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nord_1071_3
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Affects of Retinoschisis
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Senile retinoschisis usually affects people in their 50s, 60s or 70s, but it has been found in persons much younger. It affects males and females in equal numbers.Juvenile, X-linked retinoschisis affects mostly boys. However, there are very rare exceptions that occur when a girl is born to a mother who is a carrier of the disorder and an affected father. The X-linked form of the disorder is present at birth, and symptoms progress with time. The prevalence of X-linked juvenile retinoschisis is estimated at one in 5,000 to 25,000. The disorder has been detected in infants as young as three months old.
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Affects of Retinoschisis. Senile retinoschisis usually affects people in their 50s, 60s or 70s, but it has been found in persons much younger. It affects males and females in equal numbers.Juvenile, X-linked retinoschisis affects mostly boys. However, there are very rare exceptions that occur when a girl is born to a mother who is a carrier of the disorder and an affected father. The X-linked form of the disorder is present at birth, and symptoms progress with time. The prevalence of X-linked juvenile retinoschisis is estimated at one in 5,000 to 25,000. The disorder has been detected in infants as young as three months old.
| 1,071 |
Retinoschisis
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nord_1071_4
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Related disorders of Retinoschisis
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Central serous chorioretinopathy is a retinal disorder that affects the central area of the retina (macula). Its cause is unknown. Diabetic macular edema results from changes in the very small blood vessels (capillaries) that feed the retinas of individuals with diabetes. In diabetic retinopathy, the vessels become more permeable. Water, blood cells, proteins, fats, and other large molecules may leak out into the surrounding retinal tissue. Accumulation of this fluid in the central region of the retina (the macula) is called macular edema or diabetic macular edema. Macular hole is a small break in the macula, located in the center of the eye's light-sensitive tissue, the retina. The macula provides the sharp, central vision we need for reading, driving, and seeing fine detail. A macular hole can cause blurred and distorted central vision. Macular holes are related to aging and usually occur in people over age 60.Rhegmatogenous retinal detachment is the most common type of retinal detachment. It occurs when a break (tear or hole) in the retina allows fluid from the vitreous humor to enter the potential space beneath the retina. This causes the retina to separate from the layer beneath, known as the retinal pigment epithelium (RPE). This type of retinal detachment represents an emergency, and surgery is typically scheduled very quickly after diagnosis. Most cases of rhegmatogenous retinal detachment are associated with a posterior vitreous separation, which is a natural part of aging. This is due to the natural contraction, or shrinkage, of the vitreous humor, which occasionally creates traction on the retina, producing a retinal break (hole or tear).
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Related disorders of Retinoschisis. Central serous chorioretinopathy is a retinal disorder that affects the central area of the retina (macula). Its cause is unknown. Diabetic macular edema results from changes in the very small blood vessels (capillaries) that feed the retinas of individuals with diabetes. In diabetic retinopathy, the vessels become more permeable. Water, blood cells, proteins, fats, and other large molecules may leak out into the surrounding retinal tissue. Accumulation of this fluid in the central region of the retina (the macula) is called macular edema or diabetic macular edema. Macular hole is a small break in the macula, located in the center of the eye's light-sensitive tissue, the retina. The macula provides the sharp, central vision we need for reading, driving, and seeing fine detail. A macular hole can cause blurred and distorted central vision. Macular holes are related to aging and usually occur in people over age 60.Rhegmatogenous retinal detachment is the most common type of retinal detachment. It occurs when a break (tear or hole) in the retina allows fluid from the vitreous humor to enter the potential space beneath the retina. This causes the retina to separate from the layer beneath, known as the retinal pigment epithelium (RPE). This type of retinal detachment represents an emergency, and surgery is typically scheduled very quickly after diagnosis. Most cases of rhegmatogenous retinal detachment are associated with a posterior vitreous separation, which is a natural part of aging. This is due to the natural contraction, or shrinkage, of the vitreous humor, which occasionally creates traction on the retina, producing a retinal break (hole or tear).
| 1,071 |
Retinoschisis
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nord_1071_5
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Diagnosis of Retinoschisis
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The diagnosis of retinoschisis is usually made during an examination of the back of the eye (fundus) where any splits, tears or rips may be seen. One diagnostic tool is Optical Coherence Tomography (OCT), which that uses light waves to create images of the retina.Other tests may contribute to the diagnosis, especially an electroretinogram (ERG) that measures the electrical impulses stimulated by a light. Also, a measurement of the visual evoked response (VER) to a light stimulus is a good objective test to detect the function of the macular portion of the retina that controls central vision.Ultrasonography or ultrasound may show abnormalities when a hemorrhage has occurred in the eye.
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Diagnosis of Retinoschisis. The diagnosis of retinoschisis is usually made during an examination of the back of the eye (fundus) where any splits, tears or rips may be seen. One diagnostic tool is Optical Coherence Tomography (OCT), which that uses light waves to create images of the retina.Other tests may contribute to the diagnosis, especially an electroretinogram (ERG) that measures the electrical impulses stimulated by a light. Also, a measurement of the visual evoked response (VER) to a light stimulus is a good objective test to detect the function of the macular portion of the retina that controls central vision.Ultrasonography or ultrasound may show abnormalities when a hemorrhage has occurred in the eye.
| 1,071 |
Retinoschisis
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nord_1071_6
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Therapies of Retinoschisis
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TreatmentSenile retinoschisis does not usually require medical treatment of any kind.In children with juvenile X-linked retinoschisis, if bleeding occurs within the eyeball, the eye is kept as still as possible in order to promote coagulation. Later, treatment with laser or cold (cryotherapy) can be applied to close off the damaged area of the retina. Surgical procedures may be a last resort of treatment. Most persons with juvenile X-linked retinoschisis usually retain functional vision.Genetic counseling may be helpful for families of children with juvenile retinoschisis.
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Therapies of Retinoschisis. TreatmentSenile retinoschisis does not usually require medical treatment of any kind.In children with juvenile X-linked retinoschisis, if bleeding occurs within the eyeball, the eye is kept as still as possible in order to promote coagulation. Later, treatment with laser or cold (cryotherapy) can be applied to close off the damaged area of the retina. Surgical procedures may be a last resort of treatment. Most persons with juvenile X-linked retinoschisis usually retain functional vision.Genetic counseling may be helpful for families of children with juvenile retinoschisis.
| 1,071 |
Retinoschisis
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nord_1072_0
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Overview of Retroperitoneal Fibrosis
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Retroperitoneal fibrosis is a rare inflammatory disorder in which abnormal formation of fiber-like tissue (fibrosis) occurs behind the membrane that lines the cavity of the abdomen (peritoneum). This abnormal tissue growth often spreads to affect the tubes that carry urine from the kidney to the bladder (ureters). Often these tubes become blocked by the excess tissue. Specific symptoms may vary depending upon the exact location of tissue growth and how far it spreads. In most cases the cause of this disorder is unknown (idiopathic).
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Overview of Retroperitoneal Fibrosis. Retroperitoneal fibrosis is a rare inflammatory disorder in which abnormal formation of fiber-like tissue (fibrosis) occurs behind the membrane that lines the cavity of the abdomen (peritoneum). This abnormal tissue growth often spreads to affect the tubes that carry urine from the kidney to the bladder (ureters). Often these tubes become blocked by the excess tissue. Specific symptoms may vary depending upon the exact location of tissue growth and how far it spreads. In most cases the cause of this disorder is unknown (idiopathic).
| 1,072 |
Retroperitoneal Fibrosis
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nord_1072_1
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Symptoms of Retroperitoneal Fibrosis
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The most common symptom of retroperitoneal fibrosis is pain in the lower back or abdomen. In many cases this pain is dull, vague and difficult to localize. Additional symptoms may be weight loss, fever, nausea, a low level of circulating red blood cells (anemia), and loss of appetite. Impaired movement of a limb may occur intermittently and abnormal yellow discoloration (pigmentation) of the skin and the whites of the eyes (jaundice) may be present. Swelling of one leg may also occur. Reduced blood flow to the leg may cause pain and discoloration.Occasionally there may be bleeding (hemorrhaging) in the stomach and intestine. In about ten percent of the cases there may be difficulty urinating. Upon examination by a physician, a mass can be felt in the rectum or abdomen in about 15 percent of individuals with this disorder. In some cases, obstruction of one or both of the tubes that carries urine from the kidney into the bladder (ureters) may also occur (unilateral or bilateral obstructive uropathy). This results in the blockage of the flow of urine and the abnormal accumulation of urine. Depending upon where the obstruction occurs, the accumulation of urine may result in the pelvis and kidney duct becoming swollen with urine (hydronephrosis). High blood pressure (hypertension) and, eventually, kidney (renal) failure may also occur. Symptoms of renal failure include nausea and vomiting.In rare cases, retroperitoneal fibrosis may become malignant. In some affected individuals the largest vein in the body that returns blood to the heart (inferior vena cava) may be encased by the fibrous tissue. This encasement rarely causes obstruction of the vein.
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Symptoms of Retroperitoneal Fibrosis. The most common symptom of retroperitoneal fibrosis is pain in the lower back or abdomen. In many cases this pain is dull, vague and difficult to localize. Additional symptoms may be weight loss, fever, nausea, a low level of circulating red blood cells (anemia), and loss of appetite. Impaired movement of a limb may occur intermittently and abnormal yellow discoloration (pigmentation) of the skin and the whites of the eyes (jaundice) may be present. Swelling of one leg may also occur. Reduced blood flow to the leg may cause pain and discoloration.Occasionally there may be bleeding (hemorrhaging) in the stomach and intestine. In about ten percent of the cases there may be difficulty urinating. Upon examination by a physician, a mass can be felt in the rectum or abdomen in about 15 percent of individuals with this disorder. In some cases, obstruction of one or both of the tubes that carries urine from the kidney into the bladder (ureters) may also occur (unilateral or bilateral obstructive uropathy). This results in the blockage of the flow of urine and the abnormal accumulation of urine. Depending upon where the obstruction occurs, the accumulation of urine may result in the pelvis and kidney duct becoming swollen with urine (hydronephrosis). High blood pressure (hypertension) and, eventually, kidney (renal) failure may also occur. Symptoms of renal failure include nausea and vomiting.In rare cases, retroperitoneal fibrosis may become malignant. In some affected individuals the largest vein in the body that returns blood to the heart (inferior vena cava) may be encased by the fibrous tissue. This encasement rarely causes obstruction of the vein.
| 1,072 |
Retroperitoneal Fibrosis
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nord_1072_2
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Causes of Retroperitoneal Fibrosis
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The exact cause of retroperitoneal fibrosis is not known in about two-thirds of the affected individuals (idiopathic). A drug used in the treatment and prevention of migraine headaches (methysergide) may be the cause of this rare disorder in 12 percent of cases. Malignant tumors are associated with retroperitoneal fibrosis in eight percent of affected individuals. Tissue that has been injured by trauma or surgery may be a factor in some cases.
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Causes of Retroperitoneal Fibrosis. The exact cause of retroperitoneal fibrosis is not known in about two-thirds of the affected individuals (idiopathic). A drug used in the treatment and prevention of migraine headaches (methysergide) may be the cause of this rare disorder in 12 percent of cases. Malignant tumors are associated with retroperitoneal fibrosis in eight percent of affected individuals. Tissue that has been injured by trauma or surgery may be a factor in some cases.
| 1,072 |
Retroperitoneal Fibrosis
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nord_1072_3
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Affects of Retroperitoneal Fibrosis
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Retroperitoneal fibrosis affects males twice as often as females. The majority of cases occur in individuals between 40 and 60 years of age. However, the disorder can occur at any age, although it is extremely rare in children.
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Affects of Retroperitoneal Fibrosis. Retroperitoneal fibrosis affects males twice as often as females. The majority of cases occur in individuals between 40 and 60 years of age. However, the disorder can occur at any age, although it is extremely rare in children.
| 1,072 |
Retroperitoneal Fibrosis
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nord_1072_4
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Related disorders of Retroperitoneal Fibrosis
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Symptoms of the following disorders can be similar to those of Retroperitoneal Fibrosis. Comparisons may be useful for a differential diagnosis:Carcinoid Syndrome is a rare, malignant disorder that affects the small bowel, pancreas, and/or stomach. Slow growing tumors can spread to the lungs, liver and ovary. Symptoms of this disorder may include flushing, diarrhea, wheezing, stomach pain, and blockage of arteries. (For more information on this disorder, choose “Carcinoid ” as your search term in the Rare Disease Database.)Scleroderma is a group of chronic disorders characterized by fiber-like tissue growth (fibrosis), degenerative changes, and vascular abnormalities of the skin. Scleroderma is the hardening and shrinking of the connective tissues of any part of the body. (For more information on this disorder, choose “Scleroderma” as your search term in the Rare Disease Database.)Vasculitis is an inflammation of the blood vessel system which includes the veins, arteries and capillaries. This disorder may occur alone or in conjunction with allergic and rheumatic diseases. Symptoms of this disorder may be formation of blood clots, weakening of vessel walls, muscle pain, joint pain, fever, weight loss, loss of appetite, abdominal pain and shortness of breath. (For more information on this disorder, choose “Vasculitis” as your search term in the Rare Disease Database.)
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Related disorders of Retroperitoneal Fibrosis. Symptoms of the following disorders can be similar to those of Retroperitoneal Fibrosis. Comparisons may be useful for a differential diagnosis:Carcinoid Syndrome is a rare, malignant disorder that affects the small bowel, pancreas, and/or stomach. Slow growing tumors can spread to the lungs, liver and ovary. Symptoms of this disorder may include flushing, diarrhea, wheezing, stomach pain, and blockage of arteries. (For more information on this disorder, choose “Carcinoid ” as your search term in the Rare Disease Database.)Scleroderma is a group of chronic disorders characterized by fiber-like tissue growth (fibrosis), degenerative changes, and vascular abnormalities of the skin. Scleroderma is the hardening and shrinking of the connective tissues of any part of the body. (For more information on this disorder, choose “Scleroderma” as your search term in the Rare Disease Database.)Vasculitis is an inflammation of the blood vessel system which includes the veins, arteries and capillaries. This disorder may occur alone or in conjunction with allergic and rheumatic diseases. Symptoms of this disorder may be formation of blood clots, weakening of vessel walls, muscle pain, joint pain, fever, weight loss, loss of appetite, abdominal pain and shortness of breath. (For more information on this disorder, choose “Vasculitis” as your search term in the Rare Disease Database.)
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Retroperitoneal Fibrosis
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nord_1072_5
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Diagnosis of Retroperitoneal Fibrosis
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Diagnosis of Retroperitoneal Fibrosis.
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Retroperitoneal Fibrosis
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nord_1072_6
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Therapies of Retroperitoneal Fibrosis
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Treatment of retroperitoneal fibrosis depends on the location and extent of the tissue growth.Surgery is often very successful in freeing an organ that has been constricted by retroperitoneal fibrosis. Surgery may also be used to remove a fibrous mass. Obstruction of the ureter is often treated with ureterolysis, a surgical procedure used to free a ureter from surrounding tissue (e.g., abnormal fibrous tissue). In some cases, stents may be implanted within the ureter to provide temporary relief from obstruction.Corticosteroid drug therapy may be used in the early stages of the disease, in conjunction with surgery, or in affected individuals who are at high risk if surgery is performed.In some cases, abnormal fibrous growth may recur months or years after surgery or steroid therapy. In some cases, physicians may wrap a layer of fat around the ureter in an attempt to prevent the recurrence of ureter obstruction. In some reported cases, retroperitoneal fibrosis has subsided on its own without treatment (spontaneous resolution).
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Therapies of Retroperitoneal Fibrosis. Treatment of retroperitoneal fibrosis depends on the location and extent of the tissue growth.Surgery is often very successful in freeing an organ that has been constricted by retroperitoneal fibrosis. Surgery may also be used to remove a fibrous mass. Obstruction of the ureter is often treated with ureterolysis, a surgical procedure used to free a ureter from surrounding tissue (e.g., abnormal fibrous tissue). In some cases, stents may be implanted within the ureter to provide temporary relief from obstruction.Corticosteroid drug therapy may be used in the early stages of the disease, in conjunction with surgery, or in affected individuals who are at high risk if surgery is performed.In some cases, abnormal fibrous growth may recur months or years after surgery or steroid therapy. In some cases, physicians may wrap a layer of fat around the ureter in an attempt to prevent the recurrence of ureter obstruction. In some reported cases, retroperitoneal fibrosis has subsided on its own without treatment (spontaneous resolution).
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Retroperitoneal Fibrosis
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nord_1073_0
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Overview of Rett Syndrome
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SummaryRett syndrome is a progressive neurodevelopmental disorder that almost exclusively affects females. Only in rare cases are males affected. Infants with Rett syndrome generally develop normally for about 7 to 18 months after birth. At this point, they lose previously acquired skills (developmental regression) such as purposeful hand movements and the ability to communicate. Additional abnormalities occur including impaired control of voluntary movements (ataxia) and the development of distinctive, uncontrolled hand movements such as hand clapping or rubbing. Some children also have slowing of head growth (acquired microcephaly), Affected children often develop autistic-like behaviors, breathing irregularities, feeding and swallowing difficulties, growth retardation, and seizures. Most Rett syndrome cases are caused by identifiable mutations of the MECP2 gene on the X chromosome and can present with a wide range of disability ranging from mild to severe. The course and severity of Rett syndrome is determined by the location, type and severity of the MECP2 mutation and the process of random X-inactivation (see Causes section below). Therefore, two girls of the same age with the same mutation can appear significantly different.IntroductionRett syndrome was first described in the medical literature by an Austrian physician named Andreas Rett in 1960s. Many researchers now consider Rett syndrome as part of a spectrum of disease relating to mutations of the MECP2 gene. This spectrum, sometimes referred to as MECP2-related disorders, includes classic Rett syndrome, variant Rett syndrome, MECP2-related severe neonatal encephalopathy, and PPM-X syndrome. Another disorder, MECP2 duplication syndrome, has recently been described in the medical literature. This disorder is caused by duplicated material involving the MECP2 gene on the X chromosome.
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Overview of Rett Syndrome. SummaryRett syndrome is a progressive neurodevelopmental disorder that almost exclusively affects females. Only in rare cases are males affected. Infants with Rett syndrome generally develop normally for about 7 to 18 months after birth. At this point, they lose previously acquired skills (developmental regression) such as purposeful hand movements and the ability to communicate. Additional abnormalities occur including impaired control of voluntary movements (ataxia) and the development of distinctive, uncontrolled hand movements such as hand clapping or rubbing. Some children also have slowing of head growth (acquired microcephaly), Affected children often develop autistic-like behaviors, breathing irregularities, feeding and swallowing difficulties, growth retardation, and seizures. Most Rett syndrome cases are caused by identifiable mutations of the MECP2 gene on the X chromosome and can present with a wide range of disability ranging from mild to severe. The course and severity of Rett syndrome is determined by the location, type and severity of the MECP2 mutation and the process of random X-inactivation (see Causes section below). Therefore, two girls of the same age with the same mutation can appear significantly different.IntroductionRett syndrome was first described in the medical literature by an Austrian physician named Andreas Rett in 1960s. Many researchers now consider Rett syndrome as part of a spectrum of disease relating to mutations of the MECP2 gene. This spectrum, sometimes referred to as MECP2-related disorders, includes classic Rett syndrome, variant Rett syndrome, MECP2-related severe neonatal encephalopathy, and PPM-X syndrome. Another disorder, MECP2 duplication syndrome, has recently been described in the medical literature. This disorder is caused by duplicated material involving the MECP2 gene on the X chromosome.
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Rett Syndrome
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nord_1073_1
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Symptoms of Rett Syndrome
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The symptoms, progression, and severity of Rett syndrome can vary dramatically from one person to another. The disorder primarily affects females and most likely represents a spectrum of disease associated with mutations of the MECP2 gene. A wide range of disability can potentially be associated with Rett syndrome. Symptoms generally appear in stages. It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.CLASSIC RETT SYNDROME
Affected infants are generally described as having normal development until approximately 6 to 18 months of age. However, researchers have noted that affected infants are often described as being very placid and having a poor sucking ability and a weak cry. Low muscle tone (hypotonia) is also common before 6 months of age. Head growth can slow down as early as 3 months of age. Slow head growth can result in acquired microcephaly, a condition characterized by head circumference that is smaller than would normally be expected for age and gender.Between 6 and 18 months of age, affected girls may enter a period of developmental stagnation. Loss of eye contact and a lack of interest in play or games may also occur. Infants may demand little to no attention from their parents. Irritability, crying and restlessness may be seen. In some cases, development may continue but at a delayed rate. For example, an infant may learn to sit upright, but not to crawl.After this period, approximately between 1-4 years of age, affected individuals begin to lose previously acquired skills, specifically spoken language skills and hand skills. Some individuals may lose the ability to interact socially. Affected people may also exhibit a decline in intellectual function. This deterioration can be rapid or gradual. Parents may notice a sudden change in their child’s behavior and health. Affected children may show diminished interest in people and objects.During this time period, the loss of ability to make purposeful hand and finger movements occurs. Affected people then exhibit a characteristic finding of Rett syndrome, the development of stereotypic hand movements including hand wringing or squeezing, clapping, rubbing, washing, or hand to mouth movements. Screaming fits and inconsolable crying may also occur.Additional symptoms may develop including autistic-like features, panic attacks, teeth grinding (bruxism), tremors and apraxia. Apraxia is a condition characterized by the inability to perform learned (familiar) movements on command, even though the command is understood and there is a willingness to perform the movement. Apraxia can affect movement but also communication skills. Seizures are common during this period in individuals with Rett syndrome. Some individuals may experience balance issues due to problems coordinating voluntary muscles of the legs (gait ataxia). Disordered breathing patterns that occur when a child is awake such as hypoventilation or hyperventilation have also been reported. Affected people may also exhibit forced expulsion of air and saliva, swallowing air (aerophagia), temporary stopping (cessation) of breathing (apnea), and holding of one’s breath. Breathing problems tend to worsen with stress.After this period of rapid deterioration, neurological features stabilize. Some affected individuals may even show slight improvement with eye contact, communication skills, regression of autistic traits, and overall improvement with behavior and social interactions.However, many issues remain including characteristic hand movements, seizures, teeth grinding (bruxism), and breathing irregularities. Intellectual disability in Rett syndrome is difficult to access because of the inability to speak or use hands. Eventually, after 10 years of age, affected individuals may exhibit late motor impairment. Some people with classic Rett syndrome may never be able to walk. Others may lose the ability to walk. They may also experience increasing muscle weakness, joint contractures, and spasticity, a condition characterize by involuntary muscles spasms that result in slow, stiff movements of the legs. Affected people may have underdeveloped (hypotrophic) hands and feet that are frequently cold. Most affected individuals may develop dystonia, a condition characterized by sustained muscle contractions associated with abnormal, uncontrolled movements and postures. Some affected people may develop symptoms similar to those seen in Parkinson’s disease (parkinsonism), such as a decreased expression in face (hypomimia), rigidity, and tremor.Approximately 85-90% of affected people may experience growth failure and muscle wasting that worsens with age. These symptoms are due, in part, to difficulties with chewing and swallowing, which leads to poor food intake. On the other hand, some people with Rett syndrome, especially those with more retained function, may have excessive food intake and become obese.A variety of additional symptoms and physical findings can occur in people with classic Rett syndrome including gastrointestinal abnormalities such as abnormal muscle contractions or dysfunction of nerves of the bowel (bowel dysmotility), constipation, gastroesophageal reflux, and abnormal widening (dilation) of the colon (functional megacolon); cold hands and feet (vasomotor abnormalities); intermittent crossed eyes (esotropia); varying degrees of side-to-side curvature of the spine (scoliosis); and gallbladder dysfunction and gallstones, which have been show to occur with greater frequency in individuals with Rett syndrome than in the general population. Some people with Rett syndrome develop osteopenia, a condition characterized by decreased bone mineralization and bone loss. Osteopenia can result in weak, fragile bones.Many people with Rett syndrome live well into adulthood, although they may require constant care and supervision. However, there is an increased risk of sudden death in people with Rett syndrome. Approximately one quarter of deaths in Rett are sudden and unexpected. This may be due, in part, to heart irregularities, specifically a prolonged QT interval and T-wave abnormalities. The functioning of the heart is controlled by electrical nerve impulses that regulate normal rhythmic pumping activity of the heart muscle. After each heartbeat, this electrical system recharges, a process known as repolarization. During electrical stimulation, the heart muscle contracts, a process known as depolarization. The QT interval measures the amount of time required for these two processes to occur. When the QT interval is longer than normal (prolonged), the heartbeat may become irregular.VARIANT RETT SYNDROME
Variant Rett syndrome refers to people who have atypical cases or presentations of Rett syndrome. These cases may also be known as atypical Rett syndrome. These forms of Rett syndrome include:The preserved speech variant of Rett syndrome (Zappella variant) is characterized by the symptoms of classic Rett syndrome, but with the recovery of some language and motor skills. Mutations of the MECP2 gene have been found in the majority of cases. Head size is often normal in the Zapella variant, and people with this variant may be obese, more aggressive, and have more autistic features.The late childhood regression form is characterized by later and more gradual regression of motor and language skills than is found in classic Rett syndrome. Affected females have a normal head circumference.Some affected individuals have a form that is associated with seizures that occur before 6 months of age (Hanefeld variant). This variant form is rarely associated with mutations of the MECP2 gene, but rather another gene known as CDKL5. For more information on CDKL5 see the Related Disorders section below.A form known as the congenital variant of Rett syndrome (Rolando variant) is characterized loss of muscle tone and severe developmental delays during the first few months of life. This form is rarely associated with mutations in the MECP2 gene. Many children with this variant form of Rett syndrome have been shown to have mutations of the FOXG1 gene. For more information on FOXG1 see the Related Disorders section below.The ‘forme fruste’ variant of Rett syndrome is characterized by an overall milder expression than is seen in classic Rett syndrome. The clinical course is shorter (protracted) and incomplete. Regression occurs later than it does in the classic form. Affected individuals may retain hand use and the stereotypic hand movements of Rett syndrome may be mild.In rare cases, some girls with MECP2 mutations may only have mild learning disabilities or autistic features. Without regression of hand skills and language and the development of the characteristic repetitive hand stereotypies, these children should not be considered to have Rett syndrome as the prognosis is different for these people compared to people who have the characteristic features of Rett.ADDITIONAL MECP2 – RELATED DISORDERS
In rare cases, males can develop distinct symptoms associated with a mutation of the MECP2 gene.Some males with MECP2 mutations develop brain dysfunction during infancy (neonatal encephalopathy). Affected males may also exhibit microcephaly. The disorder is progressive resulting in abnormal muscle tone, involuntary movements, severe seizures and breathing irregularities. The brain dysfunction is often severe and the disorder can be fatal by 2 years of age.Some individuals with MECP2 mutations develop X-linked intellectual disability. Affected females may have mild, non-progressive intellectual disability. Affected males may develop mild to severe intellectual disability including a disorder known as PPM-X syndrome. This acronym stands for manic depressive (p)sychosis, (p)yramidal signs, (p)arkinsonism, and (m)acro-orchidism. Affected individuals may have psychotic disorders such as bipolar disorder. Additional symptoms include parkinsonism, increased muscle tone and exaggerated reflexes. Abnormal enlargement of the testes (macro-orchidism) may also occur.Some girls with a diagnosis of autism have been shown to have mutations in the MECP2 gene.
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Symptoms of Rett Syndrome. The symptoms, progression, and severity of Rett syndrome can vary dramatically from one person to another. The disorder primarily affects females and most likely represents a spectrum of disease associated with mutations of the MECP2 gene. A wide range of disability can potentially be associated with Rett syndrome. Symptoms generally appear in stages. It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.CLASSIC RETT SYNDROME
Affected infants are generally described as having normal development until approximately 6 to 18 months of age. However, researchers have noted that affected infants are often described as being very placid and having a poor sucking ability and a weak cry. Low muscle tone (hypotonia) is also common before 6 months of age. Head growth can slow down as early as 3 months of age. Slow head growth can result in acquired microcephaly, a condition characterized by head circumference that is smaller than would normally be expected for age and gender.Between 6 and 18 months of age, affected girls may enter a period of developmental stagnation. Loss of eye contact and a lack of interest in play or games may also occur. Infants may demand little to no attention from their parents. Irritability, crying and restlessness may be seen. In some cases, development may continue but at a delayed rate. For example, an infant may learn to sit upright, but not to crawl.After this period, approximately between 1-4 years of age, affected individuals begin to lose previously acquired skills, specifically spoken language skills and hand skills. Some individuals may lose the ability to interact socially. Affected people may also exhibit a decline in intellectual function. This deterioration can be rapid or gradual. Parents may notice a sudden change in their child’s behavior and health. Affected children may show diminished interest in people and objects.During this time period, the loss of ability to make purposeful hand and finger movements occurs. Affected people then exhibit a characteristic finding of Rett syndrome, the development of stereotypic hand movements including hand wringing or squeezing, clapping, rubbing, washing, or hand to mouth movements. Screaming fits and inconsolable crying may also occur.Additional symptoms may develop including autistic-like features, panic attacks, teeth grinding (bruxism), tremors and apraxia. Apraxia is a condition characterized by the inability to perform learned (familiar) movements on command, even though the command is understood and there is a willingness to perform the movement. Apraxia can affect movement but also communication skills. Seizures are common during this period in individuals with Rett syndrome. Some individuals may experience balance issues due to problems coordinating voluntary muscles of the legs (gait ataxia). Disordered breathing patterns that occur when a child is awake such as hypoventilation or hyperventilation have also been reported. Affected people may also exhibit forced expulsion of air and saliva, swallowing air (aerophagia), temporary stopping (cessation) of breathing (apnea), and holding of one’s breath. Breathing problems tend to worsen with stress.After this period of rapid deterioration, neurological features stabilize. Some affected individuals may even show slight improvement with eye contact, communication skills, regression of autistic traits, and overall improvement with behavior and social interactions.However, many issues remain including characteristic hand movements, seizures, teeth grinding (bruxism), and breathing irregularities. Intellectual disability in Rett syndrome is difficult to access because of the inability to speak or use hands. Eventually, after 10 years of age, affected individuals may exhibit late motor impairment. Some people with classic Rett syndrome may never be able to walk. Others may lose the ability to walk. They may also experience increasing muscle weakness, joint contractures, and spasticity, a condition characterize by involuntary muscles spasms that result in slow, stiff movements of the legs. Affected people may have underdeveloped (hypotrophic) hands and feet that are frequently cold. Most affected individuals may develop dystonia, a condition characterized by sustained muscle contractions associated with abnormal, uncontrolled movements and postures. Some affected people may develop symptoms similar to those seen in Parkinson’s disease (parkinsonism), such as a decreased expression in face (hypomimia), rigidity, and tremor.Approximately 85-90% of affected people may experience growth failure and muscle wasting that worsens with age. These symptoms are due, in part, to difficulties with chewing and swallowing, which leads to poor food intake. On the other hand, some people with Rett syndrome, especially those with more retained function, may have excessive food intake and become obese.A variety of additional symptoms and physical findings can occur in people with classic Rett syndrome including gastrointestinal abnormalities such as abnormal muscle contractions or dysfunction of nerves of the bowel (bowel dysmotility), constipation, gastroesophageal reflux, and abnormal widening (dilation) of the colon (functional megacolon); cold hands and feet (vasomotor abnormalities); intermittent crossed eyes (esotropia); varying degrees of side-to-side curvature of the spine (scoliosis); and gallbladder dysfunction and gallstones, which have been show to occur with greater frequency in individuals with Rett syndrome than in the general population. Some people with Rett syndrome develop osteopenia, a condition characterized by decreased bone mineralization and bone loss. Osteopenia can result in weak, fragile bones.Many people with Rett syndrome live well into adulthood, although they may require constant care and supervision. However, there is an increased risk of sudden death in people with Rett syndrome. Approximately one quarter of deaths in Rett are sudden and unexpected. This may be due, in part, to heart irregularities, specifically a prolonged QT interval and T-wave abnormalities. The functioning of the heart is controlled by electrical nerve impulses that regulate normal rhythmic pumping activity of the heart muscle. After each heartbeat, this electrical system recharges, a process known as repolarization. During electrical stimulation, the heart muscle contracts, a process known as depolarization. The QT interval measures the amount of time required for these two processes to occur. When the QT interval is longer than normal (prolonged), the heartbeat may become irregular.VARIANT RETT SYNDROME
Variant Rett syndrome refers to people who have atypical cases or presentations of Rett syndrome. These cases may also be known as atypical Rett syndrome. These forms of Rett syndrome include:The preserved speech variant of Rett syndrome (Zappella variant) is characterized by the symptoms of classic Rett syndrome, but with the recovery of some language and motor skills. Mutations of the MECP2 gene have been found in the majority of cases. Head size is often normal in the Zapella variant, and people with this variant may be obese, more aggressive, and have more autistic features.The late childhood regression form is characterized by later and more gradual regression of motor and language skills than is found in classic Rett syndrome. Affected females have a normal head circumference.Some affected individuals have a form that is associated with seizures that occur before 6 months of age (Hanefeld variant). This variant form is rarely associated with mutations of the MECP2 gene, but rather another gene known as CDKL5. For more information on CDKL5 see the Related Disorders section below.A form known as the congenital variant of Rett syndrome (Rolando variant) is characterized loss of muscle tone and severe developmental delays during the first few months of life. This form is rarely associated with mutations in the MECP2 gene. Many children with this variant form of Rett syndrome have been shown to have mutations of the FOXG1 gene. For more information on FOXG1 see the Related Disorders section below.The ‘forme fruste’ variant of Rett syndrome is characterized by an overall milder expression than is seen in classic Rett syndrome. The clinical course is shorter (protracted) and incomplete. Regression occurs later than it does in the classic form. Affected individuals may retain hand use and the stereotypic hand movements of Rett syndrome may be mild.In rare cases, some girls with MECP2 mutations may only have mild learning disabilities or autistic features. Without regression of hand skills and language and the development of the characteristic repetitive hand stereotypies, these children should not be considered to have Rett syndrome as the prognosis is different for these people compared to people who have the characteristic features of Rett.ADDITIONAL MECP2 – RELATED DISORDERS
In rare cases, males can develop distinct symptoms associated with a mutation of the MECP2 gene.Some males with MECP2 mutations develop brain dysfunction during infancy (neonatal encephalopathy). Affected males may also exhibit microcephaly. The disorder is progressive resulting in abnormal muscle tone, involuntary movements, severe seizures and breathing irregularities. The brain dysfunction is often severe and the disorder can be fatal by 2 years of age.Some individuals with MECP2 mutations develop X-linked intellectual disability. Affected females may have mild, non-progressive intellectual disability. Affected males may develop mild to severe intellectual disability including a disorder known as PPM-X syndrome. This acronym stands for manic depressive (p)sychosis, (p)yramidal signs, (p)arkinsonism, and (m)acro-orchidism. Affected individuals may have psychotic disorders such as bipolar disorder. Additional symptoms include parkinsonism, increased muscle tone and exaggerated reflexes. Abnormal enlargement of the testes (macro-orchidism) may also occur.Some girls with a diagnosis of autism have been shown to have mutations in the MECP2 gene.
