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nord_471_3 | Affects of Floating Harbor Syndrome | Floating-Harbor syndrome affects males and females in equal numbers. The exact incidence and prevalence of the disorder is unknown. Because cases may go undiagnosed or misdiagnosed, determining the true frequency of FHS in the general population is difficult. As of 2014, approximately 100 cases have been reported in the medical literature. However, some of these individuals do not fit the classical description of FHS and were found not to carry mutations in the SRCAP gene. | Affects of Floating Harbor Syndrome. Floating-Harbor syndrome affects males and females in equal numbers. The exact incidence and prevalence of the disorder is unknown. Because cases may go undiagnosed or misdiagnosed, determining the true frequency of FHS in the general population is difficult. As of 2014, approximately 100 cases have been reported in the medical literature. However, some of these individuals do not fit the classical description of FHS and were found not to carry mutations in the SRCAP gene. | 471 | Floating Harbor Syndrome |
nord_471_4 | Related disorders of Floating Harbor Syndrome | Symptoms of the following disorders can be similar to those of Floating-Harbor syndrome. Comparisons may be useful for a differential diagnosis.Rubinstein-Taybi syndrome is a rare genetic multisystem disorder that affects many organ systems of the body. The group of findings (constellation) associated with this syndrome include growth retardation and delayed bone age; intellectual disability; distinctive abnormalities of the head and face (craniofacial dysmorphism), including widely spaced eyes (hypertelorism), a broad nasal bridge, and an abnormally large or “beak-shaped” nose; abnormally broad thumbs and great toes (halluces); and/or breathing and swallowing difficulties. In addition, most affected children experience delays in attaining developmental milestones (e.g., sitting, crawling, walking, talking, etc.) and/or delays in the acquisition of skills requiring coordination of muscular and mental activity (psychomotor impairment). Additional craniofacial abnormalities may include an abnormally small head (microcephaly); a highly-arched roof of the mouth (palate); an unusually small (hypoplastic) lower jaw (micrognathia); crossed eyes (strabismus); droopy eyelids (ptosis); downwardly slanting eyelid folds (palpebral fissures); and/or an extra fold of skin on either side of the nose that may cover the eyes’ inner corners (epicanthal folds). In addition, many individuals with Rubinstein-Taybi syndrome may have malformations of the heart, kidneys, urogenital system, and/or skeletal system. In most cases, the skin is also affected. The range and severity of symptoms and physical findings may vary widely from case to case. Most cases of Rubinstein-Taybi syndrome occur randomly, for no apparent reason (sporadic). Some cases are caused by mutations in the CREBBP or EP300 genes. (For more information on this disorder, choose “Rubinstein-Taybi” as your search term in the Rare Disease Database.)Three M syndrome is an extremely rare genetic disorder characterized by low birth weight, short stature (dwarfism), characteristic abnormalities of the head and facial (craniofacial) area, distinctive skeletal malformations, and/or other physical abnormalities. Characteristic craniofacial malformations typically include a long, narrow head (dolichocephaly), an unusually prominent forehead (frontal bossing), and a triangular-shaped face with a prominent, pointed chin, large ears, and/or abnormally flat cheeks. In addition, in some affected children, the teeth may be abnormally crowded together; as a result, the upper and lower teeth may not meet properly (malocclusion). Skeletal abnormalities associated with the disorder include unusually thin bones, particularly the shafts of the long bones of the arms and legs (diaphyses); abnormally tall bones of the spinal column (vertebrae); and/or distinctive malformations of the ribs and shoulder blades (scapulae). Affected individuals may also have additional abnormalities including permanent fixation of certain fingers in a bent position (clinodactyly), unusually short fifth fingers, and/or increased flexibility (hyperextensibility) of the joints. The range and severity of symptoms and physical features may vary from case to case. Intelligence appears to be normal. Three M syndrome is inherited as an autosomal recessive genetic trait. (For more information on this disorder, choose “three m” as your search term in the Rare Disease Database.)Russell-Silver syndrome (RSS) is a rare disorder characterized by intrauterine growth retardation and postnatal growth deficiency along with a handful of common physical characteristics and a range of other symptoms. The wide spectrum of phenotype findings vary both in incidence rate and severity from one individual to another. Besides prenatal and postnatal growth retardation, the most common characteristics are normal head circumference (appearing large for the body), a large forehead that protrudes out from the plane of the face, a triangular-shaped face, a pinky that is fixed or “locked” in a bent position (clinodactyly), lack of appetite/low BMI, and undergrowth of one side or limb(s) of the body (hemihypotrophy), resulting in unequal (asymmetric) growth. The majority of children with RSS falls within the average range of intelligence, but are more likely to have motor and speech delays. Intervention at an early age (infancy) is critical. Some evidence indicates that there may be neurodevelopmental differences between the different genetic causes of RSS. RSS is genetically heterogeneous, meaning that different genetic abnormalities are believed to cause the disorder. Abnormalities affecting certain genes on chromosomes 7 or 11 have been found in up to 60% of RSS patients, leaving approximately 40% of patients where the underlying cause of RSS is not known. (For more information on this disorder, choose “Russell-Silver” as your search term in the Rare Disease Database.) | Related disorders of Floating Harbor Syndrome. Symptoms of the following disorders can be similar to those of Floating-Harbor syndrome. Comparisons may be useful for a differential diagnosis.Rubinstein-Taybi syndrome is a rare genetic multisystem disorder that affects many organ systems of the body. The group of findings (constellation) associated with this syndrome include growth retardation and delayed bone age; intellectual disability; distinctive abnormalities of the head and face (craniofacial dysmorphism), including widely spaced eyes (hypertelorism), a broad nasal bridge, and an abnormally large or “beak-shaped” nose; abnormally broad thumbs and great toes (halluces); and/or breathing and swallowing difficulties. In addition, most affected children experience delays in attaining developmental milestones (e.g., sitting, crawling, walking, talking, etc.) and/or delays in the acquisition of skills requiring coordination of muscular and mental activity (psychomotor impairment). Additional craniofacial abnormalities may include an abnormally small head (microcephaly); a highly-arched roof of the mouth (palate); an unusually small (hypoplastic) lower jaw (micrognathia); crossed eyes (strabismus); droopy eyelids (ptosis); downwardly slanting eyelid folds (palpebral fissures); and/or an extra fold of skin on either side of the nose that may cover the eyes’ inner corners (epicanthal folds). In addition, many individuals with Rubinstein-Taybi syndrome may have malformations of the heart, kidneys, urogenital system, and/or skeletal system. In most cases, the skin is also affected. The range and severity of symptoms and physical findings may vary widely from case to case. Most cases of Rubinstein-Taybi syndrome occur randomly, for no apparent reason (sporadic). Some cases are caused by mutations in the CREBBP or EP300 genes. (For more information on this disorder, choose “Rubinstein-Taybi” as your search term in the Rare Disease Database.)Three M syndrome is an extremely rare genetic disorder characterized by low birth weight, short stature (dwarfism), characteristic abnormalities of the head and facial (craniofacial) area, distinctive skeletal malformations, and/or other physical abnormalities. Characteristic craniofacial malformations typically include a long, narrow head (dolichocephaly), an unusually prominent forehead (frontal bossing), and a triangular-shaped face with a prominent, pointed chin, large ears, and/or abnormally flat cheeks. In addition, in some affected children, the teeth may be abnormally crowded together; as a result, the upper and lower teeth may not meet properly (malocclusion). Skeletal abnormalities associated with the disorder include unusually thin bones, particularly the shafts of the long bones of the arms and legs (diaphyses); abnormally tall bones of the spinal column (vertebrae); and/or distinctive malformations of the ribs and shoulder blades (scapulae). Affected individuals may also have additional abnormalities including permanent fixation of certain fingers in a bent position (clinodactyly), unusually short fifth fingers, and/or increased flexibility (hyperextensibility) of the joints. The range and severity of symptoms and physical features may vary from case to case. Intelligence appears to be normal. Three M syndrome is inherited as an autosomal recessive genetic trait. (For more information on this disorder, choose “three m” as your search term in the Rare Disease Database.)Russell-Silver syndrome (RSS) is a rare disorder characterized by intrauterine growth retardation and postnatal growth deficiency along with a handful of common physical characteristics and a range of other symptoms. The wide spectrum of phenotype findings vary both in incidence rate and severity from one individual to another. Besides prenatal and postnatal growth retardation, the most common characteristics are normal head circumference (appearing large for the body), a large forehead that protrudes out from the plane of the face, a triangular-shaped face, a pinky that is fixed or “locked” in a bent position (clinodactyly), lack of appetite/low BMI, and undergrowth of one side or limb(s) of the body (hemihypotrophy), resulting in unequal (asymmetric) growth. The majority of children with RSS falls within the average range of intelligence, but are more likely to have motor and speech delays. Intervention at an early age (infancy) is critical. Some evidence indicates that there may be neurodevelopmental differences between the different genetic causes of RSS. RSS is genetically heterogeneous, meaning that different genetic abnormalities are believed to cause the disorder. Abnormalities affecting certain genes on chromosomes 7 or 11 have been found in up to 60% of RSS patients, leaving approximately 40% of patients where the underlying cause of RSS is not known. (For more information on this disorder, choose “Russell-Silver” as your search term in the Rare Disease Database.) | 471 | Floating Harbor Syndrome |
nord_471_5 | Diagnosis of Floating Harbor Syndrome | A diagnosis of Floating-Harbor syndrome is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. The distinctive facial features that characterize FHS can be subtle and difficult to recognize during infancy. Additionally, many of the other symptoms are nonspecific to FHS, making it difficult to diagnose the disorder on clinical grounds alone.Molecular genetic testing can confirm a diagnosis of FHS. Molecular genetic testing can detect mutations in the SRCAP gene, but is available only on as a diagnostic service at specialized laboratories.Prenatal diagnosis may also be possible for families with a known mutation of the SRCAP gene. Deoxyribonucleic acid or DNA taken from fetal cells obtained through amniocentesis or chorionic villus sampling (CVS) can be studied for the disease-causing mutation. During amniocentesis, a sample of fluid that surrounds the developing fetus (amniotic fluid) is removed and studied. CVS involves the removal of tissue samples from a portion of the placenta.In cases where a parent has a known genetic abnormality, pre-implantation genetic diagnosis (PGD) may be an option. PGD can be performed on embryos created through in vitro fertilization. PGD refers to testing an embryo to determine whether it has the same genetic abnormality as the parent. Families interested such an option should seek the counsel of a certified genetics professional. | Diagnosis of Floating Harbor Syndrome. A diagnosis of Floating-Harbor syndrome is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. The distinctive facial features that characterize FHS can be subtle and difficult to recognize during infancy. Additionally, many of the other symptoms are nonspecific to FHS, making it difficult to diagnose the disorder on clinical grounds alone.Molecular genetic testing can confirm a diagnosis of FHS. Molecular genetic testing can detect mutations in the SRCAP gene, but is available only on as a diagnostic service at specialized laboratories.Prenatal diagnosis may also be possible for families with a known mutation of the SRCAP gene. Deoxyribonucleic acid or DNA taken from fetal cells obtained through amniocentesis or chorionic villus sampling (CVS) can be studied for the disease-causing mutation. During amniocentesis, a sample of fluid that surrounds the developing fetus (amniotic fluid) is removed and studied. CVS involves the removal of tissue samples from a portion of the placenta.In cases where a parent has a known genetic abnormality, pre-implantation genetic diagnosis (PGD) may be an option. PGD can be performed on embryos created through in vitro fertilization. PGD refers to testing an embryo to determine whether it has the same genetic abnormality as the parent. Families interested such an option should seek the counsel of a certified genetics professional. | 471 | Floating Harbor Syndrome |
nord_471_6 | Therapies of Floating Harbor Syndrome | TreatmentThe treatment of FHS is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, specialists who assess and treat skeletal problems (orthopedists), specialists who asses and treat hearing problems (audiologists), specialists who assess and treat vision problems (ophthalmologists), dental specialists, speech pathologists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment.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 FHS.Early developmental intervention is important to ensure that affected children reach their potential. Most affected children will benefit from occupational, physical and speech therapy. Additional medical, social, and/or vocational services including special remedial education may also be beneficial. Ongoing counseling and support for parents is beneficial as well. Genetic counseling will also be of benefit for affected individuals and their families.Growth hormone (GH) therapy has been used to treat some individuals with FHS. Referral to a specialist who deals with the system of glands that secrete hormones into the bloodstream (endocrinologists) is recommended for those considering GH therapy. However, there is limited information as to the effectiveness and side effects of GH therapy in children with FHS.Additional therapies for specific symptoms follow standard treatment guidelines. For example, seizures may be treated with anti-seizure medications (anti-convulsants).According to the medical literature, affected individuals, in general, often remain in good overall health and have a good quality of life. | Therapies of Floating Harbor Syndrome. TreatmentThe treatment of FHS is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, specialists who assess and treat skeletal problems (orthopedists), specialists who asses and treat hearing problems (audiologists), specialists who assess and treat vision problems (ophthalmologists), dental specialists, speech pathologists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment.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 FHS.Early developmental intervention is important to ensure that affected children reach their potential. Most affected children will benefit from occupational, physical and speech therapy. Additional medical, social, and/or vocational services including special remedial education may also be beneficial. Ongoing counseling and support for parents is beneficial as well. Genetic counseling will also be of benefit for affected individuals and their families.Growth hormone (GH) therapy has been used to treat some individuals with FHS. Referral to a specialist who deals with the system of glands that secrete hormones into the bloodstream (endocrinologists) is recommended for those considering GH therapy. However, there is limited information as to the effectiveness and side effects of GH therapy in children with FHS.Additional therapies for specific symptoms follow standard treatment guidelines. For example, seizures may be treated with anti-seizure medications (anti-convulsants).According to the medical literature, affected individuals, in general, often remain in good overall health and have a good quality of life. | 471 | Floating Harbor Syndrome |
nord_472_0 | Overview of Focal Dermal Hypoplasia | Focal dermal hypoplasia (FDH), also known as Goltz syndrome, is a rare multisystem disorder that principally involves the development of the skin, hands and feet and eyes. It is a type of ectodermal dysplasia, a group of heritable disorders causing the hair, teeth, nails and glands to develop and function abnormally. Most of the cases of FDH (about 90 percent) are seen in females. This disorder is characterized by skin abnormalities that develop into streaks or lines of tumor-like lumps on various parts of the body. This syndrome displays a wide array of symptoms and may affect almost any organ. FDH is caused by changes (variants or mutations) or duplications/deletions in the PORCN gene. | Overview of Focal Dermal Hypoplasia. Focal dermal hypoplasia (FDH), also known as Goltz syndrome, is a rare multisystem disorder that principally involves the development of the skin, hands and feet and eyes. It is a type of ectodermal dysplasia, a group of heritable disorders causing the hair, teeth, nails and glands to develop and function abnormally. Most of the cases of FDH (about 90 percent) are seen in females. This disorder is characterized by skin abnormalities that develop into streaks or lines of tumor-like lumps on various parts of the body. This syndrome displays a wide array of symptoms and may affect almost any organ. FDH is caused by changes (variants or mutations) or duplications/deletions in the PORCN gene. | 472 | Focal Dermal Hypoplasia |
nord_472_1 | Symptoms of Focal Dermal Hypoplasia | An extremely wide range of symptoms characterizes FDH.FDH is a rare disorder that primarily affects females and has extreme variability. It is characterized by skin lesions that look streaked, underdeveloped or “punched-out”, birth defects of the hands and feet and birth defects of the eyes. There may be inflammation, itching, reddening, blistering and crusting of the skin. Skin may be thinned, discolored or lack color (pigmentation) in some areas. The nails may be absent or appear abnormal. Enlargement of capillaries/veins under the skin (telangectasias) often develop with age. Wart-like growth (papillomas) are usually not present at birth but develop with age and are typically found on the gums, tongue, lips, nose, genetalia and anus. All individuals with focal dermal hypoplasia have at least a few of the skin abnormalities. The hair may be sparse, brittle and/or missing.Eye differences are common and are present at birth and can include drooping eyelids (ptosis); clouding of the cornea; a cleft or keyhole-shaped defect in the iris or the retina (colobmas); small or missing eye (microphthalmia/anophthalmia); wide spacing between the eyes (hypertelorism); crossed eyes (strabismus) and/or exposure of the lining of the eyelid (ectropion).Individuals with FDH may also have a variety of skeletal abnormalities, some of which may be present at birth. Curvature of the spine (scoliosis), fused vertebrae, underdeveloped or missing fingers or toes, extra fingers or toes (polydactyly), fingers or toes that have grown together (syndactyly), fingers that bend to the side (clinodactyly), permanently bent fingers (camptodactyly) and/or fusion of bones of the fingers and toes may be present. Other malformations of the skeleton may include a small skull, an underdeveloped jaw, a forward projection of the jaw, and/or uneven development of the face, limbs or trunk. Cleft lip and palate may be present and may cause feeding, breathing and vision problems.Problems within the mouth are seen in more than 50 percent of patients affected. Failure of the teeth to develop properly often occurs in these patients. The teeth may be missing or underdeveloped and are unusually small or improperly spaced. Missing enamel may result in the development of cavities.Abnormalities of the ears, the eyes, the heart, central nervous system, gastrointestinal system and the kidneys may also be present. Abnormalities within the gastrointestinal system may lead to problems with breathing and feeding. Intellectual disability can be found in some patients. Most patients with FDH are noted to be small at birth and have mild short stature. | Symptoms of Focal Dermal Hypoplasia. An extremely wide range of symptoms characterizes FDH.FDH is a rare disorder that primarily affects females and has extreme variability. It is characterized by skin lesions that look streaked, underdeveloped or “punched-out”, birth defects of the hands and feet and birth defects of the eyes. There may be inflammation, itching, reddening, blistering and crusting of the skin. Skin may be thinned, discolored or lack color (pigmentation) in some areas. The nails may be absent or appear abnormal. Enlargement of capillaries/veins under the skin (telangectasias) often develop with age. Wart-like growth (papillomas) are usually not present at birth but develop with age and are typically found on the gums, tongue, lips, nose, genetalia and anus. All individuals with focal dermal hypoplasia have at least a few of the skin abnormalities. The hair may be sparse, brittle and/or missing.Eye differences are common and are present at birth and can include drooping eyelids (ptosis); clouding of the cornea; a cleft or keyhole-shaped defect in the iris or the retina (colobmas); small or missing eye (microphthalmia/anophthalmia); wide spacing between the eyes (hypertelorism); crossed eyes (strabismus) and/or exposure of the lining of the eyelid (ectropion).Individuals with FDH may also have a variety of skeletal abnormalities, some of which may be present at birth. Curvature of the spine (scoliosis), fused vertebrae, underdeveloped or missing fingers or toes, extra fingers or toes (polydactyly), fingers or toes that have grown together (syndactyly), fingers that bend to the side (clinodactyly), permanently bent fingers (camptodactyly) and/or fusion of bones of the fingers and toes may be present. Other malformations of the skeleton may include a small skull, an underdeveloped jaw, a forward projection of the jaw, and/or uneven development of the face, limbs or trunk. Cleft lip and palate may be present and may cause feeding, breathing and vision problems.Problems within the mouth are seen in more than 50 percent of patients affected. Failure of the teeth to develop properly often occurs in these patients. The teeth may be missing or underdeveloped and are unusually small or improperly spaced. Missing enamel may result in the development of cavities.Abnormalities of the ears, the eyes, the heart, central nervous system, gastrointestinal system and the kidneys may also be present. Abnormalities within the gastrointestinal system may lead to problems with breathing and feeding. Intellectual disability can be found in some patients. Most patients with FDH are noted to be small at birth and have mild short stature. | 472 | Focal Dermal Hypoplasia |
nord_472_2 | Causes of Focal Dermal Hypoplasia | FDH is caused by changes (variants or mutations) in the PORCN gene that creates proteins important in the development of the skin, skeleton and eyes in a developing embryo and fetus. Recent studies of patients with symptoms consistent with FDH have found genetic changes in the PORCN gene in nearly all affected females.The PORCN gene is found on the X chromosome and the syndrome is inherited in an X-linked dominant pattern. X-linked dominant disorders are caused by an abnormal gene on the X chromosome and occur mostly in females. Females with these rare conditions are affected when they have an X chromosome with the gene for a particular disease. Males with an abnormal gene for an X-linked dominant disorder are more severely affected than females and often do not survive. Living males with FDH are “mosaic” for a change in the PORCN gene. This means that the change is seen in some, but not all, of the cells in their body. | Causes of Focal Dermal Hypoplasia. FDH is caused by changes (variants or mutations) in the PORCN gene that creates proteins important in the development of the skin, skeleton and eyes in a developing embryo and fetus. Recent studies of patients with symptoms consistent with FDH have found genetic changes in the PORCN gene in nearly all affected females.The PORCN gene is found on the X chromosome and the syndrome is inherited in an X-linked dominant pattern. X-linked dominant disorders are caused by an abnormal gene on the X chromosome and occur mostly in females. Females with these rare conditions are affected when they have an X chromosome with the gene for a particular disease. Males with an abnormal gene for an X-linked dominant disorder are more severely affected than females and often do not survive. Living males with FDH are “mosaic” for a change in the PORCN gene. This means that the change is seen in some, but not all, of the cells in their body. | 472 | Focal Dermal Hypoplasia |
nord_472_3 | Affects of Focal Dermal Hypoplasia | Prevalence estimates are not available for FDH. Approximately 200 to 300 affected individuals have been reported worldwide, and only about 10 percent are live born males. | Affects of Focal Dermal Hypoplasia. Prevalence estimates are not available for FDH. Approximately 200 to 300 affected individuals have been reported worldwide, and only about 10 percent are live born males. | 472 | Focal Dermal Hypoplasia |
nord_472_4 | Related disorders of Focal Dermal Hypoplasia | Symptoms of the following disorders can be similar to those of focal dermal hypoplasia. Comparisons may be useful for a differential diagnosis:Ectodermal dysplasias are a group of hereditary, non-progressive skin diseases in which the affected tissue derives primarily from the ectodermal germ layer. The skin, its derivatives, and some other organs are involved. Symptoms may include eczema, poorly functioning sweat glands, sparse or absent hair, abnormal hair, disfigured nails and difficulty with the nasal passages and ear canals. (For more information on these disorders, choose “ectodermal dysplasias” as your search term in the Rare Disease Database.)Microphthalmia with linear skin defects (MLS) is associated with similar skin and eye abnormalities as is seen in focal dermal hypoplasia. However, limb and skeletal abnormalities are uncommon in MLS.Incontinentia pigmenti (IP) is a rare genetic dermatological disorder affecting the skin, hair, teeth, nails, eyes and central nervous system. It is inherited in an X-linked dominant pattern. IP is characterized by four stages, some of which may overlap. The first stage may be present at birth or appear in early infancy and consists of redness or inflammation of the skin. This irritation includes the scalp as well as the extremities and can last from a few weeks to several months. In the second stage, blisters develop into a raised, wart-like appearance with lesions that look like pustules. The extremities are involved almost exclusively in this stage, which may last for several months but rarely as long as a year. In the third phase, the skin darkens in a swirled pattern sometimes described as a “marble cake” appearance. This phase occurs from approximately 6 months into adulthood. The fourth stage is called the “atrophic” stage. Pale, hairless patches in addition to abnormal tooth shape and nails appear among adolescent and adult patients. The skin changes may fade later in life. (For more information on this disorder, choose “incontinentia pigmenti” as your search term in the Rare Disease Database.)Rothmund-Thomson syndrome (RTS) is a multisystem disorder characterized by skin abnormalities, sparse hair, eyelashes, and/or eyebrows, small stature, skeletal and dental abnormalities, cataracts, and an increased risk for cancer, mainly osteosarcoma. The skin typically presents normally at birth, however, the rash of RTS develops between the ages of three and six months as redness (erythema), swelling, and blistering of the face and subsequently spreads to the extremities. The rash typically evolves over the course of months to years into a chronic pattern of increased or decreased skin color, skin thinning, and presence of prominent blood vessels. (For more information on this disorder, choose “Rothmund-Thomson syndrome” as your search term in the Rare Disease Database.)Proteus syndrome is a condition that involves the atypical overgrowth of skin, bones, and the body’s organs. Most medical scientists now agree that Joseph Merrick, known famously as the “Elephant Man”, suffered from Proteus syndrome. The overgrowth is progressive and limits the range of motion of affected joints making them massively overgrown and fixed. It usually begins with the fingers, toes, and knees but can occur in any part of the body. The spine is commonly affected, and the result is scoliosis. Other affected organs include the lungs, spleen, thymus, uterus and colon. Fatty tumors (lipomas) may invade the limbs, trunk and, in some instances, the spinal canal. Other serious complications are blood clots, and some patients have intellectual disability. (For more information on this disorder, choose “Proteus syndrome” as your search term in the Rare Disease Database.) | Related disorders of Focal Dermal Hypoplasia. Symptoms of the following disorders can be similar to those of focal dermal hypoplasia. Comparisons may be useful for a differential diagnosis:Ectodermal dysplasias are a group of hereditary, non-progressive skin diseases in which the affected tissue derives primarily from the ectodermal germ layer. The skin, its derivatives, and some other organs are involved. Symptoms may include eczema, poorly functioning sweat glands, sparse or absent hair, abnormal hair, disfigured nails and difficulty with the nasal passages and ear canals. (For more information on these disorders, choose “ectodermal dysplasias” as your search term in the Rare Disease Database.)Microphthalmia with linear skin defects (MLS) is associated with similar skin and eye abnormalities as is seen in focal dermal hypoplasia. However, limb and skeletal abnormalities are uncommon in MLS.Incontinentia pigmenti (IP) is a rare genetic dermatological disorder affecting the skin, hair, teeth, nails, eyes and central nervous system. It is inherited in an X-linked dominant pattern. IP is characterized by four stages, some of which may overlap. The first stage may be present at birth or appear in early infancy and consists of redness or inflammation of the skin. This irritation includes the scalp as well as the extremities and can last from a few weeks to several months. In the second stage, blisters develop into a raised, wart-like appearance with lesions that look like pustules. The extremities are involved almost exclusively in this stage, which may last for several months but rarely as long as a year. In the third phase, the skin darkens in a swirled pattern sometimes described as a “marble cake” appearance. This phase occurs from approximately 6 months into adulthood. The fourth stage is called the “atrophic” stage. Pale, hairless patches in addition to abnormal tooth shape and nails appear among adolescent and adult patients. The skin changes may fade later in life. (For more information on this disorder, choose “incontinentia pigmenti” as your search term in the Rare Disease Database.)Rothmund-Thomson syndrome (RTS) is a multisystem disorder characterized by skin abnormalities, sparse hair, eyelashes, and/or eyebrows, small stature, skeletal and dental abnormalities, cataracts, and an increased risk for cancer, mainly osteosarcoma. The skin typically presents normally at birth, however, the rash of RTS develops between the ages of three and six months as redness (erythema), swelling, and blistering of the face and subsequently spreads to the extremities. The rash typically evolves over the course of months to years into a chronic pattern of increased or decreased skin color, skin thinning, and presence of prominent blood vessels. (For more information on this disorder, choose “Rothmund-Thomson syndrome” as your search term in the Rare Disease Database.)Proteus syndrome is a condition that involves the atypical overgrowth of skin, bones, and the body’s organs. Most medical scientists now agree that Joseph Merrick, known famously as the “Elephant Man”, suffered from Proteus syndrome. The overgrowth is progressive and limits the range of motion of affected joints making them massively overgrown and fixed. It usually begins with the fingers, toes, and knees but can occur in any part of the body. The spine is commonly affected, and the result is scoliosis. Other affected organs include the lungs, spleen, thymus, uterus and colon. Fatty tumors (lipomas) may invade the limbs, trunk and, in some instances, the spinal canal. Other serious complications are blood clots, and some patients have intellectual disability. (For more information on this disorder, choose “Proteus syndrome” as your search term in the Rare Disease Database.) | 472 | Focal Dermal Hypoplasia |
nord_472_5 | Diagnosis of Focal Dermal Hypoplasia | Diagnosis is based on clinical findings and affected individuals are usually recognized at birth. DNA testing for the PORCN gene is available to confirm the diagnosis.Clinical Testing and Workup
The diagnosis of focal dermal hypoplasia should be considered in patients with either of the following: multiple skin manifestations or one typical skin manifestation in addition to characteristic limb malformations. To better establish the extent of the disease and the treatment of the patient diagnosed, the following evaluations are often recommended: chest x-ray, eye exams, abdominal MRI, kidney ultrasound, hearing evaluation and medical genetics consultation. | Diagnosis of Focal Dermal Hypoplasia. Diagnosis is based on clinical findings and affected individuals are usually recognized at birth. DNA testing for the PORCN gene is available to confirm the diagnosis.Clinical Testing and Workup
The diagnosis of focal dermal hypoplasia should be considered in patients with either of the following: multiple skin manifestations or one typical skin manifestation in addition to characteristic limb malformations. To better establish the extent of the disease and the treatment of the patient diagnosed, the following evaluations are often recommended: chest x-ray, eye exams, abdominal MRI, kidney ultrasound, hearing evaluation and medical genetics consultation. | 472 | Focal Dermal Hypoplasia |
nord_472_6 | Therapies of Focal Dermal Hypoplasia | Treatment
Treatment for patients with focal dermal hypoplasia is directed at the symptoms. Dermatological creams and protective dressings may relieve skin discomfort and prevent secondary infections. Dentures and hearing aids may be required. Heat and over-exercise should be avoided. Limb deformities may be treated with occupational therapy, assistive devices or surgery. Surgical or laser therapy may be recommended for patients demonstrating trouble swallowing due to large fat deposits in the throat. | Therapies of Focal Dermal Hypoplasia. Treatment
Treatment for patients with focal dermal hypoplasia is directed at the symptoms. Dermatological creams and protective dressings may relieve skin discomfort and prevent secondary infections. Dentures and hearing aids may be required. Heat and over-exercise should be avoided. Limb deformities may be treated with occupational therapy, assistive devices or surgery. Surgical or laser therapy may be recommended for patients demonstrating trouble swallowing due to large fat deposits in the throat. | 472 | Focal Dermal Hypoplasia |
nord_473_0 | Overview of Focal Segmental Glomerulosclerosis | Focal segmental glomerulosclerosis (FSGS) is a term for a specific pattern of damage to the kidneys. The kidneys are two bean-shaped organs in the body, one on each side of the body just below the rib cage in the back. The kidney has multiple functions including filtering the blood of waste products and other substances and producing urine to carrying waste from the body. FSGS occurs when the filters of the kidney, which are made of clusters of tiny blood vessels (capillaries) and known as renal glomeruli, become scarred or hardened (sclerosis). Each kidney has about a million glomeruli, which are part of a larger structure called the nephron; the nephron is the basic unit of the kidneys. The glomeruli help to filter out waste products and extra fluid from the blood. Scarring or damage to the glomeruli can lead to an inability of the kidneys to process waste products and eliminate those waste products from the body through the urine. Ultimately, these abnormalities lead to progressive kidney damage including decreased function and efficiency of the kidneys, and potentially kidney failure. There are different causes of FSGS and, in some instances, the cause is unknown. Depending on the cause, FSGS may be treated with certain medications, but sometimes despite treatment affected individuals will eventually require dialysis or a kidney transplant. FSGS is a varied, complex pattern of kidney damage that has several different causes and numerous names and terminology, as well as different proposed classification systems. There is disagreement in the medical literature regarding which classification system is most effective in grouping FSGS. This can be extremely confusing to patients and caregivers. The term ‘focal segmental glomerulosclerosis’ is defined as scarring or hardening (sclerosis) of parts (segmental) of some (focal) glomeruli while other glomeruli remain unaffected. These changes can be seen in kidney tissue when studied under a microscope. However, many times sclerosis progresses to affect a more widespread and global glomeruli population and the term focal segmental glomerulosclerosis, technically, does not remain accurate.There have been several different attempts to classify FSGS, with the most straightforward being – secondary, genetic, and primary (or idiopathic) – which classifies the condition based on the underlying cause. Secondary forms include adaptive (or postadaptive) FSGS, which results from conditions that cause overactivity (hyperfiltration), stress, or high blood pressure affecting the glomeruli. This also includes reduced mass of the kidneys; as a result of the healing process from a previous kidney injury; or direct toxic effect of certain drugs or viruses. The genetic forms of FSGS are caused by an abnormal version in a gene, which causes damage to the glomeruli, or in a gene that leads to a predisposition to developing kidney damage. Some families have multiple family members who have FSGS because of one of these genetic abnormalities. Recently, researchers have established a strong connection between abnormal variants in the APOL1 gene, which is found in individuals of sub-Saharan African ancestry, and the development of FSGS. Primary (or idiopathic) FSGS is the most common form of FSGS, and is diagnosed when no secondary or genetic cause can be identified.Another classification system, called the Columbia Classification, breaks down FSGS into five subtypes based on the appearance (morphology) of the FSGS lesions affecting the glomeruli as seen under a microscope. These five variants are: perihilar, cellular, tip, collapsing, and FSGS not otherwise specified. These distinctions are important when physicians decide how to treat a patient with FSGS. | Overview of Focal Segmental Glomerulosclerosis. Focal segmental glomerulosclerosis (FSGS) is a term for a specific pattern of damage to the kidneys. The kidneys are two bean-shaped organs in the body, one on each side of the body just below the rib cage in the back. The kidney has multiple functions including filtering the blood of waste products and other substances and producing urine to carrying waste from the body. FSGS occurs when the filters of the kidney, which are made of clusters of tiny blood vessels (capillaries) and known as renal glomeruli, become scarred or hardened (sclerosis). Each kidney has about a million glomeruli, which are part of a larger structure called the nephron; the nephron is the basic unit of the kidneys. The glomeruli help to filter out waste products and extra fluid from the blood. Scarring or damage to the glomeruli can lead to an inability of the kidneys to process waste products and eliminate those waste products from the body through the urine. Ultimately, these abnormalities lead to progressive kidney damage including decreased function and efficiency of the kidneys, and potentially kidney failure. There are different causes of FSGS and, in some instances, the cause is unknown. Depending on the cause, FSGS may be treated with certain medications, but sometimes despite treatment affected individuals will eventually require dialysis or a kidney transplant. FSGS is a varied, complex pattern of kidney damage that has several different causes and numerous names and terminology, as well as different proposed classification systems. There is disagreement in the medical literature regarding which classification system is most effective in grouping FSGS. This can be extremely confusing to patients and caregivers. The term ‘focal segmental glomerulosclerosis’ is defined as scarring or hardening (sclerosis) of parts (segmental) of some (focal) glomeruli while other glomeruli remain unaffected. These changes can be seen in kidney tissue when studied under a microscope. However, many times sclerosis progresses to affect a more widespread and global glomeruli population and the term focal segmental glomerulosclerosis, technically, does not remain accurate.There have been several different attempts to classify FSGS, with the most straightforward being – secondary, genetic, and primary (or idiopathic) – which classifies the condition based on the underlying cause. Secondary forms include adaptive (or postadaptive) FSGS, which results from conditions that cause overactivity (hyperfiltration), stress, or high blood pressure affecting the glomeruli. This also includes reduced mass of the kidneys; as a result of the healing process from a previous kidney injury; or direct toxic effect of certain drugs or viruses. The genetic forms of FSGS are caused by an abnormal version in a gene, which causes damage to the glomeruli, or in a gene that leads to a predisposition to developing kidney damage. Some families have multiple family members who have FSGS because of one of these genetic abnormalities. Recently, researchers have established a strong connection between abnormal variants in the APOL1 gene, which is found in individuals of sub-Saharan African ancestry, and the development of FSGS. Primary (or idiopathic) FSGS is the most common form of FSGS, and is diagnosed when no secondary or genetic cause can be identified.Another classification system, called the Columbia Classification, breaks down FSGS into five subtypes based on the appearance (morphology) of the FSGS lesions affecting the glomeruli as seen under a microscope. These five variants are: perihilar, cellular, tip, collapsing, and FSGS not otherwise specified. These distinctions are important when physicians decide how to treat a patient with FSGS. | 473 | Focal Segmental Glomerulosclerosis |
