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nord_442_6 | Therapies of Familial Encephalopathy with Neuroserpin Inclusion Bodies | Treatment
The treatment of FENIB is directed toward the specific symptoms that are apparent in each individual. Individuals with progressive dementia often experience frustration, anxiety, and depression due to their decreasing ability to function in certain aspects of their lives. These frustrations may be minimized by maintaining a stable home environment and a structured routine that does not place excessive demands on the affected individual.Eventually, most individuals with FENIB require comprehensive medical care as provided in a nursing home. Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive. | Therapies of Familial Encephalopathy with Neuroserpin Inclusion Bodies. Treatment
The treatment of FENIB is directed toward the specific symptoms that are apparent in each individual. Individuals with progressive dementia often experience frustration, anxiety, and depression due to their decreasing ability to function in certain aspects of their lives. These frustrations may be minimized by maintaining a stable home environment and a structured routine that does not place excessive demands on the affected individual.Eventually, most individuals with FENIB require comprehensive medical care as provided in a nursing home. Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive. | 442 | Familial Encephalopathy with Neuroserpin Inclusion Bodies |
nord_443_0 | Overview of Familial Eosinophilic Cellulitis | Familial eosinophilic cellulitis is a rare skin disorder. It is characterized by raised, red, swollen, and warm areas of skin, in a flame-shaped pattern with associated pain. The exact cause of the disease is unknown. However, bites of spiders, bees, mites, fleas, or ticks (arthropods) are often associated with this skin condition. | Overview of Familial Eosinophilic Cellulitis. Familial eosinophilic cellulitis is a rare skin disorder. It is characterized by raised, red, swollen, and warm areas of skin, in a flame-shaped pattern with associated pain. The exact cause of the disease is unknown. However, bites of spiders, bees, mites, fleas, or ticks (arthropods) are often associated with this skin condition. | 443 | Familial Eosinophilic Cellulitis |
nord_443_1 | Symptoms of Familial Eosinophilic Cellulitis | Familial eosinophilic cellulitis is a rare skin disorder. It sometimes occurs as an exaggerated response to bites of spiders, bees, fleas, ticks, or mites (arthropods), or it may have other causes such as surgery or drugs. The skin of the person will develop flame shaped patterns of raised, swollen, red areas that are warm to the touch. The episodes usually come on rapidly. Often, familial eosinophilic cellulitis will recur suddenly over a period of years with swelling and redness developing for no apparent reason. The attack may last up to six weeks and may continue to recur for years.Large areas of skin may be affected and testing shows microscopic changes of the tissue. An abnormal number of white blood cells (eosinophils) are found in the red and swollen areas of skin, underlying fat, and usually in the blood. Skin blistering has also been known to develop. | Symptoms of Familial Eosinophilic Cellulitis. Familial eosinophilic cellulitis is a rare skin disorder. It sometimes occurs as an exaggerated response to bites of spiders, bees, fleas, ticks, or mites (arthropods), or it may have other causes such as surgery or drugs. The skin of the person will develop flame shaped patterns of raised, swollen, red areas that are warm to the touch. The episodes usually come on rapidly. Often, familial eosinophilic cellulitis will recur suddenly over a period of years with swelling and redness developing for no apparent reason. The attack may last up to six weeks and may continue to recur for years.Large areas of skin may be affected and testing shows microscopic changes of the tissue. An abnormal number of white blood cells (eosinophils) are found in the red and swollen areas of skin, underlying fat, and usually in the blood. Skin blistering has also been known to develop. | 443 | Familial Eosinophilic Cellulitis |
nord_443_2 | Causes of Familial Eosinophilic Cellulitis | The exact cause of familial eosinophilic cellulitis is still not known. Some scientists believe that there may be an autoimmune basis for the disorder. Autoimmune disorders are caused when the body's natural defenses (antibodies, lymphocytes, etc.), against invading organisms suddenly begin to attack perfectly healthy tissue. | Causes of Familial Eosinophilic Cellulitis. The exact cause of familial eosinophilic cellulitis is still not known. Some scientists believe that there may be an autoimmune basis for the disorder. Autoimmune disorders are caused when the body's natural defenses (antibodies, lymphocytes, etc.), against invading organisms suddenly begin to attack perfectly healthy tissue. | 443 | Familial Eosinophilic Cellulitis |
nord_443_3 | Affects of Familial Eosinophilic Cellulitis | Familial eosinophilic cellulitis affects males and females in equal numbers. The disorder is more often found in adults, but it may strike children as well. | Affects of Familial Eosinophilic Cellulitis. Familial eosinophilic cellulitis affects males and females in equal numbers. The disorder is more often found in adults, but it may strike children as well. | 443 | Familial Eosinophilic Cellulitis |
nord_443_4 | Related disorders of Familial Eosinophilic Cellulitis | Symptoms of the following disorders can be similar to those of familial eosinophilic cellulitis. Comparisons may be useful for a differential diagnosis:Cellulitis is characterized by inflamed tissue of the skin. Often the skin becomes red, swollen, and painful, over a large area. There may be accompanying chills and fever. This disorder can be caused by either Group A beta-hemolytic streptococci, or in older persons it is sometimes caused by Group G streptococci.Anaphylaxis is an extreme allergic reaction that can be caused by a person's hypersensitivity to drugs, insect venom, fish, nuts, and other substances. There is often extreme swelling, itching, flushing, hives, and other physical reactions to a particular substance. These reactions can often be life-threatening. (For more information on this disorder, choose “Anaphylaxis” as your search term in the Rare Disease Database.)Contact dermatitis is a common allergic disorder characterized by skin inflammation and blisters. Redness, swelling, oozing, crusting, scaling, burning pain and usually itching are common. (For more information on this disorder choose “Contact Dermatitis” as your search term in the Rare Disease Database.) | Related disorders of Familial Eosinophilic Cellulitis. Symptoms of the following disorders can be similar to those of familial eosinophilic cellulitis. Comparisons may be useful for a differential diagnosis:Cellulitis is characterized by inflamed tissue of the skin. Often the skin becomes red, swollen, and painful, over a large area. There may be accompanying chills and fever. This disorder can be caused by either Group A beta-hemolytic streptococci, or in older persons it is sometimes caused by Group G streptococci.Anaphylaxis is an extreme allergic reaction that can be caused by a person's hypersensitivity to drugs, insect venom, fish, nuts, and other substances. There is often extreme swelling, itching, flushing, hives, and other physical reactions to a particular substance. These reactions can often be life-threatening. (For more information on this disorder, choose “Anaphylaxis” as your search term in the Rare Disease Database.)Contact dermatitis is a common allergic disorder characterized by skin inflammation and blisters. Redness, swelling, oozing, crusting, scaling, burning pain and usually itching are common. (For more information on this disorder choose “Contact Dermatitis” as your search term in the Rare Disease Database.) | 443 | Familial Eosinophilic Cellulitis |
nord_443_5 | Diagnosis of Familial Eosinophilic Cellulitis | Diagnosis of Familial Eosinophilic Cellulitis. | 443 | Familial Eosinophilic Cellulitis |
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nord_443_6 | Therapies of Familial Eosinophilic Cellulitis | Standard treatment of familial eosinophilic cellulitis may consist of administration of steroid drugs. However, the disorder often resolves itself after a number of weeks. Other treatment is symptomatic and supportive. | Therapies of Familial Eosinophilic Cellulitis. Standard treatment of familial eosinophilic cellulitis may consist of administration of steroid drugs. However, the disorder often resolves itself after a number of weeks. Other treatment is symptomatic and supportive. | 443 | Familial Eosinophilic Cellulitis |
nord_444_0 | Overview of Familial Hypercholesterolemia | SummaryFamilial hypercholesterolemia (FH) is a diagnosis which refers to individuals with very significantly elevated low-density lipoprotein (LDL) cholesterol (LDL-C) or “bad cholesterol” and an increased risk of early onset of coronary artery disease if not sufficiently treated. Most commonly, individuals have heterozygous familial hypercholesterolemia (HeFH), caused by a single DNA variant (alteration) for FH that they have inherited from one (affected) parent. In rare cases, an individual can have homozygous familial hypercholesterolemia (HoFH), caused by having two causal FH DNA variants, where one variant is inherited from each (affected) parent. Individuals with HoFH typically have a more severe form of disease. For the purposes of this report, “FH” will refer to HeFH unless otherwise stated.FH is one of the most common genetic diseases and affects approximately 1 in 250 individuals. Several standardized criteria have been developed to diagnose FH, including the Dutch Lipid Clinic Network, Simon Broome, and MEDPED diagnostic criteria. A diagnosis of FH can be made using any criteria. When evaluating someone for FH, it is important to rule out secondary causes of elevated LDL-C. If DNA testing is performed on an individual meeting clinical criteria for FH, most will be found to have a pathogenic variant in one of three relevant genes (LDLR, APOB, and PCSK9).In 20-30% of individuals that meet clinical criteria for FH, standard clinical genetic testing may be negative in individuals due to reasons such as technical limitations (e.g. clinical sensitivity of current technology) or causal genes not yet discovered. Therefore, a negative FH genetic test result does not rule out a diagnosis of FH, but may lower the suspicion for FH in circumstances where a diagnosis of FH is unclear. There is emerging data for alternative genetic causes for a clinical FH presentation, including a very high polygenic burden (see Related Disorders section) that should be considered.Having FH greatly increases the risk of hardening of the arteries (atherosclerosis), which can lead to heart attacks, strokes and other vascular conditions. Untreated individuals with FH have a 20-fold increased risk for coronary artery disease (CAD). Untreated men have a 50% risk of a nonfatal or fatal heart attack (coronary artery blockage) by age 50 years; untreated women have a 30% risk by age 60 years. If one or more other risk factors for CAD are present, especially cigarette smoking or diabetes mellitus, the risk of developing symptomatic CAD is even higher.FH is treatable and the associated cardiovascular disease is largely preventable with early and intensive treatment, using statins, additional drugs, and other means. Other non-statin medications include PCSK9 inhibitors, ezetimibe, and bempedoic acid. These are effective treatments for individuals with FH who have a persistently elevated LDL-C despite treatment with maximally tolerated statin therapy.Early identification and treatment of individuals with FH is key to preventing cardiovascular disease. Underdiagnosis of FH is a problem in most countries as high cholesterol can be an invisible and undetected problem until it leads to coronary artery disease. When an individual with FH is identified, it is important to identify other affected family members through “cascade screening” or “family screening.” Family members who have not yet exhibited cardiovascular symptoms and who are appropriately treated are likely to live a normal lifespan. Without proper family screening, family members will have undetected very high cholesterol and are at risk to develop early onset CAD. It is common for individuals with FH to have a strong family history of premature CAD (men 400 mg/dl. Severe vascular disease including CAD and aortic stenosis are often seen by the teenage years. Without very aggressive treatment including LDL-C apheresis and HoFH specific medications, mortality is common before age 30.IntroductionIn 1973, Joseph Goldstein and Michael Brown identified and characterized a cell membrane protein they called the LDL receptor and the variation in the low-density lipoprotein receptor gene (LDLR) that interfered with its function. Normally functioning receptors lower the blood levels of LDL-C by taking up the lipoproteins that carry LDL-C in the liver. Pathogenic variants in this gene cause a decrease either in the number or function of the receptors, resulting in the extreme LDL-C elevations seen in FH. Goldstein and Brown became the first investigators to identify a variation that caused a metabolic disorder when only a single abnormal gene was present. In 1985 they won the Nobel Prize in Medicine for this work. Their pioneering work and the subsequent studies of LDL-C metabolism in FH patients greatly contributed to our knowledge about the link between cholesterol and heart disease and led to the development of numerous therapeutic agents that benefit a very large number of individuals with high cholesterol. Since that time, other genes causing FH such as the apolipoprotein B-100 gene (APOB) and the proprotein convertase subtilisin/kexin type 9 gene (PCSK9) have been identified (see below). Importantly, there is a great deal of evidence showing that early diagnosis and intensive treatment can prevent illness and death due to FH. | Overview of Familial Hypercholesterolemia. SummaryFamilial hypercholesterolemia (FH) is a diagnosis which refers to individuals with very significantly elevated low-density lipoprotein (LDL) cholesterol (LDL-C) or “bad cholesterol” and an increased risk of early onset of coronary artery disease if not sufficiently treated. Most commonly, individuals have heterozygous familial hypercholesterolemia (HeFH), caused by a single DNA variant (alteration) for FH that they have inherited from one (affected) parent. In rare cases, an individual can have homozygous familial hypercholesterolemia (HoFH), caused by having two causal FH DNA variants, where one variant is inherited from each (affected) parent. Individuals with HoFH typically have a more severe form of disease. For the purposes of this report, “FH” will refer to HeFH unless otherwise stated.FH is one of the most common genetic diseases and affects approximately 1 in 250 individuals. Several standardized criteria have been developed to diagnose FH, including the Dutch Lipid Clinic Network, Simon Broome, and MEDPED diagnostic criteria. A diagnosis of FH can be made using any criteria. When evaluating someone for FH, it is important to rule out secondary causes of elevated LDL-C. If DNA testing is performed on an individual meeting clinical criteria for FH, most will be found to have a pathogenic variant in one of three relevant genes (LDLR, APOB, and PCSK9).In 20-30% of individuals that meet clinical criteria for FH, standard clinical genetic testing may be negative in individuals due to reasons such as technical limitations (e.g. clinical sensitivity of current technology) or causal genes not yet discovered. Therefore, a negative FH genetic test result does not rule out a diagnosis of FH, but may lower the suspicion for FH in circumstances where a diagnosis of FH is unclear. There is emerging data for alternative genetic causes for a clinical FH presentation, including a very high polygenic burden (see Related Disorders section) that should be considered.Having FH greatly increases the risk of hardening of the arteries (atherosclerosis), which can lead to heart attacks, strokes and other vascular conditions. Untreated individuals with FH have a 20-fold increased risk for coronary artery disease (CAD). Untreated men have a 50% risk of a nonfatal or fatal heart attack (coronary artery blockage) by age 50 years; untreated women have a 30% risk by age 60 years. If one or more other risk factors for CAD are present, especially cigarette smoking or diabetes mellitus, the risk of developing symptomatic CAD is even higher.FH is treatable and the associated cardiovascular disease is largely preventable with early and intensive treatment, using statins, additional drugs, and other means. Other non-statin medications include PCSK9 inhibitors, ezetimibe, and bempedoic acid. These are effective treatments for individuals with FH who have a persistently elevated LDL-C despite treatment with maximally tolerated statin therapy.Early identification and treatment of individuals with FH is key to preventing cardiovascular disease. Underdiagnosis of FH is a problem in most countries as high cholesterol can be an invisible and undetected problem until it leads to coronary artery disease. When an individual with FH is identified, it is important to identify other affected family members through “cascade screening” or “family screening.” Family members who have not yet exhibited cardiovascular symptoms and who are appropriately treated are likely to live a normal lifespan. Without proper family screening, family members will have undetected very high cholesterol and are at risk to develop early onset CAD. It is common for individuals with FH to have a strong family history of premature CAD (men 400 mg/dl. Severe vascular disease including CAD and aortic stenosis are often seen by the teenage years. Without very aggressive treatment including LDL-C apheresis and HoFH specific medications, mortality is common before age 30.IntroductionIn 1973, Joseph Goldstein and Michael Brown identified and characterized a cell membrane protein they called the LDL receptor and the variation in the low-density lipoprotein receptor gene (LDLR) that interfered with its function. Normally functioning receptors lower the blood levels of LDL-C by taking up the lipoproteins that carry LDL-C in the liver. Pathogenic variants in this gene cause a decrease either in the number or function of the receptors, resulting in the extreme LDL-C elevations seen in FH. Goldstein and Brown became the first investigators to identify a variation that caused a metabolic disorder when only a single abnormal gene was present. In 1985 they won the Nobel Prize in Medicine for this work. Their pioneering work and the subsequent studies of LDL-C metabolism in FH patients greatly contributed to our knowledge about the link between cholesterol and heart disease and led to the development of numerous therapeutic agents that benefit a very large number of individuals with high cholesterol. Since that time, other genes causing FH such as the apolipoprotein B-100 gene (APOB) and the proprotein convertase subtilisin/kexin type 9 gene (PCSK9) have been identified (see below). Importantly, there is a great deal of evidence showing that early diagnosis and intensive treatment can prevent illness and death due to FH. | 444 | Familial Hypercholesterolemia |
nord_444_1 | Symptoms of Familial Hypercholesterolemia | Heterozygous Familial HypercholesterolemiaVascular conditionsPeople with FH have very high levels of LDL-C from birth. In children, LDL-C levels are usually > 160 mg/dl, but can be lower, and in adults LDL-C is usually > 190 mg/dL. This very high LDL-C level is toxic to the body and causes atherosclerosis in the arteries over time. For individuals with FH, the exposure to elevated LDL-C begins at birth. When untreated, this can lead to premature CAD, cerebrovascular disease, peripheral vascular disease and/or other serious conditions. Most common is CAD due to atherosclerotic plaque build-up in the arteries supplying the heart (atherosclerosis), which can result in chest pain or discomfort (angina), heart attack (myocardial infarction) or sudden death. Untreated people with FH have an approximately 10 to 20-fold increased risk for CAD. It is estimated that 1 in 10 individuals with a heart attack at a young age ( 160 mg/dl at the time of the heart attack.Less common are cerebrovascular disease, peripheral vascular disease and aortic aneurysm. Cerebrovascular disease may occur due to cholesterol build-up in the arteries supplying the brain, which may cause stroke or transient ischemic attack (TIA).Peripheral vascular disease is due to cholesterol build-up in the arteries supplying the legs which may cause pain when walking that is relieved by rest (claudication) and at its most severe, pain at rest or critical lack of blood flow.Extravascular clinical features of FHXanthomas are firm nodules caused by cholesterol buildup as a result of the very high levels of LDL-C. The most common sites are the Achilles tendon and the tendons on top of the hands (less common). Achilles tendon xanthomas may cause tendonitis, an inflammation of the tendon that may tear or rupture. Tendon xanthomas are seen in <15% of individuals with HeFH in the current era and in a much higher percentage of those with HoFH.
Xanthesmas are cholesterol deposits on, above or under the eyelids can be seen in ~5% of patients with FH. They may also be seen in individuals with normal cholesterol levels, particularly as they age.
Corneal arcus is a white, grey or blue opaque ring around the edge of the cornea in the eye, can be seen in ~30% of patients with FH. Since corneal arcus is common in African Americans with normal cholesterol levels and becomes increasingly common in the general population with age, it is only useful as a diagnostic tool in younger individuals, particularly in those under age 45.
Of note, children with heterozygous FH are less likely to present with these physical exam findings. Additionally, the longer an individual is treated with statins, the less likely these extra-vascular findings will be present.Homozygous Familial HypercholesterolemiaIndividuals with HoFH exhibit extremely high LDL-C levels, usually above 400 mg/dL. They usually have xanthomas by early childhood. Planar xanthomas affecting the skin on the hands, elbows, buttocks and knees in a young child are diagnostic for this condition. Corneal arcus surrounding the entire inside edge of the cornea is often present. Most individuals with HoFH experience severe CAD by their mid-20’s if not aggressively treated. Narrowing of the heart valve leading to the aorta (aortic stenosis) often occurs, which may make it necessary to replace the aortic valve. Very aggressive therapy is needed to reduce the likelihood of vascular events. Most affected people will require filtering of their blood (LDL apheresis) and/or medications specifically approved by the FDA for HoFH (lomitapide, PCSK9 inhibitors or mipomersen).Often the other medications that are the mainstay of treatment for HeFH (such as statins) are relatively ineffective in HoFH. This is because the mechanism of action of statins normally “triggers” the liver to express additional LDL receptors. In the most severe cases of HoFH, the LDL receptors are completely inactive which makes this response futile. Statins can be effective in individuals with HoFH if there is some residual LDL-R activity, or if they have causal DNA variants in the APOB or PCSK9 genes. | Symptoms of Familial Hypercholesterolemia. Heterozygous Familial HypercholesterolemiaVascular conditionsPeople with FH have very high levels of LDL-C from birth. In children, LDL-C levels are usually > 160 mg/dl, but can be lower, and in adults LDL-C is usually > 190 mg/dL. This very high LDL-C level is toxic to the body and causes atherosclerosis in the arteries over time. For individuals with FH, the exposure to elevated LDL-C begins at birth. When untreated, this can lead to premature CAD, cerebrovascular disease, peripheral vascular disease and/or other serious conditions. Most common is CAD due to atherosclerotic plaque build-up in the arteries supplying the heart (atherosclerosis), which can result in chest pain or discomfort (angina), heart attack (myocardial infarction) or sudden death. Untreated people with FH have an approximately 10 to 20-fold increased risk for CAD. It is estimated that 1 in 10 individuals with a heart attack at a young age ( 160 mg/dl at the time of the heart attack.Less common are cerebrovascular disease, peripheral vascular disease and aortic aneurysm. Cerebrovascular disease may occur due to cholesterol build-up in the arteries supplying the brain, which may cause stroke or transient ischemic attack (TIA).Peripheral vascular disease is due to cholesterol build-up in the arteries supplying the legs which may cause pain when walking that is relieved by rest (claudication) and at its most severe, pain at rest or critical lack of blood flow.Extravascular clinical features of FHXanthomas are firm nodules caused by cholesterol buildup as a result of the very high levels of LDL-C. The most common sites are the Achilles tendon and the tendons on top of the hands (less common). Achilles tendon xanthomas may cause tendonitis, an inflammation of the tendon that may tear or rupture. Tendon xanthomas are seen in <15% of individuals with HeFH in the current era and in a much higher percentage of those with HoFH.
Xanthesmas are cholesterol deposits on, above or under the eyelids can be seen in ~5% of patients with FH. They may also be seen in individuals with normal cholesterol levels, particularly as they age.
Corneal arcus is a white, grey or blue opaque ring around the edge of the cornea in the eye, can be seen in ~30% of patients with FH. Since corneal arcus is common in African Americans with normal cholesterol levels and becomes increasingly common in the general population with age, it is only useful as a diagnostic tool in younger individuals, particularly in those under age 45.
Of note, children with heterozygous FH are less likely to present with these physical exam findings. Additionally, the longer an individual is treated with statins, the less likely these extra-vascular findings will be present.Homozygous Familial HypercholesterolemiaIndividuals with HoFH exhibit extremely high LDL-C levels, usually above 400 mg/dL. They usually have xanthomas by early childhood. Planar xanthomas affecting the skin on the hands, elbows, buttocks and knees in a young child are diagnostic for this condition. Corneal arcus surrounding the entire inside edge of the cornea is often present. Most individuals with HoFH experience severe CAD by their mid-20’s if not aggressively treated. Narrowing of the heart valve leading to the aorta (aortic stenosis) often occurs, which may make it necessary to replace the aortic valve. Very aggressive therapy is needed to reduce the likelihood of vascular events. Most affected people will require filtering of their blood (LDL apheresis) and/or medications specifically approved by the FDA for HoFH (lomitapide, PCSK9 inhibitors or mipomersen).Often the other medications that are the mainstay of treatment for HeFH (such as statins) are relatively ineffective in HoFH. This is because the mechanism of action of statins normally “triggers” the liver to express additional LDL receptors. In the most severe cases of HoFH, the LDL receptors are completely inactive which makes this response futile. Statins can be effective in individuals with HoFH if there is some residual LDL-R activity, or if they have causal DNA variants in the APOB or PCSK9 genes. | 444 | Familial Hypercholesterolemia |
nord_444_2 | Causes of Familial Hypercholesterolemia | Genetics of FHHeFH occurs when a child inherits a nonfunctional copy of one of their FH genes (LDLR, APOB, PCSK9) from an affected parent and a functional copy from their unaffected parent. Each egg or sperm they produce has a 50% chance of getting the nonfunctional copy (passing down FH) and a 50% chance of getting the functional copy, Therefore, the risk of passing the FH from the affected parent to a child is 50% in each pregnancy. New, spontaneous variants appear to be very rare.Most individuals with HoFH have inherited one mutated gene from each parent, such that each parent has HeFH. These parents have a 25% risk in each pregnancy to have a child with HoFH, a 50% chance of having a child with HeFH, and a 25% chance that the child will inherit a normal gene from each parent. The risk is the same for males and females.When one parent has HeFH and the other has HoFH, there is a 50% chance with each pregnancy to have a child with HeFH and a 50% chance to have a child with HoFH.When one parent has HoFH and the other has two normal genes, all children will have HeFH.When both parents have HoFH, all children will have HoFH.In FH there is a “dose effect” so that HoFH is more severe than HeFH.Variation by geneOf patients with identifiable pathogenic gene variants, a LDLR gene variant is the most common cause of HeFH, accounting for ~90% of pathogenic variants. Since the original pathogenic variant discovered by Goldstein and Brown, over 2500 other variants in the same gene have been identified. An adequate number of functioning LDL receptors are needed to remove cholesterol from the bloodstream.A pathogenic variant in the APOB gene is responsible for ~10% of FH cases; this variation is seen most commonly in those of European Caucasian ancestry. It is also associated with lower baseline LDL-C levels compared to most cases of FH, closer to 160 mg/dl. Apolipoprotein B-100 is a protein that binds to LDL receptors, which enables uptake of lipoproteins by the liver and reduces the cholesterol level in the blood. Pathogenic variants in the APOB gene lead to faulty uptake and increased cholesterol level.PCSK9 gene variants are responsible for only a small percentage of FH cases. The normal PCSK9 gene codes for an enzyme that breaks down the cholesterol receptors after they have done their job. Unlike most pathogenic variants which cause a loss of function of the affected gene, PCSK9 pathogenic variants actually increase the gene’s function. This gain in function in PCSK9 leads to excess degradation of LDL receptors and thus an increase in the LDL-C levels.Recent research suggests individuals with FH that have variants in different genes (LDLR, APOB, PCSK9) or of different types of DNA changes may have different individual risks. However, there is wide enough variation even among those data sets and it can be difficult to provide personalized risk information by one’s genotype.Polygenic inheritanceFH due to a change in LDLR, APOB or PCSK9 is referred to as a monogenic disease, where a change in any one of those genes is sufficient to cause disease. In contrast, there is growing evidence to show that some individuals with a clinical FH presentation (defined by any of the standard diagnostic criteria signs and symptoms) actually have a polygenic predisposition to hyperlipidemia as an alternative genetic cause to their disease. Polygenic disease is due to changes in many genes, often broadly related to cholesterol metabolism. The contribution of any single genetic change is very small and it takes the combination of these many, changed genes to get significantly elevated LDL-C. Polygenic hyperlipidemia can present as severe as FH, but can often also present milder or more variable than monogenic FH because the number of changes inherited by any one family member is always different. Polygenic hyperlipidemia is described in more detail in the “Related Disorders” section. | Causes of Familial Hypercholesterolemia. Genetics of FHHeFH occurs when a child inherits a nonfunctional copy of one of their FH genes (LDLR, APOB, PCSK9) from an affected parent and a functional copy from their unaffected parent. Each egg or sperm they produce has a 50% chance of getting the nonfunctional copy (passing down FH) and a 50% chance of getting the functional copy, Therefore, the risk of passing the FH from the affected parent to a child is 50% in each pregnancy. New, spontaneous variants appear to be very rare.Most individuals with HoFH have inherited one mutated gene from each parent, such that each parent has HeFH. These parents have a 25% risk in each pregnancy to have a child with HoFH, a 50% chance of having a child with HeFH, and a 25% chance that the child will inherit a normal gene from each parent. The risk is the same for males and females.When one parent has HeFH and the other has HoFH, there is a 50% chance with each pregnancy to have a child with HeFH and a 50% chance to have a child with HoFH.When one parent has HoFH and the other has two normal genes, all children will have HeFH.When both parents have HoFH, all children will have HoFH.In FH there is a “dose effect” so that HoFH is more severe than HeFH.Variation by geneOf patients with identifiable pathogenic gene variants, a LDLR gene variant is the most common cause of HeFH, accounting for ~90% of pathogenic variants. Since the original pathogenic variant discovered by Goldstein and Brown, over 2500 other variants in the same gene have been identified. An adequate number of functioning LDL receptors are needed to remove cholesterol from the bloodstream.A pathogenic variant in the APOB gene is responsible for ~10% of FH cases; this variation is seen most commonly in those of European Caucasian ancestry. It is also associated with lower baseline LDL-C levels compared to most cases of FH, closer to 160 mg/dl. Apolipoprotein B-100 is a protein that binds to LDL receptors, which enables uptake of lipoproteins by the liver and reduces the cholesterol level in the blood. Pathogenic variants in the APOB gene lead to faulty uptake and increased cholesterol level.PCSK9 gene variants are responsible for only a small percentage of FH cases. The normal PCSK9 gene codes for an enzyme that breaks down the cholesterol receptors after they have done their job. Unlike most pathogenic variants which cause a loss of function of the affected gene, PCSK9 pathogenic variants actually increase the gene’s function. This gain in function in PCSK9 leads to excess degradation of LDL receptors and thus an increase in the LDL-C levels.Recent research suggests individuals with FH that have variants in different genes (LDLR, APOB, PCSK9) or of different types of DNA changes may have different individual risks. However, there is wide enough variation even among those data sets and it can be difficult to provide personalized risk information by one’s genotype.Polygenic inheritanceFH due to a change in LDLR, APOB or PCSK9 is referred to as a monogenic disease, where a change in any one of those genes is sufficient to cause disease. In contrast, there is growing evidence to show that some individuals with a clinical FH presentation (defined by any of the standard diagnostic criteria signs and symptoms) actually have a polygenic predisposition to hyperlipidemia as an alternative genetic cause to their disease. Polygenic disease is due to changes in many genes, often broadly related to cholesterol metabolism. The contribution of any single genetic change is very small and it takes the combination of these many, changed genes to get significantly elevated LDL-C. Polygenic hyperlipidemia can present as severe as FH, but can often also present milder or more variable than monogenic FH because the number of changes inherited by any one family member is always different. Polygenic hyperlipidemia is described in more detail in the “Related Disorders” section. | 444 | Familial Hypercholesterolemia |
nord_444_3 | Affects of Familial Hypercholesterolemia | Recent studies have shown that FH is as common as 1 in 250, making it one of the most common genetic diseases. However, most individuals go undiagnosed and most are undertreated given their very high risk. Small subpopulations around the world have a higher incidence, such as Lebanese Christians (1/85), Afrikaners in South Africa (1/72 – 1/100), French Canadians (1/270), and Ashkenazi Jews originating from Lithuania (1/67) known as a founder effect.The frequency of HoFH across populations is estimated to be 1 in 1/160,000 to 1 250,000. HoFH is more likely to occur in countries where the prevalence of HeFH is very high, especially those where consanguinity (marriage between relatives) is common. | Affects of Familial Hypercholesterolemia. Recent studies have shown that FH is as common as 1 in 250, making it one of the most common genetic diseases. However, most individuals go undiagnosed and most are undertreated given their very high risk. Small subpopulations around the world have a higher incidence, such as Lebanese Christians (1/85), Afrikaners in South Africa (1/72 – 1/100), French Canadians (1/270), and Ashkenazi Jews originating from Lithuania (1/67) known as a founder effect.The frequency of HoFH across populations is estimated to be 1 in 1/160,000 to 1 250,000. HoFH is more likely to occur in countries where the prevalence of HeFH is very high, especially those where consanguinity (marriage between relatives) is common. | 444 | Familial Hypercholesterolemia |
nord_444_4 | Related disorders of Familial Hypercholesterolemia | A diagnosis of FH can be made using any of the accepted standardized diagnostic criteria described in the “Diagnosis” section. In instances when a diagnosis of FH is suspected but cannot be definitively confirmed with the available information, genetic testing can often aid in the assessment. In 2019, an international expert panel published a consensus paper supporting the utility of FH genetic testing and a statement that genetic testing should be offered as standard of care. In instances where genetic testing is negative, the technical limitations and sensitivity of FH genetic testing cannot rule out FH with certainty but may support the consideration of alternative explanations for the presenting symptoms. There are several conditions with overlapping laboratory findings or family history features similar to FH.These include the following:1.) Hypercholesterolemia secondary to obesity, diabetes mellitus, hypothyroidism, drugs such as steroids, or kidney disease. Inheritance follows a non-Mendelian pattern.2.) Polygenic hypercholesterolemia due to a combination of many small effect genetic variants in many cholesterol metabolizing genes. Polygenic hypercholesterolemia can be exacerbated by risk factors such as diabetes mellitus and obesity. Oftentimes, an individual will have a family history of hyperlipidemia and coronary artery disease though the onset of CAD may be later in life. Inheritance follows a non-Mendelian pattern and family members often present with variable expression of LDL-C levels or the associated cardiovascular risks. 3.) Autosomal recessive hypercholesterolemia caused by biallelic pathogenic variants in LDLRAP1. Persons with biallelic pathogenic variants have LDL-C >400 mg/dL (>10 mmol/L) a phenotype resembling HoFH, whereas heterozygotes have normal LDL-C levels.4.) Familial combined hyperlipidemia (FCHL) which leads to elevated LDL-C and triglycerides. While FCHL is a complex polygenic disorder, heterozygous pathogenic variants in APOB (different than the ones causing FH) and USF1 (associated with autosomal dominant inheritance) are causative in a minority of families.5.) Lipoprotein a (Lp(a)) is a cholesterol-like particle which, when elevated (>30 mg/dL), increases the risk of premature CAD. Lp(a) levels are primarily genetically determined, and are inherited in an autosomal codominant pattern. Individuals with significantly elevated Lp(a) levels may display a family history which mimics that of an individual with FH even if LDL-C levels are normal. Individuals with both FH and elevated Lp(a) are at a particularly increased risk of premature coronary artery disease. | Related disorders of Familial Hypercholesterolemia. A diagnosis of FH can be made using any of the accepted standardized diagnostic criteria described in the “Diagnosis” section. In instances when a diagnosis of FH is suspected but cannot be definitively confirmed with the available information, genetic testing can often aid in the assessment. In 2019, an international expert panel published a consensus paper supporting the utility of FH genetic testing and a statement that genetic testing should be offered as standard of care. In instances where genetic testing is negative, the technical limitations and sensitivity of FH genetic testing cannot rule out FH with certainty but may support the consideration of alternative explanations for the presenting symptoms. There are several conditions with overlapping laboratory findings or family history features similar to FH.These include the following:1.) Hypercholesterolemia secondary to obesity, diabetes mellitus, hypothyroidism, drugs such as steroids, or kidney disease. Inheritance follows a non-Mendelian pattern.2.) Polygenic hypercholesterolemia due to a combination of many small effect genetic variants in many cholesterol metabolizing genes. Polygenic hypercholesterolemia can be exacerbated by risk factors such as diabetes mellitus and obesity. Oftentimes, an individual will have a family history of hyperlipidemia and coronary artery disease though the onset of CAD may be later in life. Inheritance follows a non-Mendelian pattern and family members often present with variable expression of LDL-C levels or the associated cardiovascular risks. 3.) Autosomal recessive hypercholesterolemia caused by biallelic pathogenic variants in LDLRAP1. Persons with biallelic pathogenic variants have LDL-C >400 mg/dL (>10 mmol/L) a phenotype resembling HoFH, whereas heterozygotes have normal LDL-C levels.4.) Familial combined hyperlipidemia (FCHL) which leads to elevated LDL-C and triglycerides. While FCHL is a complex polygenic disorder, heterozygous pathogenic variants in APOB (different than the ones causing FH) and USF1 (associated with autosomal dominant inheritance) are causative in a minority of families.5.) Lipoprotein a (Lp(a)) is a cholesterol-like particle which, when elevated (>30 mg/dL), increases the risk of premature CAD. Lp(a) levels are primarily genetically determined, and are inherited in an autosomal codominant pattern. Individuals with significantly elevated Lp(a) levels may display a family history which mimics that of an individual with FH even if LDL-C levels are normal. Individuals with both FH and elevated Lp(a) are at a particularly increased risk of premature coronary artery disease. | 444 | Familial Hypercholesterolemia |
nord_444_5 | Diagnosis of Familial Hypercholesterolemia | FH should be considered in an untreated child with LDL-C above 160 mg/dL, or with LDL-C above 130 mg/dL and a positive family history of FH or premature heart disease. In untreated adults, an LDL-C above 190 mg/dL, a personal and/or family history of early CAD, physical signs such as those described under “Symptoms, or a relative known to have FH, should increase the suspicion of FH FH can be diagnosed using DNA testing or by utilizing one of three well-accepted sets of criteria — Simon Broome (UK), Dutch Lipid Clinic Network (Netherlands), or MEDPED (US). Of note, the Dutch Lipid Clinic Network criteria are unable to be used in the pediatric setting. In individuals suspected to have “definite” FH based on clinical criteria, an FH variant is identified approximately 60-80% of the time. In individuals with “possible” FH based on clinical criteria, an FH variant is identified approximately 20-40% of the time. DNA testing confirms the diagnosis and is considered the “gold standard”, but is not always necessary or feasible. DNA testing should definitely be considered when it’s not clear whether an individual is affected or not, and is very helpful for testing family members. Recent studies also suggest that individual risks for CAD vary among the affected gene and type of DNA variation (substitution vs. partial deletion of a gene, etc.). Individuals with an LDL-C >190 mg/dL and a FH pathogenic variant have been noted to have a 10 fold increased relative risk for CAD (compared to the general population) while those with an LDL-C >190 mg/dL and no FH pathogenic mutation have a 3-fold increased relative risk for CAD (compared to the general population). Therefore, individuals who test positive on genetic testing may infer an increased risk of CAD over an individual with negative genetic testing at any given LDL-C level. Once an individual is diagnosed with FH (either with or without the use of DNA testing) a process called “cascade screening”, “cascade testing” or “family screening” (testing of close relatives, in a step-wise fashion) is recommended to identify those with FH before symptoms appear, so that early and intensive treatment can be initiated and disease and death prevented. If a pathogenic variant is identified, risk in the patient’s first degree relatives (parent, sibling, child) and when appropriate, more distant relatives, can be accessed via DNA testing by tracing the altered gene through the family. If DNA testing is not performed, another version of cascade screening can be implemented using cholesterol testing. Cascade screening by either means has been shown to be effective in finding patients with FH who were not being appropriately treated. A genetic counselor can help a family through this process. (http://www.nsgc.org/page/find-a-gc-search )Cascade screening has been shown in numerous studies to be cost-effective and has been recommended by the National Institute for Health and Clinical Excellence (NICE) in the UK. The Office of Public Health Genomics at the Centers for Disease Control and Prevention considers cascade screening of relatives of those with FH a “Tier 1 application” which means that there is good evidence that implementation will prevent disease and save lives.HoFH is easily identified in infants and young children by the presence of planar xanthomas, corneal arcus, and exceedingly high total and LDL-C; LDL-C is usually greater than 400 mg/dL. The parents are “obligate heterozygotes” who are considered to have HeFH until proven otherwise.Clinical Testing and WorkupEvaluations following initial diagnosisTo establish the extent of disease and needs of an individual diagnosed with FH, the following evaluations are recommended in adults and children:
• Pre-treatment lipid values
• Lipoprotein(a) levels when possible as lipoprotein(a) is an additional risk factor for CAD
• Exclusion of concurrent illnesses (kidney disease,uncontrolled hypothyroidism, acute myocardial infarction, infection) that can affect lipid values
• Lipid panel including total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), and triglycerides
• Consultation with a lipid specialist or clinician with expertise in FH
• Medical genetics or a genetic counseling consultationIn children, noninvasive imaging modalities (e.g., measurement of carotid intima-media thickness) are recommended in some guidelines to help inform treatment decisions. | Diagnosis of Familial Hypercholesterolemia. FH should be considered in an untreated child with LDL-C above 160 mg/dL, or with LDL-C above 130 mg/dL and a positive family history of FH or premature heart disease. In untreated adults, an LDL-C above 190 mg/dL, a personal and/or family history of early CAD, physical signs such as those described under “Symptoms, or a relative known to have FH, should increase the suspicion of FH FH can be diagnosed using DNA testing or by utilizing one of three well-accepted sets of criteria — Simon Broome (UK), Dutch Lipid Clinic Network (Netherlands), or MEDPED (US). Of note, the Dutch Lipid Clinic Network criteria are unable to be used in the pediatric setting. In individuals suspected to have “definite” FH based on clinical criteria, an FH variant is identified approximately 60-80% of the time. In individuals with “possible” FH based on clinical criteria, an FH variant is identified approximately 20-40% of the time. DNA testing confirms the diagnosis and is considered the “gold standard”, but is not always necessary or feasible. DNA testing should definitely be considered when it’s not clear whether an individual is affected or not, and is very helpful for testing family members. Recent studies also suggest that individual risks for CAD vary among the affected gene and type of DNA variation (substitution vs. partial deletion of a gene, etc.). Individuals with an LDL-C >190 mg/dL and a FH pathogenic variant have been noted to have a 10 fold increased relative risk for CAD (compared to the general population) while those with an LDL-C >190 mg/dL and no FH pathogenic mutation have a 3-fold increased relative risk for CAD (compared to the general population). Therefore, individuals who test positive on genetic testing may infer an increased risk of CAD over an individual with negative genetic testing at any given LDL-C level. Once an individual is diagnosed with FH (either with or without the use of DNA testing) a process called “cascade screening”, “cascade testing” or “family screening” (testing of close relatives, in a step-wise fashion) is recommended to identify those with FH before symptoms appear, so that early and intensive treatment can be initiated and disease and death prevented. If a pathogenic variant is identified, risk in the patient’s first degree relatives (parent, sibling, child) and when appropriate, more distant relatives, can be accessed via DNA testing by tracing the altered gene through the family. If DNA testing is not performed, another version of cascade screening can be implemented using cholesterol testing. Cascade screening by either means has been shown to be effective in finding patients with FH who were not being appropriately treated. A genetic counselor can help a family through this process. (http://www.nsgc.org/page/find-a-gc-search )Cascade screening has been shown in numerous studies to be cost-effective and has been recommended by the National Institute for Health and Clinical Excellence (NICE) in the UK. The Office of Public Health Genomics at the Centers for Disease Control and Prevention considers cascade screening of relatives of those with FH a “Tier 1 application” which means that there is good evidence that implementation will prevent disease and save lives.HoFH is easily identified in infants and young children by the presence of planar xanthomas, corneal arcus, and exceedingly high total and LDL-C; LDL-C is usually greater than 400 mg/dL. The parents are “obligate heterozygotes” who are considered to have HeFH until proven otherwise.Clinical Testing and WorkupEvaluations following initial diagnosisTo establish the extent of disease and needs of an individual diagnosed with FH, the following evaluations are recommended in adults and children:
• Pre-treatment lipid values
• Lipoprotein(a) levels when possible as lipoprotein(a) is an additional risk factor for CAD
• Exclusion of concurrent illnesses (kidney disease,uncontrolled hypothyroidism, acute myocardial infarction, infection) that can affect lipid values
• Lipid panel including total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), and triglycerides
• Consultation with a lipid specialist or clinician with expertise in FH
• Medical genetics or a genetic counseling consultationIn children, noninvasive imaging modalities (e.g., measurement of carotid intima-media thickness) are recommended in some guidelines to help inform treatment decisions. | 444 | Familial Hypercholesterolemia |
nord_444_6 | Therapies of Familial Hypercholesterolemia | Treatment
Treatment of FH is focused on reducing the LDL-C levels in order to decrease the risk for atherosclerotic heart disease.Adults with FHLifestyle interventionDietary changes such as restricting saturated fat and eliminating trans-fats have significant cholesterol-lowering impact. Decreasing dietary cholesterol and increasing soluble fiber are also helpful. The diet should primarily be made up of vegetables, whole fruit and grains, nuts and legumes. Seafood, lean poultry and low fat dairy products are the preferred sources of animal protein. Weight loss and aerobic exercise have modest effects on cholesterol level but can help to lower blood pressure and blood sugar levels and thus cardiovascular disease risk.Cholesterol lowering medicationFor adults, treatment should begin as soon as possible after diagnosis. Almost all will require cholesterol-lowering drug therapy. A firm diagnosis of FH should prompt more aggressive treatment than would otherwise be undertaken in a patient with “garden variety” high cholesterol. Some guidelines state that the untreated cholesterol level should be reduced by at least 50%; others suggest that less than 100 mg/dL is the goal for individuals without a prior CVD event. LDL-C goals are more stringent (typically <70 mg/dl) when additional risk factors such as diabetes or atherosclerosis are present. Patients with FH should be referred to a lipidologist if these goals cannot be reached in the primary care setting.Pharmacotherapy should initially be statin-based, followed by addition of other drugs if the targeted LDL-C level is not achieved with statins and lifestyle changes. Preference should be given to one of the higher potency statins (atorvastatin or rosuvastatin) used at the maximal dose.Muscle injury (rhabdomyolysis) is the major risk of statins but is very rare, seen in approximately 1/10,000 of those taking these drugs. Damage to the liver does not occur at a higher rate than in people not taking a statin. However, myalgia (muscle pain) is a relatively common side effect occurring in 10-15% of patients. Mild myalgia with or without mild creatine kinase elevations (less than 5 times the upper limit of normal) are not necessarily a reason to discontinue statins or other cholesterol lowering medications.Other drugs such as ezetimibe (Zetia), bile acid sequestrants (colesevelam, Welcol), bempedoic acid (Nexletol) and icosapent ethyl (Vascepa), or PCSK9 inhibitors (evolocumab; Repatha or alirocumab; Praluent) (approved in 2015 for the treatment of HeFH and HoFH) may be necessary.In patients who cannot achieve the desired LDL-C level, a procedure called LDL apheresis (similar to dialysis for kidney disease) may be necessary.Children with HeFHParents should discuss with the pediatrician when to initiate treatment in a child with FH. Treatment should be considered when LDL-C level is greater than 190 mg/dl, or greater than 160 md/dl with at least two other risk factors present. The National Lipid Association guidelines recommend referral to a lipid specialist, management of diet and physical activity from an early age, and consideration of statin treatment. Atorvastatin and rosuvastatin, two of the stronger statins, are approved for use in children by the Federal Drug Administration, as are all of the weaker statins. The goal is at least a 50% reduction in LDL-C or LDL-C below 130 mg/dL. Statins can be initiated as early as 8 to 10 years old; adverse effects of statins in childhood have not been reported. Studies have shown that children who begin statins have a statistically significant decreased risk of developing coronary artery disease compared to their parents affected with FH. The goal of initiating statins in childhood is to reduce the cumulative lifetime burden of exposure to LDL-C levels.Children or Adults with HoFHEarly initiation of therapy and monitoring using CT coronary angiography and other imaging are recommended; these patients often require additional treatment strategies, as pharmacological treatment and lifestyle changes may not be sufficient. Statins are usually started as soon as the diagnosis is made (though may not be effective as explained above). Lomitapide is now a FDA-approved treatment for adults with HoFH and should be considered for these patients, especially if LDL-C level cannot be controlled using other drugs. A PCSK9 inhibitor, evolocumab, was also approved by the FDA for HoFH. In 2021, the FDA approved evinacumab-dgnb (Evkeeza) injection as an add-on treatment for patients aged 12 and older with HoFH and in 2023 approval was expanded to children aged 5-11. Additional options include LDL apheresis or liver transplantation.LDL apheresisUsing a process similar to kidney dialysis, blood is withdrawn from a vein via a catheter and processed to remove LDL-C particles. Normal blood products are returned via another catheter. LDL-C levels will decrease approximately 50% but will rise between apheresis sessions, so they are necessary approximately weekly or every other week. The procedure is effective and well tolerated though time-consuming and only available in 50-60 sites in the US.Liver transplantationLiver transplant is extraordinarily rare and may become even less common with the new medications available. As the donor liver will have normal LDL receptors, the LDL-C quickly normalizes after the procedure, but the risks of any organ transplant are significant and include complications from major surgery and the effects of lifelong suppression of the immune system. Donor organs are often not available. Patients with familial pathogenic APOB or PCSK9 gene variants have normal LDL receptors, so liver transplantation is not an option for them.
Various imaging modalities such as echocardiograms, CT angiograms and cardiac catheterization may be recommended to monitor individuals with HoFH. | Therapies of Familial Hypercholesterolemia. Treatment
Treatment of FH is focused on reducing the LDL-C levels in order to decrease the risk for atherosclerotic heart disease.Adults with FHLifestyle interventionDietary changes such as restricting saturated fat and eliminating trans-fats have significant cholesterol-lowering impact. Decreasing dietary cholesterol and increasing soluble fiber are also helpful. The diet should primarily be made up of vegetables, whole fruit and grains, nuts and legumes. Seafood, lean poultry and low fat dairy products are the preferred sources of animal protein. Weight loss and aerobic exercise have modest effects on cholesterol level but can help to lower blood pressure and blood sugar levels and thus cardiovascular disease risk.Cholesterol lowering medicationFor adults, treatment should begin as soon as possible after diagnosis. Almost all will require cholesterol-lowering drug therapy. A firm diagnosis of FH should prompt more aggressive treatment than would otherwise be undertaken in a patient with “garden variety” high cholesterol. Some guidelines state that the untreated cholesterol level should be reduced by at least 50%; others suggest that less than 100 mg/dL is the goal for individuals without a prior CVD event. LDL-C goals are more stringent (typically <70 mg/dl) when additional risk factors such as diabetes or atherosclerosis are present. Patients with FH should be referred to a lipidologist if these goals cannot be reached in the primary care setting.Pharmacotherapy should initially be statin-based, followed by addition of other drugs if the targeted LDL-C level is not achieved with statins and lifestyle changes. Preference should be given to one of the higher potency statins (atorvastatin or rosuvastatin) used at the maximal dose.Muscle injury (rhabdomyolysis) is the major risk of statins but is very rare, seen in approximately 1/10,000 of those taking these drugs. Damage to the liver does not occur at a higher rate than in people not taking a statin. However, myalgia (muscle pain) is a relatively common side effect occurring in 10-15% of patients. Mild myalgia with or without mild creatine kinase elevations (less than 5 times the upper limit of normal) are not necessarily a reason to discontinue statins or other cholesterol lowering medications.Other drugs such as ezetimibe (Zetia), bile acid sequestrants (colesevelam, Welcol), bempedoic acid (Nexletol) and icosapent ethyl (Vascepa), or PCSK9 inhibitors (evolocumab; Repatha or alirocumab; Praluent) (approved in 2015 for the treatment of HeFH and HoFH) may be necessary.In patients who cannot achieve the desired LDL-C level, a procedure called LDL apheresis (similar to dialysis for kidney disease) may be necessary.Children with HeFHParents should discuss with the pediatrician when to initiate treatment in a child with FH. Treatment should be considered when LDL-C level is greater than 190 mg/dl, or greater than 160 md/dl with at least two other risk factors present. The National Lipid Association guidelines recommend referral to a lipid specialist, management of diet and physical activity from an early age, and consideration of statin treatment. Atorvastatin and rosuvastatin, two of the stronger statins, are approved for use in children by the Federal Drug Administration, as are all of the weaker statins. The goal is at least a 50% reduction in LDL-C or LDL-C below 130 mg/dL. Statins can be initiated as early as 8 to 10 years old; adverse effects of statins in childhood have not been reported. Studies have shown that children who begin statins have a statistically significant decreased risk of developing coronary artery disease compared to their parents affected with FH. The goal of initiating statins in childhood is to reduce the cumulative lifetime burden of exposure to LDL-C levels.Children or Adults with HoFHEarly initiation of therapy and monitoring using CT coronary angiography and other imaging are recommended; these patients often require additional treatment strategies, as pharmacological treatment and lifestyle changes may not be sufficient. Statins are usually started as soon as the diagnosis is made (though may not be effective as explained above). Lomitapide is now a FDA-approved treatment for adults with HoFH and should be considered for these patients, especially if LDL-C level cannot be controlled using other drugs. A PCSK9 inhibitor, evolocumab, was also approved by the FDA for HoFH. In 2021, the FDA approved evinacumab-dgnb (Evkeeza) injection as an add-on treatment for patients aged 12 and older with HoFH and in 2023 approval was expanded to children aged 5-11. Additional options include LDL apheresis or liver transplantation.LDL apheresisUsing a process similar to kidney dialysis, blood is withdrawn from a vein via a catheter and processed to remove LDL-C particles. Normal blood products are returned via another catheter. LDL-C levels will decrease approximately 50% but will rise between apheresis sessions, so they are necessary approximately weekly or every other week. The procedure is effective and well tolerated though time-consuming and only available in 50-60 sites in the US.Liver transplantationLiver transplant is extraordinarily rare and may become even less common with the new medications available. As the donor liver will have normal LDL receptors, the LDL-C quickly normalizes after the procedure, but the risks of any organ transplant are significant and include complications from major surgery and the effects of lifelong suppression of the immune system. Donor organs are often not available. Patients with familial pathogenic APOB or PCSK9 gene variants have normal LDL receptors, so liver transplantation is not an option for them.
Various imaging modalities such as echocardiograms, CT angiograms and cardiac catheterization may be recommended to monitor individuals with HoFH. | 444 | Familial Hypercholesterolemia |
nord_445_0 | Overview of Familial Hypophosphatemia | Familial hypophosphatemia is a term that describes a group of rare inherited disorders characterized by impaired kidney conservation of phosphate and in some cases, altered vitamin D metabolism. In contrast, other forms of hypophosphatemia may result from inadequate dietary supply of phosphate or its poor absorption from the intestines. The chronic hypophosphatemia resulting from these impairments can lead to rickets, a childhood bone disease with characteristic bow deformities of the legs, growth plate abnormalities and progressive softening of the bone, referred to as osteomalacia. In children, growth rates may be impaired, frequently resulting in short stature. In adults, the growth plate is not present so that osteomalacia is the evident bone problem. Familial hypophosphatemia is most often inherited in an X-linked dominant manner; however, autosomal dominant and recessive forms of familial hypophosphatemia occur. | Overview of Familial Hypophosphatemia. Familial hypophosphatemia is a term that describes a group of rare inherited disorders characterized by impaired kidney conservation of phosphate and in some cases, altered vitamin D metabolism. In contrast, other forms of hypophosphatemia may result from inadequate dietary supply of phosphate or its poor absorption from the intestines. The chronic hypophosphatemia resulting from these impairments can lead to rickets, a childhood bone disease with characteristic bow deformities of the legs, growth plate abnormalities and progressive softening of the bone, referred to as osteomalacia. In children, growth rates may be impaired, frequently resulting in short stature. In adults, the growth plate is not present so that osteomalacia is the evident bone problem. Familial hypophosphatemia is most often inherited in an X-linked dominant manner; however, autosomal dominant and recessive forms of familial hypophosphatemia occur. | 445 | Familial Hypophosphatemia |
nord_445_1 | Symptoms of Familial Hypophosphatemia | Signs and symptoms of familial hypophosphatemia vary greatly and are usually first noticed at about eighteen months of age. Children often present with progressive bow or knock-knee deformities and/or short stature. Bone pain often develops when the child is actively engaged in physical activities. Adults may complain of osteomalacia-related pain, propensity to bone fracture, arthritis or pain related to excess mineralization of tendons at the site of muscular attachments.Infants may have an abnormally tall, narrow head (dolichocephaly), a relative enlargement of the front-to-back dimension (scaphocephaly) or abnormally early fusion of the skull bones (craniosynostosis). Toddlers may have an abnormal “waddling” walk (gait) due to abnormally bowed legs (genu varus). In some patients, the knees are bent inwards such that they are too close together (knock knees or genu valgum). Hip deformities in which the thighbone angles towards the center of the body (coxa vara) may occur. Affected individuals often reach a shorter adult height than would otherwise be expected. In older adults, narrowing of the spine (spinal stenosis) and abnormal side-to-side curvature of the spine (scoliosis) may occur. Osteoarthritis-like features occur frequently in adults at earlier ages than would be otherwise expected.Symptoms such as weakness and intermittent muscle cramps may also occur, although this is not a usual finding in childhood. Cases of familial hypophosphatemia may range from mild to severe. Some individuals may have no noticeable symptoms while others may be marked by pain and/or stiffness of the back, hips and shoulders possibly limiting mobility. In later adulthood, calcification of tendons and ligaments and the development of bone spurs or bony protrusions can further limit mobility and cause pain.Dental problems such as decay and abscesses or late eruption of teeth may develop in individuals with familial hypophosphatemia. Less frequently, affected individuals develop enamel defects and an increased frequency of cavities (caries). In some affected individuals, hearing impairment due to malformation of the inner ears (sensorineural hearing loss) may also be present. | Symptoms of Familial Hypophosphatemia. Signs and symptoms of familial hypophosphatemia vary greatly and are usually first noticed at about eighteen months of age. Children often present with progressive bow or knock-knee deformities and/or short stature. Bone pain often develops when the child is actively engaged in physical activities. Adults may complain of osteomalacia-related pain, propensity to bone fracture, arthritis or pain related to excess mineralization of tendons at the site of muscular attachments.Infants may have an abnormally tall, narrow head (dolichocephaly), a relative enlargement of the front-to-back dimension (scaphocephaly) or abnormally early fusion of the skull bones (craniosynostosis). Toddlers may have an abnormal “waddling” walk (gait) due to abnormally bowed legs (genu varus). In some patients, the knees are bent inwards such that they are too close together (knock knees or genu valgum). Hip deformities in which the thighbone angles towards the center of the body (coxa vara) may occur. Affected individuals often reach a shorter adult height than would otherwise be expected. In older adults, narrowing of the spine (spinal stenosis) and abnormal side-to-side curvature of the spine (scoliosis) may occur. Osteoarthritis-like features occur frequently in adults at earlier ages than would be otherwise expected.Symptoms such as weakness and intermittent muscle cramps may also occur, although this is not a usual finding in childhood. Cases of familial hypophosphatemia may range from mild to severe. Some individuals may have no noticeable symptoms while others may be marked by pain and/or stiffness of the back, hips and shoulders possibly limiting mobility. In later adulthood, calcification of tendons and ligaments and the development of bone spurs or bony protrusions can further limit mobility and cause pain.Dental problems such as decay and abscesses or late eruption of teeth may develop in individuals with familial hypophosphatemia. Less frequently, affected individuals develop enamel defects and an increased frequency of cavities (caries). In some affected individuals, hearing impairment due to malformation of the inner ears (sensorineural hearing loss) may also be present. | 445 | Familial Hypophosphatemia |
nord_445_2 | Causes of Familial Hypophosphatemia | In most individuals, familial hypophosphatemia is inherited in an X-linked dominant manner, however variant forms may be inherited in an autosomal dominant or recessive manner.In contrast to most X-linked disorders which are recessive and primarily affect males (in which the only X chromosome is affected), X-linked dominant disorders also occur in heterozygous females (with only one affected X chromosome and one normal X chromosome).X-linked hypophosphatemia (XLH) is caused by a change (variant or mutation) in the PHEX gene located on the X chromosome resulting in a variant type of PHEX protein. The PHEX protein is a member of an enzyme family of proteins, but it is not precisely clear what the cellular function of PHEX is. The bone cells that express PHEX also secrete an important hormone called FGF23, which is produced in increased amounts when there is impaired function of the PHEX protein, as occurs in XLH. FGF23 acts on the kidney and results in excessive urinary excretion of phosphate, but the mechanism by which elevated FGF23 levels occur in the setting of PHEX dysfunction is not understood.Similarly, autosomal dominant hypophosphatemic rickets (ADHR) may be caused by specific variants of the FGF23 gene located on chromosome 12. These changes result in a variant type of FGF23 protein that persists for longer than normal periods of time in the body and can result in elevated FGF23 blood levels.In familial hypophosphatemia, symptoms occur, at least in part, because of an impaired ability of the kidneys to retain phosphate. If the blood levels of phosphate become abnormally low, bone mineralization becomes impaired, thereby weakening the bones and leading to osteomalacia and bowed bones.A second renal abnormality in XLH and ADHR is impaired activation of vitamin D. Active vitamin D formation is required for the body to maintain a normal handling of calcium, another mineral important to bones. Both of these abnormalities of kidney function (phosphate conservation and conservation of vitamin D activation) are due to the high levels of circulating FGF23. | Causes of Familial Hypophosphatemia. In most individuals, familial hypophosphatemia is inherited in an X-linked dominant manner, however variant forms may be inherited in an autosomal dominant or recessive manner.In contrast to most X-linked disorders which are recessive and primarily affect males (in which the only X chromosome is affected), X-linked dominant disorders also occur in heterozygous females (with only one affected X chromosome and one normal X chromosome).X-linked hypophosphatemia (XLH) is caused by a change (variant or mutation) in the PHEX gene located on the X chromosome resulting in a variant type of PHEX protein. The PHEX protein is a member of an enzyme family of proteins, but it is not precisely clear what the cellular function of PHEX is. The bone cells that express PHEX also secrete an important hormone called FGF23, which is produced in increased amounts when there is impaired function of the PHEX protein, as occurs in XLH. FGF23 acts on the kidney and results in excessive urinary excretion of phosphate, but the mechanism by which elevated FGF23 levels occur in the setting of PHEX dysfunction is not understood.Similarly, autosomal dominant hypophosphatemic rickets (ADHR) may be caused by specific variants of the FGF23 gene located on chromosome 12. These changes result in a variant type of FGF23 protein that persists for longer than normal periods of time in the body and can result in elevated FGF23 blood levels.In familial hypophosphatemia, symptoms occur, at least in part, because of an impaired ability of the kidneys to retain phosphate. If the blood levels of phosphate become abnormally low, bone mineralization becomes impaired, thereby weakening the bones and leading to osteomalacia and bowed bones.A second renal abnormality in XLH and ADHR is impaired activation of vitamin D. Active vitamin D formation is required for the body to maintain a normal handling of calcium, another mineral important to bones. Both of these abnormalities of kidney function (phosphate conservation and conservation of vitamin D activation) are due to the high levels of circulating FGF23. | 445 | Familial Hypophosphatemia |
nord_445_3 | Affects of Familial Hypophosphatemia | XLH affects both males and females. In some families it has been anecdotally observed that females may have less severe features of the disease than males. However, such a great variation in degree of severity exists for XLH, that it is not clear that this is always the case. The most widely cited estimated prevalence of XLH is one in 20,000 individuals. XLH is the most common form of heritable rickets in the United States. The related disorders, ADHR and ARHR, are diagnosed far less frequently.Tumor-induced osteomalacia (TIO) is an acquired hypophosphatemic disorder that may mimic the inherited hypophosphatemic disorders due to the resulting elevation in FGF23 hormone levels that occur. TIO tumors are usually small but produce excess amounts of FGF23. TIO is important to recognize as it can be entirely cured by removal of the tumor.All of the above forms of hypophosphatemia have clinical features in common related to excess circulating FGF23 hormone | Affects of Familial Hypophosphatemia. XLH affects both males and females. In some families it has been anecdotally observed that females may have less severe features of the disease than males. However, such a great variation in degree of severity exists for XLH, that it is not clear that this is always the case. The most widely cited estimated prevalence of XLH is one in 20,000 individuals. XLH is the most common form of heritable rickets in the United States. The related disorders, ADHR and ARHR, are diagnosed far less frequently.Tumor-induced osteomalacia (TIO) is an acquired hypophosphatemic disorder that may mimic the inherited hypophosphatemic disorders due to the resulting elevation in FGF23 hormone levels that occur. TIO tumors are usually small but produce excess amounts of FGF23. TIO is important to recognize as it can be entirely cured by removal of the tumor.All of the above forms of hypophosphatemia have clinical features in common related to excess circulating FGF23 hormone | 445 | Familial Hypophosphatemia |
nord_445_4 | Related disorders of Familial Hypophosphatemia | Symptoms of the following disorders may have some features in common with familial hypophosphatemia but differ from the typical picture described above. Comparisons may be useful for a differential diagnosis.Rickets may occur because of vitamin D deficiency, which in turn, reduces the availability to the body of dietary calcium. Calcium is an important mineral for the formation of normal bone tissue. Vitamin-D deficiency can occur at any time of life and may be treated with vitamin D. In infancy or childhood, contributing factors are usually nutritional, sometimes in combination with a lack of sunlight exposure. Malabsorption syndromes in which the intestines do not adequately absorb nutrients from foods may also be a factor. Major symptoms of this type of rickets include bowed legs, bone pain or tenderness, restlessness and slow growth. This disorder occurs in the United States but is most frequent in other areas of the world. Calcium deficiency may also be a contributing factor in the development of nutritional rickets. Osteomalacia in adults may also arise from similar nutritional deficiencies.Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare bone disorder characterized by symptoms associated with hypophosphatemic rickets, including muscle weakness, short stature, skeletal deformities and bone pain. The disorder is inherited in an autosomal recessive pattern. There may be a tendency for the kidneys to develop calcifications or even renal stones. In contrast to XLH, the disorder is not due to elevations in FGF23 levels, but loss of function in a specific transporter protein in the kidney (NPT2c) which acts to retain phosphate. HHRH should be treated differently from XLH, because it does not have the vitamin D abnormalities that are present in the FGF23-mediated forms of hypophosphatemia.Vitamin D-1α hydroxylase deficiency (pseudovitamin D deficiency, or vitamin D-dependent rickets, type I) is usually characterized by more severe skeletal changes and weakness than those usually observed in familial hypophosphatemia. This disorder is caused by abnormal vitamin D metabolism and is inherited in an autosomal recessive pattern. This type of rickets may be evident at even earlier ages than occurs with familial hypophosphatemia. Blood levels of calcium are usually reduced in individuals with vitamin D dependent rickets, although phosphate levels may be normal or mildly decreased. Intermittent muscle cramps may occur. Additional symptoms may include muscle weakness, bowed legs, dental abnormalities, seizures and abnormalities of the spine and pelvis. Hereditary resistance to vitamin D (vitamin D dependent rickets, type II) may present in an identical manner. This is a rare autosomal recessive disorder that can be caused by variants in the gene for an important protein in the body called the vitamin D receptor (VDR), which is required for vitamin D to work properly.Fanconi syndrome is characterized by kidney dysfunction and bone abnormalities like those of familial hypophosphatemia. Excess kidney losses of a variety of substances in addition to phosphate may occur. These include amino acids, bicarbonate, glucose, potassium and uric acid. This disorder may be acquired or genetic with autosomal recessive inheritance. Bone symptoms include rickets in children and softening of bones (osteomalacia) in adults. Fanconi syndrome may be associated with a variety of inherited metabolic disorders such as cystinosis, Lowe’s syndrome, tyrosinemia, hereditary fructose intolerance, Wilson’s disease or galactosemia. | Related disorders of Familial Hypophosphatemia. Symptoms of the following disorders may have some features in common with familial hypophosphatemia but differ from the typical picture described above. Comparisons may be useful for a differential diagnosis.Rickets may occur because of vitamin D deficiency, which in turn, reduces the availability to the body of dietary calcium. Calcium is an important mineral for the formation of normal bone tissue. Vitamin-D deficiency can occur at any time of life and may be treated with vitamin D. In infancy or childhood, contributing factors are usually nutritional, sometimes in combination with a lack of sunlight exposure. Malabsorption syndromes in which the intestines do not adequately absorb nutrients from foods may also be a factor. Major symptoms of this type of rickets include bowed legs, bone pain or tenderness, restlessness and slow growth. This disorder occurs in the United States but is most frequent in other areas of the world. Calcium deficiency may also be a contributing factor in the development of nutritional rickets. Osteomalacia in adults may also arise from similar nutritional deficiencies.Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare bone disorder characterized by symptoms associated with hypophosphatemic rickets, including muscle weakness, short stature, skeletal deformities and bone pain. The disorder is inherited in an autosomal recessive pattern. There may be a tendency for the kidneys to develop calcifications or even renal stones. In contrast to XLH, the disorder is not due to elevations in FGF23 levels, but loss of function in a specific transporter protein in the kidney (NPT2c) which acts to retain phosphate. HHRH should be treated differently from XLH, because it does not have the vitamin D abnormalities that are present in the FGF23-mediated forms of hypophosphatemia.Vitamin D-1α hydroxylase deficiency (pseudovitamin D deficiency, or vitamin D-dependent rickets, type I) is usually characterized by more severe skeletal changes and weakness than those usually observed in familial hypophosphatemia. This disorder is caused by abnormal vitamin D metabolism and is inherited in an autosomal recessive pattern. This type of rickets may be evident at even earlier ages than occurs with familial hypophosphatemia. Blood levels of calcium are usually reduced in individuals with vitamin D dependent rickets, although phosphate levels may be normal or mildly decreased. Intermittent muscle cramps may occur. Additional symptoms may include muscle weakness, bowed legs, dental abnormalities, seizures and abnormalities of the spine and pelvis. Hereditary resistance to vitamin D (vitamin D dependent rickets, type II) may present in an identical manner. This is a rare autosomal recessive disorder that can be caused by variants in the gene for an important protein in the body called the vitamin D receptor (VDR), which is required for vitamin D to work properly.Fanconi syndrome is characterized by kidney dysfunction and bone abnormalities like those of familial hypophosphatemia. Excess kidney losses of a variety of substances in addition to phosphate may occur. These include amino acids, bicarbonate, glucose, potassium and uric acid. This disorder may be acquired or genetic with autosomal recessive inheritance. Bone symptoms include rickets in children and softening of bones (osteomalacia) in adults. Fanconi syndrome may be associated with a variety of inherited metabolic disorders such as cystinosis, Lowe’s syndrome, tyrosinemia, hereditary fructose intolerance, Wilson’s disease or galactosemia. | 445 | Familial Hypophosphatemia |
nord_445_5 | Diagnosis of Familial Hypophosphatemia | Diagnosis of Familial Hypophosphatemia. | 445 | Familial Hypophosphatemia |
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nord_445_6 | Therapies of Familial Hypophosphatemia | Treatment
Conventional treatment for XLH has historically consisted of using oral phosphate salts and activated forms of vitamin D such as calcitriol, given in a multiple daily dosing regimen. Symptomatic and supportive measures are important as well. The usual medication regimen must be carefully monitored to prevent excess blood or urinary calcium levels. The approach does not completely cure the disorder. The vitamin D compounds help with phosphate balance and assist with preventing the complications of excessive secretion of parathyroid hormone (PTH). Phosphate enhances the bone healing, but also does not completely cure the disease.Treatment of affected individuals with this combination of vitamin D and phosphate may result in several side effects, including calcium deposits in the kidneys (nephrocalcinosis), excess levels of calcium in the blood (hypercalcemia) and excess levels of calcium in the urine (hypercalciuria).In 2018, burosumab (Crysvita), an antibody that inhibits FGF23 activity, was approved by the U. S. Food and Drug Administration (FDA) to treat adults and children ages one year and older with X-linked hypophosphatemia. Other international regulatory agencies have also approved its use. For children, burosumab is given by subcutaneous injection every 2 weeks, whereas adults are dosed every 4 weeks.Covering teeth with sealants has been suggested as a preventive measure for the spontaneous abscesses associated with familial hypophosphatemia.Genetic counseling is recommended for affected individuals and their families | Therapies of Familial Hypophosphatemia. Treatment
Conventional treatment for XLH has historically consisted of using oral phosphate salts and activated forms of vitamin D such as calcitriol, given in a multiple daily dosing regimen. Symptomatic and supportive measures are important as well. The usual medication regimen must be carefully monitored to prevent excess blood or urinary calcium levels. The approach does not completely cure the disorder. The vitamin D compounds help with phosphate balance and assist with preventing the complications of excessive secretion of parathyroid hormone (PTH). Phosphate enhances the bone healing, but also does not completely cure the disease.Treatment of affected individuals with this combination of vitamin D and phosphate may result in several side effects, including calcium deposits in the kidneys (nephrocalcinosis), excess levels of calcium in the blood (hypercalcemia) and excess levels of calcium in the urine (hypercalciuria).In 2018, burosumab (Crysvita), an antibody that inhibits FGF23 activity, was approved by the U. S. Food and Drug Administration (FDA) to treat adults and children ages one year and older with X-linked hypophosphatemia. Other international regulatory agencies have also approved its use. For children, burosumab is given by subcutaneous injection every 2 weeks, whereas adults are dosed every 4 weeks.Covering teeth with sealants has been suggested as a preventive measure for the spontaneous abscesses associated with familial hypophosphatemia.Genetic counseling is recommended for affected individuals and their families | 445 | Familial Hypophosphatemia |
nord_446_0 | Overview of Familial Isolated Hypoparathyroidism | Familial isolated hypoparathyroidism is a group of rare genetic disorders characterized by parathyroid glands that do not produce or secrete enough parathyroid hormone to maintain normal mineral balance. The parathyroid glands are part of the endocrine system, the network of glands that regulate the chemical processes within the body controlling essential aspects of human development and metabolism throughout the lifespan. Parathyroid hormone plays a vital role in regulating the levels of calcium, magnesium, and phosphorus in the blood. Parathyroid hormone deficiency causes low levels of calcium and magnesium in the blood (hypocalcemia) and high levels of phosphorous.Familial isolated hypoparathyroidism is caused by changes (mutations) in one of several different genes1-4. The first symptoms usually appear in infancy, childhood, or young adulthood. The most common cause of hypoparathyroidism in adults is damage to or removal of the parathyroid glands due to neck surgery. | Overview of Familial Isolated Hypoparathyroidism. Familial isolated hypoparathyroidism is a group of rare genetic disorders characterized by parathyroid glands that do not produce or secrete enough parathyroid hormone to maintain normal mineral balance. The parathyroid glands are part of the endocrine system, the network of glands that regulate the chemical processes within the body controlling essential aspects of human development and metabolism throughout the lifespan. Parathyroid hormone plays a vital role in regulating the levels of calcium, magnesium, and phosphorus in the blood. Parathyroid hormone deficiency causes low levels of calcium and magnesium in the blood (hypocalcemia) and high levels of phosphorous.Familial isolated hypoparathyroidism is caused by changes (mutations) in one of several different genes1-4. The first symptoms usually appear in infancy, childhood, or young adulthood. The most common cause of hypoparathyroidism in adults is damage to or removal of the parathyroid glands due to neck surgery. | 446 | Familial Isolated Hypoparathyroidism |