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Causes of Rett Syndrome
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Approximately 90-95% of Rett syndrome cases are caused by identifiable mutations of the MECP2 gene. More than 200 different mutations have been identified. In 99% of cases, these mutations occur sporadically and are not possessed or transmitted by a child’s parents (de novo mutations). Therefore, in the vast majority of cases Rett syndrome is not an inherited disorder. In such cases, the parents have normal chromosomes and the mutation arises in one of the parent’s reproductive (germ) cells, usually on the paternal side.The chance of recurrence in subsequent children for parents who have one affected child is approximately 1%. In rare cases, more than one child can be affected. This rare occurrence may occur because of germline mosaicism. In germline mosaicism, one parent has some reproductive cells (germ cells) in the ovaries or testes that have the MECP2 gene mutation. The other cells in the parent’s body do not have the mutation, so these parents are unaffected. As a result, one or more of the parent’s children may inherit the germ cell MECP2 gene mutation. The likelihood of a parent passing on a mosaic germline mutation to a child depends upon the percentage of the parent’s germ cells that have the mutation versus the percentage that do not. There is no test for germline mutation prior to pregnancy. Testing during pregnancy may be available and is best discussed directly with a genetic specialist.In extremely rare cases, Rett syndrome may be inherited from a carrier mother who has favorable skewing of random X-chromosome inactivation and no symptoms or extremely mild symptoms of the disorder. When a mother is a known carrier of the MECP2 mutation, there is a 50% chance of passing that mutation on to her children.Random X-chromosome inactivation is a normal process in females. Females have two X chromosomes, whereas males have one X chromosome and one Y chromosome. In females, certain disease traits on the X chromosome such as a mutated gene may be “masked” by the normal gene on the other X chromosome (random X-chromosome inactivation). Basically, in each cell of the body one X chromosome is active and one is turned off or “silenced.” This occurs randomly and generally happens as a 50-50 split. However, in some cases, females may have favorable X-inactivation, in which the affected X chromosome is silenced in most of the cells. In such cases, affected females may only have mild symptoms of the disorder. In other cases, females may have unfavorable X-inactivation, in which the unaffected X chromosome is silenced in most of the cells. In such cases, affected females usually have a severe expression of the disorder.Because males only have one X chromosome, such disorders are usually fully expressed. Consequently, it is believed that in most cases MECP2 mutations are not compatible with life in males, usually resulting in miscarriage or stillbirth.In some cases, females who have a MECP2 gene do not develop symptoms of the disorder suggesting that in some cases additional factors (such as modifier genes) may serve to protect such individuals from the effects of the mutated gene. More research is necessary to fully understand the complex, underlying mechanisms that ultimately cause Rett syndrome.The MECP2 gene is located on the long arm (q) of the X chromosome (Xq28). 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. 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 Xq28” refers to band 28 on the long arm of the X chromosome. The numbered bands specify the location of the thousands of genes that are present on each chromosome.The MECP2 gene contains instructions for creating a protein (Methyl-CpG-binding protein 2) that may regulate the activity of many other genes in the body. Mutations to the MECP2 gene leads to low levels of functional MECP2 protein in the body, which, in turn, leads to the abnormal function of other genes within the body. For example, genes that should be silenced or turned off will remain active at certain times during development, ultimately leading to impaired brain development. The exact genes involved and the exact functions of the MECP2 protein are unknown or not fully understood. Rett syndrome is believed to affect normal brain development during early childhood. More research is necessary to determine the how MECP2 gene mutations ultimately cause Rett syndrome.
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Causes of Rett Syndrome. Approximately 90-95% of Rett syndrome cases are caused by identifiable mutations of the MECP2 gene. More than 200 different mutations have been identified. In 99% of cases, these mutations occur sporadically and are not possessed or transmitted by a child’s parents (de novo mutations). Therefore, in the vast majority of cases Rett syndrome is not an inherited disorder. In such cases, the parents have normal chromosomes and the mutation arises in one of the parent’s reproductive (germ) cells, usually on the paternal side.The chance of recurrence in subsequent children for parents who have one affected child is approximately 1%. In rare cases, more than one child can be affected. This rare occurrence may occur because of germline mosaicism. In germline mosaicism, one parent has some reproductive cells (germ cells) in the ovaries or testes that have the MECP2 gene mutation. The other cells in the parent’s body do not have the mutation, so these parents are unaffected. As a result, one or more of the parent’s children may inherit the germ cell MECP2 gene mutation. The likelihood of a parent passing on a mosaic germline mutation to a child depends upon the percentage of the parent’s germ cells that have the mutation versus the percentage that do not. There is no test for germline mutation prior to pregnancy. Testing during pregnancy may be available and is best discussed directly with a genetic specialist.In extremely rare cases, Rett syndrome may be inherited from a carrier mother who has favorable skewing of random X-chromosome inactivation and no symptoms or extremely mild symptoms of the disorder. When a mother is a known carrier of the MECP2 mutation, there is a 50% chance of passing that mutation on to her children.Random X-chromosome inactivation is a normal process in females. Females have two X chromosomes, whereas males have one X chromosome and one Y chromosome. In females, certain disease traits on the X chromosome such as a mutated gene may be “masked” by the normal gene on the other X chromosome (random X-chromosome inactivation). Basically, in each cell of the body one X chromosome is active and one is turned off or “silenced.” This occurs randomly and generally happens as a 50-50 split. However, in some cases, females may have favorable X-inactivation, in which the affected X chromosome is silenced in most of the cells. In such cases, affected females may only have mild symptoms of the disorder. In other cases, females may have unfavorable X-inactivation, in which the unaffected X chromosome is silenced in most of the cells. In such cases, affected females usually have a severe expression of the disorder.Because males only have one X chromosome, such disorders are usually fully expressed. Consequently, it is believed that in most cases MECP2 mutations are not compatible with life in males, usually resulting in miscarriage or stillbirth.In some cases, females who have a MECP2 gene do not develop symptoms of the disorder suggesting that in some cases additional factors (such as modifier genes) may serve to protect such individuals from the effects of the mutated gene. More research is necessary to fully understand the complex, underlying mechanisms that ultimately cause Rett syndrome.The MECP2 gene is located on the long arm (q) of the X chromosome (Xq28). 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. 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 Xq28” refers to band 28 on the long arm of the X chromosome. The numbered bands specify the location of the thousands of genes that are present on each chromosome.The MECP2 gene contains instructions for creating a protein (Methyl-CpG-binding protein 2) that may regulate the activity of many other genes in the body. Mutations to the MECP2 gene leads to low levels of functional MECP2 protein in the body, which, in turn, leads to the abnormal function of other genes within the body. For example, genes that should be silenced or turned off will remain active at certain times during development, ultimately leading to impaired brain development. The exact genes involved and the exact functions of the MECP2 protein are unknown or not fully understood. Rett syndrome is believed to affect normal brain development during early childhood. More research is necessary to determine the how MECP2 gene mutations ultimately cause Rett syndrome.
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Affects of Rett Syndrome
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Rett syndrome occurs almost exclusively in girls. The incidence of Rett syndrome in the United States is estimated to be 1 in 10,000 girls by age 12. Cases of Rett syndrome can go undiagnosed or misdiagnosed, making it difficult to determine the disorder’s true frequency in the general population. Rett syndrome is the second most common cause of severe intellectual disability after Down syndrome.
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Affects of Rett Syndrome. Rett syndrome occurs almost exclusively in girls. The incidence of Rett syndrome in the United States is estimated to be 1 in 10,000 girls by age 12. Cases of Rett syndrome can go undiagnosed or misdiagnosed, making it difficult to determine the disorder’s true frequency in the general population. Rett syndrome is the second most common cause of severe intellectual disability after Down syndrome.
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Related disorders of Rett Syndrome
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Symptoms of the following disorders can be similar to those of Rett syndrome. Comparisons may be useful for a differential diagnosis.Angelman syndrome is a rare genetic and neurological disorder characterized by severe developmental delays and learning disabilities; absence or near absence of speech; inability to coordinate voluntary movements (ataxia); tremulousness with jerky movements of the arms and legs and a distinct behavioral pattern characterized by a happy disposition and unprovoked episodes of laughter and smiling. Although those with the syndrome may be unable to speak, many gradually learn to communicate through other means such as gesturing. In addition, children may have enough receptive language ability to understand simple forms of language communication. Additional symptoms may occur including seizures, sleep disorders and feeding difficulties. Some children with Angelman syndrome may have distinctive facial features but most facial features reflect the normal parental traits. Angelman syndrome is caused by deletion or abnormal expression of the UBE3A gene. (For more information on this disorder, choose “Angelman” as your search term in the Rare Disease Database.)CDKL5 is a rare X-linked genetic disorder that results in early onset, difficult to control seizures, and severe neurodevelopmental impairment. CDKL5 stands for cyclin-dependent kinase-like 5, and is a gene located on the X chromosome. Most of the children affected by CDKL5 suffer from seizures that begin in the first few months of life. Most cannot walk, talk or feed themselves, and many are confined to a wheelchair. Many also suffer with scoliosis, visual impairment, sensory issues and various gastrointestinal difficulties. CDKL5 mutations were initially thought to be specifically associated with the Hanefeld variant of Rett syndrome, in which earlier seizures are a prominent feature. However, the characteristics of the disorder (phenotype) have been expanded to include early epileptic seizures and later onset intractable seizure disorders commonly including myoclonus without clinical features of Rett syndrome. More recent studies suggest that the predominant phenotype caused by CDKL5 mutations is the so-called epileptic encephalopathy, the onset of severe seizures in the first six months of life (often within the first 3 months), and poor subsequent neurocognitive development and commonly the presence of repetitive hand movements (stereotypies). CDKL5 mutations have been found in children diagnosed with infantile spasms, West syndrome, Lennox-Gastaut syndrome, Rett syndrome, and autism. The full spectrum of CDKL5 disorders is unknown at this time. It is likely that there are many people affected by CDKL5 who have mild symptoms and no seizures. (For more information on this disorder, choose “CDKL5” as your search term in the Rare Disease Database.)FOXG1-related disorders are a group of disorders that occurs in individuals who have a mutation of the FOXG1 gene. Affected individuals develop normally before and shortly after birth (perinatal). However, infants may develop progressive microcephaly, seizures, developmental delays, and severe intellectual disability. Some affected individuals may experience gastrointestinal abnormalities including constipation and gastroesophageal reflex, scoliosis, and foot deformities. Affected individuals may experience a variety of movement disorders including stereotypic hand movements. FOXG1-related disorders are caused by mutations of the FOXG1 gene. The FOXG1-related disorders are sometimes referred to as the congenital variant of Rett syndrome.A wide variety of additional disorders may have symptoms or physical findings that are similar to Rett syndrome. Such disorders include autism, cerebral palsy, certain metabolic disorders, perinatal or postnatal brain injury, a variety of neurodegenerative disorders, and acquired neurological disorders such as may result from trauma or infection. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Related disorders of Rett Syndrome. Symptoms of the following disorders can be similar to those of Rett syndrome. Comparisons may be useful for a differential diagnosis.Angelman syndrome is a rare genetic and neurological disorder characterized by severe developmental delays and learning disabilities; absence or near absence of speech; inability to coordinate voluntary movements (ataxia); tremulousness with jerky movements of the arms and legs and a distinct behavioral pattern characterized by a happy disposition and unprovoked episodes of laughter and smiling. Although those with the syndrome may be unable to speak, many gradually learn to communicate through other means such as gesturing. In addition, children may have enough receptive language ability to understand simple forms of language communication. Additional symptoms may occur including seizures, sleep disorders and feeding difficulties. Some children with Angelman syndrome may have distinctive facial features but most facial features reflect the normal parental traits. Angelman syndrome is caused by deletion or abnormal expression of the UBE3A gene. (For more information on this disorder, choose “Angelman” as your search term in the Rare Disease Database.)CDKL5 is a rare X-linked genetic disorder that results in early onset, difficult to control seizures, and severe neurodevelopmental impairment. CDKL5 stands for cyclin-dependent kinase-like 5, and is a gene located on the X chromosome. Most of the children affected by CDKL5 suffer from seizures that begin in the first few months of life. Most cannot walk, talk or feed themselves, and many are confined to a wheelchair. Many also suffer with scoliosis, visual impairment, sensory issues and various gastrointestinal difficulties. CDKL5 mutations were initially thought to be specifically associated with the Hanefeld variant of Rett syndrome, in which earlier seizures are a prominent feature. However, the characteristics of the disorder (phenotype) have been expanded to include early epileptic seizures and later onset intractable seizure disorders commonly including myoclonus without clinical features of Rett syndrome. More recent studies suggest that the predominant phenotype caused by CDKL5 mutations is the so-called epileptic encephalopathy, the onset of severe seizures in the first six months of life (often within the first 3 months), and poor subsequent neurocognitive development and commonly the presence of repetitive hand movements (stereotypies). CDKL5 mutations have been found in children diagnosed with infantile spasms, West syndrome, Lennox-Gastaut syndrome, Rett syndrome, and autism. The full spectrum of CDKL5 disorders is unknown at this time. It is likely that there are many people affected by CDKL5 who have mild symptoms and no seizures. (For more information on this disorder, choose “CDKL5” as your search term in the Rare Disease Database.)FOXG1-related disorders are a group of disorders that occurs in individuals who have a mutation of the FOXG1 gene. Affected individuals develop normally before and shortly after birth (perinatal). However, infants may develop progressive microcephaly, seizures, developmental delays, and severe intellectual disability. Some affected individuals may experience gastrointestinal abnormalities including constipation and gastroesophageal reflex, scoliosis, and foot deformities. Affected individuals may experience a variety of movement disorders including stereotypic hand movements. FOXG1-related disorders are caused by mutations of the FOXG1 gene. The FOXG1-related disorders are sometimes referred to as the congenital variant of Rett syndrome.A wide variety of additional disorders may have symptoms or physical findings that are similar to Rett syndrome. Such disorders include autism, cerebral palsy, certain metabolic disorders, perinatal or postnatal brain injury, a variety of neurodegenerative disorders, and acquired neurological disorders such as may result from trauma or infection. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Diagnosis of Rett Syndrome
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A diagnosis of Rett syndrome is based upon identification of characteristic symptoms, a detailed patient history, and a thorough clinical evaluation. A variety of specialized tests may be conducted to rule out other conditions that can cause similar symptoms. A set of updated diagnostic criteria was recently published (Neul et al 2010). The fulfillment of these diagnostic criteria can lead to a clinical diagnosis of Rett syndrome. The report also includes diagnostic criteria for variant forms of Rett syndrome.Molecular genetic testing can detect the presence of mutations of the MECP2 gene and confirm the clinical diagnosis of Rett syndrome.
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Diagnosis of Rett Syndrome. A diagnosis of Rett syndrome is based upon identification of characteristic symptoms, a detailed patient history, and a thorough clinical evaluation. A variety of specialized tests may be conducted to rule out other conditions that can cause similar symptoms. A set of updated diagnostic criteria was recently published (Neul et al 2010). The fulfillment of these diagnostic criteria can lead to a clinical diagnosis of Rett syndrome. The report also includes diagnostic criteria for variant forms of Rett syndrome.Molecular genetic testing can detect the presence of mutations of the MECP2 gene and confirm the clinical diagnosis of Rett syndrome.
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Therapies of Rett Syndrome
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TreatmentThe treatment of Rett syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, pediatric neurologists, gastroenterologists, speech therapists, psychiatrists, nutritionists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Genetic counseling may be of benefit for affected individuals and their families.Treatment options that may be used to treat individuals with Rett syndrome are complex and varied. The specific treatment plan will need to be highly individualized. Early developmental intervention is important to ensure that affected children reach their potential. Most affected children will benefit from occupational, physical and speech therapy. Various methods of rehabilitative and behavioral therapy may be beneficial. Additional medical, social and/or vocational services including special remedial education may be necessary. Psychosocial support for the entire family is essential as well.In 2023, trofinetide (Daybue) was approved by the U.S. Food and Drug Administration (FDA) as the first treatment for Rett syndrome in adults and children 2 years of age and older.Other treatment is symptomatic and supportive. Additional therapies for Rett syndrome depend upon the specific abnormalities present and generally follow standard guidelines.Some general therapies common for infants or children with Rett syndrome include nutritional supplements to ensure maximum caloric intake. In some cases, children may require the insertion of a tube through a small opening in the stomach (gastronomy). Some affected individuals are encouraged to follow a diet high in calories and fat.Drugs may be used to treat a variety of symptoms associated with Rett syndrome including seizures, anxiety, sleep disturbances, breathing problems, stereotypic hand movements, and certain gastrointestinal abnormalities. Drugs may also be used to improve spasticity and muscle rigidity.Individuals at risk of prolonged QT interval should be evaluated by cardiology. These individuals also need to avoid certain medications that can aggravate the condition.Scoliosis is common in individuals with Rett syndrome. Guidelines have been published detailing specific recommendations for the management of scoliosis in Rett syndrome (Downs et al 2009).
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Therapies of Rett Syndrome. TreatmentThe treatment of Rett syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, pediatric neurologists, gastroenterologists, speech therapists, psychiatrists, nutritionists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Genetic counseling may be of benefit for affected individuals and their families.Treatment options that may be used to treat individuals with Rett syndrome are complex and varied. The specific treatment plan will need to be highly individualized. Early developmental intervention is important to ensure that affected children reach their potential. Most affected children will benefit from occupational, physical and speech therapy. Various methods of rehabilitative and behavioral therapy may be beneficial. Additional medical, social and/or vocational services including special remedial education may be necessary. Psychosocial support for the entire family is essential as well.In 2023, trofinetide (Daybue) was approved by the U.S. Food and Drug Administration (FDA) as the first treatment for Rett syndrome in adults and children 2 years of age and older.Other treatment is symptomatic and supportive. Additional therapies for Rett syndrome depend upon the specific abnormalities present and generally follow standard guidelines.Some general therapies common for infants or children with Rett syndrome include nutritional supplements to ensure maximum caloric intake. In some cases, children may require the insertion of a tube through a small opening in the stomach (gastronomy). Some affected individuals are encouraged to follow a diet high in calories and fat.Drugs may be used to treat a variety of symptoms associated with Rett syndrome including seizures, anxiety, sleep disturbances, breathing problems, stereotypic hand movements, and certain gastrointestinal abnormalities. Drugs may also be used to improve spasticity and muscle rigidity.Individuals at risk of prolonged QT interval should be evaluated by cardiology. These individuals also need to avoid certain medications that can aggravate the condition.Scoliosis is common in individuals with Rett syndrome. Guidelines have been published detailing specific recommendations for the management of scoliosis in Rett syndrome (Downs et al 2009).
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Overview of Reye Syndrome
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Reye syndrome is a rare disorder of childhood and adolescence. It primarily affects individuals under 18 years of age, particularly children from approximately age four to 12 years. In rare cases, infants or young adults may be affected. The disorder's cause is unknown. However, there appears to be an association between the onset of Reye syndrome and the use of aspirin-containing medications (salicylates) in children or adolescents with certain viral illnesses, particularly upper respiratory tract infections (e.g., influenza B) or, in some cases, chickenpox (varicella). Although any organ system may be involved, Reye syndrome is primarily characterized by distinctive, fatty changes of the liver and sudden (acute) swelling of the brain (cerebral edema). Associated symptoms and findings may include the sudden onset of severe, persistent vomiting; elevated levels of certain liver enzymes in the blood (hepatic transaminases); unusually high amounts of ammonia in the blood (hyperammonemia); disturbances of consciousness; sudden episodes of uncontrolled electrical activity in the brain (seizures); and/or other abnormalities, leading to potentially life-threatening complications in some cases. Due to the potential association between the use of aspirin-containing agents and the development of Reye syndrome, it is advised that such medications be avoided for individuals under age 18 years who are affected by viral infections such as influenza or chickenpox.
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Overview of Reye Syndrome. Reye syndrome is a rare disorder of childhood and adolescence. It primarily affects individuals under 18 years of age, particularly children from approximately age four to 12 years. In rare cases, infants or young adults may be affected. The disorder's cause is unknown. However, there appears to be an association between the onset of Reye syndrome and the use of aspirin-containing medications (salicylates) in children or adolescents with certain viral illnesses, particularly upper respiratory tract infections (e.g., influenza B) or, in some cases, chickenpox (varicella). Although any organ system may be involved, Reye syndrome is primarily characterized by distinctive, fatty changes of the liver and sudden (acute) swelling of the brain (cerebral edema). Associated symptoms and findings may include the sudden onset of severe, persistent vomiting; elevated levels of certain liver enzymes in the blood (hepatic transaminases); unusually high amounts of ammonia in the blood (hyperammonemia); disturbances of consciousness; sudden episodes of uncontrolled electrical activity in the brain (seizures); and/or other abnormalities, leading to potentially life-threatening complications in some cases. Due to the potential association between the use of aspirin-containing agents and the development of Reye syndrome, it is advised that such medications be avoided for individuals under age 18 years who are affected by viral infections such as influenza or chickenpox.
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Symptoms of Reye Syndrome
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The symptoms of Reye syndrome typically begin after a viral illness, particularly an upper respiratory infection (e.g, with influenza B virus) or, in some cases, chickenpox (varicella). Less commonly, Reye syndrome may develop after infection with other viral agents, such as influenza A or rubella. (For further information, please see the “Causes” section of this report below.) About three to five days after the onset of viral infection, affected children experience sudden, persistent, uncontrolled vomiting. Disturbances of consciousness may begin simultaneously or develop within hours. Such abnormalities often include irritability, restlessness, disorientation, lethargy, and memory impairment. Some children may remain lethargic with no progression to unconsciousness. In other cases, neurological deterioration may be rapidly progressive, leading to an apparent lack of awareness of surroundings (stupor); a state of unconsciousness and unresponsiveness (coma); widening (dilation) of the pupils (mydriasis); rapid, shallow breathing (tachypnea); a rapid heart rate (tachycardia); and loss of certain reflexes (e.g., deep tendon, pupillary, oculocephalic). Severe neurological dysfunction may also lead to episodes of uncontrolled electrical disturbances in the brain (seizures); abnormal posturing (decerebrate or decorticate rigidity), indicating damage to certain areas of the brain; and potentially life-threatening complications. Findings associated with fatty degeneration of the liver may include enlargement of the liver (hepatomegaly) and abnormally increased levels of certain liver enzymes (hepatic transaminases), indicating impaired liver functioning. However, jaundice, a finding often associated with liver dysfunction, generally does not occur (anicteric) or is minimal in those with the disorder. Jaundice is a condition in which there is yellowish discoloration of the skin, eyes, and mucous membranes due to excessive accumulation of the pigment bilirubin in the blood. In individuals with Reye syndrome, disease severity may be extremely variable. According to reports in the medical literature, some affected individuals may have mild symptoms without disease progression. However, as discussed above, others with the disorder may develop rapid neurological deterioration leading to potentially life-threatening complications. Researchers have proposed a clinical staging system based upon the varying levels of severity, with Grades I, II, and III indicating relatively mild to moderate disease and Grades IV and V signifying more severe disease.
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Symptoms of Reye Syndrome. The symptoms of Reye syndrome typically begin after a viral illness, particularly an upper respiratory infection (e.g, with influenza B virus) or, in some cases, chickenpox (varicella). Less commonly, Reye syndrome may develop after infection with other viral agents, such as influenza A or rubella. (For further information, please see the “Causes” section of this report below.) About three to five days after the onset of viral infection, affected children experience sudden, persistent, uncontrolled vomiting. Disturbances of consciousness may begin simultaneously or develop within hours. Such abnormalities often include irritability, restlessness, disorientation, lethargy, and memory impairment. Some children may remain lethargic with no progression to unconsciousness. In other cases, neurological deterioration may be rapidly progressive, leading to an apparent lack of awareness of surroundings (stupor); a state of unconsciousness and unresponsiveness (coma); widening (dilation) of the pupils (mydriasis); rapid, shallow breathing (tachypnea); a rapid heart rate (tachycardia); and loss of certain reflexes (e.g., deep tendon, pupillary, oculocephalic). Severe neurological dysfunction may also lead to episodes of uncontrolled electrical disturbances in the brain (seizures); abnormal posturing (decerebrate or decorticate rigidity), indicating damage to certain areas of the brain; and potentially life-threatening complications. Findings associated with fatty degeneration of the liver may include enlargement of the liver (hepatomegaly) and abnormally increased levels of certain liver enzymes (hepatic transaminases), indicating impaired liver functioning. However, jaundice, a finding often associated with liver dysfunction, generally does not occur (anicteric) or is minimal in those with the disorder. Jaundice is a condition in which there is yellowish discoloration of the skin, eyes, and mucous membranes due to excessive accumulation of the pigment bilirubin in the blood. In individuals with Reye syndrome, disease severity may be extremely variable. According to reports in the medical literature, some affected individuals may have mild symptoms without disease progression. However, as discussed above, others with the disorder may develop rapid neurological deterioration leading to potentially life-threatening complications. Researchers have proposed a clinical staging system based upon the varying levels of severity, with Grades I, II, and III indicating relatively mild to moderate disease and Grades IV and V signifying more severe disease.
| 1,074 |
Reye Syndrome
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nord_1074_2
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Causes of Reye Syndrome
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The specific cause of Reye syndrome remains unknown. However, according to researchers, there appears to be an association between the condition’s onset and the administration of aspirin-containing medications (salicylates) in children or adolescents with certain viral illnesses. This typically includes upper respiratory tract infections caused by the influenza B virus or chickenpox (varicella). Less commonly, the development of Reye Syndrome has been reported in association with other viral infections, including influenza A, herpes simplex, rubella, or Epstein-Barr. The primary symptoms and findings associated with Reye syndrome appear to result from distinctive, fatty changes of the liver, impaired liver functioning, and an abnormal accumulation of fluid in brain tissues (cerebral edema), which may lead to increased fluid pressure and potential compression of brain tissue. In individuals with Reye Syndrome, degenerative changes of the liver are associated with an abnormal infiltration of liver cells (hepatocytes) with fatty compounds (e.g., triglycerides). In addition, to a lesser degree, there may be fatty infiltration of the spleen, the pancreas, voluntary (skeletal) muscles, heart muscle (myocardium), and/or the tubular structures within the kidneys that collect and conduct urine (renal tubules). Researchers suggest that the primary underlying defect in Reye syndrome is abnormal functioning of mitochondria with reduced activities of liver (hepatic) mitochondrial enzymes (e.g., ornithine transcarbamylase [OTC], carbamyl phosphate synthetase [CPS], pyruvate dehydrogenase [PDH]). However, the cause of such mitochondrial dysfunction remains unknown. Mitochondria are the tiny, rodlike structures (organelles) outside the nuclei of cells that function in cellular metabolism and other processes. They contain various enzymes and serve as primary sites in the generation of cellular energy. Enzymes are proteins that accelerate the rate of specific chemical reactions. The term “metabolism” refers to all the chemical processes that occur within the body. Ongoing research has determined that several metabolic disorders or inborn errors of metabolism may result in symptoms that mimic those associated with Reye syndrome (so-called “Reye-like diseases”). Metabolic disorders that may cause symptoms and findings similar to those seen in Reye Syndrome include certain urea cycle disorders (UCDs), organic acidurias, and abnormalities in fatty acid metabolism. (For information on such disorders, please see the “Related Disorders” section of this report below.) v
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Causes of Reye Syndrome. The specific cause of Reye syndrome remains unknown. However, according to researchers, there appears to be an association between the condition’s onset and the administration of aspirin-containing medications (salicylates) in children or adolescents with certain viral illnesses. This typically includes upper respiratory tract infections caused by the influenza B virus or chickenpox (varicella). Less commonly, the development of Reye Syndrome has been reported in association with other viral infections, including influenza A, herpes simplex, rubella, or Epstein-Barr. The primary symptoms and findings associated with Reye syndrome appear to result from distinctive, fatty changes of the liver, impaired liver functioning, and an abnormal accumulation of fluid in brain tissues (cerebral edema), which may lead to increased fluid pressure and potential compression of brain tissue. In individuals with Reye Syndrome, degenerative changes of the liver are associated with an abnormal infiltration of liver cells (hepatocytes) with fatty compounds (e.g., triglycerides). In addition, to a lesser degree, there may be fatty infiltration of the spleen, the pancreas, voluntary (skeletal) muscles, heart muscle (myocardium), and/or the tubular structures within the kidneys that collect and conduct urine (renal tubules). Researchers suggest that the primary underlying defect in Reye syndrome is abnormal functioning of mitochondria with reduced activities of liver (hepatic) mitochondrial enzymes (e.g., ornithine transcarbamylase [OTC], carbamyl phosphate synthetase [CPS], pyruvate dehydrogenase [PDH]). However, the cause of such mitochondrial dysfunction remains unknown. Mitochondria are the tiny, rodlike structures (organelles) outside the nuclei of cells that function in cellular metabolism and other processes. They contain various enzymes and serve as primary sites in the generation of cellular energy. Enzymes are proteins that accelerate the rate of specific chemical reactions. The term “metabolism” refers to all the chemical processes that occur within the body. Ongoing research has determined that several metabolic disorders or inborn errors of metabolism may result in symptoms that mimic those associated with Reye syndrome (so-called “Reye-like diseases”). Metabolic disorders that may cause symptoms and findings similar to those seen in Reye Syndrome include certain urea cycle disorders (UCDs), organic acidurias, and abnormalities in fatty acid metabolism. (For information on such disorders, please see the “Related Disorders” section of this report below.) v
| 1,074 |
Reye Syndrome
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nord_1074_3
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Affects of Reye Syndrome
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Reye syndrome is a rare disorder that appears to affect males and females in relatively equal numbers. The disorder occurs almost exclusively in individuals younger than age 18 years. Most cases occur at about age 6, with most affected individuals ranging in age from approximately four to 12 years. However, there have been rare instances in which Reye syndrome has affected infants and young adults. Evidence suggests that children and adolescents in rural and suburban areas appear to be affected more frequently than those in urban areas. The disorder was originally recognized as a distinct disease entity in 1963, when several cases were reported from the United States and Australia. Surveillance of Reye syndrome has indicated that the disorder tends to occur in outbreaks in association with viral infection (e.g., influenza B, varicella, various other viral infections) or may occasionally occur on a more sporadic basis, also in association with such viral infections. The incidence of the disorder has dramatically declined in the United States beginning in the late 1980s. Approximately 200 to 550 cases were reported each year in the United States during 1974 to 1984. However, since 1988, fewer than 20 cases have been reported annually. Many researchers attribute the decline to increased public awareness concerning the potential association between Reye syndrome and the use of aspirin-containing preparations for certain viral infections and the recognition that some children suspected of having Reye syndrome actually have an inborn error of metabolism. Similar decreases in incidence rates have also been reported in the United Kingdom after public health warnings were issued.
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Affects of Reye Syndrome. Reye syndrome is a rare disorder that appears to affect males and females in relatively equal numbers. The disorder occurs almost exclusively in individuals younger than age 18 years. Most cases occur at about age 6, with most affected individuals ranging in age from approximately four to 12 years. However, there have been rare instances in which Reye syndrome has affected infants and young adults. Evidence suggests that children and adolescents in rural and suburban areas appear to be affected more frequently than those in urban areas. The disorder was originally recognized as a distinct disease entity in 1963, when several cases were reported from the United States and Australia. Surveillance of Reye syndrome has indicated that the disorder tends to occur in outbreaks in association with viral infection (e.g., influenza B, varicella, various other viral infections) or may occasionally occur on a more sporadic basis, also in association with such viral infections. The incidence of the disorder has dramatically declined in the United States beginning in the late 1980s. Approximately 200 to 550 cases were reported each year in the United States during 1974 to 1984. However, since 1988, fewer than 20 cases have been reported annually. Many researchers attribute the decline to increased public awareness concerning the potential association between Reye syndrome and the use of aspirin-containing preparations for certain viral infections and the recognition that some children suspected of having Reye syndrome actually have an inborn error of metabolism. Similar decreases in incidence rates have also been reported in the United Kingdom after public health warnings were issued.
| 1,074 |
Reye Syndrome
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nord_1074_4
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Related disorders of Reye Syndrome
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Symptoms of the following disorders may be similar to those of Reye syndrome. Comparisons may be useful for a differential diagnosis: Ornithine transcarbamylase (OTC) deficiency is a rare inborn error of metabolism that is classified as a urea cycle disorder. In individuals with the disorder, deficient activity of the OTC enzyme may lead to excessive amounts of ammonia in the blood (hyperammonemia). (Ammonia, a byproduct of protein metabolism, may be toxic to the brain. During a complex series of enzyme reactions within the liver known as the “urea cycle,” ammonia is normally converted to the waste product urea, which is then eliminated by the kidneys.) OTC Deficiency is inherited as an X-linked trait. Males who inherit a single mutated gene for the disease (hemizygous males) usually are more severely affected than female carriers (heterozygous females) and may have associated symptoms and findings at birth. Heterozygous females may have mild disease that becomes apparent during infancy or early childhood or no apparent symptoms. Those with OTC deficiency may have persistent or periodic hyperammonemia, which may be associated with lack of appetite, vomiting, and neurologic symptoms and signs. Such abnormalities may include mental confusion, agitation, impaired control of voluntary movements (ataxia), and/or drowsiness and listlessness (lethargy) that may progress to coma. (For more information on this disorder, choose “ornithine transcarbamylase” as your search term in the Rare Disease Database.) Fatty acid oxidation disorders (FODs) are a group of genetic metabolic disorders that are characterized by the abnormal accumulation of fatty acids in the body. In these disorders, the body fails to break down (metabolize) complex molecules into simpler molecules. As a result, affected individuals cannot use fats for energy. Stored fat is the secondary energy source for the body (the first is glucose). When glucose runs out, the body converts stored fat for energy. The inability to break down fatty acids results in their abnormal accumulation within the body, potentially affecting any organ system of the body. Thus, the symptoms of FODs vary widely even among members of the same family. The FODs encompass many different disorders including medium chain acyl-CoA dehydrogenase (MCAD) deficiency, very long chain acyl-CoA dehydrogenase (VLCAD) deficiency, short chain acyl-coA dehydrogenase (SCAD) deficiency, and the primary carnitine deficiency syndromes. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) Medium chain acyl-CoA dehydrogenase (MCAD) deficiency is a rare genetic metabolic disorder characterized by a deficiency of the enzyme medium chain acyl-CoA dehydrogenase. This enzyme is found to be most active in the liver, certain white blood cells (leukocytes), and certain connective tissue cells (fibroblasts), and is necessary for the breakdown (oxidation) of certain fats (medium chain fatty acids). Failure to break down these fats can lead to the abnormal accumulation of fatty acids in the liver and the brain. Abnormally low levels of the MCAD enzyme may also hamper or interrupt other processes associated with the metabolism of fatty acids. In infants with MCAD deficiency, symptoms may include recurrent episodes of unusually low levels of a certain sugar (glucose) in the blood (hypoglycemia), lack of energy (lethargy), vomiting, and/or liver malfunction. These symptoms are most frequently triggered when an affected infant does not eat for an extended period of time (fasting). In some cases, a viral illness (e.g., upper respiratory infection) that limits food intake may cause the symptoms to occur. MCAD deficiency is the most common disease in a group of disorders that involve abnormalities of fatty acid metabolism (fatty acid oxidation disorders [FODs]). MCAD deficiency is inherited as an autosomal recessive trait. (For more information, choose “MCAD” as your search term in the Rare Disease Database.) Glutaricaciduria I (GA I) is a metabolic disorder characterized by deficiency of the enzyme glutaryl-CoA dehydrogenase. Onset may occur after approximately two years of age, with symptoms developing gradually or occurring suddenly following infection. Affected children may develop diminished muscle tone (hypotonia) and involuntary, irregular, jerky motions associated with relatively slow, writhing movements (choreoathetosis). Such abnormalities may progress to generalized muscle stiffness (rigidity), with involuntary, repetitive, twisting movements and abnormal postures (dystonia). Associated findings often include high concentrations of the organic acid glutaric acid in the blood and urine (organic aciduria) as well as of the derivative 3-hydroxyglutaric acid in the urine. In addition, during infection or stress, affected children may develop sudden episodes of vomiting, low blood sugar levels (hypoglycemia), increased ammonia levels in the blood, enlargement of the liver (hepatomegaly), increased blood levels of certain liver enzymes, seizures, and coma. The disorder is inherited as an autosomal recessive trait. (For more information on this disorder, choose “glutaricaciduria I” as your search term in the Rare Disease Database.) A number of other disorders and conditions may cause certain symptoms and findings similar to those associated with Reye syndrome, including additional urea cycle disorders, fatty acid oxidation disorders, organic acidurias, and other metabolic disorders; central nervous system infections, including inflammation of the brain (encephalitis) or the protective membranes covering the brain and spinal cord (meningitis); and various other disorders. (For further information, please choose the exact disease name in question as your search term in the Rare Disease Database.)