nord_473_1 | Symptoms of Focal Segmental Glomerulosclerosis | The signs and symptoms of focal segmental glomerulosclerosis are related to progressive damage to the kidneys. Some people may not have any noticeable symptoms (asymptomatic), while others may have progressive disease that can, often rapidly, result in kidney failure. In primary FSGS, the nephrotic syndrome is often the presenting complication associated with the disorder. The nephrotic syndrome is not a disease but rather a general term for symptoms that develop when the glomeruli (filters) of the kidneys are damaged, which results in loss of large amounts of protein in the urine (proteinuria). Patients experience swelling due to abnormal fluid accumulation (edema), particularly in the feet and ankles and sometimes as puffiness around the eyes when a person first gets up in the morning. Swelling of the feet or ankles may be persistent and affected individuals may find that their shoes no longer fit. Nephrotic syndrome can cause foamy urine due to the presence of excess protein in the urine, fatigue, high blood pressure (hypertension), loss of appetite, unintended weight gain, high cholesterol levels, and an increased tendency to form blood clots. FSGS can potentially progress to cause severe complications as such declining kidney function and, ultimately, kidney failure. Symptoms associated with kidney failure include abnormally pale skin (pallor), drowsiness, nausea, and/or vomiting. Severe complications of renal failure include bleeding into the stomach, a decrease in the amount of circulating red blood cells (anemia), and abnormal heart rhythms due to elevated potassium levels in the blood. When the kidneys stop working, this is called end stage renal disease. Patients with primary (idiopathic) FSGS can experience a rapid decline in their kidney function, while with secondary FSGS there is usually a slower disease progression. Secondary FSGS is usually characterized by slowly increasing amounts of protein in the urine and slowly worsening kidney function, and often, there is no swelling affecting the feet and ankles (peripheral edema).The genetic forms of FSGS are highly variable even among individuals with the same genetic variant. Signs and symptoms can range from mild disease with little to no symptoms, to severe disease with nephrotic syndrome, eventually causing kidney failure. | Symptoms of Focal Segmental Glomerulosclerosis. The signs and symptoms of focal segmental glomerulosclerosis are related to progressive damage to the kidneys. Some people may not have any noticeable symptoms (asymptomatic), while others may have progressive disease that can, often rapidly, result in kidney failure. In primary FSGS, the nephrotic syndrome is often the presenting complication associated with the disorder. The nephrotic syndrome is not a disease but rather a general term for symptoms that develop when the glomeruli (filters) of the kidneys are damaged, which results in loss of large amounts of protein in the urine (proteinuria). Patients experience swelling due to abnormal fluid accumulation (edema), particularly in the feet and ankles and sometimes as puffiness around the eyes when a person first gets up in the morning. Swelling of the feet or ankles may be persistent and affected individuals may find that their shoes no longer fit. Nephrotic syndrome can cause foamy urine due to the presence of excess protein in the urine, fatigue, high blood pressure (hypertension), loss of appetite, unintended weight gain, high cholesterol levels, and an increased tendency to form blood clots. FSGS can potentially progress to cause severe complications as such declining kidney function and, ultimately, kidney failure. Symptoms associated with kidney failure include abnormally pale skin (pallor), drowsiness, nausea, and/or vomiting. Severe complications of renal failure include bleeding into the stomach, a decrease in the amount of circulating red blood cells (anemia), and abnormal heart rhythms due to elevated potassium levels in the blood. When the kidneys stop working, this is called end stage renal disease. Patients with primary (idiopathic) FSGS can experience a rapid decline in their kidney function, while with secondary FSGS there is usually a slower disease progression. Secondary FSGS is usually characterized by slowly increasing amounts of protein in the urine and slowly worsening kidney function, and often, there is no swelling affecting the feet and ankles (peripheral edema).The genetic forms of FSGS are highly variable even among individuals with the same genetic variant. Signs and symptoms can range from mild disease with little to no symptoms, to severe disease with nephrotic syndrome, eventually causing kidney failure. | 473 | Focal Segmental Glomerulosclerosis |
nord_473_2 | Causes of Focal Segmental Glomerulosclerosis | There are many different causes for FSGS. Many researchers believe that FSGS is caused by damage to a specialized kidney cell in the glomerulus (filter) called the podocyte. Abnormalities in the health, function, or number of podocytes ultimately leads to the scarring (sclerosis) of the glomeruli that characterizes FSGS. In individuals with the primary form, the specific cause is often unknown (idiopathic). Some researchers believe that affected individuals have proteins called permeability factors in their blood that damage podocytes, which causes the glomeruli (filters) to leak protein into the urine. Research is ongoing to identify these permeability factors and how they cause primary FSGS. There are a variety of causes of secondary FSGS. Adaptive FSGS is diagnosed when a patient has a condition that causes excess stress on the glomeruli (filters), such as when the glomeruli (filters) receive increased blood flow (hyperfiltration). Conditions that can cause increased blood flow to the kidneys include obesity, diabetes, sickle cell anemia, sleep apnea, and heart disease that causes low levels of oxygen in the blood (cyanotic heart disease). In response, the glomeruli (filters) may become enlarged (hypertrophic). Adaptive FSGS is also caused by reduced mass of the kidneys which can be caused by congenital defects of the kidneys such as the absence of one kidney (unilateral renal agenesis), prematurity, or being small for gestational age as a newborn. Finally, adaptive FSGS may occur due to other types of chronic damage to the glomeruli (filters), such as when urine backs up from the bladder into the kidneys (reflux nephropathy). Other causes of secondary FSGS include the use of certain medications or drugs that have been shown to damage podocytes, such as interferon, bisphosphonates, anabolic steroids, heroin, anthracyclines, calcineurin inhibitors, lithium, and sirolimus. Certain viruses including human immunodeficiency virus (HIV), parvovirus B19, hepatitis C virus, simian virus 40, Epstein-Barr virus, and cytomegalovirus have also been associated with FSGS. Some individuals develop FSGS because of previous injury to the kidneys. During the healing phase of a previous inflammatory disease of the kidneys, it is believed that, as the body tries to heal the kidneys, scarring or hardening (sclerosis) of the glomeruli may occur. Kidney disorders such as IgA nephropathy, small vessel vasculitis, and lupus nephritis have been associated with the development of FSGS. The genetic forms of FSGS occur due to an abnormal variant in a susceptibility gene, or a disease-causing variant in a gene known to cause FSGS (monogenic FSGS). More than 40 different genes have been reported to be associated with FSGS. Some of these genes create (encode) proteins that are involved in the proper health, development, and function of podocytes. An abnormal variant in a susceptibility gene means that a person is at a greater risk of developing a disorder than someone without that gene variant, but that the disorder won’t develop unless other factors (usually environmental, immunologic, or other genetic factors) also occur. People with an abnormal variant in a susceptibility gene may never develop the disorder associated with that gene. Monogenic disorders develop because of a variation in one specific gene. Most individuals with a disease-causing variation will develop symptoms of the disorder. A variation in the single gene is all that is necessary for the disorder to develop. Other factors including variations in other genes or environmental factors can influence how a monogenic disorder progresses or the specific symptoms that develop. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation (abnormality) of a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body. Genes associated with FSGS affect proteins that are essential in maintaining the health, structure, development and function of the glomeruli (filters). These include genes in podocytes and the glomerular basement membrane, which is a vital component of the small blood vessels (capillaries) that make up glomeruli. In recent years, abnormal variants in the APOL1 gene have been shown to be associated with FSGS in patients of African ancestry. This is sometimes referred to as APOL1-associated FSGS. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes (bundles of genetic material) that an individual receives from his/her father and mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause 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 child is 50% for each pregnancy regardless of the sex of the resulting child.Recessive genetic disorders occur when an individual inherits two abnormal genes for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not develop the disease itself. 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. In rare instances, FSGS has been inherited as an X-linked trait, which are genetic disorders caused by an abnormal gene on the X chromosome. Females have two X chromosomes but one of the X chromosomes is “turned off” and all of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder because it is usually the X chromosome with the abnormal gene that is “turned off.” A male has one X-chromosome and if he inherits an X chromosome that contains a disease gene, he will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers if the other X chromosome from their mother is normal. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease, and a 25% chance to have an unaffected son. In some females, known as heterozygotes, which inherit a single copy of the disease gene, disease traits on the X chromosome may not always be masked by the normal gene on the other X chromosome. As a result, these females may exhibit some of the symptoms associated with the disorder. | Causes of Focal Segmental Glomerulosclerosis. There are many different causes for FSGS. Many researchers believe that FSGS is caused by damage to a specialized kidney cell in the glomerulus (filter) called the podocyte. Abnormalities in the health, function, or number of podocytes ultimately leads to the scarring (sclerosis) of the glomeruli that characterizes FSGS. In individuals with the primary form, the specific cause is often unknown (idiopathic). Some researchers believe that affected individuals have proteins called permeability factors in their blood that damage podocytes, which causes the glomeruli (filters) to leak protein into the urine. Research is ongoing to identify these permeability factors and how they cause primary FSGS. There are a variety of causes of secondary FSGS. Adaptive FSGS is diagnosed when a patient has a condition that causes excess stress on the glomeruli (filters), such as when the glomeruli (filters) receive increased blood flow (hyperfiltration). Conditions that can cause increased blood flow to the kidneys include obesity, diabetes, sickle cell anemia, sleep apnea, and heart disease that causes low levels of oxygen in the blood (cyanotic heart disease). In response, the glomeruli (filters) may become enlarged (hypertrophic). Adaptive FSGS is also caused by reduced mass of the kidneys which can be caused by congenital defects of the kidneys such as the absence of one kidney (unilateral renal agenesis), prematurity, or being small for gestational age as a newborn. Finally, adaptive FSGS may occur due to other types of chronic damage to the glomeruli (filters), such as when urine backs up from the bladder into the kidneys (reflux nephropathy). Other causes of secondary FSGS include the use of certain medications or drugs that have been shown to damage podocytes, such as interferon, bisphosphonates, anabolic steroids, heroin, anthracyclines, calcineurin inhibitors, lithium, and sirolimus. Certain viruses including human immunodeficiency virus (HIV), parvovirus B19, hepatitis C virus, simian virus 40, Epstein-Barr virus, and cytomegalovirus have also been associated with FSGS. Some individuals develop FSGS because of previous injury to the kidneys. During the healing phase of a previous inflammatory disease of the kidneys, it is believed that, as the body tries to heal the kidneys, scarring or hardening (sclerosis) of the glomeruli may occur. Kidney disorders such as IgA nephropathy, small vessel vasculitis, and lupus nephritis have been associated with the development of FSGS. The genetic forms of FSGS occur due to an abnormal variant in a susceptibility gene, or a disease-causing variant in a gene known to cause FSGS (monogenic FSGS). More than 40 different genes have been reported to be associated with FSGS. Some of these genes create (encode) proteins that are involved in the proper health, development, and function of podocytes. An abnormal variant in a susceptibility gene means that a person is at a greater risk of developing a disorder than someone without that gene variant, but that the disorder won’t develop unless other factors (usually environmental, immunologic, or other genetic factors) also occur. People with an abnormal variant in a susceptibility gene may never develop the disorder associated with that gene. Monogenic disorders develop because of a variation in one specific gene. Most individuals with a disease-causing variation will develop symptoms of the disorder. A variation in the single gene is all that is necessary for the disorder to develop. Other factors including variations in other genes or environmental factors can influence how a monogenic disorder progresses or the specific symptoms that develop. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation (abnormality) of a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body. Genes associated with FSGS affect proteins that are essential in maintaining the health, structure, development and function of the glomeruli (filters). These include genes in podocytes and the glomerular basement membrane, which is a vital component of the small blood vessels (capillaries) that make up glomeruli. In recent years, abnormal variants in the APOL1 gene have been shown to be associated with FSGS in patients of African ancestry. This is sometimes referred to as APOL1-associated FSGS. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes (bundles of genetic material) that an individual receives from his/her father and mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause 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 child is 50% for each pregnancy regardless of the sex of the resulting child.Recessive genetic disorders occur when an individual inherits two abnormal genes for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not develop the disease itself. 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. In rare instances, FSGS has been inherited as an X-linked trait, which are genetic disorders caused by an abnormal gene on the X chromosome. Females have two X chromosomes but one of the X chromosomes is “turned off” and all of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder because it is usually the X chromosome with the abnormal gene that is “turned off.” A male has one X-chromosome and if he inherits an X chromosome that contains a disease gene, he will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers if the other X chromosome from their mother is normal. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease, and a 25% chance to have an unaffected son. In some females, known as heterozygotes, which inherit a single copy of the disease gene, disease traits on the X chromosome may not always be masked by the normal gene on the other X chromosome. As a result, these females may exhibit some of the symptoms associated with the disorder. | 473 | Focal Segmental Glomerulosclerosis |
nord_473_3 | Affects of Focal Segmental Glomerulosclerosis | Focal segmental glomerulosclerosis is estimated to affect about 7 people per million people in the general population, although specific incidence rates vary in different populations. FSGS accounts for about 40% of adults with nephrotic syndrome and about 20% of children with nephrotic syndrome. In the United States, FSGS accounts for 5%-20% of all people who experience end stage renal disease. Some recent studies have found that the number of people who have FSGS is increasing each year. FSGS affects men slightly more often than women and can affect children or adults. It most often occurs in adults about 45 years or older. FSGS occurs more commonly in African Americans than in Caucasian, and the rate of decline of kidney function is generally more rapid in African Americans | Affects of Focal Segmental Glomerulosclerosis. Focal segmental glomerulosclerosis is estimated to affect about 7 people per million people in the general population, although specific incidence rates vary in different populations. FSGS accounts for about 40% of adults with nephrotic syndrome and about 20% of children with nephrotic syndrome. In the United States, FSGS accounts for 5%-20% of all people who experience end stage renal disease. Some recent studies have found that the number of people who have FSGS is increasing each year. FSGS affects men slightly more often than women and can affect children or adults. It most often occurs in adults about 45 years or older. FSGS occurs more commonly in African Americans than in Caucasian, and the rate of decline of kidney function is generally more rapid in African Americans | 473 | Focal Segmental Glomerulosclerosis |
nord_473_4 | Related disorders of Focal Segmental Glomerulosclerosis | Symptoms of the following disorders can be similar to those of focal segmental glomerulosclerosis. Comparisons may be useful for a differential diagnosis.Minimal change disease is a pattern of kidney damage, in which the glomeruli appear normal on microscopic examination. Affected individuals experience the signs and symptoms of nephrotic syndrome due to loss of large amounts of protein in the urine. In many instances, there is no identifiable cause for minimal change disease (idiopathic). Rarely, minimal change disease can occur secondary other disorders including autoimmune disorders, viral infection, toxic reactions to drugs, and lymphoma (blood cancer). In minimal change disease, kidney function is often normal, and the disease usually responds to treatment with corticosteroids (prednisone). Minimal change disease is the most common cause of nephrotic syndrome in children- so common, that children with nephrotic syndrome are usually treated with corticosteroids first rather than undergoing a kidney biopsy. There are many other kidney diseases that can cause signs and symptoms such as nephrotic syndrome similar to those seen FSGS. These diseases include membranous nephropathy, amyloidosis, C3 glomerulopathy, post-infectious glomerulonephritis, membranoproliferative glomerulonephritis, Alport Syndrome, lupus nephritis, and IgA nephropathy. | Related disorders of Focal Segmental Glomerulosclerosis. Symptoms of the following disorders can be similar to those of focal segmental glomerulosclerosis. Comparisons may be useful for a differential diagnosis.Minimal change disease is a pattern of kidney damage, in which the glomeruli appear normal on microscopic examination. Affected individuals experience the signs and symptoms of nephrotic syndrome due to loss of large amounts of protein in the urine. In many instances, there is no identifiable cause for minimal change disease (idiopathic). Rarely, minimal change disease can occur secondary other disorders including autoimmune disorders, viral infection, toxic reactions to drugs, and lymphoma (blood cancer). In minimal change disease, kidney function is often normal, and the disease usually responds to treatment with corticosteroids (prednisone). Minimal change disease is the most common cause of nephrotic syndrome in children- so common, that children with nephrotic syndrome are usually treated with corticosteroids first rather than undergoing a kidney biopsy. There are many other kidney diseases that can cause signs and symptoms such as nephrotic syndrome similar to those seen FSGS. These diseases include membranous nephropathy, amyloidosis, C3 glomerulopathy, post-infectious glomerulonephritis, membranoproliferative glomerulonephritis, Alport Syndrome, lupus nephritis, and IgA nephropathy. | 473 | Focal Segmental Glomerulosclerosis |
nord_473_5 | Diagnosis of Focal Segmental Glomerulosclerosis | A diagnosis of focal segmental glomerulosclerosis is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. To confirm the diagnosis, small pieces of kidney tissue are sampled in a procedure called a kidney biopsy. These tissue samples are evaluated under a microscope to look for the signs of FSGS. Clinical Testing and Workup
A sample of kidney tissue taken via biopsy and studied under a microscope can reveal characteristic changes in the kidney that indicate FSGS. During this procedure, a small needle is passed through the skin to the kidney to obtain a small sample of tissue. This sample is viewed under a microscope by a special doctor called a pathologist who studies the specific cells and characteristics of the tissue sample to identify disease. Sometimes, a biopsy sample is inconclusive, and multiple samples may need to be taken.Urine and blood tests help to suspect the condition. Urine tests reveals elevated levels of protein leakage and sometimes also find blood in the urine. Blood tests may find elevated levels of cholesterol and waste products in the blood, with lower than normal blood protein (albumin) levels. To measure kidney function, physicians order a blood test called creatinine, which allows them to calculate the glomerular filtration rate (GFR). This blood test helps to check on how well the kidneys are working. Specifically, this test will determine how well the kidneys are filtering waste products and water from the blood that passes through the kidneys. This test allows physicians to determine the rate of kidney decline and help to plan the most effective treatment. Molecular genetic testing can confirm a diagnosis of FSGS in certain cases. Molecular genetic testing can detect an abnormal variant in one of the genes known to cause the disorder. Genetic testing can be done as part of a research study, or a diagnostic service at specialized laboratories. When performed as a diagnostic service, they are often expensive, and health insurance may not cover this testing. Because of these factors, and because there are currently no proven treatments for many genetic forms of FSGS, genetic testing is not commonly performed. | Diagnosis of Focal Segmental Glomerulosclerosis. A diagnosis of focal segmental glomerulosclerosis is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. To confirm the diagnosis, small pieces of kidney tissue are sampled in a procedure called a kidney biopsy. These tissue samples are evaluated under a microscope to look for the signs of FSGS. Clinical Testing and Workup
A sample of kidney tissue taken via biopsy and studied under a microscope can reveal characteristic changes in the kidney that indicate FSGS. During this procedure, a small needle is passed through the skin to the kidney to obtain a small sample of tissue. This sample is viewed under a microscope by a special doctor called a pathologist who studies the specific cells and characteristics of the tissue sample to identify disease. Sometimes, a biopsy sample is inconclusive, and multiple samples may need to be taken.Urine and blood tests help to suspect the condition. Urine tests reveals elevated levels of protein leakage and sometimes also find blood in the urine. Blood tests may find elevated levels of cholesterol and waste products in the blood, with lower than normal blood protein (albumin) levels. To measure kidney function, physicians order a blood test called creatinine, which allows them to calculate the glomerular filtration rate (GFR). This blood test helps to check on how well the kidneys are working. Specifically, this test will determine how well the kidneys are filtering waste products and water from the blood that passes through the kidneys. This test allows physicians to determine the rate of kidney decline and help to plan the most effective treatment. Molecular genetic testing can confirm a diagnosis of FSGS in certain cases. Molecular genetic testing can detect an abnormal variant in one of the genes known to cause the disorder. Genetic testing can be done as part of a research study, or a diagnostic service at specialized laboratories. When performed as a diagnostic service, they are often expensive, and health insurance may not cover this testing. Because of these factors, and because there are currently no proven treatments for many genetic forms of FSGS, genetic testing is not commonly performed. | 473 | Focal Segmental Glomerulosclerosis |
nord_473_6 | Therapies of Focal Segmental Glomerulosclerosis | Treatment
The treatment of focal segmental glomerulosclerosis is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, general internists, specialists who asses and treat kidney disorders (nephrologists), surgeons who specialize in organ transplants, social workers, nutritionists, and other healthcare professionals may need to systematically and comprehensively plan treatment. Genetic counseling may be of benefit for affected individuals and their families for the patients with a genetic form of FSGS. Psychosocial support for the entire family is essential as well. Several of the organizations listed in the Resources section provide support and information on kidney disorders. Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as the underlying cause of FSGS; how far kidney function has declined; the presence or absence of certain symptoms; and an individual’s age and general health. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks of treatment, including possible side effects and long-term effects; patient preference; and other appropriate factors.The general goal of treatment is to decrease proteinuria and either stabilize or improve kidney function. It has been shown that patients who experience improvement in their proteinuria to the normal range generally have the best kidney outcomes (i.e. no progression of kidney disease, or need for dialysis or a kidney transplant). Patients who achieve a reduction in proteinuria also have better kidney outcomes, although not as good as patients with normal amounts of proteinuria. Patients whose proteinuria does not improve have the worse kidney outcomes.Distinguishing between primary (idiopathic) FSGS, secondary FSGS and genetic FSGS is extremely important as the treatment options and response to treatment will differ. The response to various treatments is highly individualized as well, meaning that treatments which are effective in one person may be ineffective, or poorly tolerated, in another person. Individuals with primary FSGS and nephrotic syndrome are treated with a class of steroid drugs called glucocorticoids and/or other drugs that suppress the activity of the immune system (immunosuppressive drugs). These drugs have side effects and some individuals may not be able to tolerate these medications. Other individuals may not improve despite taking these medications. Some physicians do not use immunosuppressing drugs for people with primary FSGS if they do not have nephrotic syndrome because the disease is less aggressive. Individuals with primary FSGS without nephrotic syndrome and with lower levels of protein in the urine may be treated with drugs called renin-angiotensin-aldosterone system (RAAS) inhibitors and dietary restriction of sodium, without immunosuppression. If the disease worsens, then they may be treated with glucocorticoids and other immunosuppressive drugs. These include medications called calcineurin inhibitors (cyclosporine and tacrolimus) and mycophenolate mofetil have been shown to improve proteinuria levels in patients with FSGS.In individuals with virus-associated FSGS, treatment is aimed toward treating the underlying infection. In individuals with medication-associated FSGS, discontinuation of the offending medication is required. There are several supportive therapies that are given to help manage the various symptoms associated with FSGS including water pills (diuretics) and a low sodium diet to relieve edema; blood thinning medications that help prevent blood clots (anticoagulants); drugs called statins that can help lower cholesterol levels; and RAAS inhibitors such as angiotensin converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs), which can help to control blood pressure and lower the amount of protein in the urine. Physicians may also recommend exercise, smoking cessation, supplemental vitamins, and maintaining a healthy or low protein diet. Despite treatment, some affected individuals progress to end stage renal disease, in which the kidneys no longer function. End stage renal disease cannot be reversed and requires dialysis or a kidney transplant. If a patient undergoes kidney transplant, there is a risk that FSGS will recur in the transplanted kidney; this is particularly true for individuals with primary FSGS. When FSGS recurs, additional drugs that suppress the immune system may be used. These drugs often differ from the drugs that are used to initially treat FSGS. A procedure called plasmapheresis (see below) may also be recommended. | Therapies of Focal Segmental Glomerulosclerosis. Treatment
The treatment of focal segmental glomerulosclerosis is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, general internists, specialists who asses and treat kidney disorders (nephrologists), surgeons who specialize in organ transplants, social workers, nutritionists, and other healthcare professionals may need to systematically and comprehensively plan treatment. Genetic counseling may be of benefit for affected individuals and their families for the patients with a genetic form of FSGS. Psychosocial support for the entire family is essential as well. Several of the organizations listed in the Resources section provide support and information on kidney disorders. Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as the underlying cause of FSGS; how far kidney function has declined; the presence or absence of certain symptoms; and an individual’s age and general health. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks of treatment, including possible side effects and long-term effects; patient preference; and other appropriate factors.The general goal of treatment is to decrease proteinuria and either stabilize or improve kidney function. It has been shown that patients who experience improvement in their proteinuria to the normal range generally have the best kidney outcomes (i.e. no progression of kidney disease, or need for dialysis or a kidney transplant). Patients who achieve a reduction in proteinuria also have better kidney outcomes, although not as good as patients with normal amounts of proteinuria. Patients whose proteinuria does not improve have the worse kidney outcomes.Distinguishing between primary (idiopathic) FSGS, secondary FSGS and genetic FSGS is extremely important as the treatment options and response to treatment will differ. The response to various treatments is highly individualized as well, meaning that treatments which are effective in one person may be ineffective, or poorly tolerated, in another person. Individuals with primary FSGS and nephrotic syndrome are treated with a class of steroid drugs called glucocorticoids and/or other drugs that suppress the activity of the immune system (immunosuppressive drugs). These drugs have side effects and some individuals may not be able to tolerate these medications. Other individuals may not improve despite taking these medications. Some physicians do not use immunosuppressing drugs for people with primary FSGS if they do not have nephrotic syndrome because the disease is less aggressive. Individuals with primary FSGS without nephrotic syndrome and with lower levels of protein in the urine may be treated with drugs called renin-angiotensin-aldosterone system (RAAS) inhibitors and dietary restriction of sodium, without immunosuppression. If the disease worsens, then they may be treated with glucocorticoids and other immunosuppressive drugs. These include medications called calcineurin inhibitors (cyclosporine and tacrolimus) and mycophenolate mofetil have been shown to improve proteinuria levels in patients with FSGS.In individuals with virus-associated FSGS, treatment is aimed toward treating the underlying infection. In individuals with medication-associated FSGS, discontinuation of the offending medication is required. There are several supportive therapies that are given to help manage the various symptoms associated with FSGS including water pills (diuretics) and a low sodium diet to relieve edema; blood thinning medications that help prevent blood clots (anticoagulants); drugs called statins that can help lower cholesterol levels; and RAAS inhibitors such as angiotensin converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs), which can help to control blood pressure and lower the amount of protein in the urine. Physicians may also recommend exercise, smoking cessation, supplemental vitamins, and maintaining a healthy or low protein diet. Despite treatment, some affected individuals progress to end stage renal disease, in which the kidneys no longer function. End stage renal disease cannot be reversed and requires dialysis or a kidney transplant. If a patient undergoes kidney transplant, there is a risk that FSGS will recur in the transplanted kidney; this is particularly true for individuals with primary FSGS. When FSGS recurs, additional drugs that suppress the immune system may be used. These drugs often differ from the drugs that are used to initially treat FSGS. A procedure called plasmapheresis (see below) may also be recommended. | 473 | Focal Segmental Glomerulosclerosis |
nord_474_0 | Overview of Follicular Lymphoma | Follicular lymphoma is a form of cancer. It is a type of non-Hodgkin lymphoma (NHL), which is a group of related cancers that affect the lymphatic system (lymphomas). The lymphatic system functions as part of the immune system and helps to protect the body against infection and disease. It consists of a network of tubular channels (lymph vessels) that drain a thin watery fluid known as lymph from different areas of the body into the bloodstream. Lymph accumulates in the tiny spaces between tissue cells and contains proteins, fats, and certain white blood cells known as lymphocytes. As lymph moves through the lymphatic system, it is filtered by a network of small structures known as lymph nodes that help to remove microorganisms (e.g., viruses, bacteria, etc.) and other foreign bodies. Groups of lymph nodes are located throughout the body, including, but not limited to, the neck, under the arms (axillae), at the elbows, and in the chest, abdomen, and groin. Lymphocytes are stored within lymph nodes and may also be found in other lymphatic tissues. In addition to the lymph nodes, the lymphatic system includes the spleen, which filters worn-out red blood cells and produces lymphocytes, and bone marrow, which is the spongy tissue inside the cavities of bones that manufactures blood cells. Lymphatic tissue or circulating lymphocytes may also be located in other regions of the body. There are two main types of lymphocytes: B-lymphocytes (B-cells), which may produce specific antibodies to “neutralize” certain invading microorganisms, and T-lymphocytes (T-cells), which may directly destroy microorganisms or cancer cells, or assist in the activities of other lymphocytes.Follicular lymphoma is a B-cell lymphoma. It is characterized by the transformation of a B-cell into a malignant (cancerous) cell. Abnormal, uncontrolled growth and multiplication (proliferation) of malignant B-cells can lead to enlargement of specific lymph node regions; involvement of other lymphatic tissues such as the spleen or bone marrow; and spread to other bodily tissues and organs. The term follicular lymphoma comes from the observation that the cancer cells are group in clusters (or follicles) within the lymph nodes. Non-Hodgkin lymphoma including follicular lymphoma can be characterized as “low-grade” (or indolent), meaning the cancer tends to grow slowly and results in few associated symptoms or “high-grade” (aggressive), meaning the cancer typically grows rapidly. | Overview of Follicular Lymphoma. Follicular lymphoma is a form of cancer. It is a type of non-Hodgkin lymphoma (NHL), which is a group of related cancers that affect the lymphatic system (lymphomas). The lymphatic system functions as part of the immune system and helps to protect the body against infection and disease. It consists of a network of tubular channels (lymph vessels) that drain a thin watery fluid known as lymph from different areas of the body into the bloodstream. Lymph accumulates in the tiny spaces between tissue cells and contains proteins, fats, and certain white blood cells known as lymphocytes. As lymph moves through the lymphatic system, it is filtered by a network of small structures known as lymph nodes that help to remove microorganisms (e.g., viruses, bacteria, etc.) and other foreign bodies. Groups of lymph nodes are located throughout the body, including, but not limited to, the neck, under the arms (axillae), at the elbows, and in the chest, abdomen, and groin. Lymphocytes are stored within lymph nodes and may also be found in other lymphatic tissues. In addition to the lymph nodes, the lymphatic system includes the spleen, which filters worn-out red blood cells and produces lymphocytes, and bone marrow, which is the spongy tissue inside the cavities of bones that manufactures blood cells. Lymphatic tissue or circulating lymphocytes may also be located in other regions of the body. There are two main types of lymphocytes: B-lymphocytes (B-cells), which may produce specific antibodies to “neutralize” certain invading microorganisms, and T-lymphocytes (T-cells), which may directly destroy microorganisms or cancer cells, or assist in the activities of other lymphocytes.Follicular lymphoma is a B-cell lymphoma. It is characterized by the transformation of a B-cell into a malignant (cancerous) cell. Abnormal, uncontrolled growth and multiplication (proliferation) of malignant B-cells can lead to enlargement of specific lymph node regions; involvement of other lymphatic tissues such as the spleen or bone marrow; and spread to other bodily tissues and organs. The term follicular lymphoma comes from the observation that the cancer cells are group in clusters (or follicles) within the lymph nodes. Non-Hodgkin lymphoma including follicular lymphoma can be characterized as “low-grade” (or indolent), meaning the cancer tends to grow slowly and results in few associated symptoms or “high-grade” (aggressive), meaning the cancer typically grows rapidly. | 474 | Follicular Lymphoma |
nord_474_1 | Symptoms of Follicular Lymphoma | The specific symptoms and physical findings of follicular lymphoma can vary from one person to another, depending upon the extent and region(s) of involvement and other factors. Follicular lymphoma is described as having a relapsing and remitting course; the cancer alternates between flaring up or worsening for a period of time often requiring treatment, and periods of time where the cancer is in remission or levels off. For many people, follicular lymphoma is a slow-growing cancer that develops over many years. A common finding is the enlargement of affected lymph nodes (lymphadenopathy). Lymph nodes may become hard and can be felt (palpable) underneath the skin. Lymph nodes in the neck, the armpit (axilla), and groin are most commonly affected. Lymph nodes in the abdomen can also become enlarged, but cannot be felt. Lymph node enlargement is mostly painless. The enlargement of a lymph node may come and go for several years before a diagnosis of follicular lymphoma is made. Follicular lymphoma can affect the bone marrow and the spleen, causing abnormal enlargement of the spleen (splenomegaly). When follicular lymphoma affects the bone marrow or the spleen, it can lead to low levels of the three main blood cell types: red blood cells, white blood cells, and platelets. This is called cytopenia. Red blood cells deliver oxygen to the body, white blood cells help in fighting off infections and platelets allow the body to form clots to stop bleeding. A low levels of red blood cells is called anemia and can be characterized by tiredness, shortness of breath, weakness, lightheadedness, headaches, and pale skin color. A low levels of white blood cells (neutropenia) increases the risk of contracting bacterial and fungal infections. A low levels of platelets (thrombocytopenia) makes the individual more susceptible to excessive bruising following minimal injury and spontaneous bleeding from the gums and nose. Less often, affected individuals develop symptoms that are vague and can be nonspecific, which means that the symptoms are common to many different disorders or conditions. When dealing with lymphoma, these symptoms may come and go and are sometimes referred to as ‘B symptoms.’ These symptoms can include a persistent, chronic fever; unintended weight loss, and excessive sweating, especially at night (night sweats). Follicular lymphoma affecting organs other than those in the lymphatic system or the bone morrow is rare. Sometimes, large tumors may form in the abdomen.Transformed Follicular Lymphoma
There is a risk in individuals with follicular lymphoma that the cancer can go under a transformation from a slow-growing (indolent) form into a more aggressive form called diffuse large B-cell lymphoma (DLBCL). As many as 30-40% of individuals may experience aggressive transformation of indolent follicular lymphoma. DLBCL can progress rapidly and spread to areas and organs outside of the lymphatic system (extranodal) and the bone marrow. ‘B’ symptoms are more common in transformed follicular lymphoma. Primary Gastrointestinal Follicular Lymphoma