nord_446_1 | Symptoms of Familial Isolated Hypoparathyroidism | The symptoms of hypoparathyroidism are predominantly due to low levels of calcium in the blood which lead to neuromuscular irritability and manifested by various symptoms which may include numbness, tingling, spasms (tetany) of the hands, feet, or face, and seizures. Other symptoms include fatigue and muscle weakness. The onset of symptoms of familial hypoparathyroidism is usually during early childhood but can occur at any time from birth to adulthood. Seizures during infancy or childhood may be the first sign of the disorder.Chronic hypoparathyroidism in childhood may lead to the underdevelopment of the hard-outer layer of the teeth (enamel hypoplasia). Sudden, muscular spasms affecting the larynx (laryngospasm) cause the closure of the upper end of the trachea blocking normal airflow into the lungs. Affected individuals with long-standing hypoparathyroidism may develop calcium deposits in the brain or the kidneys (nephrocalcinosis). | Symptoms of Familial Isolated Hypoparathyroidism. The symptoms of hypoparathyroidism are predominantly due to low levels of calcium in the blood which lead to neuromuscular irritability and manifested by various symptoms which may include numbness, tingling, spasms (tetany) of the hands, feet, or face, and seizures. Other symptoms include fatigue and muscle weakness. The onset of symptoms of familial hypoparathyroidism is usually during early childhood but can occur at any time from birth to adulthood. Seizures during infancy or childhood may be the first sign of the disorder.Chronic hypoparathyroidism in childhood may lead to the underdevelopment of the hard-outer layer of the teeth (enamel hypoplasia). Sudden, muscular spasms affecting the larynx (laryngospasm) cause the closure of the upper end of the trachea blocking normal airflow into the lungs. Affected individuals with long-standing hypoparathyroidism may develop calcium deposits in the brain or the kidneys (nephrocalcinosis). | 446 | Familial Isolated Hypoparathyroidism |
nord_446_2 | Causes of Familial Isolated Hypoparathyroidism | Familial isolated hypoparathyroidism is caused by variants in genes that directly or indirectly control PTH production or secretion. These genetic variants can be inherited in an autosomal dominant, autosomal recessive, or X-linked recessive pattern.1Parathyroid hormone (PTH) is produced and secreted by the four parathyroid glands that surround the thyroid gland in the neck. PTH is cleaved from a precursor peptide, pre-pro PTH, to an 84-amino acid single-chain peptide hormone (PTH 1-84), which is stored in the parathyroid glands’ secretory granules. The calcium-sensing receptor (CaSR) is a structure on parathyroid cells that responds to low or declining blood calcium levels by stimulating the release of PTH 1-84.2The CASR gene is located on the long arm of chromosome 3 (3q13.3-q21). One mutation of the CASR gene can cause autosomal dominant or sporadic (i.e., a new mutation) hypoparathyroidism. The CASR gene directs the formation of a protein that is found in the parathyroid-producing cells of the parathyroid gland and in various other parts of the body including the kidney, bone, and intestinal tract. Individuals with hypoparathyroidism due to mutations of the CASR gene have diminished parathyroid hormone secretion because the abnormal calcium sensing receptor, also called the calciostat, leads to faulty sensing of elevated levels of blood calcium even when the calcium levels are abnormally low. This disordered calcium sensing leads to excessive calcium excretion. Another rare form of isolated hypoparathyroidism is caused by variants in the GNA11 gene which encodes the Gα11 protein. This protein is directly related to the intracellular portion of the CaSR receptor signaling.The GMC2 (glial cells missing, Drosophilia homologue B) gene encodes a transcription factor protein that plays a critical role in the development of the parathyroid glands. Individuals with hypoparathyroidism due to mutations of the GCM2 gene may have residual, yet extremely low, activity of parathyroid hormone. The GCM2 gene is located on the short arm of chromosome 6 (6q24.2). This mutation has been identified in several families with isolated hypoparathyroidism.Mutations of the parathyroid hormone (PTH) gene can cause both autosomal dominant and recessive hypoparathyroidism. A mutation affecting the mature PTH (1-84) peptide has recently been identified in a family with an autosomal recessive form of hypocalcemia and has been demonstrated to impair binding of the mutant PTH peptide with the PTH receptor (PTH1R).3X-linked recessive hypoparathyroidism is caused by mutations of a gene located on the long arm (q) of the X chromosome (Xq26-q27). This gene plays a critical role in the development of the parathyroid glands.4 | Causes of Familial Isolated Hypoparathyroidism. Familial isolated hypoparathyroidism is caused by variants in genes that directly or indirectly control PTH production or secretion. These genetic variants can be inherited in an autosomal dominant, autosomal recessive, or X-linked recessive pattern.1Parathyroid hormone (PTH) is produced and secreted by the four parathyroid glands that surround the thyroid gland in the neck. PTH is cleaved from a precursor peptide, pre-pro PTH, to an 84-amino acid single-chain peptide hormone (PTH 1-84), which is stored in the parathyroid glands’ secretory granules. The calcium-sensing receptor (CaSR) is a structure on parathyroid cells that responds to low or declining blood calcium levels by stimulating the release of PTH 1-84.2The CASR gene is located on the long arm of chromosome 3 (3q13.3-q21). One mutation of the CASR gene can cause autosomal dominant or sporadic (i.e., a new mutation) hypoparathyroidism. The CASR gene directs the formation of a protein that is found in the parathyroid-producing cells of the parathyroid gland and in various other parts of the body including the kidney, bone, and intestinal tract. Individuals with hypoparathyroidism due to mutations of the CASR gene have diminished parathyroid hormone secretion because the abnormal calcium sensing receptor, also called the calciostat, leads to faulty sensing of elevated levels of blood calcium even when the calcium levels are abnormally low. This disordered calcium sensing leads to excessive calcium excretion. Another rare form of isolated hypoparathyroidism is caused by variants in the GNA11 gene which encodes the Gα11 protein. This protein is directly related to the intracellular portion of the CaSR receptor signaling.The GMC2 (glial cells missing, Drosophilia homologue B) gene encodes a transcription factor protein that plays a critical role in the development of the parathyroid glands. Individuals with hypoparathyroidism due to mutations of the GCM2 gene may have residual, yet extremely low, activity of parathyroid hormone. The GCM2 gene is located on the short arm of chromosome 6 (6q24.2). This mutation has been identified in several families with isolated hypoparathyroidism.Mutations of the parathyroid hormone (PTH) gene can cause both autosomal dominant and recessive hypoparathyroidism. A mutation affecting the mature PTH (1-84) peptide has recently been identified in a family with an autosomal recessive form of hypocalcemia and has been demonstrated to impair binding of the mutant PTH peptide with the PTH receptor (PTH1R).3X-linked recessive hypoparathyroidism is caused by mutations of a gene located on the long arm (q) of the X chromosome (Xq26-q27). This gene plays a critical role in the development of the parathyroid glands.4 | 446 | Familial Isolated Hypoparathyroidism |
nord_446_3 | Affects of Familial Isolated Hypoparathyroidism | Familial isolated hypoparathyroidism, with the exception of the X-linked form, affects males and females in equal numbers. The X-linked form affects males almost exclusively. The exact incidence and prevalence of these disorders in the general population is unknown. Some mild cases may go unrecognized, making it difficult to determine the true frequency of these disorders. | Affects of Familial Isolated Hypoparathyroidism. Familial isolated hypoparathyroidism, with the exception of the X-linked form, affects males and females in equal numbers. The X-linked form affects males almost exclusively. The exact incidence and prevalence of these disorders in the general population is unknown. Some mild cases may go unrecognized, making it difficult to determine the true frequency of these disorders. | 446 | Familial Isolated Hypoparathyroidism |
nord_446_4 | Related disorders of Familial Isolated Hypoparathyroidism | Symptoms of the following disorders can be similar to those of familial isolated hypoparathyroidism. Comparisons may be useful for a differential diagnosis.Hypoparathyroidism can occur as an acquired condition usually through damage caused by neck surgery for another condition (post-surgical hypoparathyroidism). Hypoparathyroidism can also develop as part of a larger syndrome such as in autoimmune polyglandular failure type 1 (APS1) caused by mutations of the autoimmune regulator gene (AIRE) gene causing a recessive form of hypoparathyroidism.5,6 Other complex syndromes include DiGeorge also referred to as chromosome 22q11.2 deletion syndrome, Barakat syndrome (hypoparathyroidism – sensorineural deafness – renal disease), Kenney-Caffey disease, Sanjad-Sakati syndrome (hypoparathyroidism – retardation – dysmorphism), and mitochondrial disorders such as Kearns-Sayre syndrome or MELAS syndrome. In some cases, hypoparathyroidism may occur in association with Wilson disease (due to copper accumulating in the parathyroid glands) or hemochromatosis (due to iron accumulating in the parathyroid glands). (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)Albright’s hereditary osteodystrophy is a rare disorder characterized by the resistance to parathyroid hormone. Unlike hypoparathyroidism, which is associated with low levels of functional parathyroid hormone, individuals with Albright’s hereditary osteodystrophy produce normal or elevated levels of parathyroid hormone, but the response to the hormone is not normal. This disorder is referred to as PTH resistance. | Related disorders of Familial Isolated Hypoparathyroidism. Symptoms of the following disorders can be similar to those of familial isolated hypoparathyroidism. Comparisons may be useful for a differential diagnosis.Hypoparathyroidism can occur as an acquired condition usually through damage caused by neck surgery for another condition (post-surgical hypoparathyroidism). Hypoparathyroidism can also develop as part of a larger syndrome such as in autoimmune polyglandular failure type 1 (APS1) caused by mutations of the autoimmune regulator gene (AIRE) gene causing a recessive form of hypoparathyroidism.5,6 Other complex syndromes include DiGeorge also referred to as chromosome 22q11.2 deletion syndrome, Barakat syndrome (hypoparathyroidism – sensorineural deafness – renal disease), Kenney-Caffey disease, Sanjad-Sakati syndrome (hypoparathyroidism – retardation – dysmorphism), and mitochondrial disorders such as Kearns-Sayre syndrome or MELAS syndrome. In some cases, hypoparathyroidism may occur in association with Wilson disease (due to copper accumulating in the parathyroid glands) or hemochromatosis (due to iron accumulating in the parathyroid glands). (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)Albright’s hereditary osteodystrophy is a rare disorder characterized by the resistance to parathyroid hormone. Unlike hypoparathyroidism, which is associated with low levels of functional parathyroid hormone, individuals with Albright’s hereditary osteodystrophy produce normal or elevated levels of parathyroid hormone, but the response to the hormone is not normal. This disorder is referred to as PTH resistance. | 446 | Familial Isolated Hypoparathyroidism |
nord_446_5 | Diagnosis of Familial Isolated Hypoparathyroidism | The diagnosis of familial isolated hypoparathyroidism is made based upon the identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Blood tests should include measurement of intact parathyroid hormone, calcium, phosphorous, and magnesium. Additionally, the measurement of urine mineral levels is important to identify the unusual clinical presentation associated with a heterozygous activating CaSR mutation resulting in familial hypercalciuric hypocalcemia. Urine calcium and magnesium levels are elevated in this disorder. Molecular genetic testing may confirm the diagnosis of hypoparathyroidism. This is an important first step in identifying hypoparathyroidism in family members. | Diagnosis of Familial Isolated Hypoparathyroidism. The diagnosis of familial isolated hypoparathyroidism is made based upon the identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Blood tests should include measurement of intact parathyroid hormone, calcium, phosphorous, and magnesium. Additionally, the measurement of urine mineral levels is important to identify the unusual clinical presentation associated with a heterozygous activating CaSR mutation resulting in familial hypercalciuric hypocalcemia. Urine calcium and magnesium levels are elevated in this disorder. Molecular genetic testing may confirm the diagnosis of hypoparathyroidism. This is an important first step in identifying hypoparathyroidism in family members. | 446 | Familial Isolated Hypoparathyroidism |
nord_446_6 | Therapies of Familial Isolated Hypoparathyroidism | Treatment is aimed at raising calcium levels high enough to provide symptom relief without causing abnormally high levels of calcium excretion in the urine (hypercalciuria). Vitamin D analogs and calcium supplements are the conventional FDA approved therapy for all forms of hypoparathyroidism. The main form of active vitamin D used for individuals with hypoparathyroidism is 1,25 OH vitamin D3, calcitriol. Two other synthetic forms of vitamin D that are often used are cholecalciferol and dihydrotachysterol. These forms of vitamin D have a longer duration of action than calcitriol. Many individuals receive a combination of shorter and longer acting vitamin D analogs.Patients with hypoparathyroidism are encouraged to eat foods high in calcium such as dairy products, breakfast cereals, fortified orange juice and green, leafy vegetables.7PTH Replacement TherapyA synthetic human N-terminal fragment of PTH (PTH 1-34), with full biological activity, has been used as an investigational hormonal replacement therapy of chronic hypoparathyroidism over the past two decades.8,9 Initial studies have shown decreased urinary calcium excretion compared to conventional therapy.10 Long-term controlled studies in both adults and children comparing PTH 1-34 with conventional therapy have demonstrated both safety and efficacy of twice daily PTH injections.11,12 Moreover, insulin pump delivery of PTH 1-34 provides the most physiologic approach to replacement therapy.13,14The 2002 FDA approved recombinant parathyroid hormone 1-34 (Forteo®, Teriparatide) for the treatment of severe osteoporosis. Forteo has been used off-label for treatment of hypoparathyroidism. Many individuals with hypoparathyroidism worldwide have reported improvement in their symptoms when treated with teriparatide, which is usually given as an injection under the skin (subcutaneously) once or twice a day.14,15In 2015, the FDA approved the recombinant form of parathyroid hormone 1-84 (Narpara) as an adjunct to conventional therapy in the treatment of individuals with refractory hypoparathyroidism.16,17 In August 2019, Natpara was removed from the market due to safety concerns with the pen injector. | Therapies of Familial Isolated Hypoparathyroidism. Treatment is aimed at raising calcium levels high enough to provide symptom relief without causing abnormally high levels of calcium excretion in the urine (hypercalciuria). Vitamin D analogs and calcium supplements are the conventional FDA approved therapy for all forms of hypoparathyroidism. The main form of active vitamin D used for individuals with hypoparathyroidism is 1,25 OH vitamin D3, calcitriol. Two other synthetic forms of vitamin D that are often used are cholecalciferol and dihydrotachysterol. These forms of vitamin D have a longer duration of action than calcitriol. Many individuals receive a combination of shorter and longer acting vitamin D analogs.Patients with hypoparathyroidism are encouraged to eat foods high in calcium such as dairy products, breakfast cereals, fortified orange juice and green, leafy vegetables.7PTH Replacement TherapyA synthetic human N-terminal fragment of PTH (PTH 1-34), with full biological activity, has been used as an investigational hormonal replacement therapy of chronic hypoparathyroidism over the past two decades.8,9 Initial studies have shown decreased urinary calcium excretion compared to conventional therapy.10 Long-term controlled studies in both adults and children comparing PTH 1-34 with conventional therapy have demonstrated both safety and efficacy of twice daily PTH injections.11,12 Moreover, insulin pump delivery of PTH 1-34 provides the most physiologic approach to replacement therapy.13,14The 2002 FDA approved recombinant parathyroid hormone 1-34 (Forteo®, Teriparatide) for the treatment of severe osteoporosis. Forteo has been used off-label for treatment of hypoparathyroidism. Many individuals with hypoparathyroidism worldwide have reported improvement in their symptoms when treated with teriparatide, which is usually given as an injection under the skin (subcutaneously) once or twice a day.14,15In 2015, the FDA approved the recombinant form of parathyroid hormone 1-84 (Narpara) as an adjunct to conventional therapy in the treatment of individuals with refractory hypoparathyroidism.16,17 In August 2019, Natpara was removed from the market due to safety concerns with the pen injector. | 446 | Familial Isolated Hypoparathyroidism |
nord_447_0 | Overview of Familial Lipoprotein Lipase Deficiency | SummaryFamilial lipoprotein lipase (LPL) deficiency is a rare genetic metabolic disorder characterized by a deficiency of the enzyme lipoprotein lipase. Deficiency of this enzyme prevents affected individuals from properly digesting certain fats and results in massive accumulation of fatty droplets called chylomicrons in the circulation (chylomicronemia) and consequently also an increase of the plasma concentration of fatty substances called triglycerides. Affected individuals often experience episodes of abdominal pain, acute recurrent inflammation of the pancreas (pancreatitis), abnormal enlargement of the liver and/or spleen (hepatosplenomegaly), and the development of skin lesions known as eruptive xanthomas. Familial LPL deficiency is caused by changes (mutations) in the lipoprotein lipase (LPL) gene and is inherited in an autosomal recessive pattern. Recently, mutations in other genes besides LPL were found to cause a clinical picture similar to LPL deficiency.IntroductionChylomicronemia syndrome is a general term for the symptoms that develop due to the accumulation of chylomicrons in the plasma. There are many causes of chylomicronemia syndrome. The term familial chylomicronemia is sometimes used synonymously with familial lipoprotein lipase deficiency. However, there are different causes of familial chylomicronemia. In the past, familial lipoprotein lipase deficiency has also been called hyperlipoproteinemia type I. Familial LPL deficiency was first described in the medical literature in 1932 by Drs. Burger and Grutz. | Overview of Familial Lipoprotein Lipase Deficiency. SummaryFamilial lipoprotein lipase (LPL) deficiency is a rare genetic metabolic disorder characterized by a deficiency of the enzyme lipoprotein lipase. Deficiency of this enzyme prevents affected individuals from properly digesting certain fats and results in massive accumulation of fatty droplets called chylomicrons in the circulation (chylomicronemia) and consequently also an increase of the plasma concentration of fatty substances called triglycerides. Affected individuals often experience episodes of abdominal pain, acute recurrent inflammation of the pancreas (pancreatitis), abnormal enlargement of the liver and/or spleen (hepatosplenomegaly), and the development of skin lesions known as eruptive xanthomas. Familial LPL deficiency is caused by changes (mutations) in the lipoprotein lipase (LPL) gene and is inherited in an autosomal recessive pattern. Recently, mutations in other genes besides LPL were found to cause a clinical picture similar to LPL deficiency.IntroductionChylomicronemia syndrome is a general term for the symptoms that develop due to the accumulation of chylomicrons in the plasma. There are many causes of chylomicronemia syndrome. The term familial chylomicronemia is sometimes used synonymously with familial lipoprotein lipase deficiency. However, there are different causes of familial chylomicronemia. In the past, familial lipoprotein lipase deficiency has also been called hyperlipoproteinemia type I. Familial LPL deficiency was first described in the medical literature in 1932 by Drs. Burger and Grutz. | 447 | Familial Lipoprotein Lipase Deficiency |
nord_447_1 | Symptoms of Familial Lipoprotein Lipase Deficiency | Most cases of familial LPL deficiency are identified during childhood, usually before the age of 10. In approximately 25 percent of patients, the disorder is identified during the first year of life. Some affected individuals may not be identified until adulthood. For example, some women may not be diagnosed until after becoming pregnant or when they begin taking contraceptive medication.The severity of familial LPL deficiency varies depending upon the degree of chylomicronemia, which fluctuates depending upon the amount fat in an individual’s diet. The main symptoms are abdominal pain, pancreatitis, eruptive xanthomas and hepatosplenomegaly.The most common symptom of familial LPL deficiency is episodic abdominal pain. The severity of abdominal pain can vary, ranging from mild to severe and, in some people, can be incapacitating. The pain may be located in the upper, central region (epigastric area) of the abdomen and can radiate to cause back pain. In some people, the pain may be widespread (diffuse) and can potentially resemble acute abdomen (peritonitis). In the past, this has led to unnecessary surgery.Abdominal pain in individuals with familial LPL deficiency may result from recurrent episodes of inflammation of the pancreas (pancreatitis). The pancreas is a small gland located behind the stomach. The pancreas secretes enzymes that travel to the intestines to aid in digestion and hormones that have specialized roles in the body. The main symptom of pancreatitis is pain, which is sometimes intense, and is most often felt in the upper left side or middle of the abdomen. Pancreatitis can also cause nausea, sweating, weakness, chills, clammy skin, and mild yellowing of the skin or whites of the eyes (jaundice). Some individuals will develop acute, recurrent pancreatitis, which can potentially be lethal.Chronic pancreatitis can be associated with additional complications including diabetes, hardening of the pancreas due to the accumulation of calcium salts (pancreatic calcification) and stools containing excess amounts of fat causing them to be frothy, foul smelling and to float (steatorrhea). However, these complications are unusual in individuals with familial LPL deficiency. Even in individuals with recurrent episodes of pancreatitis, such complications rarely develop until middle age. Although rare, pancreatitis in LPL deficiency can cause severe, life-threatening complications.Enlargement of the liver and spleen (hepatosplenomegaly) can also occur, especially in infants and young children. The degree of enlargement varies, often in conjunction with the amount of fat in the diet. Hepatosplenomegaly is caused by the accumulation of a special type of macrophage. Macrophages are white blood cells that ingest foreign or harmful substances. In familial LPL deficiency, macrophages ingest excess triglyceride and transform into foam cells. Foam cells are specialized macrophages that attempt to deal with excess fat in the body and usually contain fatty materials. Foam cells in individuals with familial LPL deficiency abnormally accumulate in the bone marrow, liver and spleen.Approximately 50 percent of affected individuals develop eruptive cutaneous xanthomas, which are skin lesions make up of certain fats (lipids). Xanthomas may appear as raised, reddish-yellow bumps or nodules on the skin. They often occur on the buttocks, knees and outer arms. Individuals lesions may measure about 1 millimeter in size, but xanthomas often cluster and may grow together (coalesce) to form larger lesions. Eruptive xanthomas are generally not painful or tender, unless they develop on an area of the body where they suffer repeated trauma or abrasion. Xanthomas usually appear within a few days after triglyceride levels in the plasma have begun to increase. They may contain a greasy, yellowish substance and sometimes a milky fluid. Xanthomas will disappear over a period of weeks to months as the amount of triglyceride in the plasma decreases. The persistent presence of xanthomas in individuals with familial LPL deficiency indicates inadequate therapy to lower triglyceride levels.In the presence of excessive fatty substances in the circulation the small arteries (arterioles) and small veins (venules) in the outer parts of the retina and the back of the eyeball (fundus) may appear pale pink upon examination by an eye specialist (ophthalmologist). This condition may be referred to as “lipemia retinalis”. The change is related to the degree of fatty build up (i.e., large chylomicrons), which causes incoming light to scatter. This discoloration is reversible and does not affect the vision of individuals with familial LPL deficiency.Additional symptoms have been reported in some individuals with familial LPL deficiency including a variety of reversible neuropsychiatric findings such as depression, memory loss and dementia.Some individuals with familial LPL deficiency have developed premature atherosclerosis, which is characterized by thickening and obstruction of various blood vessels due to the accumulation of fatty material, potentially causing coronary heart disease or peripheral vascular disease. However, most researchers do not believe that individuals with familial LPL deficiency have an increased risk of developing atherosclerosis. | Symptoms of Familial Lipoprotein Lipase Deficiency. Most cases of familial LPL deficiency are identified during childhood, usually before the age of 10. In approximately 25 percent of patients, the disorder is identified during the first year of life. Some affected individuals may not be identified until adulthood. For example, some women may not be diagnosed until after becoming pregnant or when they begin taking contraceptive medication.The severity of familial LPL deficiency varies depending upon the degree of chylomicronemia, which fluctuates depending upon the amount fat in an individual’s diet. The main symptoms are abdominal pain, pancreatitis, eruptive xanthomas and hepatosplenomegaly.The most common symptom of familial LPL deficiency is episodic abdominal pain. The severity of abdominal pain can vary, ranging from mild to severe and, in some people, can be incapacitating. The pain may be located in the upper, central region (epigastric area) of the abdomen and can radiate to cause back pain. In some people, the pain may be widespread (diffuse) and can potentially resemble acute abdomen (peritonitis). In the past, this has led to unnecessary surgery.Abdominal pain in individuals with familial LPL deficiency may result from recurrent episodes of inflammation of the pancreas (pancreatitis). The pancreas is a small gland located behind the stomach. The pancreas secretes enzymes that travel to the intestines to aid in digestion and hormones that have specialized roles in the body. The main symptom of pancreatitis is pain, which is sometimes intense, and is most often felt in the upper left side or middle of the abdomen. Pancreatitis can also cause nausea, sweating, weakness, chills, clammy skin, and mild yellowing of the skin or whites of the eyes (jaundice). Some individuals will develop acute, recurrent pancreatitis, which can potentially be lethal.Chronic pancreatitis can be associated with additional complications including diabetes, hardening of the pancreas due to the accumulation of calcium salts (pancreatic calcification) and stools containing excess amounts of fat causing them to be frothy, foul smelling and to float (steatorrhea). However, these complications are unusual in individuals with familial LPL deficiency. Even in individuals with recurrent episodes of pancreatitis, such complications rarely develop until middle age. Although rare, pancreatitis in LPL deficiency can cause severe, life-threatening complications.Enlargement of the liver and spleen (hepatosplenomegaly) can also occur, especially in infants and young children. The degree of enlargement varies, often in conjunction with the amount of fat in the diet. Hepatosplenomegaly is caused by the accumulation of a special type of macrophage. Macrophages are white blood cells that ingest foreign or harmful substances. In familial LPL deficiency, macrophages ingest excess triglyceride and transform into foam cells. Foam cells are specialized macrophages that attempt to deal with excess fat in the body and usually contain fatty materials. Foam cells in individuals with familial LPL deficiency abnormally accumulate in the bone marrow, liver and spleen.Approximately 50 percent of affected individuals develop eruptive cutaneous xanthomas, which are skin lesions make up of certain fats (lipids). Xanthomas may appear as raised, reddish-yellow bumps or nodules on the skin. They often occur on the buttocks, knees and outer arms. Individuals lesions may measure about 1 millimeter in size, but xanthomas often cluster and may grow together (coalesce) to form larger lesions. Eruptive xanthomas are generally not painful or tender, unless they develop on an area of the body where they suffer repeated trauma or abrasion. Xanthomas usually appear within a few days after triglyceride levels in the plasma have begun to increase. They may contain a greasy, yellowish substance and sometimes a milky fluid. Xanthomas will disappear over a period of weeks to months as the amount of triglyceride in the plasma decreases. The persistent presence of xanthomas in individuals with familial LPL deficiency indicates inadequate therapy to lower triglyceride levels.In the presence of excessive fatty substances in the circulation the small arteries (arterioles) and small veins (venules) in the outer parts of the retina and the back of the eyeball (fundus) may appear pale pink upon examination by an eye specialist (ophthalmologist). This condition may be referred to as “lipemia retinalis”. The change is related to the degree of fatty build up (i.e., large chylomicrons), which causes incoming light to scatter. This discoloration is reversible and does not affect the vision of individuals with familial LPL deficiency.Additional symptoms have been reported in some individuals with familial LPL deficiency including a variety of reversible neuropsychiatric findings such as depression, memory loss and dementia.Some individuals with familial LPL deficiency have developed premature atherosclerosis, which is characterized by thickening and obstruction of various blood vessels due to the accumulation of fatty material, potentially causing coronary heart disease or peripheral vascular disease. However, most researchers do not believe that individuals with familial LPL deficiency have an increased risk of developing atherosclerosis. | 447 | Familial Lipoprotein Lipase Deficiency |
nord_447_2 | Causes of Familial Lipoprotein Lipase Deficiency | Familial LPL deficiency is caused by changes (mutations) in the LPL gene. The LPL gene contains instructions for creating (encoding) an enzyme known as lipoprotein lipase. This enzyme is essential for the proper breakdown of certain fats in the body. Fat is obtained through the diet and is absorbed by the intestines. It is transported in the form of triglyceride by large lipoproteins known as chylomicrons. (Triglycerides are fatty molecules that are used by the cells of the body for fuel.) When chylomicrons are released into the bloodstream, a protein within chylomicrons called apolipoprotein C2 is activated. This protein is recognized by the enzyme lipoprotein lipase, ultimately resulting in the breakdown of triglyceride. When lipoprotein lipase is inadequate or impaired, chylomicrons accumulate in the plasma, which, in turn, causes abnormal amounts of triglyceride to accumulate in the plasma as well. The accumulation of excess.Familial LPL deficiency is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.Individuals who inherit one mutated gene and one normal gene (heterozygotes) do not develop familial LPL deficiency. However, these individuals may have a slightly increased risk of developing mixed dyslipidemia with low HDL cholesterol levels. Heterozygotes may also be more susceptible to developing atherosclerosis than non-carriers, especially if they gain weight or remain on a high fat diet. | Causes of Familial Lipoprotein Lipase Deficiency. Familial LPL deficiency is caused by changes (mutations) in the LPL gene. The LPL gene contains instructions for creating (encoding) an enzyme known as lipoprotein lipase. This enzyme is essential for the proper breakdown of certain fats in the body. Fat is obtained through the diet and is absorbed by the intestines. It is transported in the form of triglyceride by large lipoproteins known as chylomicrons. (Triglycerides are fatty molecules that are used by the cells of the body for fuel.) When chylomicrons are released into the bloodstream, a protein within chylomicrons called apolipoprotein C2 is activated. This protein is recognized by the enzyme lipoprotein lipase, ultimately resulting in the breakdown of triglyceride. When lipoprotein lipase is inadequate or impaired, chylomicrons accumulate in the plasma, which, in turn, causes abnormal amounts of triglyceride to accumulate in the plasma as well. The accumulation of excess.Familial LPL deficiency is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.Individuals who inherit one mutated gene and one normal gene (heterozygotes) do not develop familial LPL deficiency. However, these individuals may have a slightly increased risk of developing mixed dyslipidemia with low HDL cholesterol levels. Heterozygotes may also be more susceptible to developing atherosclerosis than non-carriers, especially if they gain weight or remain on a high fat diet. | 447 | Familial Lipoprotein Lipase Deficiency |
nord_447_3 | Affects of Familial Lipoprotein Lipase Deficiency | Familial LPL deficiency affects males and females in equal numbers. It is estimated to occur in approximately 1 in 250,000 people in the general population and has been described in all races. The prevalence is much higher in Quebec, Canada due to a founder effect. A founder effect is when a small isolated population of settlers (founders) expands over several generations leading to a high prevalence of a particular genetic trait. | Affects of Familial Lipoprotein Lipase Deficiency. Familial LPL deficiency affects males and females in equal numbers. It is estimated to occur in approximately 1 in 250,000 people in the general population and has been described in all races. The prevalence is much higher in Quebec, Canada due to a founder effect. A founder effect is when a small isolated population of settlers (founders) expands over several generations leading to a high prevalence of a particular genetic trait. | 447 | Familial Lipoprotein Lipase Deficiency |
nord_447_4 | Related disorders of Familial Lipoprotein Lipase Deficiency | Symptoms of the following disorders can be similar to those of familial LPL deficiency. Comparisons may be useful for a differential diagnosis.Abnormally high levels of triglyceride in the plasma (hypertriglyceridemia) can be caused by many different conditions including alcohol consumption, diabetes mellitus, and paraproteinemic disorders. Certain medications can also be associated with hypertriglyceridemia including estrogen, glucocorticoids, isotretinoin, Zoloft®, and certain drugs used to treat high blood pressure.Several rare genetic disorders can be associated chylomicronemia including familial apolipoprotein C-II deficiency, familial apoAV deficiency, and familial lipase maturation factor 1 (LMF1) deficiency. Familial apolipoprotein C-II deficiency is particularly similar to familial LPL deficiency. However, in familial apolipoprotein C-II deficiency, affected individuals generally develop chronic pancreatic insufficiency with foul smelling, fatty stools (steatorrhea) and insulin-dependent diabetes mellitus. In addition, age of onset is generally later in life (13-60 years) than is found with familial LPL deficiency. Familial apolipoprotein C-II is caused by mutations of the APOC2 gene and is inherited in an autosomal recessive pattern. | Related disorders of Familial Lipoprotein Lipase Deficiency. Symptoms of the following disorders can be similar to those of familial LPL deficiency. Comparisons may be useful for a differential diagnosis.Abnormally high levels of triglyceride in the plasma (hypertriglyceridemia) can be caused by many different conditions including alcohol consumption, diabetes mellitus, and paraproteinemic disorders. Certain medications can also be associated with hypertriglyceridemia including estrogen, glucocorticoids, isotretinoin, Zoloft®, and certain drugs used to treat high blood pressure.Several rare genetic disorders can be associated chylomicronemia including familial apolipoprotein C-II deficiency, familial apoAV deficiency, and familial lipase maturation factor 1 (LMF1) deficiency. Familial apolipoprotein C-II deficiency is particularly similar to familial LPL deficiency. However, in familial apolipoprotein C-II deficiency, affected individuals generally develop chronic pancreatic insufficiency with foul smelling, fatty stools (steatorrhea) and insulin-dependent diabetes mellitus. In addition, age of onset is generally later in life (13-60 years) than is found with familial LPL deficiency. Familial apolipoprotein C-II is caused by mutations of the APOC2 gene and is inherited in an autosomal recessive pattern. | 447 | Familial Lipoprotein Lipase Deficiency |
nord_447_5 | Diagnosis of Familial Lipoprotein Lipase Deficiency | A diagnosis of familial LPL deficiency may be suspected based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and certain tests including blood tests.Clinical Testing and WorkupBlood tests can reveal reduced activity of the lipoprotein lipase enzyme in the plasma, following intravenous administration of heparin. Heparin is a substance normally found in the liver that stimulates the release of lipoprotein lipase in the body.A diagnosis of familial LPL deficiency can be confirmed by the molecular genetic testing for mutations in the LPL gene. Molecular genetic testing is available through commercial and academic research laboratories. | Diagnosis of Familial Lipoprotein Lipase Deficiency. A diagnosis of familial LPL deficiency may be suspected based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and certain tests including blood tests.Clinical Testing and WorkupBlood tests can reveal reduced activity of the lipoprotein lipase enzyme in the plasma, following intravenous administration of heparin. Heparin is a substance normally found in the liver that stimulates the release of lipoprotein lipase in the body.A diagnosis of familial LPL deficiency can be confirmed by the molecular genetic testing for mutations in the LPL gene. Molecular genetic testing is available through commercial and academic research laboratories. | 447 | Familial Lipoprotein Lipase Deficiency |
nord_447_6 | Therapies of Familial Lipoprotein Lipase Deficiency | Treatment
A proportion of LPL deficient individuals can be successfully treated by dietary restriction of fats, but many are still plagued by recurrent abdominal pain and episodes of acute pancreatitis. The goal of restricting fat intake is to reduce chylomicronemia and hypertriglyceridemia enough to prevent symptoms. Many individuals learn on their own to avoid foods containing fat. However, many physicians recommend reducing fat intake significantly to no more than 20 g/day or 15 percent of total energy intake in order to prevent symptoms.Drugs that lower lipid levels in the body are not effective in reducing fat levels in individuals with familial LPL deficiency. Alcohol and drugs that increase triglyceride levels should be avoided. Such drugs include oral contraceptives, diuretics, beta-adrenergic blocking agents, isotretinoin and Zoloft®.Medium chain fatty acids can be used for cooking because they are absorbed directly by the portal vein of the liver. Many individuals have been successfully treated with a diet rich in medium chain fatty acids. Fish oil supplements are not effective for individuals with familial LPL deficiency and are contraindicated.An enlarged liver or spleen will usually shrink to normal size within one week of reducing triglyceride levels. Eruptive xanthomas usually clear up within several weeks to months. If xanthomas persist or recur despite treatment, it indicates inadequate therapeutic efforts.Pancreatitis is treated following standard guidelines.Genetic counseling is recommended for affected individuals and their families.Gene TherapyIn 2012, the European Commission approved the marketing authorization of alipogene tiparvovec gene therapy (Glybera®) developed UniQure for the treatment of individuals with familial LPL deficiency. Glybera was the first approved gene therapy in the Western world but was never approved in the US. In 2017, Glybera was taken off the market by UniQure due to low demand from the patient community. | Therapies of Familial Lipoprotein Lipase Deficiency. Treatment
A proportion of LPL deficient individuals can be successfully treated by dietary restriction of fats, but many are still plagued by recurrent abdominal pain and episodes of acute pancreatitis. The goal of restricting fat intake is to reduce chylomicronemia and hypertriglyceridemia enough to prevent symptoms. Many individuals learn on their own to avoid foods containing fat. However, many physicians recommend reducing fat intake significantly to no more than 20 g/day or 15 percent of total energy intake in order to prevent symptoms.Drugs that lower lipid levels in the body are not effective in reducing fat levels in individuals with familial LPL deficiency. Alcohol and drugs that increase triglyceride levels should be avoided. Such drugs include oral contraceptives, diuretics, beta-adrenergic blocking agents, isotretinoin and Zoloft®.Medium chain fatty acids can be used for cooking because they are absorbed directly by the portal vein of the liver. Many individuals have been successfully treated with a diet rich in medium chain fatty acids. Fish oil supplements are not effective for individuals with familial LPL deficiency and are contraindicated.An enlarged liver or spleen will usually shrink to normal size within one week of reducing triglyceride levels. Eruptive xanthomas usually clear up within several weeks to months. If xanthomas persist or recur despite treatment, it indicates inadequate therapeutic efforts.Pancreatitis is treated following standard guidelines.Genetic counseling is recommended for affected individuals and their families.Gene TherapyIn 2012, the European Commission approved the marketing authorization of alipogene tiparvovec gene therapy (Glybera®) developed UniQure for the treatment of individuals with familial LPL deficiency. Glybera was the first approved gene therapy in the Western world but was never approved in the US. In 2017, Glybera was taken off the market by UniQure due to low demand from the patient community. | 447 | Familial Lipoprotein Lipase Deficiency |
nord_448_0 | Overview of Familial Partial Lipodystrophy | Summary
Familial partial lipodystrophy (FPL) is a rare genetic disorder characterized by selective, progressive loss of body fat (adipose tissue) from various areas of the body. Individuals with FPL often have reduced subcutaneous fat in the arms and legs and the head and trunk regions may or may not have loss of fat. Conversely, affected individuals may also have excess subcutaneous fat accumulation in other areas of the body, especially the neck, face and intra-abdominal regions. Subcutaneous fat is the fatty or adipose tissue layer that lies directly beneath the skin. In most cases, adipose tissue loss begins during puberty. FPL can be associated with a variety of metabolic abnormalities. The extent of adipose tissue loss usually determines the severity of the associated metabolic complications. These complications can include an inability to properly breakdown a simple sugar known as glucose (glucose intolerance), elevated levels of triglycerides (fat) in the blood (hypertriglyceridemia), and diabetes. Additional findings can occur in some cases. Six different subtypes of FPL have been identified. Each subtype is caused by a mutation in a different gene. Four forms of FPL are inherited as autosomal dominant traits; one form is inherited as an autosomal recessive trait. The mode of inheritance of FPL, Kobberling variety is unknown.