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Related disorders of Reye Syndrome. Symptoms of the following disorders may be similar to those of Reye syndrome. Comparisons may be useful for a differential diagnosis: Ornithine transcarbamylase (OTC) deficiency is a rare inborn error of metabolism that is classified as a urea cycle disorder. In individuals with the disorder, deficient activity of the OTC enzyme may lead to excessive amounts of ammonia in the blood (hyperammonemia). (Ammonia, a byproduct of protein metabolism, may be toxic to the brain. During a complex series of enzyme reactions within the liver known as the “urea cycle,” ammonia is normally converted to the waste product urea, which is then eliminated by the kidneys.) OTC Deficiency is inherited as an X-linked trait. Males who inherit a single mutated gene for the disease (hemizygous males) usually are more severely affected than female carriers (heterozygous females) and may have associated symptoms and findings at birth. Heterozygous females may have mild disease that becomes apparent during infancy or early childhood or no apparent symptoms. Those with OTC deficiency may have persistent or periodic hyperammonemia, which may be associated with lack of appetite, vomiting, and neurologic symptoms and signs. Such abnormalities may include mental confusion, agitation, impaired control of voluntary movements (ataxia), and/or drowsiness and listlessness (lethargy) that may progress to coma. (For more information on this disorder, choose “ornithine transcarbamylase” as your search term in the Rare Disease Database.) Fatty acid oxidation disorders (FODs) are a group of genetic metabolic disorders that are characterized by the abnormal accumulation of fatty acids in the body. In these disorders, the body fails to break down (metabolize) complex molecules into simpler molecules. As a result, affected individuals cannot use fats for energy. Stored fat is the secondary energy source for the body (the first is glucose). When glucose runs out, the body converts stored fat for energy. The inability to break down fatty acids results in their abnormal accumulation within the body, potentially affecting any organ system of the body. Thus, the symptoms of FODs vary widely even among members of the same family. The FODs encompass many different disorders including medium chain acyl-CoA dehydrogenase (MCAD) deficiency, very long chain acyl-CoA dehydrogenase (VLCAD) deficiency, short chain acyl-coA dehydrogenase (SCAD) deficiency, and the primary carnitine deficiency syndromes. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) Medium chain acyl-CoA dehydrogenase (MCAD) deficiency is a rare genetic metabolic disorder characterized by a deficiency of the enzyme medium chain acyl-CoA dehydrogenase. This enzyme is found to be most active in the liver, certain white blood cells (leukocytes), and certain connective tissue cells (fibroblasts), and is necessary for the breakdown (oxidation) of certain fats (medium chain fatty acids). Failure to break down these fats can lead to the abnormal accumulation of fatty acids in the liver and the brain. Abnormally low levels of the MCAD enzyme may also hamper or interrupt other processes associated with the metabolism of fatty acids. In infants with MCAD deficiency, symptoms may include recurrent episodes of unusually low levels of a certain sugar (glucose) in the blood (hypoglycemia), lack of energy (lethargy), vomiting, and/or liver malfunction. These symptoms are most frequently triggered when an affected infant does not eat for an extended period of time (fasting). In some cases, a viral illness (e.g., upper respiratory infection) that limits food intake may cause the symptoms to occur. MCAD deficiency is the most common disease in a group of disorders that involve abnormalities of fatty acid metabolism (fatty acid oxidation disorders [FODs]). MCAD deficiency is inherited as an autosomal recessive trait. (For more information, choose “MCAD” as your search term in the Rare Disease Database.) Glutaricaciduria I (GA I) is a metabolic disorder characterized by deficiency of the enzyme glutaryl-CoA dehydrogenase. Onset may occur after approximately two years of age, with symptoms developing gradually or occurring suddenly following infection. Affected children may develop diminished muscle tone (hypotonia) and involuntary, irregular, jerky motions associated with relatively slow, writhing movements (choreoathetosis). Such abnormalities may progress to generalized muscle stiffness (rigidity), with involuntary, repetitive, twisting movements and abnormal postures (dystonia). Associated findings often include high concentrations of the organic acid glutaric acid in the blood and urine (organic aciduria) as well as of the derivative 3-hydroxyglutaric acid in the urine. In addition, during infection or stress, affected children may develop sudden episodes of vomiting, low blood sugar levels (hypoglycemia), increased ammonia levels in the blood, enlargement of the liver (hepatomegaly), increased blood levels of certain liver enzymes, seizures, and coma. The disorder is inherited as an autosomal recessive trait. (For more information on this disorder, choose “glutaricaciduria I” as your search term in the Rare Disease Database.) A number of other disorders and conditions may cause certain symptoms and findings similar to those associated with Reye syndrome, including additional urea cycle disorders, fatty acid oxidation disorders, organic acidurias, and other metabolic disorders; central nervous system infections, including inflammation of the brain (encephalitis) or the protective membranes covering the brain and spinal cord (meningitis); and various other disorders. (For further information, please choose the exact disease name in question as your search term in the Rare Disease Database.)
| 1,074 |
Reye Syndrome
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nord_1074_5
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Diagnosis of Reye Syndrome
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According to researchers, Reye syndrome should be suspected in any infants, children, or adolescents who experience severe, persistent vomiting in association with evidence of unexplained acute swelling of the brain. The condition may be diagnosed based upon a complete patient history, thorough clinical evaluation, characteristic physical findings, and the results of specialized laboratory tests. Initial tests may include liver chemistry tests (AST and ALT tests) that reveal elevated levels of certain liver enzymes (e.g., aspartate transaminase [AST], alanine transaminase [ALT]) in the blood. The results of these tests are usually available within a few hours and high levels of these enzymes are strongly suggestive of Reye syndrome. In some individuals with Reye syndrome, analysis of the cerebrospinal fluid (CSF) may confirm increased pressure. (CSF is the watery protective fluid that circulates through the brain’s four cavities [ventricles], the canal containing the spinal cord [spinal canal], and the space between layers of the protective membranes [meninges] surrounding the brain and spinal cord [i.e., subarachnoid space].) In addition, blood studies typically reveal elevated levels of certain muscle enzymes (e.g., creatine kinase) and the mitochondrial enzyme glutamate dehydrogenase. There may also be significantly increased levels of ammonia in the blood (hyperammonemia), although this is a highly variable finding. (As noted above, ammonia is a byproduct of protein metabolism that may be toxic to the brain.) Blood studies may also reveal low levels of a certain blood clotting factor (hypoprothrombinemia). According to reports in the medical literature, affected individuals with significantly elevated ammonia levels in the blood and/or hypoprothrombinemia who are unresponsive to treatment with vitamin K may have an increased likelihood of progressing to coma. (For information on therapies for individuals with Reye Syndrome, see “Treatment” below.) In those with the disorder, laboratory tests also typically reveal reduced activities of liver (hepatic) mitochondrial enzymes, such as pyruvate dehydrogenase (PDH), ornithine transcarbamylase (OTC), and carbamyl phosphate synthetase (CPS). Researchers indicate that acquired decreases in the enzyme activities of CPS and OTC may result in increased blood ammonia levels (hyperammonemia). (Both enzymes function as part of the “urea cycle” discussed above.) Laboratory tests may also confirm reduced levels of the simple sugar glucose in the blood (hypoglycemia), particularly in young children. CSF analysis may also reveal low glucose levels (hypoglycorrhachia) reflecting hypoglycemia. According to investigators, diagnostic screening tests should be performed for young patients to help rule out or detect underlying metabolic disorders that may be present. In addition, particularly for children younger than age one to two years, liver biopsy may be advised to help eliminate or confirm underlying metabolic or toxic liver disorders. Liver biopsy involves the surgical removal (biopsy) and microscopic evaluation of small samples of liver tissue. In those with Reye syndrome, liver biopsy typically reveals the abnormal accumulation of certain fatty compounds (e.g., triglycerides) within liver cells and structural changes of liver mitochondria.
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Diagnosis of Reye Syndrome. According to researchers, Reye syndrome should be suspected in any infants, children, or adolescents who experience severe, persistent vomiting in association with evidence of unexplained acute swelling of the brain. The condition may be diagnosed based upon a complete patient history, thorough clinical evaluation, characteristic physical findings, and the results of specialized laboratory tests. Initial tests may include liver chemistry tests (AST and ALT tests) that reveal elevated levels of certain liver enzymes (e.g., aspartate transaminase [AST], alanine transaminase [ALT]) in the blood. The results of these tests are usually available within a few hours and high levels of these enzymes are strongly suggestive of Reye syndrome. In some individuals with Reye syndrome, analysis of the cerebrospinal fluid (CSF) may confirm increased pressure. (CSF is the watery protective fluid that circulates through the brain’s four cavities [ventricles], the canal containing the spinal cord [spinal canal], and the space between layers of the protective membranes [meninges] surrounding the brain and spinal cord [i.e., subarachnoid space].) In addition, blood studies typically reveal elevated levels of certain muscle enzymes (e.g., creatine kinase) and the mitochondrial enzyme glutamate dehydrogenase. There may also be significantly increased levels of ammonia in the blood (hyperammonemia), although this is a highly variable finding. (As noted above, ammonia is a byproduct of protein metabolism that may be toxic to the brain.) Blood studies may also reveal low levels of a certain blood clotting factor (hypoprothrombinemia). According to reports in the medical literature, affected individuals with significantly elevated ammonia levels in the blood and/or hypoprothrombinemia who are unresponsive to treatment with vitamin K may have an increased likelihood of progressing to coma. (For information on therapies for individuals with Reye Syndrome, see “Treatment” below.) In those with the disorder, laboratory tests also typically reveal reduced activities of liver (hepatic) mitochondrial enzymes, such as pyruvate dehydrogenase (PDH), ornithine transcarbamylase (OTC), and carbamyl phosphate synthetase (CPS). Researchers indicate that acquired decreases in the enzyme activities of CPS and OTC may result in increased blood ammonia levels (hyperammonemia). (Both enzymes function as part of the “urea cycle” discussed above.) Laboratory tests may also confirm reduced levels of the simple sugar glucose in the blood (hypoglycemia), particularly in young children. CSF analysis may also reveal low glucose levels (hypoglycorrhachia) reflecting hypoglycemia. According to investigators, diagnostic screening tests should be performed for young patients to help rule out or detect underlying metabolic disorders that may be present. In addition, particularly for children younger than age one to two years, liver biopsy may be advised to help eliminate or confirm underlying metabolic or toxic liver disorders. Liver biopsy involves the surgical removal (biopsy) and microscopic evaluation of small samples of liver tissue. In those with Reye syndrome, liver biopsy typically reveals the abnormal accumulation of certain fatty compounds (e.g., triglycerides) within liver cells and structural changes of liver mitochondria.
| 1,074 |
Reye Syndrome
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nord_1074_6
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Therapies of Reye Syndrome
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According to reports in the medical literature, the mainstays of treatment include early diagnosis; prompt administration of intensive care as required; and measures to correct metabolic abnormalities and prevent or control increased pressure between the skull and brain (intracranial pressure [ICP]) secondary to cerebral edema. The specific therapies used may vary from person to person, depending upon disease severity and progression. For example, in children with mild disease (e.g., Grade I severity), treatment may primarily consist of close observation. However, in those with more severe disease, intensive, emergency treatment may be required. Such measures may include continual monitoring of vital functions (e.g., of blood circulation, fluid/electrolyte balances, breathing); delivery of fluids, electrolytes, and glucose via a vein (intravenously); and/or use of a respirator to assist breathing. ICP levels must also be closely monitored, and certain medications (e.g., mannitol, dexamethasone) may be administered to help control cerebral edema and reduce ICP. Additional measures may include administration of an antibiotic (neomycin) enema and an agent that promotes the removal of ammonia from the blood (e.g., lactulose); vitamin K therapy or transfusions (e.g., with platelets or fresh frozen plasma) for blood clotting abnormalities; use of a cooling blanket or other methods to help stabilize or prevent abnormally elevated body temperature (hyperthermia); and/or other measures. For some individuals with the disorder, additional symptomatic and supportive measures may also be recommended. Researchers indicate that there appears to be a correlation between residual cognitive effects and the severity of neurologic deterioration upon the initiation of therapy. Those with mild disease (e.g., Grade I severity) usually have a complete recovery. However, individuals with more severe disease may have residual neurologic effects, such as intellectual disability, difficulties with concept formation and visual and motor integration, or other associated abnormalities. Great care must be taken in prescribing pain-killing medications for patients suspected of having had an episode of Reye syndrome. Patients and their families should review with their physicians the reasons for choosing particular pain medications.
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Therapies of Reye Syndrome. According to reports in the medical literature, the mainstays of treatment include early diagnosis; prompt administration of intensive care as required; and measures to correct metabolic abnormalities and prevent or control increased pressure between the skull and brain (intracranial pressure [ICP]) secondary to cerebral edema. The specific therapies used may vary from person to person, depending upon disease severity and progression. For example, in children with mild disease (e.g., Grade I severity), treatment may primarily consist of close observation. However, in those with more severe disease, intensive, emergency treatment may be required. Such measures may include continual monitoring of vital functions (e.g., of blood circulation, fluid/electrolyte balances, breathing); delivery of fluids, electrolytes, and glucose via a vein (intravenously); and/or use of a respirator to assist breathing. ICP levels must also be closely monitored, and certain medications (e.g., mannitol, dexamethasone) may be administered to help control cerebral edema and reduce ICP. Additional measures may include administration of an antibiotic (neomycin) enema and an agent that promotes the removal of ammonia from the blood (e.g., lactulose); vitamin K therapy or transfusions (e.g., with platelets or fresh frozen plasma) for blood clotting abnormalities; use of a cooling blanket or other methods to help stabilize or prevent abnormally elevated body temperature (hyperthermia); and/or other measures. For some individuals with the disorder, additional symptomatic and supportive measures may also be recommended. Researchers indicate that there appears to be a correlation between residual cognitive effects and the severity of neurologic deterioration upon the initiation of therapy. Those with mild disease (e.g., Grade I severity) usually have a complete recovery. However, individuals with more severe disease may have residual neurologic effects, such as intellectual disability, difficulties with concept formation and visual and motor integration, or other associated abnormalities. Great care must be taken in prescribing pain-killing medications for patients suspected of having had an episode of Reye syndrome. Patients and their families should review with their physicians the reasons for choosing particular pain medications.
| 1,074 |
Reye Syndrome
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nord_1075_0
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Overview of Rheumatic Fever
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Rheumatic fever is an inflammatory disease that is rare in the United States but common in some other parts of the world. It primarily affects children between the ages of 6 and 16, and develops after an infection with streptococcal bacteria, such as strep throat or scarlet fever. About 5% of those with untreated strep infection will develop rheumatic fever.Rheumatic fever may affect the heart, joints, nervous system and/or skin. In more than half of all cases, it leads to serious inflammatory disease of the valves of the heart. Joint disease is the second most common consequence of rheumatic fever.
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Overview of Rheumatic Fever. Rheumatic fever is an inflammatory disease that is rare in the United States but common in some other parts of the world. It primarily affects children between the ages of 6 and 16, and develops after an infection with streptococcal bacteria, such as strep throat or scarlet fever. About 5% of those with untreated strep infection will develop rheumatic fever.Rheumatic fever may affect the heart, joints, nervous system and/or skin. In more than half of all cases, it leads to serious inflammatory disease of the valves of the heart. Joint disease is the second most common consequence of rheumatic fever.
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Rheumatic Fever
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Symptoms of Rheumatic Fever
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The streptococcal infection that precedes rheumatic fever may or may not be noticeable as a sore throat. After a latent period of two or three weeks, the patient may develop symptoms of rheumatic fever. The most common symptoms are: sore throat; swollen, red tonsils; fever; headache; and joint and muscle aches, especially in the knees. The most serious problem that can be caused by rheumatic fever is rheumatic heart disease. The membranes lining the heart chambers may be inflamed (endocarditis), the muscle walls of the heart may be inflamed (myocarditis), the membrane surrounding the heart may be inflamed (pericarditis), or any combination of these symptoms may occur. A heart murmur not previously present, enlargement of the heart (cardiomegaly), congestive heart failure, and pericardial friction rubs or leakage of blood from vessels into heart tissue may be signs of rheumatic carditis. Inflammation and subsequent scarring of heart valves occurs in patients with this disorder, and can lead to heart function abnormalities. If the disorder affects the nervous system the patient may present with abrupt, non-repetitive limb movements and grimaces (Sydenham's chorea) that typically become apparent within a couple of months after the initial streptococcal infection. Such symptoms may disappear after a few weeks or months.If the disorder affects connective tissue or the autoimmune system, painless, firm, round lumps underneath the skin (subcutaneous nodules) may develop over bones and near joints. The nodules rarely last for more than a month. However, the associated arthritis may last for some time. Heart inflammation (carditis), chorea and arthritis are complications of rheumatic fever that can occur singly or in combination. Subcutaneous nodules and a typical rash (erythema marginatum) are rarely seen without carditis. Moderate fever, a general feeling of discomfort (malaise), and fatigue usually occur, especially when carditis is present.
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Symptoms of Rheumatic Fever. The streptococcal infection that precedes rheumatic fever may or may not be noticeable as a sore throat. After a latent period of two or three weeks, the patient may develop symptoms of rheumatic fever. The most common symptoms are: sore throat; swollen, red tonsils; fever; headache; and joint and muscle aches, especially in the knees. The most serious problem that can be caused by rheumatic fever is rheumatic heart disease. The membranes lining the heart chambers may be inflamed (endocarditis), the muscle walls of the heart may be inflamed (myocarditis), the membrane surrounding the heart may be inflamed (pericarditis), or any combination of these symptoms may occur. A heart murmur not previously present, enlargement of the heart (cardiomegaly), congestive heart failure, and pericardial friction rubs or leakage of blood from vessels into heart tissue may be signs of rheumatic carditis. Inflammation and subsequent scarring of heart valves occurs in patients with this disorder, and can lead to heart function abnormalities. If the disorder affects the nervous system the patient may present with abrupt, non-repetitive limb movements and grimaces (Sydenham's chorea) that typically become apparent within a couple of months after the initial streptococcal infection. Such symptoms may disappear after a few weeks or months.If the disorder affects connective tissue or the autoimmune system, painless, firm, round lumps underneath the skin (subcutaneous nodules) may develop over bones and near joints. The nodules rarely last for more than a month. However, the associated arthritis may last for some time. Heart inflammation (carditis), chorea and arthritis are complications of rheumatic fever that can occur singly or in combination. Subcutaneous nodules and a typical rash (erythema marginatum) are rarely seen without carditis. Moderate fever, a general feeling of discomfort (malaise), and fatigue usually occur, especially when carditis is present.
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Rheumatic Fever
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nord_1075_2
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Causes of Rheumatic Fever
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Although rheumatic fever is clearly linked to Group A streptococcal infections (strep throat), the exact mechanism causing the disorder is not well understood. Strep throat is highly contagious, whereas rheumatic fever is not contagious. People who have had rheumatic fever tend to develop flare-ups with repeated strep infections.
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Causes of Rheumatic Fever. Although rheumatic fever is clearly linked to Group A streptococcal infections (strep throat), the exact mechanism causing the disorder is not well understood. Strep throat is highly contagious, whereas rheumatic fever is not contagious. People who have had rheumatic fever tend to develop flare-ups with repeated strep infections.
| 1,075 |
Rheumatic Fever
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nord_1075_3
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Affects of Rheumatic Fever
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Rheumatic fever usually affects children between the ages of 6 and 16, but may occur among young adults as well. Although outbreaks have steadily declined since the end of World War II in the United States as a result of the use of antibiotics such as penicillin and its derivatives, several outbreaks linked to a particularly virulent strain of streptococcal infection have occurred. However, throughout this period, this disorder has remained a constant ailment in India, the Middle East and some countries in Africa.
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Affects of Rheumatic Fever. Rheumatic fever usually affects children between the ages of 6 and 16, but may occur among young adults as well. Although outbreaks have steadily declined since the end of World War II in the United States as a result of the use of antibiotics such as penicillin and its derivatives, several outbreaks linked to a particularly virulent strain of streptococcal infection have occurred. However, throughout this period, this disorder has remained a constant ailment in India, the Middle East and some countries in Africa.
| 1,075 |
Rheumatic Fever
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nord_1075_4
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Related disorders of Rheumatic Fever
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Symptoms of the following disorder can be similar to those of rheumatic fever. Comparisons may be useful for a differential diagnosis:Juvenile rheumatoid arthritis, also known as Still's disease or chronic polyarthritis, is characterized by progressive pain and tenderness in one or more joints. This disorder, which tends to affect girls more than boys, may begin abruptly with high fever, joint pain, and a variety of skin rashes. Normal growth may be diminished and the spleen and/or liver may become enlarged. The exact cause is not known. Some forms of arthritis are believed to be autoimmune disorders (the body's natural defenses against invading organisms suddenly begin to attack healthy tissue).
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Related disorders of Rheumatic Fever. Symptoms of the following disorder can be similar to those of rheumatic fever. Comparisons may be useful for a differential diagnosis:Juvenile rheumatoid arthritis, also known as Still's disease or chronic polyarthritis, is characterized by progressive pain and tenderness in one or more joints. This disorder, which tends to affect girls more than boys, may begin abruptly with high fever, joint pain, and a variety of skin rashes. Normal growth may be diminished and the spleen and/or liver may become enlarged. The exact cause is not known. Some forms of arthritis are believed to be autoimmune disorders (the body's natural defenses against invading organisms suddenly begin to attack healthy tissue).
| 1,075 |
Rheumatic Fever
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nord_1075_5
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Diagnosis of Rheumatic Fever
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The diagnosis of rheumatic fever is made on the basis of a physical examination that finds either the presence of at least two major diagnostic criteria, or the presence of one major and at least two minor diagnostic criteria.The major diagnostic criteria are:Heart inflammation detected by shortness of breath and weakness, or by ECG or chest X-rayArthritic pain in the major joints, and movement of that pain from one joint to anotherInvoluntary, transient, jerky movements (chorea)Broad, pink or faint-red, non-itching patches on the skinThe minor diagnostic criteria are:Joint pain without inflammationFeverPrior RF or evidence of rheumatic heart diseaseAbnormal ECGPositive blood test for inflammationNew heart murmors
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Diagnosis of Rheumatic Fever. The diagnosis of rheumatic fever is made on the basis of a physical examination that finds either the presence of at least two major diagnostic criteria, or the presence of one major and at least two minor diagnostic criteria.The major diagnostic criteria are:Heart inflammation detected by shortness of breath and weakness, or by ECG or chest X-rayArthritic pain in the major joints, and movement of that pain from one joint to anotherInvoluntary, transient, jerky movements (chorea)Broad, pink or faint-red, non-itching patches on the skinThe minor diagnostic criteria are:Joint pain without inflammationFeverPrior RF or evidence of rheumatic heart diseaseAbnormal ECGPositive blood test for inflammationNew heart murmors
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Rheumatic Fever
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nord_1075_6
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Therapies of Rheumatic Fever
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TreatmentTreatment is designed to reduce inflammation with anti-inflammatory medications such as aspirin or corticosteroids. People with positive cultures for strep throat should also be treated with antibiotics.In addition, low-dose antibiotics, such as penicillin, sulfadiazine, or erythromycin, are taken over a period of time to prevent recurrence.
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Therapies of Rheumatic Fever. TreatmentTreatment is designed to reduce inflammation with anti-inflammatory medications such as aspirin or corticosteroids. People with positive cultures for strep throat should also be treated with antibiotics.In addition, low-dose antibiotics, such as penicillin, sulfadiazine, or erythromycin, are taken over a period of time to prevent recurrence.
| 1,075 |
Rheumatic Fever
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nord_1076_0
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Overview of Riboflavin Transporter Deficiency
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SummaryRiboflavin transporter deficiency is a rare progressive neurodegenerative disorder. Neurodegenerative refers to disorders in which there is damage or loss of nerve cells (neurons) that transmit nerve impulses from the spinal cord or brain (central nervous system) to the nerves that serve (innervate) the muscles or glandular tissue. Riboflavin transporter deficiency is also classified as a neuronopathy, which is a disorder characterized by nerve disease that develops because of damage to motor and sensory nerve cells (neurons) of the peripheral nervous system, which is all the nerves outside of the brain and spinal cord. A motor neuron is a nerve cell that passes nerve impulses from the brain or spinal cord to the muscles or glandular tissue. Sensory nerve cells respond to external stimuli like touch, pain and temperature and convert that stimuli to nerve impulses. The loss of these nerve cells leads to weakness and degeneration (atrophy) of the muscle these nerves serve. In riboflavin transporter deficiency, the nerve cells that are affected are found in the brainstem (which is the lower part of the brain that connects to the spinal cord) and the spinal cord. Symptoms can include breathing difficulties, facial weakness, hearing loss, abnormalities with the eyes, difficulty chewing and swallowing, muscle weakness of the arms and legs, and an unsteady or unbalanced way of walking (abnormal gait). Symptoms become progressively worse if untreated. Intelligence is not affected by this disorder. Riboflavin is a vitamin (vitamin B2) and is essential for proper health and development of the body. Riboflavin is not readily synthesized in the body and thus, must be obtained through dietary intake. Although there is no cure, treatment is highly effective and consists of riboflavin supplementation to restore the deficient riboflavin levels. Riboflavin supplementation should be given immediately in individuals suspected of having these disorders.Riboflavin transporter deficiency is caused by a variation (mutation) in either the SLC52A2 or SLC52A3 genes and is inherited in an autosomal recessive pattern.IntroductionRiboflavin transporter deficiency was previously referred to as Brown-Vialetto-Van Laere (BVVL) syndrome and Fazio-Londe syndrome, named after the physicians and researchers who first described the condition. Fazio-Londe syndrome was used for individuals who had similar symptoms but did not develop hearing loss. The use of these different names can be confusing for patients and caregivers. Researchers have proposed classifying the disorder as: riboflavin transporter deficiency type 2 in individuals with a variation in the SLC52A2 gene and riboflavin transporter deficiency type 3 in individuals with a variation in the SLC52A3 gene. There is also riboflavin transporter deficiency type 1, which is caused by a variation in the SLC52A1 gene, but this has only been described in one person in the medical literature. A variation in the SLC52A1 gene has been associated with maternal riboflavin deficiency leading to symptoms in a newborn infant that were resolved with riboflavin supplementation.
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Overview of Riboflavin Transporter Deficiency. SummaryRiboflavin transporter deficiency is a rare progressive neurodegenerative disorder. Neurodegenerative refers to disorders in which there is damage or loss of nerve cells (neurons) that transmit nerve impulses from the spinal cord or brain (central nervous system) to the nerves that serve (innervate) the muscles or glandular tissue. Riboflavin transporter deficiency is also classified as a neuronopathy, which is a disorder characterized by nerve disease that develops because of damage to motor and sensory nerve cells (neurons) of the peripheral nervous system, which is all the nerves outside of the brain and spinal cord. A motor neuron is a nerve cell that passes nerve impulses from the brain or spinal cord to the muscles or glandular tissue. Sensory nerve cells respond to external stimuli like touch, pain and temperature and convert that stimuli to nerve impulses. The loss of these nerve cells leads to weakness and degeneration (atrophy) of the muscle these nerves serve. In riboflavin transporter deficiency, the nerve cells that are affected are found in the brainstem (which is the lower part of the brain that connects to the spinal cord) and the spinal cord. Symptoms can include breathing difficulties, facial weakness, hearing loss, abnormalities with the eyes, difficulty chewing and swallowing, muscle weakness of the arms and legs, and an unsteady or unbalanced way of walking (abnormal gait). Symptoms become progressively worse if untreated. Intelligence is not affected by this disorder. Riboflavin is a vitamin (vitamin B2) and is essential for proper health and development of the body. Riboflavin is not readily synthesized in the body and thus, must be obtained through dietary intake. Although there is no cure, treatment is highly effective and consists of riboflavin supplementation to restore the deficient riboflavin levels. Riboflavin supplementation should be given immediately in individuals suspected of having these disorders.Riboflavin transporter deficiency is caused by a variation (mutation) in either the SLC52A2 or SLC52A3 genes and is inherited in an autosomal recessive pattern.IntroductionRiboflavin transporter deficiency was previously referred to as Brown-Vialetto-Van Laere (BVVL) syndrome and Fazio-Londe syndrome, named after the physicians and researchers who first described the condition. Fazio-Londe syndrome was used for individuals who had similar symptoms but did not develop hearing loss. The use of these different names can be confusing for patients and caregivers. Researchers have proposed classifying the disorder as: riboflavin transporter deficiency type 2 in individuals with a variation in the SLC52A2 gene and riboflavin transporter deficiency type 3 in individuals with a variation in the SLC52A3 gene. There is also riboflavin transporter deficiency type 1, which is caused by a variation in the SLC52A1 gene, but this has only been described in one person in the medical literature. A variation in the SLC52A1 gene has been associated with maternal riboflavin deficiency leading to symptoms in a newborn infant that were resolved with riboflavin supplementation.
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Riboflavin Transporter Deficiency
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nord_1076_1
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Symptoms of Riboflavin Transporter Deficiency
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The onset of signs and symptoms can range from infancy to early adulthood. One person reported in the medical literature first presented symptoms at 27 years of age, but most affected individuals show symptoms within the first few years of life. Infants and children often develop normally until symptoms first begin. Sometimes, an infection or fever will occur just before symptoms first begin. The specific signs and symptoms that develop and their severity and their progression can be very different from one person to another, even among members of the same family, but for most people who are affected, the first symptom is sensorineural deafness (hearing loss due to inner ear damage). Generally, the later the onset of symptoms, the milder the disorder is. Severe forms can progress rapidly and without treatment can be life-threatening.Pontobulbar palsy is a common symptom of riboflavin transporter deficiency. Pontobulbar refers to paralysis or impairment of the collection of nerves in the lower part of the medulla oblongata, which is the lower part of the brainstem. This includes several cranial nerves, which help to control facial expressions, hearing and balance, taste, and the muscles used to move the head, shoulders and the tongue. Pontobulbar palsy can cause weakness of facial muscles and reduced facial expressions, difficulty chewing and difficulty swallowing (dysphagia), slurring of speech or difficulty forming words (dysphonia), a high-pitched wheezing sound when breathing (stridor), and brief, spontaneous contractions (fasciculations) of the tongue and weakness of tongue, which can contribute to swallowing difficulties. Difficulties with chewing and swallowing can lead to feeding difficulties in infants, and there can be a risk of aspiration, in which food, fluid or other foreign material accidentally goes into the lungs. When the disorder begins in infancy, one of the first signs may be a breathing (respiratory) problem. This can be a life-threatening complication if left untreated. Breathing problems result from paralysis of the diaphragm, which is a muscle that separates the chest cavity from the abdominal cavity. When taking in a breath, the diaphragm contracts and moves downward, which increases the space in the chest cavity and allows the lungs to expand when filled with air. Respiratory failure, caused by denervation of the diaphragm, is the main cause of death in patients with riboflavin transporter deficiency.The most common symptom is sensorineural hearing loss. Sensorineural hearing loss occurs when the nerves within the ear cannot properly send sensory input (sound) to the brain, and is not caused by problems with the ear itself. The degree and production of sensorineural hearing loss can vary from one child to another, but children can experience significant hearing loss. Some infants may experience degeneration of the main nerve of the eyes (optic nerve), which sends sensory input from the eye to the brain to form images (optic atrophy). This can result in varying degrees of vision loss. Sometimes affected individuals also experience rapid, involuntary movements of the eyes (nystagmus). Less often, drooping of the upper eyelids (ptosis) can occur. Weakness and degeneration of the upper arm muscles (those between the elbow and the shoulder) may also occur and become progressively worse. Eventually, all muscles of the arms and the legs may be affected. There may be weakness of certain muscles of the neck. This is followed by weakness and degeneration of the muscles of the trunk, which is all of the body except for the head and arms and legs (axial muscle weakness). Some affected individuals develop sensory ataxia, in which there is a lack of control over muscle movement coordination. This can lead to an uncoordinated or unsteady manner of walking (abnormal gait). Muscle weakness can lead to an intolerance of exercise or extended activity. Some individuals eventually develop contractures. A contracture is a condition in which there is abnormal shortening of muscle. This can make muscles difficult to stretch and if a joint is involved, the joint can become permanently fixed in a bent or straightened position, completely or partially restricting the movement of the affected joint.There are differences between riboflavin transporter deficiency types 2 and 3. Type 2 is characterized by muscle weakness that is most prominent in the arms and neck, while in type 3 muscle weakness is more generalized. Vision loss, optic atrophy, and sensory ataxia are more common in type 2 whereas vocal cord paralysis is more common in type 3.
