat issues with motor skills, intellectual disability and speech and language development. Early intervention may include physical and occupational therapy, special education and speech therapy. An individualized education plan should be created at the start of school. Behavioral therapy and, in some patients, psychoactive medications such as specific serotonin reuptake inhibitors may be beneficial to manage difficult behavior or psychosis. Children should receive an ophthalmological exam to evaluate eye abnormalities potentially associated with PWS such as strabismus and to assess visual acuity. Children should also be assessed for hip dysplasia and scoliosis which can occur in patients with PWS. Evaluation and treatment of sleep disturbance is recommended as well. Some researchers recommend that all individuals with PWS be screened for hypothyroidism (which occurs with increased incidence in PWS) and central adrenal insufficiency.During childhood, a program consisting of a low-calorie diet, regular exercise and strict supervision of food intake and access should be formulated. Strict supervision of food intake should be based upon height, weight and body mass index (BMI). Such a program should begin before signs of obesity to help to prevent its development. Limiting access to food may require locking cabinets and refrigerators. Some individuals may require vitamin supplementation, especially calcium and vitamin D.Sex hormones can be replaced at puberty as they can stimulate the development of secondary sexual characteristics and improve self-image and bone density. In males, the use of such therapy has been controversial because testosterone replacement by monthly injection may contribute to behavioral issues in males; use of a testosterone patch or gel will avert this problem. Sex hormone replacement therapy may increase the risk of stroke in females, as in the general population, and hygiene issues should also be considered. Sex education and consideration of contraception are important. Decreased flow of saliva may be improved with special toothpastes, gels, mouthwash and gum.
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Therapies of Prader-Willi Syndrome. Treatment
The treatment of PWS is directed toward the specific symptoms that are apparent in each individual. Early intervention and strict maintenance to treatment can greatly improve the overall health and quality of life for affected individuals and their families. Treatment may require the coordinated efforts of a team of specialists. Clinical geneticists, pediatricians, orthopedists, endocrinologists, speech therapists, psychologists, dieticians, nutritionists and other healthcare professionals may need to systematically and comprehensively plan an effective program for the child’s treatment. Genetic counseling is recommended for affected individuals and their families to further discuss the condition and to provide information and recurrence risks once genetic testing is completed for identification of specific PWS molecular classes. Parents are strongly recommended to learn appropriate parenting techniques for the behavioral and eating issues associated with PWS; such education correlates with better prognosis.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease severity; the presence or absence of certain symptoms; an individual’s age and general health; and/or other elements. Decisions concerning the use of drug regimens and/or other treatments should be made by physicians and other members of the health care team following pharmacogenetics or a personalized medicine approach to test for and identify DNA patterns of genes involved with coding proteins (e.g., liver enzymes) that breakdown or metabolism drugs or medications prescribed to treat a patient with PWS. 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.In infants, special nipples or gavage feeding may be used to ensure adequate nutrition. Gavage feeding is a procedure in which a small, thin tube is passed through the nose and mouth to the stomach to directly feed a newborn who has feeding difficulties.In males, the treatment of hypogonadism with either testosterone or human chorionic gonadotropin may be beneficial during infancy, potentially increasing the size of the genitalia or prompting testicular descent into the scrotum when cryptorchidism is present. Although cryptorchidism may occasionally resolve spontaneously or with hormone therapy, most males require surgical treatment.Individuals with PWS also benefit from growth hormone (GH) therapy, which can help to increase height, improve lean body mass, mobility and respiratory function, decrease body fat and ultimately improve the quality of life. Some studies have shown that GH therapy may improve development and behavior. In 2000, the U.S. Food and Drug Administration (FDA) approved the use of human growth hormone for the treatment of children with genetically confirmed PWS and evidence of growth failure. Studies have shown that the earlier GH therapy is started the more beneficial it is, and that therapy can begin as early as two to three months of age. GH therapy has been shown to improve facial appearance and overall body build (body habitus). Development of standardized growth charts for PWS with and without growth hormone treatment have been generated and can be used to monitor the growth parameters at specific ages in PWS. It is recommended that affected individuals undergo a sleep study to detect and treat obstructive sleep apnea before initiating GH therapy because some reports suggest a link between premature death and GH therapy in certain individuals with PWS (e.g., those with profound hypotonia or obesity and pre-existing respiratory or cardiac problems). However, other researchers have expressed doubt as to whether GH therapy had a direct role in these cases but decisions regarding GH therapy in individuals with PWS are best made after consultation with a pediatric endocrinologist after a sleep study and assessments for adrenal gland insufficiency.Children with PWS require early intervention to assess and treat issues with motor skills, intellectual disability and speech and language development. Early intervention may include physical and occupational therapy, special education and speech therapy. An individualized education plan should be created at the start of school. Behavioral therapy and, in some patients, psychoactive medications such as specific serotonin reuptake inhibitors may be beneficial to manage difficult behavior or psychosis. Children should receive an ophthalmological exam to evaluate eye abnormalities potentially associated with PWS such as strabismus and to assess visual acuity. Children should also be assessed for hip dysplasia and scoliosis which can occur in patients with PWS. Evaluation and treatment of sleep disturbance is recommended as well. Some researchers recommend that all individuals with PWS be screened for hypothyroidism (which occurs with increased incidence in PWS) and central adrenal insufficiency.During childhood, a program consisting of a low-calorie diet, regular exercise and strict supervision of food intake and access should be formulated. Strict supervision of food intake should be based upon height, weight and body mass index (BMI). Such a program should begin before signs of obesity to help to prevent its development. Limiting access to food may require locking cabinets and refrigerators. Some individuals may require vitamin supplementation, especially calcium and vitamin D.Sex hormones can be replaced at puberty as they can stimulate the development of secondary sexual characteristics and improve self-image and bone density. In males, the use of such therapy has been controversial because testosterone replacement by monthly injection may contribute to behavioral issues in males; use of a testosterone patch or gel will avert this problem. Sex hormone replacement therapy may increase the risk of stroke in females, as in the general population, and hygiene issues should also be considered. Sex education and consideration of contraception are important. Decreased flow of saliva may be improved with special toothpastes, gels, mouthwash and gum.
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Prader-Willi Syndrome
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nord_997_0
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Overview of Precocious Puberty
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Precocious puberty means an abnormally early onset of puberty. A sequence of events occurs during which a child develops into a young adult beginning at an unexpectedly early age. Glands that secrete growth and sex hormones begin to function abnormally early in life resulting in this condition. Often, the exact cause of precocious puberty is not known.Precocious puberty (PP) is a statistical definition; that is, it is the onset of secondary sexual characteristics in children at an age that is two standard deviations younger than the mean age of pubertal onset. The actual age that defines sexual precocity is therefore dependent on the epidemiological data that one uses to define the average age of pubertal onset. Different populations and different time periods will therefore have differing definitions of PP. Classically, in North America, puberty is considered precocious if it begins before age 8 in girls or age 9 in boys. Recently, most likely because of increasing weight in the population, puberty appears to be having an earlier age of onset.
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Overview of Precocious Puberty. Precocious puberty means an abnormally early onset of puberty. A sequence of events occurs during which a child develops into a young adult beginning at an unexpectedly early age. Glands that secrete growth and sex hormones begin to function abnormally early in life resulting in this condition. Often, the exact cause of precocious puberty is not known.Precocious puberty (PP) is a statistical definition; that is, it is the onset of secondary sexual characteristics in children at an age that is two standard deviations younger than the mean age of pubertal onset. The actual age that defines sexual precocity is therefore dependent on the epidemiological data that one uses to define the average age of pubertal onset. Different populations and different time periods will therefore have differing definitions of PP. Classically, in North America, puberty is considered precocious if it begins before age 8 in girls or age 9 in boys. Recently, most likely because of increasing weight in the population, puberty appears to be having an earlier age of onset.
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Precocious Puberty
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nord_997_1
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Symptoms of Precocious Puberty
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Secondary sexual characteristics include testicular enlargement (>3 ml) and/or pubic hair development in boys, and breast and/or pubic hair development in girls. Other signs suggestive of pubertal onset include acne, growth acceleration, voice changes, vaginal discharge or bleeding, and advanced skeletal maturation. There are many terms used to describe pre-pubertal children who have isolated signs of puberty. These children, however, do not necessarily meet the criteria for true precocious puberty. These terms include premature thelarche, premature adrenarche, premature pubarche and premature menarche. The terminology is often confusing as these are also referred to by some authors as incomplete precocious puberty. Precocious puberty can occur in several forms. Normally, the hypothalamus initiates puberty by stimulating the pituitary to release gonadotropins (FSH and LH), the hormones which control growth and function of the sex organs. When gonadotropins are released, synthesis and secretion of sex steroids (such as estrogen, progesterone or testosterone) occur, leading to development of secondary sexual characteristics. If this occurs prematurely, a child starts to develop secondary sexual characteristics and proceeds to sexual maturity at an unexpectedly early age. Since the maturing of one’s bones is usually accelerated by this condition, early fusion of the growth plates occurs, resulting in shortening of adult stature. However, during childhood, children with precocious puberty are often taller than their peers.