Primary gastrointestinal follicular lymphoma often does not cause any apparent symptoms (asymptomatic). This form is generally considered to be a distinct variant of follicular lymphoma that has a better prognosis. Cancer often arises in the first section of the small intestines (duodenum), which connects to the stomach. Affected individuals can develop abdominal discomfort and heartburn. Less often, affected individuals can develop nausea, vomiting, diarrhea, abdominal pain, and intestinal bleeding, which can cause black, tarry stools. Pediatric Follicular Lymphoma
Pediatric follicular lymphoma is different from the adult form and is considered a distinct type of lymphoma by many researchers. Different genetic factors have been shown to play a role in the pediatric form than are seen in follicular lymphoma. Pediatric follicular lymphoma is characterized by the cancer remaining in the area where it first develops (localized presentation). Enlargement of the lymph nodes is the most common symptom. Overall, pediatric follicular lymphoma shows a generally benign behavior. The lymph nodes found in the neck (cervical area) and the tonsils are most often affected. The gastrointestinal tract, salivary duct, kidney, and skin can also be affected. Some researchers use the term pediatric-type follicular lymphoma because adults with this form of follicular lymphoma have been identified. | Symptoms of Follicular Lymphoma. The specific symptoms and physical findings of follicular lymphoma can vary from one person to another, depending upon the extent and region(s) of involvement and other factors. Follicular lymphoma is described as having a relapsing and remitting course; the cancer alternates between flaring up or worsening for a period of time often requiring treatment, and periods of time where the cancer is in remission or levels off. For many people, follicular lymphoma is a slow-growing cancer that develops over many years. A common finding is the enlargement of affected lymph nodes (lymphadenopathy). Lymph nodes may become hard and can be felt (palpable) underneath the skin. Lymph nodes in the neck, the armpit (axilla), and groin are most commonly affected. Lymph nodes in the abdomen can also become enlarged, but cannot be felt. Lymph node enlargement is mostly painless. The enlargement of a lymph node may come and go for several years before a diagnosis of follicular lymphoma is made. Follicular lymphoma can affect the bone marrow and the spleen, causing abnormal enlargement of the spleen (splenomegaly). When follicular lymphoma affects the bone marrow or the spleen, it can lead to low levels of the three main blood cell types: red blood cells, white blood cells, and platelets. This is called cytopenia. Red blood cells deliver oxygen to the body, white blood cells help in fighting off infections and platelets allow the body to form clots to stop bleeding. A low levels of red blood cells is called anemia and can be characterized by tiredness, shortness of breath, weakness, lightheadedness, headaches, and pale skin color. A low levels of white blood cells (neutropenia) increases the risk of contracting bacterial and fungal infections. A low levels of platelets (thrombocytopenia) makes the individual more susceptible to excessive bruising following minimal injury and spontaneous bleeding from the gums and nose. Less often, affected individuals develop symptoms that are vague and can be nonspecific, which means that the symptoms are common to many different disorders or conditions. When dealing with lymphoma, these symptoms may come and go and are sometimes referred to as ‘B symptoms.’ These symptoms can include a persistent, chronic fever; unintended weight loss, and excessive sweating, especially at night (night sweats). Follicular lymphoma affecting organs other than those in the lymphatic system or the bone morrow is rare. Sometimes, large tumors may form in the abdomen.Transformed Follicular Lymphoma
There is a risk in individuals with follicular lymphoma that the cancer can go under a transformation from a slow-growing (indolent) form into a more aggressive form called diffuse large B-cell lymphoma (DLBCL). As many as 30-40% of individuals may experience aggressive transformation of indolent follicular lymphoma. DLBCL can progress rapidly and spread to areas and organs outside of the lymphatic system (extranodal) and the bone marrow. ‘B’ symptoms are more common in transformed follicular lymphoma. Primary Gastrointestinal Follicular Lymphoma
Primary gastrointestinal follicular lymphoma often does not cause any apparent symptoms (asymptomatic). This form is generally considered to be a distinct variant of follicular lymphoma that has a better prognosis. Cancer often arises in the first section of the small intestines (duodenum), which connects to the stomach. Affected individuals can develop abdominal discomfort and heartburn. Less often, affected individuals can develop nausea, vomiting, diarrhea, abdominal pain, and intestinal bleeding, which can cause black, tarry stools. Pediatric Follicular Lymphoma
Pediatric follicular lymphoma is different from the adult form and is considered a distinct type of lymphoma by many researchers. Different genetic factors have been shown to play a role in the pediatric form than are seen in follicular lymphoma. Pediatric follicular lymphoma is characterized by the cancer remaining in the area where it first develops (localized presentation). Enlargement of the lymph nodes is the most common symptom. Overall, pediatric follicular lymphoma shows a generally benign behavior. The lymph nodes found in the neck (cervical area) and the tonsils are most often affected. The gastrointestinal tract, salivary duct, kidney, and skin can also be affected. Some researchers use the term pediatric-type follicular lymphoma because adults with this form of follicular lymphoma have been identified. | 474 | Follicular Lymphoma |
nord_474_2 | Causes of Follicular Lymphoma | The exact, underlying cause of follicular lymphoma is not fully understood. The reason why cancer develops is a complex question and researchers speculate that multiple factors are involved in the development of follicular lymphoma. These factors include genetic, environmental and immunologic factors, which all may play a role in the development of this cancer. About 85% of affected adults have a genetic abnormality that is not inherited, but found only within the cancer cells called a translocation. A translocation is a genetic abnormality in which regions of certain chromosomes break off and are rearranged, resulting in shifting of genetic material and an altered set of chromosomes. In follicular lymphoma, regions of chromosome 14 and 18 break off and trade places. 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. The genetic translocation involving chromosomes 14 and 18 leads to the overexpression of a gene called BCL-2. 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. Overexpression means that the protein product of the BCL-2 gene is overproduced. The protein produced by this gene is believed to play a role in inhibiting apoptosis, the normal process by which cells grow and then die (programmed cell death). Because the BCL-2 gene is overexpressed, it prevents cells from going through apoptosis, causing cells that do not die off when they are supposed to. This contributes to the development of cancer. Although the majority of adults with follicular lymphoma have this specific genetic translocation, there are people in the general population who also have this specific translocation, but who never develop follicular lymphoma. This suggests that additional factors, including other genetic alterations or changes, are required for the development of follicular lymphoma. For example, alterations (mutations) in a gene called EZH2 have been reported in more than 25% of people with follicular lymphoma and may play a role in the cancer’s development. More research is necessary to fully understand the complex genetic interactions that contribute to the development of follicular lymphoma. Environmental factors that have been suggested to possibly play a role in the development of follicular lymphoma include exposure to toxic substances like benzene, occupational exposure to pesticides, certain infections, and smoking including passive smoking. The underlying genetics differ between the adult and pediatric forms. Children with follicular lymphoma do not have a translocation involving chromosomes 14 and 18. The genetic factors involved in pediatric follicular lymphoma are not fully known. Mutations in the MAP2K1 gene and mutations or deletions in the TNFRSF14 gene have been commonly reported in the medical literature. More research is necessary to determine the complex genetic factors that are involved in pediatric follicular lymphoma. | Causes of Follicular Lymphoma. The exact, underlying cause of follicular lymphoma is not fully understood. The reason why cancer develops is a complex question and researchers speculate that multiple factors are involved in the development of follicular lymphoma. These factors include genetic, environmental and immunologic factors, which all may play a role in the development of this cancer. About 85% of affected adults have a genetic abnormality that is not inherited, but found only within the cancer cells called a translocation. A translocation is a genetic abnormality in which regions of certain chromosomes break off and are rearranged, resulting in shifting of genetic material and an altered set of chromosomes. In follicular lymphoma, regions of chromosome 14 and 18 break off and trade places. 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. The genetic translocation involving chromosomes 14 and 18 leads to the overexpression of a gene called BCL-2. 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. Overexpression means that the protein product of the BCL-2 gene is overproduced. The protein produced by this gene is believed to play a role in inhibiting apoptosis, the normal process by which cells grow and then die (programmed cell death). Because the BCL-2 gene is overexpressed, it prevents cells from going through apoptosis, causing cells that do not die off when they are supposed to. This contributes to the development of cancer. Although the majority of adults with follicular lymphoma have this specific genetic translocation, there are people in the general population who also have this specific translocation, but who never develop follicular lymphoma. This suggests that additional factors, including other genetic alterations or changes, are required for the development of follicular lymphoma. For example, alterations (mutations) in a gene called EZH2 have been reported in more than 25% of people with follicular lymphoma and may play a role in the cancer’s development. More research is necessary to fully understand the complex genetic interactions that contribute to the development of follicular lymphoma. Environmental factors that have been suggested to possibly play a role in the development of follicular lymphoma include exposure to toxic substances like benzene, occupational exposure to pesticides, certain infections, and smoking including passive smoking. The underlying genetics differ between the adult and pediatric forms. Children with follicular lymphoma do not have a translocation involving chromosomes 14 and 18. The genetic factors involved in pediatric follicular lymphoma are not fully known. Mutations in the MAP2K1 gene and mutations or deletions in the TNFRSF14 gene have been commonly reported in the medical literature. More research is necessary to determine the complex genetic factors that are involved in pediatric follicular lymphoma. | 474 | Follicular Lymphoma |
nord_474_3 | Affects of Follicular Lymphoma | Follicular lymphoma affects both men and women, but is slightly more common in women. This form of cancer is found all over the world and can affect people of all races. It is less common in individuals of Asian or African heritage than it is in other ethnicities. The mean age at diagnosis is 65. In the United States and Western Europe, follicular lymphoma is the second most common subtype of non-Hodgkin lymphoma accounting for about 30%-35% of people with non-Hodgkin lymphoma and almost 75% of people with indolent forms of lymphoma. Each year, 15-20,000 people in the U.S. are diagnosed with follicular lymphoma. Pediatric follicular lymphoma is extremely rare variant that makes up only 1-2% of all malignant lymphomas in children. Non-Hodgkin lymphoma, as a group, accounts for about 4.3% of people with cancer in the United States. | Affects of Follicular Lymphoma. Follicular lymphoma affects both men and women, but is slightly more common in women. This form of cancer is found all over the world and can affect people of all races. It is less common in individuals of Asian or African heritage than it is in other ethnicities. The mean age at diagnosis is 65. In the United States and Western Europe, follicular lymphoma is the second most common subtype of non-Hodgkin lymphoma accounting for about 30%-35% of people with non-Hodgkin lymphoma and almost 75% of people with indolent forms of lymphoma. Each year, 15-20,000 people in the U.S. are diagnosed with follicular lymphoma. Pediatric follicular lymphoma is extremely rare variant that makes up only 1-2% of all malignant lymphomas in children. Non-Hodgkin lymphoma, as a group, accounts for about 4.3% of people with cancer in the United States. | 474 | Follicular Lymphoma |
nord_474_4 | Related disorders of Follicular Lymphoma | Symptoms of the following disorders can be similar to those of follicular lymphoma. Comparisons may be useful for a differential diagnosis.Various types of lymphoma need to be differentiated from follicular lymphoma. There are two major categories of lymphoma called Hodgkin disease (lymphoma) and non-Hodgkin lymphoma (NHL). Hodgkin disease is typically characterized by the presence of a specific type of cancer cell known as a Reed-Sternberg cell that has more than one nucleus. This cell is a mature B-lymphocyte (B-cell) that has become malignant. NHL is broadly categorized into lymphomas that arise from two different type of cells, B-lymphocytes or T-lymphocytes (T-cells). There are many forms of NHL. Mantle cell lymphoma, cutaneous follicle center cell lymphoma, T-cell rich large B-cell lymphoma, and nodal marginal zone lymphoma are specific subtypes of NHL that should differentiated from follicular lymphoma. (For more information on some of these disorders, choose the specific type of lymphoma as your search term in the Rare Disease Database.) | Related disorders of Follicular Lymphoma. Symptoms of the following disorders can be similar to those of follicular lymphoma. Comparisons may be useful for a differential diagnosis.Various types of lymphoma need to be differentiated from follicular lymphoma. There are two major categories of lymphoma called Hodgkin disease (lymphoma) and non-Hodgkin lymphoma (NHL). Hodgkin disease is typically characterized by the presence of a specific type of cancer cell known as a Reed-Sternberg cell that has more than one nucleus. This cell is a mature B-lymphocyte (B-cell) that has become malignant. NHL is broadly categorized into lymphomas that arise from two different type of cells, B-lymphocytes or T-lymphocytes (T-cells). There are many forms of NHL. Mantle cell lymphoma, cutaneous follicle center cell lymphoma, T-cell rich large B-cell lymphoma, and nodal marginal zone lymphoma are specific subtypes of NHL that should differentiated from follicular lymphoma. (For more information on some of these disorders, choose the specific type of lymphoma as your search term in the Rare Disease Database.) | 474 | Follicular Lymphoma |
nord_474_5 | Diagnosis of Follicular Lymphoma | A diagnosis of follicular lymphoma is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Such testing is necessary to confirm the specific type (and subtype) of non-Hodgkin lymphoma, to determine the nature and extent of the cancer, and to determine the most appropriate treatments. During a complete physical examination, physicians may feel (i.e., palpate) the lymph nodes in certain regions to detect any swelling, including in the neck, tonsil, and adenoidal region; under the arms; and in the groin. They may also examine other regions to help determine whether there is enlargement of certain internal organs, particularly the spleen, and to detect swelling and abnormal fluid accumulation that may be associated with disease of the lymphatic system.For those with suspected lymphoma as suggested by thorough patient history and clinical examination, various diagnostic tests may be recommended. These may include blood tests, biopsies, specialized imaging tests, bone marrow examination, and/or other tests.Clinical Testing and Workup
A diagnosis of follicular lymphoma requires the review of an adequate biopsy sample by an expert medical pathologist. Pathologists are physicians who specialize in analyzing cells and tissues to help obtain accurate diagnosis. Biopsies typically involve the removal and microscopic (i.e., histologic) examination of small samples of tissue cells from a lymph node–or, in some instances, removal of an entire, enlarged lymph node–that is suspected of being cancerous. Depending upon the specific type of biopsy performed, the procedure may be conducted under local or whole body (general) anesthesia. In addition, in some instances, such as when involvement appears to be restricted to the abdominal or pelvic region, laparoscopy or laparotomy may be necessary to obtain biopsy samples. Laparoscopy involves examination of the abdominal cavity with an illuminated viewing tube (laparoscope) inserted through incisions in the abdominal wall. Laparotomy is a surgical procedure in which the abdomen is opened, organs are carefully examined to detect signs of disease, and samples of tissue are removed for microscopic examination. Sometimes, doctors may recommend a bone marrow biopsy to determine whether lymphoma is in the bone marrow. Blood tests may include studies to evaluate the number and appearance of white blood cells, red blood cells, and platelets; liver enzyme studies; tests to measure levels of the enzyme lactate dehydrogenase (LDH); and/or other studies. (High elevations of LDH may suggest that the lymphoma may have rapid progression, potentially requiring more intensive therapies, but only 25% of affected individuals have elevated LDH.)Advanced imaging (x-ray) techniques can also be recommended and can include a combined positron emission tomography (PET) and computerized tomography (CT) scan known as a PET/CT scan. During a PET scan, three-dimensional images are produced to evaluate how healthy and functional certain tissues and organs are. This exam involves the use of a radioactive drug called a tracer that is combined with sugar (glucose). This radioactive sugar is injected into the body. This sugar will collect in areas of the body where there is a higher demand for energy. Cancer require a lot of energy to keep growing and spreading, and will soak up the radioactive sugar. These areas will show up on the PET scan as brighter than the surrounding areas. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. A CT scan can show enlarged organs or lymph nodes. A PET/CT allows physicians to assess the metabolic and structural (anatomic) in one session and can return a more accurate image or picture of cancer than either test can by itself. A test known as fluorescent in situ hybridization or FISH may also be used to help diagnose follicular lymphoma. During a FISH exam, probes marked by a specific color of fluorescent dye are attached to a specific chromosome allowing researchers to better view a specific region of that chromosome. The test allows physicians to detect alterations in the genetic material of chromosomes including translocations such as a translocation of chromosomes 14 and 18. This can help distinguish follicular lymphoma from other forms of indolent lymphoma.A test called polymerase chain reaction or PCR may also be used to help diagnose follicular lymphoma. PCR is a test technique for identifying and making copies of specific segments of deoxyribonucleic acid (DNA). The test can identify tiny amounts of DNA including genetic material to detect alterations such as a translocation of chromosomes 14 and 18. This test tends to be less reliable in diagnosing follicular lymphoma than fluorescent in situ hybridization (FISH). Staging
When an individual is diagnosed with a non-Hodgkin lymphoma (NHL) such as follicular lymphoma, assessment is also required to determine the extent or “stage” of the disease. Staging is important to help characterize the potential disease course and determine appropriate treatment approaches. A variety of diagnostic tests may be used in staging NHL (e.g., blood tests, CT scanning, bone marrow biopsy, PET scan). In addition, in some people, additional biopsies may be obtained to assist in lymphoma staging.The specific stage of NHL may be based upon the number of lymph node regions involved; whether such lymph nodes are located above, below, or on both sides of the diaphragm*; and/or whether the malignancy has infiltrated other lymphatic tissues, such as the spleen or bone marrow, or spread to involve other organs outside the lymphatic system, such as the liver. (*The diaphragm is the dome-shaped muscle that separates the chest from the abdomen and plays an essential role in breathing.)Although various staging systems have been described, a system commonly used for adult NHL is the Ann Arbor staging system, which includes the following stages:Stage I – indicates early, localized disease in which the malignancy is limited to a single lymph node region or in a single organ or region outside the lymph node (extralymphatic organ or site).Stage II – indicates locally advanced disease in which the malignancy involves more than one lymph node region on one side of the diaphragm or is found within one extralymphatic organ or site and its regional lymph node region (with or without involvement of other lymph nodes on the same side of the diaphragm).Stage III – indicates advanced disease in which the lymphoma involves lymph node regions on both sides of (i.e., above and below) the diaphragm and may involve the spleen. There may also be localized involvement of an extralymphatic organ or site.Stage IV – indicates widespread (disseminated) disease in which the malignancy is diffusely spread throughout one or more extralymphatic organs or sites with or without associated lymph node involvement. Follicular lymphoma in the bone marrow and liver is always stage IV.Each stage of NHL may be further divided into categories A or B, based upon whether or not affected individuals have symptoms. More specifically:A indicates that no generalized (systemic) symptoms are present upon diagnosis.B indicates that an affected individual has experienced drenching night sweats, unexplained fever (above 38 degrees Celsius), and/or unexplained weight loss (i.e., loss of at least 10 percent of total body weight in the six months prior to diagnosis). In addition, category E may indicate that the malignancy affects a single organ outside the lymphatic system or has spread from a lymph node to an organ. Category S may indicate involvement of the spleen.Various additional elements may be considered as physicians determine the stage of NHL, potential disease course, and appropriate treatment options. Such factors may include patient age and general health, tumor size, levels of the enzyme lactate dehydrogenase, extranodal site involvement, and other factors. | Diagnosis of Follicular Lymphoma. A diagnosis of follicular lymphoma is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Such testing is necessary to confirm the specific type (and subtype) of non-Hodgkin lymphoma, to determine the nature and extent of the cancer, and to determine the most appropriate treatments. During a complete physical examination, physicians may feel (i.e., palpate) the lymph nodes in certain regions to detect any swelling, including in the neck, tonsil, and adenoidal region; under the arms; and in the groin. They may also examine other regions to help determine whether there is enlargement of certain internal organs, particularly the spleen, and to detect swelling and abnormal fluid accumulation that may be associated with disease of the lymphatic system.For those with suspected lymphoma as suggested by thorough patient history and clinical examination, various diagnostic tests may be recommended. These may include blood tests, biopsies, specialized imaging tests, bone marrow examination, and/or other tests.Clinical Testing and Workup
A diagnosis of follicular lymphoma requires the review of an adequate biopsy sample by an expert medical pathologist. Pathologists are physicians who specialize in analyzing cells and tissues to help obtain accurate diagnosis. Biopsies typically involve the removal and microscopic (i.e., histologic) examination of small samples of tissue cells from a lymph node–or, in some instances, removal of an entire, enlarged lymph node–that is suspected of being cancerous. Depending upon the specific type of biopsy performed, the procedure may be conducted under local or whole body (general) anesthesia. In addition, in some instances, such as when involvement appears to be restricted to the abdominal or pelvic region, laparoscopy or laparotomy may be necessary to obtain biopsy samples. Laparoscopy involves examination of the abdominal cavity with an illuminated viewing tube (laparoscope) inserted through incisions in the abdominal wall. Laparotomy is a surgical procedure in which the abdomen is opened, organs are carefully examined to detect signs of disease, and samples of tissue are removed for microscopic examination. Sometimes, doctors may recommend a bone marrow biopsy to determine whether lymphoma is in the bone marrow. Blood tests may include studies to evaluate the number and appearance of white blood cells, red blood cells, and platelets; liver enzyme studies; tests to measure levels of the enzyme lactate dehydrogenase (LDH); and/or other studies. (High elevations of LDH may suggest that the lymphoma may have rapid progression, potentially requiring more intensive therapies, but only 25% of affected individuals have elevated LDH.)Advanced imaging (x-ray) techniques can also be recommended and can include a combined positron emission tomography (PET) and computerized tomography (CT) scan known as a PET/CT scan. During a PET scan, three-dimensional images are produced to evaluate how healthy and functional certain tissues and organs are. This exam involves the use of a radioactive drug called a tracer that is combined with sugar (glucose). This radioactive sugar is injected into the body. This sugar will collect in areas of the body where there is a higher demand for energy. Cancer require a lot of energy to keep growing and spreading, and will soak up the radioactive sugar. These areas will show up on the PET scan as brighter than the surrounding areas. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. A CT scan can show enlarged organs or lymph nodes. A PET/CT allows physicians to assess the metabolic and structural (anatomic) in one session and can return a more accurate image or picture of cancer than either test can by itself. A test known as fluorescent in situ hybridization or FISH may also be used to help diagnose follicular lymphoma. During a FISH exam, probes marked by a specific color of fluorescent dye are attached to a specific chromosome allowing researchers to better view a specific region of that chromosome. The test allows physicians to detect alterations in the genetic material of chromosomes including translocations such as a translocation of chromosomes 14 and 18. This can help distinguish follicular lymphoma from other forms of indolent lymphoma.A test called polymerase chain reaction or PCR may also be used to help diagnose follicular lymphoma. PCR is a test technique for identifying and making copies of specific segments of deoxyribonucleic acid (DNA). The test can identify tiny amounts of DNA including genetic material to detect alterations such as a translocation of chromosomes 14 and 18. This test tends to be less reliable in diagnosing follicular lymphoma than fluorescent in situ hybridization (FISH). Staging
When an individual is diagnosed with a non-Hodgkin lymphoma (NHL) such as follicular lymphoma, assessment is also required to determine the extent or “stage” of the disease. Staging is important to help characterize the potential disease course and determine appropriate treatment approaches. A variety of diagnostic tests may be used in staging NHL (e.g., blood tests, CT scanning, bone marrow biopsy, PET scan). In addition, in some people, additional biopsies may be obtained to assist in lymphoma staging.The specific stage of NHL may be based upon the number of lymph node regions involved; whether such lymph nodes are located above, below, or on both sides of the diaphragm*; and/or whether the malignancy has infiltrated other lymphatic tissues, such as the spleen or bone marrow, or spread to involve other organs outside the lymphatic system, such as the liver. (*The diaphragm is the dome-shaped muscle that separates the chest from the abdomen and plays an essential role in breathing.)Although various staging systems have been described, a system commonly used for adult NHL is the Ann Arbor staging system, which includes the following stages:Stage I – indicates early, localized disease in which the malignancy is limited to a single lymph node region or in a single organ or region outside the lymph node (extralymphatic organ or site).Stage II – indicates locally advanced disease in which the malignancy involves more than one lymph node region on one side of the diaphragm or is found within one extralymphatic organ or site and its regional lymph node region (with or without involvement of other lymph nodes on the same side of the diaphragm).Stage III – indicates advanced disease in which the lymphoma involves lymph node regions on both sides of (i.e., above and below) the diaphragm and may involve the spleen. There may also be localized involvement of an extralymphatic organ or site.Stage IV – indicates widespread (disseminated) disease in which the malignancy is diffusely spread throughout one or more extralymphatic organs or sites with or without associated lymph node involvement. Follicular lymphoma in the bone marrow and liver is always stage IV.Each stage of NHL may be further divided into categories A or B, based upon whether or not affected individuals have symptoms. More specifically:A indicates that no generalized (systemic) symptoms are present upon diagnosis.B indicates that an affected individual has experienced drenching night sweats, unexplained fever (above 38 degrees Celsius), and/or unexplained weight loss (i.e., loss of at least 10 percent of total body weight in the six months prior to diagnosis). In addition, category E may indicate that the malignancy affects a single organ outside the lymphatic system or has spread from a lymph node to an organ. Category S may indicate involvement of the spleen.Various additional elements may be considered as physicians determine the stage of NHL, potential disease course, and appropriate treatment options. Such factors may include patient age and general health, tumor size, levels of the enzyme lactate dehydrogenase, extranodal site involvement, and other factors. | 474 | Follicular Lymphoma |
nord_474_6 | Therapies of Follicular Lymphoma | Treatment
The diagnosis and therapeutic management of follicular lymphoma may require the coordinated efforts of a team of medical professionals, such as physicians who specialize in the diagnosis and treatment of cancer (medical oncologists), disorders of the blood and blood-forming tissues (hematologists), or the use of radiation to treat cancers (radiation oncologists); oncology nurses; surgeons; dietitians; and/or other healthcare professionals. Psychosocial support for the entire family is essential as well. Genetic counseling may be recommended for affected individuals and their families. The course of follicular lymphoma is highly variable. The average survival rate is greater than 20 years. Some individuals do not develop symptoms or only require one therapeutic option, while other people develop severe, recurrent, and life-threatening complications and may require repeated and multiple therapies. Consequently, specific therapeutic procedures and interventions will vary, depending upon numerous factors, such as disease stage; tumor size; tumor grade (which is related to how abnormal the tumor cells look under a microscope); the presence or absence of certain symptoms; an individual’s age and general health; and/or other elements. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of their case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors. Therapies used to treat individuals with follicular lymphoma include watch and wait, radiation therapy, immunotherapy, single-agent chemotherapy and multiagent chemotherapy.In select individuals with no symptoms of follicular lymphoma (asymptomatic), physicians may recommend waiting before starting treatment until the disease leads to certain symptoms or progresses. In such instances, thorough, frequent checkups are required to ensure that appropriate therapies are begun when the disease course accelerates. This approach to disease management is often called “watch and wait” or “watchful waiting.” Most affected individuals eventually require systemic treatment. If follicular lymphoma is detected early enough, some affected individuals may be treated with radiation therapy, in which radiation is used to destroy cancerous tissue. Radiation therapy often produces prolonged periods of remission in individuals in early stage (tage I) disease and is frequently used for individuals with early stage disease. Most affected individuals are diagnosed with advanced disease. Advanced disease includes individuals with stage III or IV disease (see Staging above). Affected individuals receive treatment regimens that include a medication known as an anti-CD20 monoclonal antibody. A monoclonal antibody is a type of immune therapy; it uses the immune system to help fight off cancer. CD20 is a substance found on the surface of B-cells. Anti-CD20 monoclonal antibodies are medications that target CD20 and, therefore, target the B-cells in the body, including the cancerous B-cells that make up follicular lymphoma. Two types of anti-CD20 monoclonal antibodies are used to treat adults with follicular lymphoma and are known as rituximab (Rituxan®) and obinutuzumab (Gazyva®). In 1997, the U.S. Food and Drug Administration (FDA) approved rituximab (Rituxan®) for the treatment of individuals with follicular lymphoma that did not respond to other treatments (refractory) or returned after treatment (relapsed). In 2006, rituximab was approved as a first-line therapy for affected individuals. Rituximab can be used alone (as a single agent) as a single-agent therapy. In individuals with bulkier disease or who require a more rapid response (often due to specific symptoms or manifestations), rituximab is used as part of a drug regimen (multiagent chemotherapy) that includes other more traditional chemotherapeutic drugs. The two most popular chemotherapeutic regimens used for follicular lymphoma are bendamustine plus rituximab and CHOP-R. CHOP-R is a common chemotherapeutic regimen used to treat NHL and includes cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone given along with rituximab. Sometimes, other medications may be tried along with rituximab including chlorambucil (Leukeran®) or lenalidomide (Revlimid®). In 2017, the FDA approved obinutuzumab (Gazyva®) along with chemotherapy for the treatment of previously untreated individuals with stage II bulky, stage III, or stage IV follicular lymphoma. While some individuals with follicular lymphoma are cured, the majority of affected individuals will not be cured with initial or follow up therapy. Follicular lymphoma often recurs (relapses). Affected individuals require maintenance therapy. Maintenance therapy is designed to help maintain the effectiveness of a primary therapy in order to keep cancer in remission (i.e. prevent a relapse) and to help minimize side effects of therapy. Both rituximab and obinutuzumab can be used for maintenance therapy. Rituximab and obinutuzumab can also be used to treat follicular lymphoma when the cancer returns after treatment (relapse), or when the cancer does not respond to another type of treatment (refractory). There are additional medications that have been approved for the treatment of relapsed or refractory lymphoma. In 2014, the FDA approved the drug, idelalisib (Zydelig®), for the treatment of adults with follicular lymphoma who have received at least two other therapies. The FDA has also approved the drug copanlisib (Aliqopa®) for the treatment of adults with relapsed follicular lymphoma who have received at least two other systemic treatments. Idelalisib and copanlisib are drugs that inhibit or block that activity of a protein called phosphoinositide 3-kinase. This protein plays a role in the activation, growth and spread, and survival of B-cells. Radioimmunotherapy is also used to treat relapsed or refractory follicular lymphoma. Radioimmunotherapy uses radiation along with cancer-specific antibodies to attack cancer cells. Ibritumomab tiuxetan (Zevalin®) is a monoclonal antibody radioimmunotherapy that was approved by the FDA in 2002 for the treatment of relapsed or refractory, low-grade, follicular or transformed B-cell lymphoma. Ibritumomab tiuxetan has also been used as the sole initial therapy for some people. | Therapies of Follicular Lymphoma. Treatment
The diagnosis and therapeutic management of follicular lymphoma may require the coordinated efforts of a team of medical professionals, such as physicians who specialize in the diagnosis and treatment of cancer (medical oncologists), disorders of the blood and blood-forming tissues (hematologists), or the use of radiation to treat cancers (radiation oncologists); oncology nurses; surgeons; dietitians; and/or other healthcare professionals. Psychosocial support for the entire family is essential as well. Genetic counseling may be recommended for affected individuals and their families. The course of follicular lymphoma is highly variable. The average survival rate is greater than 20 years. Some individuals do not develop symptoms or only require one therapeutic option, while other people develop severe, recurrent, and life-threatening complications and may require repeated and multiple therapies. Consequently, specific therapeutic procedures and interventions will vary, depending upon numerous factors, such as disease stage; tumor size; tumor grade (which is related to how abnormal the tumor cells look under a microscope); the presence or absence of certain symptoms; an individual’s age and general health; and/or other elements. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of their case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors. Therapies used to treat individuals with follicular lymphoma include watch and wait, radiation therapy, immunotherapy, single-agent chemotherapy and multiagent chemotherapy.In select individuals with no symptoms of follicular lymphoma (asymptomatic), physicians may recommend waiting before starting treatment until the disease leads to certain symptoms or progresses. In such instances, thorough, frequent checkups are required to ensure that appropriate therapies are begun when the disease course accelerates. This approach to disease management is often called “watch and wait” or “watchful waiting.” Most affected individuals eventually require systemic treatment. If follicular lymphoma is detected early enough, some affected individuals may be treated with radiation therapy, in which radiation is used to destroy cancerous tissue. Radiation therapy often produces prolonged periods of remission in individuals in early stage (tage I) disease and is frequently used for individuals with early stage disease. Most affected individuals are diagnosed with advanced disease. Advanced disease includes individuals with stage III or IV disease (see Staging above). Affected individuals receive treatment regimens that include a medication known as an anti-CD20 monoclonal antibody. A monoclonal antibody is a type of immune therapy; it uses the immune system to help fight off cancer. CD20 is a substance found on the surface of B-cells. Anti-CD20 monoclonal antibodies are medications that target CD20 and, therefore, target the B-cells in the body, including the cancerous B-cells that make up follicular lymphoma. Two types of anti-CD20 monoclonal antibodies are used to treat adults with follicular lymphoma and are known as rituximab (Rituxan®) and obinutuzumab (Gazyva®). In 1997, the U.S. Food and Drug Administration (FDA) approved rituximab (Rituxan®) for the treatment of individuals with follicular lymphoma that did not respond to other treatments (refractory) or returned after treatment (relapsed). In 2006, rituximab was approved as a first-line therapy for affected individuals. Rituximab can be used alone (as a single agent) as a single-agent therapy. In individuals with bulkier disease or who require a more rapid response (often due to specific symptoms or manifestations), rituximab is used as part of a drug regimen (multiagent chemotherapy) that includes other more traditional chemotherapeutic drugs. The two most popular chemotherapeutic regimens used for follicular lymphoma are bendamustine plus rituximab and CHOP-R. CHOP-R is a common chemotherapeutic regimen used to treat NHL and includes cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone given along with rituximab. Sometimes, other medications may be tried along with rituximab including chlorambucil (Leukeran®) or lenalidomide (Revlimid®). In 2017, the FDA approved obinutuzumab (Gazyva®) along with chemotherapy for the treatment of previously untreated individuals with stage II bulky, stage III, or stage IV follicular lymphoma. While some individuals with follicular lymphoma are cured, the majority of affected individuals will not be cured with initial or follow up therapy. Follicular lymphoma often recurs (relapses). Affected individuals require maintenance therapy. Maintenance therapy is designed to help maintain the effectiveness of a primary therapy in order to keep cancer in remission (i.e. prevent a relapse) and to help minimize side effects of therapy. Both rituximab and obinutuzumab can be used for maintenance therapy. Rituximab and obinutuzumab can also be used to treat follicular lymphoma when the cancer returns after treatment (relapse), or when the cancer does not respond to another type of treatment (refractory). There are additional medications that have been approved for the treatment of relapsed or refractory lymphoma. In 2014, the FDA approved the drug, idelalisib (Zydelig®), for the treatment of adults with follicular lymphoma who have received at least two other therapies. The FDA has also approved the drug copanlisib (Aliqopa®) for the treatment of adults with relapsed follicular lymphoma who have received at least two other systemic treatments. Idelalisib and copanlisib are drugs that inhibit or block that activity of a protein called phosphoinositide 3-kinase. This protein plays a role in the activation, growth and spread, and survival of B-cells. Radioimmunotherapy is also used to treat relapsed or refractory follicular lymphoma. Radioimmunotherapy uses radiation along with cancer-specific antibodies to attack cancer cells. Ibritumomab tiuxetan (Zevalin®) is a monoclonal antibody radioimmunotherapy that was approved by the FDA in 2002 for the treatment of relapsed or refractory, low-grade, follicular or transformed B-cell lymphoma. Ibritumomab tiuxetan has also been used as the sole initial therapy for some people. | 474 | Follicular Lymphoma |