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Symptoms of Riboflavin Transporter Deficiency. The onset of signs and symptoms can range from infancy to early adulthood. One person reported in the medical literature first presented symptoms at 27 years of age, but most affected individuals show symptoms within the first few years of life. Infants and children often develop normally until symptoms first begin. Sometimes, an infection or fever will occur just before symptoms first begin. The specific signs and symptoms that develop and their severity and their progression can be very different from one person to another, even among members of the same family, but for most people who are affected, the first symptom is sensorineural deafness (hearing loss due to inner ear damage). Generally, the later the onset of symptoms, the milder the disorder is. Severe forms can progress rapidly and without treatment can be life-threatening.Pontobulbar palsy is a common symptom of riboflavin transporter deficiency. Pontobulbar refers to paralysis or impairment of the collection of nerves in the lower part of the medulla oblongata, which is the lower part of the brainstem. This includes several cranial nerves, which help to control facial expressions, hearing and balance, taste, and the muscles used to move the head, shoulders and the tongue. Pontobulbar palsy can cause weakness of facial muscles and reduced facial expressions, difficulty chewing and difficulty swallowing (dysphagia), slurring of speech or difficulty forming words (dysphonia), a high-pitched wheezing sound when breathing (stridor), and brief, spontaneous contractions (fasciculations) of the tongue and weakness of tongue, which can contribute to swallowing difficulties. Difficulties with chewing and swallowing can lead to feeding difficulties in infants, and there can be a risk of aspiration, in which food, fluid or other foreign material accidentally goes into the lungs. When the disorder begins in infancy, one of the first signs may be a breathing (respiratory) problem. This can be a life-threatening complication if left untreated. Breathing problems result from paralysis of the diaphragm, which is a muscle that separates the chest cavity from the abdominal cavity. When taking in a breath, the diaphragm contracts and moves downward, which increases the space in the chest cavity and allows the lungs to expand when filled with air. Respiratory failure, caused by denervation of the diaphragm, is the main cause of death in patients with riboflavin transporter deficiency.The most common symptom is sensorineural hearing loss. Sensorineural hearing loss occurs when the nerves within the ear cannot properly send sensory input (sound) to the brain, and is not caused by problems with the ear itself. The degree and production of sensorineural hearing loss can vary from one child to another, but children can experience significant hearing loss. Some infants may experience degeneration of the main nerve of the eyes (optic nerve), which sends sensory input from the eye to the brain to form images (optic atrophy). This can result in varying degrees of vision loss. Sometimes affected individuals also experience rapid, involuntary movements of the eyes (nystagmus). Less often, drooping of the upper eyelids (ptosis) can occur. Weakness and degeneration of the upper arm muscles (those between the elbow and the shoulder) may also occur and become progressively worse. Eventually, all muscles of the arms and the legs may be affected. There may be weakness of certain muscles of the neck. This is followed by weakness and degeneration of the muscles of the trunk, which is all of the body except for the head and arms and legs (axial muscle weakness). Some affected individuals develop sensory ataxia, in which there is a lack of control over muscle movement coordination. This can lead to an uncoordinated or unsteady manner of walking (abnormal gait). Muscle weakness can lead to an intolerance of exercise or extended activity. Some individuals eventually develop contractures. A contracture is a condition in which there is abnormal shortening of muscle. This can make muscles difficult to stretch and if a joint is involved, the joint can become permanently fixed in a bent or straightened position, completely or partially restricting the movement of the affected joint.There are differences between riboflavin transporter deficiency types 2 and 3. Type 2 is characterized by muscle weakness that is most prominent in the arms and neck, while in type 3 muscle weakness is more generalized. Vision loss, optic atrophy, and sensory ataxia are more common in type 2 whereas vocal cord paralysis is more common in type 3.
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Riboflavin Transporter Deficiency
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nord_1076_2
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Causes of Riboflavin Transporter Deficiency
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Riboflavin transporter deficiency is caused by a variation in one of three genes – SLC52A1 gene (causing riboflavin transporter deficiency type 1), the SLC52A2 gene (riboflavin transporter deficiency type 2), and the SLC52A3 gene (riboflavin transporter deficiency type 3). Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a variation 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. The SLC52A1 and SLC52A3 proteins are primarily located in the small intestine while the SLC52A2 protein is located in the brain.These three genes produce (encode) proteins that function as riboflavin transporters. These transporter proteins help riboflavin cross cell membranes and enter the cells. Riboflavin is also known as vitamin B2. The body does not produce riboflavin, but it can be found in many different types of food such as milk, yogurt, eggs, organ and lean meats, as well as enriched grain products. Riboflavin is an essential component of two coenzymes, flavin mononucleotide and riboflavin-5’-phosphate. Coenzymes are non-protein compounds that are necessary for the proper function of enzymes, which are specialized proteins that cause (catalyze) biochemical reactions in the body. These two coenzymes are essential for maintaining the body’s energy supply, the growth, development and function of cells, and the metabolism of carbohydrates, fats, and proteins. When there is a disease-causing (pathogenic) variation in one of these three genes, the proteins that these genes produce are abnormal and cannot transport the riboflavin across the cell membranes. It is not yet known how the abnormal riboflavin transporter proteins cause the riboflavin transporter deficiency. The variations that cause riboflavin transporter deficiency are inherited in an autosomal recessive pattern. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
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Causes of Riboflavin Transporter Deficiency. Riboflavin transporter deficiency is caused by a variation in one of three genes – SLC52A1 gene (causing riboflavin transporter deficiency type 1), the SLC52A2 gene (riboflavin transporter deficiency type 2), and the SLC52A3 gene (riboflavin transporter deficiency type 3). Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a variation 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. The SLC52A1 and SLC52A3 proteins are primarily located in the small intestine while the SLC52A2 protein is located in the brain.These three genes produce (encode) proteins that function as riboflavin transporters. These transporter proteins help riboflavin cross cell membranes and enter the cells. Riboflavin is also known as vitamin B2. The body does not produce riboflavin, but it can be found in many different types of food such as milk, yogurt, eggs, organ and lean meats, as well as enriched grain products. Riboflavin is an essential component of two coenzymes, flavin mononucleotide and riboflavin-5’-phosphate. Coenzymes are non-protein compounds that are necessary for the proper function of enzymes, which are specialized proteins that cause (catalyze) biochemical reactions in the body. These two coenzymes are essential for maintaining the body’s energy supply, the growth, development and function of cells, and the metabolism of carbohydrates, fats, and proteins. When there is a disease-causing (pathogenic) variation in one of these three genes, the proteins that these genes produce are abnormal and cannot transport the riboflavin across the cell membranes. It is not yet known how the abnormal riboflavin transporter proteins cause the riboflavin transporter deficiency. The variations that cause riboflavin transporter deficiency are inherited in an autosomal recessive pattern. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
| 1,076 |
Riboflavin Transporter Deficiency
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nord_1076_3
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Affects of Riboflavin Transporter Deficiency
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Riboflavin transporter deficiency is believed to affect females and males in equal numbers. The exact number of people who have this disorder is unknown. As of November 2017, about 165 affected individuals have been reported in the medical literature or to the Cure RTD Registry. Rare disorders like riboflavin transporter deficiency often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. Researchers believe that these disorders are underdiagnosed; one estimate suggests that at least 1 in 1,000,000 people in the general population have riboflavin transporter deficiency.
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Affects of Riboflavin Transporter Deficiency. Riboflavin transporter deficiency is believed to affect females and males in equal numbers. The exact number of people who have this disorder is unknown. As of November 2017, about 165 affected individuals have been reported in the medical literature or to the Cure RTD Registry. Rare disorders like riboflavin transporter deficiency often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. Researchers believe that these disorders are underdiagnosed; one estimate suggests that at least 1 in 1,000,000 people in the general population have riboflavin transporter deficiency.
| 1,076 |
Riboflavin Transporter Deficiency
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nord_1076_4
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Related disorders of Riboflavin Transporter Deficiency
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Symptoms of the following disorders can be similar to those of riboflavin transporter deficiency. Comparisons may be useful for a differential diagnosis.Glutaricaciduria II is one of the conditions termed organic acidemias. The disorder is also known as multiple Acyl-CoA dehydrogenase deficiency (MADD). Individuals with these conditions have a deficiency or absence of an enzyme that prevents them from breaking down certain chemicals in the body, resulting in the accumulation of several organic acids in the blood and urine. Two enzymes that may be deficient are electron transfer flavoprotein (ETF) and ETF-ubiquinone oxidoreductase (ETF:QO). A complete enzyme deficiency causes a severe form of the disorder termed neonatal glutaricaciduria II that is associated with a short life span and, sometimes, with specific physical birth defects. The less severe form of the disorder is termed late onset glutaricaciduria II and has an extremely variable age of onset. Symptoms include nausea, vomiting, lethargy, proximal muscle weakness, and low blood sugar (hypoglycemia). Glutaricaciduria II is inherited in an autosomal recessive pattern. (For more information on this disorder, choose “glutaricaciduria” as your search term in the Rare Disease Database.)There are several different disorders that can have signs and symptoms similar to those seen in riboflavin transporter deficiency. The disorder was first referred to as an infantile form of amyotrophic lateral sclerosis (ALS) and the symptoms of these disorders in adults can be similar to those seen in ALS. Additional disorders that can be differentiated in affected infants and children are spinal muscular atrophy with respiratory distress type I (SMARD1), Nathalie syndrome, Madras motor neuron disease, facial onset sensory motor neuronopathy, Joubert syndrome and Allgrove syndrome (also called triple A syndrome). Sometimes, riboflavin transporter deficiency is mistaken for neuroimmune disorders like chronic demyelinating polyneuropathy or acute disseminated encephalomyelitis. Neuroimmune disorders are ones that are characterized by an inflammatory response in the immune system that affects the central nervous system. (For more information on this disorder, choose the specific disorder name as your search term in the Rare Disease Database.)
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Related disorders of Riboflavin Transporter Deficiency. Symptoms of the following disorders can be similar to those of riboflavin transporter deficiency. Comparisons may be useful for a differential diagnosis.Glutaricaciduria II is one of the conditions termed organic acidemias. The disorder is also known as multiple Acyl-CoA dehydrogenase deficiency (MADD). Individuals with these conditions have a deficiency or absence of an enzyme that prevents them from breaking down certain chemicals in the body, resulting in the accumulation of several organic acids in the blood and urine. Two enzymes that may be deficient are electron transfer flavoprotein (ETF) and ETF-ubiquinone oxidoreductase (ETF:QO). A complete enzyme deficiency causes a severe form of the disorder termed neonatal glutaricaciduria II that is associated with a short life span and, sometimes, with specific physical birth defects. The less severe form of the disorder is termed late onset glutaricaciduria II and has an extremely variable age of onset. Symptoms include nausea, vomiting, lethargy, proximal muscle weakness, and low blood sugar (hypoglycemia). Glutaricaciduria II is inherited in an autosomal recessive pattern. (For more information on this disorder, choose “glutaricaciduria” as your search term in the Rare Disease Database.)There are several different disorders that can have signs and symptoms similar to those seen in riboflavin transporter deficiency. The disorder was first referred to as an infantile form of amyotrophic lateral sclerosis (ALS) and the symptoms of these disorders in adults can be similar to those seen in ALS. Additional disorders that can be differentiated in affected infants and children are spinal muscular atrophy with respiratory distress type I (SMARD1), Nathalie syndrome, Madras motor neuron disease, facial onset sensory motor neuronopathy, Joubert syndrome and Allgrove syndrome (also called triple A syndrome). Sometimes, riboflavin transporter deficiency is mistaken for neuroimmune disorders like chronic demyelinating polyneuropathy or acute disseminated encephalomyelitis. Neuroimmune disorders are ones that are characterized by an inflammatory response in the immune system that affects the central nervous system. (For more information on this disorder, choose the specific disorder name as your search term in the Rare Disease Database.)
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Riboflavin Transporter Deficiency
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nord_1076_5
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Diagnosis of Riboflavin Transporter Deficiency
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A diagnosis of riboflavin transporter deficiency is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. Riboflavin transporter deficiency has yet to be detected by newborn screening. A diagnosis is confirmed by molecular genetic testing. Molecular genetic testing can detect disease-causing variations in the genes known to cause these disorders, but is available only as a diagnostic service at specialized laboratories. Because riboflavin transporter deficiency is treatable, prompt diagnosis and early treatment is essential to prevent irreversible neurological damage. Riboflavin supplementation should be given immediately in individuals suspected of having these disorders, even before confirmation through molecular genetic testing. Clinical Testing and Workup
Affected individuals may undergo an electromyogram, which is a test that evaluates muscles and the nerves that serve those muscles. During an electromyography, a tiny needle electrode is inserted through the skin into an affected muscle. The electrode records the electrical activity of the muscle. This record shows how well a muscle responds to nerve activation and can help determine whether muscle weakness is caused by the muscles themselves or by the nerves that control those muscles. A diagnosis of riboflavin transporter deficiency can be supported by nerve conduction studies. Nerve conduction studies determine the ability of specific nerves in the peripheral nervous system to relay nerve impulses to the brain. During a nerve conduction study, electrodes are placed over specific nerves such as those of the shoulders and arms. The electrodes stimulate the nerves and record the conduction of the signal. Doctors may also measure the sensory nerve action potentials (SNAP). A SNAP value is obtained by electronically stimulating sensory fibers and measuring the nerve action potential further along that nerve to see how well nerve impulses are being conducted. In individuals with riboflavin transporter deficiency, SNAP is often absent. Another test measures visual evoked potential, which is the electrical response of the eye when is stimulated by light; this is often abnormal in riboflavin transporter deficiency. Doctors may also measure the brain stem audiometry evoked response (BAER). This can detect sensorineural deafness. During this test, electrodes are placed on the scalp. The electrodes measure the nerve activity from the ears to the brainstem. Some doctors may recommend an electroencephalogram (EEG), which is a test that measures the electrical activity of the brain. Affected individuals may undergo additional tests to rule out other disorders. An advanced imaging (x-ray) technique called magnetic resonance imaging (MRI) may be recommended. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. An MRI of the brain can reveal degeneration or damage to the brain. An MRI of the brain is usually normal in individuals with riboflavin transporter deficiency. However, in a small number of affected individuals, a brain MRI can show deterioration of neurons in the cerebellum (cerebellar atrophy). Doctors may take blood to measure for the amount of dietary metabolites such as acylcarnitine. Some affected individuals (~50% reported in the literature) have displayed abnormal levels of flavin or acylcarnitine in the blood plasma. However, this is not a reliable marker for diagnosis and normal levels do not rule out riboflavin transporter deficiency. This abnormality can confuse diagnosis due to its similarity to glutaricaciduria II / multiple Acyl-CoA dehydrogenase deficiency (MADD).
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Diagnosis of Riboflavin Transporter Deficiency. A diagnosis of riboflavin transporter deficiency is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. Riboflavin transporter deficiency has yet to be detected by newborn screening. A diagnosis is confirmed by molecular genetic testing. Molecular genetic testing can detect disease-causing variations in the genes known to cause these disorders, but is available only as a diagnostic service at specialized laboratories. Because riboflavin transporter deficiency is treatable, prompt diagnosis and early treatment is essential to prevent irreversible neurological damage. Riboflavin supplementation should be given immediately in individuals suspected of having these disorders, even before confirmation through molecular genetic testing. Clinical Testing and Workup
Affected individuals may undergo an electromyogram, which is a test that evaluates muscles and the nerves that serve those muscles. During an electromyography, a tiny needle electrode is inserted through the skin into an affected muscle. The electrode records the electrical activity of the muscle. This record shows how well a muscle responds to nerve activation and can help determine whether muscle weakness is caused by the muscles themselves or by the nerves that control those muscles. A diagnosis of riboflavin transporter deficiency can be supported by nerve conduction studies. Nerve conduction studies determine the ability of specific nerves in the peripheral nervous system to relay nerve impulses to the brain. During a nerve conduction study, electrodes are placed over specific nerves such as those of the shoulders and arms. The electrodes stimulate the nerves and record the conduction of the signal. Doctors may also measure the sensory nerve action potentials (SNAP). A SNAP value is obtained by electronically stimulating sensory fibers and measuring the nerve action potential further along that nerve to see how well nerve impulses are being conducted. In individuals with riboflavin transporter deficiency, SNAP is often absent. Another test measures visual evoked potential, which is the electrical response of the eye when is stimulated by light; this is often abnormal in riboflavin transporter deficiency. Doctors may also measure the brain stem audiometry evoked response (BAER). This can detect sensorineural deafness. During this test, electrodes are placed on the scalp. The electrodes measure the nerve activity from the ears to the brainstem. Some doctors may recommend an electroencephalogram (EEG), which is a test that measures the electrical activity of the brain. Affected individuals may undergo additional tests to rule out other disorders. An advanced imaging (x-ray) technique called magnetic resonance imaging (MRI) may be recommended. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. An MRI of the brain can reveal degeneration or damage to the brain. An MRI of the brain is usually normal in individuals with riboflavin transporter deficiency. However, in a small number of affected individuals, a brain MRI can show deterioration of neurons in the cerebellum (cerebellar atrophy). Doctors may take blood to measure for the amount of dietary metabolites such as acylcarnitine. Some affected individuals (~50% reported in the literature) have displayed abnormal levels of flavin or acylcarnitine in the blood plasma. However, this is not a reliable marker for diagnosis and normal levels do not rule out riboflavin transporter deficiency. This abnormality can confuse diagnosis due to its similarity to glutaricaciduria II / multiple Acyl-CoA dehydrogenase deficiency (MADD).
| 1,076 |
Riboflavin Transporter Deficiency
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nord_1076_6
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Therapies of Riboflavin Transporter Deficiency
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Treatment
The main treatment is high-dose supplementation of riboflavin. Most affected individuals improve on this therapy. Some individuals improve rapidly, while others improve gradually over 12 months. The optimum dose, best delivery method, or best frequency to take riboflavin supplementation are unknown. Treatment will be individualized. Doctors will give riboflavin supplementation in gradually increasing amounts until an optimal dose is reached for each individual. It should be noted that a small number of cases have been reported where patients do not respond or become stable and later experience symptom progression. It is unclear whether earlier intervention would have been beneficial in these cases. Other treatments of riboflavin transporter deficiency are symptomatic and supportive. A feeding tube may be necessary to help infants who have difficulty chewing and swallowing. Infants with breathing difficulties may require mechanical assistance with a mechanical ventilator. Sometimes, affected individuals may require a tracheostomy, which is a surgical opening in the neck to gain access to the windpipe (trachea). A tube is placed into this opening to allow for breathing. In some case reports, steroids and intravenous immunoglobulins have been given with little success; typically patients experience short periods of stabilization followed by disease progression.Speech and language therapy, occupational therapy and physical therapy can also be beneficial. Physical therapy can help to prevent contractures. Periodic reassessments and adjustment of services should be provided with all children. Some children require braces or other orthotic devices to help with walking. Severely affected individuals may require a wheelchair. Hearing loss can be treated with hearing aids called cochlear implants. Unlike regular hearing aids that amplify sound, these hearing aids work by directly stimulating the auditory nerve. The response to a cochlear implant is individualized, but generally has been positive. Children with vision loss should receive low vision aids to help amplify remaining sight. Children with hearing loss or vision loss should also receive special education services. Scoliosis should be treated as it would for children without riboflavin transporter deficiency. Surgery may be necessary in some individuals. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, physicians who specialize in diagnosing and treating disorders of brain and nervous system in children (pediatric neurologists), neurologists, physicians who specialize in diagnosing and treating disorders of the eye in children (pediatric ophthalmologists), ophthalmologists, physicians who specialize in diagnosing and treating disorders of the ears (audiologists), and other healthcare professionals may need to systematically and comprehensively plan treatment. Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well. Women who have riboflavin transporter deficiency and women who are carriers (heterozygotes) for these disorders should receive riboflavin supplementation before and during pregnancy and when breast feeding.
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Therapies of Riboflavin Transporter Deficiency. Treatment
The main treatment is high-dose supplementation of riboflavin. Most affected individuals improve on this therapy. Some individuals improve rapidly, while others improve gradually over 12 months. The optimum dose, best delivery method, or best frequency to take riboflavin supplementation are unknown. Treatment will be individualized. Doctors will give riboflavin supplementation in gradually increasing amounts until an optimal dose is reached for each individual. It should be noted that a small number of cases have been reported where patients do not respond or become stable and later experience symptom progression. It is unclear whether earlier intervention would have been beneficial in these cases. Other treatments of riboflavin transporter deficiency are symptomatic and supportive. A feeding tube may be necessary to help infants who have difficulty chewing and swallowing. Infants with breathing difficulties may require mechanical assistance with a mechanical ventilator. Sometimes, affected individuals may require a tracheostomy, which is a surgical opening in the neck to gain access to the windpipe (trachea). A tube is placed into this opening to allow for breathing. In some case reports, steroids and intravenous immunoglobulins have been given with little success; typically patients experience short periods of stabilization followed by disease progression.Speech and language therapy, occupational therapy and physical therapy can also be beneficial. Physical therapy can help to prevent contractures. Periodic reassessments and adjustment of services should be provided with all children. Some children require braces or other orthotic devices to help with walking. Severely affected individuals may require a wheelchair. Hearing loss can be treated with hearing aids called cochlear implants. Unlike regular hearing aids that amplify sound, these hearing aids work by directly stimulating the auditory nerve. The response to a cochlear implant is individualized, but generally has been positive. Children with vision loss should receive low vision aids to help amplify remaining sight. Children with hearing loss or vision loss should also receive special education services. Scoliosis should be treated as it would for children without riboflavin transporter deficiency. Surgery may be necessary in some individuals. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, physicians who specialize in diagnosing and treating disorders of brain and nervous system in children (pediatric neurologists), neurologists, physicians who specialize in diagnosing and treating disorders of the eye in children (pediatric ophthalmologists), ophthalmologists, physicians who specialize in diagnosing and treating disorders of the ears (audiologists), and other healthcare professionals may need to systematically and comprehensively plan treatment. Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well. Women who have riboflavin transporter deficiency and women who are carriers (heterozygotes) for these disorders should receive riboflavin supplementation before and during pregnancy and when breast feeding.
| 1,076 |
Riboflavin Transporter Deficiency
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nord_1077_0
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Overview of Ring Chromosome 4
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Ring chromosome 4 is a rare disorder that is typically characterized by loss (deletion) of genetic material from both ends of the 4th chromosome and joining of the chromosomal ends to form a ring. Associated symptoms and findings may vary greatly, depending on the location of lost genetic material and/or other factors. Some affected infants may have a low birth weight; growth delay; delays in the acquisition of skills requiring the coordination of mental and physical activities (psychomotor retardation); an abnormally small head (microcephaly); a broad, “beaked” nose; and/or various additional physical abnormalities that are present at birth (congenital anomalies). However, patients have also been reported in which ring chromosome 4 is primarily associated with growth delay, with no major physical anomalies and normal psychomotor development. Ring chromosome 4 is usually caused by spontaneous (de novo) errors very early in the development of the embryo that appear to occur randomly for unknown reasons (sporadically).
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Overview of Ring Chromosome 4. Ring chromosome 4 is a rare disorder that is typically characterized by loss (deletion) of genetic material from both ends of the 4th chromosome and joining of the chromosomal ends to form a ring. Associated symptoms and findings may vary greatly, depending on the location of lost genetic material and/or other factors. Some affected infants may have a low birth weight; growth delay; delays in the acquisition of skills requiring the coordination of mental and physical activities (psychomotor retardation); an abnormally small head (microcephaly); a broad, “beaked” nose; and/or various additional physical abnormalities that are present at birth (congenital anomalies). However, patients have also been reported in which ring chromosome 4 is primarily associated with growth delay, with no major physical anomalies and normal psychomotor development. Ring chromosome 4 is usually caused by spontaneous (de novo) errors very early in the development of the embryo that appear to occur randomly for unknown reasons (sporadically).
| 1,077 |
Ring Chromosome 4
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nord_1077_1
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Symptoms of Ring Chromosome 4
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As noted above, associated symptoms and physical findings may be extremely variable from person to person. Some infants with ring chromosome 4 may have multiple characteristic features, such as a low birth weight, feeding difficulties, failure to grow and gain weight at the expected rate (failure to thrive), developmental delays, malformations of the skull and facial (craniofacial) region, heart defects and/or other physical abnormalities. In addition, certain features may be similar to those seen in individuals with Wolf-Hirschhorn syndrome, which is a chromosomal disorder characterized by partial deletion (monosomy) of the short arm (p) of chromosome 4 (partial monosomy 4p) or features similar to those seen in individuals with partial deletion (monosomy) of the long arm (q) of chromosome 4 (partial monosomy 4q. (For further information on this disorder, please see the “Related Disorders” section of this report below.) Other people with ring chromosome 4 may have few symptoms and be primarily affected by growth delays (failure to thrive), with no major physical anomalies.In some infants and children, ring chromosome 4 may be associated with intellectual disability and delays in the development of physical, mental and behavioral skills that are typically acquired at particular stages (developmental milestones). For example, there are usually delays in language and speech development. However, others with ring chromosome 4 may have normal intelligence and normal psychomotor development.Craniofacial malformations associated with ring chromosome 4 may include an unusually small head (microcephaly); a broad, rounded, or “beaked” nose; a small jaw (micrognathia); and/or malformed (dysplastic) ears. In some patients, other craniofacial abnormalities may also be present, such as incomplete closure of the roof of the mouth (cleft palate), drooping of the upper eyelids (ptosis) and/or other findings.Some affected individuals may also have abnormal bending or deviation of one or more fingers (clinodactyly); abnormal skin ridge patterns on the palms of the hands (palmar creases); and/or, in affected males, abnormal placement of the urinary opening on the underside of the penis (hypospadias). There have also been a few reports in which ring chromosome 4 is associated with underdevelopment of the kidneys at birth (congenital renal hypoplasia) or a missing kidney (renal agenesis). These conditions may lead to chronic renal failure or an impaired ability of the kidneys to excrete waste products through urine, regulate the balance of salt and water in the body, and perform their other vital functions. In some patients, ring chromosome 4 may also be associated with additional congenital anomalies.
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Symptoms of Ring Chromosome 4. As noted above, associated symptoms and physical findings may be extremely variable from person to person. Some infants with ring chromosome 4 may have multiple characteristic features, such as a low birth weight, feeding difficulties, failure to grow and gain weight at the expected rate (failure to thrive), developmental delays, malformations of the skull and facial (craniofacial) region, heart defects and/or other physical abnormalities. In addition, certain features may be similar to those seen in individuals with Wolf-Hirschhorn syndrome, which is a chromosomal disorder characterized by partial deletion (monosomy) of the short arm (p) of chromosome 4 (partial monosomy 4p) or features similar to those seen in individuals with partial deletion (monosomy) of the long arm (q) of chromosome 4 (partial monosomy 4q. (For further information on this disorder, please see the “Related Disorders” section of this report below.) Other people with ring chromosome 4 may have few symptoms and be primarily affected by growth delays (failure to thrive), with no major physical anomalies.In some infants and children, ring chromosome 4 may be associated with intellectual disability and delays in the development of physical, mental and behavioral skills that are typically acquired at particular stages (developmental milestones). For example, there are usually delays in language and speech development. However, others with ring chromosome 4 may have normal intelligence and normal psychomotor development.Craniofacial malformations associated with ring chromosome 4 may include an unusually small head (microcephaly); a broad, rounded, or “beaked” nose; a small jaw (micrognathia); and/or malformed (dysplastic) ears. In some patients, other craniofacial abnormalities may also be present, such as incomplete closure of the roof of the mouth (cleft palate), drooping of the upper eyelids (ptosis) and/or other findings.Some affected individuals may also have abnormal bending or deviation of one or more fingers (clinodactyly); abnormal skin ridge patterns on the palms of the hands (palmar creases); and/or, in affected males, abnormal placement of the urinary opening on the underside of the penis (hypospadias). There have also been a few reports in which ring chromosome 4 is associated with underdevelopment of the kidneys at birth (congenital renal hypoplasia) or a missing kidney (renal agenesis). These conditions may lead to chronic renal failure or an impaired ability of the kidneys to excrete waste products through urine, regulate the balance of salt and water in the body, and perform their other vital functions. In some patients, ring chromosome 4 may also be associated with additional congenital anomalies.
| 1,077 |
Ring Chromosome 4
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nord_1077_2
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Causes of Ring Chromosome 4
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In most affected individuals, ring chromosome 4 appears to result from loss (deletion) of genetic material from both ends of the 4th chromosome and a joining of the ends to form a ring. Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as “p”, a long arm identified by the letter “q” and a narrowed region at which the two arms are joined (centromere). Chromosomes are further subdivided into bands that are numbered outward from the centromere. For example, “chromosome 4p16” refers to band 16 on the short arm of chromosome 4.In individuals with ring chromosome 4, the variability of associated symptoms and findings may depend upon the location of genetic material lost from the 4th chromosome, the percentage of cells containing the chromosomal abnormality (see below*), the stability of the ring chromosome during subsequent cellular divisions (mitosis), and/or other factors. For example, reports indicate that affected individuals with deletions of chromosome 4q35 and 4p16 have similar symptoms and findings to those with deletions of 4q33 and 4p16. These findings suggest that certain features often seen in those with ring chromosome 4 appear to result from deletions of genetic material at 4p16. In some patients, only some of an individual’s cells may contain ring chromosome 4, while other cells may have a normal chromosomal makeup (a finding known as “chromosomal mosaicism*”), potentially affecting the variability of associated symptoms and findings.Patients have been reported in which ring chromosome 4 is present with no detectable loss of genetic material (as based upon chromosomal analysis). Such cases are sometimes referred to as “ring syndrome,” a general term used to describe the presence of growth delay in the absence of major malformations due to a ring chromosome. Investigators suggest that such ring chromosomes originate with abnormal fusion of the ends (i.e., telomeres) of a particular chromosome (e.g., chromosome 4) and that “ring syndrome” results due to instability of the ring chromosome during subsequent cellular divisions.In most patients, ring chromosome 4 appears to be caused by spontaneous (de novo) errors very early in embryonic development. In such cases, the parents of the affected child usually have normal chromosomes and a relatively low risk of having another child with the chromosomal abnormality. However, chromosomal analysis and genetic counseling are typically recommended for parents of an affected child to help confirm or exclude the presence of certain chromosomal abnormalities in one of the parents, such as ring chromosome 4, potential mosaicism or a “balanced translocation” involving chromosome 4. (Translocations occur when regions of certain chromosomes break off and are rearranged, resulting in shifting of genetic material and an altered set of chromosomes. If a chromosomal rearrangement is balanced, meaning that it consists of an altered but balanced set of chromosomes; it is usually harmless to the carrier. However, such a chromosomal rearrangement may be associated with an increased risk of abnormal chromosomal development in the carrier’s offspring.)
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Causes of Ring Chromosome 4. In most affected individuals, ring chromosome 4 appears to result from loss (deletion) of genetic material from both ends of the 4th chromosome and a joining of the ends to form a ring. Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as “p”, a long arm identified by the letter “q” and a narrowed region at which the two arms are joined (centromere). Chromosomes are further subdivided into bands that are numbered outward from the centromere. For example, “chromosome 4p16” refers to band 16 on the short arm of chromosome 4.In individuals with ring chromosome 4, the variability of associated symptoms and findings may depend upon the location of genetic material lost from the 4th chromosome, the percentage of cells containing the chromosomal abnormality (see below*), the stability of the ring chromosome during subsequent cellular divisions (mitosis), and/or other factors. For example, reports indicate that affected individuals with deletions of chromosome 4q35 and 4p16 have similar symptoms and findings to those with deletions of 4q33 and 4p16. These findings suggest that certain features often seen in those with ring chromosome 4 appear to result from deletions of genetic material at 4p16. In some patients, only some of an individual’s cells may contain ring chromosome 4, while other cells may have a normal chromosomal makeup (a finding known as “chromosomal mosaicism*”), potentially affecting the variability of associated symptoms and findings.Patients have been reported in which ring chromosome 4 is present with no detectable loss of genetic material (as based upon chromosomal analysis). Such cases are sometimes referred to as “ring syndrome,” a general term used to describe the presence of growth delay in the absence of major malformations due to a ring chromosome. Investigators suggest that such ring chromosomes originate with abnormal fusion of the ends (i.e., telomeres) of a particular chromosome (e.g., chromosome 4) and that “ring syndrome” results due to instability of the ring chromosome during subsequent cellular divisions.In most patients, ring chromosome 4 appears to be caused by spontaneous (de novo) errors very early in embryonic development. In such cases, the parents of the affected child usually have normal chromosomes and a relatively low risk of having another child with the chromosomal abnormality. However, chromosomal analysis and genetic counseling are typically recommended for parents of an affected child to help confirm or exclude the presence of certain chromosomal abnormalities in one of the parents, such as ring chromosome 4, potential mosaicism or a “balanced translocation” involving chromosome 4. (Translocations occur when regions of certain chromosomes break off and are rearranged, resulting in shifting of genetic material and an altered set of chromosomes. If a chromosomal rearrangement is balanced, meaning that it consists of an altered but balanced set of chromosomes; it is usually harmless to the carrier. However, such a chromosomal rearrangement may be associated with an increased risk of abnormal chromosomal development in the carrier’s offspring.)
| 1,077 |
Ring Chromosome 4
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nord_1077_3
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Affects of Ring Chromosome 4
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Since ring chromosome 4 was originally described, close to 50 cases have been reported in the medical literature. Males and females appear to be affected relatively equally.