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Symptoms of Precocious Puberty. Secondary sexual characteristics include testicular enlargement (>3 ml) and/or pubic hair development in boys, and breast and/or pubic hair development in girls. Other signs suggestive of pubertal onset include acne, growth acceleration, voice changes, vaginal discharge or bleeding, and advanced skeletal maturation. There are many terms used to describe pre-pubertal children who have isolated signs of puberty. These children, however, do not necessarily meet the criteria for true precocious puberty. These terms include premature thelarche, premature adrenarche, premature pubarche and premature menarche. The terminology is often confusing as these are also referred to by some authors as incomplete precocious puberty. Precocious puberty can occur in several forms. Normally, the hypothalamus initiates puberty by stimulating the pituitary to release gonadotropins (FSH and LH), the hormones which control growth and function of the sex organs. When gonadotropins are released, synthesis and secretion of sex steroids (such as estrogen, progesterone or testosterone) occur, leading to development of secondary sexual characteristics. If this occurs prematurely, a child starts to develop secondary sexual characteristics and proceeds to sexual maturity at an unexpectedly early age. Since the maturing of one’s bones is usually accelerated by this condition, early fusion of the growth plates occurs, resulting in shortening of adult stature. However, during childhood, children with precocious puberty are often taller than their peers.
| 997 |
Precocious Puberty
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nord_997_2
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Causes of Precocious Puberty
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Central precocious puberty (CPP) can be caused by CNS tumors (craniopharyngioma, glioma, etc.) and other CNS disorders including: hypothalamic hamartoma of the tuber cinereum, encephalitis, brain abscess, static encephalopathy, global delays, sarcoid or tubercular granuloma, head trauma, vascular lesion, cranial irradiation, or neurofibromatosis type 1 (usually associated with optic glioma). A large proportion of CPP is idiopathic, especially in females; however, research is beginning to identify rare genetic causes for some of these cases. For instance, activating mutations of the kisspeptin gene (KISS1) and its receptor (KISS1R), which are known for their stimulatory effect on the hypothalamus ultimately leading to increased gonadotropin secretion, have been identified as precipitating precocious puberty. Additionally, inactivating mutations of a paternally inherited MKRN3 gene, similar to that seen in Prader-Willi syndrome, has been implicated in early puberty. CPP can also follow the treatment of virilizing congenital adrenal hyperplasia or the treatment of other causes of gonadotropin independent precocious puberty (GIPP).The causes of GIPP include gonadal, adrenal, ectopic, or exogenous sources of hormone production. Hypothyroidism may also cause GIPP, which is felt to be mediated by TSH stimulation of the FSH receptor, but frequently manifests as growth delay in the setting of testicular enlargement or premature menarche; this is also referred to as Van Wyk-Grumbach syndrome. Very rarely, ingestion of birth control pills, or other preparations containing estrogens, or meat containing high estrogen concentrations can cause this disorder. Hormone-secreting tumors of the gonads or adrenal glands are also associated with precocious puberty. Estrogen-secreting ovarian granulosa-thecal cell tumors are probably the most common form of sex steroid-secreting tumors among girls with GIPP. Human chorionic gonadotropin (HCG) tumors of the ovary, such as choriocarcinomas or teratomas may be associated with ovarian sex steroid stimulation and precocious puberty in girls. Benign ovarian cysts may be present in some female patients with PP. HCG-secreting tumors and Leydig cell tumors are causes GIPP in boys.
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Causes of Precocious Puberty. Central precocious puberty (CPP) can be caused by CNS tumors (craniopharyngioma, glioma, etc.) and other CNS disorders including: hypothalamic hamartoma of the tuber cinereum, encephalitis, brain abscess, static encephalopathy, global delays, sarcoid or tubercular granuloma, head trauma, vascular lesion, cranial irradiation, or neurofibromatosis type 1 (usually associated with optic glioma). A large proportion of CPP is idiopathic, especially in females; however, research is beginning to identify rare genetic causes for some of these cases. For instance, activating mutations of the kisspeptin gene (KISS1) and its receptor (KISS1R), which are known for their stimulatory effect on the hypothalamus ultimately leading to increased gonadotropin secretion, have been identified as precipitating precocious puberty. Additionally, inactivating mutations of a paternally inherited MKRN3 gene, similar to that seen in Prader-Willi syndrome, has been implicated in early puberty. CPP can also follow the treatment of virilizing congenital adrenal hyperplasia or the treatment of other causes of gonadotropin independent precocious puberty (GIPP).The causes of GIPP include gonadal, adrenal, ectopic, or exogenous sources of hormone production. Hypothyroidism may also cause GIPP, which is felt to be mediated by TSH stimulation of the FSH receptor, but frequently manifests as growth delay in the setting of testicular enlargement or premature menarche; this is also referred to as Van Wyk-Grumbach syndrome. Very rarely, ingestion of birth control pills, or other preparations containing estrogens, or meat containing high estrogen concentrations can cause this disorder. Hormone-secreting tumors of the gonads or adrenal glands are also associated with precocious puberty. Estrogen-secreting ovarian granulosa-thecal cell tumors are probably the most common form of sex steroid-secreting tumors among girls with GIPP. Human chorionic gonadotropin (HCG) tumors of the ovary, such as choriocarcinomas or teratomas may be associated with ovarian sex steroid stimulation and precocious puberty in girls. Benign ovarian cysts may be present in some female patients with PP. HCG-secreting tumors and Leydig cell tumors are causes GIPP in boys.
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Precocious Puberty
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nord_997_3
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Affects of Precocious Puberty
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This disorder is classically characterized among females by breast development beginning before the age of eight years in white girls, 6.8 years for Hispanic girls and 6.6 years for Black girls, or the onset of menstruation before the age of approximately ten years (white-10.6 years, Hispanic-10.0 years and black-9.7 years). Among males, precocious puberty can be defined as pubertal development beginning before the age of nine years for white males, 9.5 years for Hispanic males and 8 years for black males. Boys with this disorder will usually have testicular and genital enlargement occur first and then tend to exhibit pubic, underarm (axillary) and facial hair, accelerated growth, and a deepening voice. Puberty may occur even before three years of age in some cases of this disorder.CPP has an incidence of 1 in 5-10,000 children with a female to male ratio of about 20:1 although this ratio is debated. Eighty to ninety percent of girls with true PP have idiopathic CPP whereas over 50% of boys have an identifiable etiology for true PP.
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Affects of Precocious Puberty. This disorder is classically characterized among females by breast development beginning before the age of eight years in white girls, 6.8 years for Hispanic girls and 6.6 years for Black girls, or the onset of menstruation before the age of approximately ten years (white-10.6 years, Hispanic-10.0 years and black-9.7 years). Among males, precocious puberty can be defined as pubertal development beginning before the age of nine years for white males, 9.5 years for Hispanic males and 8 years for black males. Boys with this disorder will usually have testicular and genital enlargement occur first and then tend to exhibit pubic, underarm (axillary) and facial hair, accelerated growth, and a deepening voice. Puberty may occur even before three years of age in some cases of this disorder.CPP has an incidence of 1 in 5-10,000 children with a female to male ratio of about 20:1 although this ratio is debated. Eighty to ninety percent of girls with true PP have idiopathic CPP whereas over 50% of boys have an identifiable etiology for true PP.
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Precocious Puberty
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nord_997_4
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Related disorders of Precocious Puberty
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Symptoms of the following disorders can be similar to those of precocious puberty. Comparisons may be useful for a differential diagnosis:Pseudo-precocious puberty is characterized by high sex steroid levels due either to ingestion of sex steroids, hormone-producing tumors (usually of the ovaries or testes), or abnormalities of the adrenal gland which cause over-production of hormones. Although patients appear to be maturing sexually, ovulation or sperm production may not occur because the gonads are not mature. However, in children with true precocious puberty, ovulation and sperm production can occur abnormally early in life.The following disorders may precede the development of precocious puberty. They can be useful in identifying an underlying cause of some forms of this disorder:McCune-Albright syndrome is characterized by an early (precocious) sexual development, a change in bone structure, associated with pain and increasing deformity, and abnormal changes in skin pigmentation (“Coast-of-Maine” cafe-au-lait spots). This syndrome affects the endocrine and musculoskeletal systems. (For more information on this disorder, choose “McCune-Albright” as your search term in the Rare Disease Database.)Congenital adrenal hyperplasia (CAH) is a group of disorders resulting from defective synthesis of the corticosteroid hormones of the adrenal gland. The adrenal gland becomes enlarged because it is continually being stimulated to try and make appropriate levels of cortisol, a critical, life sustaining hormone; however, because of a congenital enzyme deficiency in the adrenal gland, it is unable to produce enough cortisol without over producing male sex steroids. This overproduction of male sex steroids can result in the masculinization of a female fetus. In fact, the external genitalia of some females with this disorder can become masculinized enough to allow them to be mislabeled as a male infant at birth. (For more information on this disorder, choose “Adrenal Hyperplasia” as your search term in the Rare Disease Database.)Neurofibromatosis (NF) is a genetic disorder with highly variable manifestations, which can affect many body systems. Symptoms usually begin during childhood. Early puberty can occur in this condition. The disorder tends to become more active at puberty, during pregnancy, and at menopause. Neurofibromatosis is characterized by multiple nerve tumors under the skin, which can result in disfigurement, curvature of the spine and long bones, and other complications. (For more information on this disorder, choose “Neurofibromatosis” as your search term in the Rare Disease Database.)Familial male-limited precocious puberty (FMPP), also referred to a familial testotoxicosis, is a rare genetic disorder caused by persistent activation of the LH receptor. As its name suggests, the disorder only affects males, usually presenting by 4 years of age with signs of early pubertal development.
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Related disorders of Precocious Puberty. Symptoms of the following disorders can be similar to those of precocious puberty. Comparisons may be useful for a differential diagnosis:Pseudo-precocious puberty is characterized by high sex steroid levels due either to ingestion of sex steroids, hormone-producing tumors (usually of the ovaries or testes), or abnormalities of the adrenal gland which cause over-production of hormones. Although patients appear to be maturing sexually, ovulation or sperm production may not occur because the gonads are not mature. However, in children with true precocious puberty, ovulation and sperm production can occur abnormally early in life.The following disorders may precede the development of precocious puberty. They can be useful in identifying an underlying cause of some forms of this disorder:McCune-Albright syndrome is characterized by an early (precocious) sexual development, a change in bone structure, associated with pain and increasing deformity, and abnormal changes in skin pigmentation (“Coast-of-Maine” cafe-au-lait spots). This syndrome affects the endocrine and musculoskeletal systems. (For more information on this disorder, choose “McCune-Albright” as your search term in the Rare Disease Database.)Congenital adrenal hyperplasia (CAH) is a group of disorders resulting from defective synthesis of the corticosteroid hormones of the adrenal gland. The adrenal gland becomes enlarged because it is continually being stimulated to try and make appropriate levels of cortisol, a critical, life sustaining hormone; however, because of a congenital enzyme deficiency in the adrenal gland, it is unable to produce enough cortisol without over producing male sex steroids. This overproduction of male sex steroids can result in the masculinization of a female fetus. In fact, the external genitalia of some females with this disorder can become masculinized enough to allow them to be mislabeled as a male infant at birth. (For more information on this disorder, choose “Adrenal Hyperplasia” as your search term in the Rare Disease Database.)Neurofibromatosis (NF) is a genetic disorder with highly variable manifestations, which can affect many body systems. Symptoms usually begin during childhood. Early puberty can occur in this condition. The disorder tends to become more active at puberty, during pregnancy, and at menopause. Neurofibromatosis is characterized by multiple nerve tumors under the skin, which can result in disfigurement, curvature of the spine and long bones, and other complications. (For more information on this disorder, choose “Neurofibromatosis” as your search term in the Rare Disease Database.)Familial male-limited precocious puberty (FMPP), also referred to a familial testotoxicosis, is a rare genetic disorder caused by persistent activation of the LH receptor. As its name suggests, the disorder only affects males, usually presenting by 4 years of age with signs of early pubertal development.