nord_475_0 | Overview of Food Protein-Induced Enterocolitis Syndrome | SummaryFood protein-induced enterocolitis syndrome (FPIES) is an uncommon disorder characterized by an allergic reaction to food that affects the gastrointestinal system. The term enterocolitis specially refers to inflammation of the small and large intestines. Individuals with FPIES experience profuse vomiting and diarrhea that usually develops approximately 2-6 hours after ingesting the offending food. Additional symptoms include pallor, lethargy and abdominal swelling (distension). Symptoms can be severe and can potentially cause acute dehydration and/or hypovolemic shock. The most common triggers for an episode are milk, soy and rice in children, but the disorder has been associated with a wide range of food proteins. In adults, shellfish is the most common trigger food. Many children develop a tolerance to the offending foods by the age of three, however, in some cases, the disorder persists. Removal of the offending food should lead to a complete resolution of symptoms. The exact, underlying immune system mechanisms that are involved in the development of FPIES are unknown.IntroductionSeveral different gastrointestinal disorders in children are believed to be caused by an abnormal immunologic reaction to dietary proteins. They are generally classified into three groups: IgE-mediated (as in classic food allergies), non-IgE-mediated or mixed (a combination of both). IgE stands for immunoglobulin E, an antibody that the immune system creates in response to an allergic reaction and is often implicated in food allergies. Food specific IgE antibodies are typically not involved in FPIES. The disorder is presumed to be cell-mediated. Many researchers consider FPIES the severe end of a spectrum or continuum of disease involving non-IgE-mediated gastrointestinal food allergy disorders. This spectrum also includes proctocolitis and food-protein induced enteropathy. | Overview of Food Protein-Induced Enterocolitis Syndrome. SummaryFood protein-induced enterocolitis syndrome (FPIES) is an uncommon disorder characterized by an allergic reaction to food that affects the gastrointestinal system. The term enterocolitis specially refers to inflammation of the small and large intestines. Individuals with FPIES experience profuse vomiting and diarrhea that usually develops approximately 2-6 hours after ingesting the offending food. Additional symptoms include pallor, lethargy and abdominal swelling (distension). Symptoms can be severe and can potentially cause acute dehydration and/or hypovolemic shock. The most common triggers for an episode are milk, soy and rice in children, but the disorder has been associated with a wide range of food proteins. In adults, shellfish is the most common trigger food. Many children develop a tolerance to the offending foods by the age of three, however, in some cases, the disorder persists. Removal of the offending food should lead to a complete resolution of symptoms. The exact, underlying immune system mechanisms that are involved in the development of FPIES are unknown.IntroductionSeveral different gastrointestinal disorders in children are believed to be caused by an abnormal immunologic reaction to dietary proteins. They are generally classified into three groups: IgE-mediated (as in classic food allergies), non-IgE-mediated or mixed (a combination of both). IgE stands for immunoglobulin E, an antibody that the immune system creates in response to an allergic reaction and is often implicated in food allergies. Food specific IgE antibodies are typically not involved in FPIES. The disorder is presumed to be cell-mediated. Many researchers consider FPIES the severe end of a spectrum or continuum of disease involving non-IgE-mediated gastrointestinal food allergy disorders. This spectrum also includes proctocolitis and food-protein induced enteropathy. | 475 | Food Protein-Induced Enterocolitis Syndrome |
nord_475_1 | Symptoms of Food Protein-Induced Enterocolitis Syndrome | The symptoms and severity of FPIES can vary greatly from one individual to another. Some individuals will experience vomiting and diarrhea that is not severe; other individuals can develop severe, even life-threatening complications due to profuse vomiting, diarrhea and other symptoms. Symptoms may be chronic while the offending food remains part of a child’s diet. Onset is usually during the first year of life, although the disorder can develop later during childhood. Specific rare cases due to fish or mollusks have been identified older children and adults.Vomiting and diarrhea, often profuse and repetitive, are the two most common symptoms associated with FPIES. Vomiting usually occurs 1-4 hours after ingesting the offending food. Diarrhea usually occurs 3-6 hours after ingestion. Bloody diarrhea may occur in severe cases. Additional symptoms often occur including pallor, lethargy, abdominal distension and cyanosis, a condition characterized by abnormal bluish discoloration of the skin due to low levels of circulating oxygen in the blood. Decreased body temperature (hypothermia) and abnormally high numbers of platelets, blood cells that aid the blood to clot (thrombocytosis), have also been reported.Affected infants or children usually recover quickly from an FPIES episode. However, in some cases, an episode can result in severe complications including loss of vital fluids (acute dehydration), low blood pressure (hypotension) and/or hypovolemic shock, a condition in which rapid fluid loss ultimately results in insufficient oxygen delivery to various organs of the body. Hypovolemic shock is an emergency condition that requires immediate medical intervention.Infants or children who have multiple FPIES episodes may experience weight loss and may fail to grow and gain weight at the rate expected based on gender and age (failure to thrive). Most children outgrown FPIES by two or three years of age, however, in some cases the disorder persists.Approximately 30% of affected individuals eventually develop an atopic disorder such as a chronic inflammatory disorder of the skin (atopic dermatitis), asthma or hay fever (allergic rhinitis). Atopic disorders are those that arise because of abnormal immune system responses to environmental allergens. | Symptoms of Food Protein-Induced Enterocolitis Syndrome. The symptoms and severity of FPIES can vary greatly from one individual to another. Some individuals will experience vomiting and diarrhea that is not severe; other individuals can develop severe, even life-threatening complications due to profuse vomiting, diarrhea and other symptoms. Symptoms may be chronic while the offending food remains part of a child’s diet. Onset is usually during the first year of life, although the disorder can develop later during childhood. Specific rare cases due to fish or mollusks have been identified older children and adults.Vomiting and diarrhea, often profuse and repetitive, are the two most common symptoms associated with FPIES. Vomiting usually occurs 1-4 hours after ingesting the offending food. Diarrhea usually occurs 3-6 hours after ingestion. Bloody diarrhea may occur in severe cases. Additional symptoms often occur including pallor, lethargy, abdominal distension and cyanosis, a condition characterized by abnormal bluish discoloration of the skin due to low levels of circulating oxygen in the blood. Decreased body temperature (hypothermia) and abnormally high numbers of platelets, blood cells that aid the blood to clot (thrombocytosis), have also been reported.Affected infants or children usually recover quickly from an FPIES episode. However, in some cases, an episode can result in severe complications including loss of vital fluids (acute dehydration), low blood pressure (hypotension) and/or hypovolemic shock, a condition in which rapid fluid loss ultimately results in insufficient oxygen delivery to various organs of the body. Hypovolemic shock is an emergency condition that requires immediate medical intervention.Infants or children who have multiple FPIES episodes may experience weight loss and may fail to grow and gain weight at the rate expected based on gender and age (failure to thrive). Most children outgrown FPIES by two or three years of age, however, in some cases the disorder persists.Approximately 30% of affected individuals eventually develop an atopic disorder such as a chronic inflammatory disorder of the skin (atopic dermatitis), asthma or hay fever (allergic rhinitis). Atopic disorders are those that arise because of abnormal immune system responses to environmental allergens. | 475 | Food Protein-Induced Enterocolitis Syndrome |
nord_475_2 | Causes of Food Protein-Induced Enterocolitis Syndrome | The exact underlying cause of FPIES is unknown. The disorder occurs due to an improper response of the immune system to proteins found in specific foods. Eating the offending food causes localized inflammation in the small and large intestines. Researchers speculate that this inflammation allows fluids and other substances to pass through the intestinal wall (intestinal permeability and fluid shift).The two most common foods associated with FPIES are cow’s milk and soy. In approximately 40% of cases, affected individuals may have a reaction to both cow’s milk and soy. Solid foods have also been shown to cause FPIES, including foods that are generally not considered allergens. Rice is the most common solid food associated with the disorder. Wheat, chicken, turkey, fish, mollusks, oats, barley, egg whites, vegetables, peanuts, white potatoes and sweet potatoes have also been implicated. Shellfish is the most common trigger food in adults. In recent years, children with FPIES due to ingestion of fruit proteins have also been noted. In approximately 70-90% of cases, individuals react to one to two foods. FPIES is rarely reported in infants that are exclusively breastfed, which suggests that breastfeeding may have a protective effect. Only four cases of exclusively breastfed infants developing FPIES have been reported in the medical literature.The underlying immune system process involved in FPIES is unknown, but the disorder is not IgE-mediated as is commonly found in classic food allergies. The immune system is divided into several components, the combined actions of which are responsible for defending against different infectious agents (i.e., invading microscopic life-forms [microorganisms]). The T cell system (cell-mediated immune response) is responsible for fighting yeast and fungi, several viruses and some bacteria. A cell-mediated immune response does not involve antibodies such as immunoglobulin E. The B cell system (humoral immune response) fights infection caused by other viruses and bacteria. A humoral immune response does include antibodies.Some researchers have speculated that T cells play a central role in the development of the localized inflammation in the intestinal tract that characterizes FPIES, but this theory has not been confirmed. One function of T cells is to produce cytokines, which are specialized proteins secreted from certain immune system cells that either stimulate or inhibit the function of other immune system cells. Cytokines regulate the body’s inflammatory response to disease. Proinflammatory cytokines such as tumor necrosis factor-alpha and thymus and activation regulated chemokine (TARC) may be important factors in the development of FPIES.No specific genetic or environmental factors have been identified that are involved in FPIES. A family history of atopic disease is present in approximately 40-80% of cases.Although IgE-mediated disease is not normally associated with FPIES, some affected individuals have developed a food specific IgE as is seen with classic food allergies. These children tend to have a more prolonged course of the disorder. These cases are termed “atypical FPIES”. | Causes of Food Protein-Induced Enterocolitis Syndrome. The exact underlying cause of FPIES is unknown. The disorder occurs due to an improper response of the immune system to proteins found in specific foods. Eating the offending food causes localized inflammation in the small and large intestines. Researchers speculate that this inflammation allows fluids and other substances to pass through the intestinal wall (intestinal permeability and fluid shift).The two most common foods associated with FPIES are cow’s milk and soy. In approximately 40% of cases, affected individuals may have a reaction to both cow’s milk and soy. Solid foods have also been shown to cause FPIES, including foods that are generally not considered allergens. Rice is the most common solid food associated with the disorder. Wheat, chicken, turkey, fish, mollusks, oats, barley, egg whites, vegetables, peanuts, white potatoes and sweet potatoes have also been implicated. Shellfish is the most common trigger food in adults. In recent years, children with FPIES due to ingestion of fruit proteins have also been noted. In approximately 70-90% of cases, individuals react to one to two foods. FPIES is rarely reported in infants that are exclusively breastfed, which suggests that breastfeeding may have a protective effect. Only four cases of exclusively breastfed infants developing FPIES have been reported in the medical literature.The underlying immune system process involved in FPIES is unknown, but the disorder is not IgE-mediated as is commonly found in classic food allergies. The immune system is divided into several components, the combined actions of which are responsible for defending against different infectious agents (i.e., invading microscopic life-forms [microorganisms]). The T cell system (cell-mediated immune response) is responsible for fighting yeast and fungi, several viruses and some bacteria. A cell-mediated immune response does not involve antibodies such as immunoglobulin E. The B cell system (humoral immune response) fights infection caused by other viruses and bacteria. A humoral immune response does include antibodies.Some researchers have speculated that T cells play a central role in the development of the localized inflammation in the intestinal tract that characterizes FPIES, but this theory has not been confirmed. One function of T cells is to produce cytokines, which are specialized proteins secreted from certain immune system cells that either stimulate or inhibit the function of other immune system cells. Cytokines regulate the body’s inflammatory response to disease. Proinflammatory cytokines such as tumor necrosis factor-alpha and thymus and activation regulated chemokine (TARC) may be important factors in the development of FPIES.No specific genetic or environmental factors have been identified that are involved in FPIES. A family history of atopic disease is present in approximately 40-80% of cases.Although IgE-mediated disease is not normally associated with FPIES, some affected individuals have developed a food specific IgE as is seen with classic food allergies. These children tend to have a more prolonged course of the disorder. These cases are termed “atypical FPIES”. | 475 | Food Protein-Induced Enterocolitis Syndrome |
nord_475_3 | Affects of Food Protein-Induced Enterocolitis Syndrome | FPIES is an uncommon disorder that affects males slightly more often than females. The incidence and prevalence are unknown. Like most allergic disorders, the number of FPIES cases has risen in the last few decades. The variable nature of the disorder, the lack of recognition in the medical community and frequent misdiagnosis make it difficult to determine FPIES true frequency in the general population. The estimate in the United States is 0.28-0.5% and is similar to estimates in Israel and Australia, where the incidence of 0.34%. FPIES most often affects infants or young children. In extremely rare cases, FPIES has developed in older children or adults as a reaction to shellfish. | Affects of Food Protein-Induced Enterocolitis Syndrome. FPIES is an uncommon disorder that affects males slightly more often than females. The incidence and prevalence are unknown. Like most allergic disorders, the number of FPIES cases has risen in the last few decades. The variable nature of the disorder, the lack of recognition in the medical community and frequent misdiagnosis make it difficult to determine FPIES true frequency in the general population. The estimate in the United States is 0.28-0.5% and is similar to estimates in Israel and Australia, where the incidence of 0.34%. FPIES most often affects infants or young children. In extremely rare cases, FPIES has developed in older children or adults as a reaction to shellfish. | 475 | Food Protein-Induced Enterocolitis Syndrome |
nord_475_4 | Related disorders of Food Protein-Induced Enterocolitis Syndrome | Symptoms of the following disorders can be similar to those of FPIES. Comparisons may be useful for a differential diagnosis.There are numerous conditions that can mimic the symptoms of FPIES. Such conditions include eosinophilic gastroenteritis, viral gastrointestinal illness, proctocolitis, food protein-induced enteropathy, sepsis, isomaltose-sucrose deficiency, various metabolic disorders and Celiac disease. Classic food allergies can be distinguished from FPIES by the presence of common, additional symptoms including skin disease (e.g., hives), asthma and rapid swelling of the deep layers of the skin (angioedema). FPIES can also be initially mistaken for certain medical conditions involving the intestines such as intussusception, in which a portion of the intestine folds into another portion. | Related disorders of Food Protein-Induced Enterocolitis Syndrome. Symptoms of the following disorders can be similar to those of FPIES. Comparisons may be useful for a differential diagnosis.There are numerous conditions that can mimic the symptoms of FPIES. Such conditions include eosinophilic gastroenteritis, viral gastrointestinal illness, proctocolitis, food protein-induced enteropathy, sepsis, isomaltose-sucrose deficiency, various metabolic disorders and Celiac disease. Classic food allergies can be distinguished from FPIES by the presence of common, additional symptoms including skin disease (e.g., hives), asthma and rapid swelling of the deep layers of the skin (angioedema). FPIES can also be initially mistaken for certain medical conditions involving the intestines such as intussusception, in which a portion of the intestine folds into another portion. | 475 | Food Protein-Induced Enterocolitis Syndrome |
nord_475_5 | Diagnosis of Food Protein-Induced Enterocolitis Syndrome | FPIES is a clinical diagnosis based upon the exclusion of other causes, identification of characteristic symptoms and a thorough clinical evaluation including a detailed patient history. The absence of symptoms commonly associated with IgE-mediated food allergies including skin reactions, asthma, and angioedema may be indicative of FPIES. Misdiagnosis and delays in diagnosis of FPIES are common.Clinical Testing and Work-up
In some cases, an oral food challenge (OFC) may be used to help obtain a diagnosis of FPIES. An OFC is a procedure in which the suspected offending food is gradually given to an affected child in a controlled clinical environment. An OFC for FPIES is a high-risk procedure that requires medical supervision and is conducted following a specific protocol. In addition to confirming a diagnosis, an OFC may be also used to determine whether FPIES has resolved or persists as an affected child ages. There is debate within the medical community as to whether follow up OFCs are appropriate in children with FPIES.There are no diagnostic tests by either skin or blood test that can identify the foods that might be triggering the cause of disease. | Diagnosis of Food Protein-Induced Enterocolitis Syndrome. FPIES is a clinical diagnosis based upon the exclusion of other causes, identification of characteristic symptoms and a thorough clinical evaluation including a detailed patient history. The absence of symptoms commonly associated with IgE-mediated food allergies including skin reactions, asthma, and angioedema may be indicative of FPIES. Misdiagnosis and delays in diagnosis of FPIES are common.Clinical Testing and Work-up
In some cases, an oral food challenge (OFC) may be used to help obtain a diagnosis of FPIES. An OFC is a procedure in which the suspected offending food is gradually given to an affected child in a controlled clinical environment. An OFC for FPIES is a high-risk procedure that requires medical supervision and is conducted following a specific protocol. In addition to confirming a diagnosis, an OFC may be also used to determine whether FPIES has resolved or persists as an affected child ages. There is debate within the medical community as to whether follow up OFCs are appropriate in children with FPIES.There are no diagnostic tests by either skin or blood test that can identify the foods that might be triggering the cause of disease. | 475 | Food Protein-Induced Enterocolitis Syndrome |
nord_475_6 | Therapies of Food Protein-Induced Enterocolitis Syndrome | Treatment
Removal of the offending food from the diet of an affected individual leads to the disappearance of the symptoms associated with FPIES. Many children will grow out of FPIES over time usually 2/3 of the patients by 2 years of age and most 3-4 years of age.Some infants with FPIES may be treated by being exclusively breastfed. But nutrition status needs to be monitored as many older infants need additional foods to meet caloric intake. In cases where that is not possible or in infants who are on formula, a casein hydroxylase-based formula is recommended or an elemental-amino acid formula. Casein is a milk protein. Hydroxylase means that the protein is broken down (hydrolyzed) so that the infant’s immune system will not detect them as an allergen. Such formulas are specifically designed for infants with an allergy or intolerance to cow’s milk. In some cases, affected infants will not be able to tolerate a casein hydroxylase-based formula and may require an amino acid formula, which does not contain any milk.Severe episodes of FPIES require medical intervention including intravenous fluids. Some physicians use anti-inflammatory drugs known as corticosteroids to help treat affected individuals during an episode. For acute FPIES reactions, some physicians have suggested the use of ondansetron intravenous for acute symptoms of vomiting.Pediatricians, pediatric gastroenterologists, pediatric allergist-immunologists, pediatric nutritionists and other healthcare professionals may need to plan an affected child’s treatment systematically and comprehensively (e.g., such as when to attempt to reintroduce foods into an affected child’s diet). | Therapies of Food Protein-Induced Enterocolitis Syndrome. Treatment
Removal of the offending food from the diet of an affected individual leads to the disappearance of the symptoms associated with FPIES. Many children will grow out of FPIES over time usually 2/3 of the patients by 2 years of age and most 3-4 years of age.Some infants with FPIES may be treated by being exclusively breastfed. But nutrition status needs to be monitored as many older infants need additional foods to meet caloric intake. In cases where that is not possible or in infants who are on formula, a casein hydroxylase-based formula is recommended or an elemental-amino acid formula. Casein is a milk protein. Hydroxylase means that the protein is broken down (hydrolyzed) so that the infant’s immune system will not detect them as an allergen. Such formulas are specifically designed for infants with an allergy or intolerance to cow’s milk. In some cases, affected infants will not be able to tolerate a casein hydroxylase-based formula and may require an amino acid formula, which does not contain any milk.Severe episodes of FPIES require medical intervention including intravenous fluids. Some physicians use anti-inflammatory drugs known as corticosteroids to help treat affected individuals during an episode. For acute FPIES reactions, some physicians have suggested the use of ondansetron intravenous for acute symptoms of vomiting.Pediatricians, pediatric gastroenterologists, pediatric allergist-immunologists, pediatric nutritionists and other healthcare professionals may need to plan an affected child’s treatment systematically and comprehensively (e.g., such as when to attempt to reintroduce foods into an affected child’s diet). | 475 | Food Protein-Induced Enterocolitis Syndrome |
nord_476_0 | Overview of Formaldehyde Poisoning | Formaldehyde Poisoning is a disorder brought about by breathing the fumes of formaldehyde. This can occur while working directly with formaldehyde, or using equipment cleaned with formaldehyde. Major symptoms may include eye, nose, and throat irritation; headaches; and/or skin rashes. | Overview of Formaldehyde Poisoning. Formaldehyde Poisoning is a disorder brought about by breathing the fumes of formaldehyde. This can occur while working directly with formaldehyde, or using equipment cleaned with formaldehyde. Major symptoms may include eye, nose, and throat irritation; headaches; and/or skin rashes. | 476 | Formaldehyde Poisoning |
nord_476_1 | Symptoms of Formaldehyde Poisoning | Symptoms of Formaldehyde Poisoning are varied. There may be eye irritation, breathing problems, skin irritations and headaches. If formaldehyde is swallowed it causes burns to the esophagus and stomach. Poisoning of patients using dialysis machines cleaned with formaldehyde can cause loss of red blood cells (acute hemolysis). In extreme cases Formaldehyde Poisoning may include low blood pressure (hypotension), abnormalities of heart rhythm, irregular breathing, restlessness, unconsciousness and coma. | Symptoms of Formaldehyde Poisoning. Symptoms of Formaldehyde Poisoning are varied. There may be eye irritation, breathing problems, skin irritations and headaches. If formaldehyde is swallowed it causes burns to the esophagus and stomach. Poisoning of patients using dialysis machines cleaned with formaldehyde can cause loss of red blood cells (acute hemolysis). In extreme cases Formaldehyde Poisoning may include low blood pressure (hypotension), abnormalities of heart rhythm, irregular breathing, restlessness, unconsciousness and coma. | 476 | Formaldehyde Poisoning |
nord_476_2 | Causes of Formaldehyde Poisoning | Formaldehyde Poisoning may be caused in a variety of ways. Some people are affected when they work with products made with formaldehyde such as chip board and foam insulation. Persons may be poisoned by accidentally ingesting or swallowing formaldehyde. Breathing the vapors given off by the chemical itself in plants that manufacture it, or by working in areas where formaldehyde is used to produce other products can also cause dangerous physical reactions to the chemical. Poisoning may also occur when the chemical is being administered directly to a patient as formalin soaked packs for cysts. A form of formaldehyde (Formalin) is sometimes used as a cleaning agent for dialysis machines and other hospital equipment, and it must be carefully and completely removed before the equipment can be used on patients in order to avoid Formaldehyde Poisoning. | Causes of Formaldehyde Poisoning. Formaldehyde Poisoning may be caused in a variety of ways. Some people are affected when they work with products made with formaldehyde such as chip board and foam insulation. Persons may be poisoned by accidentally ingesting or swallowing formaldehyde. Breathing the vapors given off by the chemical itself in plants that manufacture it, or by working in areas where formaldehyde is used to produce other products can also cause dangerous physical reactions to the chemical. Poisoning may also occur when the chemical is being administered directly to a patient as formalin soaked packs for cysts. A form of formaldehyde (Formalin) is sometimes used as a cleaning agent for dialysis machines and other hospital equipment, and it must be carefully and completely removed before the equipment can be used on patients in order to avoid Formaldehyde Poisoning. | 476 | Formaldehyde Poisoning |
nord_476_3 | Affects of Formaldehyde Poisoning | Formaldehyde Poisoning affects males and females in equal numbers. People exposed in the workplace are most likely to be affected if they are not protected by appropriate air filtering equipment. | Affects of Formaldehyde Poisoning. Formaldehyde Poisoning affects males and females in equal numbers. People exposed in the workplace are most likely to be affected if they are not protected by appropriate air filtering equipment. | 476 | Formaldehyde Poisoning |
nord_476_4 | Related disorders of Formaldehyde Poisoning | Symptoms of the following disorders can be similar to those of Formaldehyde Poisoning. Comparisons may be useful for a differential diagnosis:Heavy Metal Poisoning is caused by an overexposure to several types of metals. This may occur from industrial exposure, from air or water pollution, or from foods, medicines or improperly coated food containers. Symptoms of metal poisoning vary according to which type of metal overexposure is involved. (For more information on this disorder, choose “Heavy Metal” as your search term in the Rare Disease Database.)Berylliosis is a metal poisoning or allergic disorder caused by exposure to beryllium dust or fumes. It primarily affects the lungs and coughing can become violent and exhausting. Breathing becomes difficult and blood may appear in sputum. The skin may be affected by the appearance of reddened, raised patches. There may be discolored spots on the face, neck, arms, and hands. Lymph nodes near affected skin may become enlarged. (For more information on this disorder, choose “Berylliosis” as your search term in the Rare Disease Database.)Arsenic Poisoning can occur during the use and manufacture of pesticides. The gas from arsenic also has some industrial uses and can also cause airborne poisoning. Overexposure may cause headache, drowsiness, confusion, delirium, seizures and sometimes death. In cases of chronic arsenic poisoning, weakness, muscle aches, chills and fever may develop. (For more information on this disorder, choose “Heavy Metal” as your search term in the Rare Disease Database.) | Related disorders of Formaldehyde Poisoning. Symptoms of the following disorders can be similar to those of Formaldehyde Poisoning. Comparisons may be useful for a differential diagnosis:Heavy Metal Poisoning is caused by an overexposure to several types of metals. This may occur from industrial exposure, from air or water pollution, or from foods, medicines or improperly coated food containers. Symptoms of metal poisoning vary according to which type of metal overexposure is involved. (For more information on this disorder, choose “Heavy Metal” as your search term in the Rare Disease Database.)Berylliosis is a metal poisoning or allergic disorder caused by exposure to beryllium dust or fumes. It primarily affects the lungs and coughing can become violent and exhausting. Breathing becomes difficult and blood may appear in sputum. The skin may be affected by the appearance of reddened, raised patches. There may be discolored spots on the face, neck, arms, and hands. Lymph nodes near affected skin may become enlarged. (For more information on this disorder, choose “Berylliosis” as your search term in the Rare Disease Database.)Arsenic Poisoning can occur during the use and manufacture of pesticides. The gas from arsenic also has some industrial uses and can also cause airborne poisoning. Overexposure may cause headache, drowsiness, confusion, delirium, seizures and sometimes death. In cases of chronic arsenic poisoning, weakness, muscle aches, chills and fever may develop. (For more information on this disorder, choose “Heavy Metal” as your search term in the Rare Disease Database.) | 476 | Formaldehyde Poisoning |
nord_476_5 | Diagnosis of Formaldehyde Poisoning | Diagnosis of Formaldehyde Poisoning. | 476 | Formaldehyde Poisoning |
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nord_476_6 | Therapies of Formaldehyde Poisoning | PreventionStrict control and protective measures must be employed in the workplace to minimize formaldehyde exposure to the lowest possible limits. Employees should follow all workplace and safety guidelines and take any additional, appropriate steps to reduce their exposure. For example, workers who are exposed to formaldehyde must use personal protective equipment as required, such as appropriate face and eye protection, protective aprons and gloves, etc.TreatmentFor affected individuals, there is no specific medication that may oppose the action of the formaldehyde (antidote). The treatment of individuals affected by Formaldehyde Poisoning consists of appropriate symptomatic and supportive measures. Those who have experienced severe formaldehyde exposure must undergo close medical monitoring as required. With prompt, appropriate treatment, most affected individuals experience a full recovery. | Therapies of Formaldehyde Poisoning. PreventionStrict control and protective measures must be employed in the workplace to minimize formaldehyde exposure to the lowest possible limits. Employees should follow all workplace and safety guidelines and take any additional, appropriate steps to reduce their exposure. For example, workers who are exposed to formaldehyde must use personal protective equipment as required, such as appropriate face and eye protection, protective aprons and gloves, etc.TreatmentFor affected individuals, there is no specific medication that may oppose the action of the formaldehyde (antidote). The treatment of individuals affected by Formaldehyde Poisoning consists of appropriate symptomatic and supportive measures. Those who have experienced severe formaldehyde exposure must undergo close medical monitoring as required. With prompt, appropriate treatment, most affected individuals experience a full recovery. | 476 | Formaldehyde Poisoning |
nord_477_0 | Overview of Fountain Syndrome | Fountain syndrome is an extremely rare genetic multisystem disorder that is characterized by intellectual disability; abnormal swelling of the cheeks and lips due to the excessive accumulation of body fluids under the skin (subcutaneous) of the face (edema); skeletal abnormalities; and/or deafness due to malformation of a structure (cochlea) within the inner ear. The exact underlying cause of Fountain syndrome is unknown. The disorder is believed to be inherited as an autosomal recessive trait. | Overview of Fountain Syndrome. Fountain syndrome is an extremely rare genetic multisystem disorder that is characterized by intellectual disability; abnormal swelling of the cheeks and lips due to the excessive accumulation of body fluids under the skin (subcutaneous) of the face (edema); skeletal abnormalities; and/or deafness due to malformation of a structure (cochlea) within the inner ear. The exact underlying cause of Fountain syndrome is unknown. The disorder is believed to be inherited as an autosomal recessive trait. | 477 | Fountain Syndrome |
nord_477_1 | Symptoms of Fountain Syndrome | Although researchers have been able to establish a syndrome with characteristic or “core” symptoms, much about the disorder is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of other genes influencing the disorder prevent physicians from developing a complete picture of associated symptoms and prognosis.In all cases reported in the medical literature, affected individuals have exhibited mild to severe intellectual disability. Individuals with Fountain syndrome may also exhibit several physical abnormalities. For example, fluid may abnormally accumulate under the skin (edema) of the face, especially the lips and cheeks. As a result, the face may appear coarse, abnormally “full,” and swollen. These distinctive facial characteristics may be more pronounced with age. Fountain syndrome may also be characterized by deafness at birth (congenital deafness) due to a defect in a bony spiral organ in the inner ear (cochlea). In this type of deafness, although sound is transmitted normally through the external and middle ear, the cochlear malformation in the inner ear causes the hearing loss (congenital sensorineural deafness). The cochlea normally transforms sound vibrations into nerve impulses that are transmitted to the brain. Because congenital sensorineural deafness results in an inability to hear spoken language, affected infants and children may be unable to develop and comprehend verbal language structure, resulting in an inability to communicate through speech (deaf mutism). Individuals with Fountain syndrome may also have skeletal abnormalities including abnormal thickening of the cap of the skull (calvaria) and/or unusually broad, short, and stubby hands and feet. In addition, in some cases, affected individuals may exhibit extreme front-to-back curvature of the spine (hyperkyphosis) and/or short stature. In some cases, individuals with Fountain syndrome may exhibit additional physical abnormalities. For example, during infancy, some individuals may experience episodes of repeated, uncontrolled electrical disturbances involving both sides of the brain (generalized seizures), be below average height for their age (short stature), an abnormally large head circumference (macrocephaly), and broad, plump hands. | Symptoms of Fountain Syndrome. Although researchers have been able to establish a syndrome with characteristic or “core” symptoms, much about the disorder is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of other genes influencing the disorder prevent physicians from developing a complete picture of associated symptoms and prognosis.In all cases reported in the medical literature, affected individuals have exhibited mild to severe intellectual disability. Individuals with Fountain syndrome may also exhibit several physical abnormalities. For example, fluid may abnormally accumulate under the skin (edema) of the face, especially the lips and cheeks. As a result, the face may appear coarse, abnormally “full,” and swollen. These distinctive facial characteristics may be more pronounced with age. Fountain syndrome may also be characterized by deafness at birth (congenital deafness) due to a defect in a bony spiral organ in the inner ear (cochlea). In this type of deafness, although sound is transmitted normally through the external and middle ear, the cochlear malformation in the inner ear causes the hearing loss (congenital sensorineural deafness). The cochlea normally transforms sound vibrations into nerve impulses that are transmitted to the brain. Because congenital sensorineural deafness results in an inability to hear spoken language, affected infants and children may be unable to develop and comprehend verbal language structure, resulting in an inability to communicate through speech (deaf mutism). Individuals with Fountain syndrome may also have skeletal abnormalities including abnormal thickening of the cap of the skull (calvaria) and/or unusually broad, short, and stubby hands and feet. In addition, in some cases, affected individuals may exhibit extreme front-to-back curvature of the spine (hyperkyphosis) and/or short stature. In some cases, individuals with Fountain syndrome may exhibit additional physical abnormalities. For example, during infancy, some individuals may experience episodes of repeated, uncontrolled electrical disturbances involving both sides of the brain (generalized seizures), be below average height for their age (short stature), an abnormally large head circumference (macrocephaly), and broad, plump hands. | 477 | Fountain Syndrome |
nord_477_2 | Causes of Fountain Syndrome | The exact underlying cause Fountain syndrome is unknown. The disorder is believed to be inherited in an autosomal recessive manner. Genetic diseases are determined by two genes, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. | Causes of Fountain Syndrome. The exact underlying cause Fountain syndrome is unknown. The disorder is believed to be inherited in an autosomal recessive manner. Genetic diseases are determined by two genes, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. | 477 | Fountain Syndrome |
nord_477_3 | Affects of Fountain Syndrome | Fountain syndrome is an extremely rare inherited disorder that is believed to affect males and females in equal numbers. Only several cases have been reported in the medical literature. The exact incidence or prevalence of the disorder is unknown. Because cases may go undiagnosed or misdiagnosed, determining the true frequency of Fountain syndrome in the general population is difficult. | Affects of Fountain Syndrome. Fountain syndrome is an extremely rare inherited disorder that is believed to affect males and females in equal numbers. Only several cases have been reported in the medical literature. The exact incidence or prevalence of the disorder is unknown. Because cases may go undiagnosed or misdiagnosed, determining the true frequency of Fountain syndrome in the general population is difficult. | 477 | Fountain Syndrome |
nord_477_4 | Related disorders of Fountain Syndrome | Symptoms of the following disorders can be similar to those of Fountain syndrome. Comparisons may be useful for a differential diagnosis: Melkersson-Rosenthal syndrome is a rare disorder characterized by swelling in certain areas of the face, particularly the upper and/or lower lips; recurrent loss of motor nerve function in muscles in one or both sides of the face (unilateral or bilateral facial nerve palsy); and/or, in some cases, the presence of deep grooves in the surface of the tongue that may radiate outward. In some cases, the facial swelling may also affect the forehead, eyelids, nose, and/or chin. Facial palsy tends to follow facial swelling, though, in some cases, it may occur before or in association with swelling. In many cases, affected individuals experience temporary, recurrent episodes of facial nerve palsy and swelling. However, in some cases, episodes of swelling may become more persistent and/or, rarely, facial nerve palsy may become permanent. Although the exact cause of Melkersson-Rosenthal syndrome is unknown, it is thought to be inherited as an autosomal dominant genetic trait. (For more information on this disorder, choose “Melkersson-Rosenthal” as your search term in the Rare Disease Database.) There are some additional congenital disorders that may be characterized by intellectual disability occurring in association with coarse, full facial features; skeletal abnormalities; hearing impairment or deafness; and/or other physical abnormalities similar to those potentially associated with Fountain syndrome. (For more information on these disorders, choose the exact disease name in question as your search term in the Rare Disease Database.) | Related disorders of Fountain Syndrome. Symptoms of the following disorders can be similar to those of Fountain syndrome. Comparisons may be useful for a differential diagnosis: Melkersson-Rosenthal syndrome is a rare disorder characterized by swelling in certain areas of the face, particularly the upper and/or lower lips; recurrent loss of motor nerve function in muscles in one or both sides of the face (unilateral or bilateral facial nerve palsy); and/or, in some cases, the presence of deep grooves in the surface of the tongue that may radiate outward. In some cases, the facial swelling may also affect the forehead, eyelids, nose, and/or chin. Facial palsy tends to follow facial swelling, though, in some cases, it may occur before or in association with swelling. In many cases, affected individuals experience temporary, recurrent episodes of facial nerve palsy and swelling. However, in some cases, episodes of swelling may become more persistent and/or, rarely, facial nerve palsy may become permanent. Although the exact cause of Melkersson-Rosenthal syndrome is unknown, it is thought to be inherited as an autosomal dominant genetic trait. (For more information on this disorder, choose “Melkersson-Rosenthal” as your search term in the Rare Disease Database.) There are some additional congenital disorders that may be characterized by intellectual disability occurring in association with coarse, full facial features; skeletal abnormalities; hearing impairment or deafness; and/or other physical abnormalities similar to those potentially associated with Fountain syndrome. (For more information on these disorders, choose the exact disease name in question as your search term in the Rare Disease Database.) | 477 | Fountain Syndrome |