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Affects of Ring Chromosome 4. Since ring chromosome 4 was originally described, close to 50 cases have been reported in the medical literature. Males and females appear to be affected relatively equally.
| 1,077 |
Ring Chromosome 4
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nord_1077_4
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Related disorders of Ring Chromosome 4
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Symptoms of the following disorders may be similar to those of ring chromosome 4. Comparisons may be useful for a differential diagnosis:Wolf-Hirschhorn syndrome, also known as Wolf syndrome, is a rare chromosomal disorder in which there is partial deletion (monosomy) of the short arm (p) of chromosome 4 (4p). Although the size and location of the 4p deletion vary from person to person, it is believed that deletion of band 4p16.3 is the critical region leading to characteristic features of the disorder. Associated abnormalities typically include a low birth weight, growth delay, poor muscle tone (hypotonia) and delays in the acquisition of skills requiring the coordination of physical and mental activities (psychomotor delay). Most affected infants and children also have distinctive malformations of the skull and facial (craniofacial) region. These may include a small head (microcephaly) and high forehead; highly arched eyebrows; widely spaced eyes (ocular hypertelorism); vertical skin folds that cover the eyes’ inner corners (epicanthal folds); a “beaked” nose with an abnormally wide nasal bridge; a downturned mouth; an unusually short vertical groove in the middle of the upper lip (philtrum); and/or large, malformed ears. Due to these and/or additional craniofacial malformations, the face may appear relatively dissimilar from one side to the other (craniofacial asymmetry). Additional physical abnormalities may also be present. Such features may include abnormal deviation of one eye in relation to the other (strabismus); partial absence of tissue from the colored region of the eye (iris coloboma); incomplete closure of the roof of the mouth (cleft palate); undescended testes (cryptorchidism) and abnormal placement of the urinary opening on the underside of the penis (hypospadias) in affected males; structural malformations of the heart; sudden episodes of uncontrolled electrical activity in the brain (seizures); skeletal abnormalities; and/or other findings. Wolf-Hirschhorn syndrome usually appears to occur spontaneously (de novo) for unknown reasons very early in embryonic development. Less commonly, it may appear to result from a balanced translocation in one of the parents.4q deletion syndrome is a rare chromosomal disorder in which there is deletion (monosomy) of the long arm (q) of chromosome 4 (4q). Although the size and location of the 4p deletion vary from person to person, it is believed that deletion of band 4q31 is the critical region leading to characteristic features of the disorder. Associated abnormalities typically include short stature, small head (microcephaly), wide spaced eyes (hypertelorism), mild growth delay and sever to profound intellectual disability. Most affected infants and children also have distinctive low set and posteriorly rotated ears, vertical skin folds that cover the eyes’ inner corners (epicanthal folds), wide nasal bridge, Robin malformation which includes incomplete closure of the roof of the mouth (cleft palate), abnormal placement of the tongue (glossoptosis), and a small jaw (mandible). Additional physical abnormalities may also be present. Such features may include heart defects, duplication of the kidneys, and abnormal bending or deviation of one or more fingers (clinodactyly); abnormal skin ridge patterns on the palms of the hands (palmar creases). 4q deletion syndrome usually appears to occur spontaneously (de novo) for unknown reasons very early in embryonic development. Less commonly, it may appear to result from a balanced translocation in one of the parents.Additional chromosomal disorders may have features similar to those associated with ring chromosome 4. Chromosomal testing is necessary to confirm the specific chromosomal abnormality present. (For further information on such disorders, choose the name of the specific chromosomal disorder in question or use “chromosome” as your search term in the Rare Disease Database.
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Related disorders of Ring Chromosome 4. Symptoms of the following disorders may be similar to those of ring chromosome 4. Comparisons may be useful for a differential diagnosis:Wolf-Hirschhorn syndrome, also known as Wolf syndrome, is a rare chromosomal disorder in which there is partial deletion (monosomy) of the short arm (p) of chromosome 4 (4p). Although the size and location of the 4p deletion vary from person to person, it is believed that deletion of band 4p16.3 is the critical region leading to characteristic features of the disorder. Associated abnormalities typically include a low birth weight, growth delay, poor muscle tone (hypotonia) and delays in the acquisition of skills requiring the coordination of physical and mental activities (psychomotor delay). Most affected infants and children also have distinctive malformations of the skull and facial (craniofacial) region. These may include a small head (microcephaly) and high forehead; highly arched eyebrows; widely spaced eyes (ocular hypertelorism); vertical skin folds that cover the eyes’ inner corners (epicanthal folds); a “beaked” nose with an abnormally wide nasal bridge; a downturned mouth; an unusually short vertical groove in the middle of the upper lip (philtrum); and/or large, malformed ears. Due to these and/or additional craniofacial malformations, the face may appear relatively dissimilar from one side to the other (craniofacial asymmetry). Additional physical abnormalities may also be present. Such features may include abnormal deviation of one eye in relation to the other (strabismus); partial absence of tissue from the colored region of the eye (iris coloboma); incomplete closure of the roof of the mouth (cleft palate); undescended testes (cryptorchidism) and abnormal placement of the urinary opening on the underside of the penis (hypospadias) in affected males; structural malformations of the heart; sudden episodes of uncontrolled electrical activity in the brain (seizures); skeletal abnormalities; and/or other findings. Wolf-Hirschhorn syndrome usually appears to occur spontaneously (de novo) for unknown reasons very early in embryonic development. Less commonly, it may appear to result from a balanced translocation in one of the parents.4q deletion syndrome is a rare chromosomal disorder in which there is deletion (monosomy) of the long arm (q) of chromosome 4 (4q). Although the size and location of the 4p deletion vary from person to person, it is believed that deletion of band 4q31 is the critical region leading to characteristic features of the disorder. Associated abnormalities typically include short stature, small head (microcephaly), wide spaced eyes (hypertelorism), mild growth delay and sever to profound intellectual disability. Most affected infants and children also have distinctive low set and posteriorly rotated ears, vertical skin folds that cover the eyes’ inner corners (epicanthal folds), wide nasal bridge, Robin malformation which includes incomplete closure of the roof of the mouth (cleft palate), abnormal placement of the tongue (glossoptosis), and a small jaw (mandible). Additional physical abnormalities may also be present. Such features may include heart defects, duplication of the kidneys, and abnormal bending or deviation of one or more fingers (clinodactyly); abnormal skin ridge patterns on the palms of the hands (palmar creases). 4q deletion syndrome usually appears to occur spontaneously (de novo) for unknown reasons very early in embryonic development. Less commonly, it may appear to result from a balanced translocation in one of the parents.Additional chromosomal disorders may have features similar to those associated with ring chromosome 4. Chromosomal testing is necessary to confirm the specific chromosomal abnormality present. (For further information on such disorders, choose the name of the specific chromosomal disorder in question or use “chromosome” as your search term in the Rare Disease Database.
| 1,077 |
Ring Chromosome 4
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nord_1077_5
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Diagnosis of Ring Chromosome 4
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The disorder may be diagnosed or confirmed after birth (postnatally) based upon thorough clinical evaluation, detection of characteristic physical findings, and chromosomal analysis. Specialized tests may also be performed to help detect and/or characterize certain abnormalities that may be associated with the disorder.In some cases, ring chromosome 4 may be suggested before birth (prenatally) by specialized tests such as ultrasound, amniocentesis, and/or chorionic villus sampling (CVS). During fetal ultrasonography, reflected sound waves create an image of the developing fetus, potentially revealing certain findings that suggest a chromosomal disorder or other abnormalities in the fetus. With amniocentesis, a sample of fluid that surrounds the developing fetus is removed and analyzed, while CVS involves the removal of tissue samples from a portion of the placenta. Chromosomal analysis performed on such fluid or tissue samples may reveal the presence of ring chromosome 4.
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Diagnosis of Ring Chromosome 4. The disorder may be diagnosed or confirmed after birth (postnatally) based upon thorough clinical evaluation, detection of characteristic physical findings, and chromosomal analysis. Specialized tests may also be performed to help detect and/or characterize certain abnormalities that may be associated with the disorder.In some cases, ring chromosome 4 may be suggested before birth (prenatally) by specialized tests such as ultrasound, amniocentesis, and/or chorionic villus sampling (CVS). During fetal ultrasonography, reflected sound waves create an image of the developing fetus, potentially revealing certain findings that suggest a chromosomal disorder or other abnormalities in the fetus. With amniocentesis, a sample of fluid that surrounds the developing fetus is removed and analyzed, while CVS involves the removal of tissue samples from a portion of the placenta. Chromosomal analysis performed on such fluid or tissue samples may reveal the presence of ring chromosome 4.
| 1,077 |
Ring Chromosome 4
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nord_1077_6
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Therapies of Ring Chromosome 4
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TreatmentThe treatment of ring chromosome 4 is directed toward the specific symptoms that are apparent in each individual. In some patients, physicians may recommend surgical repair of certain malformations potentially associated with the disorder. The specific surgical procedures performed will depend upon the severity and location of the anatomical abnormalities, their associated symptoms and other factors.Early intervention may be important in ensuring that affected children reach their potential. Special services that may be beneficial include special education, speech therapy and/or other medical, social and/or vocational services. Genetic counseling is recommended for affected individuals and their families. Other treatment for this disorder is symptomatic and supportive.
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Therapies of Ring Chromosome 4. TreatmentThe treatment of ring chromosome 4 is directed toward the specific symptoms that are apparent in each individual. In some patients, physicians may recommend surgical repair of certain malformations potentially associated with the disorder. The specific surgical procedures performed will depend upon the severity and location of the anatomical abnormalities, their associated symptoms and other factors.Early intervention may be important in ensuring that affected children reach their potential. Special services that may be beneficial include special education, speech therapy and/or other medical, social and/or vocational services. Genetic counseling is recommended for affected individuals and their families. Other treatment for this disorder is symptomatic and supportive.
| 1,077 |
Ring Chromosome 4
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nord_1078_0
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Overview of Robinow Syndrome
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Robinow syndrome is an extremely rare inherited disorder that affects development of the bones and other parts of the body. There are two forms of Robinow syndrome that are distinguished by signs and symptoms, severity, mode of inheritance, and the genes associated with them. Autosomal recessive Robinow syndrome is more severe and is characterized by shortening of the long bones in the arms and legs; short fingers and toes; wedge-shaped spinal bones that leads to abnormal curvature of the spine (kyphoscoliosis); fused or missing ribs; short stature; and distinctive facial features that are sometimes described as “fetal facies” because the face is similar to the face of a developing fetus. Other features may include underdeveloped genitalia; dental problems; kidney or heart defects; or delayed development. Children with autosomal dominant Robinow syndrome have similar but milder features. Spine and rib anomalies are usually not present and short stature is less severe. Some individuals with autosomal dominant Robinow syndrome also have increased bone mineral density (osteosclerosis).
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Overview of Robinow Syndrome. Robinow syndrome is an extremely rare inherited disorder that affects development of the bones and other parts of the body. There are two forms of Robinow syndrome that are distinguished by signs and symptoms, severity, mode of inheritance, and the genes associated with them. Autosomal recessive Robinow syndrome is more severe and is characterized by shortening of the long bones in the arms and legs; short fingers and toes; wedge-shaped spinal bones that leads to abnormal curvature of the spine (kyphoscoliosis); fused or missing ribs; short stature; and distinctive facial features that are sometimes described as “fetal facies” because the face is similar to the face of a developing fetus. Other features may include underdeveloped genitalia; dental problems; kidney or heart defects; or delayed development. Children with autosomal dominant Robinow syndrome have similar but milder features. Spine and rib anomalies are usually not present and short stature is less severe. Some individuals with autosomal dominant Robinow syndrome also have increased bone mineral density (osteosclerosis).
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Robinow Syndrome
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nord_1078_1
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Symptoms of Robinow Syndrome
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Autosomal recessive Robinow syndrome is characterized by short stature, characteristic facial features, skeletal abnormalities, and/or genital abnormalities. The range and severity of symptoms vary from person to person. Most children with Robinow syndrome experience growth delays after birth, resulting in slight to moderate short stature. Most children have normal intelligence but approximately 20 percent of those affected may have intellectual disability, delays in reaching developmental milestones, and/or delays in developing language skills. Facial features resemble those of a developing fetus, a finding often termed “fetal facies” in the medical literature. Characteristic abnormalities of the head and facial area may include a large head (macrocephaly) with a bulging forehead (frontal bossing) and underdevelopment of the middle portion of the face (midface hypoplasia). Affected infants may also have widely spaced eyes (ocular hypertelorism) that are prominent (exophthalmos); unusually wide, downwardly slanting eyelid folds (palpebral fissures); a small, upturned nose with nostrils that are flared forward (anteverted); a sunken (depressed) nasal bridge; and/or abnormally positioned (i.e. low-set, posteriorly rotated) ears. Some affected infants may have a broad, triangularly-shaped downwardly turned mouth with a long groove (philtrum) in the center of the upper lip; a small chin; a small jaw (micrognathia); and/or overgrown gums (gingival hyperplasia). Dental abnormalities may also be present including misaligned teeth, crowding of the back (posterior) teeth, and/or delayed eruption of the secondary (permanent) teeth. The soft-tissue structure at the back of the throat (uvula) may be underdeveloped or abnormally divided (bifid). Affected infants may also have incomplete closure of the roof of the mouth (cleft palate), an abnormal vertical groove or opening in the upper lip (cleft lip), and/or restricted movements of the tongue (ankyloglossia). Aankyloglossia may contribute to delays in language skill development. In most children, the facial abnormalities associated with Robinow syndrome become less pronounced as children age. Skeletal abnormalities may include forearm bones (radius and ulna) that are abnormally short and underdeveloped (forearm brachymelia); abnormal deviation of the thumb side of the forearm (radius) due to shortening of the radius (Madelung deformity of the wrist); unusually short fingers (brachydactyly); permanent fixation of the fifth fingers in a bent position (clinodactyly); and/or abnormally small hands with broad thumbs. The end bones (terminal phalanges) of the thumbs and great toes may be abnormally divided (bifid) and/or the bones (phalanges) of the fingers and toes may be underdeveloped (hypoplastic). Additional abnormalities may include dislocation of the hips, limited extension of the elbows, abnormal fusion or absence of certain ribs, abnormal side-to-side curvature of the spine (scoliosis), underdevelopment of one side of the bones (vertebrae) in the middle (thoracic) portion of the spinal column (hemivertebrae), and/or fusion of certain vertebrae. Affected infants may exhibit abnormal depression of the bone forming the center of the chest (“funnel chest” or pectus excavatum).Infants may also have malformed (dysplastic) nails and/or abnormalities of the skin ridge patterns (dermatoglyphics) on the fingers and palms. Most infants with Robinow syndrome also have abnormalities of the genitals and some may have external genitals that are not distinctly male or female (ambiguous genitalia). Gender can usually be properly determined during early infancy. In females, the clitoris and the outer, elongated folds of skin on either side of the vaginal opening (labia majora) may be underdeveloped (hypoplastic). In males, the penis may be abnormally small (micropenis) and may be hidden under the surrounding skin; in addition, one or both of the testes may fail to descend into the scrotum (cryptorchidism).Rarely, affected males may have abnormally low levels of testicular function (partial primary hypogonadism, but experience normal development of secondary sexual characteristics (e.g., deepening of the voice, characteristic hair growth patterns, sudden increase in growth and development of the testes and scrotum, etc.) with the exception of the persistence of micropenis. Affected females exhibit normal function of the ovaries (normal gonadal function) and normal fertility. Individuals with Robinow syndrome may have additional physical abnormalities such as duplication of the kidneys, unusual accumulation of urine in the kidney (hydronephrosis), protrusion of portions of the large intestine through an abnormal opening in the muscular lining of the abdominal cavity (inguinal hernia), and/or protrusion of portions of the large intestine through the abdominal wall near the navel (umbilical hernia). In addition, approximately 13 percent of infants with Robinow syndrome have heart (cardiac) defects that are present at birth (congenital heart defects). In such cases, the most common heart defect has been “right ventricular outlet obstruction,” in which the flow of blood from the lower chamber of the heart (ventricle) was obstructed due to abnormal narrowing (stenosis) or closure (atresia) of the vessel that arises from the ventricle (pulmonary trunk) and divides into the left and right pulmonary arteries. Symptoms associated with this heart defect vary greatly depending upon the size and location of the obstruction. In some infants with Robinow syndrome, other cardiac abnormalities may be present including complex congenital heart defects that may lead to life-threatening complications. Rarely, infants and children with Robinow syndrome may be prone to repeated infections of the lungs (pneumonia). In rare, severe cases, without appropriate treatment, pneumonia may result in life-threatening complications. The dominant and recessive forms of Robinow syndrome share many of the same symptoms and physical findings (e.g., craniofacial abnormalities, short stature, skeletal malformations, and genital hypoplasia). However, the symptoms and physical findings associated with the recessive form tend to be more severe. Infants with the recessive form of Robinow syndrome exhibit more numerous rib abnormalities (e.g., abnormal displacement, fusion, and/or absence of certain ribs) and defects affecting bones of the spinal column (vertebrae) than those infants with the dominant form of the disorder. In addition, short stature, underdevelopment of the forearm bones (radioulnar hypoplasia), and abnormalities of the fingers are more severe. Affected children may exhibit dislocation of the head of one of the forearm bones (radial head dislocation), an abnormality rarely seen in individuals with the dominant form of Robinow syndrome. Individuals with the recessive form may also tend to have a more triangularly-shaped mouth.A variant form of autosomal dominant Robinow syndrome, the osteosclerotic form, is characterized by increased bone mineral density, particularly in the skull; normal height; large head; and hearing loss, in addition to the typical signs and symptoms.
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Symptoms of Robinow Syndrome. Autosomal recessive Robinow syndrome is characterized by short stature, characteristic facial features, skeletal abnormalities, and/or genital abnormalities. The range and severity of symptoms vary from person to person. Most children with Robinow syndrome experience growth delays after birth, resulting in slight to moderate short stature. Most children have normal intelligence but approximately 20 percent of those affected may have intellectual disability, delays in reaching developmental milestones, and/or delays in developing language skills. Facial features resemble those of a developing fetus, a finding often termed “fetal facies” in the medical literature. Characteristic abnormalities of the head and facial area may include a large head (macrocephaly) with a bulging forehead (frontal bossing) and underdevelopment of the middle portion of the face (midface hypoplasia). Affected infants may also have widely spaced eyes (ocular hypertelorism) that are prominent (exophthalmos); unusually wide, downwardly slanting eyelid folds (palpebral fissures); a small, upturned nose with nostrils that are flared forward (anteverted); a sunken (depressed) nasal bridge; and/or abnormally positioned (i.e. low-set, posteriorly rotated) ears. Some affected infants may have a broad, triangularly-shaped downwardly turned mouth with a long groove (philtrum) in the center of the upper lip; a small chin; a small jaw (micrognathia); and/or overgrown gums (gingival hyperplasia). Dental abnormalities may also be present including misaligned teeth, crowding of the back (posterior) teeth, and/or delayed eruption of the secondary (permanent) teeth. The soft-tissue structure at the back of the throat (uvula) may be underdeveloped or abnormally divided (bifid). Affected infants may also have incomplete closure of the roof of the mouth (cleft palate), an abnormal vertical groove or opening in the upper lip (cleft lip), and/or restricted movements of the tongue (ankyloglossia). Aankyloglossia may contribute to delays in language skill development. In most children, the facial abnormalities associated with Robinow syndrome become less pronounced as children age. Skeletal abnormalities may include forearm bones (radius and ulna) that are abnormally short and underdeveloped (forearm brachymelia); abnormal deviation of the thumb side of the forearm (radius) due to shortening of the radius (Madelung deformity of the wrist); unusually short fingers (brachydactyly); permanent fixation of the fifth fingers in a bent position (clinodactyly); and/or abnormally small hands with broad thumbs. The end bones (terminal phalanges) of the thumbs and great toes may be abnormally divided (bifid) and/or the bones (phalanges) of the fingers and toes may be underdeveloped (hypoplastic). Additional abnormalities may include dislocation of the hips, limited extension of the elbows, abnormal fusion or absence of certain ribs, abnormal side-to-side curvature of the spine (scoliosis), underdevelopment of one side of the bones (vertebrae) in the middle (thoracic) portion of the spinal column (hemivertebrae), and/or fusion of certain vertebrae. Affected infants may exhibit abnormal depression of the bone forming the center of the chest (“funnel chest” or pectus excavatum).Infants may also have malformed (dysplastic) nails and/or abnormalities of the skin ridge patterns (dermatoglyphics) on the fingers and palms. Most infants with Robinow syndrome also have abnormalities of the genitals and some may have external genitals that are not distinctly male or female (ambiguous genitalia). Gender can usually be properly determined during early infancy. In females, the clitoris and the outer, elongated folds of skin on either side of the vaginal opening (labia majora) may be underdeveloped (hypoplastic). In males, the penis may be abnormally small (micropenis) and may be hidden under the surrounding skin; in addition, one or both of the testes may fail to descend into the scrotum (cryptorchidism).Rarely, affected males may have abnormally low levels of testicular function (partial primary hypogonadism, but experience normal development of secondary sexual characteristics (e.g., deepening of the voice, characteristic hair growth patterns, sudden increase in growth and development of the testes and scrotum, etc.) with the exception of the persistence of micropenis. Affected females exhibit normal function of the ovaries (normal gonadal function) and normal fertility. Individuals with Robinow syndrome may have additional physical abnormalities such as duplication of the kidneys, unusual accumulation of urine in the kidney (hydronephrosis), protrusion of portions of the large intestine through an abnormal opening in the muscular lining of the abdominal cavity (inguinal hernia), and/or protrusion of portions of the large intestine through the abdominal wall near the navel (umbilical hernia). In addition, approximately 13 percent of infants with Robinow syndrome have heart (cardiac) defects that are present at birth (congenital heart defects). In such cases, the most common heart defect has been “right ventricular outlet obstruction,” in which the flow of blood from the lower chamber of the heart (ventricle) was obstructed due to abnormal narrowing (stenosis) or closure (atresia) of the vessel that arises from the ventricle (pulmonary trunk) and divides into the left and right pulmonary arteries. Symptoms associated with this heart defect vary greatly depending upon the size and location of the obstruction. In some infants with Robinow syndrome, other cardiac abnormalities may be present including complex congenital heart defects that may lead to life-threatening complications. Rarely, infants and children with Robinow syndrome may be prone to repeated infections of the lungs (pneumonia). In rare, severe cases, without appropriate treatment, pneumonia may result in life-threatening complications. The dominant and recessive forms of Robinow syndrome share many of the same symptoms and physical findings (e.g., craniofacial abnormalities, short stature, skeletal malformations, and genital hypoplasia). However, the symptoms and physical findings associated with the recessive form tend to be more severe. Infants with the recessive form of Robinow syndrome exhibit more numerous rib abnormalities (e.g., abnormal displacement, fusion, and/or absence of certain ribs) and defects affecting bones of the spinal column (vertebrae) than those infants with the dominant form of the disorder. In addition, short stature, underdevelopment of the forearm bones (radioulnar hypoplasia), and abnormalities of the fingers are more severe. Affected children may exhibit dislocation of the head of one of the forearm bones (radial head dislocation), an abnormality rarely seen in individuals with the dominant form of Robinow syndrome. Individuals with the recessive form may also tend to have a more triangularly-shaped mouth.A variant form of autosomal dominant Robinow syndrome, the osteosclerotic form, is characterized by increased bone mineral density, particularly in the skull; normal height; large head; and hearing loss, in addition to the typical signs and symptoms.
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Robinow Syndrome
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nord_1078_2
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Causes of Robinow Syndrome
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The autosomal recessive and autosomal dominant forms of Robinow syndrome are caused by changes (mutations) in different genes.Autosomal recessive Robinow syndrome occurs due to mutations in the ROR2 gene resulting in a lack of ROR2 protein. Without this protein, development is disrupted, particularly the formation of the skeleton, heart and genitals.Autosomal dominant Robinow syndrome occurs due to mutations in the WNT5A gene or DVL1 gene, resulting in a lack of specific proteins necessary for normal development. The osteosclerotic form is caused by DVL1 gene mutations. Some people with Robinow syndrome do not have mutations in any of these genes and the cause of the condition is unknown.Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females. In some individuals, the disorder is due to a spontaneous (de novo) genetic mutation that occurs in the egg or sperm cell. In such situations, the disorder is not inherited from the parents.
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Causes of Robinow Syndrome. The autosomal recessive and autosomal dominant forms of Robinow syndrome are caused by changes (mutations) in different genes.Autosomal recessive Robinow syndrome occurs due to mutations in the ROR2 gene resulting in a lack of ROR2 protein. Without this protein, development is disrupted, particularly the formation of the skeleton, heart and genitals.Autosomal dominant Robinow syndrome occurs due to mutations in the WNT5A gene or DVL1 gene, resulting in a lack of specific proteins necessary for normal development. The osteosclerotic form is caused by DVL1 gene mutations. Some people with Robinow syndrome do not have mutations in any of these genes and the cause of the condition is unknown.Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females. In some individuals, the disorder is due to a spontaneous (de novo) genetic mutation that occurs in the egg or sperm cell. In such situations, the disorder is not inherited from the parents.
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Robinow Syndrome
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Affects of Robinow Syndrome
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Autosomal recessive Robinow syndrome has been reported in fewer than 200 people in families from various ethnic backgrounds. Autosomal dominant Robinow syndrome has been reported in fewer than 50 families.
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Affects of Robinow Syndrome. Autosomal recessive Robinow syndrome has been reported in fewer than 200 people in families from various ethnic backgrounds. Autosomal dominant Robinow syndrome has been reported in fewer than 50 families.
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Robinow Syndrome
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nord_1078_4
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Related disorders of Robinow Syndrome
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Symptoms of the following disorders may be similar to those of Robinow syndrome. Comparisons may be useful for a differential diagnosis: Achondroplasia is an inherited disorder characterized by abnormally short arms and legs and short stature (short-limbed dwarfism), abnormal facial features, and/or skeletal malformations. Characteristic facial features may include an abnormally large head (macrocephaly), unusual prominence of the forehead (frontal bossing), a low nasal bridge, and/or underdevelopment of the middle portion of the face (midface hypoplasia). Skeletal malformations may include unusually short fingers and toes (brachydactyly), abnormally increased backward curvature of the spine (lordosis), legs that bow outward (genu varum), and/or narrowing (stenosis) of the spine. Additional abnormalities may include limited extension of the elbows and hips, diminished muscle tone (hypotonia), and/or frequent infections of the middle ear (otitis media). Achondroplasia is an autosomal dominant genetic condition. (For more information on this disorder, choose “Achondroplasia” as your search term in the Rare Disease Database.) Aarskog syndrome is a very rare inherited disorder characterized by abnormalities of the head and facial (craniofacial) area, slight to moderate short stature, malformations of the skeleton, and/or abnormalities of the genitals. Characteristic facial features may include widely spaced eyes (ocular hypertelorism), downwardly slanting eyelid folds (palpebral fissures), a small nose with nostrils that are flared forward (anteverted nares), and/or underdevelopment of the upper jaw (maxillary hypoplasia). Skeletal malformations may include abnormally short fingers (brachydactyly), permanent fixation of the fifth fingers in a bent position (clinodactyly), and/or unusually broad thumbs and great toes. Genital abnormalities may include an abnormal fold of skin extending around the base of the penis (shawl scrotum) and/or failure of one or both of the testes to descend into the scrotum (cryptorchidism). Some affected children have mild intellectual disability. Aarskog syndrome is a X-linked genetic condition. (For more information on this disorder, choose “Aarskog” as your search term in the Rare Disease Database.) Omodysplasia is a rare inherited bone disorder that may be characterized by abnormal shortness of certain long bones of the arms (i.e., humeri) and legs (i.e., thigh bone or femora), short stature, and characteristic facial features including a depressed nasal bridge, broad base of the nose, and/or an unusually long vertical groove (philtrum) in the center of the upper lip. In addition, affected individuals may demonstrate abnormal separation of the two bones of the forearms (radioulnar diastasis), dislocation of the head of the radius, and/or underdevelopment (hypoplasia) of the rounded mass of bone (condyle) at the end of the humerus. Omodysplasia can be inherited as an autosomal recessive or autosomal dominant genetic condition.
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Related disorders of Robinow Syndrome. Symptoms of the following disorders may be similar to those of Robinow syndrome. Comparisons may be useful for a differential diagnosis: Achondroplasia is an inherited disorder characterized by abnormally short arms and legs and short stature (short-limbed dwarfism), abnormal facial features, and/or skeletal malformations. Characteristic facial features may include an abnormally large head (macrocephaly), unusual prominence of the forehead (frontal bossing), a low nasal bridge, and/or underdevelopment of the middle portion of the face (midface hypoplasia). Skeletal malformations may include unusually short fingers and toes (brachydactyly), abnormally increased backward curvature of the spine (lordosis), legs that bow outward (genu varum), and/or narrowing (stenosis) of the spine. Additional abnormalities may include limited extension of the elbows and hips, diminished muscle tone (hypotonia), and/or frequent infections of the middle ear (otitis media). Achondroplasia is an autosomal dominant genetic condition. (For more information on this disorder, choose “Achondroplasia” as your search term in the Rare Disease Database.) Aarskog syndrome is a very rare inherited disorder characterized by abnormalities of the head and facial (craniofacial) area, slight to moderate short stature, malformations of the skeleton, and/or abnormalities of the genitals. Characteristic facial features may include widely spaced eyes (ocular hypertelorism), downwardly slanting eyelid folds (palpebral fissures), a small nose with nostrils that are flared forward (anteverted nares), and/or underdevelopment of the upper jaw (maxillary hypoplasia). Skeletal malformations may include abnormally short fingers (brachydactyly), permanent fixation of the fifth fingers in a bent position (clinodactyly), and/or unusually broad thumbs and great toes. Genital abnormalities may include an abnormal fold of skin extending around the base of the penis (shawl scrotum) and/or failure of one or both of the testes to descend into the scrotum (cryptorchidism). Some affected children have mild intellectual disability. Aarskog syndrome is a X-linked genetic condition. (For more information on this disorder, choose “Aarskog” as your search term in the Rare Disease Database.) Omodysplasia is a rare inherited bone disorder that may be characterized by abnormal shortness of certain long bones of the arms (i.e., humeri) and legs (i.e., thigh bone or femora), short stature, and characteristic facial features including a depressed nasal bridge, broad base of the nose, and/or an unusually long vertical groove (philtrum) in the center of the upper lip. In addition, affected individuals may demonstrate abnormal separation of the two bones of the forearms (radioulnar diastasis), dislocation of the head of the radius, and/or underdevelopment (hypoplasia) of the rounded mass of bone (condyle) at the end of the humerus. Omodysplasia can be inherited as an autosomal recessive or autosomal dominant genetic condition.
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Robinow Syndrome
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nord_1078_5
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Diagnosis of Robinow Syndrome
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Diagnosis of Robinow syndrome is usually made shortly after birth based on physical findings including short stature, limb and genital abnormalities and characteristic facial features. Molecular genetic testing for mutations in the ROR2 gene is available to confirm the diagnosis of autosomal recessive Robinow syndrome. Molecular genetic testing for mutations in the WNT5A gene and DVL1 gene is available to confirm the diagnosis of autosomal dominant Robinow syndrome.
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Diagnosis of Robinow Syndrome. Diagnosis of Robinow syndrome is usually made shortly after birth based on physical findings including short stature, limb and genital abnormalities and characteristic facial features. Molecular genetic testing for mutations in the ROR2 gene is available to confirm the diagnosis of autosomal recessive Robinow syndrome. Molecular genetic testing for mutations in the WNT5A gene and DVL1 gene is available to confirm the diagnosis of autosomal dominant Robinow syndrome.
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Robinow Syndrome
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nord_1078_6
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Therapies of Robinow Syndrome
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TreatmentThe treatment of Robinow syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, specialists who treat skeletal abnormalities (orthopedists), surgeons, specialists who diagnose and treat heart problems (cardiologists), physical therapists, and/or other health care professionals may need to systematically and comprehensively plan an affected child's treatment. In affected infants who have ambiguous genitalia, gender may be properly determined by clinical examination during the newborn period. In some children, surgery may be performed and/or other measures may be taken to correct cryptorchidism and/or other genital abnormalities. Additionally, hormone supplements such as human chorionic gonadotropin and/or testosterone are sometimes administered in order to treat micropenis by improving penile length and testicular volume. Growth hormone deficiency in some patients has been found to respond positively to growth hormone therapy. These forms of hormone therapy however, must be closely monitored by a pediatric endocrinologist.Braces, casts, special exercises, and/or surgery may be beneficial in treating certain vertebral abnormalities. Surgery may also be performed to correct inguinal hernias, certain craniofacial abnormalities, severe curvature of the spine (scoliosis) secondary to hemivertebrae and rib abnormalities, wholly or partly united fingers/toes (syndactyly), cleft lip/palate, and/or other malformations. Use of braces, dental surgery, and/or other supportive techniques may be used to help correct misalignment of the teeth and/or other dental abnormalities. Infants and children with Robinow syndrome should receive thorough medical evaluations to ensure prompt detection and immediate appropriate treatment of heart (cardiac) abnormalities that may be potentially associated with the disorder. Affected infants and children should also be carefully monitored to help prevent and/or immediately detect infections of the lungs (pneumonia) and to ensure prompt, appropriate treatment. Early intervention is important to ensure that children with Robinow syndrome reach their potential. Special services that may be beneficial to affected children may include special remedial education, special social support, physical therapy, and/or other medical, social, and/or vocational services. Genetic counseling is recommended for affected individuals and their families. Other treatment for this disorder is symptomatic and supportive.