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Precocious Puberty
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nord_997_5
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Diagnosis of Precocious Puberty
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Normal puberty begins with hypothalamic production of kisspeptin, which stimulates the pulsatile release of GnRH from the hypothalamus. This results in an increase in the frequency and magnitude of gonadotropin release, especially LH. Unfortunately, it is challenging to determine the initial clinical corollary to these biochemical events. It has been suggested that there is a continuum of sexual development in girls from uncomplicated premature thelarche to true precocious puberty; the former being more likely to develop in girls under 2 years of age. This spectrum exists both clinically and biochemically and emphasizes the need for the clinician to distinguish between these conditions in patients when making decisions about treatment. The criteria for diagnosis and treatment of CPP need to be reached through a synthesis of clinical findings as well as laboratory evidence for activation of the hypothalamic-pituitary-gonadal axis. The gold standard for determination of pubertal gonadotropin secretion is the GnRH stimulation test, though many clinicians start with a sensitive measurement of serum LH. Skeletal age determination is frequently obtained early in the work-up, and can be helpful in distinguishing isolated signs of puberty, which do not typically cause advancement in bone age as compared to true PP, which will advance bone maturity. In boys, serum DHEAS, testosterone, 17-OH progesterone and β-HCG levels are useful for the diagnosis of GIPP. In girls, serum DHEAS, estradiol and 17-OH progesterone levels are useful. Diagnostic studies including head MRI and pelvic ultrasound are frequently required in the work-up of children with PP.
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Diagnosis of Precocious Puberty. Normal puberty begins with hypothalamic production of kisspeptin, which stimulates the pulsatile release of GnRH from the hypothalamus. This results in an increase in the frequency and magnitude of gonadotropin release, especially LH. Unfortunately, it is challenging to determine the initial clinical corollary to these biochemical events. It has been suggested that there is a continuum of sexual development in girls from uncomplicated premature thelarche to true precocious puberty; the former being more likely to develop in girls under 2 years of age. This spectrum exists both clinically and biochemically and emphasizes the need for the clinician to distinguish between these conditions in patients when making decisions about treatment. The criteria for diagnosis and treatment of CPP need to be reached through a synthesis of clinical findings as well as laboratory evidence for activation of the hypothalamic-pituitary-gonadal axis. The gold standard for determination of pubertal gonadotropin secretion is the GnRH stimulation test, though many clinicians start with a sensitive measurement of serum LH. Skeletal age determination is frequently obtained early in the work-up, and can be helpful in distinguishing isolated signs of puberty, which do not typically cause advancement in bone age as compared to true PP, which will advance bone maturity. In boys, serum DHEAS, testosterone, 17-OH progesterone and β-HCG levels are useful for the diagnosis of GIPP. In girls, serum DHEAS, estradiol and 17-OH progesterone levels are useful. Diagnostic studies including head MRI and pelvic ultrasound are frequently required in the work-up of children with PP.
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Precocious Puberty
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nord_997_6
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Therapies of Precocious Puberty
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TreatmentThe aims of treatment are to arrest physical maturation, prevent early menarche, bring final adult height closer to genetic expectation and allow normal psychosocial development. Treatment with very potent, long acting GnRH analogues have resulted in significant improvement in height in many, although not all, children with PP caused by both organic conditions and idiopathic CPP, with the best treatment outcomes seen in those with onset of puberty before 6 years of age. These can be given as subcutaneous injections, intra-nasally, and as subcutaneous implants. These GnRH superactive agonists work by first stimulating and then, after a few days, suppressing pulsatile LH and FSH release. This leads to suppression of gonadal steroid production. In general, treatment is required for those who progress rapidly through puberty. The degree of bone age advancement is helpful for determining the tempo of pubertal progression. Those who progress more slowly will likely have the unsustained or slowly progressive variety of precocious puberty and will often do well without intervention. Management of GIPP requires treatment of the underlying disorder. In most cases, this entails removal of the hormone source (i.e. gonadal or adrenal tumor, exogenous hormone etc.); however, for conditions such as McCune-Albright Syndrome (MAS) and familial male-limited precocious puberty, treatment is targeted at blocking the production of and/or the response to sex-steroid hormones. This is primarily achieved through aromatase inhibitors, such as letrozole. The addition of androgen receptor blockers has been helpful in treating FMPP and MAS in boys. Pure estrogen receptor blocker, fulvestrant, is currently being investigated for the treatment of MAS in females with promising results. In 2017, Triptodur was approved by the US Food and Drug Administration (FDA) for pediatric patients ages 2 years and older with central precocious puberty. Triptodur is manufactured by Arbor Pharmaceuticals, Inc.Genetic counseling is recommended for families of patients with genetic forms of precocious puberty.
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Therapies of Precocious Puberty. TreatmentThe aims of treatment are to arrest physical maturation, prevent early menarche, bring final adult height closer to genetic expectation and allow normal psychosocial development. Treatment with very potent, long acting GnRH analogues have resulted in significant improvement in height in many, although not all, children with PP caused by both organic conditions and idiopathic CPP, with the best treatment outcomes seen in those with onset of puberty before 6 years of age. These can be given as subcutaneous injections, intra-nasally, and as subcutaneous implants. These GnRH superactive agonists work by first stimulating and then, after a few days, suppressing pulsatile LH and FSH release. This leads to suppression of gonadal steroid production. In general, treatment is required for those who progress rapidly through puberty. The degree of bone age advancement is helpful for determining the tempo of pubertal progression. Those who progress more slowly will likely have the unsustained or slowly progressive variety of precocious puberty and will often do well without intervention. Management of GIPP requires treatment of the underlying disorder. In most cases, this entails removal of the hormone source (i.e. gonadal or adrenal tumor, exogenous hormone etc.); however, for conditions such as McCune-Albright Syndrome (MAS) and familial male-limited precocious puberty, treatment is targeted at blocking the production of and/or the response to sex-steroid hormones. This is primarily achieved through aromatase inhibitors, such as letrozole. The addition of androgen receptor blockers has been helpful in treating FMPP and MAS in boys. Pure estrogen receptor blocker, fulvestrant, is currently being investigated for the treatment of MAS in females with promising results. In 2017, Triptodur was approved by the US Food and Drug Administration (FDA) for pediatric patients ages 2 years and older with central precocious puberty. Triptodur is manufactured by Arbor Pharmaceuticals, Inc.Genetic counseling is recommended for families of patients with genetic forms of precocious puberty.
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Precocious Puberty
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nord_998_0
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Overview of Primary Biliary Cholangitis
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Primary biliary cholangitis (PBC) is a chronic (e.g.,long lasting), progressive liver disorder that mostly affects women and usually appears during middle age. Approximately 25% of patients with PBC are women younger than 40 years of age, and about 10% of patients are men. PBC leads to inflammation and scarring of the small bile ducts (the ‘plumbing’ system of the liver which transports bile, the substance that helps digest fat). When PBC is very severe, it can lead to yellow discoloration of the skin (jaundice), which occurs when bilirubin levels rise above 2 to 3mg/dL or 34 to 51 µmol/L). If PBC is untreated or there is incomplete response to medical treatment, it can lead to cirrhosis (e.g., scarring of the entire liver), which can lead to liver failure. PBC is divided into four stages from stage 1 (early disease, without significant scarring of the liver) to stage 4 (cirrhosis). Although the exact cause of PBC is unknown, it is thought that it is likely due to a combination of factors such as autoimmune (when a person’s own immune system attacks their body), genetic, and environmental factors.
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Overview of Primary Biliary Cholangitis. Primary biliary cholangitis (PBC) is a chronic (e.g.,long lasting), progressive liver disorder that mostly affects women and usually appears during middle age. Approximately 25% of patients with PBC are women younger than 40 years of age, and about 10% of patients are men. PBC leads to inflammation and scarring of the small bile ducts (the ‘plumbing’ system of the liver which transports bile, the substance that helps digest fat). When PBC is very severe, it can lead to yellow discoloration of the skin (jaundice), which occurs when bilirubin levels rise above 2 to 3mg/dL or 34 to 51 µmol/L). If PBC is untreated or there is incomplete response to medical treatment, it can lead to cirrhosis (e.g., scarring of the entire liver), which can lead to liver failure. PBC is divided into four stages from stage 1 (early disease, without significant scarring of the liver) to stage 4 (cirrhosis). Although the exact cause of PBC is unknown, it is thought that it is likely due to a combination of factors such as autoimmune (when a person’s own immune system attacks their body), genetic, and environmental factors.