Introduction
Lipodystrophy is a general term for a group of disorders that are characterized by complete (generalized) or partial loss of adipose tissue. In addition to FPL, there are other inherited forms of lipodystrophy. Some forms of lipodystrophy are acquired at some point during life. The degree of severity and the specific areas of the body affected can vary greatly among the lipodystrophies. Some individuals may only develop cosmetic problems; other can develop life-threatening complications. The loss of adipose tissue that characterizes these disorders is sometimes referred to as lipoatrophy rather than lipodystrophy by some physicians. FPL was first described in the medical literature in 1970s independently by three groups of physicians, including Doctors Ozer, Kobberling and Dunnigan. | Overview of Familial Partial Lipodystrophy. Summary
Familial partial lipodystrophy (FPL) is a rare genetic disorder characterized by selective, progressive loss of body fat (adipose tissue) from various areas of the body. Individuals with FPL often have reduced subcutaneous fat in the arms and legs and the head and trunk regions may or may not have loss of fat. Conversely, affected individuals may also have excess subcutaneous fat accumulation in other areas of the body, especially the neck, face and intra-abdominal regions. Subcutaneous fat is the fatty or adipose tissue layer that lies directly beneath the skin. In most cases, adipose tissue loss begins during puberty. FPL can be associated with a variety of metabolic abnormalities. The extent of adipose tissue loss usually determines the severity of the associated metabolic complications. These complications can include an inability to properly breakdown a simple sugar known as glucose (glucose intolerance), elevated levels of triglycerides (fat) in the blood (hypertriglyceridemia), and diabetes. Additional findings can occur in some cases. Six different subtypes of FPL have been identified. Each subtype is caused by a mutation in a different gene. Four forms of FPL are inherited as autosomal dominant traits; one form is inherited as an autosomal recessive trait. The mode of inheritance of FPL, Kobberling variety is unknown.
Introduction
Lipodystrophy is a general term for a group of disorders that are characterized by complete (generalized) or partial loss of adipose tissue. In addition to FPL, there are other inherited forms of lipodystrophy. Some forms of lipodystrophy are acquired at some point during life. The degree of severity and the specific areas of the body affected can vary greatly among the lipodystrophies. Some individuals may only develop cosmetic problems; other can develop life-threatening complications. The loss of adipose tissue that characterizes these disorders is sometimes referred to as lipoatrophy rather than lipodystrophy by some physicians. FPL was first described in the medical literature in 1970s independently by three groups of physicians, including Doctors Ozer, Kobberling and Dunnigan. | 448 | Familial Partial Lipodystrophy |
nord_448_1 | Symptoms of Familial Partial Lipodystrophy | FPL encompasses several subtypes differentiated by the underlying genetic mutation. The specific symptoms present, severity, and prognosis can vary greatly depending upon the specific type of FPL and the presence and extent of associated symptoms. The specific symptoms and severity can also vary among individuals with the same subtype and even among members of the same family. In addition, some subtypes of FPL have only been reported in a handful of individuals, which prevents physicians from developing an accurate picture of associated symptoms, severity, and prognosis. Therefore, it is important to note that affected individuals will not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms, and overall prognosis.
Common symptoms of FPL include selective, progressive loss of subcutaneous fat in the arms and legs and chest and trunk regions, abnormal accumulation of subcutaneous fat in other areas, and a variety of metabolic complications. Generally, women are more severely affected than men by the metabolic complications of FPL. Additional symptoms including those affecting the liver or heart may also occur.
FPL Type 2, Dunnigan Variety (FPL2)
This is the most common form of FPL. Affected individuals usually have normal fat distribution during early childhood. However, around the time of puberty, fat in the arms and legs and trunk is gradually lost. In women, the loss of fat may be most striking in the buttocks and hips. At this time, fat may accumulate in other areas of the body including the face, causing a double chin, and the neck and upper back between the shoulder blades, causing a hump. Affected individuals may have a round face similar to individuals with Cushing’s syndrome. This characteristic distribution of fat and the overall muscular appearance makes the disorder more easily recognizable in women than men.
Insulin resistance is common and may be associated with a condition called acanthosis nigricans, a skin condition characterized by abnormally increased coloration (hyperpigmentation) and “velvety” thickening (hyperkeratosis) of the skin, particularly of skin fold regions, such as of the neck and groin and under the arms (axillae). An enlarged liver (hepatomegaly) is also common. Hepatomegaly is caused by the accumulation of fat in the liver (fatty liver or steatosis). Progressive accumulation of fat in the liver can cause scarring and damage to the liver (cirrhosis) and, eventually, liver dysfunction.
Other complications of insulin resistance may occur including glucose intolerance, hypertriglyceridemia, and diabetes. These symptoms are often very difficult to control and diabetes is often severe. Affected women are at a greater risk of developing diabetes than affected men and often experience more severe metabolic complications. Some individuals may experience extreme hypertriglyceridemia, resulting in episodes of acute inflammation of the pancreas (pancreatitis). Pancreatitis can be associated with abdominal pain, chills, jaundice, weakness, sweating, vomiting, and weight loss.
After puberty, some women with FPL may develop polycystic ovary syndrome (PCOS), a complex of symptoms that are not always present in every case. PCOS is often characterized by an imbalance of sex hormones as affected women may have too much androgen, a male hormone, in the body. PCOS can result in irregular menstrual periods or a lack of menstruation, oily skin that is prone to acne, cysts on the ovaries, failure of the ovary to release eggs, and mild hirsutism (a male pattern of hair growth). Hair may develop on the upper lip, chin and other parts of the body.
Individuals with FPL, Dunnigan variety are predisposed to coronary artery disease and other types of atherosclerotic vascular disease. In rare cases, in which individuals have a specific mutation of the lamin A/C (LMNA) gene, they are at an increased risk of developing disease of the heart muscles (cardiomyopathy), which can result in congestive heart failure and irregular heartbeats (cardiac arrhythmias) such as heart block or atrial fibrillation. Some individuals also develop muscular dystrophies (diseases of muscles causing loss of strength and joint contractures).
FPL Type 1, Kobberling Variety (FPL1)
This form of FPL has only been reported in a handful of individuals. The symptoms are similar to those seen in FPL2, Dunnigan variety. However, fat loss is generally confined to the arms and legs. Fat loss is usually more prominent on the lower (distal) portions of the arms and legs. Affected individuals have normal or slightly increased fat distribution on the face, neck, and trunk. In addition, some affected individuals may develop excess belly fat (central obesity). Metabolic abnormalities including insulin resistance, high blood pressure (hypertension), and severe hypertriglyceridemia have also been reported. This form of FPL has only been reported in women.
FPL Type 3, due to PPARG Mutations (FPL3)
This form of FPL has only been reported in approximately 30 individuals. It is generally milder than the FPL2, Dunnigan variety. Consequently, it is believed that many cases may go undiagnosed. Fat loss is more prominent in the calves and forearms than in the upper arms and thighs. Diabetes, hypertriglyceridemia, hypertension, fatty liver, pancreatitis, and hirsutism have also been reported. Metabolic abnormalities are more prominent than the lipodystrophy in this form of the disorder.
FPL4, due to PLIN1 Mutations (FPL4)
This form of FPL has only been reported in a handful of individuals. Lipodystrophy is most prominent in the lower limbs and buttocks. Muscular hypertrophy may be prominent in the calves. Insulin resistance, severe hypertriglyceridemia, and diabetes were also reported.
FPL5, due to AKT2 Mutations (FPL5)
This form of FPL has been reported in four members of one family who had hypertension, severe insulin resistance, and diabetes mellitus. Insulin resistance appears around the ages of 20 to 30. Lipodystrophy most prominently affects the arms and legs.
Autosomal Recessive FPL (Type 6 due to CIDEC mutation)
This form of FPL has only been reported in one individual in the medical literature. The reported symptoms include partial lipodystrophy, severe insulin resistance, fatty liver, acanthosis nigricans, and diabetes. | Symptoms of Familial Partial Lipodystrophy. FPL encompasses several subtypes differentiated by the underlying genetic mutation. The specific symptoms present, severity, and prognosis can vary greatly depending upon the specific type of FPL and the presence and extent of associated symptoms. The specific symptoms and severity can also vary among individuals with the same subtype and even among members of the same family. In addition, some subtypes of FPL have only been reported in a handful of individuals, which prevents physicians from developing an accurate picture of associated symptoms, severity, and prognosis. Therefore, it is important to note that affected individuals will not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms, and overall prognosis.
Common symptoms of FPL include selective, progressive loss of subcutaneous fat in the arms and legs and chest and trunk regions, abnormal accumulation of subcutaneous fat in other areas, and a variety of metabolic complications. Generally, women are more severely affected than men by the metabolic complications of FPL. Additional symptoms including those affecting the liver or heart may also occur.
FPL Type 2, Dunnigan Variety (FPL2)
This is the most common form of FPL. Affected individuals usually have normal fat distribution during early childhood. However, around the time of puberty, fat in the arms and legs and trunk is gradually lost. In women, the loss of fat may be most striking in the buttocks and hips. At this time, fat may accumulate in other areas of the body including the face, causing a double chin, and the neck and upper back between the shoulder blades, causing a hump. Affected individuals may have a round face similar to individuals with Cushing’s syndrome. This characteristic distribution of fat and the overall muscular appearance makes the disorder more easily recognizable in women than men.
Insulin resistance is common and may be associated with a condition called acanthosis nigricans, a skin condition characterized by abnormally increased coloration (hyperpigmentation) and “velvety” thickening (hyperkeratosis) of the skin, particularly of skin fold regions, such as of the neck and groin and under the arms (axillae). An enlarged liver (hepatomegaly) is also common. Hepatomegaly is caused by the accumulation of fat in the liver (fatty liver or steatosis). Progressive accumulation of fat in the liver can cause scarring and damage to the liver (cirrhosis) and, eventually, liver dysfunction.
Other complications of insulin resistance may occur including glucose intolerance, hypertriglyceridemia, and diabetes. These symptoms are often very difficult to control and diabetes is often severe. Affected women are at a greater risk of developing diabetes than affected men and often experience more severe metabolic complications. Some individuals may experience extreme hypertriglyceridemia, resulting in episodes of acute inflammation of the pancreas (pancreatitis). Pancreatitis can be associated with abdominal pain, chills, jaundice, weakness, sweating, vomiting, and weight loss.
After puberty, some women with FPL may develop polycystic ovary syndrome (PCOS), a complex of symptoms that are not always present in every case. PCOS is often characterized by an imbalance of sex hormones as affected women may have too much androgen, a male hormone, in the body. PCOS can result in irregular menstrual periods or a lack of menstruation, oily skin that is prone to acne, cysts on the ovaries, failure of the ovary to release eggs, and mild hirsutism (a male pattern of hair growth). Hair may develop on the upper lip, chin and other parts of the body.
Individuals with FPL, Dunnigan variety are predisposed to coronary artery disease and other types of atherosclerotic vascular disease. In rare cases, in which individuals have a specific mutation of the lamin A/C (LMNA) gene, they are at an increased risk of developing disease of the heart muscles (cardiomyopathy), which can result in congestive heart failure and irregular heartbeats (cardiac arrhythmias) such as heart block or atrial fibrillation. Some individuals also develop muscular dystrophies (diseases of muscles causing loss of strength and joint contractures).
FPL Type 1, Kobberling Variety (FPL1)
This form of FPL has only been reported in a handful of individuals. The symptoms are similar to those seen in FPL2, Dunnigan variety. However, fat loss is generally confined to the arms and legs. Fat loss is usually more prominent on the lower (distal) portions of the arms and legs. Affected individuals have normal or slightly increased fat distribution on the face, neck, and trunk. In addition, some affected individuals may develop excess belly fat (central obesity). Metabolic abnormalities including insulin resistance, high blood pressure (hypertension), and severe hypertriglyceridemia have also been reported. This form of FPL has only been reported in women.
FPL Type 3, due to PPARG Mutations (FPL3)
This form of FPL has only been reported in approximately 30 individuals. It is generally milder than the FPL2, Dunnigan variety. Consequently, it is believed that many cases may go undiagnosed. Fat loss is more prominent in the calves and forearms than in the upper arms and thighs. Diabetes, hypertriglyceridemia, hypertension, fatty liver, pancreatitis, and hirsutism have also been reported. Metabolic abnormalities are more prominent than the lipodystrophy in this form of the disorder.
FPL4, due to PLIN1 Mutations (FPL4)
This form of FPL has only been reported in a handful of individuals. Lipodystrophy is most prominent in the lower limbs and buttocks. Muscular hypertrophy may be prominent in the calves. Insulin resistance, severe hypertriglyceridemia, and diabetes were also reported.
FPL5, due to AKT2 Mutations (FPL5)
This form of FPL has been reported in four members of one family who had hypertension, severe insulin resistance, and diabetes mellitus. Insulin resistance appears around the ages of 20 to 30. Lipodystrophy most prominently affects the arms and legs.
Autosomal Recessive FPL (Type 6 due to CIDEC mutation)
This form of FPL has only been reported in one individual in the medical literature. The reported symptoms include partial lipodystrophy, severe insulin resistance, fatty liver, acanthosis nigricans, and diabetes. | 448 | Familial Partial Lipodystrophy |
nord_448_2 | Causes of Familial Partial Lipodystrophy | FPL is caused by mutations of specific genes. So far, mutations in five genes that cause FPL have been identified including the LMNA gene, which causes FPL2, Dunnigan variety; the PPARG gene, which causes FPL3; the PLIN1 gene, which causes FPL4; the AKT2 gene, which cases FPL5; and the CIDEC gene, which causes autosomal recessive FPL. The gene that causes FPL1, Kobberling variety has not been identified. Some individuals with FPL do not have mutations in any of these genes, suggesting that additional, as yet unidentified genes can cause the disorder.
Four types of FPL for which the genes have been identified are inherited as autosomal dominant traits. Another type with mutation in the CIDEC gene is inherited as an autosomal recessive trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes, one received from the father and one received from the mother. Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 1q21-22” refers to bands 21-22 on the long arm of chromosome 1. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.
Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
Investigators have determined that the LMNA gene is located on the long arm (q) of chromosome 1 (1q21-q22). The LMNA gene contains instructions for creating (encoding) the proteins lamin A and lamin C. These proteins are active in the nuclear lamina, a structure found within many types of cells. Mutations of this gene lead to disruption of the normal functions of lamins A and C. Researchers believe that this gene mutation ultimately results in premature cell death of fat cells (adipocytes) in individuals with FPL2, Dunnigan variety.
Mutations of the LMNA gene have also been shown to cause a variety of other disorders (allelic disorders) including a form of mandibuloacral dysplasia, a couple forms of Emery-Dreifuss muscular dystrophy, a form of limb-girdle muscular dystrophy, a form of hereditary spastic paraplegia, a form of Charcot-Marie-Tooth disease, a form of dilated cardiomyopathy, Malouf syndrome, and Hutchinson-Gilford progeria syndrome. Individuals whose symptoms overlap among these disorders have been reported in the medical literature. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
The PPARG gene is located on the short arm of chromosome 3 (3p25) and encodes for a type of protein that acts as a transcription factor known as PPAR gamma. This protein is essential for proper adipocyte cell differentiation. Cell differentiation is the process by which a less specialized or generic cell becomes a more specialized or specific cell type. FPL due to PPARG mutations results from improper adipocyte cell differentiation.
The PLIN1 gene is located on the long arm of chromosome 15 (15q26) and encodes for a protein known as perilipin. Perilipin is the most abundant protein coating the surface of lipid droplets where the fat is stored within the adipose cells. Researchers believe that perilipin is essential for the storage of triglycerides and for the release of fatty acids from lipid droplets. Lipid droplets are organelles, specialized subunits found within cells (such as fat cells) that have specific functions. One function of lipid droplets is the storage of lipids. Perilipin is also believed to be essential for the proper formation and development of lipid droplets.
The AKT2 gene is located on the long arm of chromosome 19 (19q13.2) and encodes for protein kinase B beta. The exact role of this protein in the body is not fully understood, although it is believed that this protein plays a role in post receptor insulin signaling and may be involved in regulating the expression of PPAR gamma (see above). The loss of adipose tissue in individuals with a mutation of the AKT2 gene may be due to reduced adipocyte differentiation due to improper regulation of PPAR gamma or to dysfunctional post receptor signaling.
The CIDEC gene is located on the short arm of chromosome 3 (3p25.3) and encodes for the CIDEC protein. CIDEC is expressed in the lipid droplets and plays a role in storage of fat within these structures. Mutation of the CIDEC gene resulted in low levels of functional CIDEC protein, resulting in lack of ability of lipid droplets to store fat.
Researchers believe that various genes and gene products associated with FPL are involved with the proper creation, function, and/or health of adipocytes. Adipocytes are fat cells. Each adipocyte has a lipid droplet that accounts for approximately 90% of its cell volume. An adipocyte stores fats (triglycerides) within its lipid droplet. Mutations in the abovementioned genes ultimately lead to a loss of adipocytes and an inability to store fat. Consequently, fat is stored in other tissues of the body such as the liver and skeletal muscle causing symptoms such as liver disease and insulin resistance. The cause of other symptoms sometimes associated with FPL such as cardiomyopathy is not fully understood. More research is necessary to understand the exact, underlying mechanisms that ultimately cause FPL and its associated symptoms. | Causes of Familial Partial Lipodystrophy. FPL is caused by mutations of specific genes. So far, mutations in five genes that cause FPL have been identified including the LMNA gene, which causes FPL2, Dunnigan variety; the PPARG gene, which causes FPL3; the PLIN1 gene, which causes FPL4; the AKT2 gene, which cases FPL5; and the CIDEC gene, which causes autosomal recessive FPL. The gene that causes FPL1, Kobberling variety has not been identified. Some individuals with FPL do not have mutations in any of these genes, suggesting that additional, as yet unidentified genes can cause the disorder.
Four types of FPL for which the genes have been identified are inherited as autosomal dominant traits. Another type with mutation in the CIDEC gene is inherited as an autosomal recessive trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes, one received from the father and one received from the mother. Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 1q21-22” refers to bands 21-22 on the long arm of chromosome 1. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.
Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
Investigators have determined that the LMNA gene is located on the long arm (q) of chromosome 1 (1q21-q22). The LMNA gene contains instructions for creating (encoding) the proteins lamin A and lamin C. These proteins are active in the nuclear lamina, a structure found within many types of cells. Mutations of this gene lead to disruption of the normal functions of lamins A and C. Researchers believe that this gene mutation ultimately results in premature cell death of fat cells (adipocytes) in individuals with FPL2, Dunnigan variety.
Mutations of the LMNA gene have also been shown to cause a variety of other disorders (allelic disorders) including a form of mandibuloacral dysplasia, a couple forms of Emery-Dreifuss muscular dystrophy, a form of limb-girdle muscular dystrophy, a form of hereditary spastic paraplegia, a form of Charcot-Marie-Tooth disease, a form of dilated cardiomyopathy, Malouf syndrome, and Hutchinson-Gilford progeria syndrome. Individuals whose symptoms overlap among these disorders have been reported in the medical literature. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
The PPARG gene is located on the short arm of chromosome 3 (3p25) and encodes for a type of protein that acts as a transcription factor known as PPAR gamma. This protein is essential for proper adipocyte cell differentiation. Cell differentiation is the process by which a less specialized or generic cell becomes a more specialized or specific cell type. FPL due to PPARG mutations results from improper adipocyte cell differentiation.
The PLIN1 gene is located on the long arm of chromosome 15 (15q26) and encodes for a protein known as perilipin. Perilipin is the most abundant protein coating the surface of lipid droplets where the fat is stored within the adipose cells. Researchers believe that perilipin is essential for the storage of triglycerides and for the release of fatty acids from lipid droplets. Lipid droplets are organelles, specialized subunits found within cells (such as fat cells) that have specific functions. One function of lipid droplets is the storage of lipids. Perilipin is also believed to be essential for the proper formation and development of lipid droplets.
The AKT2 gene is located on the long arm of chromosome 19 (19q13.2) and encodes for protein kinase B beta. The exact role of this protein in the body is not fully understood, although it is believed that this protein plays a role in post receptor insulin signaling and may be involved in regulating the expression of PPAR gamma (see above). The loss of adipose tissue in individuals with a mutation of the AKT2 gene may be due to reduced adipocyte differentiation due to improper regulation of PPAR gamma or to dysfunctional post receptor signaling.
The CIDEC gene is located on the short arm of chromosome 3 (3p25.3) and encodes for the CIDEC protein. CIDEC is expressed in the lipid droplets and plays a role in storage of fat within these structures. Mutation of the CIDEC gene resulted in low levels of functional CIDEC protein, resulting in lack of ability of lipid droplets to store fat.
Researchers believe that various genes and gene products associated with FPL are involved with the proper creation, function, and/or health of adipocytes. Adipocytes are fat cells. Each adipocyte has a lipid droplet that accounts for approximately 90% of its cell volume. An adipocyte stores fats (triglycerides) within its lipid droplet. Mutations in the abovementioned genes ultimately lead to a loss of adipocytes and an inability to store fat. Consequently, fat is stored in other tissues of the body such as the liver and skeletal muscle causing symptoms such as liver disease and insulin resistance. The cause of other symptoms sometimes associated with FPL such as cardiomyopathy is not fully understood. More research is necessary to understand the exact, underlying mechanisms that ultimately cause FPL and its associated symptoms. | 448 | Familial Partial Lipodystrophy |
nord_448_3 | Affects of Familial Partial Lipodystrophy | FPL is a rare disorder that has been reported in women more often than in men. This may be due to ascertainment bias because women are more severely affected and more easily recognized. The prevalence of FPL is estimated to be 1 in 1,000,000 people in the general population. However, many cases may go misdiagnosed or undiagnosed, making it difficult to determine the true frequency of the disorder in the general population. The majority of individuals reported in the medical literature have been of European descent. The disorder has also been reported individuals of African and Asian Indian descent. | Affects of Familial Partial Lipodystrophy. FPL is a rare disorder that has been reported in women more often than in men. This may be due to ascertainment bias because women are more severely affected and more easily recognized. The prevalence of FPL is estimated to be 1 in 1,000,000 people in the general population. However, many cases may go misdiagnosed or undiagnosed, making it difficult to determine the true frequency of the disorder in the general population. The majority of individuals reported in the medical literature have been of European descent. The disorder has also been reported individuals of African and Asian Indian descent. | 448 | Familial Partial Lipodystrophy |
nord_448_4 | Related disorders of Familial Partial Lipodystrophy | Symptoms of the following disorders can be similar to those of FPL. Comparisons may be useful for a differential diagnosis.
Congenital generalized lipodystrophy (CGL), also known as Berardinelli-Seip syndrome, is a rare genetic disorder characterized by the loss of body fat (adipose tissue). In CGL, there is often a near total loss of body fat that is present at birth (congenital). Affected individuals also have a marked muscular appearance from birth. CGL is often associated with metabolic complications related to insulin resistance such as an inability to break down glucose (glucose intolerance), elevated levels of triglycerides (a type of fat) in the blood (hypertriglyceridemia), and diabetes. Diabetes associated with CGL is often very difficult to treat. Additional complications such as those affecting the liver and heart can also occur. The symptoms and severity of CGL can vary greatly from person to another. There are four different subtypes of CGL each caused by mutations in a different gene. All of the known types of CGL are inherited as autosomal recessive conditions. (For more information on this disorder, choose “congenital generalized lipodystrophy” as your search term in the Rare Disease Database.)
Acquired lipodystrophy is a general term for types of lipodystrophy that are not inherited, but rather acquired at some point during life. Acquired lipodystrophies do not have a direct genetic cause, but rather many different factors may be involved. Acquired lipodystrophies may be caused by medications, autoimmunity or for unknown reasons (idiopathic). Subtypes of acquired lipodystrophy include localized lipodystrophy, acquired generalized lipodystrophy (Lawrence syndrome), acquired partial lipodystrophy (Barraquer-Simons syndrome), and high active antiretroviral induced lipodystrophy, which may develop in HIV-infected individuals undergoing a specific form of treatment. Onset of acquired forms of lipodystrophy can occur during childhood, adolescence or adulthood. Affected individuals develop characteristic loss of body fat (adipose tissue) affecting certain areas of the body, especially the arms, legs, face, neck, and chest or thoracic regions. In some cases, metabolic complications associated with insulin resistance may occur. Such complications include an inability to break down glucose (glucose intolerance), elevated levels of triglycerides (fat) in the blood (hypertriglyceridemia), diabetes, and fat accumulation in the liver (fatty liver or hepatic steatosis). (For more information on these disorders, choose “acquired lipodystrophy” as your search term in the Rare Disease Database.)
Cushing’s syndrome is a rare endocrine disorder that results from excessive production of the hormone cortisol by the adrenal glands or by glucocorticoid therapy. Affected individuals may gain excessive amounts of weight (central obesity) and/or may have a round, moon-shaped face. They may also have abnormally pigmented, thin, fragile skin; abnormally high blood pressure (hypertension) and blood sugar (hyperglycemia); and/or weakened bones that may fracture easily. In addition, some individuals with Cushing syndrome may demonstrate depression or other emotional changes. (For more information on this disorder, choose “Cushing” as your search term in the Rare Disease Database.)
A variety of syndromic disorders may be associated with lipodystrophy and/or have symptoms similar to FPL including Rabson-Mendenhall syndrome, SHORT syndrome, mandibuloacral dysplasia, Wiedemann-Rautenstrauch syndrome (neonatal progeroid syndrome), Hutchinson-Gilford progeria syndrome, Werner syndrome, and leprechaunism. Individuals with lipodystrophy should also be differentiated from individuals with anorexia nervosa, cachexia, diencephalic syndrome (associated with brain tumors), multiple symmetric lipomatosis (mostly due to heavy alcohol intake), and other disorders that affect growth and development. NORD has individual reports on most of these disorders. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | Related disorders of Familial Partial Lipodystrophy. Symptoms of the following disorders can be similar to those of FPL. Comparisons may be useful for a differential diagnosis.
Congenital generalized lipodystrophy (CGL), also known as Berardinelli-Seip syndrome, is a rare genetic disorder characterized by the loss of body fat (adipose tissue). In CGL, there is often a near total loss of body fat that is present at birth (congenital). Affected individuals also have a marked muscular appearance from birth. CGL is often associated with metabolic complications related to insulin resistance such as an inability to break down glucose (glucose intolerance), elevated levels of triglycerides (a type of fat) in the blood (hypertriglyceridemia), and diabetes. Diabetes associated with CGL is often very difficult to treat. Additional complications such as those affecting the liver and heart can also occur. The symptoms and severity of CGL can vary greatly from person to another. There are four different subtypes of CGL each caused by mutations in a different gene. All of the known types of CGL are inherited as autosomal recessive conditions. (For more information on this disorder, choose “congenital generalized lipodystrophy” as your search term in the Rare Disease Database.)
Acquired lipodystrophy is a general term for types of lipodystrophy that are not inherited, but rather acquired at some point during life. Acquired lipodystrophies do not have a direct genetic cause, but rather many different factors may be involved. Acquired lipodystrophies may be caused by medications, autoimmunity or for unknown reasons (idiopathic). Subtypes of acquired lipodystrophy include localized lipodystrophy, acquired generalized lipodystrophy (Lawrence syndrome), acquired partial lipodystrophy (Barraquer-Simons syndrome), and high active antiretroviral induced lipodystrophy, which may develop in HIV-infected individuals undergoing a specific form of treatment. Onset of acquired forms of lipodystrophy can occur during childhood, adolescence or adulthood. Affected individuals develop characteristic loss of body fat (adipose tissue) affecting certain areas of the body, especially the arms, legs, face, neck, and chest or thoracic regions. In some cases, metabolic complications associated with insulin resistance may occur. Such complications include an inability to break down glucose (glucose intolerance), elevated levels of triglycerides (fat) in the blood (hypertriglyceridemia), diabetes, and fat accumulation in the liver (fatty liver or hepatic steatosis). (For more information on these disorders, choose “acquired lipodystrophy” as your search term in the Rare Disease Database.)
Cushing’s syndrome is a rare endocrine disorder that results from excessive production of the hormone cortisol by the adrenal glands or by glucocorticoid therapy. Affected individuals may gain excessive amounts of weight (central obesity) and/or may have a round, moon-shaped face. They may also have abnormally pigmented, thin, fragile skin; abnormally high blood pressure (hypertension) and blood sugar (hyperglycemia); and/or weakened bones that may fracture easily. In addition, some individuals with Cushing syndrome may demonstrate depression or other emotional changes. (For more information on this disorder, choose “Cushing” as your search term in the Rare Disease Database.)
A variety of syndromic disorders may be associated with lipodystrophy and/or have symptoms similar to FPL including Rabson-Mendenhall syndrome, SHORT syndrome, mandibuloacral dysplasia, Wiedemann-Rautenstrauch syndrome (neonatal progeroid syndrome), Hutchinson-Gilford progeria syndrome, Werner syndrome, and leprechaunism. Individuals with lipodystrophy should also be differentiated from individuals with anorexia nervosa, cachexia, diencephalic syndrome (associated with brain tumors), multiple symmetric lipomatosis (mostly due to heavy alcohol intake), and other disorders that affect growth and development. NORD has individual reports on most of these disorders. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | 448 | Familial Partial Lipodystrophy |
nord_448_5 | Diagnosis of Familial Partial Lipodystrophy | A diagnosis of FPL is based upon identification of characteristic symptoms, a detailed patient history, and a thorough clinical evaluation. A diagnosis of FPL should be suspected in individuals who lose subcutaneous fat around puberty and gain a muscular appearance. Lipodystrophy, in general, should be suspected in individuals who are lean or “non-obese” and who present with early diabetes, severe hypertriglyceridemia, hepatic steatosis, hepatosplenomegaly, acanthosis nigricans and/or polycystic ovarian syndrome.
Clinical Testing and Workup
Although the diagnosis of lipodystrophy is primarily clinical, a variety of tests can be used to aid in the diagnosis and/or rule out other conditions. A blood chemical profile may be conducted to assess the levels of glucose, lipids, liver enzymes, and uric acid.
The characteristic pattern of fat loss in the arms and legs and trunk, but fat gain in muscular fasciae can be noted on magnetic resonance imaging (MRI).
Molecular genetic testing can confirm a diagnosis of FPL in most cases. Molecular genetic testing can detect mutations in specific genes that cause FPL, but is only available on a clinical basis for only few genes such as LMNA.
Individuals with FPL may undergo tests to detect and/or evaluate the presence of potential complications including heart abnormalities. Holter monitoring, echocardiography, and a stress test are conducted for individuals suspected of have cardiomyopathy or coronary heart disease. A Holter monitor is a portable device that continually monitors the heart’s rhythms. An echocardiography uses reflected sound waves to create a picture of the heart. A stress test measures the heart's ability to respond to external stress in a controlled environment.
Individuals with FPL may be evaluated to determine their leptin levels. Leptin is a hormone found in adipocytes. Some affected individuals have low levels of leptin. | Diagnosis of Familial Partial Lipodystrophy. A diagnosis of FPL is based upon identification of characteristic symptoms, a detailed patient history, and a thorough clinical evaluation. A diagnosis of FPL should be suspected in individuals who lose subcutaneous fat around puberty and gain a muscular appearance. Lipodystrophy, in general, should be suspected in individuals who are lean or “non-obese” and who present with early diabetes, severe hypertriglyceridemia, hepatic steatosis, hepatosplenomegaly, acanthosis nigricans and/or polycystic ovarian syndrome.
Clinical Testing and Workup
Although the diagnosis of lipodystrophy is primarily clinical, a variety of tests can be used to aid in the diagnosis and/or rule out other conditions. A blood chemical profile may be conducted to assess the levels of glucose, lipids, liver enzymes, and uric acid.
The characteristic pattern of fat loss in the arms and legs and trunk, but fat gain in muscular fasciae can be noted on magnetic resonance imaging (MRI).
Molecular genetic testing can confirm a diagnosis of FPL in most cases. Molecular genetic testing can detect mutations in specific genes that cause FPL, but is only available on a clinical basis for only few genes such as LMNA.
Individuals with FPL may undergo tests to detect and/or evaluate the presence of potential complications including heart abnormalities. Holter monitoring, echocardiography, and a stress test are conducted for individuals suspected of have cardiomyopathy or coronary heart disease. A Holter monitor is a portable device that continually monitors the heart’s rhythms. An echocardiography uses reflected sound waves to create a picture of the heart. A stress test measures the heart's ability to respond to external stress in a controlled environment.
Individuals with FPL may be evaluated to determine their leptin levels. Leptin is a hormone found in adipocytes. Some affected individuals have low levels of leptin. | 448 | Familial Partial Lipodystrophy |
nord_448_6 | Therapies of Familial Partial Lipodystrophy | Treatment
The treatment of FPL is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, plastic surgeons, cardiologists, endocrinologists, nutritionists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment.
Individuals with FPL and their families are encouraged to seek counseling after a diagnosis because the diagnosis can cause anxiety, stress, and extreme psychological distress. Psychological support and counseling both professionally and through support groups is recommended for affected individuals and their families. Genetic counseling may be of benefit for affected individuals and their families as well.
Despite the lack of clinical trial evaluation, individuals with FPL are encouraged to follow a high carbohydrate, low-fat diet. Such a diet can improve chylomicronemia associated with acute pancreatitis. Chylomicronemia is a condition characterized by the accumulation of fatty droplets called chylomicrons in the plasma. However, such diets may also raise very low density lipoprotein triglyceride concentration.
Because individuals with FPL have an increased risk of coronary heart disease, they should limit the intake of saturated and trans-unsaturated fats and dietary cholesterol. It is unknown whether such measures will be beneficial over the long term to reduce fatty liver or serum triglycerides levels, or whether they can improve glycemic control.
Regular exercise and maintaining a healthy weight are also encouraged as a way to decrease the chances of developing diabetes. In individuals with FPL, exercise and reducing energy intake can is also necessary to avoid excess fat deposition and accumulation in non-lipodystrophic areas such as the face, neck, and intra-abdominal region.