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Therapies of Robinow Syndrome. TreatmentThe treatment of Robinow syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, specialists who treat skeletal abnormalities (orthopedists), surgeons, specialists who diagnose and treat heart problems (cardiologists), physical therapists, and/or other health care professionals may need to systematically and comprehensively plan an affected child's treatment. In affected infants who have ambiguous genitalia, gender may be properly determined by clinical examination during the newborn period. In some children, surgery may be performed and/or other measures may be taken to correct cryptorchidism and/or other genital abnormalities. Additionally, hormone supplements such as human chorionic gonadotropin and/or testosterone are sometimes administered in order to treat micropenis by improving penile length and testicular volume. Growth hormone deficiency in some patients has been found to respond positively to growth hormone therapy. These forms of hormone therapy however, must be closely monitored by a pediatric endocrinologist.Braces, casts, special exercises, and/or surgery may be beneficial in treating certain vertebral abnormalities. Surgery may also be performed to correct inguinal hernias, certain craniofacial abnormalities, severe curvature of the spine (scoliosis) secondary to hemivertebrae and rib abnormalities, wholly or partly united fingers/toes (syndactyly), cleft lip/palate, and/or other malformations. Use of braces, dental surgery, and/or other supportive techniques may be used to help correct misalignment of the teeth and/or other dental abnormalities. Infants and children with Robinow syndrome should receive thorough medical evaluations to ensure prompt detection and immediate appropriate treatment of heart (cardiac) abnormalities that may be potentially associated with the disorder. Affected infants and children should also be carefully monitored to help prevent and/or immediately detect infections of the lungs (pneumonia) and to ensure prompt, appropriate treatment. Early intervention is important to ensure that children with Robinow syndrome reach their potential. Special services that may be beneficial to affected children may include special remedial education, special social support, physical therapy, and/or other medical, social, and/or vocational services. Genetic counseling is recommended for affected individuals and their families. Other treatment for this disorder is symptomatic and supportive.
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Robinow Syndrome
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nord_1079_0
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Overview of Rocky Mountain Spotted Fever
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Rocky Mountain spotted fever (RMSF) is an infectious disease that belongs to a group of diseases known as the spotted fever group rickettsioses. It is caused by infection with the bacterium Rickettsia rickettsii (R. rickettsii), which is usually transmitted by a tick bite. When introduced into the body, the bacterium spreads by the bloodstream or lymphatic vessels and multiplies within and damages certain cells lining the inside of small blood (vascular) vessels (i.e., endothelial cells) as well as vascular smooth muscle cells. Such damage leads to inflammatory changes of affected blood vessels (vasculitis), leakage of fluid from the blood vessels, an abnormal accumulation of fluid in body tissues (edema), and additional abnormalities, resulting in the symptoms and findings associated with the disease.Approximately two to 14 days after initial infection, early symptoms may include a high fever, severe headaches, muscle pain (myalgia), nausea, vomiting, loss of appetite (anorexia), abdominal pain, and/or features. In addition, in most individuals with RMSF, a distinctive rash develops about three to five days after fever onset. The rash often initially appears on the skin of the wrists and ankles and spreads to involve the palms of the hands, the soles of the feet, the forearms, the trunk, the buttocks, and the neck and facial areas. The rash typically initially consists of small, flat pinkish spots (macules) that eventually become raised (papules) and darker. The lesions usually develop “pin-point” reddish spots (petechia) due to localized bleeding (hemorrhaging) and may merge to form larger hemorrhagic patches. In some severe cases, insufficient oxygenated blood supply to certain tissues may lead to areas of tissue loss (necrosis).R. rickettsii infection may affect blood vessels, tissues, and organs throughout the body, including the lungs, brain and spinal cord (central nervous system), heart, liver, and kidneys. Associated symptoms and findings may vary, depending upon the specific tissues and organs affected. Without timely, appropriate treatment, individuals with severe disease may develop potentially life-threatening complications due to tissue and organ injury and dysfunction.As its name indicates, the disease was originally recognized in the Rocky Mountain states. It has since been reported throughout the continental United States as well as Mexico, Canada, Central America, and South America. As noted above, in most cases, infection with the R. rickettsii bacterium results from tick bites. Several different types of ticks serve as “vectors” for the disease, transmitting the R. rickettsii bacterium to humans.
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Overview of Rocky Mountain Spotted Fever. Rocky Mountain spotted fever (RMSF) is an infectious disease that belongs to a group of diseases known as the spotted fever group rickettsioses. It is caused by infection with the bacterium Rickettsia rickettsii (R. rickettsii), which is usually transmitted by a tick bite. When introduced into the body, the bacterium spreads by the bloodstream or lymphatic vessels and multiplies within and damages certain cells lining the inside of small blood (vascular) vessels (i.e., endothelial cells) as well as vascular smooth muscle cells. Such damage leads to inflammatory changes of affected blood vessels (vasculitis), leakage of fluid from the blood vessels, an abnormal accumulation of fluid in body tissues (edema), and additional abnormalities, resulting in the symptoms and findings associated with the disease.Approximately two to 14 days after initial infection, early symptoms may include a high fever, severe headaches, muscle pain (myalgia), nausea, vomiting, loss of appetite (anorexia), abdominal pain, and/or features. In addition, in most individuals with RMSF, a distinctive rash develops about three to five days after fever onset. The rash often initially appears on the skin of the wrists and ankles and spreads to involve the palms of the hands, the soles of the feet, the forearms, the trunk, the buttocks, and the neck and facial areas. The rash typically initially consists of small, flat pinkish spots (macules) that eventually become raised (papules) and darker. The lesions usually develop “pin-point” reddish spots (petechia) due to localized bleeding (hemorrhaging) and may merge to form larger hemorrhagic patches. In some severe cases, insufficient oxygenated blood supply to certain tissues may lead to areas of tissue loss (necrosis).R. rickettsii infection may affect blood vessels, tissues, and organs throughout the body, including the lungs, brain and spinal cord (central nervous system), heart, liver, and kidneys. Associated symptoms and findings may vary, depending upon the specific tissues and organs affected. Without timely, appropriate treatment, individuals with severe disease may develop potentially life-threatening complications due to tissue and organ injury and dysfunction.As its name indicates, the disease was originally recognized in the Rocky Mountain states. It has since been reported throughout the continental United States as well as Mexico, Canada, Central America, and South America. As noted above, in most cases, infection with the R. rickettsii bacterium results from tick bites. Several different types of ticks serve as “vectors” for the disease, transmitting the R. rickettsii bacterium to humans.
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Rocky Mountain Spotted Fever
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nord_1079_1
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Symptoms of Rocky Mountain Spotted Fever
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Rocky Mountain spotted fever (RMSF) is considered the most potentially severe form of the spotted fevers. The onset of symptoms typically occurs approximately two to 14 days (with an average of seven days) after having been bitten by a tick carrying the R. rickettsii bacterium. Early symptoms usually include a fever that may reach 103 or 104 degrees Fahrenheit; chills; extreme exhaustion (prostration); muscle pain (myalgia); and severe headaches that are often associated with pain upon moving the eyes and increased sensitivity to light (photophobia). Many also develop nausea, with or without vomiting, and loss of appetite (anorexia). Additional early symptoms may include diarrhea, abdominal tenderness, and abdominal pain. The disease may be difficult to diagnose in early stages since its early symptoms and signs are nonspecific, resembling those associated with many other infectious and non-infectious diseases.Most affected individuals develop a skin rash between the third to fifth days after onset of fever. Thus, in some instances, the rash may not be present or may be subtle when affected individuals initially seek medical attention. Less commonly, the rash may appear as early as the first day of illness or past five days. In addition, in some rare cases, a rash may never develop (“spotless fever”). In those who do develop a rash, it often initially develops on the wrists and ankles and then spreads to the palms and soles, forearms, neck, face, under the arms (axilla), buttocks, and trunk. Rarely, the rash may be atypical in distribution, beginning on the trunk, being widespread at onset, or remaining limited to one region.The skin rash typically begins as small, flat pinkish spots (macules) that initially become white (blanch) when pressure is applied. The lesions eventually become raised (papular) and darker and may develop reddish spots (petechia) due to small areas of abnormal bleeding (hemorrhages). With continued disease progression, petechial areas may begin to merge (coalesce) into larger patches that later ulcerate. In severe cases, inadequate oxygenated blood supply to certain tissues (ischemia) may lead to areas of tissue loss and possible decay (gangrene). Particularly susceptible areas may include the ear lobes, the tip of the nose, fingers and/or toes (digits), and/or the scrotum in affected males.In individuals with RMSF, endothelial cell damage and associated changes may affect blood vessels throughout the body. Therefore, the disease may affect multiple tissues and organ systems, including respiratory, neurologic, heart (cardiac), digestive, and kidney (renal) functioning. Individuals with severe disease may develop life-threatening complications approximately eight to 15 days after onset if prompt, appropriate treatment has not been received. Reports indicate that certain factors may be associated with an increased risk of such complications, including advanced age, male sex, and, possibly, alcohol abuse. In addition, a genetic disorder known as glucose-6-phosphate dehydrogenase (G6PD) deficiency has been associated with rare, fulminant RMSF (see below).In some affected individuals, there may be extensive infection of the pulmonary circulation, which is the network of blood vessels between the heart and lungs. Endothelial cell injury and leakage of fluid from the blood vessels may lead to abnormal fluid accumulation within lung tissues and air sacs (pulmonary edema). Lung (pulmonary) involvement may be suggested by various symptoms and findings, such as coughing; increasing difficulties breathing (dyspnea); inflammation of the lungs (pneumonia); an abnormal accumulation of fluid between layers of the membrane lining the lungs and chest cavity (pleural effusion); and/or other abnormalities. Some individuals with RMSF may also have cardiac involvement, with inflammation of muscular walls of the heart (myocarditis), potentially leading to disturbances of the normal heart rhythm (dysrhythmias), chest pain, reduced pumping efficiency (heart failure), and/or other findings.Central nervous system (CNS) involvement may also occur in association with severe cases of RMSF. Vascular injury may lead to inflammation of the brain (encephalitis), which may initially be associated with confusion, listlessness, and/or drowsiness. Symptoms and findings that may suggest progressively severe encephalitis may include restless, disorientation, impaired control of voluntary movements (ataxia), sudden episodes of uncontrolled electrical activity in the brain (seizures), unresponsiveness to surroundings (stupor), and/or coma. Various other neurologic abnormalities have also been reported in severe cases of RMSF. Such symptoms and findings have included hearing loss; abnormal, involuntary, rapid eye movements (nystagmus); a sensation that the environment or one's body is revolving (vertigo); abnormally increased reflex responses (hyperreflexia); difficulty articulating speech (dysarthria); impairment of certain cranial nerve pairs arising from the brain (cranial nerve palsy); inability to control urination or defecation (incontinence); muscle weakness or paralysis; and/or other abnormalities. As noted above, many affected individuals may develop certain digestive symptoms, such as nausea, vomiting, diarrhea, and/or abdominal tenderness or pain. In some cases, there may be blood in the contents expelled from the stomach during vomiting and/or in the stools due to abnormal bleeding (hemorrhaging) in the digestive (gastrointestinal [GI]) tract. In severe cases, affected individuals may develop severe hemorrhaging in the upper GI tract.Some individuals with RMSF may also develop abnormal enlargement of the liver and/or spleen (hepatosplenomegaly). In some cases, infection may result in injury of certain liver (hepatic) cells, leading to abnormalities of liver function; however, reports indicate that liver failure does not result. Some affected individuals may develop abnormal yellowing of the skin, mucous membranes, and whites of the eyes (jaundice), which is thought to be due to both liver cell injury and destruction of red blood cells (hemolysis).In some cases, sudden (acute) renal failure may occur in association with severe RMSF. Endothelial injury, leakage of fluid from blood vessels, and additional changes may lead to an abnormally decreased volume of blood circulating in the body (hypovolemia) and low blood pressure (hypotension). Such changes may result in reduced filtering of blood by the kidneys (glomeruli filtration); retention of excessive amounts of certain toxic compounds in the blood (prerenal azotemia); and, in severe cases, associated renal failure.In some cases, additional abnormalities have been reported in association with RMSF. These have included voluntary (skeletal) muscle injury and changes that may reflect eye (ocular) involvement, such as inflammatory changes of certain blood vessels of the retina and swelling of the head of the optic nerve (papilledema).Fulminant Rocky Mountain Spotted FeverIn rare cases, R. rickettsii infection may cause an unusually rapid onset of severe RMSF, known as fulminant RMSF. Individuals with particular forms of glucose-6-phosphate dehydrogenase (G6PD) deficiency may be prone to developing fulminant RMSF when infected with the R. rickettsii bacterium. G6PD deficiency is an X-linked genetic condition that affects approximately 10 percent of the black male population. It is characterized by deficiency of the enzyme G6PD from the red blood cell membranes. This enzyme plays a crucial role in processing glucose, a simple sugar that is the primary energy source for red blood cells. In those with G6PD deficiency, certain infections, medications, stress, or other factors may trigger sudden (acute) episodes of premature red blood cell destruction (hemolysis), leading to reduced concentrations of the oxygen-carrying component (hemoglobin) in the blood (anemia). In individuals with G6PD deficiency, fulminant RMSF is thought to be related to unknown secondary effects of acute hemolysis on the R. rickettsii infection. In individuals with fulminant RMSF, life-threatening complications may develop within five days after onset.
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Symptoms of Rocky Mountain Spotted Fever. Rocky Mountain spotted fever (RMSF) is considered the most potentially severe form of the spotted fevers. The onset of symptoms typically occurs approximately two to 14 days (with an average of seven days) after having been bitten by a tick carrying the R. rickettsii bacterium. Early symptoms usually include a fever that may reach 103 or 104 degrees Fahrenheit; chills; extreme exhaustion (prostration); muscle pain (myalgia); and severe headaches that are often associated with pain upon moving the eyes and increased sensitivity to light (photophobia). Many also develop nausea, with or without vomiting, and loss of appetite (anorexia). Additional early symptoms may include diarrhea, abdominal tenderness, and abdominal pain. The disease may be difficult to diagnose in early stages since its early symptoms and signs are nonspecific, resembling those associated with many other infectious and non-infectious diseases.Most affected individuals develop a skin rash between the third to fifth days after onset of fever. Thus, in some instances, the rash may not be present or may be subtle when affected individuals initially seek medical attention. Less commonly, the rash may appear as early as the first day of illness or past five days. In addition, in some rare cases, a rash may never develop (“spotless fever”). In those who do develop a rash, it often initially develops on the wrists and ankles and then spreads to the palms and soles, forearms, neck, face, under the arms (axilla), buttocks, and trunk. Rarely, the rash may be atypical in distribution, beginning on the trunk, being widespread at onset, or remaining limited to one region.The skin rash typically begins as small, flat pinkish spots (macules) that initially become white (blanch) when pressure is applied. The lesions eventually become raised (papular) and darker and may develop reddish spots (petechia) due to small areas of abnormal bleeding (hemorrhages). With continued disease progression, petechial areas may begin to merge (coalesce) into larger patches that later ulcerate. In severe cases, inadequate oxygenated blood supply to certain tissues (ischemia) may lead to areas of tissue loss and possible decay (gangrene). Particularly susceptible areas may include the ear lobes, the tip of the nose, fingers and/or toes (digits), and/or the scrotum in affected males.In individuals with RMSF, endothelial cell damage and associated changes may affect blood vessels throughout the body. Therefore, the disease may affect multiple tissues and organ systems, including respiratory, neurologic, heart (cardiac), digestive, and kidney (renal) functioning. Individuals with severe disease may develop life-threatening complications approximately eight to 15 days after onset if prompt, appropriate treatment has not been received. Reports indicate that certain factors may be associated with an increased risk of such complications, including advanced age, male sex, and, possibly, alcohol abuse. In addition, a genetic disorder known as glucose-6-phosphate dehydrogenase (G6PD) deficiency has been associated with rare, fulminant RMSF (see below).In some affected individuals, there may be extensive infection of the pulmonary circulation, which is the network of blood vessels between the heart and lungs. Endothelial cell injury and leakage of fluid from the blood vessels may lead to abnormal fluid accumulation within lung tissues and air sacs (pulmonary edema). Lung (pulmonary) involvement may be suggested by various symptoms and findings, such as coughing; increasing difficulties breathing (dyspnea); inflammation of the lungs (pneumonia); an abnormal accumulation of fluid between layers of the membrane lining the lungs and chest cavity (pleural effusion); and/or other abnormalities. Some individuals with RMSF may also have cardiac involvement, with inflammation of muscular walls of the heart (myocarditis), potentially leading to disturbances of the normal heart rhythm (dysrhythmias), chest pain, reduced pumping efficiency (heart failure), and/or other findings.Central nervous system (CNS) involvement may also occur in association with severe cases of RMSF. Vascular injury may lead to inflammation of the brain (encephalitis), which may initially be associated with confusion, listlessness, and/or drowsiness. Symptoms and findings that may suggest progressively severe encephalitis may include restless, disorientation, impaired control of voluntary movements (ataxia), sudden episodes of uncontrolled electrical activity in the brain (seizures), unresponsiveness to surroundings (stupor), and/or coma. Various other neurologic abnormalities have also been reported in severe cases of RMSF. Such symptoms and findings have included hearing loss; abnormal, involuntary, rapid eye movements (nystagmus); a sensation that the environment or one's body is revolving (vertigo); abnormally increased reflex responses (hyperreflexia); difficulty articulating speech (dysarthria); impairment of certain cranial nerve pairs arising from the brain (cranial nerve palsy); inability to control urination or defecation (incontinence); muscle weakness or paralysis; and/or other abnormalities. As noted above, many affected individuals may develop certain digestive symptoms, such as nausea, vomiting, diarrhea, and/or abdominal tenderness or pain. In some cases, there may be blood in the contents expelled from the stomach during vomiting and/or in the stools due to abnormal bleeding (hemorrhaging) in the digestive (gastrointestinal [GI]) tract. In severe cases, affected individuals may develop severe hemorrhaging in the upper GI tract.Some individuals with RMSF may also develop abnormal enlargement of the liver and/or spleen (hepatosplenomegaly). In some cases, infection may result in injury of certain liver (hepatic) cells, leading to abnormalities of liver function; however, reports indicate that liver failure does not result. Some affected individuals may develop abnormal yellowing of the skin, mucous membranes, and whites of the eyes (jaundice), which is thought to be due to both liver cell injury and destruction of red blood cells (hemolysis).In some cases, sudden (acute) renal failure may occur in association with severe RMSF. Endothelial injury, leakage of fluid from blood vessels, and additional changes may lead to an abnormally decreased volume of blood circulating in the body (hypovolemia) and low blood pressure (hypotension). Such changes may result in reduced filtering of blood by the kidneys (glomeruli filtration); retention of excessive amounts of certain toxic compounds in the blood (prerenal azotemia); and, in severe cases, associated renal failure.In some cases, additional abnormalities have been reported in association with RMSF. These have included voluntary (skeletal) muscle injury and changes that may reflect eye (ocular) involvement, such as inflammatory changes of certain blood vessels of the retina and swelling of the head of the optic nerve (papilledema).Fulminant Rocky Mountain Spotted FeverIn rare cases, R. rickettsii infection may cause an unusually rapid onset of severe RMSF, known as fulminant RMSF. Individuals with particular forms of glucose-6-phosphate dehydrogenase (G6PD) deficiency may be prone to developing fulminant RMSF when infected with the R. rickettsii bacterium. G6PD deficiency is an X-linked genetic condition that affects approximately 10 percent of the black male population. It is characterized by deficiency of the enzyme G6PD from the red blood cell membranes. This enzyme plays a crucial role in processing glucose, a simple sugar that is the primary energy source for red blood cells. In those with G6PD deficiency, certain infections, medications, stress, or other factors may trigger sudden (acute) episodes of premature red blood cell destruction (hemolysis), leading to reduced concentrations of the oxygen-carrying component (hemoglobin) in the blood (anemia). In individuals with G6PD deficiency, fulminant RMSF is thought to be related to unknown secondary effects of acute hemolysis on the R. rickettsii infection. In individuals with fulminant RMSF, life-threatening complications may develop within five days after onset.
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Rocky Mountain Spotted Fever
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nord_1079_2
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Causes of Rocky Mountain Spotted Fever
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The group of infectious diseases known as spotted fevers (i.e., spotted fever group rickettsioses), including Rocky Mountain spotted fever (RMSF), are caused by bacteria belonging to the “Rickettsiae” family. RMSF is caused by a bacterium called Rickettsia rickettsii (R. rickettsii), named after its discoverer, Howard T. Ricketts. As noted above, the disease is usually transmitted to humans via a tick bite. In many cases, the R. rickettsii bacterium is transmitted from infected ticks to their offspring; in other instances, uninfected ticks may become carriers (i.e., vectors) by feeding on infected mammals (e.g., rodents or dogs).Rarely, RMSF may be transmitted due to exposure to infected tick tissues. For example, such exposure may occur when removing an infected tick from a person or pet, particularly if the engorged tick is crushed between the fingers. There have also been reports in which laboratory workers have been infected due to inhaling droplets from solutions containing the bacterium (i.e., resulting from accidental formation of aerosolized infectious specimens). However, according to the medical literature, it is important to note that direct person-to-person airborne transmission does not occur.Upon entering the body, usually via the skin, the R. rickettsii bacterium spreads through blood (vascular) or lymphatic vessels. (The lymphatic system functions as part of the immune system, helping to protect the body against infection and disease. It consists of a network of tubular channels known as lymph vessels that branch into all bodily regions, including the skin. The lymph vessels drain a thin watery fluid called lymph from different areas of the body into the bloodstream. Lymph accumulates in the tiny spaces between tissue cells and contains proteins, fats, and the infection-fighting white blood cells known as lymphocytes.)The R. rickettsii bacterium characteristically invades, multiples within, and directly damages cells lining the inside of small blood vessels (i.e., endothelial cells) as well as involuntary (smooth) muscle cells within these vessels. Such damage may lead to an inflammatory response; increased permeability of blood vessels (vascular permeability*); and increased accumulations of blood cells involved in blood clotting (i.e., platelets) within affected areas, with an associated depletion in the numbers of circulating platelets in the bloodstream (thrombocytopenia). (*Vascular permeability indicates the degree to which the blood vessel wall structure allows blood elements and waste products to pass through.) Some have speculated that the tissue and organ injury in RMSF may be due to the widespread development of obstructive blood clots (thromboses) within blood vessels, leading to a decreased supply of oxygenated blood to certain tissues (ischemia) and associated, localized areas of tissue death (necrosis). However, evidence suggests that such organ injury and dysfunction is primarily due to increased vascular permeability, with resulting leakage of fluid from blood vessels; abnormal accumulation of fluid in body tissues (edema); bleeding (hemorrhaging); a low volume of blood circulating in the body (hypovolemia); low blood pressure (hypotension); and insufficient blood supply to certain organs or tissues (ischemia). Reports indicate that widespread, obstructive blood clotting within vessels (occlusive vascular thrombosis) and associated reduction in the elements involved in clotting (i.e., disseminated intravascular coagulation) occur only rarely in RMSF. As noted above, in affected individuals with G6PD deficiency, fulminant RMSF is thought to result from certain unknown effects of acute, premature red blood cell destruction (hemolysis) on the progression of R. rickettsii infection. (For more information on G6PD deficiency, choose “glucose-6-phosphate dehydrogenase” as your search term in the Rare Disease Database.)
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Causes of Rocky Mountain Spotted Fever. The group of infectious diseases known as spotted fevers (i.e., spotted fever group rickettsioses), including Rocky Mountain spotted fever (RMSF), are caused by bacteria belonging to the “Rickettsiae” family. RMSF is caused by a bacterium called Rickettsia rickettsii (R. rickettsii), named after its discoverer, Howard T. Ricketts. As noted above, the disease is usually transmitted to humans via a tick bite. In many cases, the R. rickettsii bacterium is transmitted from infected ticks to their offspring; in other instances, uninfected ticks may become carriers (i.e., vectors) by feeding on infected mammals (e.g., rodents or dogs).Rarely, RMSF may be transmitted due to exposure to infected tick tissues. For example, such exposure may occur when removing an infected tick from a person or pet, particularly if the engorged tick is crushed between the fingers. There have also been reports in which laboratory workers have been infected due to inhaling droplets from solutions containing the bacterium (i.e., resulting from accidental formation of aerosolized infectious specimens). However, according to the medical literature, it is important to note that direct person-to-person airborne transmission does not occur.Upon entering the body, usually via the skin, the R. rickettsii bacterium spreads through blood (vascular) or lymphatic vessels. (The lymphatic system functions as part of the immune system, helping to protect the body against infection and disease. It consists of a network of tubular channels known as lymph vessels that branch into all bodily regions, including the skin. The lymph vessels drain a thin watery fluid called lymph from different areas of the body into the bloodstream. Lymph accumulates in the tiny spaces between tissue cells and contains proteins, fats, and the infection-fighting white blood cells known as lymphocytes.)The R. rickettsii bacterium characteristically invades, multiples within, and directly damages cells lining the inside of small blood vessels (i.e., endothelial cells) as well as involuntary (smooth) muscle cells within these vessels. Such damage may lead to an inflammatory response; increased permeability of blood vessels (vascular permeability*); and increased accumulations of blood cells involved in blood clotting (i.e., platelets) within affected areas, with an associated depletion in the numbers of circulating platelets in the bloodstream (thrombocytopenia). (*Vascular permeability indicates the degree to which the blood vessel wall structure allows blood elements and waste products to pass through.) Some have speculated that the tissue and organ injury in RMSF may be due to the widespread development of obstructive blood clots (thromboses) within blood vessels, leading to a decreased supply of oxygenated blood to certain tissues (ischemia) and associated, localized areas of tissue death (necrosis). However, evidence suggests that such organ injury and dysfunction is primarily due to increased vascular permeability, with resulting leakage of fluid from blood vessels; abnormal accumulation of fluid in body tissues (edema); bleeding (hemorrhaging); a low volume of blood circulating in the body (hypovolemia); low blood pressure (hypotension); and insufficient blood supply to certain organs or tissues (ischemia). Reports indicate that widespread, obstructive blood clotting within vessels (occlusive vascular thrombosis) and associated reduction in the elements involved in clotting (i.e., disseminated intravascular coagulation) occur only rarely in RMSF. As noted above, in affected individuals with G6PD deficiency, fulminant RMSF is thought to result from certain unknown effects of acute, premature red blood cell destruction (hemolysis) on the progression of R. rickettsii infection. (For more information on G6PD deficiency, choose “glucose-6-phosphate dehydrogenase” as your search term in the Rare Disease Database.)
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Rocky Mountain Spotted Fever
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nord_1079_3
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Affects of Rocky Mountain Spotted Fever
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Rocky Mountain spotted fever (RMSF) was first described in the late 1800s in Idaho. The disease was initially recognized as existing in only the Rocky Mountain (western) area of the United States. However, beginning in the 1930s, the disease was noted in other regions of the country. Currently, the frequency of the disease is higher in the west south-central region and the South Atlantic states than in the Rocky Mountain states. RMSF has been reported in almost every state as well as other countries, including Canada, Mexico, Brazil, Columbia, Costa Rica, and Panama. Most cases of RMSF occur between April to September, when outdoor activities are most frequent. However, some cases may occur in winter, particularly in the southern states. RMSF is most commonly seen in wooded areas or those with high grasses (i.e., within rural and suburban regions), although the disease has also been reported in urban areas. The frequency of reported cases is highest in children younger than age 15 years and others who participate in recreational or occupational activities in tick-infested areas. In addition, males are more commonly affected than females. Individuals who live in such regions and who have frequent exposure to dogs may also have an increased risk. Evidence indicates that up to one-third of individuals diagnosed with RMSF do not remember having experienced a recent tick bite or tick contact. Several different types of hard-shelled ticks serve as “vectors” for the disease, carrying and transmitting the R. rickettsii bacterium to humans. A vector is any organism that may transmit a particular infectious agent, such as a bacterium or virus, to another organism. The primary vector for RMSF within the eastern two-thirds of the United States and the far west is the American dog tick (Dermacentor variabilis). The Rocky Mountain wood tick (Dermacentor andersoni) is the principal vector in the western United States and is also found in southwestern Canada. Other prevalent vectors include the brown dog tick (Rhipicephalus sanguineus) in Mexico and another species (Amblyomma cajennense) in Central and South America.According to the results of specialized blood studies (i.e., serologic assays) conducted among those residing in or exposed to tick-infested regions, some suggest that some individuals may develop antibodies in response to R. rickettsii infection without experiencing symptoms typically associated with RMSF (asymptomatic or subclinical infection). (Antibodies are specialized proteins that are an important part of the body's immune system. They are produced by certain white blood cells in response to typically foreign proteins [antigens], helping the body to neutralize or destroy invading microorganisms or other antigens.) However, researchers have questioned some of the methods used during such studies as well as whether the bacterium triggering the antibody response was indeed R. rickettsii rather than another rickettsial or other bacterium. Thus, it remains unclear whether subclinical infections occur with the R. rickettsii bacterium.As mentioned above, risk factors for severe RMSF include male sex, advanced age, and alcoholism. In addition, rare, fulminant RMSF is most frequently seen in black males with G6PD deficiency.
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Affects of Rocky Mountain Spotted Fever. Rocky Mountain spotted fever (RMSF) was first described in the late 1800s in Idaho. The disease was initially recognized as existing in only the Rocky Mountain (western) area of the United States. However, beginning in the 1930s, the disease was noted in other regions of the country. Currently, the frequency of the disease is higher in the west south-central region and the South Atlantic states than in the Rocky Mountain states. RMSF has been reported in almost every state as well as other countries, including Canada, Mexico, Brazil, Columbia, Costa Rica, and Panama. Most cases of RMSF occur between April to September, when outdoor activities are most frequent. However, some cases may occur in winter, particularly in the southern states. RMSF is most commonly seen in wooded areas or those with high grasses (i.e., within rural and suburban regions), although the disease has also been reported in urban areas. The frequency of reported cases is highest in children younger than age 15 years and others who participate in recreational or occupational activities in tick-infested areas. In addition, males are more commonly affected than females. Individuals who live in such regions and who have frequent exposure to dogs may also have an increased risk. Evidence indicates that up to one-third of individuals diagnosed with RMSF do not remember having experienced a recent tick bite or tick contact. Several different types of hard-shelled ticks serve as “vectors” for the disease, carrying and transmitting the R. rickettsii bacterium to humans. A vector is any organism that may transmit a particular infectious agent, such as a bacterium or virus, to another organism. The primary vector for RMSF within the eastern two-thirds of the United States and the far west is the American dog tick (Dermacentor variabilis). The Rocky Mountain wood tick (Dermacentor andersoni) is the principal vector in the western United States and is also found in southwestern Canada. Other prevalent vectors include the brown dog tick (Rhipicephalus sanguineus) in Mexico and another species (Amblyomma cajennense) in Central and South America.According to the results of specialized blood studies (i.e., serologic assays) conducted among those residing in or exposed to tick-infested regions, some suggest that some individuals may develop antibodies in response to R. rickettsii infection without experiencing symptoms typically associated with RMSF (asymptomatic or subclinical infection). (Antibodies are specialized proteins that are an important part of the body's immune system. They are produced by certain white blood cells in response to typically foreign proteins [antigens], helping the body to neutralize or destroy invading microorganisms or other antigens.) However, researchers have questioned some of the methods used during such studies as well as whether the bacterium triggering the antibody response was indeed R. rickettsii rather than another rickettsial or other bacterium. Thus, it remains unclear whether subclinical infections occur with the R. rickettsii bacterium.As mentioned above, risk factors for severe RMSF include male sex, advanced age, and alcoholism. In addition, rare, fulminant RMSF is most frequently seen in black males with G6PD deficiency.
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Rocky Mountain Spotted Fever
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nord_1079_4
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Related disorders of Rocky Mountain Spotted Fever
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Symptoms of the following disorders may be similar to those of Rocky Mountain spotted fever (RMSF). Comparisons may be useful for a differential diagnosis: In addition to the bacterium responsible for RMSF, there are several other bacteria belonging to the “Rickettsia” family (e.g., R. conorii, R. sibirica, R. japonica, R. australis, R. africae) that may cause infectious disease in humans (“spotted fever group rickettsioses”), including boutonneuse fever and African tick bite fever. In most cases, the bacteria responsible for the spotted fevers are thought to be carried and transmitted by certain ticks. The severity of the spotted fever rickettsioses may vary greatly. Some spotted fevers usually cause mild symptoms, while others may potentially lead to life-threatening complications. As noted above, RMSF is usually considered the most potentially severe form of the spotted fevers. Symptoms associated with spotted fever rickettsioses may include headache, fever, chills, muscle aches (myalgia), joint pain (arthralgia), extreme exhaustion (prostration), and/or a characteristic skin rash. In some cases, additional symptoms may include nausea, vomiting, abdominal pain, and/or other abnormalities. In addition, some forms of spotted fever are characterized by the formation of a characteristic, black, crusted-over blemish (tache noir) at the site of the tick bite. In some severe forms of spotted fever, damage to endothelial cells lining blood vessels may result in tissue injury of the heart, lungs, central nervous system, kidneys, liver, and/or other organs, leading to potentially life-threatening complications. Spotted fever rickettsioses have been reported in the United States, France, Spain, Italy, Australia, Israel, Russia, Japan, China, Pakistan, India, South Africa, and many other countries. Meningococcemia is an infectious disease caused by the bacterium Neisseria meningitidis in the bloodstream. Associated symptoms and findings may include fever, chills, headache, muscle and joint pain, extreme exhaustion, weakness, a rash that appears as “pin-point” reddish spots (petechia) due to localized bleeding (hemorrhaging), and/or low blood pressure (hypotension). In some severe cases, affected individuals may develop inflammation of the protective membranes around the brain and spinal cord (meningococcal meningitis). Associated symptoms may include the sudden onset of fever, chills, nausea, vomiting, and/or stiff neck, followed by confusion, drowsiness, and loss of consciousness. In such cases, life-threatening complications may result without immediate, appropriate treatment. (For more information on this disease, choose “meningococcemia” or “meningococcal meningitis” as your search term in the Rare Disease Database.) Measles is a common, highly contagious disease caused by a paramyxovirus. The disease, which primarily occurs in children, is usually transmitted by airborne droplets from an affected individual's nose, throat, or mouth. Initial symptoms may include fever, a general feeling of ill health (malaise), cough, sore throat, runny nose, and redness of the “whites” of the eyes (conjunctivitis). Small red spots with bluish or whitish centers may appear on the inside of the mouth (Koplik's spots). In addition, a characteristic red rash develops consisting of small, flat spots (macules) that soon become raised (papules). The rash typically initially develops on the skin around the ears, hairline, and neck and may spread to the trunk, arms, and legs. In addition, in some cases, affected individuals may experience abdominal pain, nausea, vomiting, diarrhea, and/or ear or chest infections. In rare, severe cases, affected individuals may develop inflammation of the brain (encephalitis).The ehrlichioses are rare infectious diseases caused by bacteria of the Ehrlichia family. Three forms of human ehrlichial infection have been identified, including human granulocytic ehrlichiosis (HGE), human monocytic ehrlichiosis (HME), and Sennetsu fever. The bacteria that cause HGE and HME are carried and transmitted by certain ticks. Cases of Sennetu fever, which have been limited to Malaysia and Western Japan, are thought to result from ingestion of raw fish. Though caused by different strains of Ehrlichia bacteria, the three disorders are characterized by similar symptoms. Such symptoms may include a sudden high fever, headache, muscle aches (myalgia), chills, a general feeling of ill health (malaise), and fatigue. Some affected individuals may also develop nausea, vomiting, sore throat, cough, diarrhea, loss of appetite, weight loss, and/or other symptoms. Rarely, a skin rash may appear. Laboratory testing may reveal abnormally low numbers of circulating blood platelets (thrombocytopenia), reduced numbers of white blood cells (leukopenia), and increased levels of certain liver enzymes. Without prompt, appropriate treatment, potentially life-threatening complications may occur in some cases. (For further information, choose “Ehrlichiosis” as your search term in the Rare Disease Database.)Toxic shock syndrome is a rare multisystemic disease caused by toxins produced by certain strains of the bacterium Staphylococcus aureus. Initial symptoms may include a sudden high fever, nausea, vomiting, diarrhea, headache, sore throat, and/or a characteristic widespread skin rash. With disease progression, affected individuals may develop abnormally low blood pressure (hypotension), confusion, abnormal liver function, and kidney failure. Without early diagnosis and appropriate treatment, life-threatening complications may result. Toxic shock syndrome is most common in menstruating women who use highly absorbent tampons. Other cases have been reported in association with postoperative wound infections, nasal packing, or other factors. (For more information on this disorder, choose “toxic shock” as your search term in the Rare Disease Database.)A number of additional infectious and non-infectious diseases may be associated with certain symptoms and findings similar to those potentially associated with RMSF. (For further information on such disorders, choose the exact disease name in question as your search term in the Rare Disease Database.)