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Primary Biliary Cholangitis
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nord_998_1
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Symptoms of Primary Biliary Cholangitis
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The most common symptoms of PBC are:
•Fatigue
•Pruritus (itchiness)
•JaundiceThe cause of fatigue in PBC is unknown and can be very debilitating. Unfortunately, there are no accepted drug treatments for the fatigue in PBC, though research for medicines that can help fatigue is ongoing. Since fatigue is very common, it is important to rule out other causes of fatigue. The fatigue in PBC is not linked to the severity of the liver disease. Patients can have early disease but still have profound fatigue, while others with more advanced disease may have no fatigue at all. The fatigue is also not linked to how quickly the disease will get worse.Like fatigue, the cause of pruritus in PBC is unknown and it is not always linked to the severity of the liver disease. It is likely that the pruritus is caused by substances in the blood, rather than in the skin, unlike pruritus caused by allergies. Fortunately, unlike fatigue, there are a number of drug treatments for pruritus that work for most people (see below under Standard Therapies). As mentioned above, jaundice occurs when PBC is very severe. Sometimes, it can be reversed with treatment of the PBC, but sometimes, patients who have jaundice will require a liver transplant. Jaundice usually happens when the liver is so damaged that the normal function of the liver is impaired. Complications of PBC:
•Portal hypertension (ascites, varices, hepatic encephalopathy)
•Fat malabsorption
•Fat deposits
•Osteoporosis/osteomalaciaPortal hypertension usually occurs after a patient develops cirrhosis. It can lead to fluid build-up in the abdomen (ascites), or big veins (similar to varicose veins) in the esophagus (the structure where food goes when you swallow). It can also lead to confusion (due to a build-up of toxins that are not removed by the liver). Fat malabsorption occurs only when PBC is very advanced, and it is very rare. If it does happen, it will cause diarrhea, oily stool and weight loss. Fat deposits under the skin are more common, as there is a higher amount of cholesterol in the blood of people with PBC. These fat deposits appear as yellow bumps beneath the skin, usually under the eyes or over joints. The high cholesterol levels in PBC are not linked to an increase risk of heart attack, strokes or other complications.Osteoporosis is the most common complication in PBC, though it is also very common in people without PBC. It leads to thinning of the bones and can be treated with medicines for the bones.Other autoimmune diseases can occur more commonly in patients with PBC. Some examples of these other diseases include:•Thyroid disease
•Sjogren’s syndrome: A disease that causes dry eyes and dry mouth
•Celiac disease: A disease that affects the small intestine, causing an allergy to gluten (the proteins in products with wheat, rye, bran)
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Symptoms of Primary Biliary Cholangitis. The most common symptoms of PBC are:
•Fatigue
•Pruritus (itchiness)
•JaundiceThe cause of fatigue in PBC is unknown and can be very debilitating. Unfortunately, there are no accepted drug treatments for the fatigue in PBC, though research for medicines that can help fatigue is ongoing. Since fatigue is very common, it is important to rule out other causes of fatigue. The fatigue in PBC is not linked to the severity of the liver disease. Patients can have early disease but still have profound fatigue, while others with more advanced disease may have no fatigue at all. The fatigue is also not linked to how quickly the disease will get worse.Like fatigue, the cause of pruritus in PBC is unknown and it is not always linked to the severity of the liver disease. It is likely that the pruritus is caused by substances in the blood, rather than in the skin, unlike pruritus caused by allergies. Fortunately, unlike fatigue, there are a number of drug treatments for pruritus that work for most people (see below under Standard Therapies). As mentioned above, jaundice occurs when PBC is very severe. Sometimes, it can be reversed with treatment of the PBC, but sometimes, patients who have jaundice will require a liver transplant. Jaundice usually happens when the liver is so damaged that the normal function of the liver is impaired. Complications of PBC:
•Portal hypertension (ascites, varices, hepatic encephalopathy)
•Fat malabsorption
•Fat deposits
•Osteoporosis/osteomalaciaPortal hypertension usually occurs after a patient develops cirrhosis. It can lead to fluid build-up in the abdomen (ascites), or big veins (similar to varicose veins) in the esophagus (the structure where food goes when you swallow). It can also lead to confusion (due to a build-up of toxins that are not removed by the liver). Fat malabsorption occurs only when PBC is very advanced, and it is very rare. If it does happen, it will cause diarrhea, oily stool and weight loss. Fat deposits under the skin are more common, as there is a higher amount of cholesterol in the blood of people with PBC. These fat deposits appear as yellow bumps beneath the skin, usually under the eyes or over joints. The high cholesterol levels in PBC are not linked to an increase risk of heart attack, strokes or other complications.Osteoporosis is the most common complication in PBC, though it is also very common in people without PBC. It leads to thinning of the bones and can be treated with medicines for the bones.Other autoimmune diseases can occur more commonly in patients with PBC. Some examples of these other diseases include:•Thyroid disease
•Sjogren’s syndrome: A disease that causes dry eyes and dry mouth
•Celiac disease: A disease that affects the small intestine, causing an allergy to gluten (the proteins in products with wheat, rye, bran)
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Primary Biliary Cholangitis
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nord_998_2
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Causes of Primary Biliary Cholangitis
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The exact cause of PBC is unknown. Possible immunological, autoimmune, genetic, and/or environmental factors are under investigation as potential causes.Immunological abnormalities may be an important contributing factor in the development of PBC. The immune system is divided into several components, the combined actions of which are responsible for defending against different infections. The T cell system (cell-mediated immune response) is responsible for fighting yeast and fungi, several viruses, and some bacteria. The B cell system (humoral immune response) fights infection caused by other viruses and bacteria. It does so by secreting immune factors called antibodies (also known as immunoglobulins) into the fluid portion of the blood (serum) and body secretions (e.g., saliva). Individuals with PBC have unusually decreased numbers of circulating T cells in the blood and abnormalities in T cell function and regulation (i.e., helper and suppressor T cells). The role of T cell abnormalities in contributing to the symptoms associated with PBC is unknown.Autoimmunity may also play a contributing role in causing PBC. Autoimmune disorders are caused when the body’s natural defenses against invading microorganisms mistakenly attack healthy tissue. For example, antibodies typically directly kill “invaders” (e.g., microorganisms, toxins, and other foreign substances) or coat them so they are more easily destroyed by white blood cells. (The white blood cells [leukocytes] are part of the body’s system of defenses, playing an essential role in protecting against infection as well as fighting infection once it occurs.) However, in some patients, antibodies may improperly form against certain of the body’s own tissues, causing autoimmune disease.Approximately 95 percent of people with PBC produce antibodies (known as “autoantibodies”) that act upon certain of the body’s own mitochondria (mitochondrial autoantigens, e.g., E2 component of pyruvate dehydrogenase complex [PDC-E2], E2 component of branched chain 2-oxo-acid dehydrogenase complex [BCOADC-E2]). Mitochondria are found by the hundreds within cells in the body and carry the blueprints for making energy. They have their own genetic instructions (mtDNA) and are located outside of the nucleus of the cell (cytoplasm). The role of anti-mitochondrial antibodies in potentially causing the symptoms associated with PBC is not clearly understood.In addition, in some individuals with PBC, specialized laboratory tests conducted on the fluid portion of the blood (serum) have revealed the presence of certain antibodies typically produced in response to certain viruses (e.g., retroviral antigens). Antigens are those substances, such as microorganisms, toxins, or other foreign substances, that may trigger production of particular antibodies as part of an immune response. This suggests that in individuals with PBC, certain antibodies may be mistakenly reacting to one or more of the body’s own proteins that are very similar to protein fragments from certain invading viruses (i.e., the immune system is unable to distinguish between the “mimic” protein on the surface of certain viruses and the body’s own proteins). On the other hand, such findings may provide evidence that PBC may be due, at least in part, to a previous bacterial or viral infection, a finding that has been demonstrated in other autoimmune disorders.Because a number of familial cases of PBC have been reported in the medical literature, it is also suspected that certain genetic factors may play some role in the development of PBC. Environmental or other factors may trigger symptoms in those with a genetic predisposition to the disorder.Further studies are needed to determine the potential role(s) that immunological, autoimmune, genetic, environmental, and/or other factors may play in causing PBC.
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Causes of Primary Biliary Cholangitis. The exact cause of PBC is unknown. Possible immunological, autoimmune, genetic, and/or environmental factors are under investigation as potential causes.Immunological abnormalities may be an important contributing factor in the development of PBC. The immune system is divided into several components, the combined actions of which are responsible for defending against different infections. The T cell system (cell-mediated immune response) is responsible for fighting yeast and fungi, several viruses, and some bacteria. The B cell system (humoral immune response) fights infection caused by other viruses and bacteria. It does so by secreting immune factors called antibodies (also known as immunoglobulins) into the fluid portion of the blood (serum) and body secretions (e.g., saliva). Individuals with PBC have unusually decreased numbers of circulating T cells in the blood and abnormalities in T cell function and regulation (i.e., helper and suppressor T cells). The role of T cell abnormalities in contributing to the symptoms associated with PBC is unknown.Autoimmunity may also play a contributing role in causing PBC. Autoimmune disorders are caused when the body’s natural defenses against invading microorganisms mistakenly attack healthy tissue. For example, antibodies typically directly kill “invaders” (e.g., microorganisms, toxins, and other foreign substances) or coat them so they are more easily destroyed by white blood cells. (The white blood cells [leukocytes] are part of the body’s system of defenses, playing an essential role in protecting against infection as well as fighting infection once it occurs.) However, in some patients, antibodies may improperly form against certain of the body’s own tissues, causing autoimmune disease.Approximately 95 percent of people with PBC produce antibodies (known as “autoantibodies”) that act upon certain of the body’s own mitochondria (mitochondrial autoantigens, e.g., E2 component of pyruvate dehydrogenase complex [PDC-E2], E2 component of branched chain 2-oxo-acid dehydrogenase complex [BCOADC-E2]). Mitochondria are found by the hundreds within cells in the body and carry the blueprints for making energy. They have their own genetic instructions (mtDNA) and are located outside of the nucleus of the cell (cytoplasm). The role of anti-mitochondrial antibodies in potentially causing the symptoms associated with PBC is not clearly understood.In addition, in some individuals with PBC, specialized laboratory tests conducted on the fluid portion of the blood (serum) have revealed the presence of certain antibodies typically produced in response to certain viruses (e.g., retroviral antigens). Antigens are those substances, such as microorganisms, toxins, or other foreign substances, that may trigger production of particular antibodies as part of an immune response. This suggests that in individuals with PBC, certain antibodies may be mistakenly reacting to one or more of the body’s own proteins that are very similar to protein fragments from certain invading viruses (i.e., the immune system is unable to distinguish between the “mimic” protein on the surface of certain viruses and the body’s own proteins). On the other hand, such findings may provide evidence that PBC may be due, at least in part, to a previous bacterial or viral infection, a finding that has been demonstrated in other autoimmune disorders.Because a number of familial cases of PBC have been reported in the medical literature, it is also suspected that certain genetic factors may play some role in the development of PBC. Environmental or other factors may trigger symptoms in those with a genetic predisposition to the disorder.Further studies are needed to determine the potential role(s) that immunological, autoimmune, genetic, environmental, and/or other factors may play in causing PBC.