nord_477_5 | Diagnosis of Fountain Syndrome | Fountain syndrome is usually diagnosed during infancy or early childhood, based upon a thorough clinical evaluation, characteristic physical findings, and a variety of specialized tests. Clinical Testing and Workup
Various audiological tests may be conducted to help assess the nature of the hearing loss, and an X-ray scanning procedure (computerized tomography or CT scan) may be performed to confirm inner ear (i.e., cochlear) malformation as the cause of sensorineural deafness in individuals with Fountain syndrome. During such CT scanning, a computer and X-rays are used to create a film showing cross-sectional images of the structures of the inner ear. X-ray studies may also be used to confirm the presence of certain skeletal abnormalities suspected during clinical observation. If affected infants experience seizures, a complete neurological evaluation may be conducted including electroencephalography (EEG) and CT scanning. During an EEG, the brain's electrical impulses are recorded; such studies may reveal brain wave patterns that are characteristic of certain types of seizures. CT scanning may be used to create cross-sectional images of the brain's tissue structure. | Diagnosis of Fountain Syndrome. Fountain syndrome is usually diagnosed during infancy or early childhood, based upon a thorough clinical evaluation, characteristic physical findings, and a variety of specialized tests. Clinical Testing and Workup
Various audiological tests may be conducted to help assess the nature of the hearing loss, and an X-ray scanning procedure (computerized tomography or CT scan) may be performed to confirm inner ear (i.e., cochlear) malformation as the cause of sensorineural deafness in individuals with Fountain syndrome. During such CT scanning, a computer and X-rays are used to create a film showing cross-sectional images of the structures of the inner ear. X-ray studies may also be used to confirm the presence of certain skeletal abnormalities suspected during clinical observation. If affected infants experience seizures, a complete neurological evaluation may be conducted including electroencephalography (EEG) and CT scanning. During an EEG, the brain's electrical impulses are recorded; such studies may reveal brain wave patterns that are characteristic of certain types of seizures. CT scanning may be used to create cross-sectional images of the brain's tissue structure. | 477 | Fountain Syndrome |
nord_477_6 | Therapies of Fountain Syndrome | Treatment
The treatment of Fountain syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the efforts of a team of specialists working together to systematically and comprehensively plan an affected child's treatment. Such specialists may include pediatricians; physicians who diagnose and treat disorders of the ears, nose, and throat (otolaryngologists); specialists who assess and treat hearing problems (audiologists); those who specialize in abnormalities of speech and language development (speech-language pathologists); specialists who diagnose and treat skeletal disorders (orthopedists); neurologists; physical therapists; surgeons; and/or other health care professionals. Genetic counseling may also be of benefit for affected individuals and their families.Specific therapies for the treatment of Fountain syndrome are symptomatic and supportive. In some cases, various orthopedic techniques may be used to help treat and/or correct skeletal abnormalities associated with Fountain syndrome. For example, extreme front-to-back curvature of the spine (kyphosis) may be treated with a combination of exercises and physical therapy, other supportive techniques, braces, and/or casts. For individuals with Fountain syndrome who experience generalized infantile seizures, anticonvulsant drug therapy may be prescribed to help prevent, reduce, or control such seizures. Early intervention is important in ensuring that children with Fountain syndrome reach their potential. Services that may be beneficial may include special remedial education, special services for children with congenital sensorineural deafness and mutism, and other medical, social, and/or vocational services. | Therapies of Fountain Syndrome. Treatment
The treatment of Fountain syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the efforts of a team of specialists working together to systematically and comprehensively plan an affected child's treatment. Such specialists may include pediatricians; physicians who diagnose and treat disorders of the ears, nose, and throat (otolaryngologists); specialists who assess and treat hearing problems (audiologists); those who specialize in abnormalities of speech and language development (speech-language pathologists); specialists who diagnose and treat skeletal disorders (orthopedists); neurologists; physical therapists; surgeons; and/or other health care professionals. Genetic counseling may also be of benefit for affected individuals and their families.Specific therapies for the treatment of Fountain syndrome are symptomatic and supportive. In some cases, various orthopedic techniques may be used to help treat and/or correct skeletal abnormalities associated with Fountain syndrome. For example, extreme front-to-back curvature of the spine (kyphosis) may be treated with a combination of exercises and physical therapy, other supportive techniques, braces, and/or casts. For individuals with Fountain syndrome who experience generalized infantile seizures, anticonvulsant drug therapy may be prescribed to help prevent, reduce, or control such seizures. Early intervention is important in ensuring that children with Fountain syndrome reach their potential. Services that may be beneficial may include special remedial education, special services for children with congenital sensorineural deafness and mutism, and other medical, social, and/or vocational services. | 477 | Fountain Syndrome |
nord_478_0 | Overview of Fournier Gangrene | Fournier gangrene is an acute necrotic infection of the scrotum; penis; or perineum. It is characterized by scrotum pain and redness with rapid progression to gangrene and sloughing of tissue. Fournier gangrene is usually secondary to perirectal or periurethral infections associated with local trauma, operative procedures, or urinary tract disease.Since 1950, more than 1,800 cases for study have been reported in English language medical literature. This disease occurs worldwide and, although it is recognized more frequently among male adults, has been identified also among women and children. Treatment usually consists of the surgical removal (debridement) of extensive areas of dead tissue (necrosis, necrotic) and the administration of broad-spectrum intravenous antibiotics. Surgical reconstruction may follow where necessary. | Overview of Fournier Gangrene. Fournier gangrene is an acute necrotic infection of the scrotum; penis; or perineum. It is characterized by scrotum pain and redness with rapid progression to gangrene and sloughing of tissue. Fournier gangrene is usually secondary to perirectal or periurethral infections associated with local trauma, operative procedures, or urinary tract disease.Since 1950, more than 1,800 cases for study have been reported in English language medical literature. This disease occurs worldwide and, although it is recognized more frequently among male adults, has been identified also among women and children. Treatment usually consists of the surgical removal (debridement) of extensive areas of dead tissue (necrosis, necrotic) and the administration of broad-spectrum intravenous antibiotics. Surgical reconstruction may follow where necessary. | 478 | Fournier Gangrene |
nord_478_1 | Symptoms of Fournier Gangrene | Symptoms include fever, general discomfort (malaise), moderate to severe pain and swelling in the genital and anal areas (perineal) followed by rankness and smell of the affected tissues (fetid suppuration) leading to full blown (fulminating) gangrene. Rubbing the affected area yields the distinct sounds (crepitus) of gas in the wound and of tissues moving against one another (palpable crepitus). In severe cases, the death of tissue can extend to parts of the thighs, through the abdominal wall and up to the chest wall.This disease is commonly found in conjunction with other disorders (comorbidity), especially those that weaken the immune system. Some disorders that increase the predisposition to Fournier gangrene are diabetes mellitus, profound obesity, cirrhosis, interference with the blood supply to the pelvis, and various malignancies. | Symptoms of Fournier Gangrene. Symptoms include fever, general discomfort (malaise), moderate to severe pain and swelling in the genital and anal areas (perineal) followed by rankness and smell of the affected tissues (fetid suppuration) leading to full blown (fulminating) gangrene. Rubbing the affected area yields the distinct sounds (crepitus) of gas in the wound and of tissues moving against one another (palpable crepitus). In severe cases, the death of tissue can extend to parts of the thighs, through the abdominal wall and up to the chest wall.This disease is commonly found in conjunction with other disorders (comorbidity), especially those that weaken the immune system. Some disorders that increase the predisposition to Fournier gangrene are diabetes mellitus, profound obesity, cirrhosis, interference with the blood supply to the pelvis, and various malignancies. | 478 | Fournier Gangrene |
nord_478_2 | Causes of Fournier Gangrene | Portals of entry for the bacteria, fungi, and/or viruses responsible for a particular case of Fournier gangrene are generally colorectal, urogenital or cutaneous in origin. Anorectal abscesses, urinary tract infections, surgical instrumentation and other contributing factors have all been implicated. Some cases continue to be of unknown cause (idiopathic). Why this process occasionally develops in individuals with common ailments is still not understood.There are many ways for the virulent microorganism to gain access to the host, where the compromised immunological system is unable to prevent the infection from taking hold. The virulence of the resulting disorder is thought to be enhanced by the toxins and enzymes produced by the combination of microorganisms (synergy). | Causes of Fournier Gangrene. Portals of entry for the bacteria, fungi, and/or viruses responsible for a particular case of Fournier gangrene are generally colorectal, urogenital or cutaneous in origin. Anorectal abscesses, urinary tract infections, surgical instrumentation and other contributing factors have all been implicated. Some cases continue to be of unknown cause (idiopathic). Why this process occasionally develops in individuals with common ailments is still not understood.There are many ways for the virulent microorganism to gain access to the host, where the compromised immunological system is unable to prevent the infection from taking hold. The virulence of the resulting disorder is thought to be enhanced by the toxins and enzymes produced by the combination of microorganisms (synergy). | 478 | Fournier Gangrene |
nord_478_3 | Affects of Fournier Gangrene | The mean age of presentation is about 50 years, but the range of patient ages in reported cases is from eight days to 90 years. Fournier gangrene is diagnosed more frequently among males. It may be that the high male to female ratio in the diagnosis is the result of the lack of recognition of this entity among women by physicians. It is believed that the male to female proportion may be anywhere from 5:1 to 10:1. | Affects of Fournier Gangrene. The mean age of presentation is about 50 years, but the range of patient ages in reported cases is from eight days to 90 years. Fournier gangrene is diagnosed more frequently among males. It may be that the high male to female ratio in the diagnosis is the result of the lack of recognition of this entity among women by physicians. It is believed that the male to female proportion may be anywhere from 5:1 to 10:1. | 478 | Fournier Gangrene |
nord_478_4 | Related disorders of Fournier Gangrene | Symptoms of the following disorders can be similar to those of Fournier gangrene. Comparisons may be useful for a differential diagnosis.Epididymitis is inflammation of the long, tightly coiled tube behind each testicle (epididymis) that carries sperm from the testicle to the spermatic duct. Affected individuals usually have painful swelling of the one epididymitis and the associated testicle. In some cases, the second testicle may also be tender. In addition, affected individuals have fever, painful swelling and redness (erythema) of the scrotum, and/or inflammation of the tube from which urine is carried from the bladder (urethritis). The two main forms of epididymitis are the sexually-transmitted form and the nonspecific bacterial form. (For more information on this disorder, choose “Epididymitis” as your search term in the Rare Disease Database.)Gas gangrene is a severe form of tissue death usually caused by bacteria that do not need oxygen (anaerobes) to survive, such as Clostridium perfringens. It can also result from infections caused by Group A Streptococcus bacteria and Staphlococcus aureus and Vibrio vulnificus. Clostridium bacteria in an environment of low oxygen concentration produce toxins that cause tissue death and associated symptoms. Gas gangrene is rare, with only 1,000 to 3,000 cases occurring in the United States annually.Hydrocele is a fluid-filled sack along the spermatic cord within the scrotum. Hydroceles are common in the newborn infant. They may be unilateral or bilateral and result when there is failure of the tract through which the testis descends from the abdomen into the scrotum to close. Peritoneal fluid drains through the open tract from the abdomen into the scrotum where it becomes trapped causing enlargement of the scrotum. Hydroceles may also be caused by inflammation or trauma of the testicle or epididymis or by fluid or blood obstruction within the spermatic cord. The incidence of this type of hydrocele is higher in older men.Orchitis is an inflammation of one or both of the testicles, often caused by infection. Orchitis may be caused by numerous bacterial and viral organisms. It is usually a consequence of epididymitis (see above). The most common viral cause of orchitis is mumps. Approximately 30% of patients who have mumps will develop orchitis during the course of the illness. It is most common in post-pubertal boys (rare before 10 years of age). It usually manifests 4 to 6 days after the onset of mumps. In one-third of boys who get orchitis caused by mumps, testicular atrophy (shrinking of the testicles) will result.Debilitating illnesses, such as diabetes, alcoholism, HIV infection, and malnutrition seem to increase the susceptibility of a person to Fournier gangrene but are not related disorders. | Related disorders of Fournier Gangrene. Symptoms of the following disorders can be similar to those of Fournier gangrene. Comparisons may be useful for a differential diagnosis.Epididymitis is inflammation of the long, tightly coiled tube behind each testicle (epididymis) that carries sperm from the testicle to the spermatic duct. Affected individuals usually have painful swelling of the one epididymitis and the associated testicle. In some cases, the second testicle may also be tender. In addition, affected individuals have fever, painful swelling and redness (erythema) of the scrotum, and/or inflammation of the tube from which urine is carried from the bladder (urethritis). The two main forms of epididymitis are the sexually-transmitted form and the nonspecific bacterial form. (For more information on this disorder, choose “Epididymitis” as your search term in the Rare Disease Database.)Gas gangrene is a severe form of tissue death usually caused by bacteria that do not need oxygen (anaerobes) to survive, such as Clostridium perfringens. It can also result from infections caused by Group A Streptococcus bacteria and Staphlococcus aureus and Vibrio vulnificus. Clostridium bacteria in an environment of low oxygen concentration produce toxins that cause tissue death and associated symptoms. Gas gangrene is rare, with only 1,000 to 3,000 cases occurring in the United States annually.Hydrocele is a fluid-filled sack along the spermatic cord within the scrotum. Hydroceles are common in the newborn infant. They may be unilateral or bilateral and result when there is failure of the tract through which the testis descends from the abdomen into the scrotum to close. Peritoneal fluid drains through the open tract from the abdomen into the scrotum where it becomes trapped causing enlargement of the scrotum. Hydroceles may also be caused by inflammation or trauma of the testicle or epididymis or by fluid or blood obstruction within the spermatic cord. The incidence of this type of hydrocele is higher in older men.Orchitis is an inflammation of one or both of the testicles, often caused by infection. Orchitis may be caused by numerous bacterial and viral organisms. It is usually a consequence of epididymitis (see above). The most common viral cause of orchitis is mumps. Approximately 30% of patients who have mumps will develop orchitis during the course of the illness. It is most common in post-pubertal boys (rare before 10 years of age). It usually manifests 4 to 6 days after the onset of mumps. In one-third of boys who get orchitis caused by mumps, testicular atrophy (shrinking of the testicles) will result.Debilitating illnesses, such as diabetes, alcoholism, HIV infection, and malnutrition seem to increase the susceptibility of a person to Fournier gangrene but are not related disorders. | 478 | Fournier Gangrene |
nord_478_5 | Diagnosis of Fournier Gangrene | The diagnosis is basically made on clinical findings. Ultrasound evaluation may achieve early differentiation between Fournier gangrene and an acute inflammatory process, such as epididymitis or orchitis. Computed tomography may help to determine the portal of entry and extension of the process, but is not indispensable and should not delay surgical treatment.X-ray studies are useful to confirm the location and extent of gas distribution in the wounds. Ultrasonography is useful to detect gases and/or fluids, but patients with severe pain may not be able to tolerate the pressures on the skin required to obtain an acceptable image. Computerized tomographic (CT) images are preferred because they resolve smaller amounts of soft tissue gases and fluids. | Diagnosis of Fournier Gangrene. The diagnosis is basically made on clinical findings. Ultrasound evaluation may achieve early differentiation between Fournier gangrene and an acute inflammatory process, such as epididymitis or orchitis. Computed tomography may help to determine the portal of entry and extension of the process, but is not indispensable and should not delay surgical treatment.X-ray studies are useful to confirm the location and extent of gas distribution in the wounds. Ultrasonography is useful to detect gases and/or fluids, but patients with severe pain may not be able to tolerate the pressures on the skin required to obtain an acceptable image. Computerized tomographic (CT) images are preferred because they resolve smaller amounts of soft tissue gases and fluids. | 478 | Fournier Gangrene |
nord_478_6 | Therapies of Fournier Gangrene | TreatmentIt is critical to recognize the disorder and to initiate aggressive resuscitation and administration of broad-spectrum intravenous antibiotics as quickly as possible. Such antibiotics must be followed by urgent surgical debridement of all affected dead (necrotic) skin and subcutaneous tissue involved, with repeated removal of wound margins as necessary. If colorectal or urogenital origin is established, source control is imperative, in accordance with each case. Patients with severe blood infection (sepsis) are at increased risk for developing blood clots (thrombembolic phenomena) and may require medication to reduce the risk for thrombosis Reconstructive surgery is undertaken, once infection is under control.Colostomy remains controversial as a means of decreasing fecal contamination. Foley catheters generally get rid of urine adequately.When available, a burn center may be a good location for the treatment of patients with necrotizing soft-tissue surgical infections, including Fournier gangrene. | Therapies of Fournier Gangrene. TreatmentIt is critical to recognize the disorder and to initiate aggressive resuscitation and administration of broad-spectrum intravenous antibiotics as quickly as possible. Such antibiotics must be followed by urgent surgical debridement of all affected dead (necrotic) skin and subcutaneous tissue involved, with repeated removal of wound margins as necessary. If colorectal or urogenital origin is established, source control is imperative, in accordance with each case. Patients with severe blood infection (sepsis) are at increased risk for developing blood clots (thrombembolic phenomena) and may require medication to reduce the risk for thrombosis Reconstructive surgery is undertaken, once infection is under control.Colostomy remains controversial as a means of decreasing fecal contamination. Foley catheters generally get rid of urine adequately.When available, a burn center may be a good location for the treatment of patients with necrotizing soft-tissue surgical infections, including Fournier gangrene. | 478 | Fournier Gangrene |
nord_479_0 | Overview of Fox Fordyce Disease | Fox-Fordyce disease is a rare skin disorder that primarily affects women. The disorder is characterized by intense itching especially in the underarm area, the pubic area and around the nipples. In Fox-Fordyce disease abnormalities affecting the apocrine sweat glands causes inflammation, and enlargement of the glands and the characteristic intense itching. Skin near an affected area may become darkened and dry and multiple, small, raised bumps (papules) may develop. Hair follicles in the affected area can become secondarily damaged, resulting in hair loss. The exact cause of Fox-Fordyce disease is unknown. | Overview of Fox Fordyce Disease. Fox-Fordyce disease is a rare skin disorder that primarily affects women. The disorder is characterized by intense itching especially in the underarm area, the pubic area and around the nipples. In Fox-Fordyce disease abnormalities affecting the apocrine sweat glands causes inflammation, and enlargement of the glands and the characteristic intense itching. Skin near an affected area may become darkened and dry and multiple, small, raised bumps (papules) may develop. Hair follicles in the affected area can become secondarily damaged, resulting in hair loss. The exact cause of Fox-Fordyce disease is unknown. | 479 | Fox Fordyce Disease |
nord_479_1 | Symptoms of Fox Fordyce Disease | The symptoms of Fox-Fordyce disease may appear suddenly usually following conditions of heat, humidity or friction. The disease is characterized by an eruption of multiple, small, raised bumps on the skin near the apocrine glands. The apocrine glands are specialized sweat glands that play a pheromonic role in animals; a similar role has been postulated in humans. Pheromones are chemicals secreted by animals that influence social or sexual behavior of other animals of that species. Apocrine glands respond to sex and stress stimuli. Apocrine glands become extremely active during puberty. Most apocrine glands are found in the armpits or the groin. They may also be found by the nipples, external ear canal, eyelids, and around the bellybutton. The papules are usually skin-colored, but may be yellowish or reddish in color. They are usually dome-shaped and smooth. Affected areas usually have many small papules. Papules are most often found in the armpits (axillae). The affected areas are often extremely itchy (pruritus) and sweating in these areas may also be absent (anhidrosis). Itching may be mild or may be severe enough to disturb sleep. Hairs within follicles in the affected area may fall out. | Symptoms of Fox Fordyce Disease. The symptoms of Fox-Fordyce disease may appear suddenly usually following conditions of heat, humidity or friction. The disease is characterized by an eruption of multiple, small, raised bumps on the skin near the apocrine glands. The apocrine glands are specialized sweat glands that play a pheromonic role in animals; a similar role has been postulated in humans. Pheromones are chemicals secreted by animals that influence social or sexual behavior of other animals of that species. Apocrine glands respond to sex and stress stimuli. Apocrine glands become extremely active during puberty. Most apocrine glands are found in the armpits or the groin. They may also be found by the nipples, external ear canal, eyelids, and around the bellybutton. The papules are usually skin-colored, but may be yellowish or reddish in color. They are usually dome-shaped and smooth. Affected areas usually have many small papules. Papules are most often found in the armpits (axillae). The affected areas are often extremely itchy (pruritus) and sweating in these areas may also be absent (anhidrosis). Itching may be mild or may be severe enough to disturb sleep. Hairs within follicles in the affected area may fall out. | 479 | Fox Fordyce Disease |
nord_479_2 | Causes of Fox Fordyce Disease | The exact cause of Fox-Fordyce disease is unknown. Researchers have speculated that obstruction of the apocrine gland ducts is necessary for the development of Fox-Fordyce disease, but studies have not been able to definitely confirm this theory. Researchers speculate that blocked ducts rupture causing inflammation where the duct comes close to the hair follicle. The inflammatory reaction around hair follicles includes specialized leukocytes (white blood cells) that engulf extruded secretory debris.Researchers have also speculated that additional factors such as hormonal or genetic ones may play a role in the development of Fox-Fordyce disease. However, research into the cause(s) of Fox-Fordyce disease has not yielded any definitive answers as yet. More research is necessary to determine the exact cause of Fox-Fordyce disease. | Causes of Fox Fordyce Disease. The exact cause of Fox-Fordyce disease is unknown. Researchers have speculated that obstruction of the apocrine gland ducts is necessary for the development of Fox-Fordyce disease, but studies have not been able to definitely confirm this theory. Researchers speculate that blocked ducts rupture causing inflammation where the duct comes close to the hair follicle. The inflammatory reaction around hair follicles includes specialized leukocytes (white blood cells) that engulf extruded secretory debris.Researchers have also speculated that additional factors such as hormonal or genetic ones may play a role in the development of Fox-Fordyce disease. However, research into the cause(s) of Fox-Fordyce disease has not yielded any definitive answers as yet. More research is necessary to determine the exact cause of Fox-Fordyce disease. | 479 | Fox Fordyce Disease |
nord_479_3 | Affects of Fox Fordyce Disease | Fox-Fordyce disease occurs primarily in women between 13 and 35 years of age. However, in rare cases, it can affect men and children and women who are post-menopausal. Some reports place the ration of affected women to men at 9:1. The incidence of Fox-Fordyce disease is unknown. Heat, humidity, stress and exercise have been noted as exacerbating factors. In addition, Fox-Fordyce disease may be more severe during menstruation and tends to disappear (spontaneously resolve) during pregnancy. Fox-Fordyce disease was first described in the medical literature in 1902. | Affects of Fox Fordyce Disease. Fox-Fordyce disease occurs primarily in women between 13 and 35 years of age. However, in rare cases, it can affect men and children and women who are post-menopausal. Some reports place the ration of affected women to men at 9:1. The incidence of Fox-Fordyce disease is unknown. Heat, humidity, stress and exercise have been noted as exacerbating factors. In addition, Fox-Fordyce disease may be more severe during menstruation and tends to disappear (spontaneously resolve) during pregnancy. Fox-Fordyce disease was first described in the medical literature in 1902. | 479 | Fox Fordyce Disease |
nord_479_4 | Related disorders of Fox Fordyce Disease | Symptoms of the following disorders can be similar to those of Fox-Fordyce disease. Comparisons may be useful for a differential diagnosis.Hidradenitis suppurativa is a chronic, pus-producing (suppurative), scarring (cicatricial) disease process that occurs due to obstruction of hair follicles and secondary infection and inflammation of certain sweat glands (apocrine glands), particularly those under the arms (axillae) or within the anal/genital (anogenital) region. The disease is characterized by the development of recurrent, boil-like nodular lesions and deep pus-containing pockets of infection (abscesses) that may eventually rupture through the skin. Healing of affected areas is typically associated with progressive scarring (fibrosis). The specific underlying cause of hidradentitis suppurativa is unknown. (For more information on this disorder, choose “hidradentitis suppurativa” as your search term in the Rare Disease Database.)Keratosis follicularis, also known as Darier disease, is a rare, genetic skin disorder. Affected individuals develop skin lesions that consist of thickened, rough bumps (papules) or plaques that may also be greasy or have a brown or yellow crust. These hardened, scaly lesions are progressive and may gradually grow bigger or spread. The nails and mucous membranes are also affected in many cases. Additional symptoms may be present in some cases. Individuals may have periods of time when signs improve (remission), but the lesions usually recur (relapse). The specific problems vary from one individual to another. Keratosis follicularis is inherited as an autosomal dominant trait. (For more information on this disorder, choose “keratosis follicularis” as your search term in the Rare Disease Database.)Hailey-Hailey disease is a rare genetic disorder that is characterized by blisters and lesions most often affecting the neck, armpits, skin folds and genitals. The lesions may come and go and usually heal without scarring. Heat, sweating and friction often aggravate the disorder. The symptoms of Hailey-Hailey disease occur because of the failure of skin cells to stick together resulting in the breakdown of affected skin layers. Hailey-Hailey disease occurs due to a mutation in a specific gene that creates a protein that is essential for the proper health of skin. The disorder becomes apparent after puberty, usually by the third or fourth decade, but symptoms can develop at any age. (For more information on this disorder, choose “Hailey-Hailey” as your search term in the Rare Disease Database.)Miliaria is a common occurrence and is usually known as “heat rash”. The sweat gland is blocked and fluid is trapped in the surrounding area. There are various types. However, they do not involve the hair follicle and do not result in hair loss. Cooling the patient with water or compresses or putting them in a cooler place usually results in the disappearance of the rash. | Related disorders of Fox Fordyce Disease. Symptoms of the following disorders can be similar to those of Fox-Fordyce disease. Comparisons may be useful for a differential diagnosis.Hidradenitis suppurativa is a chronic, pus-producing (suppurative), scarring (cicatricial) disease process that occurs due to obstruction of hair follicles and secondary infection and inflammation of certain sweat glands (apocrine glands), particularly those under the arms (axillae) or within the anal/genital (anogenital) region. The disease is characterized by the development of recurrent, boil-like nodular lesions and deep pus-containing pockets of infection (abscesses) that may eventually rupture through the skin. Healing of affected areas is typically associated with progressive scarring (fibrosis). The specific underlying cause of hidradentitis suppurativa is unknown. (For more information on this disorder, choose “hidradentitis suppurativa” as your search term in the Rare Disease Database.)Keratosis follicularis, also known as Darier disease, is a rare, genetic skin disorder. Affected individuals develop skin lesions that consist of thickened, rough bumps (papules) or plaques that may also be greasy or have a brown or yellow crust. These hardened, scaly lesions are progressive and may gradually grow bigger or spread. The nails and mucous membranes are also affected in many cases. Additional symptoms may be present in some cases. Individuals may have periods of time when signs improve (remission), but the lesions usually recur (relapse). The specific problems vary from one individual to another. Keratosis follicularis is inherited as an autosomal dominant trait. (For more information on this disorder, choose “keratosis follicularis” as your search term in the Rare Disease Database.)Hailey-Hailey disease is a rare genetic disorder that is characterized by blisters and lesions most often affecting the neck, armpits, skin folds and genitals. The lesions may come and go and usually heal without scarring. Heat, sweating and friction often aggravate the disorder. The symptoms of Hailey-Hailey disease occur because of the failure of skin cells to stick together resulting in the breakdown of affected skin layers. Hailey-Hailey disease occurs due to a mutation in a specific gene that creates a protein that is essential for the proper health of skin. The disorder becomes apparent after puberty, usually by the third or fourth decade, but symptoms can develop at any age. (For more information on this disorder, choose “Hailey-Hailey” as your search term in the Rare Disease Database.)Miliaria is a common occurrence and is usually known as “heat rash”. The sweat gland is blocked and fluid is trapped in the surrounding area. There are various types. However, they do not involve the hair follicle and do not result in hair loss. Cooling the patient with water or compresses or putting them in a cooler place usually results in the disappearance of the rash. | 479 | Fox Fordyce Disease |
nord_479_5 | Diagnosis of Fox Fordyce Disease | A diagnosis of Fox-Fordyce disease is made based upon identification of characteristic symptoms (i.e., papular eruptions on apocrine gland areas), a detailed patient history, and a thorough clinical evaluation. Surgical removal and microscopic evaluation (biopsy) of affected tissue may be useful in obtaining a diagnosis. An experienced dermatopathologist will be necessary to correctly diagnose the disease from a biopsy. | Diagnosis of Fox Fordyce Disease. A diagnosis of Fox-Fordyce disease is made based upon identification of characteristic symptoms (i.e., papular eruptions on apocrine gland areas), a detailed patient history, and a thorough clinical evaluation. Surgical removal and microscopic evaluation (biopsy) of affected tissue may be useful in obtaining a diagnosis. An experienced dermatopathologist will be necessary to correctly diagnose the disease from a biopsy. | 479 | Fox Fordyce Disease |
nord_479_6 | Therapies of Fox Fordyce Disease | TreatmentThe treatment of Fox-Fordyce disease is directed toward the specific symptoms that are apparent in each individual. Consultation with a dermatologist is recommended. Specific therapies that have been used include estrogen hormones, oral retinoids, steroid creams, and topical antibiotics. No therapy is universally effective in all patients.Estrogen hormones, usually given as part of estrogen-based oral contraceptives, have been most effective in treating women with Fox-Fordyce disease. Less effective therapies include oral retinoids (such as tretinoin), corticosteroid creams and topical antibiotics (such as clindamycin) have been beneficial in some cases while ineffective in others. Some of these therapies may be associated with irritation, limiting their ability to be used a long-term therapy.Some women with Fox-Fordyce disease see a significant improvement or resolution of the disease during pregnancy. | Therapies of Fox Fordyce Disease. TreatmentThe treatment of Fox-Fordyce disease is directed toward the specific symptoms that are apparent in each individual. Consultation with a dermatologist is recommended. Specific therapies that have been used include estrogen hormones, oral retinoids, steroid creams, and topical antibiotics. No therapy is universally effective in all patients.Estrogen hormones, usually given as part of estrogen-based oral contraceptives, have been most effective in treating women with Fox-Fordyce disease. Less effective therapies include oral retinoids (such as tretinoin), corticosteroid creams and topical antibiotics (such as clindamycin) have been beneficial in some cases while ineffective in others. Some of these therapies may be associated with irritation, limiting their ability to be used a long-term therapy.Some women with Fox-Fordyce disease see a significant improvement or resolution of the disease during pregnancy. | 479 | Fox Fordyce Disease |
nord_480_0 | Overview of Fragile X Syndrome | Fragile X syndrome is characterized by moderate intellectual disability in affected males and mild intellectual disability in affected females. Distinctive physical features are sometimes present in affected males including a large head, long face, prominent forehead and chin, protruding ears, loose joints and large testes, but these features develop over time and may not be obvious until puberty. Motor and language delays are usually present but also become more apparent over time. Behavioral abnormalities including autistic behaviors are common.Fragile X syndrome has been found in all major ethnic groups and races, and is caused by an abnormality (mutation) in the FMR1 gene. FMR1 is a gene located on the X chromosome that produces a protein called FMRP needed for proper cell function. The syndrome became known as the fragile X syndrome because some individuals with the disorder were found to have a segment of their X chromosome that appeared to be broken or fragile (although not completely disconnected). Later it was learned that the FMR1 gene is located precisely where the X chromosome appears to be “fragile” in affected individuals.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 Xq27.3” refers to band 27.3 on the long arm of the X chromosome where the FMR1 gene is located. The numbered bands specify the location of the thousands of genes that are present on each chromosome.X-linked dominant disorders such as fragile X syndrome are caused by an abnormal gene located on the X chromosome. Females with the abnormal gene may be affected by this disorder. Males are usually more severely affected than females).It is the absence or severe reduction of the protein made by the FMR1 gene, FMRP, that causes fragile X syndrome. Mutation of the FMR1 gene causes the loss or reduction of FMRP. Nearly all affected individuals have an instability within the gene leading to an increased number of copies of a portion of the gene called the CGG repeat region (also sometimes called “trinucleotide” or “triplet” repeat region). When greater than 200 repeats are present, abnormal chemical changes occur in FMR1 called methylation. The expansion of the CGG repeat region to greater than 200 repeats accompanied by methylation of the gene, called a “full mutation”, causes the loss of FMRP leading to the fragile X syndrome. Fragile X syndrome occurs more often in males and results in more severe disorder in males.Mutations in FMR1 are unusual when compared to mutations found in other genes. Some individuals carry between 55 – 200 CGG repeats called a “premutation,” usually without having symptoms associated with fragile X syndrome. These individuals are at risk for having children or grandchildren with fragile X syndrome, however, and also at risk for two adult onset disorders, fragile X tremor-ataxia syndrome (FXTAS) and primary ovarian insufficiency (POI). The conditions have been termed FMR1-Related Disorders. (Please see the Causes and Related Disorders sections of this report for a more detailed explanation regarding premutations and brief summaries of these FMR1-related disorders). | Overview of Fragile X Syndrome. Fragile X syndrome is characterized by moderate intellectual disability in affected males and mild intellectual disability in affected females. Distinctive physical features are sometimes present in affected males including a large head, long face, prominent forehead and chin, protruding ears, loose joints and large testes, but these features develop over time and may not be obvious until puberty. Motor and language delays are usually present but also become more apparent over time. Behavioral abnormalities including autistic behaviors are common.Fragile X syndrome has been found in all major ethnic groups and races, and is caused by an abnormality (mutation) in the FMR1 gene. FMR1 is a gene located on the X chromosome that produces a protein called FMRP needed for proper cell function. The syndrome became known as the fragile X syndrome because some individuals with the disorder were found to have a segment of their X chromosome that appeared to be broken or fragile (although not completely disconnected). Later it was learned that the FMR1 gene is located precisely where the X chromosome appears to be “fragile” in affected individuals.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 Xq27.3” refers to band 27.3 on the long arm of the X chromosome where the FMR1 gene is located. The numbered bands specify the location of the thousands of genes that are present on each chromosome.X-linked dominant disorders such as fragile X syndrome are caused by an abnormal gene located on the X chromosome. Females with the abnormal gene may be affected by this disorder. Males are usually more severely affected than females).It is the absence or severe reduction of the protein made by the FMR1 gene, FMRP, that causes fragile X syndrome. Mutation of the FMR1 gene causes the loss or reduction of FMRP. Nearly all affected individuals have an instability within the gene leading to an increased number of copies of a portion of the gene called the CGG repeat region (also sometimes called “trinucleotide” or “triplet” repeat region). When greater than 200 repeats are present, abnormal chemical changes occur in FMR1 called methylation. The expansion of the CGG repeat region to greater than 200 repeats accompanied by methylation of the gene, called a “full mutation”, causes the loss of FMRP leading to the fragile X syndrome. Fragile X syndrome occurs more often in males and results in more severe disorder in males.Mutations in FMR1 are unusual when compared to mutations found in other genes. Some individuals carry between 55 – 200 CGG repeats called a “premutation,” usually without having symptoms associated with fragile X syndrome. These individuals are at risk for having children or grandchildren with fragile X syndrome, however, and also at risk for two adult onset disorders, fragile X tremor-ataxia syndrome (FXTAS) and primary ovarian insufficiency (POI). The conditions have been termed FMR1-Related Disorders. (Please see the Causes and Related Disorders sections of this report for a more detailed explanation regarding premutations and brief summaries of these FMR1-related disorders). | 480 | Fragile X Syndrome |