Individuals with extreme hypertriglyceridemia may be treated with fibric acid derivatives, statins, or n-3 polyunsaturated fatty acids.The characteristic loss of adipose tissue in individuals with FPL cannot be reversed. Consequently, cosmetic surgery may be beneficial in improving appearance and management metabolic complications. Procedures such as liposuction can be performed to remove excess, unwanted fat in areas where fat accumulates (e.g. chin).In some cases, liver disease associated with FPL can ultimately require a liver transplantation.Periodic cardiac examinations may be recommended for individuals with FPL to detect symptoms that can be potentially associated with the disorder including coronary heart disease and/or conduction defects. Affected individuals with heart abnormalities such as heart block or atrial fibrillation may require the use of a pacemaker. In some cases, a heart transplant may ultimately be necessary.Additional therapies to treat individuals with FPL are symptomatic and supportive and follow regular, standard guidelines. Diabetes is treated with standard therapies. After the onset of diabetes, hyperglycemic drugs such as metformin and sulfonylureas may be recommended to treat hyperglycemia. Insulin can also be used to treat individuals with FPL and diabetes, although extremely high doses are often required. High blood pressure (anti-hypertensives) may also be recommended. Although drug therapy is commonly used, there have been no clinical trials to establish the optimal use of drug therapy to treat the metabolic complications in individuals with FPL. | Therapies of Familial Partial Lipodystrophy. Treatment
The treatment of FPL is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, plastic surgeons, cardiologists, endocrinologists, nutritionists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment.
Individuals with FPL and their families are encouraged to seek counseling after a diagnosis because the diagnosis can cause anxiety, stress, and extreme psychological distress. Psychological support and counseling both professionally and through support groups is recommended for affected individuals and their families. Genetic counseling may be of benefit for affected individuals and their families as well.
Despite the lack of clinical trial evaluation, individuals with FPL are encouraged to follow a high carbohydrate, low-fat diet. Such a diet can improve chylomicronemia associated with acute pancreatitis. Chylomicronemia is a condition characterized by the accumulation of fatty droplets called chylomicrons in the plasma. However, such diets may also raise very low density lipoprotein triglyceride concentration.
Because individuals with FPL have an increased risk of coronary heart disease, they should limit the intake of saturated and trans-unsaturated fats and dietary cholesterol. It is unknown whether such measures will be beneficial over the long term to reduce fatty liver or serum triglycerides levels, or whether they can improve glycemic control.
Regular exercise and maintaining a healthy weight are also encouraged as a way to decrease the chances of developing diabetes. In individuals with FPL, exercise and reducing energy intake can is also necessary to avoid excess fat deposition and accumulation in non-lipodystrophic areas such as the face, neck, and intra-abdominal region.
Individuals with extreme hypertriglyceridemia may be treated with fibric acid derivatives, statins, or n-3 polyunsaturated fatty acids.The characteristic loss of adipose tissue in individuals with FPL cannot be reversed. Consequently, cosmetic surgery may be beneficial in improving appearance and management metabolic complications. Procedures such as liposuction can be performed to remove excess, unwanted fat in areas where fat accumulates (e.g. chin).In some cases, liver disease associated with FPL can ultimately require a liver transplantation.Periodic cardiac examinations may be recommended for individuals with FPL to detect symptoms that can be potentially associated with the disorder including coronary heart disease and/or conduction defects. Affected individuals with heart abnormalities such as heart block or atrial fibrillation may require the use of a pacemaker. In some cases, a heart transplant may ultimately be necessary.Additional therapies to treat individuals with FPL are symptomatic and supportive and follow regular, standard guidelines. Diabetes is treated with standard therapies. After the onset of diabetes, hyperglycemic drugs such as metformin and sulfonylureas may be recommended to treat hyperglycemia. Insulin can also be used to treat individuals with FPL and diabetes, although extremely high doses are often required. High blood pressure (anti-hypertensives) may also be recommended. Although drug therapy is commonly used, there have been no clinical trials to establish the optimal use of drug therapy to treat the metabolic complications in individuals with FPL. | 448 | Familial Partial Lipodystrophy |
nord_449_0 | Overview of Familial Platelet Disorder with Associated Myeloid Malignancy | SummaryFamilial platelet disorder with associated myeloid malignancy (FPD/AML) is a very rare disorder caused by changes (mutations) in the RUNX1 gene. The RUNX1 gene was previously known as AML1 or CBFA2. FPD/AML is an inherited disorder, meaning that the mutated RUNX1 gene is passed down (inherited) from an affected parent such that patients with FPD/AML are born with the abnormal gene. FPD/AML is characterized by mild to moderately low platelet count (thrombocytopenia), abnormal platelet function, and an increased risk of developing other blood disorders or cancers such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).Platelets are a type of blood cell that help to stop bleeding. Because platelets can be low or not function properly in FPD/AML, patients can have symptoms of easy bruising and bleeding. The severity of symptoms can vary a lot between patients with FPD/AML. Some patients may have no problems with bleeding or bruising whereas other patients may seek medical attention for these reasons. All patients with FPD/AML have a high risk (35-40%) of developing MDS and/or AML in their life-time; both of which are potentially life-threatening conditions without treatment. The average age of onset of MDS or AML is 33 years. Symptoms of MDS or AML may include tiredness (fatigue), weakness, shortness of breath, and frequent infections.IntroductionSymptoms of FPD/AML were first described in several members of a multigenerational family in 1969. Since that time additional families with similar symptoms and signs were found and in 1996 studies on a large family with FPD/AML isolated the problem to an abnormality on chromosome 21. More information on chromosomes is given in the “Causes” section of this report. In 1999 it was discovered that inherited (germline) alterations (mutations) in the RUNX1 gene, located on chromosome 21, was the cause of FPD/AML. | Overview of Familial Platelet Disorder with Associated Myeloid Malignancy. SummaryFamilial platelet disorder with associated myeloid malignancy (FPD/AML) is a very rare disorder caused by changes (mutations) in the RUNX1 gene. The RUNX1 gene was previously known as AML1 or CBFA2. FPD/AML is an inherited disorder, meaning that the mutated RUNX1 gene is passed down (inherited) from an affected parent such that patients with FPD/AML are born with the abnormal gene. FPD/AML is characterized by mild to moderately low platelet count (thrombocytopenia), abnormal platelet function, and an increased risk of developing other blood disorders or cancers such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).Platelets are a type of blood cell that help to stop bleeding. Because platelets can be low or not function properly in FPD/AML, patients can have symptoms of easy bruising and bleeding. The severity of symptoms can vary a lot between patients with FPD/AML. Some patients may have no problems with bleeding or bruising whereas other patients may seek medical attention for these reasons. All patients with FPD/AML have a high risk (35-40%) of developing MDS and/or AML in their life-time; both of which are potentially life-threatening conditions without treatment. The average age of onset of MDS or AML is 33 years. Symptoms of MDS or AML may include tiredness (fatigue), weakness, shortness of breath, and frequent infections.IntroductionSymptoms of FPD/AML were first described in several members of a multigenerational family in 1969. Since that time additional families with similar symptoms and signs were found and in 1996 studies on a large family with FPD/AML isolated the problem to an abnormality on chromosome 21. More information on chromosomes is given in the “Causes” section of this report. In 1999 it was discovered that inherited (germline) alterations (mutations) in the RUNX1 gene, located on chromosome 21, was the cause of FPD/AML. | 449 | Familial Platelet Disorder with Associated Myeloid Malignancy |
nord_449_1 | Symptoms of Familial Platelet Disorder with Associated Myeloid Malignancy | Common signs and symptoms of FPD/AML relate to the impact of inherited RUNX1 mutations on platelets and the increased likelihood of developing MDS and/or AML. Platelets are a type of blood cell that are made by specialized cells in the bone marrow (megakaryocytes). Platelets are an important component of our blood and their main function is to help to stop bleeding and form clots. This process is known as hemostasis. Patients with FPD/AML may have a reduced number of platelets in their blood (thrombocytopenia) or may have platelets that do not function normally. Symptoms of low or dysfunctional platelets can include: easy or spontaneous bruising, frequent or severe nose bleeds (epistaxis), prolonged or excessive bleeding after procedures or surgery, heavy menstrual bleeding, bleeding from the gums, and small red spots on the skin (petechiae). Not every patient with FPD/AML is affected in the same way. The type and severity of symptoms can vary, even between patients in the same family. Importantly, some patients with FPD/AML may have only a minor decrease in platelet count with normal platelet function and have no symptoms of easy bruising or bleeding. Mutations in the RUNX1 gene are also associated with a 35-40% life-time risk of developing MDS or AML. MDS is a type of blood disorder characterized by abnormal production and development of blood cells (red blood cells, white blood cells, and platelets) within the bone marrow, resulting in low blood counts. Common symptoms of MDS can include fatigue, weakness, easy bruising and bleeding, and frequent infections. (For more information on this disorder, choose “Myelodysplastic Syndromes” as your search term in the Rare Disease Database.)AML is a type of blood and bone marrow cancer that progresses quickly and is fatal without treatment. Symptoms and signs of AML may include low blood counts, presence of immature cells (myeloblasts) circulating in the blood, fatigue, shortness of breath, weakness, abnormal bleeding or bruising, swollen sore gums, fevers, night sweats, weight loss, and frequent infections. (For more information on this disorder, choose “Acute Myeloid Leukemia” as your search term in the Rare Disease Database.) | Symptoms of Familial Platelet Disorder with Associated Myeloid Malignancy. Common signs and symptoms of FPD/AML relate to the impact of inherited RUNX1 mutations on platelets and the increased likelihood of developing MDS and/or AML. Platelets are a type of blood cell that are made by specialized cells in the bone marrow (megakaryocytes). Platelets are an important component of our blood and their main function is to help to stop bleeding and form clots. This process is known as hemostasis. Patients with FPD/AML may have a reduced number of platelets in their blood (thrombocytopenia) or may have platelets that do not function normally. Symptoms of low or dysfunctional platelets can include: easy or spontaneous bruising, frequent or severe nose bleeds (epistaxis), prolonged or excessive bleeding after procedures or surgery, heavy menstrual bleeding, bleeding from the gums, and small red spots on the skin (petechiae). Not every patient with FPD/AML is affected in the same way. The type and severity of symptoms can vary, even between patients in the same family. Importantly, some patients with FPD/AML may have only a minor decrease in platelet count with normal platelet function and have no symptoms of easy bruising or bleeding. Mutations in the RUNX1 gene are also associated with a 35-40% life-time risk of developing MDS or AML. MDS is a type of blood disorder characterized by abnormal production and development of blood cells (red blood cells, white blood cells, and platelets) within the bone marrow, resulting in low blood counts. Common symptoms of MDS can include fatigue, weakness, easy bruising and bleeding, and frequent infections. (For more information on this disorder, choose “Myelodysplastic Syndromes” as your search term in the Rare Disease Database.)AML is a type of blood and bone marrow cancer that progresses quickly and is fatal without treatment. Symptoms and signs of AML may include low blood counts, presence of immature cells (myeloblasts) circulating in the blood, fatigue, shortness of breath, weakness, abnormal bleeding or bruising, swollen sore gums, fevers, night sweats, weight loss, and frequent infections. (For more information on this disorder, choose “Acute Myeloid Leukemia” as your search term in the Rare Disease Database.) | 449 | Familial Platelet Disorder with Associated Myeloid Malignancy |
nord_449_2 | Causes of Familial Platelet Disorder with Associated Myeloid Malignancy | FPD/AML is caused by inherited alterations (mutations) is the RUNX1 gene, located on chromosome 21. The RUNX1 gene is responsible for production of the RUNX1 protein. The RUNX1 protein is an important regulator of normal blood cell production (hematopoiesis). Mutations in the RUNX1 gene can lead to a decrease in or altered function of the RUNX1 protein, which can result in symptoms of low platelets, impairment of platelet function, and a significantly increased risk of developing MDS and/or AML (as discussed above). There are many different mutations in the RUNX1 gene that can cause FPD/AML and most families affected by this condition carry a unique mutation that is different from other families with this same disorder. The way in which mutations in RUNX1 cause a decrease in platelets and predispose patients to MDS and AML is not yet fully understood. In FPD/AML, the mutation in RUNX1 is passed down (inherited) from the patient’s parents such that the patient is born with the gene mutation (a germline mutation). FPD/AML is an autosomal dominant disorder. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.Spontaneous (de novo) genetic mutations are mutations that occur in the egg or sperm cell and are not inherited from the parents. De novo mutations in RUNX1 do not result in FPD/AML. | Causes of Familial Platelet Disorder with Associated Myeloid Malignancy. FPD/AML is caused by inherited alterations (mutations) is the RUNX1 gene, located on chromosome 21. The RUNX1 gene is responsible for production of the RUNX1 protein. The RUNX1 protein is an important regulator of normal blood cell production (hematopoiesis). Mutations in the RUNX1 gene can lead to a decrease in or altered function of the RUNX1 protein, which can result in symptoms of low platelets, impairment of platelet function, and a significantly increased risk of developing MDS and/or AML (as discussed above). There are many different mutations in the RUNX1 gene that can cause FPD/AML and most families affected by this condition carry a unique mutation that is different from other families with this same disorder. The way in which mutations in RUNX1 cause a decrease in platelets and predispose patients to MDS and AML is not yet fully understood. In FPD/AML, the mutation in RUNX1 is passed down (inherited) from the patient’s parents such that the patient is born with the gene mutation (a germline mutation). FPD/AML is an autosomal dominant disorder. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.Spontaneous (de novo) genetic mutations are mutations that occur in the egg or sperm cell and are not inherited from the parents. De novo mutations in RUNX1 do not result in FPD/AML. | 449 | Familial Platelet Disorder with Associated Myeloid Malignancy |
nord_449_3 | Affects of Familial Platelet Disorder with Associated Myeloid Malignancy | FPD/AML is a very rare disorder with an unknown incidence and prevalence. To date, more than 70 FPD/AML families (pedigrees) with inherited RUNX1 mutations have been identified. Patients with FPD/AML have a lifetime risk of approximately 35-40% of developing MDS and/or AML. The average age of onset of MDS or AML is 33 years but has also occurred in patients as young as 6 years and as old as 77 years. Males and females seem to be equally affected and there is no known racial predilection. | Affects of Familial Platelet Disorder with Associated Myeloid Malignancy. FPD/AML is a very rare disorder with an unknown incidence and prevalence. To date, more than 70 FPD/AML families (pedigrees) with inherited RUNX1 mutations have been identified. Patients with FPD/AML have a lifetime risk of approximately 35-40% of developing MDS and/or AML. The average age of onset of MDS or AML is 33 years but has also occurred in patients as young as 6 years and as old as 77 years. Males and females seem to be equally affected and there is no known racial predilection. | 449 | Familial Platelet Disorder with Associated Myeloid Malignancy |
nord_449_4 | Related disorders of Familial Platelet Disorder with Associated Myeloid Malignancy | Patients with FPD/AML with inherited RUNX1 mutations often have mild to moderately low levels of platelets resulting in symptoms like those seen in immune thrombocytopenia (ITP). ITP is an autoimmune disorder characterized by a low platelet count and symptoms of easy bruising and bleeding. A normal platelet count ranges between approximately 100,000 to 400,000 per microliter of blood. ITP is suspected when a person’s platelet count is persistently below 100,000 per microliter of blood and no other cause has been found. The lower the platelet count, the higher the risk of bleeding. Patients with ITP often present to their doctor with symptoms and signs of bleeding into the skin causing bruising (ecchymosis), small red spots (petechiae), or larger red or purple patches (purpura), or bleeding from the nose (epistaxis), gums, or heavy vaginal bleeding. There are no definitive tests to diagnose ITP so it remains a diagnosis of exclusion, meaning that no other cause for the low platelet count has been found. Treatment of ITP depends on a number of factors including how severe the symptoms are, the platelet count, the patient’s age, the patient’s lifestyle, and personal preferences. (For more information on this disorder, choose “Immune Thrombocytopenia” as your search term in the Rare Disease Database.) Patients with FPD/AML are at high risk of developing potentially life-threatening blood (hematologic) disorders including MDS and AML.AML is a type of blood and bone marrow cancer, with many subtypes, characterized by incomplete maturation of blood cells and reduced production of normal blood cells. In AML changes to the genetic material (DNA) of a single immature cell in the bone marrow, called a blast cell or myeloblast, causes this cell to continually reproduce itself. Unlike in FPD/AML, where patients have an inherited (germline) mutation, most patients with AML acquire a mutation or mutations (sporadic mutations) later in life. These blasts cells cause crowding in the bone marrow and result in the disrupted production of healthy blood cells including red cells, white cells, and platelets. AML progresses quickly without treatment and is the most common type of leukemia in adults. Most patients are aged 65 years or older at the time of diagnosis. Patients with FPD/AML develop AML at abnormally young ages with and average age of diagnosis of 33 years. (For more information on this disorder, choose “Acute Myeloid Leukemia” as your search term in the Rare Disease Database.)MDS is a rare group of blood disorders that results from abnormal development of blood cells within the bone marrow. The three main types of blood cells (red cells, white cells, and platelets) can be affected. The abnormal (dysplastic) cells do not mature normally and have difficulty exiting the bone marrow and entering the bloodstream, resulting in low blood counts. General symptoms of MDS were discussed above in the “signs and symptoms” section. Over time MDS can progress into acute leukemia. The exact cause of MDS is unknown. Most patients with MDS are elderly. Patients with FPD/AML develop MDS at much younger ages than average (33 years versus 70 years for those without inherited RUNX1 mutations). (For more information on this disorder, choose “Myelodysplastic Syndrome” as your search term in the Rare Disease Database.)There are also rare reports of FPD/AML patients developing other rare types of blood cancers (hematologic malignancies) including T-cell acute lymphoblastic leukemia (T-ALL), hairy cell leukemia, and chronic myelomonocytic leukemia (CMML). | Related disorders of Familial Platelet Disorder with Associated Myeloid Malignancy. Patients with FPD/AML with inherited RUNX1 mutations often have mild to moderately low levels of platelets resulting in symptoms like those seen in immune thrombocytopenia (ITP). ITP is an autoimmune disorder characterized by a low platelet count and symptoms of easy bruising and bleeding. A normal platelet count ranges between approximately 100,000 to 400,000 per microliter of blood. ITP is suspected when a person’s platelet count is persistently below 100,000 per microliter of blood and no other cause has been found. The lower the platelet count, the higher the risk of bleeding. Patients with ITP often present to their doctor with symptoms and signs of bleeding into the skin causing bruising (ecchymosis), small red spots (petechiae), or larger red or purple patches (purpura), or bleeding from the nose (epistaxis), gums, or heavy vaginal bleeding. There are no definitive tests to diagnose ITP so it remains a diagnosis of exclusion, meaning that no other cause for the low platelet count has been found. Treatment of ITP depends on a number of factors including how severe the symptoms are, the platelet count, the patient’s age, the patient’s lifestyle, and personal preferences. (For more information on this disorder, choose “Immune Thrombocytopenia” as your search term in the Rare Disease Database.) Patients with FPD/AML are at high risk of developing potentially life-threatening blood (hematologic) disorders including MDS and AML.AML is a type of blood and bone marrow cancer, with many subtypes, characterized by incomplete maturation of blood cells and reduced production of normal blood cells. In AML changes to the genetic material (DNA) of a single immature cell in the bone marrow, called a blast cell or myeloblast, causes this cell to continually reproduce itself. Unlike in FPD/AML, where patients have an inherited (germline) mutation, most patients with AML acquire a mutation or mutations (sporadic mutations) later in life. These blasts cells cause crowding in the bone marrow and result in the disrupted production of healthy blood cells including red cells, white cells, and platelets. AML progresses quickly without treatment and is the most common type of leukemia in adults. Most patients are aged 65 years or older at the time of diagnosis. Patients with FPD/AML develop AML at abnormally young ages with and average age of diagnosis of 33 years. (For more information on this disorder, choose “Acute Myeloid Leukemia” as your search term in the Rare Disease Database.)MDS is a rare group of blood disorders that results from abnormal development of blood cells within the bone marrow. The three main types of blood cells (red cells, white cells, and platelets) can be affected. The abnormal (dysplastic) cells do not mature normally and have difficulty exiting the bone marrow and entering the bloodstream, resulting in low blood counts. General symptoms of MDS were discussed above in the “signs and symptoms” section. Over time MDS can progress into acute leukemia. The exact cause of MDS is unknown. Most patients with MDS are elderly. Patients with FPD/AML develop MDS at much younger ages than average (33 years versus 70 years for those without inherited RUNX1 mutations). (For more information on this disorder, choose “Myelodysplastic Syndrome” as your search term in the Rare Disease Database.)There are also rare reports of FPD/AML patients developing other rare types of blood cancers (hematologic malignancies) including T-cell acute lymphoblastic leukemia (T-ALL), hairy cell leukemia, and chronic myelomonocytic leukemia (CMML). | 449 | Familial Platelet Disorder with Associated Myeloid Malignancy |
nord_449_5 | Diagnosis of Familial Platelet Disorder with Associated Myeloid Malignancy | The diagnosis of FPD/AML is based on clinical suspicion following a thorough clinical history, physical examination, specialized blood tests, and confirmed through genetic testing detecting mutations in the RUNX1 gene. Persons newly diagnosed with AML or MDS, especially at a relatively young age, who have a history of low or abnormally functioning platelets or those with a family history of AML, MDS or other hematologic malignancies such as T-ALL or CMML may be referred for specialist evaluation and genetic testing. Clinical Testing and Work-up
A detailed personal and family history will be taken. The doctor will be looking for clues for an underlying inherited disorder such as a personal history of easy bruising or bleeding, low platelets found on previous blood tests, or a family history of these same features as well as blood disorders or cancers. Laboratory testing will include a complete blood count (CBC), peripheral blood smear, coagulation testing, and other routine blood tests. A CBC determines the number of red cells, white cells, and platelets in the blood. A peripheral blood smear involves looking at blood under a microscope to see if the blood cells appear irregular of if there any abnormal cells, like blast cells, circulating in the blood. Coagulation testing, such as the INR and PTT, provide information on the person’s ability to form blood clots and how long it takes to do so. Platelet function testing may also be performed. These tests are performed on blood samples taken from the patient’s vein (a process called venipuncture). Patients will be followed with a CBC at regular intervals to detect any changes. A bone marrow aspirate and biopsy may be performed at the initial evaluation and/or at subsequent visits if there is any suspicion that the affected individual has developed AML, MDS, or another blood or bone marrow disorder. A bone marrow biopsy involves taking a sample of tissue (the bone marrow) and sending it to a laboratory specialist (pathologist) for further testing and examination under a microscope. The biopsy is usually, but not always, taken from the back part of the hip bone. During this procedure, the patient’s skin around the hip bone is cleaned and the skin and tissue covering the bone (periosteum) is then frozen with local anesthetic. A needle is inserted into the bone and samples of the liquid bone marrow (known as the bone marrow aspirate) as well as a small piece of the bone (the core biopsy) are removed. To confirm a suspected diagnosis of FPD/AML, genetic testing can be performed on a tissue sample from the affected patient. Numerous tissues can be used for this purpose including the bone marrow, saliva samples, finger nails, hair, or skin. A skin biopsy is the preferred tissue source and can be obtained at the time of bone marrow biopsy by cutting a small piece of skin from around the bone marrow needle insertion point or by a punch biopsy. A punch biopsy is test where a small tube shaped portion of skin is removed using a pencil-like instrument with a sharp circular cutting edge. If the diagnosis is confirmed and an inherited genetic mutation in RUNX1 is confirmed, the affected patient may be referred to a genetic counselor. | Diagnosis of Familial Platelet Disorder with Associated Myeloid Malignancy. The diagnosis of FPD/AML is based on clinical suspicion following a thorough clinical history, physical examination, specialized blood tests, and confirmed through genetic testing detecting mutations in the RUNX1 gene. Persons newly diagnosed with AML or MDS, especially at a relatively young age, who have a history of low or abnormally functioning platelets or those with a family history of AML, MDS or other hematologic malignancies such as T-ALL or CMML may be referred for specialist evaluation and genetic testing. Clinical Testing and Work-up
A detailed personal and family history will be taken. The doctor will be looking for clues for an underlying inherited disorder such as a personal history of easy bruising or bleeding, low platelets found on previous blood tests, or a family history of these same features as well as blood disorders or cancers. Laboratory testing will include a complete blood count (CBC), peripheral blood smear, coagulation testing, and other routine blood tests. A CBC determines the number of red cells, white cells, and platelets in the blood. A peripheral blood smear involves looking at blood under a microscope to see if the blood cells appear irregular of if there any abnormal cells, like blast cells, circulating in the blood. Coagulation testing, such as the INR and PTT, provide information on the person’s ability to form blood clots and how long it takes to do so. Platelet function testing may also be performed. These tests are performed on blood samples taken from the patient’s vein (a process called venipuncture). Patients will be followed with a CBC at regular intervals to detect any changes. A bone marrow aspirate and biopsy may be performed at the initial evaluation and/or at subsequent visits if there is any suspicion that the affected individual has developed AML, MDS, or another blood or bone marrow disorder. A bone marrow biopsy involves taking a sample of tissue (the bone marrow) and sending it to a laboratory specialist (pathologist) for further testing and examination under a microscope. The biopsy is usually, but not always, taken from the back part of the hip bone. During this procedure, the patient’s skin around the hip bone is cleaned and the skin and tissue covering the bone (periosteum) is then frozen with local anesthetic. A needle is inserted into the bone and samples of the liquid bone marrow (known as the bone marrow aspirate) as well as a small piece of the bone (the core biopsy) are removed. To confirm a suspected diagnosis of FPD/AML, genetic testing can be performed on a tissue sample from the affected patient. Numerous tissues can be used for this purpose including the bone marrow, saliva samples, finger nails, hair, or skin. A skin biopsy is the preferred tissue source and can be obtained at the time of bone marrow biopsy by cutting a small piece of skin from around the bone marrow needle insertion point or by a punch biopsy. A punch biopsy is test where a small tube shaped portion of skin is removed using a pencil-like instrument with a sharp circular cutting edge. If the diagnosis is confirmed and an inherited genetic mutation in RUNX1 is confirmed, the affected patient may be referred to a genetic counselor. | 449 | Familial Platelet Disorder with Associated Myeloid Malignancy |
nord_449_6 | Therapies of Familial Platelet Disorder with Associated Myeloid Malignancy | Treatment
Diagnosis and management of FPD/AML may involve several medical professionals including: general practitioners, physicians who specialize in cancer (medical oncologists) or blood and bone marrow disorders (hematologists), genetics experts (medical geneticists or genetic councillors), nurses, pharmacists, and/or other health care professionals. At present, there are no specific treatments available for patients with FPD/AML, however patients with this disorder who have significant bleeding problems should avoid medications that impair platelet function, such as nonsteroidal anti-inflammatories (NSAIDs), and should check with their pharmacist or doctor before starting a new medication or taking a non-prescription medication or supplement. Patients may require platelet transfusions if they have severe bleeding or a very low platelet count prior to a surgery or procedure. Most surgeries can be performed safely with a platelet count greater than 50,000 per microliter of blood. For those who have developed AML or MDS, treatment is directed for that disorder. (For more information on treatment of these disorders, choose the specific disorder name as your search term in the Rare Disease Database and scroll down to the “Treatment” section.) The only potential cure for patients who develop MDS is an allogeneic stem cell transplant, a type of bone marrow transplant. In an allogeneic stem cell transplant, hematopoietic stem cells (cells that can make red cells, white cells, and platelets) are typically donated from a closely matched sibling family member or unrelated donor and infused into the affected patient after receiving high doses of chemotherapy with or without radiation. Allogeneic stem cell transplant is also commonly used in the treatment of AML. For FPD/AML patients who require an allogeneic stem cell transplant, it is important to perform genetic testing on their siblings for RUNX1 mutations prior to using them as a donor because they may carry the same inherited mutation. If the sibling has a RUNX1 mutation they should not be used as a donor. If they are used as a donor it can result in poor outcomes such as failure of the transplant (engraftment failure) and future development of leukemia or MDS arising from the donor’s cells. | Therapies of Familial Platelet Disorder with Associated Myeloid Malignancy. Treatment
Diagnosis and management of FPD/AML may involve several medical professionals including: general practitioners, physicians who specialize in cancer (medical oncologists) or blood and bone marrow disorders (hematologists), genetics experts (medical geneticists or genetic councillors), nurses, pharmacists, and/or other health care professionals. At present, there are no specific treatments available for patients with FPD/AML, however patients with this disorder who have significant bleeding problems should avoid medications that impair platelet function, such as nonsteroidal anti-inflammatories (NSAIDs), and should check with their pharmacist or doctor before starting a new medication or taking a non-prescription medication or supplement. Patients may require platelet transfusions if they have severe bleeding or a very low platelet count prior to a surgery or procedure. Most surgeries can be performed safely with a platelet count greater than 50,000 per microliter of blood. For those who have developed AML or MDS, treatment is directed for that disorder. (For more information on treatment of these disorders, choose the specific disorder name as your search term in the Rare Disease Database and scroll down to the “Treatment” section.) The only potential cure for patients who develop MDS is an allogeneic stem cell transplant, a type of bone marrow transplant. In an allogeneic stem cell transplant, hematopoietic stem cells (cells that can make red cells, white cells, and platelets) are typically donated from a closely matched sibling family member or unrelated donor and infused into the affected patient after receiving high doses of chemotherapy with or without radiation. Allogeneic stem cell transplant is also commonly used in the treatment of AML. For FPD/AML patients who require an allogeneic stem cell transplant, it is important to perform genetic testing on their siblings for RUNX1 mutations prior to using them as a donor because they may carry the same inherited mutation. If the sibling has a RUNX1 mutation they should not be used as a donor. If they are used as a donor it can result in poor outcomes such as failure of the transplant (engraftment failure) and future development of leukemia or MDS arising from the donor’s cells. | 449 | Familial Platelet Disorder with Associated Myeloid Malignancy |
nord_450_0 | Overview of Fanconi Anemia | SummaryFanconi anemia (FA) is a rare genetic disorder, in the category of inherited bone marrow failure syndromes. Half the patients are diagnosed prior to age 10, while about 10% are diagnosed as adults. Early diagnoses are facilitated in patients with birth defects, such as small size, abnormal thumbs and/or radial bones, skin pigmentation, small heads, small eyes, abnormal kidney structures, and cardiac and skeletal anomalies. The disorder is often associated with a progressive deficiency of all bone marrow production of blood cells, red blood cells, white blood cells, and platelets. Affected individuals have an increased risk of developing a cancer of blood-forming cells in the bone marrow called acute myeloid leukemia (AML), or tumors of the head, neck, skin, gastrointestinal system, or genital tract. FA occurs equally in males and females, and is found in all ethnic groups. It is usually inherited as an autosomal recessive genetic disorder, but X-linked inheritance has also been reported.IntroductionThere are several subtypes of FA that result from the inheritance of two gene mutations in each of at least 18 different genes. Most of the subtypes share the characteristic symptoms and findings. Fanconi anemia is not the same as Fanconi syndrome, a rare kidney function disorder. | Overview of Fanconi Anemia. SummaryFanconi anemia (FA) is a rare genetic disorder, in the category of inherited bone marrow failure syndromes. Half the patients are diagnosed prior to age 10, while about 10% are diagnosed as adults. Early diagnoses are facilitated in patients with birth defects, such as small size, abnormal thumbs and/or radial bones, skin pigmentation, small heads, small eyes, abnormal kidney structures, and cardiac and skeletal anomalies. The disorder is often associated with a progressive deficiency of all bone marrow production of blood cells, red blood cells, white blood cells, and platelets. Affected individuals have an increased risk of developing a cancer of blood-forming cells in the bone marrow called acute myeloid leukemia (AML), or tumors of the head, neck, skin, gastrointestinal system, or genital tract. FA occurs equally in males and females, and is found in all ethnic groups. It is usually inherited as an autosomal recessive genetic disorder, but X-linked inheritance has also been reported.IntroductionThere are several subtypes of FA that result from the inheritance of two gene mutations in each of at least 18 different genes. Most of the subtypes share the characteristic symptoms and findings. Fanconi anemia is not the same as Fanconi syndrome, a rare kidney function disorder. | 450 | Fanconi Anemia |
nord_450_1 | Symptoms of Fanconi Anemia | The symptoms of FA vary from person to person. Identified symptoms include a variety of physical abnormalities, bone marrow failure, and an increased risk of malignancy. Physical abnormalities normally reveal themselves in early childhood, but in rare cases diagnoses are made in adulthood. Blood production problems often develop between 6 to 8 years of age. Bone marrow failure eventually occurs in the majority of affected individuals, although the progression and age of onset vary. Patients who live into adulthood are likely to develop head and neck, gynecologic, and/or gastrointestinal cancer at a much earlier age than the general population, whether or not they had earlier blood problems.Physical Abnormalities
At least 60% of individuals affected with FA are born with at least one physical anomaly. This may include any of the following:-short stature
-thumb and arm anomalies: an extra or misshaped or missing thumbs and fingers or an incompletely developed or missing radius (one of the forearm bones)
-skeletal anomalies of the hips, spine, or ribs
-kidney structural problems
-skin pigmentation (called café au lait spots)
-small head
-small, crossed, or widely spaced eyes
-low birth weight
-gastrointestinal difficulties
-small reproductive organs in males
-defects in tissues separating chambers of the heartIndividuals with anemia may experience tiredness, increased need for sleep, weakness, lightheadedness, dizziness, irritability, headaches, pale skin color, difficulty breathing, and cardiac symptoms.There may be excessive bruising following minimal injury and spontaneous bleeding from the mucous membranes, especially those of the gums and nose.Bone Marrow Failure
Bone marrow is the spongy substance found in the center of the long bones of the body. The bone marrow produces specialized cells (hematopoietic stem cells) that grow and eventually develop into red blood cells (erythrocytes), white blood cells (leukocytes), and platelets. The cells are released into the bloodstream to travel throughout the body performing their specific functions. Red blood cells deliver oxygen to the body, white blood cells help in fighting off infections and platelets allow the body to form clots to stop bleeding.Progressive bone marrow failure typically presents by the age of 10 and is usually accompanied with low platelet levels or low white blood cells. By age 40 to 50 years, the estimated incidence of bone marrow failure as the first serious event is more than 50%.Affected individuals develop low levels of all the cellular elements of the bone marrow- red and white blood cells and platelets- which can lead to the following:
-low level of circulating red blood cells – anemia
-low level of white blood cells – leukopenia
-low level of neutrophils (a type of white blood cell) – neutropenia
-low level of platelets – thrombocytopeniaIncreased Risk of Malignancy
Individuals with FA have a higher risk than the general population of developing certain forms of cancer including acute myeloid leukemia and specific solid tumors. Affected individuals may are at extremely high risk of developing cancer affecting the head and neck region, gastrointestinal tract, esophagus or gynecologic regions. Most of these are a specific form of cancer, known as squamous cell carcinoma. FA patients whose bone marrow failure is treated with male hormones (called “androgens”) have in increased risk of liver tumors.In approximately 30 percent of cases associated with cancer, the development of malignancy precedes a diagnosis of FA. | Symptoms of Fanconi Anemia. The symptoms of FA vary from person to person. Identified symptoms include a variety of physical abnormalities, bone marrow failure, and an increased risk of malignancy. Physical abnormalities normally reveal themselves in early childhood, but in rare cases diagnoses are made in adulthood. Blood production problems often develop between 6 to 8 years of age. Bone marrow failure eventually occurs in the majority of affected individuals, although the progression and age of onset vary. Patients who live into adulthood are likely to develop head and neck, gynecologic, and/or gastrointestinal cancer at a much earlier age than the general population, whether or not they had earlier blood problems.Physical Abnormalities
At least 60% of individuals affected with FA are born with at least one physical anomaly. This may include any of the following:-short stature
-thumb and arm anomalies: an extra or misshaped or missing thumbs and fingers or an incompletely developed or missing radius (one of the forearm bones)
-skeletal anomalies of the hips, spine, or ribs
-kidney structural problems
-skin pigmentation (called café au lait spots)
-small head
-small, crossed, or widely spaced eyes
-low birth weight
-gastrointestinal difficulties
-small reproductive organs in males
-defects in tissues separating chambers of the heartIndividuals with anemia may experience tiredness, increased need for sleep, weakness, lightheadedness, dizziness, irritability, headaches, pale skin color, difficulty breathing, and cardiac symptoms.There may be excessive bruising following minimal injury and spontaneous bleeding from the mucous membranes, especially those of the gums and nose.Bone Marrow Failure