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Primary Biliary Cholangitis
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Affects of Primary Biliary Cholangitis
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PBC affects mostly women, but more men are now being diagnosed. The disorder usually becomes apparent during middle age, initially affecting most individuals between the ages of 45 to 65 years. However, the disorder has been diagnosed in females as young as 22 years of age and in females in their early 90s. It has been estimated that PBC is one of the most common autoimmune diseases, affecting nearly 1 in 1000 women over the age of 40.
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Affects of Primary Biliary Cholangitis. PBC affects mostly women, but more men are now being diagnosed. The disorder usually becomes apparent during middle age, initially affecting most individuals between the ages of 45 to 65 years. However, the disorder has been diagnosed in females as young as 22 years of age and in females in their early 90s. It has been estimated that PBC is one of the most common autoimmune diseases, affecting nearly 1 in 1000 women over the age of 40.
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Primary Biliary Cholangitis
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Related disorders of Primary Biliary Cholangitis
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Other diseases that may need to be ruled out include the following:Primary sclerosing cholangitis (PSC)
While the names of PBC and PSC are similar, they are very different diseases and should not be confused with one another. Whereas PBC affects the small ducts of the liver, PSC affects the large bile ducts of the liver. This leads to narrowing, inflammation and scarring of the large bile ducts, which may lead to blockage of the bile ducts with symptoms of fever, pain and jaundice (yellow skin). Unlike PBC, jaundice in PSC may occur even when the disease is in early stages, because of a blockage of the large bile duct. As PSC also presents with high alkaline phosphatase (a liver test that indicates damage to the bile ducts), it can sometimes be confused with PBC. If a patient with a high alkaline phosphatase has a negative anti-mitochondrial antibody test, and a biopsy that does not look like PBC, then a test called a magnetic resonance cholangiopancreaticogram (MRCP) should be done. This test is a special type of magnetic resonance imaging (MRI) that looks closely at the bile ducts to determine if they are normal. If the bile ducts look abnormal on MRI, one of the diagnoses to consider is PSC.PSC can also lead to gallstone formation in the bile ducts (not just in the gallbladder), which can also cause blockages leading to fever, pain and jaundice. Sometimes patients need a special test called an endoscopic retrograde pancreaticogram (ERCP) to open up the narrowed bile ducts and/or to remove gallstones from the bile ducts. Patients with PSC may also need antibiotics to treat infection in the bile ducts.Unlike PBC, there is currently no medical treatment that is known to delay or halt the progression of PSC. However, sometimes ursodeoxycholic acid is prescribed in PSC. Importantly, PSC and PBC cannot occur in the same patient at the same time. (For more information on this disorder, choose “PSC” as your search term in the Rare Disease Database.)Autoimmune hepatitis (AIH)
AIH is a type of autoimmune liver disease that sometimes occurs in patients with PBC or PSC. It is a disease that generally affects the liver tissue around the bile ducts, rather than the bile ducts themselves. The diagnosis of AIH usually requires a liver biopsy. The treatment of AIH involves medications that help control the over-active immune system, such as steroids, azathioprine, 6-mercaptopurine, mycophenolate mofetil/sodium, tacrolimus or cyclosporine. (For more information on this disorder, choose “AIH” as your search term in the Rare Disease Database.)Non-alcoholic steatohepatitis (NASH)
NASH is a chronic, slowly progressive disorder characterized by fatty infiltration of the liver (hepatic steatosis), hepatic inflammation (hepatitis), and/or the abnormal formation of scar tissue (fibrosis) within the liver, potentially leading to cirrhosis in some cases. The hepatic inflammation may resemble that associated with alcohol-induced liver disease. Symptoms associated with the disorder may include upper abdominal pain, an enlarged liver (hepatomegaly), and/or abnormally increased levels of certain hepatic enzymes. Although the exact cause of NASH is not understood, the disorder often appears to occur in association with obesity; diabetes; and/or the presence of abnormally high levels of fat in plasma, the fluid portion of blood (hyperlipidemia). In some cases, NASH has also occurred in association with generalized poor health, malnutrition, and weakness due to cancer (cancerous cachexia).
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Related disorders of Primary Biliary Cholangitis. Other diseases that may need to be ruled out include the following:Primary sclerosing cholangitis (PSC)
While the names of PBC and PSC are similar, they are very different diseases and should not be confused with one another. Whereas PBC affects the small ducts of the liver, PSC affects the large bile ducts of the liver. This leads to narrowing, inflammation and scarring of the large bile ducts, which may lead to blockage of the bile ducts with symptoms of fever, pain and jaundice (yellow skin). Unlike PBC, jaundice in PSC may occur even when the disease is in early stages, because of a blockage of the large bile duct. As PSC also presents with high alkaline phosphatase (a liver test that indicates damage to the bile ducts), it can sometimes be confused with PBC. If a patient with a high alkaline phosphatase has a negative anti-mitochondrial antibody test, and a biopsy that does not look like PBC, then a test called a magnetic resonance cholangiopancreaticogram (MRCP) should be done. This test is a special type of magnetic resonance imaging (MRI) that looks closely at the bile ducts to determine if they are normal. If the bile ducts look abnormal on MRI, one of the diagnoses to consider is PSC.PSC can also lead to gallstone formation in the bile ducts (not just in the gallbladder), which can also cause blockages leading to fever, pain and jaundice. Sometimes patients need a special test called an endoscopic retrograde pancreaticogram (ERCP) to open up the narrowed bile ducts and/or to remove gallstones from the bile ducts. Patients with PSC may also need antibiotics to treat infection in the bile ducts.Unlike PBC, there is currently no medical treatment that is known to delay or halt the progression of PSC. However, sometimes ursodeoxycholic acid is prescribed in PSC. Importantly, PSC and PBC cannot occur in the same patient at the same time. (For more information on this disorder, choose “PSC” as your search term in the Rare Disease Database.)Autoimmune hepatitis (AIH)
AIH is a type of autoimmune liver disease that sometimes occurs in patients with PBC or PSC. It is a disease that generally affects the liver tissue around the bile ducts, rather than the bile ducts themselves. The diagnosis of AIH usually requires a liver biopsy. The treatment of AIH involves medications that help control the over-active immune system, such as steroids, azathioprine, 6-mercaptopurine, mycophenolate mofetil/sodium, tacrolimus or cyclosporine. (For more information on this disorder, choose “AIH” as your search term in the Rare Disease Database.)Non-alcoholic steatohepatitis (NASH)
NASH is a chronic, slowly progressive disorder characterized by fatty infiltration of the liver (hepatic steatosis), hepatic inflammation (hepatitis), and/or the abnormal formation of scar tissue (fibrosis) within the liver, potentially leading to cirrhosis in some cases. The hepatic inflammation may resemble that associated with alcohol-induced liver disease. Symptoms associated with the disorder may include upper abdominal pain, an enlarged liver (hepatomegaly), and/or abnormally increased levels of certain hepatic enzymes. Although the exact cause of NASH is not understood, the disorder often appears to occur in association with obesity; diabetes; and/or the presence of abnormally high levels of fat in plasma, the fluid portion of blood (hyperlipidemia). In some cases, NASH has also occurred in association with generalized poor health, malnutrition, and weakness due to cancer (cancerous cachexia).
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Primary Biliary Cholangitis
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Diagnosis of Primary Biliary Cholangitis
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The diagnosis of PBC requires the presence of:
1)High alkaline phosphatase (ALP, a liver blood test) along with
2)Positive anti-mitochondrial antibody (+AMA)If AMA testing is negative, then a patient would need a liver biopsy to confirm the diagnosis of PBC, since a number of diseases can cause a high ALP.
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Diagnosis of Primary Biliary Cholangitis. The diagnosis of PBC requires the presence of:
1)High alkaline phosphatase (ALP, a liver blood test) along with
2)Positive anti-mitochondrial antibody (+AMA)If AMA testing is negative, then a patient would need a liver biopsy to confirm the diagnosis of PBC, since a number of diseases can cause a high ALP.