nord_480_1 | Symptoms of Fragile X Syndrome | Fragile X syndrome is characterized by moderate intellectual disability in affected males and mild intellectual disability in affected females. The physical features in affected males are variable and may not be obvious until puberty. These symptoms can include a large head, long face, prominent forehead and chin, protruding ears, loose joints and large testes. Other symptoms can include flat feet, frequent ear infections, low muscle tone, a long narrow face, high arched palate, dental problems, crossed eyes (strabismus) and heart problems including mitral valve prolapse. Delayed motor development, hyperactivity, behavior problems, toe walking, and/or occasional seizures can also occur in some patients. Autistic behaviors such as poor eye contact, hand flapping, and/or self-stimulating behaviors are also common. Motor and language delays are usually present but become more apparent over time. | Symptoms of Fragile X Syndrome. Fragile X syndrome is characterized by moderate intellectual disability in affected males and mild intellectual disability in affected females. The physical features in affected males are variable and may not be obvious until puberty. These symptoms can include a large head, long face, prominent forehead and chin, protruding ears, loose joints and large testes. Other symptoms can include flat feet, frequent ear infections, low muscle tone, a long narrow face, high arched palate, dental problems, crossed eyes (strabismus) and heart problems including mitral valve prolapse. Delayed motor development, hyperactivity, behavior problems, toe walking, and/or occasional seizures can also occur in some patients. Autistic behaviors such as poor eye contact, hand flapping, and/or self-stimulating behaviors are also common. Motor and language delays are usually present but become more apparent over time. | 480 | Fragile X Syndrome |
nord_480_2 | Causes of Fragile X Syndrome | As mentioned above, fragile X syndrome is caused by a mutation in the FMR1 gene located on the X chromosome at Xq27.3. Individuals with fragile X syndrome nearly always have (in greater than 99% of cases) a full mutation of the FMR1 gene which means that they have over 200 CGG repeats and abnormal methylation of the gene. Methylation is a chemical change to the DNA that carries the genetic code of a gene and the abnormal methylation associated with fragile X syndrome causes the gene to be unable to produce FMRP, the protein made by the FMR1 gene, needed for normal development. On rare occasions some patients with fragile X syndrome are partially or completely missing the FMR1 gene due to a deletion of the DNA on the X chromosome where FMR1 is located and have the syndrome because their cells do not produce FMRP. Ultra-rare patients with fragile X syndrome have been found to have a mutation in a single DNA base (called point mutations) resulting in absent or defective FMRP. FMRP is involved in making connections between neurons (nerve cells) in the brain. The absence or severe reduction of this protein leads to the symptoms of fragile X syndrome.Premutations have 55-200 CGG repeats and are potentially unstable. Individuals having a premutation do not have the fragile X syndrome but are at risk for having the adult onset FMR1 disorders FXTAS and POI.When passed from generation to generation premutations may be unstable and become full mutations, but the risk for instability is different depending upon whether a female or male premutation carrier is transmitting the premutation. Females with a premutation of the FMR1 gene are at risk to have children with fragile X syndrome because the number of CGG repeats can increase when the gene is passed into the next generation. The greater the number of copies of CGG in a premutation, the more likely these will increase to become a full mutation causing the fragile X syndrome in offspring.When males with a premutation reproduce, their male offspring have no risk to inherit the premutation because fathers do not contribute an X chromosome to their sons. In contrast, female offspring whose fathers have a premutation always inherit it and thus grandchildren of males with the premutation are at risk to have fragile X syndrome. Because the premutation is relatively stable when transmitted from father to daughter, the daughters almost never are affected with fragile X syndrome. However, their children are at increased risk because the premutation may be unstable when transmitted to the next generation.Normal FMR1 genes have approximately 5-44 CGG repeats and this number remains stable from generation to generation. Occasionally, in some individuals with 45-54 repeats there will be some minor instability such that these individuals will have several more (or less) repeats than their parents. A FMR1 repeat number between 45 and 54 is called “intermediate” or “gray zone”, but this minor instability does not lead to any symptoms of fragile X syndrome or the FMR1-related disorders. Having an intermediate number of CGG repeats is still considered as being in the normal range of repeat number. | Causes of Fragile X Syndrome. As mentioned above, fragile X syndrome is caused by a mutation in the FMR1 gene located on the X chromosome at Xq27.3. Individuals with fragile X syndrome nearly always have (in greater than 99% of cases) a full mutation of the FMR1 gene which means that they have over 200 CGG repeats and abnormal methylation of the gene. Methylation is a chemical change to the DNA that carries the genetic code of a gene and the abnormal methylation associated with fragile X syndrome causes the gene to be unable to produce FMRP, the protein made by the FMR1 gene, needed for normal development. On rare occasions some patients with fragile X syndrome are partially or completely missing the FMR1 gene due to a deletion of the DNA on the X chromosome where FMR1 is located and have the syndrome because their cells do not produce FMRP. Ultra-rare patients with fragile X syndrome have been found to have a mutation in a single DNA base (called point mutations) resulting in absent or defective FMRP. FMRP is involved in making connections between neurons (nerve cells) in the brain. The absence or severe reduction of this protein leads to the symptoms of fragile X syndrome.Premutations have 55-200 CGG repeats and are potentially unstable. Individuals having a premutation do not have the fragile X syndrome but are at risk for having the adult onset FMR1 disorders FXTAS and POI.When passed from generation to generation premutations may be unstable and become full mutations, but the risk for instability is different depending upon whether a female or male premutation carrier is transmitting the premutation. Females with a premutation of the FMR1 gene are at risk to have children with fragile X syndrome because the number of CGG repeats can increase when the gene is passed into the next generation. The greater the number of copies of CGG in a premutation, the more likely these will increase to become a full mutation causing the fragile X syndrome in offspring.When males with a premutation reproduce, their male offspring have no risk to inherit the premutation because fathers do not contribute an X chromosome to their sons. In contrast, female offspring whose fathers have a premutation always inherit it and thus grandchildren of males with the premutation are at risk to have fragile X syndrome. Because the premutation is relatively stable when transmitted from father to daughter, the daughters almost never are affected with fragile X syndrome. However, their children are at increased risk because the premutation may be unstable when transmitted to the next generation.Normal FMR1 genes have approximately 5-44 CGG repeats and this number remains stable from generation to generation. Occasionally, in some individuals with 45-54 repeats there will be some minor instability such that these individuals will have several more (or less) repeats than their parents. A FMR1 repeat number between 45 and 54 is called “intermediate” or “gray zone”, but this minor instability does not lead to any symptoms of fragile X syndrome or the FMR1-related disorders. Having an intermediate number of CGG repeats is still considered as being in the normal range of repeat number. | 480 | Fragile X Syndrome |
nord_480_3 | Affects of Fragile X Syndrome | The fragile X syndrome affects about 1 in 4,000 males and 1 in 6,000 to 8,000 females in the USA; that is, it affects about twice as many males as it does females. However, about four times as many females appear to be carriers of the altered gene as do males (1:250 females and 1:1000 males). Fragile X syndrome has been found in all major ethnic groups and races. | Affects of Fragile X Syndrome. The fragile X syndrome affects about 1 in 4,000 males and 1 in 6,000 to 8,000 females in the USA; that is, it affects about twice as many males as it does females. However, about four times as many females appear to be carriers of the altered gene as do males (1:250 females and 1:1000 males). Fragile X syndrome has been found in all major ethnic groups and races. | 480 | Fragile X Syndrome |
nord_480_4 | Related disorders of Fragile X Syndrome | Premutations of the FMR1 gene are associated with two other disorders and these conditions have been termed FMR1-Related disorders. Not all individuals with a premutation will develop FMR1 – Related disorders, but having a premutation increases the risks for developing these.Fragile X tremor-ataxia syndrome (FXTAS) is characterized by a progressive adult-onset movement abnormalities (ataxia) and rhythmic, involuntary movements (tremors) that affect mostly men. Individuals with this condition have a premutation in the FMR1 gene (55-200 CGG repeats). Diagnosis of FXTAS can be complicated by its similarity to other late adult onset disorders such as Parkinson disease.FMR1-related primary ovarian insufficiency (POI) is defined as menopause before age 40 years in women who have a premutation in the FMR1 gene (55-200 CGG repeats). The risk of POI in premutation carriers is approximately 21%. Women with POI of unknown cause have a risk of 1/50 to be a carrier of a premutation in the FMR1 gene.Some symptoms of the following disorders can be similar to those of fragile X syndrome. Comparisons may be useful for a differential diagnosis:Fragile XE syndrome (FRAXE) is rare and caused by an abnormal FMR2 gene located on the X chromosome very close to the site of the FMR1 gene. The normal FMR2 gene contains 6-35 copies of CCG and people with the disorder have over 200 copies of CCG in the FMR2 gene. The effect of FMR2 genes with 35-200 copies of CCG has not yet been determined likely because the disorder has a mild clinical presentation. Common symptoms of FRAXE include mild intellectual disability, learning deficits, and possible developmental delays.Renpenning syndrome is one of the chromosome X-linked intellectual disability disorders that affects males almost to the exclusion of females. Very rarely females will present with this syndrome. It is characterized by intellectual disability that can be severe, short stature, a smaller than normal head circumference (microcephaly), and small testes. The syndrome has been mapped to gene map locus Xp11.2-p11.4 and the term “Renpenning syndrome” should be limited to the condition that maps to this region. The prevalence is unknown.Developmental delay is present in Renpenning syndrome early with males learning to walk at age 2 – 3 years and able to say simple words at age 3 – 4 years. Although an affected male may appear physically normal, his head circumference and height will be at the lower limits of normal. After puberty, testes will be smaller than normal. Diagnosis is very difficult especially if there is only one male with intellectual disability in a family. The diagnosis must be based on evidence of inheritance as an X-linked trait, and determining that the affected gene is located on the short arm (at Xp11.1-p11.4) of the X chromosome. | Related disorders of Fragile X Syndrome. Premutations of the FMR1 gene are associated with two other disorders and these conditions have been termed FMR1-Related disorders. Not all individuals with a premutation will develop FMR1 – Related disorders, but having a premutation increases the risks for developing these.Fragile X tremor-ataxia syndrome (FXTAS) is characterized by a progressive adult-onset movement abnormalities (ataxia) and rhythmic, involuntary movements (tremors) that affect mostly men. Individuals with this condition have a premutation in the FMR1 gene (55-200 CGG repeats). Diagnosis of FXTAS can be complicated by its similarity to other late adult onset disorders such as Parkinson disease.FMR1-related primary ovarian insufficiency (POI) is defined as menopause before age 40 years in women who have a premutation in the FMR1 gene (55-200 CGG repeats). The risk of POI in premutation carriers is approximately 21%. Women with POI of unknown cause have a risk of 1/50 to be a carrier of a premutation in the FMR1 gene.Some symptoms of the following disorders can be similar to those of fragile X syndrome. Comparisons may be useful for a differential diagnosis:Fragile XE syndrome (FRAXE) is rare and caused by an abnormal FMR2 gene located on the X chromosome very close to the site of the FMR1 gene. The normal FMR2 gene contains 6-35 copies of CCG and people with the disorder have over 200 copies of CCG in the FMR2 gene. The effect of FMR2 genes with 35-200 copies of CCG has not yet been determined likely because the disorder has a mild clinical presentation. Common symptoms of FRAXE include mild intellectual disability, learning deficits, and possible developmental delays.Renpenning syndrome is one of the chromosome X-linked intellectual disability disorders that affects males almost to the exclusion of females. Very rarely females will present with this syndrome. It is characterized by intellectual disability that can be severe, short stature, a smaller than normal head circumference (microcephaly), and small testes. The syndrome has been mapped to gene map locus Xp11.2-p11.4 and the term “Renpenning syndrome” should be limited to the condition that maps to this region. The prevalence is unknown.Developmental delay is present in Renpenning syndrome early with males learning to walk at age 2 – 3 years and able to say simple words at age 3 – 4 years. Although an affected male may appear physically normal, his head circumference and height will be at the lower limits of normal. After puberty, testes will be smaller than normal. Diagnosis is very difficult especially if there is only one male with intellectual disability in a family. The diagnosis must be based on evidence of inheritance as an X-linked trait, and determining that the affected gene is located on the short arm (at Xp11.1-p11.4) of the X chromosome. | 480 | Fragile X Syndrome |
nord_480_5 | Diagnosis of Fragile X Syndrome | Over 99% of individuals with fragile X syndrome have a full mutation (over 200 CGG repeats and abnormal methylation) in the FMR1 gene. Molecular genetic testing is used to determine the number of CGG repeats in the FMR1 gene and testing to determine methylation status of the FMR1 gene is often used to follow up a finding of an expanded CGG region.Chromosome analysis using special techniques to induce fragile sites in chromosomes was once used to diagnose fragile X syndrome, but is no longer used for this purpose. Fragile X syndrome is the name given to this condition because some affected individuals have an X chromosome that looked as if it had “broken” or was “fragile” and was held together by the slightest of ties. This technique is no longer used in the diagnosis of this syndrome because it is both less accurate and costlier than are molecular techniques. | Diagnosis of Fragile X Syndrome. Over 99% of individuals with fragile X syndrome have a full mutation (over 200 CGG repeats and abnormal methylation) in the FMR1 gene. Molecular genetic testing is used to determine the number of CGG repeats in the FMR1 gene and testing to determine methylation status of the FMR1 gene is often used to follow up a finding of an expanded CGG region.Chromosome analysis using special techniques to induce fragile sites in chromosomes was once used to diagnose fragile X syndrome, but is no longer used for this purpose. Fragile X syndrome is the name given to this condition because some affected individuals have an X chromosome that looked as if it had “broken” or was “fragile” and was held together by the slightest of ties. This technique is no longer used in the diagnosis of this syndrome because it is both less accurate and costlier than are molecular techniques. | 480 | Fragile X Syndrome |
nord_480_6 | Therapies of Fragile X Syndrome | Treatment
There are many treatments for fragile X syndrome that can improve the lives of affected individuals and their families. These include special education, speech, occupational, and sensory integration training, and behavior modification programs. With educational efforts, therapy, and support, all individuals with fragile X syndrome can make progress. Other treatment may depend on an affected individual’s specific symptoms. Genetic counseling is recommended for affected individuals and their families.There are numerous Fragile X Clinics in the US and throughout the world. These clinics specialize in treatments, therapies, and support for individuals with fragile X syndrome and can guide parents to medication options to address specific symptoms. New medications are likely to become available to treat affected individual and the specialty clinics can assist parents with current information. For a detailed discussion of Treatments and Interventions please go to the National Fragile X Foundation website (https://fragilex.org/learn/treatment-and-intervention/). | Therapies of Fragile X Syndrome. Treatment
There are many treatments for fragile X syndrome that can improve the lives of affected individuals and their families. These include special education, speech, occupational, and sensory integration training, and behavior modification programs. With educational efforts, therapy, and support, all individuals with fragile X syndrome can make progress. Other treatment may depend on an affected individual’s specific symptoms. Genetic counseling is recommended for affected individuals and their families.There are numerous Fragile X Clinics in the US and throughout the world. These clinics specialize in treatments, therapies, and support for individuals with fragile X syndrome and can guide parents to medication options to address specific symptoms. New medications are likely to become available to treat affected individual and the specialty clinics can assist parents with current information. For a detailed discussion of Treatments and Interventions please go to the National Fragile X Foundation website (https://fragilex.org/learn/treatment-and-intervention/). | 480 | Fragile X Syndrome |
nord_481_0 | Overview of Fraser Syndrome | SummaryFraser syndrome (FS) is a rare genetic disorder characterized by several malformations that are present at birth. These include eyes that are completely covered by the skin and usually malformed (cryptophthalmos) causing blindness; fusion of the skin between the fingers and toes (cutaneous syndactyly), a blocked or missing anal opening (imperforate anus); limb anomalies; kidney (renal) abnormalities; external genital malformations; a narrow, blocked and malformed voice box and lower respiratory tract (nostrils, larynx and lungs); skeletal defects; umbilical hernia and intellectual disability. Infants and children with Fraser syndrome may also have additional abnormalities including malformations of the middle and outer ear that may result in hearing impairment. More recently, missing eyes (bilateral anophthalmia) and liver malformations (intrahepatic biliary atresia) have been found in children with FS. Fraser syndrome is inherited in an autosomal recessive pattern. There is currently no cure for FS but surgery is available to correct some malformations associated with this disorder, depending on the severity of the malformations. Fraser syndrome is named after the Canadian geneticist George R. Fraser who first described the syndrome in 1962. | Overview of Fraser Syndrome. SummaryFraser syndrome (FS) is a rare genetic disorder characterized by several malformations that are present at birth. These include eyes that are completely covered by the skin and usually malformed (cryptophthalmos) causing blindness; fusion of the skin between the fingers and toes (cutaneous syndactyly), a blocked or missing anal opening (imperforate anus); limb anomalies; kidney (renal) abnormalities; external genital malformations; a narrow, blocked and malformed voice box and lower respiratory tract (nostrils, larynx and lungs); skeletal defects; umbilical hernia and intellectual disability. Infants and children with Fraser syndrome may also have additional abnormalities including malformations of the middle and outer ear that may result in hearing impairment. More recently, missing eyes (bilateral anophthalmia) and liver malformations (intrahepatic biliary atresia) have been found in children with FS. Fraser syndrome is inherited in an autosomal recessive pattern. There is currently no cure for FS but surgery is available to correct some malformations associated with this disorder, depending on the severity of the malformations. Fraser syndrome is named after the Canadian geneticist George R. Fraser who first described the syndrome in 1962. | 481 | Fraser Syndrome |
nord_481_1 | Symptoms of Fraser Syndrome | Fraser syndrome is characterized by multiple physical abnormalities.Failure of the eyelids to form properly (cryptophthalmos) is the most common abnormality, seen in 93% of affected individuals. Other less common forms of cryptophtalmos seen in these individuals are only one eye completely covered by skin, or one or both eyes partially covered. In addition, there are other possible malformations of the eyes such as small eyes (microphthalmia), missing eyes (anophthalmia), absent or malformed lacrimal tear ducts (nasolacriminal ducts) and increased distance between the eyes (hypertelorism). These eye abnormalities lead to vision loss or impairment.Cutaneous syndactyly is another common abnormality in people with Fraser syndrome. Affected individuals typically have their three middle fingers joined and their three middle toes joined, but the other fingers/toes can also be joined.Another common sign is kidney abnormalities such as the absence of one or both kidneys (unilateral or bilateral renal agenesis). Other kidney malformations may include improper development (dysplasia) and underdevelopment (hypoplasia).Genital malformations are common in individuals with FS. In affected males, one or both testes may fail to descend into the scrotum (cryptorchidism), the urinary opening (meatus) may be abnormally placed on the underside of the penis (hypospadias), and/or the penis may be abnormally small (micropenis). Affected females may have malformed fallopian tubes, an abnormally enlarged clitoris (clitoromegaly), an abnormally shaped uterus with two horn-like extensions (bicornate uterus) and/or abnormally closed or absent vagina (vaginal atresia). Some affected individuals’ outer genitals may not have the typical appearance of either a male or female (ambiguous genitalia).Respiratory tract abnormalities are another common sign in people with FS. There may be malformations of the voice box (larynx) (laryngeal stenosis or atresia), meaning it is more narrow than average or blocked. Malformations of the nose and lungs are also common. This can cause breathing difficulties leading to potentially fatal respiratory insufficiency.Other possible signs and symptoms are: | Symptoms of Fraser Syndrome. Fraser syndrome is characterized by multiple physical abnormalities.Failure of the eyelids to form properly (cryptophthalmos) is the most common abnormality, seen in 93% of affected individuals. Other less common forms of cryptophtalmos seen in these individuals are only one eye completely covered by skin, or one or both eyes partially covered. In addition, there are other possible malformations of the eyes such as small eyes (microphthalmia), missing eyes (anophthalmia), absent or malformed lacrimal tear ducts (nasolacriminal ducts) and increased distance between the eyes (hypertelorism). These eye abnormalities lead to vision loss or impairment.Cutaneous syndactyly is another common abnormality in people with Fraser syndrome. Affected individuals typically have their three middle fingers joined and their three middle toes joined, but the other fingers/toes can also be joined.Another common sign is kidney abnormalities such as the absence of one or both kidneys (unilateral or bilateral renal agenesis). Other kidney malformations may include improper development (dysplasia) and underdevelopment (hypoplasia).Genital malformations are common in individuals with FS. In affected males, one or both testes may fail to descend into the scrotum (cryptorchidism), the urinary opening (meatus) may be abnormally placed on the underside of the penis (hypospadias), and/or the penis may be abnormally small (micropenis). Affected females may have malformed fallopian tubes, an abnormally enlarged clitoris (clitoromegaly), an abnormally shaped uterus with two horn-like extensions (bicornate uterus) and/or abnormally closed or absent vagina (vaginal atresia). Some affected individuals’ outer genitals may not have the typical appearance of either a male or female (ambiguous genitalia).Respiratory tract abnormalities are another common sign in people with FS. There may be malformations of the voice box (larynx) (laryngeal stenosis or atresia), meaning it is more narrow than average or blocked. Malformations of the nose and lungs are also common. This can cause breathing difficulties leading to potentially fatal respiratory insufficiency.Other possible signs and symptoms are: | 481 | Fraser Syndrome |
nord_481_2 | Causes of Fraser Syndrome | Fraser syndrome is caused by changes (mutations) in the FRAS1, FREM1, FREM2 or GRIP1 genes). More specifically, Fraser syndrome 1 (FRASRS1) is caused by mutations in the Fraser extracellular matrix complex subunit 1 (FRAS1) gene. Fraser syndrome 2 (FRASRS2) is caused by mutations in the FRAS1-related extracellular matrix protein 2 (FREM2) gene. Fraser syndrome 3 (FRASRS3) is caused by mutations in the glutamate receptor-interacting protein 1 (GRIP1) gene. FRAS1 gene mutations are the most common cause for Fraser syndrome, representing approximately half of the FS cases; whereas FREM2 gene and GRIP1 gene mutations account for a smaller percentage of cases. 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 particular protein, this can affect many organ systems of the body, including the brain. The FRAS1 and FREM2 genes produce proteins (FRAS1 and FREM2 proteins, respectively) that work together as part of the FRAS/FREM complex. One of the FRAS/FREM complex’s functions is to connect the different layers of skin together, one on top of the other, to essentially form the skin. Its function is important during the embryonic period before birth. This group of proteins play a role in the proper development of the skin, internal organs including kidneys and other tissues. Therefore, a mutation in the FRAS1 or FREM2 gene causes its respective protein to be faulty, thus the FRAS/FREM complex cannot function properly and therefore leading to improper development of the skin, internal organs and other tissues. This improper development ultimately causes signs and symptoms such as cryptophthalmos, cutaneous syndactyly and renal agenesis. The GRIP1 gene produces the GRIP1 protein that ensures that FRAS1 and FREM2 proteins get to their correct location within the cell to carry out their function. Mutations in the GRIP1 gene prevent normal function of the FRAS1 and FREM2 proteins, causing an improper development of the skin, internal organs and other tissues. Fraser syndrome is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits the same abnormal/mutated gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.All individuals carry a few abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. | Causes of Fraser Syndrome. Fraser syndrome is caused by changes (mutations) in the FRAS1, FREM1, FREM2 or GRIP1 genes). More specifically, Fraser syndrome 1 (FRASRS1) is caused by mutations in the Fraser extracellular matrix complex subunit 1 (FRAS1) gene. Fraser syndrome 2 (FRASRS2) is caused by mutations in the FRAS1-related extracellular matrix protein 2 (FREM2) gene. Fraser syndrome 3 (FRASRS3) is caused by mutations in the glutamate receptor-interacting protein 1 (GRIP1) gene. FRAS1 gene mutations are the most common cause for Fraser syndrome, representing approximately half of the FS cases; whereas FREM2 gene and GRIP1 gene mutations account for a smaller percentage of cases. 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 particular protein, this can affect many organ systems of the body, including the brain. The FRAS1 and FREM2 genes produce proteins (FRAS1 and FREM2 proteins, respectively) that work together as part of the FRAS/FREM complex. One of the FRAS/FREM complex’s functions is to connect the different layers of skin together, one on top of the other, to essentially form the skin. Its function is important during the embryonic period before birth. This group of proteins play a role in the proper development of the skin, internal organs including kidneys and other tissues. Therefore, a mutation in the FRAS1 or FREM2 gene causes its respective protein to be faulty, thus the FRAS/FREM complex cannot function properly and therefore leading to improper development of the skin, internal organs and other tissues. This improper development ultimately causes signs and symptoms such as cryptophthalmos, cutaneous syndactyly and renal agenesis. The GRIP1 gene produces the GRIP1 protein that ensures that FRAS1 and FREM2 proteins get to their correct location within the cell to carry out their function. Mutations in the GRIP1 gene prevent normal function of the FRAS1 and FREM2 proteins, causing an improper development of the skin, internal organs and other tissues. Fraser syndrome is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits the same abnormal/mutated gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.All individuals carry a few abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. | 481 | Fraser Syndrome |
nord_481_3 | Affects of Fraser Syndrome | Fraser syndrome affects males and females in equal numbers. The age of onset for this disorder is neonatal/antenatal, meaning an affected individual develops this disorder before birth. FS is seen to be more prevalent in gypsy populations (Roma ethnicity) of southern and eastern Europe. The incidence of FS is 0.43 in 10,000 or 1 in 200,000 newborns and 11.06 in 10,000 babies that die before birth (stillbirths). | Affects of Fraser Syndrome. Fraser syndrome affects males and females in equal numbers. The age of onset for this disorder is neonatal/antenatal, meaning an affected individual develops this disorder before birth. FS is seen to be more prevalent in gypsy populations (Roma ethnicity) of southern and eastern Europe. The incidence of FS is 0.43 in 10,000 or 1 in 200,000 newborns and 11.06 in 10,000 babies that die before birth (stillbirths). | 481 | Fraser Syndrome |
nord_481_4 | Related disorders of Fraser Syndrome | Symptoms of the following disorders can be similar to those of Fraser syndrome. Comparisons may be useful for a differential diagnosis:Bilateral renal agenesis is the absence of both kidneys at birth. It is a genetic disorder characterized by a failure of the kidneys to develop in a fetus. This absence of kidneys causes a deficiency of amniotic fluid in a pregnant woman. Normally the amniotic fluid acts as a cushion for the developing fetus. When there is an insufficient amount of this fluid, compression of the fetus may occur resulting in further malformations of the baby. (For more information on this disorder, choose “Renal Agenesis, Bilateral” as your search term in the Rare Disease Database.)Cat eye syndrome (coloboma of iris-anal atresis syndrome), is a disorder which is characterized by a fissure in the iris of the eye and the absence of an anal opening. Other abnormalities may include missing kidneys (renal agenesis). (For more information on this disorder, choose “cat eye” as your search term in the Rare Disease Database.)Branchiootorenal spectrum disorders are genetic disorders characterized by hearing loss and kidney malformations, including renal agenesis. (For more information on this disorder, choose “Branchiootorenal” as your search term in the Rare Disease Database.)Trigonocephaly 2: Children with trigonocephaly have intellectual disability stemming from FREM1 gene mutations, but these newborns have a characteristic triangularly shaped head in contrast to those with Fraser syndrome.Manitoba oculotrichonal syndrome: These children have FREM1 gene mutations but appear different from children with FS and usually have a nose divided into two parts (bifid nose), widely spaced eyes (hypertelorism) and small eyes (microphthalmia). | Related disorders of Fraser Syndrome. Symptoms of the following disorders can be similar to those of Fraser syndrome. Comparisons may be useful for a differential diagnosis:Bilateral renal agenesis is the absence of both kidneys at birth. It is a genetic disorder characterized by a failure of the kidneys to develop in a fetus. This absence of kidneys causes a deficiency of amniotic fluid in a pregnant woman. Normally the amniotic fluid acts as a cushion for the developing fetus. When there is an insufficient amount of this fluid, compression of the fetus may occur resulting in further malformations of the baby. (For more information on this disorder, choose “Renal Agenesis, Bilateral” as your search term in the Rare Disease Database.)Cat eye syndrome (coloboma of iris-anal atresis syndrome), is a disorder which is characterized by a fissure in the iris of the eye and the absence of an anal opening. Other abnormalities may include missing kidneys (renal agenesis). (For more information on this disorder, choose “cat eye” as your search term in the Rare Disease Database.)Branchiootorenal spectrum disorders are genetic disorders characterized by hearing loss and kidney malformations, including renal agenesis. (For more information on this disorder, choose “Branchiootorenal” as your search term in the Rare Disease Database.)Trigonocephaly 2: Children with trigonocephaly have intellectual disability stemming from FREM1 gene mutations, but these newborns have a characteristic triangularly shaped head in contrast to those with Fraser syndrome.Manitoba oculotrichonal syndrome: These children have FREM1 gene mutations but appear different from children with FS and usually have a nose divided into two parts (bifid nose), widely spaced eyes (hypertelorism) and small eyes (microphthalmia). | 481 | Fraser Syndrome |
nord_481_5 | Diagnosis of Fraser Syndrome | Fraser syndrome can be diagnosed before birth by ultrasound at 18 weeks of gestation. Prenatal ultrasonographic diagnosis is usually done when there is family history for the disorder. The diagnosis can be made if two of the following signs are present on ultrasound of the fetus: microphthalmia (one eye being abnormally small), syndactyly, enlarged echogenic lungs, oligohydramnios (deficiency in amniotic fluid during pregnancy).Fraser syndrome is usually diagnosed at birth based on the signs and symptoms found in the child. IT Thomas and colleagues suggested the following criteria to diagnose FS: the presence of one major criterion and one minor criterion or alternatively the presence of two major criteria and one minor criterion. Major criteria include cutaneous syndactyly, cryptophthalmos, ambiguous external genitalia, anorectal abnormalities and limb anomalies. Minor criteria are ear and nose anomalies, skull bone defects, umbilical hernia, intellectual disability and urinary and respiratory tract anomalies. None of the major criteria are mandatory for diagnosis. Genetic testing for mutations in the FRAS1, FREM1, FREM2 or GRIP1 genes can confirm the diagnosis of Fraser syndrome. | Diagnosis of Fraser Syndrome. Fraser syndrome can be diagnosed before birth by ultrasound at 18 weeks of gestation. Prenatal ultrasonographic diagnosis is usually done when there is family history for the disorder. The diagnosis can be made if two of the following signs are present on ultrasound of the fetus: microphthalmia (one eye being abnormally small), syndactyly, enlarged echogenic lungs, oligohydramnios (deficiency in amniotic fluid during pregnancy).Fraser syndrome is usually diagnosed at birth based on the signs and symptoms found in the child. IT Thomas and colleagues suggested the following criteria to diagnose FS: the presence of one major criterion and one minor criterion or alternatively the presence of two major criteria and one minor criterion. Major criteria include cutaneous syndactyly, cryptophthalmos, ambiguous external genitalia, anorectal abnormalities and limb anomalies. Minor criteria are ear and nose anomalies, skull bone defects, umbilical hernia, intellectual disability and urinary and respiratory tract anomalies. None of the major criteria are mandatory for diagnosis. Genetic testing for mutations in the FRAS1, FREM1, FREM2 or GRIP1 genes can confirm the diagnosis of Fraser syndrome. | 481 | Fraser Syndrome |
nord_481_6 | Therapies of Fraser Syndrome | Treatment
There is currently no cure for Fraser syndrome. Treatment of FS may include surgery to correct some of the malformations associated with this disorder depending on their severity. Other treatment is symptomatic and supportive. A team of specialists is required to evaluate each patient and determine ways to treat the symptoms. The prognosis without treatment depends on the severity of the specific anomalies in the patient, especially respiratory tract malformations and anal imperforations. Unfortunately, death in the first year of life is common in children with severe anomalies. Genetic counseling is recommended for families of children with this disorder. | Therapies of Fraser Syndrome. Treatment
There is currently no cure for Fraser syndrome. Treatment of FS may include surgery to correct some of the malformations associated with this disorder depending on their severity. Other treatment is symptomatic and supportive. A team of specialists is required to evaluate each patient and determine ways to treat the symptoms. The prognosis without treatment depends on the severity of the specific anomalies in the patient, especially respiratory tract malformations and anal imperforations. Unfortunately, death in the first year of life is common in children with severe anomalies. Genetic counseling is recommended for families of children with this disorder. | 481 | Fraser Syndrome |
nord_482_0 | Overview of Freeman Sheldon Syndrome | SummaryFreeman-Sheldon syndrome (FSS) or “whistling face syndrome” is an exceptionally rare disorder present before birth (congenital) that primarily affects muscles of the face and skull (craniofacial muscles) but frequently involves problems with joints of the hands and feet. Diagnosis requires the presence of an exceptionally small mouth (microstomia), whistling face appearance (pursed lips), “H” or “V” shaped chin dimple and very obvious crease from the nostril to the corners of the mouth (nasolabial creases). While some include restricted movement (contractures) in the hands and feet as requirements, these are not specific findings to FSS. In FSS, normal muscle is present but is interspersed or sometimes replaced by tendon-like matter that reduces the muscles’ ability to move well and causes deformities. FSS happens with widely varying degrees of severity. Some muscles are unaffected, while others may be completely non-functional, causing affected joints, muscles of facial expression, and muscles between the ribs (intercostal muscles) to be immobile. The face muscles tend to be most severely affected, with persons having an expressionless mask-like appearance. Diagnosis before birth (with genetic testing or sonography) may be possible if a parent has FSS, but diagnosis before birth is not considered definitive. Both biologic genders and all geographic areas and ethnicities are affected equally, and there is no known link with environmental or parental factors, such as exposure to illnesses, toxins, drugs or harsh substances. FSS can be passed on from a person who has the disorder, but most persons with FSS have no family history of the syndrome. Persons with FSS have normal intelligence, but most children with FSS have developmental delays that are caused by physical deformities. IntroductionFSS is named for Mr. Ernest Arthur Freeman, an orthopedic surgeon from Wolverhampton, England, UK, and Prof. Fredrick Burian, a plastic surgeon from Prague, Czech Republic. In 1938, Mr. Freeman and Dr. John Howard Sheldon, who described a different but similar appearing condition now known as Sheldon-Hall syndrome (SHS), published the first description of FSS, which they called “cranio-carpo-tarsal dystrophy”. In 1962, Prof. Burian independently verified the existence of FSS, coining the term “whistling face syndrome” and giving the first complete description of classic FSS. | Overview of Freeman Sheldon Syndrome. SummaryFreeman-Sheldon syndrome (FSS) or “whistling face syndrome” is an exceptionally rare disorder present before birth (congenital) that primarily affects muscles of the face and skull (craniofacial muscles) but frequently involves problems with joints of the hands and feet. Diagnosis requires the presence of an exceptionally small mouth (microstomia), whistling face appearance (pursed lips), “H” or “V” shaped chin dimple and very obvious crease from the nostril to the corners of the mouth (nasolabial creases). While some include restricted movement (contractures) in the hands and feet as requirements, these are not specific findings to FSS. In FSS, normal muscle is present but is interspersed or sometimes replaced by tendon-like matter that reduces the muscles’ ability to move well and causes deformities. FSS happens with widely varying degrees of severity. Some muscles are unaffected, while others may be completely non-functional, causing affected joints, muscles of facial expression, and muscles between the ribs (intercostal muscles) to be immobile. The face muscles tend to be most severely affected, with persons having an expressionless mask-like appearance. Diagnosis before birth (with genetic testing or sonography) may be possible if a parent has FSS, but diagnosis before birth is not considered definitive. Both biologic genders and all geographic areas and ethnicities are affected equally, and there is no known link with environmental or parental factors, such as exposure to illnesses, toxins, drugs or harsh substances. FSS can be passed on from a person who has the disorder, but most persons with FSS have no family history of the syndrome. Persons with FSS have normal intelligence, but most children with FSS have developmental delays that are caused by physical deformities. IntroductionFSS is named for Mr. Ernest Arthur Freeman, an orthopedic surgeon from Wolverhampton, England, UK, and Prof. Fredrick Burian, a plastic surgeon from Prague, Czech Republic. In 1938, Mr. Freeman and Dr. John Howard Sheldon, who described a different but similar appearing condition now known as Sheldon-Hall syndrome (SHS), published the first description of FSS, which they called “cranio-carpo-tarsal dystrophy”. In 1962, Prof. Burian independently verified the existence of FSS, coining the term “whistling face syndrome” and giving the first complete description of classic FSS. | 482 | Freeman Sheldon Syndrome |