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Related disorders of Rocky Mountain Spotted Fever. Symptoms of the following disorders may be similar to those of Rocky Mountain spotted fever (RMSF). Comparisons may be useful for a differential diagnosis: In addition to the bacterium responsible for RMSF, there are several other bacteria belonging to the “Rickettsia” family (e.g., R. conorii, R. sibirica, R. japonica, R. australis, R. africae) that may cause infectious disease in humans (“spotted fever group rickettsioses”), including boutonneuse fever and African tick bite fever. In most cases, the bacteria responsible for the spotted fevers are thought to be carried and transmitted by certain ticks. The severity of the spotted fever rickettsioses may vary greatly. Some spotted fevers usually cause mild symptoms, while others may potentially lead to life-threatening complications. As noted above, RMSF is usually considered the most potentially severe form of the spotted fevers. Symptoms associated with spotted fever rickettsioses may include headache, fever, chills, muscle aches (myalgia), joint pain (arthralgia), extreme exhaustion (prostration), and/or a characteristic skin rash. In some cases, additional symptoms may include nausea, vomiting, abdominal pain, and/or other abnormalities. In addition, some forms of spotted fever are characterized by the formation of a characteristic, black, crusted-over blemish (tache noir) at the site of the tick bite. In some severe forms of spotted fever, damage to endothelial cells lining blood vessels may result in tissue injury of the heart, lungs, central nervous system, kidneys, liver, and/or other organs, leading to potentially life-threatening complications. Spotted fever rickettsioses have been reported in the United States, France, Spain, Italy, Australia, Israel, Russia, Japan, China, Pakistan, India, South Africa, and many other countries. Meningococcemia is an infectious disease caused by the bacterium Neisseria meningitidis in the bloodstream. Associated symptoms and findings may include fever, chills, headache, muscle and joint pain, extreme exhaustion, weakness, a rash that appears as “pin-point” reddish spots (petechia) due to localized bleeding (hemorrhaging), and/or low blood pressure (hypotension). In some severe cases, affected individuals may develop inflammation of the protective membranes around the brain and spinal cord (meningococcal meningitis). Associated symptoms may include the sudden onset of fever, chills, nausea, vomiting, and/or stiff neck, followed by confusion, drowsiness, and loss of consciousness. In such cases, life-threatening complications may result without immediate, appropriate treatment. (For more information on this disease, choose “meningococcemia” or “meningococcal meningitis” as your search term in the Rare Disease Database.) Measles is a common, highly contagious disease caused by a paramyxovirus. The disease, which primarily occurs in children, is usually transmitted by airborne droplets from an affected individual's nose, throat, or mouth. Initial symptoms may include fever, a general feeling of ill health (malaise), cough, sore throat, runny nose, and redness of the “whites” of the eyes (conjunctivitis). Small red spots with bluish or whitish centers may appear on the inside of the mouth (Koplik's spots). In addition, a characteristic red rash develops consisting of small, flat spots (macules) that soon become raised (papules). The rash typically initially develops on the skin around the ears, hairline, and neck and may spread to the trunk, arms, and legs. In addition, in some cases, affected individuals may experience abdominal pain, nausea, vomiting, diarrhea, and/or ear or chest infections. In rare, severe cases, affected individuals may develop inflammation of the brain (encephalitis).The ehrlichioses are rare infectious diseases caused by bacteria of the Ehrlichia family. Three forms of human ehrlichial infection have been identified, including human granulocytic ehrlichiosis (HGE), human monocytic ehrlichiosis (HME), and Sennetsu fever. The bacteria that cause HGE and HME are carried and transmitted by certain ticks. Cases of Sennetu fever, which have been limited to Malaysia and Western Japan, are thought to result from ingestion of raw fish. Though caused by different strains of Ehrlichia bacteria, the three disorders are characterized by similar symptoms. Such symptoms may include a sudden high fever, headache, muscle aches (myalgia), chills, a general feeling of ill health (malaise), and fatigue. Some affected individuals may also develop nausea, vomiting, sore throat, cough, diarrhea, loss of appetite, weight loss, and/or other symptoms. Rarely, a skin rash may appear. Laboratory testing may reveal abnormally low numbers of circulating blood platelets (thrombocytopenia), reduced numbers of white blood cells (leukopenia), and increased levels of certain liver enzymes. Without prompt, appropriate treatment, potentially life-threatening complications may occur in some cases. (For further information, choose “Ehrlichiosis” as your search term in the Rare Disease Database.)Toxic shock syndrome is a rare multisystemic disease caused by toxins produced by certain strains of the bacterium Staphylococcus aureus. Initial symptoms may include a sudden high fever, nausea, vomiting, diarrhea, headache, sore throat, and/or a characteristic widespread skin rash. With disease progression, affected individuals may develop abnormally low blood pressure (hypotension), confusion, abnormal liver function, and kidney failure. Without early diagnosis and appropriate treatment, life-threatening complications may result. Toxic shock syndrome is most common in menstruating women who use highly absorbent tampons. Other cases have been reported in association with postoperative wound infections, nasal packing, or other factors. (For more information on this disorder, choose “toxic shock” as your search term in the Rare Disease Database.)A number of additional infectious and non-infectious diseases may be associated with certain symptoms and findings similar to those potentially associated with RMSF. (For further information on such disorders, choose the exact disease name in question as your search term in the Rare Disease Database.)
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Rocky Mountain Spotted Fever
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nord_1079_5
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Diagnosis of Rocky Mountain Spotted Fever
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Because its early symptoms and findings may be similar to those associated with many other infectious and non-infectious diseases, Rocky Mountain spotted fever (RMSF) may be difficult to diagnose in its early stages. The classic "triad" of the disease is fever, rash, and a history of tick bite. However, rash often is not present when affected individuals initially seek medical attention. In addition, as noted above, some do not recall recent tick exposure.According to the medical literature, a diagnosis of RMSF should be considered in any individual who has developed sudden unexplained high fever, severe headache, and extreme exhaustion (prostration) and who has recently been exposed to or resides in tick-infested regions, particularly in the spring or summer months. In addition, the appearance of a faint pinkish rash on the wrists and ankles subsequent to fever onset should suggest RMSF as a diagnosis. However, it is important to note that the initial skin rash may be overlooked in some cases and, again, that some affected individuals may not develop a rash during the course of R. rickettsii infection.In addition to a thorough clinical evaluation, specialized laboratory tests play an important role in helping to determine a diagnosis of RMSF and identifying specific abnormalities potentially associated with the infection. The findings revealed by certain laboratory tests may vary, depending upon the stage of the disease and the specific tissues and organ systems affected.For most affected individuals, during early stages of the disease, blood tests reveal that white blood cells are within normal levels. However, in some cases, the white blood cell count may be abnormally low or elevated. Abnormal laboratory findings that may be suggestive of RMSF as a possible diagnosis include low levels of circulating blood platelets (thrombocytopenia); elevated levels of certain liver enzymes; and low levels of sodium in the blood (hyponatremia). (The latter may result due to inappropriate secretion of the antidiuretic hormone [ADH] in reaction to hypovolemia; ADH acts on the kidneys to increase their reabsorption of water into the blood to maintain optimal water levels in the body.. As just noted, thrombocytopenia is a common finding; however, in only rare cases of RMSF, testing may reveal an abnormal reduction in certain additional elements (e.g., fibrinogen) that play a role in blood clotting (coagulation) due to their involvement in coagulation within blood vessels throughout the body (disseminated intravascular coagulation).Confirming the presence of the R. rickettsii bacterium is essential in making a firm diagnosis of RMSF. A diagnosis may be confirmed by specialized laboratory procedures in which the R. rickettsii bacterium is isolated from an affected individual's blood and cultivated (e.g., in cell culture). However, few laboratories undertake such diagnostic procedures.In most cases, specialized laboratory tests conducted on blood serum (serologic assays) are used to confirm a diagnosis of R. rickettsii infection. (Blood serum is the clear fluid that separates from blood on clotting. It contains no blood cells nor the protein that helps blood clotting [fibrinogen]; it does contain glucose, various antibodies, and other proteins.. Indirect immunofluorescence assay (IFA) is the serologic test that is most commonly used and considered the most specific and sensitive for confirming RMSF. With IFA, specific antibodies are labeled with special fluorescent dyes and a microscope that projects ultraviolet light is used, enabling researchers to observe antibody response to certain microorganisms. Diagnostic rises in antibody response to the R. rickettsii bacterium usually are not detected until approximately seven to 14 days after the disease's onset, with peak antibody levels typically occurring at about two to three weeks. Therefore, diagnostic antibody levels typically are not present within the initial five days of symptoms, when antibiotic therapy should be begun (see "Treatment" below). (In addition, individuals who receive treatment within 48 hours after symptom onset may have a reduced antibody response.)In some cases, if affected individuals develop a rash, small samples of skin tissue may be removed (biopsied) and microscopically examined (e.g., via direct immunofluorescence or immunoenzyme staining) before antibiotic therapy is initiated or within the first 48 hours of such therapy, potentially confirming RMSF during acute illness. However, because the bacteria are locally distributed within the skin lesions, this diagnostic method may not detect R. rickettsii in all patients (i.e., 70 percent sensitivity). In addition, it is not as widely available as IFA.
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Diagnosis of Rocky Mountain Spotted Fever. Because its early symptoms and findings may be similar to those associated with many other infectious and non-infectious diseases, Rocky Mountain spotted fever (RMSF) may be difficult to diagnose in its early stages. The classic "triad" of the disease is fever, rash, and a history of tick bite. However, rash often is not present when affected individuals initially seek medical attention. In addition, as noted above, some do not recall recent tick exposure.According to the medical literature, a diagnosis of RMSF should be considered in any individual who has developed sudden unexplained high fever, severe headache, and extreme exhaustion (prostration) and who has recently been exposed to or resides in tick-infested regions, particularly in the spring or summer months. In addition, the appearance of a faint pinkish rash on the wrists and ankles subsequent to fever onset should suggest RMSF as a diagnosis. However, it is important to note that the initial skin rash may be overlooked in some cases and, again, that some affected individuals may not develop a rash during the course of R. rickettsii infection.In addition to a thorough clinical evaluation, specialized laboratory tests play an important role in helping to determine a diagnosis of RMSF and identifying specific abnormalities potentially associated with the infection. The findings revealed by certain laboratory tests may vary, depending upon the stage of the disease and the specific tissues and organ systems affected.For most affected individuals, during early stages of the disease, blood tests reveal that white blood cells are within normal levels. However, in some cases, the white blood cell count may be abnormally low or elevated. Abnormal laboratory findings that may be suggestive of RMSF as a possible diagnosis include low levels of circulating blood platelets (thrombocytopenia); elevated levels of certain liver enzymes; and low levels of sodium in the blood (hyponatremia). (The latter may result due to inappropriate secretion of the antidiuretic hormone [ADH] in reaction to hypovolemia; ADH acts on the kidneys to increase their reabsorption of water into the blood to maintain optimal water levels in the body.. As just noted, thrombocytopenia is a common finding; however, in only rare cases of RMSF, testing may reveal an abnormal reduction in certain additional elements (e.g., fibrinogen) that play a role in blood clotting (coagulation) due to their involvement in coagulation within blood vessels throughout the body (disseminated intravascular coagulation).Confirming the presence of the R. rickettsii bacterium is essential in making a firm diagnosis of RMSF. A diagnosis may be confirmed by specialized laboratory procedures in which the R. rickettsii bacterium is isolated from an affected individual's blood and cultivated (e.g., in cell culture). However, few laboratories undertake such diagnostic procedures.In most cases, specialized laboratory tests conducted on blood serum (serologic assays) are used to confirm a diagnosis of R. rickettsii infection. (Blood serum is the clear fluid that separates from blood on clotting. It contains no blood cells nor the protein that helps blood clotting [fibrinogen]; it does contain glucose, various antibodies, and other proteins.. Indirect immunofluorescence assay (IFA) is the serologic test that is most commonly used and considered the most specific and sensitive for confirming RMSF. With IFA, specific antibodies are labeled with special fluorescent dyes and a microscope that projects ultraviolet light is used, enabling researchers to observe antibody response to certain microorganisms. Diagnostic rises in antibody response to the R. rickettsii bacterium usually are not detected until approximately seven to 14 days after the disease's onset, with peak antibody levels typically occurring at about two to three weeks. Therefore, diagnostic antibody levels typically are not present within the initial five days of symptoms, when antibiotic therapy should be begun (see "Treatment" below). (In addition, individuals who receive treatment within 48 hours after symptom onset may have a reduced antibody response.)In some cases, if affected individuals develop a rash, small samples of skin tissue may be removed (biopsied) and microscopically examined (e.g., via direct immunofluorescence or immunoenzyme staining) before antibiotic therapy is initiated or within the first 48 hours of such therapy, potentially confirming RMSF during acute illness. However, because the bacteria are locally distributed within the skin lesions, this diagnostic method may not detect R. rickettsii in all patients (i.e., 70 percent sensitivity). In addition, it is not as widely available as IFA.
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Rocky Mountain Spotted Fever
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nord_1079_6
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Therapies of Rocky Mountain Spotted Fever
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TreatmentEvidence indicates that beginning treatment within the first five days of symptoms is essential, since delaying therapy carries an increased risk of life-threatening complications. Thus, appropriate antibiotic therapy should be begun immediately when a diagnosis of RMSF is clinically suspected and should not be delayed until definitive laboratory findings are available.The treatment of choice for both children and most adults is administration of the antibiotic tetracycline doxycycline. Although tetracycline agents can cause teeth staining in young children, the risk is minimal with a short course of doxycycline. Therapy with the antibiotic agent chloramphenicol is recommended for women who are pregnant (due to the potential effects of tetracycline agents on fetal bone development) and as an alternative for other patients who are unable to receive tetracycline antibiotics (e.g., due to allergy). Antibiotic therapy for RMSF is usually administered for five to seven days, continuing for at least three days after the fever abates. If an affected individual is treated with appropriate antibiotic therapy within the first three to five days of illness, the fever usually subsides within two to three days. However, for those who are severely ill, the fever may take longer to subside on appropriate antibiotic therapy.In many cases, antibiotic medications may be given by mouth (orally). However, when affected individuals are experiencing nausea or vomiting or are seriously ill, medications may be administered by infusion through veins (intravenously).Individuals who are severely ill require hospitalization and intensive supportive care. Such measures include careful administration of fluids and monitoring of blood flow (hemodynamics) to obtain appropriate restoration of fluid content without causing abnormal fluid accumulation within lung tissues and air spaces (pulmonary edema) due to increased vascular permeability. Seriously ill individuals who have low levels of circulating oxygen in the blood (hypoxemia) may require the use of a machine to deliver oxygen to the lungs (mechanical ventilation). In some cases, acute kidney failure may necessitate hemodialysis, a procedure in which excess waste products are removed from the blood by filtering the blood through a machine. Transfusion of red blood cells may be required for those who have abnormally low levels of the oxygen-carrying component of red blood cells (anemia) or who experience severe bleeding (hemorrhaging). In some cases, severely reduced levels of circulating blood platelets (thrombocytopenia) and hemorrhaging may necessitate platelet transfusions. In addition, individuals with neurologic involvement who experience seizures may require the administration of medications that prevent or help to control such seizure episodes (anticonvulsants). In extremely severe cases of restricted oxygenated blood supply to certain tissues (ischemia) and associated tissue loss and decay (gangrene), certain affected areas (e.g., fingers, toes, limbs) may need to be surgically removed (amputated).Those who receive appropriate, timely treatment generally have a complete recovery. However, a small percentage of those with severe RMSF may have long-term health problems following the disease, such as hearing loss, muscle weakness or partial paralysis of one side of the body (hemiparesis), incontinence, and/or other abnormalities. Other treatment for this disease is symptomatic and supportive.PreventionIndividuals who will be exposed to areas with high numbers of tick vectors for the R. rickettsii bacterium (e.g., fields, wooded or marsh areas, etc.) should consider taking certain steps to prevent infection. Such steps include using appropriate tick repellents; wearing long-sleeved shirts, long pants, and hats; wearing light-colored clothing to make ticks more visible; and tucking pants into socks or boots. In addition, it is important to carefully check clothing and the body (including scalp, pubic, and underarm hair) after being in such locations. If engorged ticks are discovered, they must be removed with caution, such as with the use of fine-tipped tweezers. They should not be crushed between the fingers, since this has been associated with disease transmission.Preventive (prophylactic) antibiotic therapy is not advised for individuals with known tick bites. However, such individuals should immediately seek medical attention should they develop any generalized symptoms, particularly fever and headache, within the two weeks following the recent tick bite.
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Therapies of Rocky Mountain Spotted Fever. TreatmentEvidence indicates that beginning treatment within the first five days of symptoms is essential, since delaying therapy carries an increased risk of life-threatening complications. Thus, appropriate antibiotic therapy should be begun immediately when a diagnosis of RMSF is clinically suspected and should not be delayed until definitive laboratory findings are available.The treatment of choice for both children and most adults is administration of the antibiotic tetracycline doxycycline. Although tetracycline agents can cause teeth staining in young children, the risk is minimal with a short course of doxycycline. Therapy with the antibiotic agent chloramphenicol is recommended for women who are pregnant (due to the potential effects of tetracycline agents on fetal bone development) and as an alternative for other patients who are unable to receive tetracycline antibiotics (e.g., due to allergy). Antibiotic therapy for RMSF is usually administered for five to seven days, continuing for at least three days after the fever abates. If an affected individual is treated with appropriate antibiotic therapy within the first three to five days of illness, the fever usually subsides within two to three days. However, for those who are severely ill, the fever may take longer to subside on appropriate antibiotic therapy.In many cases, antibiotic medications may be given by mouth (orally). However, when affected individuals are experiencing nausea or vomiting or are seriously ill, medications may be administered by infusion through veins (intravenously).Individuals who are severely ill require hospitalization and intensive supportive care. Such measures include careful administration of fluids and monitoring of blood flow (hemodynamics) to obtain appropriate restoration of fluid content without causing abnormal fluid accumulation within lung tissues and air spaces (pulmonary edema) due to increased vascular permeability. Seriously ill individuals who have low levels of circulating oxygen in the blood (hypoxemia) may require the use of a machine to deliver oxygen to the lungs (mechanical ventilation). In some cases, acute kidney failure may necessitate hemodialysis, a procedure in which excess waste products are removed from the blood by filtering the blood through a machine. Transfusion of red blood cells may be required for those who have abnormally low levels of the oxygen-carrying component of red blood cells (anemia) or who experience severe bleeding (hemorrhaging). In some cases, severely reduced levels of circulating blood platelets (thrombocytopenia) and hemorrhaging may necessitate platelet transfusions. In addition, individuals with neurologic involvement who experience seizures may require the administration of medications that prevent or help to control such seizure episodes (anticonvulsants). In extremely severe cases of restricted oxygenated blood supply to certain tissues (ischemia) and associated tissue loss and decay (gangrene), certain affected areas (e.g., fingers, toes, limbs) may need to be surgically removed (amputated).Those who receive appropriate, timely treatment generally have a complete recovery. However, a small percentage of those with severe RMSF may have long-term health problems following the disease, such as hearing loss, muscle weakness or partial paralysis of one side of the body (hemiparesis), incontinence, and/or other abnormalities. Other treatment for this disease is symptomatic and supportive.PreventionIndividuals who will be exposed to areas with high numbers of tick vectors for the R. rickettsii bacterium (e.g., fields, wooded or marsh areas, etc.) should consider taking certain steps to prevent infection. Such steps include using appropriate tick repellents; wearing long-sleeved shirts, long pants, and hats; wearing light-colored clothing to make ticks more visible; and tucking pants into socks or boots. In addition, it is important to carefully check clothing and the body (including scalp, pubic, and underarm hair) after being in such locations. If engorged ticks are discovered, they must be removed with caution, such as with the use of fine-tipped tweezers. They should not be crushed between the fingers, since this has been associated with disease transmission.Preventive (prophylactic) antibiotic therapy is not advised for individuals with known tick bites. However, such individuals should immediately seek medical attention should they develop any generalized symptoms, particularly fever and headache, within the two weeks following the recent tick bite.
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Rocky Mountain Spotted Fever
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nord_1080_0
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Overview of Rosai-Dorfman Disease
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Rosai-Dorfman disease is a rare disorder characterized by overproduction (proliferation) and accumulation of a specific type of white blood cell (histiocyte) in the lymph nodes of the body (lymphadenopathy), most often those of the neck (cervical lymphadenopathy). In some cases, abnormal accumulation of histiocytes may occur in other areas of the body besides the lymph nodes (extranodal). These areas include the skin, central nervous system, kidney, and digestive tract. The symptoms and physical findings associated with Rosai-Dorfman disease vary depending upon the specific areas of the body that are affected. The disorder predominantly affects children, adolescents or young adults. The exact cause of Rosai-Dorfman disease is unknown.
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Overview of Rosai-Dorfman Disease. Rosai-Dorfman disease is a rare disorder characterized by overproduction (proliferation) and accumulation of a specific type of white blood cell (histiocyte) in the lymph nodes of the body (lymphadenopathy), most often those of the neck (cervical lymphadenopathy). In some cases, abnormal accumulation of histiocytes may occur in other areas of the body besides the lymph nodes (extranodal). These areas include the skin, central nervous system, kidney, and digestive tract. The symptoms and physical findings associated with Rosai-Dorfman disease vary depending upon the specific areas of the body that are affected. The disorder predominantly affects children, adolescents or young adults. The exact cause of Rosai-Dorfman disease is unknown.
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Rosai-Dorfman Disease
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nord_1080_1
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Symptoms of Rosai-Dorfman Disease
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The symptoms and physical findings associated with Rosai-Dorfman disease vary greatly from one person to another depending upon the extent of the disorder and the specific organ systems affected. Some cases may only affect the lymph nodes and may not cause any serious complications. Less often, some cases may affect various organ systems of the body and may potentially cause serious complications. Any organ system of the body may become affected.In most cases, affected individuals exhibit painless swelling or enlargement of affected lymph nodes (lymphadenopathy), most often those of the neck (cervical lymphadenopathy). Many individuals with Rosai-Dorfman disease do not develop any additional symptoms of the disorder (asymptomatic). In some cases, affected individual may experience nonspecific symptoms that are common to many different conditions including fever, paleness of the skin (pallor), unintended weight loss, a general feeling of ill health (malaise) and a chronically runny nose (rhinitis). In extremely rare cases, affected individuals may experience abnormal enlargement of the liver and/or spleen (hepatosplenomegaly). In approximately 43 percent of cases, other areas of the body besides the lymph nodes may also be affected (extranodal). Some individuals may have extranodal disease without the presence of lymphadenopathy. The skin is the most common extranodal site. Skin lesions associated with Rosai-Dorfman disease are usually yellow or purple. A reddish rash-like inflammation of the skin (erythema), small solid elevations on the skin (papules), or knots visible under the skin (nodules) may be present. Skin lesions may occur anywhere on the body, but most often affect the head and neck. In some cases, skin abnormalities precede the development of lymphadenopathy.The salivary glands, nasal cavity, upper respiratory tract, various bones, and the eyes and eye sockets (orbits) may also be affected. In rare cases, the central nervous system, digestive system, or the kidneys may be affected. Involvement of these areas may result in additional (secondary) symptoms. For example, loss of vision may occur secondary to the involvement of the eyes, and seizures may occur secondary to involvement of the central nervous system. In some cases of Rosai-Dorfman disease, the accumulation of histiocytes into masses may cause compression of vital organs potentially resulting in serious complications.In some cases, the lymph nodes may not be affected. Instead a specific area of the body such as the skin, a solitary bone, or the central nervous system may be affected. These cases may be known as isolated Rosai-Dorfman disease. A distinct type of isolated Rosai-Dorfman disease has been identified called cutaneous Rosai-Dorfman disease, in which only the skin is affected. Initial reports indicate that cutaneous Rosai-Dorfman disease is more common in female adults.
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Symptoms of Rosai-Dorfman Disease. The symptoms and physical findings associated with Rosai-Dorfman disease vary greatly from one person to another depending upon the extent of the disorder and the specific organ systems affected. Some cases may only affect the lymph nodes and may not cause any serious complications. Less often, some cases may affect various organ systems of the body and may potentially cause serious complications. Any organ system of the body may become affected.In most cases, affected individuals exhibit painless swelling or enlargement of affected lymph nodes (lymphadenopathy), most often those of the neck (cervical lymphadenopathy). Many individuals with Rosai-Dorfman disease do not develop any additional symptoms of the disorder (asymptomatic). In some cases, affected individual may experience nonspecific symptoms that are common to many different conditions including fever, paleness of the skin (pallor), unintended weight loss, a general feeling of ill health (malaise) and a chronically runny nose (rhinitis). In extremely rare cases, affected individuals may experience abnormal enlargement of the liver and/or spleen (hepatosplenomegaly). In approximately 43 percent of cases, other areas of the body besides the lymph nodes may also be affected (extranodal). Some individuals may have extranodal disease without the presence of lymphadenopathy. The skin is the most common extranodal site. Skin lesions associated with Rosai-Dorfman disease are usually yellow or purple. A reddish rash-like inflammation of the skin (erythema), small solid elevations on the skin (papules), or knots visible under the skin (nodules) may be present. Skin lesions may occur anywhere on the body, but most often affect the head and neck. In some cases, skin abnormalities precede the development of lymphadenopathy.The salivary glands, nasal cavity, upper respiratory tract, various bones, and the eyes and eye sockets (orbits) may also be affected. In rare cases, the central nervous system, digestive system, or the kidneys may be affected. Involvement of these areas may result in additional (secondary) symptoms. For example, loss of vision may occur secondary to the involvement of the eyes, and seizures may occur secondary to involvement of the central nervous system. In some cases of Rosai-Dorfman disease, the accumulation of histiocytes into masses may cause compression of vital organs potentially resulting in serious complications.In some cases, the lymph nodes may not be affected. Instead a specific area of the body such as the skin, a solitary bone, or the central nervous system may be affected. These cases may be known as isolated Rosai-Dorfman disease. A distinct type of isolated Rosai-Dorfman disease has been identified called cutaneous Rosai-Dorfman disease, in which only the skin is affected. Initial reports indicate that cutaneous Rosai-Dorfman disease is more common in female adults.
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Rosai-Dorfman Disease
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nord_1080_2
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Causes of Rosai-Dorfman Disease
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The exact cause of Rosai-Dorfman disease is unknown (idiopathic), but it does not seem to be of neoplastic nature. Researchers have suggested that the disorder may be caused by an infectious agent, immunodeficiency, or autoimmunity. Symptoms of Rosai-Dorfman disease develop due to the overproduction and accumulation of histiocytes in the channels (sinuses) that allow for the passage of lymph (sinus histiocytosis).
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Causes of Rosai-Dorfman Disease. The exact cause of Rosai-Dorfman disease is unknown (idiopathic), but it does not seem to be of neoplastic nature. Researchers have suggested that the disorder may be caused by an infectious agent, immunodeficiency, or autoimmunity. Symptoms of Rosai-Dorfman disease develop due to the overproduction and accumulation of histiocytes in the channels (sinuses) that allow for the passage of lymph (sinus histiocytosis).
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Affects of Rosai-Dorfman Disease
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Some studies suggest that Rosai-Dorfman disease affects males more often than females. The disorder can affected individuals of any age, but most often affects young adults under the age of 20. Cutaneous Rosai-Dorfman disease occurs more often in females in their 20s or 30s. More than 650 cases have been reported in the medical literature since the disorder's first description in the medical literature in 1969.
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Affects of Rosai-Dorfman Disease. Some studies suggest that Rosai-Dorfman disease affects males more often than females. The disorder can affected individuals of any age, but most often affects young adults under the age of 20. Cutaneous Rosai-Dorfman disease occurs more often in females in their 20s or 30s. More than 650 cases have been reported in the medical literature since the disorder's first description in the medical literature in 1969.
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Related disorders of Rosai-Dorfman Disease
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Symptoms of the following disorders can be similar to those of Rosai-Dorfman disease. Comparisons may be useful for a differential diagnosis: Langerhans cell histiocytosis (LCH) is a rare spectrum of disorders characterized by over-production (proliferation) and accumulation of a specific type of white blood cell (histiocyte) in the various tissues and organs of the body (lesions). Associated symptoms and findings may vary from case to case, depending upon the specific tissues and organs affected and the extent of involvement. Most affected individuals have single or multiple bone lesions characterized by degenerative changes and loss of the calcium of bone (osteolysis). Although the skull is most commonly affected, there may also be involvement of other bones, such as those of the spine (vertebrae) and the long bones of the arms and legs. Affected individuals may have no apparent symptoms (asymptomatic), experience associated pain and swelling, and/or develop certain complications, such as fractures or secondary compression of the spinal cord. In some cases, other tissues and organs may also be affected, including the skin, lungs, or other areas. In some individuals, LCH may be associated with involvement of the pituitary gland leading to diabetes insipidus. The exact cause of Langerhans cell histiocytosis is unknown. (For more information on this disorder, choose “Langerhans cell histiocytosis” as your search term in the Rare Disease Database.) Meningiomas are benign, slow-growing tumors, classified as brain tumors, but actually growing in the three protective membranes that surround the brain (meninges). Sometimes they cause thickening or thinning of adjoining skull bones. Meningiomas do not spread to other areas of the body. Symptoms of meningiomas vary according to the size and location of the tumor and may include progressive weakness on one side of the body or in a localized area such as a leg, seizures that may be limited to one area (focal), or generalized, and mental changes. Some cases of Rosai-Dorfman disease that affect the central nervous system may resemble meningiomas. (For more information on this disorder, choose “Meningioma” as your search term in the Rare Disease Database.) Lymphoma is a general term for a group of cancers affecting the lymphatic system. Functioning as part of the immune system, the lymphatic system 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. Abnormal enlargement of the lymph nodes, liver, and spleen may occur. A malignant lymphoma may spread to affect other areas of the body such as the central nervous system and gastrointestinal tract. Affected individuals may experience fevers, fatigue, and weight loss. Lymphoma may be slow-growing or rapidly-growing. The main two types of lymphoma are Hodgkin lymphoma and non-Hodgkin lymphoma. (For more information on lymphoma, choose “lymphoma” as your search term in the Rare Disease Database.)Lyme disease is an infectious disease caused by the spirochete bacterium Borrelia burgdorferi. The bacterium is carried and transmitted by deer ticks (Ixodes scapularis). In most cases, Lyme disease is first characterized by the appearance of a red skin lesion (erythema chronicum migrans), which begins as a small elevated round spot (papule) that expands to at least five centimeters in diameter. Symptoms may then progress to include low-grade fever, chills, muscle aches (myalgia), headaches, a general feeling of weakness and fatigue (malaise), and/or pain and stiffness of the large joints (infectious arthritis), especially in the knees. Such symptoms may tend to occur in recurrent cycles. In severe cases, heart muscle (myocardial) and/or neurological abnormalities may occur. (For more information, choose “Lyme disease” as your search term in the Rare Disease Database.)
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Related disorders of Rosai-Dorfman Disease. Symptoms of the following disorders can be similar to those of Rosai-Dorfman disease. Comparisons may be useful for a differential diagnosis: Langerhans cell histiocytosis (LCH) is a rare spectrum of disorders characterized by over-production (proliferation) and accumulation of a specific type of white blood cell (histiocyte) in the various tissues and organs of the body (lesions). Associated symptoms and findings may vary from case to case, depending upon the specific tissues and organs affected and the extent of involvement. Most affected individuals have single or multiple bone lesions characterized by degenerative changes and loss of the calcium of bone (osteolysis). Although the skull is most commonly affected, there may also be involvement of other bones, such as those of the spine (vertebrae) and the long bones of the arms and legs. Affected individuals may have no apparent symptoms (asymptomatic), experience associated pain and swelling, and/or develop certain complications, such as fractures or secondary compression of the spinal cord. In some cases, other tissues and organs may also be affected, including the skin, lungs, or other areas. In some individuals, LCH may be associated with involvement of the pituitary gland leading to diabetes insipidus. The exact cause of Langerhans cell histiocytosis is unknown. (For more information on this disorder, choose “Langerhans cell histiocytosis” as your search term in the Rare Disease Database.) Meningiomas are benign, slow-growing tumors, classified as brain tumors, but actually growing in the three protective membranes that surround the brain (meninges). Sometimes they cause thickening or thinning of adjoining skull bones. Meningiomas do not spread to other areas of the body. Symptoms of meningiomas vary according to the size and location of the tumor and may include progressive weakness on one side of the body or in a localized area such as a leg, seizures that may be limited to one area (focal), or generalized, and mental changes. Some cases of Rosai-Dorfman disease that affect the central nervous system may resemble meningiomas. (For more information on this disorder, choose “Meningioma” as your search term in the Rare Disease Database.) Lymphoma is a general term for a group of cancers affecting the lymphatic system. Functioning as part of the immune system, the lymphatic system 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. Abnormal enlargement of the lymph nodes, liver, and spleen may occur. A malignant lymphoma may spread to affect other areas of the body such as the central nervous system and gastrointestinal tract. Affected individuals may experience fevers, fatigue, and weight loss. Lymphoma may be slow-growing or rapidly-growing. The main two types of lymphoma are Hodgkin lymphoma and non-Hodgkin lymphoma. (For more information on lymphoma, choose “lymphoma” as your search term in the Rare Disease Database.)Lyme disease is an infectious disease caused by the spirochete bacterium Borrelia burgdorferi. The bacterium is carried and transmitted by deer ticks (Ixodes scapularis). In most cases, Lyme disease is first characterized by the appearance of a red skin lesion (erythema chronicum migrans), which begins as a small elevated round spot (papule) that expands to at least five centimeters in diameter. Symptoms may then progress to include low-grade fever, chills, muscle aches (myalgia), headaches, a general feeling of weakness and fatigue (malaise), and/or pain and stiffness of the large joints (infectious arthritis), especially in the knees. Such symptoms may tend to occur in recurrent cycles. In severe cases, heart muscle (myocardial) and/or neurological abnormalities may occur. (For more information, choose “Lyme disease” as your search term in the Rare Disease Database.)