Bone marrow is the spongy substance found in the center of the long bones of the body. The bone marrow produces specialized cells (hematopoietic stem cells) that grow and eventually develop into red blood cells (erythrocytes), white blood cells (leukocytes), and platelets. The cells are released into the bloodstream to travel throughout the body performing their specific functions. Red blood cells deliver oxygen to the body, white blood cells help in fighting off infections and platelets allow the body to form clots to stop bleeding.Progressive bone marrow failure typically presents by the age of 10 and is usually accompanied with low platelet levels or low white blood cells. By age 40 to 50 years, the estimated incidence of bone marrow failure as the first serious event is more than 50%.Affected individuals develop low levels of all the cellular elements of the bone marrow- red and white blood cells and platelets- which can lead to the following:
-low level of circulating red blood cells – anemia
-low level of white blood cells – leukopenia
-low level of neutrophils (a type of white blood cell) – neutropenia
-low level of platelets – thrombocytopeniaIncreased Risk of Malignancy
Individuals with FA have a higher risk than the general population of developing certain forms of cancer including acute myeloid leukemia and specific solid tumors. Affected individuals may are at extremely high risk of developing cancer affecting the head and neck region, gastrointestinal tract, esophagus or gynecologic regions. Most of these are a specific form of cancer, known as squamous cell carcinoma. FA patients whose bone marrow failure is treated with male hormones (called “androgens”) have in increased risk of liver tumors.In approximately 30 percent of cases associated with cancer, the development of malignancy precedes a diagnosis of FA. | 450 | Fanconi Anemia |
nord_450_2 | Causes of Fanconi Anemia | The chromosomes within the cells of individuals with FA are unable to repair deoxyribonucleic acid (DNA) damage, and thus break and rearrange easily (chromosome instability). DNA is the carrier of the genetic code and damage to DNA is a normal daily occurrence. In most people, damage to DNA is repaired. However, in individuals with FA, breaks and rearrangements occur more often and their bodies are slow or fail to repair the damage.Mutations in at least 18 genes can cause FA. The proteins encoded by these genes work together in a common pathway called the FA pathway that goes into operation when DNA damage occurs. The FA pathway sends certain proteins to the area of damage so DNA can be repaired and DNA can continue to be copied (replicated). Eight proteins form a complex known as the FA core complex, which activates two genes to make proteins, called FANCD2 and FANCI. The activation of these two proteins brings DNA repair proteins to the area of DNA damage.Eighty to 90 percent of cases of FA are due to mutations in one of three genes, FANCA, FANCC, and FANCG. These genes provide instructions for producing components of the FA core complex. Mutations in any of the many genes associated with the FA core complex will cause the complex to be nonfunctional and disrupt the entire FA pathway. Disruption of this pathway results in a build-up of DNA damage that can lead to abnormal cell death or abnormal cell growth. The death of cells results in a decrease in blood cells and physical abnormalities associated with FA. Uncontrolled cell growth can lead to the development of acute myeloid leukemia or other cancers.Most cases of FA are inherited in an autosomal recessive manner. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.Mutations in the following genes also cause FA and are inherited in an autosomal recessive manner: BRCA2, BRIP1, FANCB, FANCD2, FANCE, FANCF, FANCI, ERCC4, FANCL, FANCM, PALB2, RAD51C, SLX4, and UBE2T.The FANCB gene is located on the X chromosome, and causes less than 1 percent of all cases of FA. This FA gene is inherited as an X-linked recessive trait.X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and manifest mostly in males. Females that have an altered 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 altered gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains an altered gene he will develop the disease. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son. If a male with an X-linked disorder is able to reproduce, he will pass the altered 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.Mutations in the RAD51 gene cause autosomal dominant FA. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females. To date, all affected individuals with FA due to a RAD51 gene mutation have a spontaneous (de novo) genetic mutation that occurs in the egg or sperm cell. In such situations, the disorder is not inherited from the parents. | Causes of Fanconi Anemia. The chromosomes within the cells of individuals with FA are unable to repair deoxyribonucleic acid (DNA) damage, and thus break and rearrange easily (chromosome instability). DNA is the carrier of the genetic code and damage to DNA is a normal daily occurrence. In most people, damage to DNA is repaired. However, in individuals with FA, breaks and rearrangements occur more often and their bodies are slow or fail to repair the damage.Mutations in at least 18 genes can cause FA. The proteins encoded by these genes work together in a common pathway called the FA pathway that goes into operation when DNA damage occurs. The FA pathway sends certain proteins to the area of damage so DNA can be repaired and DNA can continue to be copied (replicated). Eight proteins form a complex known as the FA core complex, which activates two genes to make proteins, called FANCD2 and FANCI. The activation of these two proteins brings DNA repair proteins to the area of DNA damage.Eighty to 90 percent of cases of FA are due to mutations in one of three genes, FANCA, FANCC, and FANCG. These genes provide instructions for producing components of the FA core complex. Mutations in any of the many genes associated with the FA core complex will cause the complex to be nonfunctional and disrupt the entire FA pathway. Disruption of this pathway results in a build-up of DNA damage that can lead to abnormal cell death or abnormal cell growth. The death of cells results in a decrease in blood cells and physical abnormalities associated with FA. Uncontrolled cell growth can lead to the development of acute myeloid leukemia or other cancers.Most cases of FA are inherited in an autosomal recessive manner. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.Mutations in the following genes also cause FA and are inherited in an autosomal recessive manner: BRCA2, BRIP1, FANCB, FANCD2, FANCE, FANCF, FANCI, ERCC4, FANCL, FANCM, PALB2, RAD51C, SLX4, and UBE2T.The FANCB gene is located on the X chromosome, and causes less than 1 percent of all cases of FA. This FA gene is inherited as an X-linked recessive trait.X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and manifest mostly in males. Females that have an altered 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 altered gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains an altered gene he will develop the disease. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son. If a male with an X-linked disorder is able to reproduce, he will pass the altered 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.Mutations in the RAD51 gene cause autosomal dominant FA. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females. To date, all affected individuals with FA due to a RAD51 gene mutation have a spontaneous (de novo) genetic mutation that occurs in the egg or sperm cell. In such situations, the disorder is not inherited from the parents. | 450 | Fanconi Anemia |
nord_450_3 | Affects of Fanconi Anemia | The incidence rate of FA is estimated to be about 1 in 136,000 births. This condition is more common among people of Ashkenazi Jewish descent, the Roma population of Spain, and black South Africans. | Affects of Fanconi Anemia. The incidence rate of FA is estimated to be about 1 in 136,000 births. This condition is more common among people of Ashkenazi Jewish descent, the Roma population of Spain, and black South Africans. | 450 | Fanconi Anemia |
nord_450_4 | Related disorders of Fanconi Anemia | Symptoms of the following disorders may be similar to those of FA. Comparisons may be useful for a differential diagnosis.Chromosome instability syndromes: autosomal recessive inherited disorders that are associated with increased chromosomal breakage and genetic instability. These chromosomal abnormalities place affected individuals at a higher than average risk for developing certain cancers, especially leukemia. Additional abnormalities are present in most affected individuals. Chromosomal instability syndromes include Bloom syndrome, ataxia telangiectasia, Nijmegen breakage syndrome, and xeroderma pigmentosum. (For more information on these disorders choose the specific disorder name as your search terms in the Rare Disease Database.)Acquired aplastic anemia: a rare disorder caused by profound, almost complete bone marrow failure. Bone marrow is the spongy substance found in the center of the long bones of the body. The bone marrow produces specialized cells (hematopoietic stem cells) that grow and eventually develop into red blood cells (erythrocytes), white blood cells (leukocytes), and platelets. In acquired aplastic anemia, an almost complete absence of hematopoietic stem cells eventually results in low levels of red and white blood cells and platelets (pancytopenia). Specific symptoms associated with acquired aplastic anemia may vary, but include fatigue, chronic infections, dizziness, weakness, headaches, and episodes of excessive bleeding. Although some cases of acquired aplastic anemia occur secondary to other disorders, researchers now believe that many cases result from a disorder of the patient’s immune system, in which the immune system mistakenly targets the bone marrow (autoimmunity). This is based on the response of approximately half of patients to immunotherapy, whether it is ATG, cyclosporine, high-dose steroids or cyclophosphamide. (For more information on this disorder, choose “aplastic anemia” as your search term in the Rare Disease Database.)Thrombocytopenia-absent radius (TAR) syndrome: a rare genetic disorder that is apparent at birth (congenital). The disorder is characterized by low levels of platelets in the blood (thrombocytopenia), resulting in potentially severe bleeding episodes (hemorrhaging) primarily during infancy. Other characteristic findings include absence (aplasia) of the bone on the thumb side of the forearms (radii) and sometimes underdevelopment (hypoplasia) or absence of the bone on the “pinky” side of the forearms (ulnae). Other abnormalities may also be present, such as structural malformations of the heart (congenital heart defects), kidney (renal) defects, and/or intellectual disability that may be secondary to bleeding episodes in the skull (intracranial hemorrhages) during infancy. TAR syndrome is inherited as an autosomal recessive trait. (For more information on this disorder, choose “thrombocytopenia-absent radius” as your search term in the Rare Disease Database.)Dyskeratosis congenita, also known as Zinsser-Cole-Engman syndrome: a rare genetic disorder characterized by darkening and/or unusual absence of skin color (hyper/hypopigmentation), abnormal changes in the nails (dystrophy), and progressive degenerative changes of the mucous membranes (leukoplakia) in the mouth, and rarely the anus or urethra. Many patients have eye problems, including tearing due to narrowing of the ducts that drain tears. Additional symptoms may include the reduction of red and white blood cells and platelets in the blood (pancytopenia), resulting in bone marrow failure. Affected individuals may also have thickening of skin on the palms of the hands and soles of the feet, excessive sweating of the palms and soles, sparse or absent hair, fragile bones, underdeveloped testes, and dental abnormalities. This disorder may be inherited or occur sporadically. X-linked recessive is the most common inheritance pattern, but autosomal dominant (a parent with a mutated gene passes it to their child) is common, and autosomal recessive is rare. (For more information on this disorder, choose “dyskeratosis congenita” as your search term in the Rare Disease Database.)VACTERL association: a nonrandom association of birth defects that affects multiple organ systems. The term VACTERL is an acronym with each letter representing the first letter of one of the more common findings seen in affected children: (V) = vertebral abnormalities; (A) = anal atresia; (C) = cardiac (heart) defects; (T) = tracheoesophageal fistula; (E) = esophageal atresia; (R) = renal (kidney) abnormalities; (L) = limb abnormalities (including thumbs and radii). In addition to the above mentioned features, affected children may also exhibit less frequent abnormalities including growth deficiencies and failure to gain weight and grow at the expected rate (failure to thrive). In some cases, the acronym VATER association is used. Mental functioning and intelligence are usually unaffected. Most cases occur randomly, for no apparent reason (sporadic). However, at least 5 % of FA patients have this association. (For more information on this disorder, choose “VACTERL” as your search term in the Rare Disease Database.)The following disorders may be associated with FA as secondary complications. They are not necessary for a differential diagnosis.Myelodysplastic syndromes (MDS): a rare group of blood disorders that occur as a result of improper development of blood cells within the bone marrow. The three main types of blood cells (i.e., red blood cells, white blood cells and platelets) are affected. Red blood cells deliver oxygen to the body, white blood cells help fight infections, and platelets assist in clotting to stop blood loss. These improperly developed blood cells fail to develop normally and enter the bloodstream. As a result, individuals with MDS have abnormally low blood cell levels (low blood counts). General symptoms associated with MDS include fatigue, dizziness, weakness, bruising and bleeding, frequent infections, and headaches. In some cases, MDS may progress to life-threatening failure of the bone marrow or develop into an acute leukemia. The exact cause of MDS is unknown. There are no certain environmental risk factors. (For more information on this disorder, choose “myelodysplastic syndrome” as your search term in the Rare Disease Database.)Acute myeloid leukemia (AML): a rare form of blood cancer that begins in cells that normally develop into certain types of white blood cells. The transition to leukemia is accompanied by worsening marrow function and the accumulation, first in the marrow and subsequently in the blood, of undeveloped “immature” cells called blasts which suppress any remaining marrow cell production. As a consequence, the complications from anemia, bleeding, and infection become life-threatening. The abnormal (leukemic) cells may eventually spread via the bloodstream to other organ systems of the body. (For more information on this disorder, choose “acute myeloid leukemia” as your search term in the Rare Disease Database.) | Related disorders of Fanconi Anemia. Symptoms of the following disorders may be similar to those of FA. Comparisons may be useful for a differential diagnosis.Chromosome instability syndromes: autosomal recessive inherited disorders that are associated with increased chromosomal breakage and genetic instability. These chromosomal abnormalities place affected individuals at a higher than average risk for developing certain cancers, especially leukemia. Additional abnormalities are present in most affected individuals. Chromosomal instability syndromes include Bloom syndrome, ataxia telangiectasia, Nijmegen breakage syndrome, and xeroderma pigmentosum. (For more information on these disorders choose the specific disorder name as your search terms in the Rare Disease Database.)Acquired aplastic anemia: a rare disorder caused by profound, almost complete bone marrow failure. Bone marrow is the spongy substance found in the center of the long bones of the body. The bone marrow produces specialized cells (hematopoietic stem cells) that grow and eventually develop into red blood cells (erythrocytes), white blood cells (leukocytes), and platelets. In acquired aplastic anemia, an almost complete absence of hematopoietic stem cells eventually results in low levels of red and white blood cells and platelets (pancytopenia). Specific symptoms associated with acquired aplastic anemia may vary, but include fatigue, chronic infections, dizziness, weakness, headaches, and episodes of excessive bleeding. Although some cases of acquired aplastic anemia occur secondary to other disorders, researchers now believe that many cases result from a disorder of the patient’s immune system, in which the immune system mistakenly targets the bone marrow (autoimmunity). This is based on the response of approximately half of patients to immunotherapy, whether it is ATG, cyclosporine, high-dose steroids or cyclophosphamide. (For more information on this disorder, choose “aplastic anemia” as your search term in the Rare Disease Database.)Thrombocytopenia-absent radius (TAR) syndrome: a rare genetic disorder that is apparent at birth (congenital). The disorder is characterized by low levels of platelets in the blood (thrombocytopenia), resulting in potentially severe bleeding episodes (hemorrhaging) primarily during infancy. Other characteristic findings include absence (aplasia) of the bone on the thumb side of the forearms (radii) and sometimes underdevelopment (hypoplasia) or absence of the bone on the “pinky” side of the forearms (ulnae). Other abnormalities may also be present, such as structural malformations of the heart (congenital heart defects), kidney (renal) defects, and/or intellectual disability that may be secondary to bleeding episodes in the skull (intracranial hemorrhages) during infancy. TAR syndrome is inherited as an autosomal recessive trait. (For more information on this disorder, choose “thrombocytopenia-absent radius” as your search term in the Rare Disease Database.)Dyskeratosis congenita, also known as Zinsser-Cole-Engman syndrome: a rare genetic disorder characterized by darkening and/or unusual absence of skin color (hyper/hypopigmentation), abnormal changes in the nails (dystrophy), and progressive degenerative changes of the mucous membranes (leukoplakia) in the mouth, and rarely the anus or urethra. Many patients have eye problems, including tearing due to narrowing of the ducts that drain tears. Additional symptoms may include the reduction of red and white blood cells and platelets in the blood (pancytopenia), resulting in bone marrow failure. Affected individuals may also have thickening of skin on the palms of the hands and soles of the feet, excessive sweating of the palms and soles, sparse or absent hair, fragile bones, underdeveloped testes, and dental abnormalities. This disorder may be inherited or occur sporadically. X-linked recessive is the most common inheritance pattern, but autosomal dominant (a parent with a mutated gene passes it to their child) is common, and autosomal recessive is rare. (For more information on this disorder, choose “dyskeratosis congenita” as your search term in the Rare Disease Database.)VACTERL association: a nonrandom association of birth defects that affects multiple organ systems. The term VACTERL is an acronym with each letter representing the first letter of one of the more common findings seen in affected children: (V) = vertebral abnormalities; (A) = anal atresia; (C) = cardiac (heart) defects; (T) = tracheoesophageal fistula; (E) = esophageal atresia; (R) = renal (kidney) abnormalities; (L) = limb abnormalities (including thumbs and radii). In addition to the above mentioned features, affected children may also exhibit less frequent abnormalities including growth deficiencies and failure to gain weight and grow at the expected rate (failure to thrive). In some cases, the acronym VATER association is used. Mental functioning and intelligence are usually unaffected. Most cases occur randomly, for no apparent reason (sporadic). However, at least 5 % of FA patients have this association. (For more information on this disorder, choose “VACTERL” as your search term in the Rare Disease Database.)The following disorders may be associated with FA as secondary complications. They are not necessary for a differential diagnosis.Myelodysplastic syndromes (MDS): a rare group of blood disorders that occur as a result of improper development of blood cells within the bone marrow. The three main types of blood cells (i.e., red blood cells, white blood cells and platelets) are affected. Red blood cells deliver oxygen to the body, white blood cells help fight infections, and platelets assist in clotting to stop blood loss. These improperly developed blood cells fail to develop normally and enter the bloodstream. As a result, individuals with MDS have abnormally low blood cell levels (low blood counts). General symptoms associated with MDS include fatigue, dizziness, weakness, bruising and bleeding, frequent infections, and headaches. In some cases, MDS may progress to life-threatening failure of the bone marrow or develop into an acute leukemia. The exact cause of MDS is unknown. There are no certain environmental risk factors. (For more information on this disorder, choose “myelodysplastic syndrome” as your search term in the Rare Disease Database.)Acute myeloid leukemia (AML): a rare form of blood cancer that begins in cells that normally develop into certain types of white blood cells. The transition to leukemia is accompanied by worsening marrow function and the accumulation, first in the marrow and subsequently in the blood, of undeveloped “immature” cells called blasts which suppress any remaining marrow cell production. As a consequence, the complications from anemia, bleeding, and infection become life-threatening. The abnormal (leukemic) cells may eventually spread via the bloodstream to other organ systems of the body. (For more information on this disorder, choose “acute myeloid leukemia” as your search term in the Rare Disease Database.) | 450 | Fanconi Anemia |
nord_450_5 | Diagnosis of Fanconi Anemia | A diagnosis of FA is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic findings, and a variety of specialized tests.The definitive test for FA at the present time is a chromosome breakage test: some of the patient’s blood cells are treated, in a test tube, with a chemical that crosslinks DNA. Normal cells are able to correct most of the damage and are not severely affected whereas FA cells show marked chromosome breakage. There are two chemicals commonly used for this test: DEB (diepoxybutane) and MMC (mitomycin C). These tests can be performed prenatally on cells from chorionic villi or from the amniotic fluid.Blood tests may be performed to determine the levels of red and white blood cells and platelets. X-ray examinations may reveal the presence and extent of skeletal malformations and internal structural abnormalities.Many cases of FA are not diagnosed at all or are not diagnosed in a timely manner. FA should be suspected and tested for in any infant born with the thumb and arm abnormalities described previously. Anyone developing aplastic anemia at any age should be tested for FA, even if no other defects are present. Any patient who develops squamous cell carcinoma of the head and neck, gastrointestinal or gynecologic system at an early age with or without a history of tobacco or alcohol use, should be tested for FA. Many FA patients show no other abnormalities. It is essential to test for FA before contemplating stem cell transplantation for aplastic anemia or treatment for cancer, as standard chemotherapy and radiation protocols may prove toxic to FA patients.Molecular genetic testing is available for all 18 genes associated with FA. Complementation testing is usually done first in order to identify which FA gene is mutated. Sequence analysis of the appropriate gene can then be done to determine the specific mutation in that gene. If a mutation is not identified, deletion/duplication analysis is available clinically for the genes associated with FA.Targeted mutation analysis is available for the common Ashkenazi Jewish FANCC mutation.Clinical Testing/ Work Up
To establish the extent of disease in an individual diagnosed with FA, the following evaluations are recommended as needed:-Ultrasound examination of the kidneys and urinary tract
-Formal hearing test
-Developmental assessment (particularly important for toddlers and school-age children)
-Referral to an ophthalmologist, otolaryngologist, endocrinologist, hand surgeon, gynecologist (for females as indicated), gastroenterologist, urologist, dermatologist, ENT surgeon, genetic counselor
-Evaluation by a hematologist, to include complete blood count, fetal hemoglobin, and bone marrow aspirate for cell morphology and chromosome study (cytogenetics), as well as biopsy for cellularity
-HLA typing of the affected individual, siblings, and parents for consideration of hematopoietic stem cell transplantation
-Full blood typing
-Blood chemistries (assessing liver, kidney, thyroid, lipids, and iron status) | Diagnosis of Fanconi Anemia. A diagnosis of FA is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic findings, and a variety of specialized tests.The definitive test for FA at the present time is a chromosome breakage test: some of the patient’s blood cells are treated, in a test tube, with a chemical that crosslinks DNA. Normal cells are able to correct most of the damage and are not severely affected whereas FA cells show marked chromosome breakage. There are two chemicals commonly used for this test: DEB (diepoxybutane) and MMC (mitomycin C). These tests can be performed prenatally on cells from chorionic villi or from the amniotic fluid.Blood tests may be performed to determine the levels of red and white blood cells and platelets. X-ray examinations may reveal the presence and extent of skeletal malformations and internal structural abnormalities.Many cases of FA are not diagnosed at all or are not diagnosed in a timely manner. FA should be suspected and tested for in any infant born with the thumb and arm abnormalities described previously. Anyone developing aplastic anemia at any age should be tested for FA, even if no other defects are present. Any patient who develops squamous cell carcinoma of the head and neck, gastrointestinal or gynecologic system at an early age with or without a history of tobacco or alcohol use, should be tested for FA. Many FA patients show no other abnormalities. It is essential to test for FA before contemplating stem cell transplantation for aplastic anemia or treatment for cancer, as standard chemotherapy and radiation protocols may prove toxic to FA patients.Molecular genetic testing is available for all 18 genes associated with FA. Complementation testing is usually done first in order to identify which FA gene is mutated. Sequence analysis of the appropriate gene can then be done to determine the specific mutation in that gene. If a mutation is not identified, deletion/duplication analysis is available clinically for the genes associated with FA.Targeted mutation analysis is available for the common Ashkenazi Jewish FANCC mutation.Clinical Testing/ Work Up
To establish the extent of disease in an individual diagnosed with FA, the following evaluations are recommended as needed:-Ultrasound examination of the kidneys and urinary tract
-Formal hearing test
-Developmental assessment (particularly important for toddlers and school-age children)
-Referral to an ophthalmologist, otolaryngologist, endocrinologist, hand surgeon, gynecologist (for females as indicated), gastroenterologist, urologist, dermatologist, ENT surgeon, genetic counselor
-Evaluation by a hematologist, to include complete blood count, fetal hemoglobin, and bone marrow aspirate for cell morphology and chromosome study (cytogenetics), as well as biopsy for cellularity
-HLA typing of the affected individual, siblings, and parents for consideration of hematopoietic stem cell transplantation
-Full blood typing
-Blood chemistries (assessing liver, kidney, thyroid, lipids, and iron status) | 450 | Fanconi Anemia |
nord_450_6 | Therapies of Fanconi Anemia | TreatmentThe treatment of FA is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, cardiologists, kidney specialists (nephrologists), urologists, gastroenterologists, specialists who assess and treat hearing problems (audiologists and otolaryngologists), eye specialists and other health care professionals may need to systematically and comprehensively plan an affected individual’s treatment.Recommendations for treatment were agreed upon at a 2014 consensus conference.https://www.fanconi.org/images/uploads/other/FA_Guidelines_4th_Edition_Revised_Names_in_Appendix.pdf -Androgen (male hormone) administration: Androgens improve the blood counts in approximately 50% of individuals with FA. The earliest response is seen in red cells, with increase in hemoglobin generally occurring within the first month or two of treatment. Responses in the white cell count and platelet count are variable. Platelet responses are generally incomplete and may not be seen before several months of therapy. Improvement is generally greatest for the red cell count. Resistance to therapy may develop over time.-Hematopoietic growth factors: Granulocyte colony-stimulating factor (G-CSF) may improve the neutrophil count in some individuals. It is usually used only for support during intercurrent illnesses.-Hematopoietic stem cell transplantation (HSCT): the only curative therapy for the hematologic manifestations of FA. Donor stem cells may be obtained from bone marrow, peripheral blood, or cord blood.-Cancer treatment: Treatment of malignancies is challenging secondary to the increased toxicity associated with chemotherapy and radiation in FA. Care should be obtained from centers experienced in the treatment of FA patients.Surgery may be necessary to correct skeletal malformations such as those affecting the thumbs and forearm bones, cardiac defects, and gastrointestinal abnormalities such as tracheoesophageal fistula or esophageal atresia, as well as anal atresia.Certain chemicals may increase the risk of chromosomal breakage in individuals with FA and should be avoided whenever possible. These chemicals include tobacco smoke, formaldehyde, herbicides, and organic solvents such as gasoline or paint thinner.Genetic counseling is recommended for affected individuals and their families. | Therapies of Fanconi Anemia. TreatmentThe treatment of FA is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, cardiologists, kidney specialists (nephrologists), urologists, gastroenterologists, specialists who assess and treat hearing problems (audiologists and otolaryngologists), eye specialists and other health care professionals may need to systematically and comprehensively plan an affected individual’s treatment.Recommendations for treatment were agreed upon at a 2014 consensus conference.https://www.fanconi.org/images/uploads/other/FA_Guidelines_4th_Edition_Revised_Names_in_Appendix.pdf -Androgen (male hormone) administration: Androgens improve the blood counts in approximately 50% of individuals with FA. The earliest response is seen in red cells, with increase in hemoglobin generally occurring within the first month or two of treatment. Responses in the white cell count and platelet count are variable. Platelet responses are generally incomplete and may not be seen before several months of therapy. Improvement is generally greatest for the red cell count. Resistance to therapy may develop over time.-Hematopoietic growth factors: Granulocyte colony-stimulating factor (G-CSF) may improve the neutrophil count in some individuals. It is usually used only for support during intercurrent illnesses.-Hematopoietic stem cell transplantation (HSCT): the only curative therapy for the hematologic manifestations of FA. Donor stem cells may be obtained from bone marrow, peripheral blood, or cord blood.-Cancer treatment: Treatment of malignancies is challenging secondary to the increased toxicity associated with chemotherapy and radiation in FA. Care should be obtained from centers experienced in the treatment of FA patients.Surgery may be necessary to correct skeletal malformations such as those affecting the thumbs and forearm bones, cardiac defects, and gastrointestinal abnormalities such as tracheoesophageal fistula or esophageal atresia, as well as anal atresia.Certain chemicals may increase the risk of chromosomal breakage in individuals with FA and should be avoided whenever possible. These chemicals include tobacco smoke, formaldehyde, herbicides, and organic solvents such as gasoline or paint thinner.Genetic counseling is recommended for affected individuals and their families. | 450 | Fanconi Anemia |
nord_451_0 | Overview of Fascioliasis | Fascioliasis is a rare infectious disorder caused by parasites. These parasites are liver flukes that live in plant-eating animals. Liver flukes can be found on water plants in certain parts of the world. When the parasite invades the liver, bile passages may be blocked. A subdivision of Fascioliasis called Halzoun Syndrome affects the throat (pharynx). This infection can usually be controlled and/or cured with timely treatment. | Overview of Fascioliasis. Fascioliasis is a rare infectious disorder caused by parasites. These parasites are liver flukes that live in plant-eating animals. Liver flukes can be found on water plants in certain parts of the world. When the parasite invades the liver, bile passages may be blocked. A subdivision of Fascioliasis called Halzoun Syndrome affects the throat (pharynx). This infection can usually be controlled and/or cured with timely treatment. | 451 | Fascioliasis |
nord_451_1 | Symptoms of Fascioliasis | The disease has three phases: acute, latent, and chronic. The acute phase begins approximately four days after infection and can last for two to four months. Symptoms during this phase include fever, abdominal pain with tender liver, gastrointestinal disturbances, and hives (urticaria) accompanied by bouts of bronchial asthma. The latent phase begins when mature flukes reach the bile duct and can last for several months. Individuals in this phase are asymptomatic. The chronic phase can persist for several years. Symptoms include gastrointestinal pain, fatty food intolerance, nausea, jaundice, itching, and abdominal tenderness. | Symptoms of Fascioliasis. The disease has three phases: acute, latent, and chronic. The acute phase begins approximately four days after infection and can last for two to four months. Symptoms during this phase include fever, abdominal pain with tender liver, gastrointestinal disturbances, and hives (urticaria) accompanied by bouts of bronchial asthma. The latent phase begins when mature flukes reach the bile duct and can last for several months. Individuals in this phase are asymptomatic. The chronic phase can persist for several years. Symptoms include gastrointestinal pain, fatty food intolerance, nausea, jaundice, itching, and abdominal tenderness. | 451 | Fascioliasis |
nord_451_2 | Causes of Fascioliasis | Fascioliasis is caused by infection with the parasitic worms of the genus Fasciola, of which “Fasciola hepatica”, found in temperate climates, and “Fasciola gigantica”, found in tropical climates, are the most common. Encysted parasitic larvae of these parasites live on water plants, such as watercress, that may be eaten by man or eaten by animals that subsequently are eaten by man. Once ingested, the larvae escape from the cysts in the small intestine and migrate across the intestinal wall into the abdominal cavity. They transform into immature worms and, once they reach the liver, move around for up to six weeks, feeding on liver tissue. Eventually, they take up residence in the bile ducts, where they cause lesions and chronic liver disease. Generally, the parasite can be killed by adequate cooking of foods before they are eaten. | Causes of Fascioliasis. Fascioliasis is caused by infection with the parasitic worms of the genus Fasciola, of which “Fasciola hepatica”, found in temperate climates, and “Fasciola gigantica”, found in tropical climates, are the most common. Encysted parasitic larvae of these parasites live on water plants, such as watercress, that may be eaten by man or eaten by animals that subsequently are eaten by man. Once ingested, the larvae escape from the cysts in the small intestine and migrate across the intestinal wall into the abdominal cavity. They transform into immature worms and, once they reach the liver, move around for up to six weeks, feeding on liver tissue. Eventually, they take up residence in the bile ducts, where they cause lesions and chronic liver disease. Generally, the parasite can be killed by adequate cooking of foods before they are eaten. | 451 | Fascioliasis |
nord_451_3 | Affects of Fascioliasis | Fascioliasis is rare in the United States, but sometimes occurs in southern and western areas of the nation where goats and sheep are raised. The parasites can be passed to man through goat or sheep meat that is inadequately cooked. This disorder tends to be more prevalent in the Orient and the tropics. An estimated that 2.4 million people are infected worldwide. An outbreak in northern Iran in 1989 and 1991 affected more than 10,000 people. Other outbreaks have occurred in Algeria, Cuba, and France. According to the World Health Organization, the infection is present in domestic animals in almost all countries where cattle and sheet are reared.The disease affects both sexes and all ages. It is highly prevalent in Ecuador, Peru, Bolivia, Chile, Iran, and Egypt. Sporadic outbreaks occur in countries such as Portugal, France, and Spain. | Affects of Fascioliasis. Fascioliasis is rare in the United States, but sometimes occurs in southern and western areas of the nation where goats and sheep are raised. The parasites can be passed to man through goat or sheep meat that is inadequately cooked. This disorder tends to be more prevalent in the Orient and the tropics. An estimated that 2.4 million people are infected worldwide. An outbreak in northern Iran in 1989 and 1991 affected more than 10,000 people. Other outbreaks have occurred in Algeria, Cuba, and France. According to the World Health Organization, the infection is present in domestic animals in almost all countries where cattle and sheet are reared.The disease affects both sexes and all ages. It is highly prevalent in Ecuador, Peru, Bolivia, Chile, Iran, and Egypt. Sporadic outbreaks occur in countries such as Portugal, France, and Spain. | 451 | Fascioliasis |
nord_451_4 | Related disorders of Fascioliasis | Other infectious disorders caused by parasites may be due to round worms, tape worms, protozoan organisms, flukes and other bacteria.Halzoun Syndrome is a variant of Fascioliasis. This disorder affects the throat. It is caused by eating “Fasciola Hepatica”, “Fasciola Gigantica” or other parasites known as “Linguatulid” larvae. | Related disorders of Fascioliasis. Other infectious disorders caused by parasites may be due to round worms, tape worms, protozoan organisms, flukes and other bacteria.Halzoun Syndrome is a variant of Fascioliasis. This disorder affects the throat. It is caused by eating “Fasciola Hepatica”, “Fasciola Gigantica” or other parasites known as “Linguatulid” larvae. | 451 | Fascioliasis |
nord_451_5 | Diagnosis of Fascioliasis | Liver fluke disease should be suspected if the patient recently spent time in a region where infection is prevalent in animals and/or humans. Patients usually report eating wild watercress, algae, or other aquatic plants. Acute and chronic infection can be confirmed by testing that detects liver fluke-specific antibodies in body fluids. Also, parasite eggs may be detected in the stool at the chronic stage of infection. | Diagnosis of Fascioliasis. Liver fluke disease should be suspected if the patient recently spent time in a region where infection is prevalent in animals and/or humans. Patients usually report eating wild watercress, algae, or other aquatic plants. Acute and chronic infection can be confirmed by testing that detects liver fluke-specific antibodies in body fluids. Also, parasite eggs may be detected in the stool at the chronic stage of infection. | 451 | Fascioliasis |
nord_451_6 | Therapies of Fascioliasis | Prompt treatment of Fascioliasis is necessary to prevent liver complications caused by this disorder. Liver fluke disease can be successfully treated using the drug, Triclabendazole. This drug is administered after consumption of food and usually in a single dose. In severe cases, two doses may be administered, 12 hours apart. It is effective against both adult and immature worms.The drug previously used, bithionol, had to be administered orally over five days, and another drug, praziquantel, which is effective against some similar parasitic organisms, is not effective against the Fasciola species.Inspection programs of animals in high risk areas can do much to control the spread of this infection. Most importantly, all meats should be well cooked before they are eaten by man. | Therapies of Fascioliasis. Prompt treatment of Fascioliasis is necessary to prevent liver complications caused by this disorder. Liver fluke disease can be successfully treated using the drug, Triclabendazole. This drug is administered after consumption of food and usually in a single dose. In severe cases, two doses may be administered, 12 hours apart. It is effective against both adult and immature worms.The drug previously used, bithionol, had to be administered orally over five days, and another drug, praziquantel, which is effective against some similar parasitic organisms, is not effective against the Fasciola species.Inspection programs of animals in high risk areas can do much to control the spread of this infection. Most importantly, all meats should be well cooked before they are eaten by man. | 451 | Fascioliasis |
nord_452_0 | Overview of Fatal Familial Insomnia | Summary
Fatal familial insomnia (FFI) is a rare genetic degenerative brain disorder. It is characterized by an inability to sleep (insomnia) that may be initially mild, but progressively worsens, leading to significant physical and mental deterioration. Affected individuals may also develop dysfunction of the autonomic nervous system, the part of the nervous system that controls involuntary or automatic body processes – which are things that happen without a person thinking about them, such as body temperature regulation, sweating, breathing or regulating the heart rate. Specific symptoms depend on the part of the autonomic nervous system that is affected by the disease. In all instances, FFI is caused by an abnormal variant in the prion-related protein (PRNP) gene, although sometimes, the disorder occurs randomly, without a variant PRNP gene (sporadic fatal insomnia, or SFI). The PRNP gene regulates the production of human prion protein. Alterations in this gene lead to the generation of abnormally shaped (misfolded) prion protein, also known simply as a “prion”, which is toxic to the body. In FFI, the abnormal prions build up primarily within the thalamus of the brain. This leads to the progressive loss of nerve cells (neurons) and the various symptoms associated with this disorder. There is no cure, but investigators are researching ways to best treat and manage FFI.Introduction
FFI is classified as a transmissible spongiform encephalopathy (TSE) or a prion disease. Prion diseases are caused by the accumulation of misfolded prion proteins in the brain. Two other prion diseases, Creutzfeldt-Jakob disease and Gerstmann-Straussler-Scheinker syndrome, may also occur because of variations of the PRNP gene, although some prion diseases occur in the absence of a genetic variation. Generally, prion disorders are characterized by long incubation periods and short clinical duration, which means the abnormal prions may accumulate for many years without causing symptoms (long incubation period), but once symptoms begin the disorder rapidly worsens. | Overview of Fatal Familial Insomnia. Summary