nord_482_1 | Symptoms of Freeman Sheldon Syndrome | Certain problems are required to be present for diagnosis of FSS. All persons with FSS have the following problems: very small mouth (microstomia), whistling-face appearance (pursed lips), “H” or “V” shaped chin dimple and very obvious crease from the nostril to the corners of the mouth (nasolabial creases). Classically, persons also have restricted movement in joints (contractures) of two or more body areas, often hands and feet, with fingers and toes frequently overlapping. Many additional problems have been associated with FSS, especially problems of the face, including: over-crowded teeth (dental crowding), poorly aligned teeth (class II malocclusion), very high roof of the mouth (vaulted or highly arched palate), extra distance between the nose and upper lip (long philtrum), bulging ridges above the eyes (prominent superciliary ridges or frontal bossing), very small tongue (microglossia), drooping eyelids (blepharoptosis), cross-eyed problem (strabismus), extra inner skin-fold of the eye next to the nose (epicanthal folds), down-slanting eyelid folds (palpebral fissures), very small eyelid opening (blepharophimosis), sunken appearance of eyes (enophthalmos), widely spaced eyes (ocular hypertelorism), low set and tilted ears, mild to moderate hearing impairment, under-developed chin (microgenia), under-developed (micrognathia) and recessed (retrognathia) jaw, wide nasal bridge, small nose, under-developed nostrils (hypoplastic alae nasi), long face and flat mid-face (mid-face hypoplasia). Skull bones may come together too early (craniosynostosis) and a small skull (microcephaly).Hand or foot deformities may be present on both (bilateral) or only one (unilateral) side. Fingers (phalanges) may be tightly bent (camptodactyly) and pointed outward from the thumb (ulnar deviation or windmill vane appearance). The thumb (pollex) may be tightly bent into the palm (adducted or thumb-in-palm deformity). The wrist often has limited movement and is frequently bent up (dorsoflexed or cock-up deformity). Feet often resemble a golf club (talipes equinovarus or club foot condition) and may have a rocker bottom appearance (vertical talus), with toes (phalanges) tightly bent (camptodactyly) and turned inward (metatarsus varus). Sometimes there is overriding of fingers or toes shortly after birth that improves spontaneously or with mild therapy.Different deformities of the back, ribs, and chest have been observed. Many persons with FSS have humpback (kyphosis), swayback (lordosis) or sideways (scoliosis) curves in the back bones. If the abnormalities in the curves of the spine and breastbone are significant, they can restrict internal organs of the chest and abdomen and cause gastrointestinal, lung, and heart problems. In people with FSS, the muscles between the ribs (intercostal muscles) often are non-functional, making breathing and coughing difficult (reduced respiratory effort and tussive ability) and rarely causing harm to the lungs (pulmonary hypertension) and heart (right heart strain and cor pulmonale). Not being able to breathe deeply and cough well also can make it difficult to recover from lower respiratory infections. When present, the combination of severely abnormal curves of the backbone and non-functional muscles between the ribs (intercostal muscles) may result in chronic lung problems (reduced intrathoracic volume, impaired thoracic cage compliance, impaired exercise tolerance, reduced ventilation of oxygen, and restrictive pulmonary disease). Notably, there is no evidence of FSS directly causing lung or heart problems. Some of the indirect or secondary lung and heart problems that persons with FSS may experience because of non-functional muscles between the ribs and possibly other areas of the chest can resolve or have improvement with exercise and medical treatment. Less frequently, some people may have deformities of the ribs and breastbone (sternum) cartilage, causing either a sunken (pectus excavatum) or jutted out (pectus carinatum) appearance of the chest. Rarely, persons may have small openings in the spinal bones (spina bifida occulta).Persons with FSS often have a short neck that does not move well and may have extra skin, giving a “webbed” appearance (pterygium colli). Hips and knees and, less frequently, shoulders and elbows may have limited movement (contractures) and dislocations. The knee cap (patella) may repeatedly partially dislocate (habitual subluxation). Joints with limited or no movement (contractures) may have decreased or absent reflexes (deep tendon reflexes). Some patients have experienced abdominal hernias (inguinal, epigastric).Under-development of the jaw (micrognathia) may contribute to swallowing (dysphagia) and breathing problems (lower airway obstruction), but typically, patients have a very small tongue (microglossia), preventing breathing problems caused by the tongue that happen in patients with other conditions involving under-development of the jaw. Mouth breathing is caused by very thin (hypoplastic) nasal cartilages and narrowed nasal passages (nasopharynx). Poor coughing (tussive) ability and swallowing problems (dysphagia) may put the person with FSS at greater risk for airway obstruction and inhalation (aspiration) of food, saliva or vomit into the lungs, which may cause lower respiratory infections (bronchitis and pneumonia). Mouth breathing, which causes inhalation of unconditioned air and potentially aerosol droplets from people with contagious respiratory infections, may further complicate the potential respiratory risk for patients with FSS. Upper respiratory infections may progress more often to bronchitis or pneumonia infections, as well. Mouth breathing, swallowing problems (dysphagia), and the not uncommon need for a high calorie diet can also cause persons with FSS to be more at risk for developing dental cavities (caries). Persons may be more at-risk for middle ear infections, which can lead to hearing loss. Persons with FSS may also experience sinus infections and frontal headaches more often because of deformities of the skull.While severe swallowing problems (dysphagia) may reduce eating efficiency—slowing growth in infancy and childhood, swallowing problems (dysphagia) typically improve spontaneously with age. Rarely, dysphagia may not improve. Persons with FSS typically have difficulty creating a suction with the lips and mouth because of ineffective facial muscles. Persons with FSS are typically short and may be thin into early adulthood, while others are normal weight or overweight as adults. There are some reports of persons with FSS experiencing more chronic constipation, vomiting, and gastroesophageal reflux, suggesting that gut (visceral) muscle may be secondarily affected. A few persons with FSS seem to use energy at higher rates and require high calorie foods, but the cause is unknown.Speech problems (dysphasia), which typically include both a nasal voice (hyponasality) and articulation problems, are caused by multiple structural and functional problems, specifically problems with regional muscles; a very small tongue (microglossia); highly arched roof of the mouth (hard palate); very thin (hypoplastic) nasal cartilages; narrowed nasal passages (nasopharynx); and under-developed facial bones (midface hypoplasia). Except those who have had severe respiratory complications and not enough oxygen reached the brain, persons with FSS have normal intelligence. Most persons have developmental delays that are caused by physical deformities.Because of head, neck, throat (pharynx) and mouth problems, it is challenging for healthcare providers to protect the airway of persons with FSS who are unconscious. It is also difficult for healthcare providers to access blood vessels to draw blood or give medicine or fluid. These problems seriously complicate anesthesia, sedation and surgery planning for persons with FSS. | Symptoms of Freeman Sheldon Syndrome. Certain problems are required to be present for diagnosis of FSS. All persons with FSS have the following problems: very small mouth (microstomia), whistling-face appearance (pursed lips), “H” or “V” shaped chin dimple and very obvious crease from the nostril to the corners of the mouth (nasolabial creases). Classically, persons also have restricted movement in joints (contractures) of two or more body areas, often hands and feet, with fingers and toes frequently overlapping. Many additional problems have been associated with FSS, especially problems of the face, including: over-crowded teeth (dental crowding), poorly aligned teeth (class II malocclusion), very high roof of the mouth (vaulted or highly arched palate), extra distance between the nose and upper lip (long philtrum), bulging ridges above the eyes (prominent superciliary ridges or frontal bossing), very small tongue (microglossia), drooping eyelids (blepharoptosis), cross-eyed problem (strabismus), extra inner skin-fold of the eye next to the nose (epicanthal folds), down-slanting eyelid folds (palpebral fissures), very small eyelid opening (blepharophimosis), sunken appearance of eyes (enophthalmos), widely spaced eyes (ocular hypertelorism), low set and tilted ears, mild to moderate hearing impairment, under-developed chin (microgenia), under-developed (micrognathia) and recessed (retrognathia) jaw, wide nasal bridge, small nose, under-developed nostrils (hypoplastic alae nasi), long face and flat mid-face (mid-face hypoplasia). Skull bones may come together too early (craniosynostosis) and a small skull (microcephaly).Hand or foot deformities may be present on both (bilateral) or only one (unilateral) side. Fingers (phalanges) may be tightly bent (camptodactyly) and pointed outward from the thumb (ulnar deviation or windmill vane appearance). The thumb (pollex) may be tightly bent into the palm (adducted or thumb-in-palm deformity). The wrist often has limited movement and is frequently bent up (dorsoflexed or cock-up deformity). Feet often resemble a golf club (talipes equinovarus or club foot condition) and may have a rocker bottom appearance (vertical talus), with toes (phalanges) tightly bent (camptodactyly) and turned inward (metatarsus varus). Sometimes there is overriding of fingers or toes shortly after birth that improves spontaneously or with mild therapy.Different deformities of the back, ribs, and chest have been observed. Many persons with FSS have humpback (kyphosis), swayback (lordosis) or sideways (scoliosis) curves in the back bones. If the abnormalities in the curves of the spine and breastbone are significant, they can restrict internal organs of the chest and abdomen and cause gastrointestinal, lung, and heart problems. In people with FSS, the muscles between the ribs (intercostal muscles) often are non-functional, making breathing and coughing difficult (reduced respiratory effort and tussive ability) and rarely causing harm to the lungs (pulmonary hypertension) and heart (right heart strain and cor pulmonale). Not being able to breathe deeply and cough well also can make it difficult to recover from lower respiratory infections. When present, the combination of severely abnormal curves of the backbone and non-functional muscles between the ribs (intercostal muscles) may result in chronic lung problems (reduced intrathoracic volume, impaired thoracic cage compliance, impaired exercise tolerance, reduced ventilation of oxygen, and restrictive pulmonary disease). Notably, there is no evidence of FSS directly causing lung or heart problems. Some of the indirect or secondary lung and heart problems that persons with FSS may experience because of non-functional muscles between the ribs and possibly other areas of the chest can resolve or have improvement with exercise and medical treatment. Less frequently, some people may have deformities of the ribs and breastbone (sternum) cartilage, causing either a sunken (pectus excavatum) or jutted out (pectus carinatum) appearance of the chest. Rarely, persons may have small openings in the spinal bones (spina bifida occulta).Persons with FSS often have a short neck that does not move well and may have extra skin, giving a “webbed” appearance (pterygium colli). Hips and knees and, less frequently, shoulders and elbows may have limited movement (contractures) and dislocations. The knee cap (patella) may repeatedly partially dislocate (habitual subluxation). Joints with limited or no movement (contractures) may have decreased or absent reflexes (deep tendon reflexes). Some patients have experienced abdominal hernias (inguinal, epigastric).Under-development of the jaw (micrognathia) may contribute to swallowing (dysphagia) and breathing problems (lower airway obstruction), but typically, patients have a very small tongue (microglossia), preventing breathing problems caused by the tongue that happen in patients with other conditions involving under-development of the jaw. Mouth breathing is caused by very thin (hypoplastic) nasal cartilages and narrowed nasal passages (nasopharynx). Poor coughing (tussive) ability and swallowing problems (dysphagia) may put the person with FSS at greater risk for airway obstruction and inhalation (aspiration) of food, saliva or vomit into the lungs, which may cause lower respiratory infections (bronchitis and pneumonia). Mouth breathing, which causes inhalation of unconditioned air and potentially aerosol droplets from people with contagious respiratory infections, may further complicate the potential respiratory risk for patients with FSS. Upper respiratory infections may progress more often to bronchitis or pneumonia infections, as well. Mouth breathing, swallowing problems (dysphagia), and the not uncommon need for a high calorie diet can also cause persons with FSS to be more at risk for developing dental cavities (caries). Persons may be more at-risk for middle ear infections, which can lead to hearing loss. Persons with FSS may also experience sinus infections and frontal headaches more often because of deformities of the skull.While severe swallowing problems (dysphagia) may reduce eating efficiency—slowing growth in infancy and childhood, swallowing problems (dysphagia) typically improve spontaneously with age. Rarely, dysphagia may not improve. Persons with FSS typically have difficulty creating a suction with the lips and mouth because of ineffective facial muscles. Persons with FSS are typically short and may be thin into early adulthood, while others are normal weight or overweight as adults. There are some reports of persons with FSS experiencing more chronic constipation, vomiting, and gastroesophageal reflux, suggesting that gut (visceral) muscle may be secondarily affected. A few persons with FSS seem to use energy at higher rates and require high calorie foods, but the cause is unknown.Speech problems (dysphasia), which typically include both a nasal voice (hyponasality) and articulation problems, are caused by multiple structural and functional problems, specifically problems with regional muscles; a very small tongue (microglossia); highly arched roof of the mouth (hard palate); very thin (hypoplastic) nasal cartilages; narrowed nasal passages (nasopharynx); and under-developed facial bones (midface hypoplasia). Except those who have had severe respiratory complications and not enough oxygen reached the brain, persons with FSS have normal intelligence. Most persons have developmental delays that are caused by physical deformities.Because of head, neck, throat (pharynx) and mouth problems, it is challenging for healthcare providers to protect the airway of persons with FSS who are unconscious. It is also difficult for healthcare providers to access blood vessels to draw blood or give medicine or fluid. These problems seriously complicate anesthesia, sedation and surgery planning for persons with FSS. | 482 | Freeman Sheldon Syndrome |
nord_482_2 | Causes of Freeman Sheldon Syndrome | There is no known link between FSS and environmental or parental factors, such as exposure to illnesses, toxins, drugs or harsh substances. Though the cause remains uncertain for a small percentage of people, FSS can be caused by a change (mutation or allelic variation) in the embryonic myosin heavy chain (MYH3) gene, which is located on band 13.1 of the short arm (p) of chromosome 17 (a locus of 17p13.1). FSS is believed to impair muscle development in the embryo and disrupt muscle function throughout life by causing the energy [adenosine triphosphate (ATP)] needed for muscles to tense (muscle contraction) and relax properly to have difficulty attaching to the myosin, one of the main parts of muscles fibers. This may happen because of reduced activity of enzymes that break the ATP bonds to the myosin (ATPase) that could be caused by mechanical problems with actin, the other main part of muscle fibers. When muscles cannot function normally, deformities in the bones, joints, and other areas can result.Most patients with FSS are born to normal healthy parents, and in this situation, FSS is not inherited but arises from a new change in the gene (new mutation). When FSS is inherited, almost all of the time one of the parents has FSS and passes on one copy of the gene to a child (autosomal dominant inheritance). In extremely rare situations, however, a parent may be healthy but have a MYH3 gene variant only in their reproductive cells (germline mosaicism). In this case, still only one copy of the changed gene is needed to cause FSS in a child.Dominant means that only a single copy of a changed gene is necessary to cause the condition. Autosomal means the changed gene is not located on one of the gender determining chromosomes, and the risk of an affected parent of either biologic gender passing the changed gene in an autosomal dominant condition like FSS to an offspring is 50% for each pregnancy.Except for women with FSS considering using in vetro fertilization to avoid an FSS pregnancy, determining if there is a change in the MYH3 gene or possibly another gene is not needed for diagnosis and does not affect or improve treatment. Diagnosis is based on the strict criteria of physical findings, which has strong agreement with genetic testing. While FSS severity differs greatly between individuals, each person affected has the same basic types of problems, and treatments have similar outcomes. | Causes of Freeman Sheldon Syndrome. There is no known link between FSS and environmental or parental factors, such as exposure to illnesses, toxins, drugs or harsh substances. Though the cause remains uncertain for a small percentage of people, FSS can be caused by a change (mutation or allelic variation) in the embryonic myosin heavy chain (MYH3) gene, which is located on band 13.1 of the short arm (p) of chromosome 17 (a locus of 17p13.1). FSS is believed to impair muscle development in the embryo and disrupt muscle function throughout life by causing the energy [adenosine triphosphate (ATP)] needed for muscles to tense (muscle contraction) and relax properly to have difficulty attaching to the myosin, one of the main parts of muscles fibers. This may happen because of reduced activity of enzymes that break the ATP bonds to the myosin (ATPase) that could be caused by mechanical problems with actin, the other main part of muscle fibers. When muscles cannot function normally, deformities in the bones, joints, and other areas can result.Most patients with FSS are born to normal healthy parents, and in this situation, FSS is not inherited but arises from a new change in the gene (new mutation). When FSS is inherited, almost all of the time one of the parents has FSS and passes on one copy of the gene to a child (autosomal dominant inheritance). In extremely rare situations, however, a parent may be healthy but have a MYH3 gene variant only in their reproductive cells (germline mosaicism). In this case, still only one copy of the changed gene is needed to cause FSS in a child.Dominant means that only a single copy of a changed gene is necessary to cause the condition. Autosomal means the changed gene is not located on one of the gender determining chromosomes, and the risk of an affected parent of either biologic gender passing the changed gene in an autosomal dominant condition like FSS to an offspring is 50% for each pregnancy.Except for women with FSS considering using in vetro fertilization to avoid an FSS pregnancy, determining if there is a change in the MYH3 gene or possibly another gene is not needed for diagnosis and does not affect or improve treatment. Diagnosis is based on the strict criteria of physical findings, which has strong agreement with genetic testing. While FSS severity differs greatly between individuals, each person affected has the same basic types of problems, and treatments have similar outcomes. | 482 | Freeman Sheldon Syndrome |
nord_482_3 | Affects of Freeman Sheldon Syndrome | FSS appears to occur all ethnicities, both biologic genders and all geographic regions, evenly. FSS is an exceptionally rare disorder. It is estimated that 200-300 individuals worldwide may be affected, but the number of diagnosed and undiagnosed persons with FSS (population prevalence) remains uncertain. | Affects of Freeman Sheldon Syndrome. FSS appears to occur all ethnicities, both biologic genders and all geographic regions, evenly. FSS is an exceptionally rare disorder. It is estimated that 200-300 individuals worldwide may be affected, but the number of diagnosed and undiagnosed persons with FSS (population prevalence) remains uncertain. | 482 | Freeman Sheldon Syndrome |
nord_482_4 | Related disorders of Freeman Sheldon Syndrome | Problems associated with other arthrogryposis and craniofacial disorders may resemble FSS. Generally, other disorders called distal arthrogryposis (DA) and arthrogryposis multiplex congenita (AMC), both broad groups of disorders that include hand, foot, head and face problems, may overlap with FSS. DAs and AMCs vary greatly in severity but are generally not inherited from parents. The major form of AMC is called amyoplasia. (For more information on this disorder, choose “arthrogryposis multiplex congenita” as your search term in the Rare Disease Database.)In the past, it was believed that persons with FSS could have cognitive problems, but it is now known that there are two lethal neurologic conditions that outwardly appear very similar to FSS but are distinct from it. Congenital contractures of the limbs and face, hypotonia, and developmental delay (CLIFAHDD; MIM 616266) is a distinct autosomal dominant lethal condition caused by changes in the sodium leak channel, non-selective (NALCN; MIM 611549) gene. Illum syndrome (MIM 208155) is lethal whistling face with limb deformities. These conditions are distinguished from FSS by profound and progressive neurologic motor and cognitive impairment. They also have different genetic causes than FSS.Distal arthrogryposis type 2B or Sheldon-Hall syndrome (SHS) resembles but is not as severe as FSS. SHS includes the following: minimal if any feeding problems after birth, less severe small mouth, neck webbing (pterygium colli), and small, prominent chin. Persons with SHS also are more likely to have outwardly turned feet (equinovagus) than inwardly turned feet (equinovarus), as happens in FSS. SHS can be inherited as autosomal dominant and can be associated with gene changes on either chromosome 17 or 11. Distal arthrogryposis type 1 (DA1) is less severe than FSS and SHS but lacks skull and face (craniofacial) problems. DA1 hand and foot problems can resemble FSS-associated problems. DA1 can be passed on in an autosomal dominant pattern and can be associated with gene changes on chromosome 9p13.2-13.1. Distal arthrogryposis type 3 (DA3 or Gordon syndrome) includes the same hand and foot problems as happen in FSS, SHS, and DA1, but DA3 most resembles DA1. Persons with DA3 have other problems not present in DA1, including: gap in the roof of the mouth (cleft palate), drooping eyelid (blepharoptosis), and backbone curve problems, but these problems are less severe than in either FSS or SHS. SHS, DA1, and DA3 can be passed on in an autosomal dominant pattern. Other disorders and conditions that may have some of the same problems that are associated with FSS but do not include joint and skull and face problems to the degree of similarity of the above syndromes include: Schwartz-Jampel syndrome, trismuspseudocamptodactyly syndrome, and multiple pterygium syndrome. Problems in Schwartz-Jampel syndrome that may resemble those observed in FSS are muscle weakness and stiffness (myotonic myopathy), which is not present in persons with FSS, and various joint, spine, and eye problems that may be similar to FSS. Persons with trismus-pseudocamptodactyly syndrome are unable to fully open their mouth and have short tendons attaching to flexing type muscles, which mimics abnormal bending of fingers (camptodactyly). Persons with trismus-pseudocamptodactyly syndrome may have some other problems that can be similar to FSS, including under-developed jaw (micrognathia), swallowing problems (dysphagia), and too much space between the nose and upper lip (long philtrum). The main problem of multiple pterygium syndrome that may be present in persons with FSS, as well is webbed-appearance (pterygium) of skin around certain joints. | Related disorders of Freeman Sheldon Syndrome. Problems associated with other arthrogryposis and craniofacial disorders may resemble FSS. Generally, other disorders called distal arthrogryposis (DA) and arthrogryposis multiplex congenita (AMC), both broad groups of disorders that include hand, foot, head and face problems, may overlap with FSS. DAs and AMCs vary greatly in severity but are generally not inherited from parents. The major form of AMC is called amyoplasia. (For more information on this disorder, choose “arthrogryposis multiplex congenita” as your search term in the Rare Disease Database.)In the past, it was believed that persons with FSS could have cognitive problems, but it is now known that there are two lethal neurologic conditions that outwardly appear very similar to FSS but are distinct from it. Congenital contractures of the limbs and face, hypotonia, and developmental delay (CLIFAHDD; MIM 616266) is a distinct autosomal dominant lethal condition caused by changes in the sodium leak channel, non-selective (NALCN; MIM 611549) gene. Illum syndrome (MIM 208155) is lethal whistling face with limb deformities. These conditions are distinguished from FSS by profound and progressive neurologic motor and cognitive impairment. They also have different genetic causes than FSS.Distal arthrogryposis type 2B or Sheldon-Hall syndrome (SHS) resembles but is not as severe as FSS. SHS includes the following: minimal if any feeding problems after birth, less severe small mouth, neck webbing (pterygium colli), and small, prominent chin. Persons with SHS also are more likely to have outwardly turned feet (equinovagus) than inwardly turned feet (equinovarus), as happens in FSS. SHS can be inherited as autosomal dominant and can be associated with gene changes on either chromosome 17 or 11. Distal arthrogryposis type 1 (DA1) is less severe than FSS and SHS but lacks skull and face (craniofacial) problems. DA1 hand and foot problems can resemble FSS-associated problems. DA1 can be passed on in an autosomal dominant pattern and can be associated with gene changes on chromosome 9p13.2-13.1. Distal arthrogryposis type 3 (DA3 or Gordon syndrome) includes the same hand and foot problems as happen in FSS, SHS, and DA1, but DA3 most resembles DA1. Persons with DA3 have other problems not present in DA1, including: gap in the roof of the mouth (cleft palate), drooping eyelid (blepharoptosis), and backbone curve problems, but these problems are less severe than in either FSS or SHS. SHS, DA1, and DA3 can be passed on in an autosomal dominant pattern. Other disorders and conditions that may have some of the same problems that are associated with FSS but do not include joint and skull and face problems to the degree of similarity of the above syndromes include: Schwartz-Jampel syndrome, trismuspseudocamptodactyly syndrome, and multiple pterygium syndrome. Problems in Schwartz-Jampel syndrome that may resemble those observed in FSS are muscle weakness and stiffness (myotonic myopathy), which is not present in persons with FSS, and various joint, spine, and eye problems that may be similar to FSS. Persons with trismus-pseudocamptodactyly syndrome are unable to fully open their mouth and have short tendons attaching to flexing type muscles, which mimics abnormal bending of fingers (camptodactyly). Persons with trismus-pseudocamptodactyly syndrome may have some other problems that can be similar to FSS, including under-developed jaw (micrognathia), swallowing problems (dysphagia), and too much space between the nose and upper lip (long philtrum). The main problem of multiple pterygium syndrome that may be present in persons with FSS, as well is webbed-appearance (pterygium) of skin around certain joints. | 482 | Freeman Sheldon Syndrome |
nord_482_5 | Diagnosis of Freeman Sheldon Syndrome | FSS is diagnosed by thorough physical examination and medical history. Plastic surgeons and anesthesiologists who specialize in treating patients with skull and face problems are the best to diagnose and evaluate patients who may have FSS. The following problems must be present for diagnosis of FSS: small mouth (microstomia), whistling-face (pursed lips as in someone trying to whistle), down-slanting crease from the nostril to the corners of the mouth (nasolabial creases), and “H” or “V” shaped chin dimple. Classically, there must be two or more body areas with limited movement of joints, frequently the hands or feet and ankles, but FSS may be diagnosed without problems beyond the face. Patients who have the facial deformities plus two or more body areas with limited movement of joints are considered to have FSS type 1, classic. Patients who have only the facial deformities are considered to have FSS type 2, craniofacial. Patients who have the facial deformities plus one body areas with limited movement of joints are considered to have FSS type 3, mixed (upper or lower extremities). Patients with FSS type 2 tend to be the most mild and have the least complications, and patients with FSS type 1 or “classic” tend to be the most seriously affected and more likely to have medical complications. Patients with FSS type 3 fall between FSS types 1 and 2.Medical imaging, muscle and nerve function tests, and breathing tests, may add more information needed for treatment but not for diagnosis. Diagnosis of FSS before birth (prenatal) may be possible if a parent has FSS, but it is not considered definitive. If in vitro fertilization is used by a woman with FSS and the gene change causing FSS is known, pre-pregnancy (before eggs are fertilized) diagnosis can be made by testing polar bodies from eggs, which have the same genetic material as the egg but do not develop. | Diagnosis of Freeman Sheldon Syndrome. FSS is diagnosed by thorough physical examination and medical history. Plastic surgeons and anesthesiologists who specialize in treating patients with skull and face problems are the best to diagnose and evaluate patients who may have FSS. The following problems must be present for diagnosis of FSS: small mouth (microstomia), whistling-face (pursed lips as in someone trying to whistle), down-slanting crease from the nostril to the corners of the mouth (nasolabial creases), and “H” or “V” shaped chin dimple. Classically, there must be two or more body areas with limited movement of joints, frequently the hands or feet and ankles, but FSS may be diagnosed without problems beyond the face. Patients who have the facial deformities plus two or more body areas with limited movement of joints are considered to have FSS type 1, classic. Patients who have only the facial deformities are considered to have FSS type 2, craniofacial. Patients who have the facial deformities plus one body areas with limited movement of joints are considered to have FSS type 3, mixed (upper or lower extremities). Patients with FSS type 2 tend to be the most mild and have the least complications, and patients with FSS type 1 or “classic” tend to be the most seriously affected and more likely to have medical complications. Patients with FSS type 3 fall between FSS types 1 and 2.Medical imaging, muscle and nerve function tests, and breathing tests, may add more information needed for treatment but not for diagnosis. Diagnosis of FSS before birth (prenatal) may be possible if a parent has FSS, but it is not considered definitive. If in vitro fertilization is used by a woman with FSS and the gene change causing FSS is known, pre-pregnancy (before eggs are fertilized) diagnosis can be made by testing polar bodies from eggs, which have the same genetic material as the egg but do not develop. | 482 | Freeman Sheldon Syndrome |
nord_482_6 | Therapies of Freeman Sheldon Syndrome | Treatment
The underlying cause of the problems in persons with FSS is not fully understood, and treatment targets specific, functional problems. Since FSS is primarily a condition of the face and skull (craniofacial), overall care is best provided and coordinated by a craniofacial surgeon. Patients with FSS who receive overall care from a doctor in another speciality may have poorer outcomes. Doctors from other specialities may not have the training or experience to understand how the patient’s face and skull problems can affect their general health and psychosocial functioning. Treatment includes physical, occupational, and speech therapy; and limited, specific use of surgery, especially oral-maxillofacial (dental and mouth problems) and plastic surgery (face, head, and hand problems). Surgery may be used to extend benefits gained in physical, occupational, and speech therapy. Abnormal muscle function sometimes limits surgical options and causes unfavorable surgical outcomes. It should be expected that surgeries will need to be repeated periodically because of the abnormalities of the muscle. Follow-up surgeries target the muscles to release the abnormal areas to reduce tension and allow greater movement.To gain the greatest functional benefit and lessen psychosocial consequences, any face and skull reconstructive surgery deemed feasible should occur before early school years. Failure to operate on the face and skull early in the child’s life reduces treatment options later to improve speech, ability to breathe through the nose, access to the mouth to allow dental care, and facial appearance, as facial deformities can be a significant burden to the child throughout their life, impacting all areas of interpersonal interaction. If the eyelids cause obstruction of vision, failure to operate early can result in blindness. For patients with FSS, the ability to improve the appearance of the face is, however, limited. Deformities of the hands, feet, and spine are best treated with aggressive physical therapy and without surgery. Braces and splints may be helpful to maintain the corrections gained by physical and occupational therapy. While physical therapy for the hands is best done soon after birth and in early childhood, it may be possible to do some corrective physical therapy into early adulthood. Generally, surgery for deformities of the feet should not be attempted, as the feet present a very poor surgical risk in most patients with FSS. Failure of surgery on the feet can result in non-functional feet or loss of one or both feet. For patients whose foot deformities cannot be corrected with physical therapy and braces, prosthetics (without need for amputation) can be used to transfer the weight-bearing to the knee and leg and allow the person to walk comfortably.With appropriate therapy, including limited use of surgery, prognosis can be very good for most persons with FSS. Early diagnosis, aggressive physical therapy and maintaining a healthy, active lifestyle is associated with the best outcomes and minimizes the impact of physical problems on development. | Therapies of Freeman Sheldon Syndrome. Treatment
The underlying cause of the problems in persons with FSS is not fully understood, and treatment targets specific, functional problems. Since FSS is primarily a condition of the face and skull (craniofacial), overall care is best provided and coordinated by a craniofacial surgeon. Patients with FSS who receive overall care from a doctor in another speciality may have poorer outcomes. Doctors from other specialities may not have the training or experience to understand how the patient’s face and skull problems can affect their general health and psychosocial functioning. Treatment includes physical, occupational, and speech therapy; and limited, specific use of surgery, especially oral-maxillofacial (dental and mouth problems) and plastic surgery (face, head, and hand problems). Surgery may be used to extend benefits gained in physical, occupational, and speech therapy. Abnormal muscle function sometimes limits surgical options and causes unfavorable surgical outcomes. It should be expected that surgeries will need to be repeated periodically because of the abnormalities of the muscle. Follow-up surgeries target the muscles to release the abnormal areas to reduce tension and allow greater movement.To gain the greatest functional benefit and lessen psychosocial consequences, any face and skull reconstructive surgery deemed feasible should occur before early school years. Failure to operate on the face and skull early in the child’s life reduces treatment options later to improve speech, ability to breathe through the nose, access to the mouth to allow dental care, and facial appearance, as facial deformities can be a significant burden to the child throughout their life, impacting all areas of interpersonal interaction. If the eyelids cause obstruction of vision, failure to operate early can result in blindness. For patients with FSS, the ability to improve the appearance of the face is, however, limited. Deformities of the hands, feet, and spine are best treated with aggressive physical therapy and without surgery. Braces and splints may be helpful to maintain the corrections gained by physical and occupational therapy. While physical therapy for the hands is best done soon after birth and in early childhood, it may be possible to do some corrective physical therapy into early adulthood. Generally, surgery for deformities of the feet should not be attempted, as the feet present a very poor surgical risk in most patients with FSS. Failure of surgery on the feet can result in non-functional feet or loss of one or both feet. For patients whose foot deformities cannot be corrected with physical therapy and braces, prosthetics (without need for amputation) can be used to transfer the weight-bearing to the knee and leg and allow the person to walk comfortably.With appropriate therapy, including limited use of surgery, prognosis can be very good for most persons with FSS. Early diagnosis, aggressive physical therapy and maintaining a healthy, active lifestyle is associated with the best outcomes and minimizes the impact of physical problems on development. | 482 | Freeman Sheldon Syndrome |
nord_483_0 | Overview of Frey Syndrome | SummaryFrey syndrome is a rare disorder that most often occurs as a result of surgery in the area near the parotid glands. The parotid glands are the largest salivary glands in the body located just below the ears on either side of the face. The main symptoms of Frey syndrome are undesirable sweating and flushing occurring on the cheek, temple (temporal region), or behind the ears (retroauricular region) after eating certain foods, especially those that produce a strong salivary response. Symptoms are often mild and well-tolerated. In some people , symptoms may be more severe and therapy may be necessary. The exact underlying mechanisms that cause Frey syndrome are not fully understood. Frey syndrome most often occurs as a complication of surgery to the area of the face near the parotid glands.IntroductionThe disorder was first reported in the medical literature by Baillarger in 1853. A neurologist from Poland, Dr. Lucja Frey, provided a detailed assessment of the disorder and coined the term “auriculotemporal syndrome” in 1923. | Overview of Frey Syndrome. SummaryFrey syndrome is a rare disorder that most often occurs as a result of surgery in the area near the parotid glands. The parotid glands are the largest salivary glands in the body located just below the ears on either side of the face. The main symptoms of Frey syndrome are undesirable sweating and flushing occurring on the cheek, temple (temporal region), or behind the ears (retroauricular region) after eating certain foods, especially those that produce a strong salivary response. Symptoms are often mild and well-tolerated. In some people , symptoms may be more severe and therapy may be necessary. The exact underlying mechanisms that cause Frey syndrome are not fully understood. Frey syndrome most often occurs as a complication of surgery to the area of the face near the parotid glands.IntroductionThe disorder was first reported in the medical literature by Baillarger in 1853. A neurologist from Poland, Dr. Lucja Frey, provided a detailed assessment of the disorder and coined the term “auriculotemporal syndrome” in 1923. | 483 | Frey Syndrome |