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Primary Biliary Cholangitis
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Therapies of Primary Biliary Cholangitis
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In 2004, the drug ursodiol (Urso), also known as ursodeoxycholic acid (UDCA), was approved by the US Food and Drug Administration (FDA) for the treatment of PBC. Ursodiol is manufactured by Axan Pharma and Schwarz Pharma US. In 2016, the drug obeticholic acid (Ocaliva) was approved by the FDA for the treatment of PBC in combination with UDCA in adults with inadequate response to UDCA (i.e. lack of significant improvement or normalization of ALP), or as a single therapy in adults unable to tolerate UDCA. Obeticholic acid is manufactured by Intercept Pharmaceuticals Inc. Other treatments for PBC are used to treat symptoms. Pruritus (itching)
The treatment of pruritus requires medications in addition to UDCA, as UDCA doesn’t usually treat the itch in PBC. Cholestyramine or colestipol hydrochloride are usually the first drugs that are tried because they stop itching in many people, and have limited side effects, the most common one being constipation. Other drugs for pruritus include rifampin (an old antibiotic that is no longer used as an antibiotic because there are better antibiotics on the market), gabapentin, sertraline, naltrexone, fibrates. Anti-itch medications such as anti-histamines do not usually work. Very rarely, treatments such as UV therapy and plasmapheresis (an invasive medical procedure that filters the blood) are needed. Sometimes, none of these treatments work and patients require a liver transplant. This is very rarely done. Fat Malabsorption
Malabsorption of fat-soluble vitamins may be treated with vitamin K, A, D, and calcium supplementation. Iron deficiency anemia responds to oral iron supplements. Additional folic acid can be given to individuals taking cholestyramine because this drug can sometimes cause a folic acid deficiency. Folic acid and cholestyramine should be taken several hours apart since they may react and prevent folic acid absorption when taken together. Loss of fat in the stools (steatorrhea) may be treated by a low-fat diet supplemented with medium-chain triglycerides to maintain high caloric intake.Portal hypertension
The treatments for portal hypertension depend on the severity of the complications. For mild ascites, salt restriction may be the only treatment that is needed. When the ascites is severe, it may be necessary to take diuretics (water pills that make patients urinate more in order to decrease the fluid retention) or undergo paracentesis (procedure where fluid is removed). Treatment of varices is either medical (ie. beta blockers to reduce the pressure in the varices) or endoscopic (ie. a very small camera that enters the esophagus and is used for banding, which is a procedure that shrinks the varices). Hepatic encephalopathy can be treated with a specific laxative called lactulose, or rifaximin, a non-absorbable antibiotic.
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Therapies of Primary Biliary Cholangitis. In 2004, the drug ursodiol (Urso), also known as ursodeoxycholic acid (UDCA), was approved by the US Food and Drug Administration (FDA) for the treatment of PBC. Ursodiol is manufactured by Axan Pharma and Schwarz Pharma US. In 2016, the drug obeticholic acid (Ocaliva) was approved by the FDA for the treatment of PBC in combination with UDCA in adults with inadequate response to UDCA (i.e. lack of significant improvement or normalization of ALP), or as a single therapy in adults unable to tolerate UDCA. Obeticholic acid is manufactured by Intercept Pharmaceuticals Inc. Other treatments for PBC are used to treat symptoms. Pruritus (itching)
The treatment of pruritus requires medications in addition to UDCA, as UDCA doesn’t usually treat the itch in PBC. Cholestyramine or colestipol hydrochloride are usually the first drugs that are tried because they stop itching in many people, and have limited side effects, the most common one being constipation. Other drugs for pruritus include rifampin (an old antibiotic that is no longer used as an antibiotic because there are better antibiotics on the market), gabapentin, sertraline, naltrexone, fibrates. Anti-itch medications such as anti-histamines do not usually work. Very rarely, treatments such as UV therapy and plasmapheresis (an invasive medical procedure that filters the blood) are needed. Sometimes, none of these treatments work and patients require a liver transplant. This is very rarely done. Fat Malabsorption
Malabsorption of fat-soluble vitamins may be treated with vitamin K, A, D, and calcium supplementation. Iron deficiency anemia responds to oral iron supplements. Additional folic acid can be given to individuals taking cholestyramine because this drug can sometimes cause a folic acid deficiency. Folic acid and cholestyramine should be taken several hours apart since they may react and prevent folic acid absorption when taken together. Loss of fat in the stools (steatorrhea) may be treated by a low-fat diet supplemented with medium-chain triglycerides to maintain high caloric intake.Portal hypertension
The treatments for portal hypertension depend on the severity of the complications. For mild ascites, salt restriction may be the only treatment that is needed. When the ascites is severe, it may be necessary to take diuretics (water pills that make patients urinate more in order to decrease the fluid retention) or undergo paracentesis (procedure where fluid is removed). Treatment of varices is either medical (ie. beta blockers to reduce the pressure in the varices) or endoscopic (ie. a very small camera that enters the esophagus and is used for banding, which is a procedure that shrinks the varices). Hepatic encephalopathy can be treated with a specific laxative called lactulose, or rifaximin, a non-absorbable antibiotic.
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Primary Biliary Cholangitis
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Overview of Primary Central Nervous System Lymphoma
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SummaryA primary central nervous system lymphoma (PCNSL) is a type of cancer originating from immune cells known as lymphocytes (lymphoma) that develops in the brain and/or spinal cord (central nervous system; CNS). Around 1,500 patients are diagnosed each year in the United States. Older individuals and those with an impaired immune system (immunocompromised), especially those living with HIV/AIDS, are at an increased risk of developing a primary CNS lymphoma. PCNSL is an AIDS-defining illness, meaning that a HIV-positive individual with a PCNSL will be considered to have AIDS. The symptoms of PCNSL are similar to those of other brain tumors and can include arm and leg weakness, cognitive and behavioral changes, brain swelling, language deficits, and vision changes. Chemotherapy, notably with high-dose methotrexate (HD-MTX) is the main treatment modality for PCNSL and might be combined with radiation therapy in certain cases. Corticosteroids are also often used as an adjunct treatment.
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Overview of Primary Central Nervous System Lymphoma. SummaryA primary central nervous system lymphoma (PCNSL) is a type of cancer originating from immune cells known as lymphocytes (lymphoma) that develops in the brain and/or spinal cord (central nervous system; CNS). Around 1,500 patients are diagnosed each year in the United States. Older individuals and those with an impaired immune system (immunocompromised), especially those living with HIV/AIDS, are at an increased risk of developing a primary CNS lymphoma. PCNSL is an AIDS-defining illness, meaning that a HIV-positive individual with a PCNSL will be considered to have AIDS. The symptoms of PCNSL are similar to those of other brain tumors and can include arm and leg weakness, cognitive and behavioral changes, brain swelling, language deficits, and vision changes. Chemotherapy, notably with high-dose methotrexate (HD-MTX) is the main treatment modality for PCNSL and might be combined with radiation therapy in certain cases. Corticosteroids are also often used as an adjunct treatment.
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Primary Central Nervous System Lymphoma
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Symptoms of Primary Central Nervous System Lymphoma
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The potential symptoms of primary CNS lymphoma are varied and mostly depend on the anatomical location of the tumor. Symptoms typically develop over weeks (subacute). Most patients present with focal neurological deficits such as asymmetric upper and/or lower extremity weakness or impaired movement (paresis). Many patients also develop neurocognitive deficits, especially in the case of AIDS-related PCNSL. Personality, language, and behavioral changes can also occur. Bladder and bowel dysfunction can develop and lead to incontinence. Pressure from the mass and fluid that surrounds it (edema) can lead to brain swelling and increased pressure inside the skull (intracranial pressure), which is associated with symptoms such as headaches, vomiting (emesis), and vision changes (papilledema). Seizures can occur and are more common in patients with AIDS-related PCNSL. If specific structures within the brain (such as the pituitary gland and hypothalamus) are damaged, PCNSL can be associated with excessive eating (hyperphagia), decreased libido (hyposexuality), central diabetes insipidus, and syndrome of inappropriate antidiuretic hormone secretion (which leads to a decreased concentration of sodium in the blood, a condition known as hyponatremia). (For more information on central diabetes insipidus, choose “central diabetes insipidus” as your search term in the Rare Disease Database.)Involvement of the brainstem, which connects the brain and the spinal cord, can lead to gait imbalance (ataxia), vertigo, impairment of eye movements (dysconjugate gaze), and intractable vomiting.Spinal cord involvement is rare in PCNSL. When the spinal cord is compressed and damaged (myelopathy) by a mass, affected individuals can experience weakness, loss of sensation, and bladder and bowel dysfunction. Other structures that can be compromised by a primary CNS lymphoma include the coverings of the brain (meninges) and the peripheral and cranial nerves (neurolymphomatosis). The latter can lead to nerve pain and deficits specific to the function of the cranial nerve affected (for instance, face droop if the facial nerve is affected).As primary CNS lymphomas are malignant tumors, they can spread to other sites of the body. Eye (ocular) involvement is present in 20 to 40% of patients at presentation and in almost all patients later in the course of the disease. Blurry vision and floaters are the most common visual symptoms. Systemic dissemination is rare but can notably affect the prostate, the skin, and the gastrointestinal tract. Systemic spread of a PCNSL can lead to weight loss, fever, and night sweats. Those symptoms are known as constitutional or B symptoms and are present in most patients with AIDS-related PCNSL even in the absence of systemic spread.Primary CNS lymphoma most commonly occurs in individuals around age 60, but rare cases have also been described in children. AIDS-related PCNSL tends to develop around age 45 and is typically more aggressive. With proper treatment, primary CNS lymphoma regresses in around 85% of patients. However, relapse occurs in 50% of cases, most often within two years. The average survival after a diagnosis of PCNSL is 44 months. Overall, 30% of affected individuals survive more than five years after diagnosis, and long-term survival is achieved in 15 to 20% of patients. Age under 60 years and high level of autonomy and functioning are associated with increased survival, while HIV infection and involvement of deep regions of the brain are associated with lower survival. Elevated blood levels of lactate dehydrogenase (LDH) and elevated protein concentration in the cerebrospinal fluid, both of which are usually measured during diagnostic workup, are also associated with lower survival.