Fatal familial insomnia (FFI) is a rare genetic degenerative brain disorder. It is characterized by an inability to sleep (insomnia) that may be initially mild, but progressively worsens, leading to significant physical and mental deterioration. Affected individuals may also develop dysfunction of the autonomic nervous system, the part of the nervous system that controls involuntary or automatic body processes – which are things that happen without a person thinking about them, such as body temperature regulation, sweating, breathing or regulating the heart rate. Specific symptoms depend on the part of the autonomic nervous system that is affected by the disease. In all instances, FFI is caused by an abnormal variant in the prion-related protein (PRNP) gene, although sometimes, the disorder occurs randomly, without a variant PRNP gene (sporadic fatal insomnia, or SFI). The PRNP gene regulates the production of human prion protein. Alterations in this gene lead to the generation of abnormally shaped (misfolded) prion protein, also known simply as a “prion”, which is toxic to the body. In FFI, the abnormal prions build up primarily within the thalamus of the brain. This leads to the progressive loss of nerve cells (neurons) and the various symptoms associated with this disorder. There is no cure, but investigators are researching ways to best treat and manage FFI.Introduction
FFI is classified as a transmissible spongiform encephalopathy (TSE) or a prion disease. Prion diseases are caused by the accumulation of misfolded prion proteins in the brain. Two other prion diseases, Creutzfeldt-Jakob disease and Gerstmann-Straussler-Scheinker syndrome, may also occur because of variations of the PRNP gene, although some prion diseases occur in the absence of a genetic variation. Generally, prion disorders are characterized by long incubation periods and short clinical duration, which means the abnormal prions may accumulate for many years without causing symptoms (long incubation period), but once symptoms begin the disorder rapidly worsens. | 452 | Fatal Familial Insomnia |
nord_452_1 | Symptoms of Fatal Familial Insomnia | The characteristic symptom in FFI is progressive insomnia. Insomnia often begins during middle age, but it can occur earlier or later in life. Insomnia may first be mild, but it then becomes progressively worse until an affected individual gets very little sleep. Insomnia usually begins suddenly and can rapidly worsen over the next few months. When sleep is achieved, vivid dreams may occur. The lack of sleep leads to physical and mental deterioration and the disease ultimately progresses to coma and death.Although insomnia is usually the first symptom, some individuals may present with progressive dementia, in which there are worsening problems with thought, cognition, memory, language and behavior. Initially, the signs may be subtle and include unintended weight loss, forgetfulness, inattentiveness, problems concentrating or speech problems. Episodes of confusion or hallucinations can eventually occur.Some affected individuals experience double vision (diplopia) or abnormal, jerky eye movements (nystagmus). There may be problems with swallowing (dysphagia) or slurred speech (dysarthria). Some individuals eventually have trouble coordinating voluntary movements (ataxia). Abnormal movements including tremors or twitchy, jerking muscle spasms (myoclonus), or Parkinson’s-like symptoms may also develop.Additional symptoms involving dysfunction of the autonomic nervous system often develop. Specific symptoms can vary from one person to another based on the specific part of the autonomic nervous system affected. Common symptoms can include fever, rapid heart rate (tachycardia), high blood pressure (hypertension), increased sweating (hyperhidrosis), increased production of tears, constipation, variations in body temperature and sexual dysfunction including erectile dysfunction. Anxiety and depression are common findings as well. | Symptoms of Fatal Familial Insomnia. The characteristic symptom in FFI is progressive insomnia. Insomnia often begins during middle age, but it can occur earlier or later in life. Insomnia may first be mild, but it then becomes progressively worse until an affected individual gets very little sleep. Insomnia usually begins suddenly and can rapidly worsen over the next few months. When sleep is achieved, vivid dreams may occur. The lack of sleep leads to physical and mental deterioration and the disease ultimately progresses to coma and death.Although insomnia is usually the first symptom, some individuals may present with progressive dementia, in which there are worsening problems with thought, cognition, memory, language and behavior. Initially, the signs may be subtle and include unintended weight loss, forgetfulness, inattentiveness, problems concentrating or speech problems. Episodes of confusion or hallucinations can eventually occur.Some affected individuals experience double vision (diplopia) or abnormal, jerky eye movements (nystagmus). There may be problems with swallowing (dysphagia) or slurred speech (dysarthria). Some individuals eventually have trouble coordinating voluntary movements (ataxia). Abnormal movements including tremors or twitchy, jerking muscle spasms (myoclonus), or Parkinson’s-like symptoms may also develop.Additional symptoms involving dysfunction of the autonomic nervous system often develop. Specific symptoms can vary from one person to another based on the specific part of the autonomic nervous system affected. Common symptoms can include fever, rapid heart rate (tachycardia), high blood pressure (hypertension), increased sweating (hyperhidrosis), increased production of tears, constipation, variations in body temperature and sexual dysfunction including erectile dysfunction. Anxiety and depression are common findings as well. | 452 | Fatal Familial Insomnia |
nord_452_2 | Causes of Fatal Familial Insomnia | FFI is caused by an abnormal variant (gene mutation) of the PRNP gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent or overproduced. Depending upon the functions of the protein, this can affect many organ systems of the body, including the brain.In rare instances, the change (variation) in the PRNP gene in individuals with FFI occurs spontaneously, without a family history of the disease. This is called a new or de novo variant. The gene variation has occurred at the time of the formation of the egg or sperm for that child only, and no other family member will be affected. The disorder is usually not inherited from or “carried” by a healthy parent. However, the person who has this de novo variant could pass on the variant gene to their children in an autosomal dominant manner.Dominant genetic disorders occur when only a single copy of a mutated gene is necessary to cause the disease. The mutated gene can be inherited from either parent or can be the result of a changed gene in the affected individual. The risk of passing the mutated gene from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females. Some individuals have developed fatal insomnia (FI) without a variation in the PRNP gene. These individuals are said to have sporadic fatal insomnia (SFI) and although this is a non-genetic form of FFI, the underlying trigger for its development is unknown. Thus, SFI occurs randomly, by chance, with a much rarer occurrence than FFI.The PRNP gene produces a protein called prion protein, or PrP. The exact function of PrP in the body is not fully understood. However, because of the variant gene, the PrP that is produced develops an abnormal 3-dimensional shape that is described simply as “misfolded”. The misfolded PrP is toxic to the body, especially cells of the nervous system. In FFI, misfolded PrP is primarily found in the thalamus, which is a structure deep within the brain that helps to regulate many functions of the body including sleep, appetite and body temperature. As the misfolded PrP builds up in the thalamus, it results in a progressive destruction of nerve cells (neurons), which leads to the symptoms of the disorder. The damage to brain tissue may appear as sponge-like holes or gaps when examined under a microscope, which is why prion diseases like FFI are called transmissible spongiform encephalopathies.The term “prion” was coined to designate a “proteinaceous infectious agent” to explain the transmissible nature of prion diseases. Extensive research has shown that a prion is essentially the misfolded PrP. However, it is important to know that FFI is not contagious in the traditional sense because the only way to transmit prion disease to a healthy individual is through direct exposure to disease-affected brain tissue, perhaps by ingestion or injection. If a person without an underlying genetic abnormality develops a prion disease because of exposure to prions from an external source, they are said to have an ‘acquired’ form. For example, variant Creutzfeldt-Jakob disease occurred in the United Kingdom when people ate prion-contaminated beef. A lesser-known example is kuru. Kuru is a virtually extinct prion disease that occurred in the Fore people of Papua New Guinea. The disease spread throughout this population because of the villagers’ practice of eating the brains of deceased kuru-affected tribesmen (ritualistic cannibalism). All other forms of prion disease are considered “sporadic” and occur spontaneously in a patient. | Causes of Fatal Familial Insomnia. FFI is caused by an abnormal variant (gene mutation) of the PRNP gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent or overproduced. Depending upon the functions of the protein, this can affect many organ systems of the body, including the brain.In rare instances, the change (variation) in the PRNP gene in individuals with FFI occurs spontaneously, without a family history of the disease. This is called a new or de novo variant. The gene variation has occurred at the time of the formation of the egg or sperm for that child only, and no other family member will be affected. The disorder is usually not inherited from or “carried” by a healthy parent. However, the person who has this de novo variant could pass on the variant gene to their children in an autosomal dominant manner.Dominant genetic disorders occur when only a single copy of a mutated gene is necessary to cause the disease. The mutated gene can be inherited from either parent or can be the result of a changed gene in the affected individual. The risk of passing the mutated gene from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females. Some individuals have developed fatal insomnia (FI) without a variation in the PRNP gene. These individuals are said to have sporadic fatal insomnia (SFI) and although this is a non-genetic form of FFI, the underlying trigger for its development is unknown. Thus, SFI occurs randomly, by chance, with a much rarer occurrence than FFI.The PRNP gene produces a protein called prion protein, or PrP. The exact function of PrP in the body is not fully understood. However, because of the variant gene, the PrP that is produced develops an abnormal 3-dimensional shape that is described simply as “misfolded”. The misfolded PrP is toxic to the body, especially cells of the nervous system. In FFI, misfolded PrP is primarily found in the thalamus, which is a structure deep within the brain that helps to regulate many functions of the body including sleep, appetite and body temperature. As the misfolded PrP builds up in the thalamus, it results in a progressive destruction of nerve cells (neurons), which leads to the symptoms of the disorder. The damage to brain tissue may appear as sponge-like holes or gaps when examined under a microscope, which is why prion diseases like FFI are called transmissible spongiform encephalopathies.The term “prion” was coined to designate a “proteinaceous infectious agent” to explain the transmissible nature of prion diseases. Extensive research has shown that a prion is essentially the misfolded PrP. However, it is important to know that FFI is not contagious in the traditional sense because the only way to transmit prion disease to a healthy individual is through direct exposure to disease-affected brain tissue, perhaps by ingestion or injection. If a person without an underlying genetic abnormality develops a prion disease because of exposure to prions from an external source, they are said to have an ‘acquired’ form. For example, variant Creutzfeldt-Jakob disease occurred in the United Kingdom when people ate prion-contaminated beef. A lesser-known example is kuru. Kuru is a virtually extinct prion disease that occurred in the Fore people of Papua New Guinea. The disease spread throughout this population because of the villagers’ practice of eating the brains of deceased kuru-affected tribesmen (ritualistic cannibalism). All other forms of prion disease are considered “sporadic” and occur spontaneously in a patient. | 452 | Fatal Familial Insomnia |
nord_452_3 | Affects of Fatal Familial Insomnia | FFI is an extremely rare disorder. The exact incidence and prevalence of the disorder is unknown. The sporadic form of FFI, known as sporadic fatal insomnia (SFI), is extremely rare and has only been described in the medical literature in a few dozen people. Collectively, prion disorders affect 1 to 2 persons per million people in the general population per year. Genetic prion diseases are thought to make up about 15% of all individuals with prion diseases. Because rare diseases often go undiagnosed or misdiagnosed, it is difficult to determine their true frequency in the general population. FFI affects males and females in equal numbers. The average age of onset is 45-50 years old, although the disorder has been described in individuals in their teens and as late as their 70s. FFI has been described in populations around the world. | Affects of Fatal Familial Insomnia. FFI is an extremely rare disorder. The exact incidence and prevalence of the disorder is unknown. The sporadic form of FFI, known as sporadic fatal insomnia (SFI), is extremely rare and has only been described in the medical literature in a few dozen people. Collectively, prion disorders affect 1 to 2 persons per million people in the general population per year. Genetic prion diseases are thought to make up about 15% of all individuals with prion diseases. Because rare diseases often go undiagnosed or misdiagnosed, it is difficult to determine their true frequency in the general population. FFI affects males and females in equal numbers. The average age of onset is 45-50 years old, although the disorder has been described in individuals in their teens and as late as their 70s. FFI has been described in populations around the world. | 452 | Fatal Familial Insomnia |
nord_452_4 | Related disorders of Fatal Familial Insomnia | Symptoms of the following disorders can be similar to those of FFI. Comparisons may be useful for a differential diagnosis.Other prion disorders may have symptoms similar to those seen in FFI. There are five major additional prion diseases that have been identified affecting humans. These include kuru, Creutzfeldt-Jakob disease, variant Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker syndrome, and variably protease-sensitive prionopathy. These disorders are characterized by nerve cell loss and damage to the brain. Prion diseases also affect animals including bovine spongiform encephalopathy (mad cow disease) in cows and scrapie in sheep. Variant Creutzfeldt-Jakob disease has been acquired from eating beef contaminated with the abnormal prions that cause bovine spongiform encephalopathy.Frontotemporal degeneration is a group of varied disorders that are characterized by neurodegenerative changes that affect the brain, especially the frontal and temporal lobes, which control behavior and language. The clinical presentation of frontotemporal degeneration is diverse. Affected individuals can experience gradual changes in their behavior and personality, and they may have difficulties thinking and communicating effectively. The progression and the specific symptoms that develop can vary from one person to another. Generally, the clinical symptoms of these disorders can be broadly grouped into three categories which include changes in behavior, language and/or motor function. Frontotemporal degeneration is caused by progressive damage and loss of nerve cells in the frontal and temporal lobes of the brain. In most people, this is accompanied by a buildup of one or the other of two proteins, tau or TDP-43. In FTD these proteins are misfolded, which leads to their inappropriate buildup within brain cells and eventual disruption of the normal function of these cells. The FTD clinical subtypes can also be classified as ‘tauopathies’ or TDP43-opathies, depending on which misfolded protein accumulates in the brain. In about 10% of cases, a third protein, FUS, accumulates instead of tau or TDP43. The accumulation of tau protein or TDP-43 protein can also be observed in other neurological disorders. (For more information on this disorder, choose “frontotemporal degeneration” as your search term in the Rare Disease Database.)Alzheimer’s disease is a progressive condition of the brain that affects memory, thought, and language. The degenerative changes of Alzheimer’s disease lead to plaques, or clumps, of misfolded protein in the brain and the accumulation of misfolded protein inside the neuron (neurofibrillary tangles). Memory loss and behavioral changes occur because of these protein accumulations in brain tissue. Alzheimer’s disease is usually a slow progressive illness that is more common over the age of 65, in contrast to frontotemporal degeneration, which is more common in midlife and under age 65. Difficulty with short-term memory is usually the first symptom and early behavioral changes may not be noticed. As the disease progresses, memory loss increases and there are changes in personality, mood and behavior. Disturbances of judgment and concentration occur, along with confusion and restlessness. The type, severity, sequence and progression of mental changes vary widely. Long periods with little change are common, although occasionally the disease can be rapidly progressive. Additional disorders can cause signs and symptoms similar to those seen in prion diseases like FFI including Huntington disease, progressive supranuclear palsy, dementia with Lewy Bodies, corticobasal degeneration, Hashimoto encephalopathy, paraneoplastic syndromes and multiple system atrophy. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | Related disorders of Fatal Familial Insomnia. Symptoms of the following disorders can be similar to those of FFI. Comparisons may be useful for a differential diagnosis.Other prion disorders may have symptoms similar to those seen in FFI. There are five major additional prion diseases that have been identified affecting humans. These include kuru, Creutzfeldt-Jakob disease, variant Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker syndrome, and variably protease-sensitive prionopathy. These disorders are characterized by nerve cell loss and damage to the brain. Prion diseases also affect animals including bovine spongiform encephalopathy (mad cow disease) in cows and scrapie in sheep. Variant Creutzfeldt-Jakob disease has been acquired from eating beef contaminated with the abnormal prions that cause bovine spongiform encephalopathy.Frontotemporal degeneration is a group of varied disorders that are characterized by neurodegenerative changes that affect the brain, especially the frontal and temporal lobes, which control behavior and language. The clinical presentation of frontotemporal degeneration is diverse. Affected individuals can experience gradual changes in their behavior and personality, and they may have difficulties thinking and communicating effectively. The progression and the specific symptoms that develop can vary from one person to another. Generally, the clinical symptoms of these disorders can be broadly grouped into three categories which include changes in behavior, language and/or motor function. Frontotemporal degeneration is caused by progressive damage and loss of nerve cells in the frontal and temporal lobes of the brain. In most people, this is accompanied by a buildup of one or the other of two proteins, tau or TDP-43. In FTD these proteins are misfolded, which leads to their inappropriate buildup within brain cells and eventual disruption of the normal function of these cells. The FTD clinical subtypes can also be classified as ‘tauopathies’ or TDP43-opathies, depending on which misfolded protein accumulates in the brain. In about 10% of cases, a third protein, FUS, accumulates instead of tau or TDP43. The accumulation of tau protein or TDP-43 protein can also be observed in other neurological disorders. (For more information on this disorder, choose “frontotemporal degeneration” as your search term in the Rare Disease Database.)Alzheimer’s disease is a progressive condition of the brain that affects memory, thought, and language. The degenerative changes of Alzheimer’s disease lead to plaques, or clumps, of misfolded protein in the brain and the accumulation of misfolded protein inside the neuron (neurofibrillary tangles). Memory loss and behavioral changes occur because of these protein accumulations in brain tissue. Alzheimer’s disease is usually a slow progressive illness that is more common over the age of 65, in contrast to frontotemporal degeneration, which is more common in midlife and under age 65. Difficulty with short-term memory is usually the first symptom and early behavioral changes may not be noticed. As the disease progresses, memory loss increases and there are changes in personality, mood and behavior. Disturbances of judgment and concentration occur, along with confusion and restlessness. The type, severity, sequence and progression of mental changes vary widely. Long periods with little change are common, although occasionally the disease can be rapidly progressive. Additional disorders can cause signs and symptoms similar to those seen in prion diseases like FFI including Huntington disease, progressive supranuclear palsy, dementia with Lewy Bodies, corticobasal degeneration, Hashimoto encephalopathy, paraneoplastic syndromes and multiple system atrophy. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | 452 | Fatal Familial Insomnia |
nord_452_5 | Diagnosis of Fatal Familial Insomnia | A diagnosis of FFI is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests.Clinical Testing and Workup
Molecular genetic testing can confirm a diagnosis in some patients. Molecular genetic testing can detect an abnormal variant in the PRNP gene known to cause the disorder, but such testing is available only as a diagnostic service at specialized laboratories. In all cases of FFI, there will be an abnormal PRNP variant that is detectable, although negative genetic testing does not rule out SFI.Polysomnography, also called a sleep study, may be performed to demonstrate a reduced amount of time sleeping and difficulties transitioning through the various sleep stages.Positron emission tomography or PET scan is an advanced imaging technique that can be useful in diagnosing FFI or SFI. During a PET scan, three-dimensional images are produced that reflect the brain’s metabolic activity and can show reduced activity within the thalamus (thalamic hypometabolism), as a characteristic feature.Other neuroimaging techniques include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). CT scanning is not useful in the diagnosis of FFI or prion disease, while the MRI can show some abnormalities in the scan that may support prion disease, although its application to diagnose FFI is not well characterized. However, MRI and CT may be helpful in ruling out other conditions that may mimic FFI or prion disease. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of organs and body tissues.Tests may be ordered to detect the presence of the 14-3-3 protein. This is a normal protein produced when nerve cells die. Sometimes in individuals with FFI, levels of this protein increase substantially in the cerebrospinal fluid (CSF). CSF is the colorless fluid that surrounds the brain and spinal cord and provides protection and support. Elevated levels of 14-3-3 in the CSF do not always occur, and normal levels of this protein does not rule out FFI. The tau protein is also often elevated in the CSF of prion disease, although because of the rarity of FFI, the usefulness of testing for tau in FFI is not fully understood. More recently, a test called RTQuIC (real-time quaking induced conversion), that helps to detect low levels of prions in CSF, is now being used to assist in the diagnosis of prion disease and may be useful for FFI, but there is currently not enough data on that. | Diagnosis of Fatal Familial Insomnia. A diagnosis of FFI is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests.Clinical Testing and Workup
Molecular genetic testing can confirm a diagnosis in some patients. Molecular genetic testing can detect an abnormal variant in the PRNP gene known to cause the disorder, but such testing is available only as a diagnostic service at specialized laboratories. In all cases of FFI, there will be an abnormal PRNP variant that is detectable, although negative genetic testing does not rule out SFI.Polysomnography, also called a sleep study, may be performed to demonstrate a reduced amount of time sleeping and difficulties transitioning through the various sleep stages.Positron emission tomography or PET scan is an advanced imaging technique that can be useful in diagnosing FFI or SFI. During a PET scan, three-dimensional images are produced that reflect the brain’s metabolic activity and can show reduced activity within the thalamus (thalamic hypometabolism), as a characteristic feature.Other neuroimaging techniques include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). CT scanning is not useful in the diagnosis of FFI or prion disease, while the MRI can show some abnormalities in the scan that may support prion disease, although its application to diagnose FFI is not well characterized. However, MRI and CT may be helpful in ruling out other conditions that may mimic FFI or prion disease. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of organs and body tissues.Tests may be ordered to detect the presence of the 14-3-3 protein. This is a normal protein produced when nerve cells die. Sometimes in individuals with FFI, levels of this protein increase substantially in the cerebrospinal fluid (CSF). CSF is the colorless fluid that surrounds the brain and spinal cord and provides protection and support. Elevated levels of 14-3-3 in the CSF do not always occur, and normal levels of this protein does not rule out FFI. The tau protein is also often elevated in the CSF of prion disease, although because of the rarity of FFI, the usefulness of testing for tau in FFI is not fully understood. More recently, a test called RTQuIC (real-time quaking induced conversion), that helps to detect low levels of prions in CSF, is now being used to assist in the diagnosis of prion disease and may be useful for FFI, but there is currently not enough data on that. | 452 | Fatal Familial Insomnia |
nord_452_6 | Therapies of Fatal Familial Insomnia | Treatment
There is no cure for FFI. Treatment is directed toward management of the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Neurologists, psychiatrists, psychologists, pain specialists, social workers and other healthcare professionals may need to plan treatment systematically and comprehensively. Psychosocial support for the entire family is essential as well. Genetic counseling is recommended for affected individuals and their families.There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with FFI.Symptomatic treatments include anti-seizure (anti-epileptics) medications for seizures or clonazepam for twitching movements (myoclonus). Affected individuals may be advised to discontinue any medications that worsen confusion, memory or insomnia. | Therapies of Fatal Familial Insomnia. Treatment
There is no cure for FFI. Treatment is directed toward management of the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Neurologists, psychiatrists, psychologists, pain specialists, social workers and other healthcare professionals may need to plan treatment systematically and comprehensively. Psychosocial support for the entire family is essential as well. Genetic counseling is recommended for affected individuals and their families.There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with FFI.Symptomatic treatments include anti-seizure (anti-epileptics) medications for seizures or clonazepam for twitching movements (myoclonus). Affected individuals may be advised to discontinue any medications that worsen confusion, memory or insomnia. | 452 | Fatal Familial Insomnia |
nord_453_0 | Overview of Felty Syndrome | Felty syndrome is usually described as associated with or a complication of rheumatoid arthritis. This disorder is generally defined by the presence of three conditions: rheumatoid arthritis (RA), an enlarged spleen (spenomelgaly) and a low white blood cell count (neutropenia). The presence of RA gives rise to painful, stiff and swollen joints. A low white blood cell count, especially when accompanied by an abnormally large spleen, leads to a greater chance for infections. Other symptoms associated with Felty syndrome may include fatigue, fever, weight loss, and/or discoloration of patches of skin (brown pigmentation). The exact cause of Felty syndrome is unknown. It is believed to be an autoimmune disorder that may be genetically transmitted as an autosomal dominant trait. | Overview of Felty Syndrome. Felty syndrome is usually described as associated with or a complication of rheumatoid arthritis. This disorder is generally defined by the presence of three conditions: rheumatoid arthritis (RA), an enlarged spleen (spenomelgaly) and a low white blood cell count (neutropenia). The presence of RA gives rise to painful, stiff and swollen joints. A low white blood cell count, especially when accompanied by an abnormally large spleen, leads to a greater chance for infections. Other symptoms associated with Felty syndrome may include fatigue, fever, weight loss, and/or discoloration of patches of skin (brown pigmentation). The exact cause of Felty syndrome is unknown. It is believed to be an autoimmune disorder that may be genetically transmitted as an autosomal dominant trait. | 453 | Felty Syndrome |
nord_453_1 | Symptoms of Felty Syndrome | The symptoms of Felty syndrome are similar to those of rheumatoid arthritis. Patients suffer from painful, stiff, and swollen joints, most commonly in the joints of the hands, feet, and arms. In some affected individuals, Felty syndrome may develop during a period when the symptoms and physical findings associated with rheumatoid arthritis have subsided or are not present. In this case, Felty syndrome may remain undiagnosed. In more rare instances, the development of Felty syndrome may precede the development of the symptoms and physical findings associated with rheumatoid arthritis.Felty syndrome is also characterized by an abnormally enlarged spleen (splenomegaly) and abnormally low levels of certain white blood cells (neutropenia). As a result of neutropenia, affected individuals are increasingly susceptible to certain infections.Individuals with Felty syndrome may also experience fever, weight loss, and/or fatigue. In some cases, affected individuals may have discoloration of the skin, particularly of the leg (abnormal brown pigmentation), sores (ulcers) on the lower leg, and/or an abnormally large liver (hepatomegaly). In addition, affected individuals may have abnormally low levels of circulating red blood cells (anemia), a decrease in circulating blood platelets that assist in blood clotting functions (thrombocytopenia), and/or inflammation of the blood vessels (vasculitis). (For more information on this disorder, choose “Vasculitis” as your search term in the Rare Disease Database.) In rare cases, eye abnormalities have been associated with Felty syndrome. | Symptoms of Felty Syndrome. The symptoms of Felty syndrome are similar to those of rheumatoid arthritis. Patients suffer from painful, stiff, and swollen joints, most commonly in the joints of the hands, feet, and arms. In some affected individuals, Felty syndrome may develop during a period when the symptoms and physical findings associated with rheumatoid arthritis have subsided or are not present. In this case, Felty syndrome may remain undiagnosed. In more rare instances, the development of Felty syndrome may precede the development of the symptoms and physical findings associated with rheumatoid arthritis.Felty syndrome is also characterized by an abnormally enlarged spleen (splenomegaly) and abnormally low levels of certain white blood cells (neutropenia). As a result of neutropenia, affected individuals are increasingly susceptible to certain infections.Individuals with Felty syndrome may also experience fever, weight loss, and/or fatigue. In some cases, affected individuals may have discoloration of the skin, particularly of the leg (abnormal brown pigmentation), sores (ulcers) on the lower leg, and/or an abnormally large liver (hepatomegaly). In addition, affected individuals may have abnormally low levels of circulating red blood cells (anemia), a decrease in circulating blood platelets that assist in blood clotting functions (thrombocytopenia), and/or inflammation of the blood vessels (vasculitis). (For more information on this disorder, choose “Vasculitis” as your search term in the Rare Disease Database.) In rare cases, eye abnormalities have been associated with Felty syndrome. | 453 | Felty Syndrome |
nord_453_2 | Causes of Felty Syndrome | The exact causes of Felty syndrome are not clear at this time. Scientists believe that the blood cell abnormalities, an allergy, or some unknown immunity disturbance may lead to the frequent infections that are commonly associated with this disorder. These clinicians think that Felty syndrome may be an autoimmune disorder. Autoimmune disorders occur when the body's natural defenses (antibodies) against invading or “foreign” organisms begin to attack the body's own tissue, often for unknown reasons.At least some cases of Felty syndrome are thought to be genetically determined. Some studies of families with Felty syndrome across several generations lead clinical geneticists to suggest that a spontaneous mutation may occur that is transmitted as an autosomal dominant trait. However, the character of the mutant gene and its location has not been determined.Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For exampled, “chromosome 11p13” refers to band 13 on the short arm of chromosome 11. The numbered bands specify the location of the thousands of genes that are present on each chromosome.Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the diseases, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. This risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.All individuals carry a few abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. | Causes of Felty Syndrome. The exact causes of Felty syndrome are not clear at this time. Scientists believe that the blood cell abnormalities, an allergy, or some unknown immunity disturbance may lead to the frequent infections that are commonly associated with this disorder. These clinicians think that Felty syndrome may be an autoimmune disorder. Autoimmune disorders occur when the body's natural defenses (antibodies) against invading or “foreign” organisms begin to attack the body's own tissue, often for unknown reasons.At least some cases of Felty syndrome are thought to be genetically determined. Some studies of families with Felty syndrome across several generations lead clinical geneticists to suggest that a spontaneous mutation may occur that is transmitted as an autosomal dominant trait. However, the character of the mutant gene and its location has not been determined.Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For exampled, “chromosome 11p13” refers to band 13 on the short arm of chromosome 11. The numbered bands specify the location of the thousands of genes that are present on each chromosome.Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the diseases, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. This risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.All individuals carry a few abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. | 453 | Felty Syndrome |
nord_453_3 | Affects of Felty Syndrome | It is estimated that 1 to 3 percent of all patients with rheumatoid arthritis are affected by Felty syndrome. This is a large number, but most of these go undiagnosed. The disorder is about three times more common in women than in men. Felty syndrome is not found as frequently among those of African descent as among Caucasian populations. The disorder generally affects persons 50 to 70 years of age. | Affects of Felty Syndrome. It is estimated that 1 to 3 percent of all patients with rheumatoid arthritis are affected by Felty syndrome. This is a large number, but most of these go undiagnosed. The disorder is about three times more common in women than in men. Felty syndrome is not found as frequently among those of African descent as among Caucasian populations. The disorder generally affects persons 50 to 70 years of age. | 453 | Felty Syndrome |
nord_453_4 | Related disorders of Felty Syndrome | The differential diagnosis of Felty syndrome may include sarcoidosis, amyloidosis, reactions to certain drugs, and/or myeloproliferative disorders. (For more information on these disorders, choose “Sarcoidosis” or “Amyloidosis” as your search term in the Rare Disease Database.) | Related disorders of Felty Syndrome. The differential diagnosis of Felty syndrome may include sarcoidosis, amyloidosis, reactions to certain drugs, and/or myeloproliferative disorders. (For more information on these disorders, choose “Sarcoidosis” or “Amyloidosis” as your search term in the Rare Disease Database.) | 453 | Felty Syndrome |
nord_453_5 | Diagnosis of Felty Syndrome | Felty syndrome is usually diagnosed as a result of a thorough clinical evaluation, a detailed patient history, and the identification of the classic triad of physical findings (i.e. the presence of rheumatoid arthritis, low white blood count, and splenomegaly). | Diagnosis of Felty Syndrome. Felty syndrome is usually diagnosed as a result of a thorough clinical evaluation, a detailed patient history, and the identification of the classic triad of physical findings (i.e. the presence of rheumatoid arthritis, low white blood count, and splenomegaly). | 453 | Felty Syndrome |
nord_453_6 | Therapies of Felty Syndrome | TreatmentThe treatment of Felty syndrome is symptomatic and supportive. Rheumatoid arthritis should be treated as it would in the absence of Felty syndrome (e.g. bedrest, appropriate exercise, heat treatments, gold salts, nonsteroidal anti-inflammatory drugs (NSAIDS), penicillamine, etc).In many cases, treatment may include removal of the spleen (splenectomy). Splenectomy has had beneficial effects on anemia, thrombocytopenia, neutropenia, and/or chronic infections often associated with Felty syndrome. However, according to the medical literature, the long-term value of this procedure is not yet clear. | Therapies of Felty Syndrome. TreatmentThe treatment of Felty syndrome is symptomatic and supportive. Rheumatoid arthritis should be treated as it would in the absence of Felty syndrome (e.g. bedrest, appropriate exercise, heat treatments, gold salts, nonsteroidal anti-inflammatory drugs (NSAIDS), penicillamine, etc).In many cases, treatment may include removal of the spleen (splenectomy). Splenectomy has had beneficial effects on anemia, thrombocytopenia, neutropenia, and/or chronic infections often associated with Felty syndrome. However, according to the medical literature, the long-term value of this procedure is not yet clear. | 453 | Felty Syndrome |
nord_454_0 | Overview of Femoral Facial Syndrome | Summary Femoral facial syndrome is a rare disorder that occurs randomly (sporadically) in the population. There have been, however, two patients reported in which the disorder appeared to be inherited in an autosomal dominant pattern. The major symptoms of this disorder are underdeveloped thigh bones (femoral hypoplasia) and unusual facial features. | Overview of Femoral Facial Syndrome. Summary Femoral facial syndrome is a rare disorder that occurs randomly (sporadically) in the population. There have been, however, two patients reported in which the disorder appeared to be inherited in an autosomal dominant pattern. The major symptoms of this disorder are underdeveloped thigh bones (femoral hypoplasia) and unusual facial features. | 454 | Femoral Facial Syndrome |
nord_454_1 | Symptoms of Femoral Facial Syndrome | Femoral facial syndrome is a rare disorder characterized by underdeveloped thigh bones (femurs) and unusual facial characteristics. It presents with a very broad range and variety of symptoms. One source lists 31 clinical signs, classified as very frequent, relatively frequent and less frequent. Clinical signs characterized as very frequent are (80-99%): – Cleft palate
– Femur absent/abnormal
– Unusually small and/or retracted jaw (micrognathia/retrognathia)
– Short limbs (micromelia, femur especially)
– Abnormal vertebral size or shape Clinical signs characterized as relatively frequent are (20-30%): – Upwardly slanting eyelids (upslanted fissures)
– Thin lips + Long vertical groove in the middle of the upper lip (philtrum)
– Low-set and poorly formed ears / Small or virtually absent ears (microtia/anotia)
– Fused bones of the spine (sacrum and coccyx)
– Short stature (dwarfism)
– Hip dysplasia
– Femoral neck anomaly (coxa vara)
– Abnormal fibula morphology
– Deformation of the foot that may be turned outward or inward (talipes-equinovarus)
– Extra toes (preaxial foot polydactyly)
– Maternal diabetes Clinical signs characterized as less frequent are (5-29%): – Cross sided eyes (strabismus)
– Sprengel anomaly
– Rib fusion
– Radius and ulna bone fusion (radioulnar synostosis)
– Scoliosis
– Underdeveloped kidneys (renal hypoplasia)
– Kidney function anomaly (polycystic kidney dysplasia)
– Enlarged penis
– Enlarged heart ventricles (ventriculomegaly) | Symptoms of Femoral Facial Syndrome. Femoral facial syndrome is a rare disorder characterized by underdeveloped thigh bones (femurs) and unusual facial characteristics. It presents with a very broad range and variety of symptoms. One source lists 31 clinical signs, classified as very frequent, relatively frequent and less frequent. Clinical signs characterized as very frequent are (80-99%): – Cleft palate
– Femur absent/abnormal
– Unusually small and/or retracted jaw (micrognathia/retrognathia)
– Short limbs (micromelia, femur especially)
– Abnormal vertebral size or shape Clinical signs characterized as relatively frequent are (20-30%): – Upwardly slanting eyelids (upslanted fissures)
– Thin lips + Long vertical groove in the middle of the upper lip (philtrum)
– Low-set and poorly formed ears / Small or virtually absent ears (microtia/anotia)
– Fused bones of the spine (sacrum and coccyx)
– Short stature (dwarfism)
– Hip dysplasia
– Femoral neck anomaly (coxa vara)
– Abnormal fibula morphology
– Deformation of the foot that may be turned outward or inward (talipes-equinovarus)
– Extra toes (preaxial foot polydactyly)
– Maternal diabetes Clinical signs characterized as less frequent are (5-29%): – Cross sided eyes (strabismus)
– Sprengel anomaly
– Rib fusion
– Radius and ulna bone fusion (radioulnar synostosis)
– Scoliosis
– Underdeveloped kidneys (renal hypoplasia)
– Kidney function anomaly (polycystic kidney dysplasia)
– Enlarged penis
– Enlarged heart ventricles (ventriculomegaly) | 454 | Femoral Facial Syndrome |
nord_454_2 | Causes of Femoral Facial Syndrome | The exact cause of femoral facial syndrome is not known. Most cases of this disorder occur for no apparent reason (sporadically). However, there have been at least two reported cases of affected relatives that are thought to have been inherited as an autosomal dominant pattern. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females. In addition, a significant number of reported patients seem to show an association with diabetes in the mother during pregnancy. | Causes of Femoral Facial Syndrome. The exact cause of femoral facial syndrome is not known. Most cases of this disorder occur for no apparent reason (sporadically). However, there have been at least two reported cases of affected relatives that are thought to have been inherited as an autosomal dominant pattern. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females. In addition, a significant number of reported patients seem to show an association with diabetes in the mother during pregnancy. | 454 | Femoral Facial Syndrome |