nord_483_1 | Symptoms of Frey Syndrome | The symptoms of Frey syndrome typically develop within the first year after surgery in the area near the parotid glands. In some cases, Frey syndrome may not develop until several years after surgery. The characteristic symptom of Frey syndrome is gustatory sweating, which is excessive sweating on the cheek, forehead, and around the ears shortly after eating certain foods, specifically foods that produce a strong salivary response such as sour, spicy or salty foods.Additional symptoms that may be associated with Frey syndrome include flushing and warmth in the affected areas. This is rarely an important complaint.While other symptoms have been associated with the syndrome, they are probably unrelated. Pain is sometimes described, but it is probably more related to the surgery than actually to Frey syndrome. The specific area affected, the size of the area, and the degree of sweating and flushing vary greatly among affected individuals. In some patients, symptoms may be mild and affected individuals may not be bothered by the symptoms. In other cases, such as those that experience profuse sweating, affected individuals may require therapy. | Symptoms of Frey Syndrome. The symptoms of Frey syndrome typically develop within the first year after surgery in the area near the parotid glands. In some cases, Frey syndrome may not develop until several years after surgery. The characteristic symptom of Frey syndrome is gustatory sweating, which is excessive sweating on the cheek, forehead, and around the ears shortly after eating certain foods, specifically foods that produce a strong salivary response such as sour, spicy or salty foods.Additional symptoms that may be associated with Frey syndrome include flushing and warmth in the affected areas. This is rarely an important complaint.While other symptoms have been associated with the syndrome, they are probably unrelated. Pain is sometimes described, but it is probably more related to the surgery than actually to Frey syndrome. The specific area affected, the size of the area, and the degree of sweating and flushing vary greatly among affected individuals. In some patients, symptoms may be mild and affected individuals may not be bothered by the symptoms. In other cases, such as those that experience profuse sweating, affected individuals may require therapy. | 483 | Frey Syndrome |
nord_483_2 | Causes of Frey Syndrome | The exact underlying cause of Frey syndrome is not completely understood. The most widely held theory is that Frey syndrome results from simultaneous damage to sympathetic and parasympathetic nerves in the region of the face or neck near the parotid glands. Parasympathetic nerves are part of the autonomic nervous system, which is the portion of the nerve system that controls or regulates involuntary body functions (i.e., those functions that occur without instruction from the conscious mind). One function of parasympathetic nerves is to regulate the activity of glands including the parotid glands, but not the sweat glands. Sweat glands and blood vessels throughout the body are controlled by sympathetic fibers.In Frey syndrome, researchers believe that the parasympathetic and sympathetic nerves near the parotid glands are cut, especially tiny branches originating from the auriculotemporal nerve. The auriculotemporal nerve supplies nerves (innervates) to certain structures in the face including the parotid glands.Normally, damaged nerve fiber(s) eventually heal themselves (regenerate). In Frey syndrome, it is believed that damaged nerve fibers regenerate abnormally by growing along the sympathetic fiber pathways, ultimately connecting to the miniscule sweat glands found along the skin. Therefore, the parasympathetic nerves that normally tell the parotid glands to produce saliva in response to tasting food now respond by instructing the sweat glands to produce sweat and the blood vessels to widen (dilate). The cumulative result is excessive sweating and flushing when eating certain foods.Damage to the nerves in the parotid gland region of the face may occur for several different reasons including as a complication of surgery or blunt trauma to the side of the face. In older reports, infections of the parotid glands were suspected, but a detailed examination always points to a surgical drainage of a parotid abscess. The most common reported cause of Frey syndrome is a surgical procedure called a parotidectomy (the surgical removal of a parotid gland). Although the exact percentage is not agreed upon in the medical literature, some sources suggest that more than half of all individuals who undergo a parotidectomy eventually develop Frey syndrome. A recent meta-analysis concluded that the interposition of tissue after parotidectomy might decrease the incidence of Frey syndrome after parotidectomy.Another rarely described cause (etiology) of Frey syndrome is damage to the main sympathetic nerve chain in the neck.In extremely rare cases, Frey syndrome has been described in newborns, possibly following trauma due to delivery with forceps. Actual careful examination reveals that the principal symptom is flushing which might be physiologic at a younger age. The key symptom of facial sweating is not emphasized in newborns rising doubts about the correctness of these observations. | Causes of Frey Syndrome. The exact underlying cause of Frey syndrome is not completely understood. The most widely held theory is that Frey syndrome results from simultaneous damage to sympathetic and parasympathetic nerves in the region of the face or neck near the parotid glands. Parasympathetic nerves are part of the autonomic nervous system, which is the portion of the nerve system that controls or regulates involuntary body functions (i.e., those functions that occur without instruction from the conscious mind). One function of parasympathetic nerves is to regulate the activity of glands including the parotid glands, but not the sweat glands. Sweat glands and blood vessels throughout the body are controlled by sympathetic fibers.In Frey syndrome, researchers believe that the parasympathetic and sympathetic nerves near the parotid glands are cut, especially tiny branches originating from the auriculotemporal nerve. The auriculotemporal nerve supplies nerves (innervates) to certain structures in the face including the parotid glands.Normally, damaged nerve fiber(s) eventually heal themselves (regenerate). In Frey syndrome, it is believed that damaged nerve fibers regenerate abnormally by growing along the sympathetic fiber pathways, ultimately connecting to the miniscule sweat glands found along the skin. Therefore, the parasympathetic nerves that normally tell the parotid glands to produce saliva in response to tasting food now respond by instructing the sweat glands to produce sweat and the blood vessels to widen (dilate). The cumulative result is excessive sweating and flushing when eating certain foods.Damage to the nerves in the parotid gland region of the face may occur for several different reasons including as a complication of surgery or blunt trauma to the side of the face. In older reports, infections of the parotid glands were suspected, but a detailed examination always points to a surgical drainage of a parotid abscess. The most common reported cause of Frey syndrome is a surgical procedure called a parotidectomy (the surgical removal of a parotid gland). Although the exact percentage is not agreed upon in the medical literature, some sources suggest that more than half of all individuals who undergo a parotidectomy eventually develop Frey syndrome. A recent meta-analysis concluded that the interposition of tissue after parotidectomy might decrease the incidence of Frey syndrome after parotidectomy.Another rarely described cause (etiology) of Frey syndrome is damage to the main sympathetic nerve chain in the neck.In extremely rare cases, Frey syndrome has been described in newborns, possibly following trauma due to delivery with forceps. Actual careful examination reveals that the principal symptom is flushing which might be physiologic at a younger age. The key symptom of facial sweating is not emphasized in newborns rising doubts about the correctness of these observations. | 483 | Frey Syndrome |
nord_483_3 | Affects of Frey Syndrome | The exact incidence of Frey syndrome is unknown. The disorder most often occurs as a complication of the surgical removal of a parotid gland (parotidectomy). The percentage of individuals who develop Frey syndrome after a parotidectomy is controversial and reported estimates range from 30-50 percent. In follow-up examinations, approximately 15 percent of affected individuals rated their symptoms as severe. Frey syndrome affects males and females in equal numbers. | Affects of Frey Syndrome. The exact incidence of Frey syndrome is unknown. The disorder most often occurs as a complication of the surgical removal of a parotid gland (parotidectomy). The percentage of individuals who develop Frey syndrome after a parotidectomy is controversial and reported estimates range from 30-50 percent. In follow-up examinations, approximately 15 percent of affected individuals rated their symptoms as severe. Frey syndrome affects males and females in equal numbers. | 483 | Frey Syndrome |
nord_483_4 | Related disorders of Frey Syndrome | Symptoms of the following disorders can be similar to those of Frey syndrome. Comparisons may be useful for a differential diagnosis.General hyperhidrosis refers to any condition that causes excessive sweating (hyperhidrosis) on large areas of the body. A wide variety of conditions can cause profuse sweating as a symptom. These conditions include, but are not limited to, impaired thyroid function, pituitary abnormalities, allergies, metabolic diseases, infectious diseases, diabetes, menopause and a variety of tumors. General hyperhidrosis may occur as a complication of drug use. Generalized hyperhidrosis can affect individuals of any age, race, gender or ethnic background. (For more information on this disorder, choose the specific disorder name as your search term in the Rare Disease Database.) | Related disorders of Frey Syndrome. Symptoms of the following disorders can be similar to those of Frey syndrome. Comparisons may be useful for a differential diagnosis.General hyperhidrosis refers to any condition that causes excessive sweating (hyperhidrosis) on large areas of the body. A wide variety of conditions can cause profuse sweating as a symptom. These conditions include, but are not limited to, impaired thyroid function, pituitary abnormalities, allergies, metabolic diseases, infectious diseases, diabetes, menopause and a variety of tumors. General hyperhidrosis may occur as a complication of drug use. Generalized hyperhidrosis can affect individuals of any age, race, gender or ethnic background. (For more information on this disorder, choose the specific disorder name as your search term in the Rare Disease Database.) | 483 | Frey Syndrome |
nord_483_5 | Diagnosis of Frey Syndrome | A diagnosis of Frey syndrome is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a specialized test called the minor iodine-starch test. During this test, an iodine solution is applied to the affected areas of the face. Then, a starch powder such as corn starch is applied over the iodine solution. Individuals are then given an oral stimulus usually a highly acidic food such as a lemon wedge. In affected individuals, discoloration (usually purple) due to excessive sweating occurs on the affected areas. | Diagnosis of Frey Syndrome. A diagnosis of Frey syndrome is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a specialized test called the minor iodine-starch test. During this test, an iodine solution is applied to the affected areas of the face. Then, a starch powder such as corn starch is applied over the iodine solution. Individuals are then given an oral stimulus usually a highly acidic food such as a lemon wedge. In affected individuals, discoloration (usually purple) due to excessive sweating occurs on the affected areas. | 483 | Frey Syndrome |
nord_483_6 | Therapies of Frey Syndrome | Treatment
Although Frey syndrome can be mild and well-tolerated, in some individuals, it can cause excessive discomfort. Treatment is symptomatic and directed toward relief of symptoms. Until recently, most treatment measures have generally been unsatisfactory. Treatment options include drug therapy or surgery.Topical application of drugs that block certain activities of the nervous system (anticholinergics) or drugs that hinder sweating (antihidrotics) have been used. Surgical removal (excision) of the affected skin and the insertion (interposition) of new tissue to the affected area (muscle flaps) has been described, but are considered risky because of the presence of facial nerve fibers right below the skin after parotidectomy.In the last decade botulinum A toxin has become established as a therapy for individuals with bothersome Frey syndrome. The therapy consists of local injections of botulinum A toxin in the affected skin. Initial results have demonstrated that this therapy results in the suppression of sweating and causes no significant side effects. Another advantage of botulinum A toxin is that it is minimally invasive compared to other therapies. As in other indications, the effect of botulinum toxin is not permanent, lasting on average about 9-12 months. | Therapies of Frey Syndrome. Treatment
Although Frey syndrome can be mild and well-tolerated, in some individuals, it can cause excessive discomfort. Treatment is symptomatic and directed toward relief of symptoms. Until recently, most treatment measures have generally been unsatisfactory. Treatment options include drug therapy or surgery.Topical application of drugs that block certain activities of the nervous system (anticholinergics) or drugs that hinder sweating (antihidrotics) have been used. Surgical removal (excision) of the affected skin and the insertion (interposition) of new tissue to the affected area (muscle flaps) has been described, but are considered risky because of the presence of facial nerve fibers right below the skin after parotidectomy.In the last decade botulinum A toxin has become established as a therapy for individuals with bothersome Frey syndrome. The therapy consists of local injections of botulinum A toxin in the affected skin. Initial results have demonstrated that this therapy results in the suppression of sweating and causes no significant side effects. Another advantage of botulinum A toxin is that it is minimally invasive compared to other therapies. As in other indications, the effect of botulinum toxin is not permanent, lasting on average about 9-12 months. | 483 | Frey Syndrome |
nord_484_0 | Overview of Friedreich’s Ataxia | Friedreich’s ataxia (FRDA) is a genetic, progressive, neurodegenerative movement disorder, with a typical age of onset between 10 and 15 years. Initial symptoms may include unsteady posture, frequent falling, and progressive difficulty in walking due to impaired ability to coordinate voluntary movements (ataxia). Affected individuals often develop slurred speech (dysarthria), characteristic foot deformities, and an irregular curvature of the spine (scoliosis). FRDA is often associated with cardiomyopathy, a disease of cardiac muscle that may lead to heart failure or irregularities in heart rhythm (cardiac arrhythmias). About a third of the people with FRDA develop diabetes mellitus. The symptoms and clinical findings associated with FRDA result primarily from degenerative changes in the sensory nerve fibers at the point where they enter the spinal cord in structures known as dorsal root ganglia. This results in secondary degeneration of nerve fibers in the spinal cord which leads to a deficiency of sensory signals to the cerebellum, the part of the brain that helps to coordinate voluntary movements. FRDA is caused by abnormalities (mutations) in the FXN gene and people with FRDA inherit a mutation from each parent, so they have mutations in both copies of their FXN gene. This pattern, wherein parents who are clinically unaffected because they only carry a single mutated FXN gene but can have a child who is affected because he / she inherits a mutation from both carrier parents, is called autosomal recessive inheritance. | Overview of Friedreich’s Ataxia. Friedreich’s ataxia (FRDA) is a genetic, progressive, neurodegenerative movement disorder, with a typical age of onset between 10 and 15 years. Initial symptoms may include unsteady posture, frequent falling, and progressive difficulty in walking due to impaired ability to coordinate voluntary movements (ataxia). Affected individuals often develop slurred speech (dysarthria), characteristic foot deformities, and an irregular curvature of the spine (scoliosis). FRDA is often associated with cardiomyopathy, a disease of cardiac muscle that may lead to heart failure or irregularities in heart rhythm (cardiac arrhythmias). About a third of the people with FRDA develop diabetes mellitus. The symptoms and clinical findings associated with FRDA result primarily from degenerative changes in the sensory nerve fibers at the point where they enter the spinal cord in structures known as dorsal root ganglia. This results in secondary degeneration of nerve fibers in the spinal cord which leads to a deficiency of sensory signals to the cerebellum, the part of the brain that helps to coordinate voluntary movements. FRDA is caused by abnormalities (mutations) in the FXN gene and people with FRDA inherit a mutation from each parent, so they have mutations in both copies of their FXN gene. This pattern, wherein parents who are clinically unaffected because they only carry a single mutated FXN gene but can have a child who is affected because he / she inherits a mutation from both carrier parents, is called autosomal recessive inheritance. | 484 | Friedreich’s Ataxia |
nord_484_1 | Symptoms of Friedreich’s Ataxia | The primary symptom of FRDA is progressive ataxia of the limbs and during walking. Ataxia involves inadequate muscle coordination that results in an unsteady gait, and poor control of fine movements of the limbs. Involvement of muscles in the mouth and throat may lead to slurred speech and impaired swallowing. Intellect is generally unaffected. Sideways curvature of the spine (scoliosis) or foot abnormalities may develop. A form of heart disease (cardiomyopathy) may develop in over half of the people with FRDA. Since there is no effective therapy for FRDA, the clinical features continue to progress and after initially making use of walking aids people with FRDA ultimately require the use of a wheelchair for mobility.Atypical PresentationsLate-onset FRDA (LOFA)/Very late onset FRDA (VLOFA)
Most people with FRDA are diagnosed before age 25. LOFA and VLOFA are subtypes that affect approximately 15% of individuals with Friedreich’s ataxia. For LOFA the age of onset is between the ages of 26 and 39 years, and for VLOFA the age of onset is after the age of 40 years. Typically, disease progression in these individuals is slower than that associated with typical FRDA.FRDA with retained reflexes (FARR)
FARR affects approximately 12% of individuals with FRDA. Tendon reflexes in these individuals can be retained for up to 10 years from the time of onset. This variation of FRDA is often also associated with LOFA / VLOFA (see above). | Symptoms of Friedreich’s Ataxia. The primary symptom of FRDA is progressive ataxia of the limbs and during walking. Ataxia involves inadequate muscle coordination that results in an unsteady gait, and poor control of fine movements of the limbs. Involvement of muscles in the mouth and throat may lead to slurred speech and impaired swallowing. Intellect is generally unaffected. Sideways curvature of the spine (scoliosis) or foot abnormalities may develop. A form of heart disease (cardiomyopathy) may develop in over half of the people with FRDA. Since there is no effective therapy for FRDA, the clinical features continue to progress and after initially making use of walking aids people with FRDA ultimately require the use of a wheelchair for mobility.Atypical PresentationsLate-onset FRDA (LOFA)/Very late onset FRDA (VLOFA)
Most people with FRDA are diagnosed before age 25. LOFA and VLOFA are subtypes that affect approximately 15% of individuals with Friedreich’s ataxia. For LOFA the age of onset is between the ages of 26 and 39 years, and for VLOFA the age of onset is after the age of 40 years. Typically, disease progression in these individuals is slower than that associated with typical FRDA.FRDA with retained reflexes (FARR)
FARR affects approximately 12% of individuals with FRDA. Tendon reflexes in these individuals can be retained for up to 10 years from the time of onset. This variation of FRDA is often also associated with LOFA / VLOFA (see above). | 484 | Friedreich’s Ataxia |
nord_484_2 | Causes of Friedreich’s Ataxia | The gene responsible for FRDA has been designated FXN. The FXN gene codes for frataxin, a protein that is required for proper functioning of mitochondria, which are the energy producing parts of our cells. In people with FRDA, since both copies of the FXN gene are abnormal and they do not produce adequate amounts of frataxin, tissues that are especially dependent on cellular energy production (e.g. nerve and heart cells) start to degenerate.In most affected individuals, the FXN gene contains a very specific type of error called an expanded GAA trinucleotide repeat. Every gene consists of different arrangements of four chemical units (nucleotides) called adenine (A), cytosine (C), guanine (G), and thymine (T). In most people with FRDA, both copies of the FXN gene contain abnormally long tracts of repeating units consisting of guanine-adenine-adenine (GAA trinucleotide repeat). So, while people without FRDA have less than 30 GAA repeats, individuals with FRDA typically have expanded tracts ranging from 100 to 1300 repeats in both copies of the FXN gene, with the majority containing >400 repeats. Even though this expanded GAA repeat mutation is located within a “non-coding” region of the FXN gene (called intron 1) it results in gene silencing and reduction in capacity to produce frataxin protein. Indeed, the severity of FXN gene silencing is proportional to the length of the expanded GAA repeat mutation. The variability of associated symptoms and findings is also correlated with the size of expanded GAA repeats. For example, shorter expansions (<400 GAA repeats) are often associated with later age of onset, slower progression of clinical features, and absence of or mild cardiomyopathy. Parents of individuals with FRDA have one copy of the expanded GAA repeat mutation and one normal FXN gene, and they do not develop any signs of disease. While the majority of people with FRDA have the expanded GAA repeat mutation in both copies of the FXN gene, a few (<5-10%) have the expanded GAA repeat mutation on one copy of the FXN gene and another type of abnormality (mutation) in the other FXN gene copy.FRDA is inherited as an autosomal recessive condition. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same condition, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease and will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The chance of having a child who is an unaffected 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 condition is 25%. The risk is the same for both males and females. | Causes of Friedreich’s Ataxia. The gene responsible for FRDA has been designated FXN. The FXN gene codes for frataxin, a protein that is required for proper functioning of mitochondria, which are the energy producing parts of our cells. In people with FRDA, since both copies of the FXN gene are abnormal and they do not produce adequate amounts of frataxin, tissues that are especially dependent on cellular energy production (e.g. nerve and heart cells) start to degenerate.In most affected individuals, the FXN gene contains a very specific type of error called an expanded GAA trinucleotide repeat. Every gene consists of different arrangements of four chemical units (nucleotides) called adenine (A), cytosine (C), guanine (G), and thymine (T). In most people with FRDA, both copies of the FXN gene contain abnormally long tracts of repeating units consisting of guanine-adenine-adenine (GAA trinucleotide repeat). So, while people without FRDA have less than 30 GAA repeats, individuals with FRDA typically have expanded tracts ranging from 100 to 1300 repeats in both copies of the FXN gene, with the majority containing >400 repeats. Even though this expanded GAA repeat mutation is located within a “non-coding” region of the FXN gene (called intron 1) it results in gene silencing and reduction in capacity to produce frataxin protein. Indeed, the severity of FXN gene silencing is proportional to the length of the expanded GAA repeat mutation. The variability of associated symptoms and findings is also correlated with the size of expanded GAA repeats. For example, shorter expansions (<400 GAA repeats) are often associated with later age of onset, slower progression of clinical features, and absence of or mild cardiomyopathy. Parents of individuals with FRDA have one copy of the expanded GAA repeat mutation and one normal FXN gene, and they do not develop any signs of disease. While the majority of people with FRDA have the expanded GAA repeat mutation in both copies of the FXN gene, a few (<5-10%) have the expanded GAA repeat mutation on one copy of the FXN gene and another type of abnormality (mutation) in the other FXN gene copy.FRDA is inherited as an autosomal recessive condition. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same condition, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease and will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The chance of having a child who is an unaffected 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 condition is 25%. The risk is the same for both males and females. | 484 | Friedreich’s Ataxia |
nord_484_3 | Affects of Friedreich’s Ataxia | The prevalence of FRDA is approximately 1 in 40,000 people. FRDA is the most common inherited ataxia in Europe, the Middle East, South Asia (Indian subcontinent), and North Africa. It is rarely identified in other populations. | Affects of Friedreich’s Ataxia. The prevalence of FRDA is approximately 1 in 40,000 people. FRDA is the most common inherited ataxia in Europe, the Middle East, South Asia (Indian subcontinent), and North Africa. It is rarely identified in other populations. | 484 | Friedreich’s Ataxia |
nord_484_4 | Related disorders of Friedreich’s Ataxia | Symptoms of the following disorders can be similar to those of Friedreich’s ataxia. Careful examination may be useful for differential diagnosis.Ataxia is a group of disorders that are characterized by an unsteady gait caused by the failure of voluntary muscle coordination. There are many forms of ataxia. Some ataxias are hereditary and some may have other causes. (To locate information about other types of ataxia choose “Ataxia” as your search term in the Rare Disease Database.)Ataxia with vitamin E deficiency (AVED) is an autosomal recessive genetic disorder caused by mutations in the TTPA gene, and symptoms may be similar to those associated with FRDA. Unlike FRDA, AVED can be treated with life-long vitamin E supplements.Charcot Marie Tooth disease is a group of disorders in which the motor and/or sensory peripheral nerves are affected, resulting in muscle weakness and atrophy, as well as sensory loss. The nerve cells in individuals with this disorder are not able to send electrical signals properly because of abnormalities in the nerve axon or abnormalities in the insulation (myelin) around the axon. Specific gene mutations are responsible for Charcot Marie Tooth disease, which can be inherited in an autosomal dominant, autosomal recessive or X-linked mode of inheritance. (For more information on this disorder, choose “Charcot-Marie-Tooth disease” as your search term in the Rare Disease Database.)Spinocerebellar ataxia with axonal neuropathy (SCAN1) is an autosomal recessive neurodegenerative disorder caused by mutations in the TDP1 gene and characterized by late childhood-onset of a slowly progressive cerebellar ataxia, followed by absence of reflexes and signs of peripheral neuropathy such as numbness, tingling, pricking sensations or muscle weakness.Ataxia telangiectasia is an inherited progressive cerebellar ataxia that is characterized by the loss of motor coordination in the limbs and head. An early sign of this disorder is impaired muscle coordination which is most evident when walking. Dilated blood vessels (telangiectasias) appear in the eyes at 3-6 years of age and also appear eventually on the face and the roof of the mouth. Ataxia telangiectasia may be misdiagnosed as FRDA until telangiectasias appear. (For more information on this disorder, choose “Ataxia Telangiectasia” as your search term in the Rare Disease Database.) | Related disorders of Friedreich’s Ataxia. Symptoms of the following disorders can be similar to those of Friedreich’s ataxia. Careful examination may be useful for differential diagnosis.Ataxia is a group of disorders that are characterized by an unsteady gait caused by the failure of voluntary muscle coordination. There are many forms of ataxia. Some ataxias are hereditary and some may have other causes. (To locate information about other types of ataxia choose “Ataxia” as your search term in the Rare Disease Database.)Ataxia with vitamin E deficiency (AVED) is an autosomal recessive genetic disorder caused by mutations in the TTPA gene, and symptoms may be similar to those associated with FRDA. Unlike FRDA, AVED can be treated with life-long vitamin E supplements.Charcot Marie Tooth disease is a group of disorders in which the motor and/or sensory peripheral nerves are affected, resulting in muscle weakness and atrophy, as well as sensory loss. The nerve cells in individuals with this disorder are not able to send electrical signals properly because of abnormalities in the nerve axon or abnormalities in the insulation (myelin) around the axon. Specific gene mutations are responsible for Charcot Marie Tooth disease, which can be inherited in an autosomal dominant, autosomal recessive or X-linked mode of inheritance. (For more information on this disorder, choose “Charcot-Marie-Tooth disease” as your search term in the Rare Disease Database.)Spinocerebellar ataxia with axonal neuropathy (SCAN1) is an autosomal recessive neurodegenerative disorder caused by mutations in the TDP1 gene and characterized by late childhood-onset of a slowly progressive cerebellar ataxia, followed by absence of reflexes and signs of peripheral neuropathy such as numbness, tingling, pricking sensations or muscle weakness.Ataxia telangiectasia is an inherited progressive cerebellar ataxia that is characterized by the loss of motor coordination in the limbs and head. An early sign of this disorder is impaired muscle coordination which is most evident when walking. Dilated blood vessels (telangiectasias) appear in the eyes at 3-6 years of age and also appear eventually on the face and the roof of the mouth. Ataxia telangiectasia may be misdiagnosed as FRDA until telangiectasias appear. (For more information on this disorder, choose “Ataxia Telangiectasia” as your search term in the Rare Disease Database.) | 484 | Friedreich’s Ataxia |
nord_484_5 | Diagnosis of Friedreich’s Ataxia | FRDA is suspected in an individual based on clinical examination. The diagnosis is generally confirmed by molecular genetic testing to look for mutations in the FXN gene that cause the disease. The most common type of mutation – which is observed in both the maternal and paternal copies of the FXN gene of more than 90% of individuals with FRDA – is an abnormally expanded GAA repeat mutation in intron 1 of the gene. | Diagnosis of Friedreich’s Ataxia. FRDA is suspected in an individual based on clinical examination. The diagnosis is generally confirmed by molecular genetic testing to look for mutations in the FXN gene that cause the disease. The most common type of mutation – which is observed in both the maternal and paternal copies of the FXN gene of more than 90% of individuals with FRDA – is an abnormally expanded GAA repeat mutation in intron 1 of the gene. | 484 | Friedreich’s Ataxia |
nord_484_6 | Therapies of Friedreich’s Ataxia | Treatment
Treatment of FRDA is symptomatic and supportive. A multidisciplinary treatment strategy is the most appropriate approach given that the condition affects multiple organ systems. Continuous medical supervision to avoid potential complications involving the heart, spine, feet, muscles, vision and hearing are recommended.Prostheses, walking aids, wheelchairs, and physical therapy help maintain an active lifestyle. Orthopedic surgery or non-surgical interventions may help curvature of the spine and abnormalities of the feet, but should be carefully considered in consultation with a neurologist and orthopedic surgeon.Heart problems and/or diabetes mellitus associated with FRDA may be treated with medication. Anti-arrhythmic agents and anti-cardiac failure medication may be used to treat heart disease. Dietary modification, oral hypoglycemic therapeutics, and / or insulin may be considered for controlling diabetes mellitus. Vision and hearing problems may be alleviated with either corrective devices and / or drugs. Intelligence remains unaffected. Emotional strain can affect patients and their families, and psychological counseling may be helpful. Speech therapy helps maximize verbal communication skills.In 2023, omaveloxolone (Skyclarys) was approved by the U.S. Food and Drug Administration (FDA) as the first treatment for Friedreich’s ataxia.Genetic counseling is recommended for affected individuals and their families. | Therapies of Friedreich’s Ataxia. Treatment
Treatment of FRDA is symptomatic and supportive. A multidisciplinary treatment strategy is the most appropriate approach given that the condition affects multiple organ systems. Continuous medical supervision to avoid potential complications involving the heart, spine, feet, muscles, vision and hearing are recommended.Prostheses, walking aids, wheelchairs, and physical therapy help maintain an active lifestyle. Orthopedic surgery or non-surgical interventions may help curvature of the spine and abnormalities of the feet, but should be carefully considered in consultation with a neurologist and orthopedic surgeon.Heart problems and/or diabetes mellitus associated with FRDA may be treated with medication. Anti-arrhythmic agents and anti-cardiac failure medication may be used to treat heart disease. Dietary modification, oral hypoglycemic therapeutics, and / or insulin may be considered for controlling diabetes mellitus. Vision and hearing problems may be alleviated with either corrective devices and / or drugs. Intelligence remains unaffected. Emotional strain can affect patients and their families, and psychological counseling may be helpful. Speech therapy helps maximize verbal communication skills.In 2023, omaveloxolone (Skyclarys) was approved by the U.S. Food and Drug Administration (FDA) as the first treatment for Friedreich’s ataxia.Genetic counseling is recommended for affected individuals and their families. | 484 | Friedreich’s Ataxia |
nord_485_0 | Overview of Froelich Syndrome | Froehlich syndrome, also known as adiposogenital dystrophy, is a group of endocrine abnormalities believed to result from damage to the hypothalamus, a part of the brain that links the nervous system to the endocrine system via the pituitary gland. The hypothalamus regulates sleep cycles and body temperature and composition while stimulating the pituitary gland to release a variety of hormones that control growth, metabolism and body development. Thus, numerous pituitary gland hormones could be indirectly disrupted by damage to the hypothalamus. Unlike similar diseases such as Prader-Willi syndrome, Froehlich syndrome is acquired, not inherited, and is associated with tumors of the hypothalamus area or their surgical treatment, causing increased appetite and reduced secretion of gonadotropin. This syndrome affects males more often than females.The more obvious and frequently encountered characteristics include delayed onset of puberty, short stature, small testes and obesity. Teenage boys with this disorder must be distinguished from those who have inherited growth delay disorders or Prader-Willi syndrome. | Overview of Froelich Syndrome. Froehlich syndrome, also known as adiposogenital dystrophy, is a group of endocrine abnormalities believed to result from damage to the hypothalamus, a part of the brain that links the nervous system to the endocrine system via the pituitary gland. The hypothalamus regulates sleep cycles and body temperature and composition while stimulating the pituitary gland to release a variety of hormones that control growth, metabolism and body development. Thus, numerous pituitary gland hormones could be indirectly disrupted by damage to the hypothalamus. Unlike similar diseases such as Prader-Willi syndrome, Froehlich syndrome is acquired, not inherited, and is associated with tumors of the hypothalamus area or their surgical treatment, causing increased appetite and reduced secretion of gonadotropin. This syndrome affects males more often than females.The more obvious and frequently encountered characteristics include delayed onset of puberty, short stature, small testes and obesity. Teenage boys with this disorder must be distinguished from those who have inherited growth delay disorders or Prader-Willi syndrome. | 485 | Froelich Syndrome |
nord_485_1 | Symptoms of Froelich Syndrome | Froehlich syndrome is characterized by increased or excessive eating that leads to obesity, small testes and a delay in the onset of puberty. It is also common for children with Froehlich syndrome to experience the delay in physical growth and the development of secondary sexual characteristics. In addition to delayed growth and puberty, children with this syndrome tend to be short in stature. As a result of tumor growth, some children with Froehlich syndrome may also develop intellectual difficulties, poor vision due optic nerve damage, lower than normal body temperature (hypothermia), very delicate skin and infundibulo-tuberal syndrome. The infundibulo-tuberal syndrome may result in small testes, obesity, diabetes insipidus and drowsiness (somnolence). | Symptoms of Froelich Syndrome. Froehlich syndrome is characterized by increased or excessive eating that leads to obesity, small testes and a delay in the onset of puberty. It is also common for children with Froehlich syndrome to experience the delay in physical growth and the development of secondary sexual characteristics. In addition to delayed growth and puberty, children with this syndrome tend to be short in stature. As a result of tumor growth, some children with Froehlich syndrome may also develop intellectual difficulties, poor vision due optic nerve damage, lower than normal body temperature (hypothermia), very delicate skin and infundibulo-tuberal syndrome. The infundibulo-tuberal syndrome may result in small testes, obesity, diabetes insipidus and drowsiness (somnolence). | 485 | Froelich Syndrome |
nord_485_2 | Causes of Froelich Syndrome | Froehlich syndrome results from an injury to a part of the hypothalamus (arcuatus nucleus and ventromedial nueclei). The hypothalamus then fails to produce substances that stimulate the front portion (anterior) of the pituitary that is necessary for the onset of normal puberty and regulation of appetite. The most frequent causes of Froehlich syndrome are a specific tumor of the pituitary-hypothalamus area, craniopharyngioma, an expanding hollow (cystic) lesion or injury of this area during surgery.Lesions resulting from inflammation from an infection such as tuberculosis or an acute inflammation of the brain (encephalitis) can also be responsible for causing Froehlich syndrome. | Causes of Froelich Syndrome. Froehlich syndrome results from an injury to a part of the hypothalamus (arcuatus nucleus and ventromedial nueclei). The hypothalamus then fails to produce substances that stimulate the front portion (anterior) of the pituitary that is necessary for the onset of normal puberty and regulation of appetite. The most frequent causes of Froehlich syndrome are a specific tumor of the pituitary-hypothalamus area, craniopharyngioma, an expanding hollow (cystic) lesion or injury of this area during surgery.Lesions resulting from inflammation from an infection such as tuberculosis or an acute inflammation of the brain (encephalitis) can also be responsible for causing Froehlich syndrome. | 485 | Froelich Syndrome |
nord_485_3 | Affects of Froelich Syndrome | Froehlich syndrome is a very rare condition that affects more males than females. | Affects of Froelich Syndrome. Froehlich syndrome is a very rare condition that affects more males than females. | 485 | Froelich Syndrome |
nord_485_4 | Related disorders of Froelich Syndrome | Symptoms of the following disorders can be similar to those of Froelich syndrome. Comparisons may be useful for a differential diagnosis:Prader-Willi syndrome (PWS) is a genetic multisystem disorder characterized during infancy by lethargy, diminished muscle tone (hypotonia), a weak suck and feeding difficulties with poor weight gain and growth and other hormone deficiency. In childhood, features of this disorder include short stature, small genitals and an excessive appetite. (For more information on this disorder, choose “Prader Willi” as your search term in the Rare Disease Database.)Bardet-Biedl syndrome is a rare disorder affecting many systems in the body. The major symptoms of this disorder may include intellectual disability, obesity, delayed sexual development, underdeveloped reproductive organs, degeneration of the retina of the eyes, kidney abnormalities and/or abnormal fingers or toes. This disorder affects males and females in equal numbers. (For more information on this disorder, choose “Bardet-Biedl” as your search term in the Rare Disease Database.)Borjeson syndrome is an extremely rare disorder characterized by intellectual disability, obesity, seizures, failure of the testes in males or the ovaries in females to produce hormones (hypogonadism) and distinctive facial features. (For more information on this disorder, choose “Borjeson” as your search term in the Rare Disease Database.) | Related disorders of Froelich Syndrome. Symptoms of the following disorders can be similar to those of Froelich syndrome. Comparisons may be useful for a differential diagnosis:Prader-Willi syndrome (PWS) is a genetic multisystem disorder characterized during infancy by lethargy, diminished muscle tone (hypotonia), a weak suck and feeding difficulties with poor weight gain and growth and other hormone deficiency. In childhood, features of this disorder include short stature, small genitals and an excessive appetite. (For more information on this disorder, choose “Prader Willi” as your search term in the Rare Disease Database.)Bardet-Biedl syndrome is a rare disorder affecting many systems in the body. The major symptoms of this disorder may include intellectual disability, obesity, delayed sexual development, underdeveloped reproductive organs, degeneration of the retina of the eyes, kidney abnormalities and/or abnormal fingers or toes. This disorder affects males and females in equal numbers. (For more information on this disorder, choose “Bardet-Biedl” as your search term in the Rare Disease Database.)Borjeson syndrome is an extremely rare disorder characterized by intellectual disability, obesity, seizures, failure of the testes in males or the ovaries in females to produce hormones (hypogonadism) and distinctive facial features. (For more information on this disorder, choose “Borjeson” as your search term in the Rare Disease Database.) | 485 | Froelich Syndrome |
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