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Symptoms of Primary Central Nervous System Lymphoma. The potential symptoms of primary CNS lymphoma are varied and mostly depend on the anatomical location of the tumor. Symptoms typically develop over weeks (subacute). Most patients present with focal neurological deficits such as asymmetric upper and/or lower extremity weakness or impaired movement (paresis). Many patients also develop neurocognitive deficits, especially in the case of AIDS-related PCNSL. Personality, language, and behavioral changes can also occur. Bladder and bowel dysfunction can develop and lead to incontinence. Pressure from the mass and fluid that surrounds it (edema) can lead to brain swelling and increased pressure inside the skull (intracranial pressure), which is associated with symptoms such as headaches, vomiting (emesis), and vision changes (papilledema). Seizures can occur and are more common in patients with AIDS-related PCNSL. If specific structures within the brain (such as the pituitary gland and hypothalamus) are damaged, PCNSL can be associated with excessive eating (hyperphagia), decreased libido (hyposexuality), central diabetes insipidus, and syndrome of inappropriate antidiuretic hormone secretion (which leads to a decreased concentration of sodium in the blood, a condition known as hyponatremia). (For more information on central diabetes insipidus, choose “central diabetes insipidus” as your search term in the Rare Disease Database.)Involvement of the brainstem, which connects the brain and the spinal cord, can lead to gait imbalance (ataxia), vertigo, impairment of eye movements (dysconjugate gaze), and intractable vomiting.Spinal cord involvement is rare in PCNSL. When the spinal cord is compressed and damaged (myelopathy) by a mass, affected individuals can experience weakness, loss of sensation, and bladder and bowel dysfunction. Other structures that can be compromised by a primary CNS lymphoma include the coverings of the brain (meninges) and the peripheral and cranial nerves (neurolymphomatosis). The latter can lead to nerve pain and deficits specific to the function of the cranial nerve affected (for instance, face droop if the facial nerve is affected).As primary CNS lymphomas are malignant tumors, they can spread to other sites of the body. Eye (ocular) involvement is present in 20 to 40% of patients at presentation and in almost all patients later in the course of the disease. Blurry vision and floaters are the most common visual symptoms. Systemic dissemination is rare but can notably affect the prostate, the skin, and the gastrointestinal tract. Systemic spread of a PCNSL can lead to weight loss, fever, and night sweats. Those symptoms are known as constitutional or B symptoms and are present in most patients with AIDS-related PCNSL even in the absence of systemic spread.Primary CNS lymphoma most commonly occurs in individuals around age 60, but rare cases have also been described in children. AIDS-related PCNSL tends to develop around age 45 and is typically more aggressive. With proper treatment, primary CNS lymphoma regresses in around 85% of patients. However, relapse occurs in 50% of cases, most often within two years. The average survival after a diagnosis of PCNSL is 44 months. Overall, 30% of affected individuals survive more than five years after diagnosis, and long-term survival is achieved in 15 to 20% of patients. Age under 60 years and high level of autonomy and functioning are associated with increased survival, while HIV infection and involvement of deep regions of the brain are associated with lower survival. Elevated blood levels of lactate dehydrogenase (LDH) and elevated protein concentration in the cerebrospinal fluid, both of which are usually measured during diagnostic workup, are also associated with lower survival.
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Primary Central Nervous System Lymphoma
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Causes of Primary Central Nervous System Lymphoma
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Primary CNS lymphomas most often develop from the uncontrolled proliferation of cells derived from B lymphocytes (also known as B cells), which are a type of immune cell. More rarely, PCNSL can also develop from T lymphocytes (also known as T cells), but our understanding of prognosis and therapies for PCNSL is based on patients who specifically have primary diffuse large B-cell lymphoma of the CNS. The exact mechanism by which malignant lymphocytes invade the brain is not understood yet, but two main hypotheses prevail: lymphocytes might be drawn to the CNS and then replicate and lead to a malignant tumor. Alternatively, already malignant lymphocytes might be drawn to the CNS via the expression of specific adhesion molecules that mediate traffic to the brain. Several molecular processes are thought to be involved in the malignant transformation of cells of primary CNS lymphomas. These processes lead to uncontrolled cell proliferation and avoidance of destruction of malignant cells, notably by evasion of the immune system (which would normally destroy abnormal cells). Gain and loss of genetic material is also involved in the development of primary CNS lymphoma. The net result of these genetic changes is to allow malignant cells to escape from regulation of the immune system and to proliferate, notably via amplification of a molecular pathway known as NF-κB. Silencing of tumor suppressor genes is also one of the mechanisms by which PCNSL develops.In addition to the malignant cells themselves, the environment in which the tumor grows might also play a role in PCNSL development. The vasculature of the brain might be involved, as PCNSL cells tend to accumulate around blood vessels. Evidence also shows that the tumor cells and surrounding cells secrete B cell surviving factors (notably interleukin-4) and promote a local inflammatory response.A feature of primary CNS lymphoma that is mostly identified in immunocompromised individuals (such as those living with HIV/AIDS) is the presence of genetic material of the Epstein-Barr virus (EBV; which is the virus involved in most cases of infectious mononucleosis). EBV infection is thought to lead to malignancy by the excessive activation of human cell growth factors, activation of viral cell growth factors, and chronic stimulation of the immune system.
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Causes of Primary Central Nervous System Lymphoma. Primary CNS lymphomas most often develop from the uncontrolled proliferation of cells derived from B lymphocytes (also known as B cells), which are a type of immune cell. More rarely, PCNSL can also develop from T lymphocytes (also known as T cells), but our understanding of prognosis and therapies for PCNSL is based on patients who specifically have primary diffuse large B-cell lymphoma of the CNS. The exact mechanism by which malignant lymphocytes invade the brain is not understood yet, but two main hypotheses prevail: lymphocytes might be drawn to the CNS and then replicate and lead to a malignant tumor. Alternatively, already malignant lymphocytes might be drawn to the CNS via the expression of specific adhesion molecules that mediate traffic to the brain. Several molecular processes are thought to be involved in the malignant transformation of cells of primary CNS lymphomas. These processes lead to uncontrolled cell proliferation and avoidance of destruction of malignant cells, notably by evasion of the immune system (which would normally destroy abnormal cells). Gain and loss of genetic material is also involved in the development of primary CNS lymphoma. The net result of these genetic changes is to allow malignant cells to escape from regulation of the immune system and to proliferate, notably via amplification of a molecular pathway known as NF-κB. Silencing of tumor suppressor genes is also one of the mechanisms by which PCNSL develops.In addition to the malignant cells themselves, the environment in which the tumor grows might also play a role in PCNSL development. The vasculature of the brain might be involved, as PCNSL cells tend to accumulate around blood vessels. Evidence also shows that the tumor cells and surrounding cells secrete B cell surviving factors (notably interleukin-4) and promote a local inflammatory response.A feature of primary CNS lymphoma that is mostly identified in immunocompromised individuals (such as those living with HIV/AIDS) is the presence of genetic material of the Epstein-Barr virus (EBV; which is the virus involved in most cases of infectious mononucleosis). EBV infection is thought to lead to malignancy by the excessive activation of human cell growth factors, activation of viral cell growth factors, and chronic stimulation of the immune system.
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Primary Central Nervous System Lymphoma
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Affects of Primary Central Nervous System Lymphoma
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Primary central nervous system lymphoma constitutes 4% of all brain tumors and develops in around five individuals per million each year, for a total of approximately 1,500 new cases per year in the United States. PCNSL is slightly more common in males. The most common risk factor for the development of a primary CNS lymphoma is an impaired immune system (immunosuppression). This is notably the case of patients living with HIV/ AIDS, especially those who are not treated who have a high viral load and low CD4+ cell count. Other immunosuppressed groups include organ transplant recipients and individuals with congenital immunodeficiency syndromes. In fact, primary CNS lymphoma is the most common brain tumor in immunosuppressed patients. The other main risk factor for developing a PCNSL is age. Most immunocompetent patients are diagnosed around age 60, although cases of PCNSL have also been reported in children. AIDS-related PCNSL most often develop during the fifth decade of life (age 40-49).
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Affects of Primary Central Nervous System Lymphoma. Primary central nervous system lymphoma constitutes 4% of all brain tumors and develops in around five individuals per million each year, for a total of approximately 1,500 new cases per year in the United States. PCNSL is slightly more common in males. The most common risk factor for the development of a primary CNS lymphoma is an impaired immune system (immunosuppression). This is notably the case of patients living with HIV/ AIDS, especially those who are not treated who have a high viral load and low CD4+ cell count. Other immunosuppressed groups include organ transplant recipients and individuals with congenital immunodeficiency syndromes. In fact, primary CNS lymphoma is the most common brain tumor in immunosuppressed patients. The other main risk factor for developing a PCNSL is age. Most immunocompetent patients are diagnosed around age 60, although cases of PCNSL have also been reported in children. AIDS-related PCNSL most often develop during the fifth decade of life (age 40-49).
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Primary Central Nervous System Lymphoma
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Related disorders of Primary Central Nervous System Lymphoma
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Symptoms of the following disorders can be similar to those of primary central nervous system lymphoma. Comparisons may be useful for a differential diagnosis:Toxoplasmosis is a disease caused by infection by a parasite known as Toxoplasma gondii. Most infected individuals have no symptoms (asymptomatic). In severely immunosuppressed individuals, particularly those with AIDS, cerebral toxoplasmosis can develop and lead to inflammation of the brain (encephalitis). Symptoms of toxoplasmic encephalitis notably include headache, fever, confusion, drowsiness, weakness, and seizures. Cerebral toxoplasmosis is the most common brain lesion in AIDS patients. Other types of brain tumors have symptoms similar to primary CNS lymphoma. They are classified according to their origin. Examples include gliomas, meningiomas, medulloblastomas, and brain metastases, which are more common than tumors arising in the brain (primary brain tumors) and come from cancers elsewhere in the body, including the lungs, breasts, and gastrointestinal tract (For more information on a specific kind of brain tumor, choose the name of the tumor as your search term in the Rare Disease Database).Intracranial abscesses can also lead to neurological symptoms similar to those present in a primary CNS lymphoma. Causes of brain abscesses are multiple and include bacterial meningitis, fungal and parasitic infections (cryptococcosis and cysticercosis, respectively), infection of a blood clot in the brain (septic cerebral embolus), and inflammation of the brain (encephalitis). In addition to primary CNS lymphoma, other types of systemic non-Hodgkin lymphoma can invade the brain and cause neurologic symptoms. Lymphomas are divided into the Hodgkin and non-Hodgkin types; the latter being divided in several subtypes such as diffuse large B cell lymphoma, follicular lymphoma, and mantle cell lymphoma.