nord_454_3 | Affects of Femoral Facial Syndrome | Femoral facial syndrome is a very rare disorder that seems to affect more males than females. As of 1993, about 55 patients had been reported and one-third of are associated with maternal diabetes. | Affects of Femoral Facial Syndrome. Femoral facial syndrome is a very rare disorder that seems to affect more males than females. As of 1993, about 55 patients had been reported and one-third of are associated with maternal diabetes. | 454 | Femoral Facial Syndrome |
nord_454_4 | Related disorders of Femoral Facial Syndrome | Symptoms of the following disorders can be similar to those of femoral facial syndrome. Comparisons may be useful for a differential diagnosis: Camptomelic syndrome is a rare congenital skeletal disorder that is inherited in an autosomal recessive pattern. It is characterized by short stature with bowing and an angular shape of the long bones of the legs. The bones of the pelvic and shoulder area are often abnormal. A flat face with widely spaced eyes and a small jaw may also be found in patients with camptomelic syndrome. (For more information on this disorder, choose “camptomelic syndrome” as your search term in the Rare Disease Database.) Caudal regression syndrome is a rare disorder characterized by abnormal development of the tail (caudal) end region of the developing fetus. Abnormalities associated with this disorder may include partial absence of the tailbone (coccyx) and/or a wide range of developmental abnormalities involving the lower portion of the body. (For more information on this disorder choose “caudal regression syndrome” as your search term in the Rare Disease Database.) | Related disorders of Femoral Facial Syndrome. Symptoms of the following disorders can be similar to those of femoral facial syndrome. Comparisons may be useful for a differential diagnosis: Camptomelic syndrome is a rare congenital skeletal disorder that is inherited in an autosomal recessive pattern. It is characterized by short stature with bowing and an angular shape of the long bones of the legs. The bones of the pelvic and shoulder area are often abnormal. A flat face with widely spaced eyes and a small jaw may also be found in patients with camptomelic syndrome. (For more information on this disorder, choose “camptomelic syndrome” as your search term in the Rare Disease Database.) Caudal regression syndrome is a rare disorder characterized by abnormal development of the tail (caudal) end region of the developing fetus. Abnormalities associated with this disorder may include partial absence of the tailbone (coccyx) and/or a wide range of developmental abnormalities involving the lower portion of the body. (For more information on this disorder choose “caudal regression syndrome” as your search term in the Rare Disease Database.) | 454 | Femoral Facial Syndrome |
nord_454_5 | Diagnosis of Femoral Facial Syndrome | Diagnosis of Femoral Facial Syndrome. | 454 | Femoral Facial Syndrome |
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nord_454_6 | Therapies of Femoral Facial Syndrome | Treatment
Orthopedic medical care including surgery may help alleviate some of the more serious bone deformities associated with femoral facial syndrome. Treatment requires the coordinated efforts of a team of specialists. Pediatricians, dental specialists, surgeons, speech pathologists and others may systematically and comprehensively plan the child's treatment and rehabilitation. Cleft palate may be repaired by surgery or covered by an artificial device (prosthesis) that closes or blocks the opening in the roof of the mouth. Genetic counseling is recommended for patients and their families. Other treatment is symptomatic and supportive. | Therapies of Femoral Facial Syndrome. Treatment
Orthopedic medical care including surgery may help alleviate some of the more serious bone deformities associated with femoral facial syndrome. Treatment requires the coordinated efforts of a team of specialists. Pediatricians, dental specialists, surgeons, speech pathologists and others may systematically and comprehensively plan the child's treatment and rehabilitation. Cleft palate may be repaired by surgery or covered by an artificial device (prosthesis) that closes or blocks the opening in the roof of the mouth. Genetic counseling is recommended for patients and their families. Other treatment is symptomatic and supportive. | 454 | Femoral Facial Syndrome |
nord_455_0 | Overview of Ferroportin Disease | Ferroportin disease, also known as hemochromatosis type 4, is a rare genetic disorder characterized by the abnormal accumulation of iron in the body. Ferroportin disease is caused by changes (variants or mutations) of the SLC40A1 gene. The specific symptoms associated with ferroportin disease can vary greatly from one person to another. Some individuals may only have elevated levels of ferritin, a protein that binds to iron and is used as an indicator of the body’s iron stores in the blood plasma. Other individuals may develop symptoms similar to classic HFE-related hemochromatosis.Ferroportin disease is classified as an iron overload disorder, a group of disorders characterized by the abnormal accumulation of iron in the body. It is a separate, distinct disorder from classic hereditary hemochromatosis. Ferroportin disease is caused by variants in a different gene and is inherited in a different manner from other forms of hemochromatosis. | Overview of Ferroportin Disease. Ferroportin disease, also known as hemochromatosis type 4, is a rare genetic disorder characterized by the abnormal accumulation of iron in the body. Ferroportin disease is caused by changes (variants or mutations) of the SLC40A1 gene. The specific symptoms associated with ferroportin disease can vary greatly from one person to another. Some individuals may only have elevated levels of ferritin, a protein that binds to iron and is used as an indicator of the body’s iron stores in the blood plasma. Other individuals may develop symptoms similar to classic HFE-related hemochromatosis.Ferroportin disease is classified as an iron overload disorder, a group of disorders characterized by the abnormal accumulation of iron in the body. It is a separate, distinct disorder from classic hereditary hemochromatosis. Ferroportin disease is caused by variants in a different gene and is inherited in a different manner from other forms of hemochromatosis. | 455 | Ferroportin Disease |
nord_455_1 | Symptoms of Ferroportin Disease | The symptoms of ferroportin disease vary greatly from one person to another. Researchers believe that different variants in the SLC40A1 gene are associated with different symptoms. Generally, ferroportin disease is separated into two main forms.Most individuals with ferroportin disease develop a mild form of the disorder. These individuals have elevated levels of ferritin in the blood plasma (hyperferritinemia) and low levels of saturated transferrin (the protein that carries iron in the blood). As affected individuals age, mild liver damage (hepatic fibrosis) and joint symptoms may occur.Other individuals develop a rarer form of ferroportin disease that resembles the more common classic form of hemochromatosis (hemochromatosis type 1 or HFE-related). The transferrin saturation is significantly elevated in this form. Symptoms associated with this form include joint pain, abnormalities in the heart’s rhythm or heartbeat pattern (arrhythmias) and diabetes. Liver damage is more prevalent in this form of ferroportin disease and can progress to cause advanced scarring (cirrhosis) of the liver. | Symptoms of Ferroportin Disease. The symptoms of ferroportin disease vary greatly from one person to another. Researchers believe that different variants in the SLC40A1 gene are associated with different symptoms. Generally, ferroportin disease is separated into two main forms.Most individuals with ferroportin disease develop a mild form of the disorder. These individuals have elevated levels of ferritin in the blood plasma (hyperferritinemia) and low levels of saturated transferrin (the protein that carries iron in the blood). As affected individuals age, mild liver damage (hepatic fibrosis) and joint symptoms may occur.Other individuals develop a rarer form of ferroportin disease that resembles the more common classic form of hemochromatosis (hemochromatosis type 1 or HFE-related). The transferrin saturation is significantly elevated in this form. Symptoms associated with this form include joint pain, abnormalities in the heart’s rhythm or heartbeat pattern (arrhythmias) and diabetes. Liver damage is more prevalent in this form of ferroportin disease and can progress to cause advanced scarring (cirrhosis) of the liver. | 455 | Ferroportin Disease |
nord_455_2 | Causes of Ferroportin Disease | Ferroportin disease is caused by variants in the SLC40A1 gene. The SLC40A1 gene contains instructions for creating ferroportin, a specialized protein that is crucial to the proper export of iron from cells. Ferroportin also plays a role in the proper breakdown (metabolism) of iron. Iron is a critical mineral that is found in all cells of the body and is essential for the body to function and grow properly. Iron is found in many types of food including red meat, poultry, eggs and vegetables. Iron levels must remain in a specific range within the body, otherwise they can cause anemia (due to low iron levels) or damage affected organs (due to high iron levels).Variants in the SLC40A1 gene result in low levels of functional ferroportin. The lack of functional ferroportin ultimately results in the abnormal accumulation of iron in the cells and tissues of the body. Different variants of the SLC40A1 gene affect the ferroportin protein in different ways, altering the export and metabolism of iron accordingly. Researchers believe that the different ways in which SLC40A1 variants affect ferroportin account for the two different forms of the disorder.Ferroportin disease is inherited as an autosomal dominant genetic condition. 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 gene change in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy. The risk is the same for males and females. | Causes of Ferroportin Disease. Ferroportin disease is caused by variants in the SLC40A1 gene. The SLC40A1 gene contains instructions for creating ferroportin, a specialized protein that is crucial to the proper export of iron from cells. Ferroportin also plays a role in the proper breakdown (metabolism) of iron. Iron is a critical mineral that is found in all cells of the body and is essential for the body to function and grow properly. Iron is found in many types of food including red meat, poultry, eggs and vegetables. Iron levels must remain in a specific range within the body, otherwise they can cause anemia (due to low iron levels) or damage affected organs (due to high iron levels).Variants in the SLC40A1 gene result in low levels of functional ferroportin. The lack of functional ferroportin ultimately results in the abnormal accumulation of iron in the cells and tissues of the body. Different variants of the SLC40A1 gene affect the ferroportin protein in different ways, altering the export and metabolism of iron accordingly. Researchers believe that the different ways in which SLC40A1 variants affect ferroportin account for the two different forms of the disorder.Ferroportin disease is inherited as an autosomal dominant genetic condition. 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 gene change in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy. The risk is the same for males and females. | 455 | Ferroportin Disease |
nord_455_3 | Affects of Ferroportin Disease | Ferroportin disease affects males and females in equal numbers. The exact incidence of ferroportin disease is unknown. Researchers believe that the disorder occurs more frequently than has been reported in the medical literature. Ferroportin affects individuals of all races and ethnicities. Some researchers believe that ferroportin disease is the most common form of hereditary iron overload after classic (type 1 or HFE-related) hemochromatosis. | Affects of Ferroportin Disease. Ferroportin disease affects males and females in equal numbers. The exact incidence of ferroportin disease is unknown. Researchers believe that the disorder occurs more frequently than has been reported in the medical literature. Ferroportin affects individuals of all races and ethnicities. Some researchers believe that ferroportin disease is the most common form of hereditary iron overload after classic (type 1 or HFE-related) hemochromatosis. | 455 | Ferroportin Disease |
nord_455_4 | Related disorders of Ferroportin Disease | Symptoms of the following disorders can be similar to those of ferroportin disease. Comparisons may be useful for a differential diagnosis.Primary disorders of iron overload are a group of rare disorders characterized by iron accumulation in the body. This group includes hemochromatosis, atransferrinemia, acaeruloplasminemia, neonatal hemochromatosis and African iron overload. Hemochromatosis has been separated into four distinct disorders – hereditary (classic) hemochromatosis, also known as HFE-related hemochromatosis; hemochromatosis type 2 (juvenile hemochromatosis); hemochromatosis type 3, also known as TFR2-related hemochromatosis and hemochromatosis type 4, also known as ferroportin disease. Types 2-4 have been more recently bracketed as ‘non-HFE’ hemochromatosis. The specific symptoms related to these disorders can vary depending upon the location and extent of iron accumulation. Common symptoms include fatigue, abdominal pain, lack of sex drive, joint pain and heart abnormalities. If left untreated, iron can build up in various organs in the body causing serious, life-threatening complications. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | Related disorders of Ferroportin Disease. Symptoms of the following disorders can be similar to those of ferroportin disease. Comparisons may be useful for a differential diagnosis.Primary disorders of iron overload are a group of rare disorders characterized by iron accumulation in the body. This group includes hemochromatosis, atransferrinemia, acaeruloplasminemia, neonatal hemochromatosis and African iron overload. Hemochromatosis has been separated into four distinct disorders – hereditary (classic) hemochromatosis, also known as HFE-related hemochromatosis; hemochromatosis type 2 (juvenile hemochromatosis); hemochromatosis type 3, also known as TFR2-related hemochromatosis and hemochromatosis type 4, also known as ferroportin disease. Types 2-4 have been more recently bracketed as ‘non-HFE’ hemochromatosis. The specific symptoms related to these disorders can vary depending upon the location and extent of iron accumulation. Common symptoms include fatigue, abdominal pain, lack of sex drive, joint pain and heart abnormalities. If left untreated, iron can build up in various organs in the body causing serious, life-threatening complications. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | 455 | Ferroportin Disease |
nord_455_5 | Diagnosis of Ferroportin Disease | A diagnosis of ferroportin disease is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. A family history with affected individuals in successive generations is highly suggestive (autosomal dominant inheritance). Blood tests can reveal certain findings associated with ferroportin disease including high levels of ferritin in the blood and, in the milder form of the disease, low or normal saturation of transferrin, another protein that plays a role in the proper transport of iron within the body. Molecular genetic testing for variants in the SLC40A1 gene is available and necessary to confirm the diagnosis. | Diagnosis of Ferroportin Disease. A diagnosis of ferroportin disease is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. A family history with affected individuals in successive generations is highly suggestive (autosomal dominant inheritance). Blood tests can reveal certain findings associated with ferroportin disease including high levels of ferritin in the blood and, in the milder form of the disease, low or normal saturation of transferrin, another protein that plays a role in the proper transport of iron within the body. Molecular genetic testing for variants in the SLC40A1 gene is available and necessary to confirm the diagnosis. | 455 | Ferroportin Disease |
nord_455_6 | Therapies of Ferroportin Disease | Treatment
The treatment of ferroportin disease is directed toward the specific symptoms that are apparent in each individual. Specific treatment may depend on the severity and form of ferroportin disease.Individuals with the form of ferroportin disease that resembles classic hemochromatosis may be treated with regular phlebotomy, a procedure in which blood is removed via a vein. Individuals with the mild form of ferroportin disease may not necessarily require treatment and phlebotomy in these individuals is often complicated by anemia.Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive. | Therapies of Ferroportin Disease. Treatment
The treatment of ferroportin disease is directed toward the specific symptoms that are apparent in each individual. Specific treatment may depend on the severity and form of ferroportin disease.Individuals with the form of ferroportin disease that resembles classic hemochromatosis may be treated with regular phlebotomy, a procedure in which blood is removed via a vein. Individuals with the mild form of ferroportin disease may not necessarily require treatment and phlebotomy in these individuals is often complicated by anemia.Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive. | 455 | Ferroportin Disease |
nord_456_0 | Overview of Fetal and Neonatal Alloimmune Thrombocytopenia | SummaryFetal and neonatal alloimmune thrombocytopenia (FNAIT) is a rare immune disorder. FNAIT occurs when the baby's platelets are attacked and destroyed by the mother's immune cells in her blood stream. This occurs when platelets from the baby are identified as foreign and the mother develops an antibody response against them. This immune response can develop when the mother's blood is exposed to her baby's blood, either during development of the fetus in the womb or when the baby is being born. FNAIT can occur in a woman's first pregnancy and/or in subsequent pregnancies.A mother's immune system attacks her baby's platelets if they are recognized as foreign. A baby's platelets may be recognized as foreign when they're different from the mother's platelets because of genes inherited from the father. Platelets are a type of blood cell that helps blood clot. An abnormally low level of platelets (thrombocytopenia) can lead to easy bleeding and rupture of blood vessels.IntroductionFNAIT was first reported in the medical literature in 1953. Antigens, or targets for the immune system on platelet cells, were first described in the 1950s and 1960s. As of 2022, 35 different platelet-specific antigens in FNAIT have been described. FNAIT is the leading cause of severe thrombocytopenia in newborns. | Overview of Fetal and Neonatal Alloimmune Thrombocytopenia. SummaryFetal and neonatal alloimmune thrombocytopenia (FNAIT) is a rare immune disorder. FNAIT occurs when the baby's platelets are attacked and destroyed by the mother's immune cells in her blood stream. This occurs when platelets from the baby are identified as foreign and the mother develops an antibody response against them. This immune response can develop when the mother's blood is exposed to her baby's blood, either during development of the fetus in the womb or when the baby is being born. FNAIT can occur in a woman's first pregnancy and/or in subsequent pregnancies.A mother's immune system attacks her baby's platelets if they are recognized as foreign. A baby's platelets may be recognized as foreign when they're different from the mother's platelets because of genes inherited from the father. Platelets are a type of blood cell that helps blood clot. An abnormally low level of platelets (thrombocytopenia) can lead to easy bleeding and rupture of blood vessels.IntroductionFNAIT was first reported in the medical literature in 1953. Antigens, or targets for the immune system on platelet cells, were first described in the 1950s and 1960s. As of 2022, 35 different platelet-specific antigens in FNAIT have been described. FNAIT is the leading cause of severe thrombocytopenia in newborns. | 456 | Fetal and Neonatal Alloimmune Thrombocytopenia |
nord_456_1 | Symptoms of Fetal and Neonatal Alloimmune Thrombocytopenia | Signs and symptoms of FNAIT vary depending on how low the platelet levels drop in the baby due to increased platelet destruction and reduced platelet production. Signs and symptoms may occur before birth or up to four weeks after birth.Many babies with FNAIT have mild symptoms and some babies may have no signs of the disease other than low platelet levels. The most common sign is skin discolorations called petechiae and purpura, which occur from bleeding under the skin. Petechiae are pinpoint spots on the skin that are often redder in color than purpura, which are larger areas of skin discoloration that tend to be more purple in color. These skin discolorations may occur on much of the body and typically appear within a few hours after birth. Easy formation of severe bruises, or hematomas, may also occur. When symptoms are mild, they will eventually disappear with time and after treatment.Babies with a severe case of FNAIT may have bleeding in major organs, such as the brain, gastrointestinal tract, lungs or eyes. Bleeding in the brain is known as intracranial hemorrhage (ICH). Severe symptoms can cause death or lead to life-long disability. Typically, babies with a severe case also have signs of petechiae or purpura along with cephalohematoma, a condition where blood collects under the scalp, resulting in a bulge on the baby's head. Cephalohematoma is associated with an increased risk for ICH, which can lead to long-term neurological abnormalities due to brain damage. Neurological deficits can include cerebral palsy, intellectual disability, seizures and a type of hearing loss known as bilateral sensorineural hearing loss that occurs in both ears. Cerebral palsy includes permanent disorders of posture and movement that do not worsen with time. This is the same as a hemorrhagic stroke in an adult.The severity of thrombocytopenia does not accurately predict whether a baby will develop ICH. Only a small portion of babies with severely low platelet levels develop ICH and ICH may develop in some babies with only moderately low platelet levels.Without treatment, ICH is estimated to affect up to 26% of babies with FNAIT. Most of these cases are thought to occur before birth and in firstborn children, before a mother is aware of FNAIT. When a mother has one child with FNAIT with ICH as a symptom, her next child with FNAIT has a high risk of ICH as well.The gastrointestinal tract is the second most common body system where bleeding occurs. Signs can include bloody stools. Bleeding can also occur in the lungs and eyes. Bleeding in the eyes can lead to blindness.Mothers of children with FNAIT may have a higher risk for miscarriage. | Symptoms of Fetal and Neonatal Alloimmune Thrombocytopenia. Signs and symptoms of FNAIT vary depending on how low the platelet levels drop in the baby due to increased platelet destruction and reduced platelet production. Signs and symptoms may occur before birth or up to four weeks after birth.Many babies with FNAIT have mild symptoms and some babies may have no signs of the disease other than low platelet levels. The most common sign is skin discolorations called petechiae and purpura, which occur from bleeding under the skin. Petechiae are pinpoint spots on the skin that are often redder in color than purpura, which are larger areas of skin discoloration that tend to be more purple in color. These skin discolorations may occur on much of the body and typically appear within a few hours after birth. Easy formation of severe bruises, or hematomas, may also occur. When symptoms are mild, they will eventually disappear with time and after treatment.Babies with a severe case of FNAIT may have bleeding in major organs, such as the brain, gastrointestinal tract, lungs or eyes. Bleeding in the brain is known as intracranial hemorrhage (ICH). Severe symptoms can cause death or lead to life-long disability. Typically, babies with a severe case also have signs of petechiae or purpura along with cephalohematoma, a condition where blood collects under the scalp, resulting in a bulge on the baby's head. Cephalohematoma is associated with an increased risk for ICH, which can lead to long-term neurological abnormalities due to brain damage. Neurological deficits can include cerebral palsy, intellectual disability, seizures and a type of hearing loss known as bilateral sensorineural hearing loss that occurs in both ears. Cerebral palsy includes permanent disorders of posture and movement that do not worsen with time. This is the same as a hemorrhagic stroke in an adult.The severity of thrombocytopenia does not accurately predict whether a baby will develop ICH. Only a small portion of babies with severely low platelet levels develop ICH and ICH may develop in some babies with only moderately low platelet levels.Without treatment, ICH is estimated to affect up to 26% of babies with FNAIT. Most of these cases are thought to occur before birth and in firstborn children, before a mother is aware of FNAIT. When a mother has one child with FNAIT with ICH as a symptom, her next child with FNAIT has a high risk of ICH as well.The gastrointestinal tract is the second most common body system where bleeding occurs. Signs can include bloody stools. Bleeding can also occur in the lungs and eyes. Bleeding in the eyes can lead to blindness.Mothers of children with FNAIT may have a higher risk for miscarriage. | 456 | Fetal and Neonatal Alloimmune Thrombocytopenia |
nord_456_2 | Causes of Fetal and Neonatal Alloimmune Thrombocytopenia | FNAIT occurs when a mother makes antibodies that destroy her baby's platelets. A mother's immune system may target her child's platelets when they contain an antigen inherited from the child's father that the mother does not have. An antigen is an identifying tag on a cell that all individuals have. The presence of the tag signals the immune system to make antibodies specific to the tag. Those antibodies then turn on the immune system to destroy the foreign cell. When this is the case, the mother's immune system recognizes her child's platelets as foreign and mounts an immune response against them. Common platelet antigens in Caucasians with FNAIT are human platelet antigen (HPA)-1a and HPA-5b. Other platelet antigens exist and may include HPA-2, HPA-3, HPA-4 and HPA-15. The mother's antibodies that attack these antigens are known as anti-HPA antibodies. The HPA-1 antigen is involved in 80-90% of FNAIT cases, and FNAIT associated with anti-HPA-1a antibodies is usually more severe. Babies who develop FNAIT inherited the human platelet antigen from their father in an autosomal dominant pattern. For mothers who already produce anti-HPA antibodies, this means that their children will have a 50% chance of developing FNAIT if the father has one copy of the gene that encodes for the targeted human platelet antigen. If the father has two copies of the gene that encodes for the targeted HPA antigen, the child has a 100% chance of developing FNAIT. The risk is the same regardless of the baby's sex.It is not known why a mother's immune system begins to attack her child's platelets when they're different from her own. The presence of platelet antigens involved in FNAIT doesn't mean FNAIT will develop. For instance, only 10% of mothers without HPA-1a on their platelets will develop anti-HPA-1 antibodies to their baby.A mother's immune system forms these alloantibodies after her immune system has been exposed to the fetus or newborn's platelets. For HPA-1a-associated FNAIT, alloantibodies are estimated to form during pregnancy 25% of the time and during delivery 75% of the time. | Causes of Fetal and Neonatal Alloimmune Thrombocytopenia. FNAIT occurs when a mother makes antibodies that destroy her baby's platelets. A mother's immune system may target her child's platelets when they contain an antigen inherited from the child's father that the mother does not have. An antigen is an identifying tag on a cell that all individuals have. The presence of the tag signals the immune system to make antibodies specific to the tag. Those antibodies then turn on the immune system to destroy the foreign cell. When this is the case, the mother's immune system recognizes her child's platelets as foreign and mounts an immune response against them. Common platelet antigens in Caucasians with FNAIT are human platelet antigen (HPA)-1a and HPA-5b. Other platelet antigens exist and may include HPA-2, HPA-3, HPA-4 and HPA-15. The mother's antibodies that attack these antigens are known as anti-HPA antibodies. The HPA-1 antigen is involved in 80-90% of FNAIT cases, and FNAIT associated with anti-HPA-1a antibodies is usually more severe. Babies who develop FNAIT inherited the human platelet antigen from their father in an autosomal dominant pattern. For mothers who already produce anti-HPA antibodies, this means that their children will have a 50% chance of developing FNAIT if the father has one copy of the gene that encodes for the targeted human platelet antigen. If the father has two copies of the gene that encodes for the targeted HPA antigen, the child has a 100% chance of developing FNAIT. The risk is the same regardless of the baby's sex.It is not known why a mother's immune system begins to attack her child's platelets when they're different from her own. The presence of platelet antigens involved in FNAIT doesn't mean FNAIT will develop. For instance, only 10% of mothers without HPA-1a on their platelets will develop anti-HPA-1 antibodies to their baby.A mother's immune system forms these alloantibodies after her immune system has been exposed to the fetus or newborn's platelets. For HPA-1a-associated FNAIT, alloantibodies are estimated to form during pregnancy 25% of the time and during delivery 75% of the time. | 456 | Fetal and Neonatal Alloimmune Thrombocytopenia |
nord_456_3 | Affects of Fetal and Neonatal Alloimmune Thrombocytopenia | FNAIT is the most frequent cause of thrombocytopenia in newborns with an estimated incidence of 1 in 1,500 pregnancies. Fetal intracranial hemorrhage (ICH) associated with FNAIT is estimated to occur in 1 in 10,000 pregnancies. In Caucasians, FNAIT is usually associated with anti-HPA-1a antibodies and estimated to occur in 1/1000 Caucasian births. In African Americans, FNAIT is more likely to occur in babies with HPA-2 and HPA-5 antigens. In Japanese populations, HPA-4 and HPA-5 antigens in babies with FNAIT are more common. FNAIT may appear in first pregnancies and/or subsequent pregnancies. In subsequent pregnancies where the baby has the same human platelet antigens targeted in a previous pregnancy, FNAIT will occur early. In first pregnancies, although FNAIT is more likely to occur at birth, it can also occur early in pregnancy. FNAIT occurs in first pregnancies in 50% of cases and has a 90% chance of recurring in subsequent pregnancies. | Affects of Fetal and Neonatal Alloimmune Thrombocytopenia. FNAIT is the most frequent cause of thrombocytopenia in newborns with an estimated incidence of 1 in 1,500 pregnancies. Fetal intracranial hemorrhage (ICH) associated with FNAIT is estimated to occur in 1 in 10,000 pregnancies. In Caucasians, FNAIT is usually associated with anti-HPA-1a antibodies and estimated to occur in 1/1000 Caucasian births. In African Americans, FNAIT is more likely to occur in babies with HPA-2 and HPA-5 antigens. In Japanese populations, HPA-4 and HPA-5 antigens in babies with FNAIT are more common. FNAIT may appear in first pregnancies and/or subsequent pregnancies. In subsequent pregnancies where the baby has the same human platelet antigens targeted in a previous pregnancy, FNAIT will occur early. In first pregnancies, although FNAIT is more likely to occur at birth, it can also occur early in pregnancy. FNAIT occurs in first pregnancies in 50% of cases and has a 90% chance of recurring in subsequent pregnancies. | 456 | Fetal and Neonatal Alloimmune Thrombocytopenia |
nord_456_4 | Related disorders of Fetal and Neonatal Alloimmune Thrombocytopenia | Other disorders can cause thrombocytopenia in a fetus or newborn. This can occur in autoimmune thrombocytopenia where the mother makes antibodies to her own platelets that may also attack her baby's platelets if they carry the same antigen as her own. Autoimmune thrombocytopenia can occur when a mother has a disease such as idiopathic thrombocytopenic purpura, systemic lupus erythematosus or hyperthyroidism. Symptoms associated with autoimmune thrombocytopenia are typically milder than those of FNAIT and may include petechiae and purpura that appear several days after delivery.Thrombocytopenia in babies can also occur as a response to infections with toxoplasmosis, rubella and cytomegalovirus or as a reaction to medications or an enlarged spleen (hypersplenism).Another condition that may be confused with FNAIT because of increased bleeding is disseminated intravascular coagulation (DIC). DIC causes multiple, small blood clots to form in response to another illness or condition. When this happens, too many platelets are used up in the body’s response to the illness, so easy bleeding may occur.Kasabach-Merritt syndrome also causes thrombocytopenia in infants. Thrombocytopenia in this syndrome is thought to be caused by platelets getting trapped in vascular tumors associated with the disorder. | Related disorders of Fetal and Neonatal Alloimmune Thrombocytopenia. Other disorders can cause thrombocytopenia in a fetus or newborn. This can occur in autoimmune thrombocytopenia where the mother makes antibodies to her own platelets that may also attack her baby's platelets if they carry the same antigen as her own. Autoimmune thrombocytopenia can occur when a mother has a disease such as idiopathic thrombocytopenic purpura, systemic lupus erythematosus or hyperthyroidism. Symptoms associated with autoimmune thrombocytopenia are typically milder than those of FNAIT and may include petechiae and purpura that appear several days after delivery.Thrombocytopenia in babies can also occur as a response to infections with toxoplasmosis, rubella and cytomegalovirus or as a reaction to medications or an enlarged spleen (hypersplenism).Another condition that may be confused with FNAIT because of increased bleeding is disseminated intravascular coagulation (DIC). DIC causes multiple, small blood clots to form in response to another illness or condition. When this happens, too many platelets are used up in the body’s response to the illness, so easy bleeding may occur.Kasabach-Merritt syndrome also causes thrombocytopenia in infants. Thrombocytopenia in this syndrome is thought to be caused by platelets getting trapped in vascular tumors associated with the disorder. | 456 | Fetal and Neonatal Alloimmune Thrombocytopenia |
nord_456_5 | Diagnosis of Fetal and Neonatal Alloimmune Thrombocytopenia | FNAIT is not routinely screened for during pregnancy and is thought to be underdiagnosed. Babies are screened for FNAIT when they have older siblings who have had it, but for firstborn children with FNAIT, diagnosis is not made until further testing after birth, usually after the baby has developed widespread skin petechiae and thrombocytopenia.Diagnostic tests are available for FNAIT. They include testing the mother's blood for anti-HPA antibodies and HPA genotyping of the mother, father and newborn. Genotyping of human platelet antigens (HPA) is done to check for the presence or absence of HPA genes that would further support the diagnosis. If common alloantibodies are not found in the mother's blood, a test that examines how the mother's blood interacts with the father's platelets can be performed to look for less common alloantibodies to HPA. When FNAIT is suspected in a fetus, blood samples are taken from only the mother and father due to the risk for complications in attempting to get a blood sample from a fetus. HPA genotyping of the fetus based on the mother's blood samples is available for HPA-1a antigens only. | Diagnosis of Fetal and Neonatal Alloimmune Thrombocytopenia. FNAIT is not routinely screened for during pregnancy and is thought to be underdiagnosed. Babies are screened for FNAIT when they have older siblings who have had it, but for firstborn children with FNAIT, diagnosis is not made until further testing after birth, usually after the baby has developed widespread skin petechiae and thrombocytopenia.Diagnostic tests are available for FNAIT. They include testing the mother's blood for anti-HPA antibodies and HPA genotyping of the mother, father and newborn. Genotyping of human platelet antigens (HPA) is done to check for the presence or absence of HPA genes that would further support the diagnosis. If common alloantibodies are not found in the mother's blood, a test that examines how the mother's blood interacts with the father's platelets can be performed to look for less common alloantibodies to HPA. When FNAIT is suspected in a fetus, blood samples are taken from only the mother and father due to the risk for complications in attempting to get a blood sample from a fetus. HPA genotyping of the fetus based on the mother's blood samples is available for HPA-1a antigens only. | 456 | Fetal and Neonatal Alloimmune Thrombocytopenia |
nord_456_6 | Therapies of Fetal and Neonatal Alloimmune Thrombocytopenia | Treatment differs depending on the timing of diagnosis (fetus or newborn). Because of the risk of severe complications like ICH, treatment in a newborn found to have severe thrombocytopenia should begin before diagnostic test results confirm FNAIT.In a newborn suspected to have FNAIT, treatment includes a platelet transfusion. When there is no ICH, the baby is likely to recover, and platelet levels should increase to a normal level.When a fetus is suspected to be at risk for FNAIT, treatment may include giving the mother intravenous immunoglobulin (IVIG), steroids or serial intrauterine platelet transfusions (IUPT). IVIG is the delivery of antibodies from donors into the mother's blood. IVIG and steroids are used to suppress the mother's immune response against the fetus's platelets. IUPT is used to increase platelet counts in the fetus to prevent hemorrhages. IUPT, however, is considered invasive and risky to the fetus and may be reserved for cases that don't respond to IVIG or steroids. Early delivery via C-section is also thought to reduce the likelihood of ICH.After birth, a baby with FNAIT should undergo a cranial ultrasound to make sure there is no intracranial hemorrhage. Newborns with FNAIT may need platelet transfusions or IVIG to raise their platelet counts. | Therapies of Fetal and Neonatal Alloimmune Thrombocytopenia. Treatment differs depending on the timing of diagnosis (fetus or newborn). Because of the risk of severe complications like ICH, treatment in a newborn found to have severe thrombocytopenia should begin before diagnostic test results confirm FNAIT.In a newborn suspected to have FNAIT, treatment includes a platelet transfusion. When there is no ICH, the baby is likely to recover, and platelet levels should increase to a normal level.When a fetus is suspected to be at risk for FNAIT, treatment may include giving the mother intravenous immunoglobulin (IVIG), steroids or serial intrauterine platelet transfusions (IUPT). IVIG is the delivery of antibodies from donors into the mother's blood. IVIG and steroids are used to suppress the mother's immune response against the fetus's platelets. IUPT is used to increase platelet counts in the fetus to prevent hemorrhages. IUPT, however, is considered invasive and risky to the fetus and may be reserved for cases that don't respond to IVIG or steroids. Early delivery via C-section is also thought to reduce the likelihood of ICH.After birth, a baby with FNAIT should undergo a cranial ultrasound to make sure there is no intracranial hemorrhage. Newborns with FNAIT may need platelet transfusions or IVIG to raise their platelet counts. | 456 | Fetal and Neonatal Alloimmune Thrombocytopenia |
nord_457_0 | Overview of Fetal Hydantoin Syndrome | SummaryFetal hydantoin syndrome is a characteristic pattern of mental and physical birth defects that results from maternal use of the anti-seizure (anticonvulsant) drug phenytoin (Dilantin) during pregnancy. The range and severity of associated abnormalities will vary greatly from one infant to another. However, characteristic features may include distinctive skull and facial features, growth deficiencies, underdeveloped (hypoplastic) nails of the fingers and toes, and/or mild developmental delays. Other findings occasionally associated with this syndrome include cleft lip and palate, a head circumference that is smaller than would be expected based upon an infant’s age and gender (microcephaly), and skeletal malformations particularly of the fingers or hands. The exact risk of a fetus developing fetal hydantoin syndrome is not fully understood, but only approximately 5-10% of fetuses exposed to phenytoin develop the disorder.IntroductionAnti-seizure medications, also known as antiepileptic or anticonvulsant medications are among the most common teratogens prescribed to women of childbearing age. A teratogen is a drug that interferes with the development of a fetus. Affected infants often develop similar symptoms regardless of the associated drug, particularly symptoms affecting the head and face region (craniofacial abnormalities). Studies have indicated that fetal valproate syndrome is associated with greater risk of neurological and cognitive abnormalities than other anti-seizure medications. NORD has a separate report on fetal valproate syndrome.Although some disorders due to specific drugs (e.g. fetal hydantoin syndrome) are rare, many researchers believe that when considering the teratogenic effects of all antiepileptic drugs collectively these disorders are not rare. The concept of fetal antiepileptic syndromes in this regard is less useful than in the past and the broad consideration of the major and minor congenital malformations, various cognitive impairments, and behavioral abnormalities taken as a broader, collective concept is more appropriate. | Overview of Fetal Hydantoin Syndrome. SummaryFetal hydantoin syndrome is a characteristic pattern of mental and physical birth defects that results from maternal use of the anti-seizure (anticonvulsant) drug phenytoin (Dilantin) during pregnancy. The range and severity of associated abnormalities will vary greatly from one infant to another. However, characteristic features may include distinctive skull and facial features, growth deficiencies, underdeveloped (hypoplastic) nails of the fingers and toes, and/or mild developmental delays. Other findings occasionally associated with this syndrome include cleft lip and palate, a head circumference that is smaller than would be expected based upon an infant’s age and gender (microcephaly), and skeletal malformations particularly of the fingers or hands. The exact risk of a fetus developing fetal hydantoin syndrome is not fully understood, but only approximately 5-10% of fetuses exposed to phenytoin develop the disorder.IntroductionAnti-seizure medications, also known as antiepileptic or anticonvulsant medications are among the most common teratogens prescribed to women of childbearing age. A teratogen is a drug that interferes with the development of a fetus. Affected infants often develop similar symptoms regardless of the associated drug, particularly symptoms affecting the head and face region (craniofacial abnormalities). Studies have indicated that fetal valproate syndrome is associated with greater risk of neurological and cognitive abnormalities than other anti-seizure medications. NORD has a separate report on fetal valproate syndrome.Although some disorders due to specific drugs (e.g. fetal hydantoin syndrome) are rare, many researchers believe that when considering the teratogenic effects of all antiepileptic drugs collectively these disorders are not rare. The concept of fetal antiepileptic syndromes in this regard is less useful than in the past and the broad consideration of the major and minor congenital malformations, various cognitive impairments, and behavioral abnormalities taken as a broader, collective concept is more appropriate. | 457 | Fetal Hydantoin Syndrome |
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