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Related disorders of Primary Central Nervous System Lymphoma. Symptoms of the following disorders can be similar to those of primary central nervous system lymphoma. Comparisons may be useful for a differential diagnosis:Toxoplasmosis is a disease caused by infection by a parasite known as Toxoplasma gondii. Most infected individuals have no symptoms (asymptomatic). In severely immunosuppressed individuals, particularly those with AIDS, cerebral toxoplasmosis can develop and lead to inflammation of the brain (encephalitis). Symptoms of toxoplasmic encephalitis notably include headache, fever, confusion, drowsiness, weakness, and seizures. Cerebral toxoplasmosis is the most common brain lesion in AIDS patients. Other types of brain tumors have symptoms similar to primary CNS lymphoma. They are classified according to their origin. Examples include gliomas, meningiomas, medulloblastomas, and brain metastases, which are more common than tumors arising in the brain (primary brain tumors) and come from cancers elsewhere in the body, including the lungs, breasts, and gastrointestinal tract (For more information on a specific kind of brain tumor, choose the name of the tumor as your search term in the Rare Disease Database).Intracranial abscesses can also lead to neurological symptoms similar to those present in a primary CNS lymphoma. Causes of brain abscesses are multiple and include bacterial meningitis, fungal and parasitic infections (cryptococcosis and cysticercosis, respectively), infection of a blood clot in the brain (septic cerebral embolus), and inflammation of the brain (encephalitis). In addition to primary CNS lymphoma, other types of systemic non-Hodgkin lymphoma can invade the brain and cause neurologic symptoms. Lymphomas are divided into the Hodgkin and non-Hodgkin types; the latter being divided in several subtypes such as diffuse large B cell lymphoma, follicular lymphoma, and mantle cell lymphoma.
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Diagnosis of Primary Central Nervous System Lymphoma
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The diagnosis of primary CNS lymphoma is complex and requires a combination of patient history, physical examination, laboratory testing, medical imaging, as well as microscopic, cellular and genetic (cytogenetic) analysis of the tumor cells. Initially, history from the patient and a physical examination performed by a physician might identify signs and symptoms that are suggestive of a brain lesion (see “Signs & Symptoms” section for more detail). If such signs and symptoms are identified, medical imaging of the brain will be performed, notably by computed tomography (CT) scan or magnetic resonance imaging (MRI). Imaging of the spine can also be performed if the symptoms suggest spinal involvement. While medical imaging can lead to suspicion of a primary CNS lymphoma, definitive diagnosis is only possible by analysis of the cells of the tumor. A lumbar puncture, which is a procedure where a needle is placed in the spinal column of the patient to collect cerebrospinal fluid (CSF), is typically performed to look for the presence of tumor cells. Fluid from the eye (vitreous fluid) can also be collected for the same reason. If tumor cells are not identified in these fluids, a neurosurgeon will have to perform a brain biopsy to extract a piece of the lesion. Once tumor cells are obtained, they can be analyzed in multiple ways to confirm the diagnosis of primary CNS lymphoma. Flow cytometry is a laboratory method that allows identification of cells based on their size, shape, and the presence of specific markers. Immunohistochemistry can complement microscopic analysis by staining cells based on their origin. The DNA of tumor cells can also be analyzed to identify the presence of specific alterations (mutations).The diagnosis of primary CNS lymphoma is usually followed by an extensive workup to evaluate the severity and spread of the disease. Patients are usually tested for HIV due the association between HIV infection and PCNSL. A full eye examination with a slit lamp is performed to see if there is eye (ocular) involvement, as this can occur even in the absence of visual symptoms. The level of protein in CSF and of lactate dehydrogenase (LDH) in the blood can be measured and are markers of aggressive disease when they are elevated. The CSF can also be tested for the presence of Epstein-Barr virus, which is associated with PCNSL in immunocompromised individuals. A full body CT or PET scan, a testicular ultrasound (in male patients) and a bone marrow biopsy are also part of the diagnostic workup and are useful to determine if other organs are involved. If a patient is found to have lymphoma outside of the brain, spinal cord, spinal fluid or eyes, then they will be diagnosed with a systemic lymphoma and the brain involvement is considered a secondary CNS lymphoma. Many other general tests are also typically performed to evaluate the baseline health of the patient and to determine the best treatment options. These tests might include blood tests to look for blood cells (complete blood count) and level of different electrolytes (biochemical serum profile), cognitive function test, renal function test, liver (hepatic) function tests, and cardiac function tests.
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Diagnosis of Primary Central Nervous System Lymphoma. The diagnosis of primary CNS lymphoma is complex and requires a combination of patient history, physical examination, laboratory testing, medical imaging, as well as microscopic, cellular and genetic (cytogenetic) analysis of the tumor cells. Initially, history from the patient and a physical examination performed by a physician might identify signs and symptoms that are suggestive of a brain lesion (see “Signs & Symptoms” section for more detail). If such signs and symptoms are identified, medical imaging of the brain will be performed, notably by computed tomography (CT) scan or magnetic resonance imaging (MRI). Imaging of the spine can also be performed if the symptoms suggest spinal involvement. While medical imaging can lead to suspicion of a primary CNS lymphoma, definitive diagnosis is only possible by analysis of the cells of the tumor. A lumbar puncture, which is a procedure where a needle is placed in the spinal column of the patient to collect cerebrospinal fluid (CSF), is typically performed to look for the presence of tumor cells. Fluid from the eye (vitreous fluid) can also be collected for the same reason. If tumor cells are not identified in these fluids, a neurosurgeon will have to perform a brain biopsy to extract a piece of the lesion. Once tumor cells are obtained, they can be analyzed in multiple ways to confirm the diagnosis of primary CNS lymphoma. Flow cytometry is a laboratory method that allows identification of cells based on their size, shape, and the presence of specific markers. Immunohistochemistry can complement microscopic analysis by staining cells based on their origin. The DNA of tumor cells can also be analyzed to identify the presence of specific alterations (mutations).The diagnosis of primary CNS lymphoma is usually followed by an extensive workup to evaluate the severity and spread of the disease. Patients are usually tested for HIV due the association between HIV infection and PCNSL. A full eye examination with a slit lamp is performed to see if there is eye (ocular) involvement, as this can occur even in the absence of visual symptoms. The level of protein in CSF and of lactate dehydrogenase (LDH) in the blood can be measured and are markers of aggressive disease when they are elevated. The CSF can also be tested for the presence of Epstein-Barr virus, which is associated with PCNSL in immunocompromised individuals. A full body CT or PET scan, a testicular ultrasound (in male patients) and a bone marrow biopsy are also part of the diagnostic workup and are useful to determine if other organs are involved. If a patient is found to have lymphoma outside of the brain, spinal cord, spinal fluid or eyes, then they will be diagnosed with a systemic lymphoma and the brain involvement is considered a secondary CNS lymphoma. Many other general tests are also typically performed to evaluate the baseline health of the patient and to determine the best treatment options. These tests might include blood tests to look for blood cells (complete blood count) and level of different electrolytes (biochemical serum profile), cognitive function test, renal function test, liver (hepatic) function tests, and cardiac function tests.
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Therapies of Primary Central Nervous System Lymphoma
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Treatment & Management
Unlike most other brain tumors, surgery is typically avoided in primary central nervous system lymphoma. The mainstay of treatment is based on chemotherapy, notably with high-dose methotrexate (HD-MTX). Leucovorin (folinic acid) is often added to prevent systemic and bone marrow toxicity from MTX. Depending on the patient, HD-MTX can be combined with other chemotherapeutic drugs such as alkylating agents, cytarabine, and rituximab. Chemotherapy regimens also vary depending on the center where the patient is treated, as many experimental treatments are being investigated. In certain cases, whole-brain radiation can be performed but is used with caution due to an association with increased neurocognitive deficits, especially in elderly patients. Corticosteroids such as dexamethasone can be used to decrease fluid accumulation (edema) around the tumor but are usually only administered after definitive diagnosis as they can decrease diagnostic accuracy by altering the tumor. Anticonvulsants are used for patients that develop seizures. Highly active antiretroviral therapy (HAART) should be initiated or optimized in HIV-positive patients. Treatment of Epstein-Barr virus (EBV) with ganciclovir or zidovudine might be beneficial, although this as yet to be confirmed and clinical trials are needed.The treatment of relapsing primary CNS lymphoma is based on the characteristics of the patients and on the response of previous treatment. Whole-brain radiation can be considered in patients that have not previously received such treatment. High-dose chemotherapy can also be combined with autologous stem cell transplant, especially in younger patients. Autologous stem cell transplant is a medical procedure where healthy stem cells from a person’s own body are used to replace bone marrow cells damaged by chemotherapy.
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Therapies of Primary Central Nervous System Lymphoma. Treatment & Management
Unlike most other brain tumors, surgery is typically avoided in primary central nervous system lymphoma. The mainstay of treatment is based on chemotherapy, notably with high-dose methotrexate (HD-MTX). Leucovorin (folinic acid) is often added to prevent systemic and bone marrow toxicity from MTX. Depending on the patient, HD-MTX can be combined with other chemotherapeutic drugs such as alkylating agents, cytarabine, and rituximab. Chemotherapy regimens also vary depending on the center where the patient is treated, as many experimental treatments are being investigated. In certain cases, whole-brain radiation can be performed but is used with caution due to an association with increased neurocognitive deficits, especially in elderly patients. Corticosteroids such as dexamethasone can be used to decrease fluid accumulation (edema) around the tumor but are usually only administered after definitive diagnosis as they can decrease diagnostic accuracy by altering the tumor. Anticonvulsants are used for patients that develop seizures. Highly active antiretroviral therapy (HAART) should be initiated or optimized in HIV-positive patients. Treatment of Epstein-Barr virus (EBV) with ganciclovir or zidovudine might be beneficial, although this as yet to be confirmed and clinical trials are needed.The treatment of relapsing primary CNS lymphoma is based on the characteristics of the patients and on the response of previous treatment. Whole-brain radiation can be considered in patients that have not previously received such treatment. High-dose chemotherapy can also be combined with autologous stem cell transplant, especially in younger patients. Autologous stem cell transplant is a medical procedure where healthy stem cells from a person’s own body are used to replace bone marrow cells damaged by chemotherapy.
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