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Diagnosis of Rosai-Dorfman Disease
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The diagnosis of Rosai-Dorfman disease may be confirmed by a thorough clinical evaluation, a detailed patient history and a variety of specialized tests, such as surgical removal and microscopic examination of affected tissue (biopsy).
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Diagnosis of Rosai-Dorfman Disease. The diagnosis of Rosai-Dorfman disease may be confirmed by a thorough clinical evaluation, a detailed patient history and a variety of specialized tests, such as surgical removal and microscopic examination of affected tissue (biopsy).
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Therapies of Rosai-Dorfman Disease
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TreatmentIn many cases, the symptoms of Rosai-Dorfman disease may disappear without treatment (spontaneous remission) within in months or a few years. Clinical observation without treatment is preferred for individuals with Rosai-Dorfman disease whenever possible. In many cases, no therapy will be necessary.In some cases, various treatment options may become necessary. In these cases, the treatment of Rosai-Dorfman disease is directed toward the specific symptoms that are apparent in each individual. Several different treatment options have been used to treat individuals with Rosai-Dorfman disease including surgical removal of histiocytic lesions. In more serious cases, additional treatment options have included therapy with certain drugs including steroids (e.g., prednisone), alfa-interferon, and a regimen of certain anticancer drugs (chemotherapy). In some cases, affected individuals have shown improvement of symptoms with these treatments. In other cases, drug therapies have been ineffective.Other treatment is symptomatic and supportive.
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Therapies of Rosai-Dorfman Disease. TreatmentIn many cases, the symptoms of Rosai-Dorfman disease may disappear without treatment (spontaneous remission) within in months or a few years. Clinical observation without treatment is preferred for individuals with Rosai-Dorfman disease whenever possible. In many cases, no therapy will be necessary.In some cases, various treatment options may become necessary. In these cases, the treatment of Rosai-Dorfman disease is directed toward the specific symptoms that are apparent in each individual. Several different treatment options have been used to treat individuals with Rosai-Dorfman disease including surgical removal of histiocytic lesions. In more serious cases, additional treatment options have included therapy with certain drugs including steroids (e.g., prednisone), alfa-interferon, and a regimen of certain anticancer drugs (chemotherapy). In some cases, affected individuals have shown improvement of symptoms with these treatments. In other cases, drug therapies have been ineffective.Other treatment is symptomatic and supportive.
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Overview of Rosenberg Chutorian Syndrome
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Rosenberg-Chutorian syndrome is an extremely rare genetic disorder characterized by the triad of hearing loss, degeneration of the optic nerve (optic atrophy) and neurological abnormalities, specifically disease of the nerves outside of the central nervous system (peripheral neuropathy). The arms and legs are most often affected by peripheral neuropathy. Rosenberg-Chutorian syndrome is inherited as an X-linked disorder with occasional mild symptoms present in the female carrier.At least two other disorders are characterized by optic atrophy, hearing loss and peripheral neuropathy: Iwashita syndrome and Hagemoser syndrome. Most researchers consider these two disorders and Rosenberg-Chutorian syndrome separate disorders.
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Overview of Rosenberg Chutorian Syndrome. Rosenberg-Chutorian syndrome is an extremely rare genetic disorder characterized by the triad of hearing loss, degeneration of the optic nerve (optic atrophy) and neurological abnormalities, specifically disease of the nerves outside of the central nervous system (peripheral neuropathy). The arms and legs are most often affected by peripheral neuropathy. Rosenberg-Chutorian syndrome is inherited as an X-linked disorder with occasional mild symptoms present in the female carrier.At least two other disorders are characterized by optic atrophy, hearing loss and peripheral neuropathy: Iwashita syndrome and Hagemoser syndrome. Most researchers consider these two disorders and Rosenberg-Chutorian syndrome separate disorders.
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Symptoms of Rosenberg Chutorian Syndrome
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The symptoms of Rosenberg-Chutorian syndrome often become apparent during infancy or early childhood. The clinical triad of hearing loss, optic atrophy, and peripheral neuropathy characterizes the disorder. Individuals with Rosenberg-Chutorian syndrome develop sensorineural hearing loss. In people with type of hearing impairment, sound may be conducted normally through the external and middle ear. However, sound vibrations are not properly transmitted to the brain due to a defect of the inner ear or the auditory nerve, resulting in hearing loss. (With normal hearing, a portion of the inner ear serves to convert sound vibrations to nerve impulses, which are then transmitted via the auditory nerve to the brain.) Although such sensorineural hearing loss is usually present at birth, it may not be detected until later during infancy. As affected children age, deafness may cause delays or impairment in speech development. Hearing loss may be slowly progressive.Individuals with Rosenberg-Chutorian syndrome also develop degeneration (atrophy) of the optic nerve (optic atrophy). The optic nerve is the structure that sends electrical impulses from the retina to the brain. Optic atrophy results in the loss of visual acuity. Noninflammatory disease affecting many nerves (polyneuropathy) is another sign of Rosenberg-Chutorian syndrome. The nerves outside the central nervous system, especially those of the arms and legs are affected (peripheral neuropathy). Individuals may develop weakness and wasting (atrophy) of the muscles in the arms and legs. Destruction of the fatty covering surrounding nerves (demyelination) has been present in a few affected individuals.
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Symptoms of Rosenberg Chutorian Syndrome. The symptoms of Rosenberg-Chutorian syndrome often become apparent during infancy or early childhood. The clinical triad of hearing loss, optic atrophy, and peripheral neuropathy characterizes the disorder. Individuals with Rosenberg-Chutorian syndrome develop sensorineural hearing loss. In people with type of hearing impairment, sound may be conducted normally through the external and middle ear. However, sound vibrations are not properly transmitted to the brain due to a defect of the inner ear or the auditory nerve, resulting in hearing loss. (With normal hearing, a portion of the inner ear serves to convert sound vibrations to nerve impulses, which are then transmitted via the auditory nerve to the brain.) Although such sensorineural hearing loss is usually present at birth, it may not be detected until later during infancy. As affected children age, deafness may cause delays or impairment in speech development. Hearing loss may be slowly progressive.Individuals with Rosenberg-Chutorian syndrome also develop degeneration (atrophy) of the optic nerve (optic atrophy). The optic nerve is the structure that sends electrical impulses from the retina to the brain. Optic atrophy results in the loss of visual acuity. Noninflammatory disease affecting many nerves (polyneuropathy) is another sign of Rosenberg-Chutorian syndrome. The nerves outside the central nervous system, especially those of the arms and legs are affected (peripheral neuropathy). Individuals may develop weakness and wasting (atrophy) of the muscles in the arms and legs. Destruction of the fatty covering surrounding nerves (demyelination) has been present in a few affected individuals.
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Causes of Rosenberg Chutorian Syndrome
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Rosenberg-Chutorian syndrome is caused by a mutation in the phosphoribosylpyrophosphate synthetase I (PRPS1) gene located on the X chromosome.Rosenberg-Chutorian syndrome is inherited as an X-linked disorder. X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and occur mostly in males. Females that have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and one is inactivated so that the genes on that chromosome are nonfunctioning. It is usually the X chromosome with the abnormal gene that is inactivated. However, some females who carry a PRPS1 gene mutation show variably mild symptoms. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a disease gene he will develop the disease. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son. Males with X-linked disorders pass the disease gene to all of their daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.
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Causes of Rosenberg Chutorian Syndrome. Rosenberg-Chutorian syndrome is caused by a mutation in the phosphoribosylpyrophosphate synthetase I (PRPS1) gene located on the X chromosome.Rosenberg-Chutorian syndrome is inherited as an X-linked disorder. X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and occur mostly in males. Females that have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and one is inactivated so that the genes on that chromosome are nonfunctioning. It is usually the X chromosome with the abnormal gene that is inactivated. However, some females who carry a PRPS1 gene mutation show variably mild symptoms. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a disease gene he will develop the disease. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son. Males with X-linked disorders pass the disease gene to all of their daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.
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Affects of Rosenberg Chutorian Syndrome
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Rosenberg-Chutorian syndrome is a rare genetic disorder that affects males more often than females. Symptoms are more severe in males. Some carrier females may exhibit symptoms of the disorder. Fewer than 10 cases have been reported in the medical literature. The disorder was first described in the medical literature in 1967.
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Affects of Rosenberg Chutorian Syndrome. Rosenberg-Chutorian syndrome is a rare genetic disorder that affects males more often than females. Symptoms are more severe in males. Some carrier females may exhibit symptoms of the disorder. Fewer than 10 cases have been reported in the medical literature. The disorder was first described in the medical literature in 1967.
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Related disorders of Rosenberg Chutorian Syndrome
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Symptoms of the following disorders can be similar to those of Rosenberg-Chutorian syndrome. Comparisons may be useful for a differential diagnosis: Iwashita syndrome is an extremely rare disorder characterized by optic atrophy, hearing loss and progressive disease of the many nerves (polyneuropathy). Fewer than 10 cases of Iwashita syndrome have been reported in the medical literature. Iwashita syndrome is differentiated from Rosenberg-Chutorian syndrome by mode of inheritance. Iwashita syndrome is inherited as an autosomal recessive trait. Hagemoser syndrome is an extremely rare disorder characterized by optic atrophy, hearing loss, and disease affecting the nerves outside of the central nervous system (peripheral neuropathy). Fewer than 10 cases of Hagemoser syndrome have been reported in the medical literature. Hagemoser syndrome is differentiated from Rosenberg-Chutorian syndrome by mode of inheritance. Hagemoser syndrome is inherited as an autosomal dominant trait. Charcot Marie Tooth disease encompasses a group of hereditary neuropathies in which the motor and sensory peripheral nerves are affected, resulting in muscle weakness and atrophy, primarily in the legs and sometimes in the hands. CMT hereditary neuropathy affects the nerves that control many muscles in the body. 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 the abnormal function of the peripheral nerves. Charcot Marie Tooth hereditary neuropathy 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” as your search term in the Rare Disease Database.)
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Related disorders of Rosenberg Chutorian Syndrome. Symptoms of the following disorders can be similar to those of Rosenberg-Chutorian syndrome. Comparisons may be useful for a differential diagnosis: Iwashita syndrome is an extremely rare disorder characterized by optic atrophy, hearing loss and progressive disease of the many nerves (polyneuropathy). Fewer than 10 cases of Iwashita syndrome have been reported in the medical literature. Iwashita syndrome is differentiated from Rosenberg-Chutorian syndrome by mode of inheritance. Iwashita syndrome is inherited as an autosomal recessive trait. Hagemoser syndrome is an extremely rare disorder characterized by optic atrophy, hearing loss, and disease affecting the nerves outside of the central nervous system (peripheral neuropathy). Fewer than 10 cases of Hagemoser syndrome have been reported in the medical literature. Hagemoser syndrome is differentiated from Rosenberg-Chutorian syndrome by mode of inheritance. Hagemoser syndrome is inherited as an autosomal dominant trait. Charcot Marie Tooth disease encompasses a group of hereditary neuropathies in which the motor and sensory peripheral nerves are affected, resulting in muscle weakness and atrophy, primarily in the legs and sometimes in the hands. CMT hereditary neuropathy affects the nerves that control many muscles in the body. 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 the abnormal function of the peripheral nerves. Charcot Marie Tooth hereditary neuropathy 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” as your search term in the Rare Disease Database.)
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Diagnosis of Rosenberg Chutorian Syndrome
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A diagnosis of Rosenberg-Chutorian syndrome is made based upon a thorough clinical evaluation, a detailed patient history and identification of characteristic findings. Molecular genetic testing for PRSP1 gene mutations is available to confirm the diagnosis. Carrier testing and prenatal diagnosis are available if a PRSP1 gene mutation has been identified in an affected family member.
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Diagnosis of Rosenberg Chutorian Syndrome. A diagnosis of Rosenberg-Chutorian syndrome is made based upon a thorough clinical evaluation, a detailed patient history and identification of characteristic findings. Molecular genetic testing for PRSP1 gene mutations is available to confirm the diagnosis. Carrier testing and prenatal diagnosis are available if a PRSP1 gene mutation has been identified in an affected family member.
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Therapies of Rosenberg Chutorian Syndrome
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TreatmentThe treatment of Rosenberg-Chutorian syndrome 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, speech pathologists, specialists who asses and treat hearing problems (audiologists), eye specialists, and other healthcare professionals may need to systematically and comprehensively plan an affected child's treatment.Physical and occupational therapy may be useful to maintain as much functioning as possible. A cochlear implant may help individuals with hearing loss. Braces and other orthopedic devices may also be of aid in walking and moving.Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.
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Therapies of Rosenberg Chutorian Syndrome. TreatmentThe treatment of Rosenberg-Chutorian syndrome 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, speech pathologists, specialists who asses and treat hearing problems (audiologists), eye specialists, and other healthcare professionals may need to systematically and comprehensively plan an affected child's treatment.Physical and occupational therapy may be useful to maintain as much functioning as possible. A cochlear implant may help individuals with hearing loss. Braces and other orthopedic devices may also be of aid in walking and moving.Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.
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Overview of Rothmund-Thomson Syndrome
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Summary
Rothmund-Thomson syndrome (RTS) is a rare genetic disorder that can affect many parts of the body. The disorder is characterized by distinctive abnormalities of the skin, sparse hair, eyelashes and/or eyebrows, small stature, skeletal and dental abnormalities and a predisposition to cancer. Patients typically begin having signs of RTS during infancy and the first feature to appear is a rash that starts on the cheeks and later spreads to other parts of the body. The rash gradually becomes chronic and persists for life. Other features may appear that involve other areas of the body such as the eyes, bones, teeth and hair, and patients may be small compared to their peers. Patients are at an increased risk for developing cancer, particularly certain types of skin and bone cancer (osteosarcoma). Lifespan is generally thought to be normal in patients who do not develop cancer, but follow-up data in the published literature are limited. RTS is inherited as an autosomal recessive genetic condition. Approximately two-thirds of patients have changes (variants or mutations) in one of two genes, the RECQL4 and ANAPC1 genes. For the remaining cases of RTS, the gene(s) involved has not yet been identified.Introduction
RTS was first described in 1868 by Dr. Auguste Rothmund, a German ophthalmologist who described the characteristic rash and juvenile cataracts in his patients. In 1921, Dr. Sydney Thomson, who was a British dermatologist, described a very similar rash along with bone findings in his patients. Later in 1957, Dr. William Taylor in the United States proposed that the disorders were the same and coined the eponym “Rothmund-Thomson syndrome”. Since the original reporting of RTS, the characteristics associated with RTS have been widened. Specific gene variants have been found to be associated with certain characteristics (genotype-phenotype correlations). Currently, RTS is divided into two types: type 1 RTS, caused by variants in the ANAPC1 gene and characterized by bilateral juvenile cataracts and type 2 RTS, caused by variants in the RECQL4 gene, and characterized by bone abnormalities and increased risk for osteosarcoma.
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Overview of Rothmund-Thomson Syndrome. Summary
Rothmund-Thomson syndrome (RTS) is a rare genetic disorder that can affect many parts of the body. The disorder is characterized by distinctive abnormalities of the skin, sparse hair, eyelashes and/or eyebrows, small stature, skeletal and dental abnormalities and a predisposition to cancer. Patients typically begin having signs of RTS during infancy and the first feature to appear is a rash that starts on the cheeks and later spreads to other parts of the body. The rash gradually becomes chronic and persists for life. Other features may appear that involve other areas of the body such as the eyes, bones, teeth and hair, and patients may be small compared to their peers. Patients are at an increased risk for developing cancer, particularly certain types of skin and bone cancer (osteosarcoma). Lifespan is generally thought to be normal in patients who do not develop cancer, but follow-up data in the published literature are limited. RTS is inherited as an autosomal recessive genetic condition. Approximately two-thirds of patients have changes (variants or mutations) in one of two genes, the RECQL4 and ANAPC1 genes. For the remaining cases of RTS, the gene(s) involved has not yet been identified.Introduction
RTS was first described in 1868 by Dr. Auguste Rothmund, a German ophthalmologist who described the characteristic rash and juvenile cataracts in his patients. In 1921, Dr. Sydney Thomson, who was a British dermatologist, described a very similar rash along with bone findings in his patients. Later in 1957, Dr. William Taylor in the United States proposed that the disorders were the same and coined the eponym “Rothmund-Thomson syndrome”. Since the original reporting of RTS, the characteristics associated with RTS have been widened. Specific gene variants have been found to be associated with certain characteristics (genotype-phenotype correlations). Currently, RTS is divided into two types: type 1 RTS, caused by variants in the ANAPC1 gene and characterized by bilateral juvenile cataracts and type 2 RTS, caused by variants in the RECQL4 gene, and characterized by bone abnormalities and increased risk for osteosarcoma.
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Symptoms of Rothmund-Thomson Syndrome
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Rothmund-Thomson syndrome is a rare genetic disorder that manifests in early infancy. The range and severity of symptoms may vary from person to person. RTS is typically characterized by skin rash, sparse hair, malformed bones, abnormal clouding of the lenses of the eyes (juvenile cataracts), small stature and other physical abnormalities. Intelligence is usually normal, but some affected individuals have been reported to have intellectual disability.Skin and hair
Between the ages of approximately three to six months, infants with RTS typically develop redness (erythema) on the cheeks that may appear as patches or inflamed plaques and may resemble sunburn or even eczema. The redness may be accompanied by swelling (edema). In some children, the rash may be apparent earlier in life or may develop as late as two years old. The rash typically spreads to the arms and legs and may or may not involve the buttocks. The trunk and belly are generally spared. Over time and usually by early childhood, the inflammation tends to recede and the skin of affected areas develops into a more chronic pattern of rash known as poikiloderma, characterized by telangiectasis (prominent, small, spider-like blood vessels); small spots of atrophy (skin tissue degeneration or thinning); and areas of abnormal skin pigmentation alternating between increased pigment (hyperpigmentation) and decreased pigment (hypopigmentation), giving a lacy, web-like or mottled appearance.Sensitivity of the skin to sun exposure (photosensitivity) has been reported in some patients, and the rash tends to affect areas that are more sun exposed. However, it is important to note that the rash is not always limited to sun-exposed areas (e.g., buttocks). Some affected individuals report a history of blistering (bullae) on the skin that may or may not be related to sun exposure. Blistering tends to diminish as patients reach late childhood.One of the other skin manifestations of RTS that tends to be more prominent in adulthood is a condition called hyperkeratosis, where certain areas such as the palms and soles, knees and sometimes around the fingers or toes, become thickened and overgrown and develop a rough, wart-like (verrucous) texture. In severe cases, large, verrucous overgrowth of certain areas may cause significant discomfort or restriction of activities.In addition, many patients with RTS have sparse scalp hair, and some may have complete baldness (alopecia). In many people, eyebrows, eyelashes and body hair may also be sparse or absent. In some patients, the nails may be malformed (dystrophic) and/or unusually small (hypoplastic).Eyes
Between the ages of approximately two to seven years of age, some children with RTS may also develop sudden clouding of the lenses of both eyes (bilateral juvenile cataracts). Such cataracts typically are opaque, semisolid, white dots appearing on one broad or narrow area of an otherwise clear lens (zonular or lamellar cataract). Development of such cataracts may result in severe visual impairment or loss within weeks, and prompt surgical intervention by an eye specialist (ophthalmologist) can usually restore vision.Growth and development
A large percentage of individuals with RTS experience abnormally slow growth before and after birth (prenatal and postnatal growth delay), leading to mild to moderate small stature. This small stature is symmetrical for height and weight, and patients have proportional development of the upper and lower body.Bones and teeth
A large percentage of patients have bone abnormalities that may or may not be visible clinically. One of the most obvious abnormalities is a radial ray defect which manifests as small, malformed or missing thumbs or shortened forearms. Other bones in the body, particularly those in the arms, hands and legs, can also be abnormally formed, shortened, or fused, and some of these bone findings can only be seen on x-rays. Some patients may also have characteristic abnormalities of the craniofacial area including a prominent forehead (frontal bossing) or a sunken nasal bridge (saddle nose). Patients may also have decreased bone density (osteopenia or osteoporosis) which in severe cases could lead to fractures. The teeth in patients with RTS may be small or malformed.Gastrointestinal and feeding
Many infants and young children with RTS experience gastrointestinal disturbances including non-specific vomiting and diarrhea that are often attributed to intolerance of milk or formula. Some patients require feeding tubes to maintain nutritional intake. However, in virtually all patients, these issues resolve by later childhood.Cancer
Individuals with RTS have an increased risk of developing cancer, particularly osteosarcoma and non-melanoma skin cancers (squamous and basal cell carcinomas). While these are the most frequent cancers encountered in RTS, there have been a few patients reported who developed squamous cell carcinoma of the head and neck region and hematologic malignancies such as leukemia.Fertility
Some individuals with RTS have hypogonadism, a condition characterized by deficient activity of the gonads (i.e., ovaries in females or testes in males). As a result, affected females may experience irregular menstruation, while both affected males and females may have delayed sexual development. In individuals with hypogonadism, fertility may be reduced; however, some patients (both male and female) have had children.
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Symptoms of Rothmund-Thomson Syndrome. Rothmund-Thomson syndrome is a rare genetic disorder that manifests in early infancy. The range and severity of symptoms may vary from person to person. RTS is typically characterized by skin rash, sparse hair, malformed bones, abnormal clouding of the lenses of the eyes (juvenile cataracts), small stature and other physical abnormalities. Intelligence is usually normal, but some affected individuals have been reported to have intellectual disability.Skin and hair
Between the ages of approximately three to six months, infants with RTS typically develop redness (erythema) on the cheeks that may appear as patches or inflamed plaques and may resemble sunburn or even eczema. The redness may be accompanied by swelling (edema). In some children, the rash may be apparent earlier in life or may develop as late as two years old. The rash typically spreads to the arms and legs and may or may not involve the buttocks. The trunk and belly are generally spared. Over time and usually by early childhood, the inflammation tends to recede and the skin of affected areas develops into a more chronic pattern of rash known as poikiloderma, characterized by telangiectasis (prominent, small, spider-like blood vessels); small spots of atrophy (skin tissue degeneration or thinning); and areas of abnormal skin pigmentation alternating between increased pigment (hyperpigmentation) and decreased pigment (hypopigmentation), giving a lacy, web-like or mottled appearance.Sensitivity of the skin to sun exposure (photosensitivity) has been reported in some patients, and the rash tends to affect areas that are more sun exposed. However, it is important to note that the rash is not always limited to sun-exposed areas (e.g., buttocks). Some affected individuals report a history of blistering (bullae) on the skin that may or may not be related to sun exposure. Blistering tends to diminish as patients reach late childhood.One of the other skin manifestations of RTS that tends to be more prominent in adulthood is a condition called hyperkeratosis, where certain areas such as the palms and soles, knees and sometimes around the fingers or toes, become thickened and overgrown and develop a rough, wart-like (verrucous) texture. In severe cases, large, verrucous overgrowth of certain areas may cause significant discomfort or restriction of activities.In addition, many patients with RTS have sparse scalp hair, and some may have complete baldness (alopecia). In many people, eyebrows, eyelashes and body hair may also be sparse or absent. In some patients, the nails may be malformed (dystrophic) and/or unusually small (hypoplastic).Eyes
Between the ages of approximately two to seven years of age, some children with RTS may also develop sudden clouding of the lenses of both eyes (bilateral juvenile cataracts). Such cataracts typically are opaque, semisolid, white dots appearing on one broad or narrow area of an otherwise clear lens (zonular or lamellar cataract). Development of such cataracts may result in severe visual impairment or loss within weeks, and prompt surgical intervention by an eye specialist (ophthalmologist) can usually restore vision.Growth and development
A large percentage of individuals with RTS experience abnormally slow growth before and after birth (prenatal and postnatal growth delay), leading to mild to moderate small stature. This small stature is symmetrical for height and weight, and patients have proportional development of the upper and lower body.Bones and teeth
A large percentage of patients have bone abnormalities that may or may not be visible clinically. One of the most obvious abnormalities is a radial ray defect which manifests as small, malformed or missing thumbs or shortened forearms. Other bones in the body, particularly those in the arms, hands and legs, can also be abnormally formed, shortened, or fused, and some of these bone findings can only be seen on x-rays. Some patients may also have characteristic abnormalities of the craniofacial area including a prominent forehead (frontal bossing) or a sunken nasal bridge (saddle nose). Patients may also have decreased bone density (osteopenia or osteoporosis) which in severe cases could lead to fractures. The teeth in patients with RTS may be small or malformed.Gastrointestinal and feeding
Many infants and young children with RTS experience gastrointestinal disturbances including non-specific vomiting and diarrhea that are often attributed to intolerance of milk or formula. Some patients require feeding tubes to maintain nutritional intake. However, in virtually all patients, these issues resolve by later childhood.Cancer
Individuals with RTS have an increased risk of developing cancer, particularly osteosarcoma and non-melanoma skin cancers (squamous and basal cell carcinomas). While these are the most frequent cancers encountered in RTS, there have been a few patients reported who developed squamous cell carcinoma of the head and neck region and hematologic malignancies such as leukemia.Fertility
Some individuals with RTS have hypogonadism, a condition characterized by deficient activity of the gonads (i.e., ovaries in females or testes in males). As a result, affected females may experience irregular menstruation, while both affected males and females may have delayed sexual development. In individuals with hypogonadism, fertility may be reduced; however, some patients (both male and female) have had children.
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Causes of Rothmund-Thomson Syndrome
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Rothmund-Thompson syndrome is a genetic disorder that is inherited in an autosomal recessive pattern. Approximately 2/3 of individuals with RTS are found to have an abnormality (variant or mutation) in the RECQL4 gene (type 2 RTS) or the ANAPC1 gene (type 1 RTS). The RECQL4 gene is responsible for production of a protein that is involved in the replication and repair of DNA, the genetic material in the cells of the body. ANAPC1 encodes a protein, APC1, which is important for cell cycle progression and also plays a role in DNA replication and repair. Since about 1/3 of affected individuals do not have detectable variants in these genes, other as yet undiscovered genes are probably also associated with RTS.Recessive genetic disorders occur when an individual inherits a mutated gene from each parent. If an individual receives one normal gene and one mutated 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 mutated gene and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
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Causes of Rothmund-Thomson Syndrome. Rothmund-Thompson syndrome is a genetic disorder that is inherited in an autosomal recessive pattern. Approximately 2/3 of individuals with RTS are found to have an abnormality (variant or mutation) in the RECQL4 gene (type 2 RTS) or the ANAPC1 gene (type 1 RTS). The RECQL4 gene is responsible for production of a protein that is involved in the replication and repair of DNA, the genetic material in the cells of the body. ANAPC1 encodes a protein, APC1, which is important for cell cycle progression and also plays a role in DNA replication and repair. Since about 1/3 of affected individuals do not have detectable variants in these genes, other as yet undiscovered genes are probably also associated with RTS.Recessive genetic disorders occur when an individual inherits a mutated gene from each parent. If an individual receives one normal gene and one mutated 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 mutated gene and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
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Affects of Rothmund-Thomson Syndrome
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RTS has been diagnosed in people of all races and has been described in multiple nationalities; therefore, it does not appear that there is any particular population at increased risk for developing the disease.
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Affects of Rothmund-Thomson Syndrome. RTS has been diagnosed in people of all races and has been described in multiple nationalities; therefore, it does not appear that there is any particular population at increased risk for developing the disease.
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Related disorders of Rothmund-Thomson Syndrome
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The following disorders share some overlapping clinical features with those of RTS. RAPADILINO and Baller-Gerold syndromes are related to RTS because they can also be caused in some cases by variants in the RECQL4 gene. Bloom and Werner syndromes are related to RTS because they are caused by variants in the BLM and WRN genes, respectively, which both belong to the same gene family as RECQL4.RAPADILINO syndrome is an autosomal recessive genetic condition that is characterized by abnormal skin pigmentation (but not poikiloderma), small size, radial ray defects of the bone, abnormal palate, absent or poorly developed kneecaps and gastrointestinal abnormalities. These patients are prone to developing lymphomas as well as osteosarcomas.Baller-Gerold syndrome is characterized by small size, radial ray defects and other bone abnormalities, including premature closure of the bones of the skull (craniosynostosis).Bloom syndrome is a rare genetic disorder characterized by short stature; increased sensitivity to light (photosensitivity); multiple small, dilated blood vessels on the face (facial telangiectasia), often resembling a butterfly in shape; immune deficiency leading to increased susceptibility to infections; and, perhaps most importantly, a markedly increased susceptibility to cancer of any organ, but especially to leukemia and lymphoma. Variants in the BLM gene are causative. Bloom syndrome is inherited in an autosomal recessive pattern. (For more information on this disorder, choose “Bloom” as your search term in the Rare Disease Database.)Werner syndrome is a rare progressive disorder that is characterized by early onset of features associated with aging as well as increased risk of cancer. The first symptom is usually the lack of a growth spurt during the early teen years. Myocardial infarction and cancer are the most common causes of death, typically about age 48 years. Variants in the WRN gene are causative. Werner syndrome is inherited in an autosomal recessive pattern. As a result, affected individuals have unusually short stature and low weight even relative to height. Initial findings usually observed in the 20s include loss and graying of hair, hoarseness, and scleroderma-like skin changes. As the disease progresses, additional abnormalities include loss of the layer of fat beneath the skin; severe wasting (atrophy) of muscle tissue in certain areas of the body; and degenerative skin changes. Due to degenerative changes affecting the facial area, individuals with Werner syndrome may have unusually prominent eyes, a beaked or pinched nose and/or other characteristic facial abnormalities.Werner syndrome may also be characterized by development of a distinctive high-pitched voice, eye abnormalities, including premature clouding of the lenses of the eyes due to aging (bilateral senile cataracts) and certain endocrine defects, such as hypogonadism and diabetes mellitus. In addition, individuals with Werner syndrome can develop age-associated heart disease such as atherosclerosis. Patients are also at risk for developing cancers, particularly thyroid cancer and sarcomas (cancers of the supporting, connective or soft tissues). Progressive heart disease, diabetes, or malignancy may result in potentially life-threatening complications by approximately the fourth or fifth decade of life. (For further information, choose “Werner” as your search term in the Rare Disease Database.)Other diseases that have some clinical features in common with RTS include:Poikiloderma with neutropenia (PN, Navajo poikiloderma), which was first described in Navajo individuals but has now been described in other ethnicities as well. These patients also have poikiloderma, but the onset and pattern of spread of rash in individuals with PN differs from that seen in RTS. Individuals with PN have clinically significant neutropenia (low white blood counts) and can develop recurrent lung infections. They also have abnormally thickened nails. Radial ray defects and hair abnormalities are not generally seen. PN is caused by variants in the USB1 gene.Dyskeratosis congenita (DC) is a genetically and clinically heterogeneous disorder. Patients have overlapping features with RTS including abnormal skin pigmentation, nail dystrophy, sparse hair, dental and bone abnormalities and small stature. In addition, patients can have oral leukoplakia, pulmonary fibrosis and other findings, and they have an increased risk of developing cancer (leukemia, head and neck and anogenital cancers) and bone marrow failure (aplastic anemia, myelodysplastic syndrome). DC is caused by many different mutations in genes involved in telomere maintenance.Individuals with Kindler syndrome also display poikiloderma. They usually present with blisters at birth and after minor trauma and their skin is markedly photosensitive. They can also develop thickened plaques on the hands, feet, elbows and knees. Other features include esophageal and urethral strictures, and webbing of fingers and toes.
Fanconi anemia (FA) is an autosomal recessive condition that is characterized by a range of physical abnormalities. Among those that are shared with RTS include radial ray defects, small stature, abnormal skin pigmentation, hypogonadism and increased risk for cancer, most often hematologic malignancies and solid tumors of the head and neck, skin, GI tract, and genital tract. Variants in multiple different genes can result in FA.
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Related disorders of Rothmund-Thomson Syndrome. The following disorders share some overlapping clinical features with those of RTS. RAPADILINO and Baller-Gerold syndromes are related to RTS because they can also be caused in some cases by variants in the RECQL4 gene. Bloom and Werner syndromes are related to RTS because they are caused by variants in the BLM and WRN genes, respectively, which both belong to the same gene family as RECQL4.RAPADILINO syndrome is an autosomal recessive genetic condition that is characterized by abnormal skin pigmentation (but not poikiloderma), small size, radial ray defects of the bone, abnormal palate, absent or poorly developed kneecaps and gastrointestinal abnormalities. These patients are prone to developing lymphomas as well as osteosarcomas.Baller-Gerold syndrome is characterized by small size, radial ray defects and other bone abnormalities, including premature closure of the bones of the skull (craniosynostosis).Bloom syndrome is a rare genetic disorder characterized by short stature; increased sensitivity to light (photosensitivity); multiple small, dilated blood vessels on the face (facial telangiectasia), often resembling a butterfly in shape; immune deficiency leading to increased susceptibility to infections; and, perhaps most importantly, a markedly increased susceptibility to cancer of any organ, but especially to leukemia and lymphoma. Variants in the BLM gene are causative. Bloom syndrome is inherited in an autosomal recessive pattern. (For more information on this disorder, choose “Bloom” as your search term in the Rare Disease Database.)Werner syndrome is a rare progressive disorder that is characterized by early onset of features associated with aging as well as increased risk of cancer. The first symptom is usually the lack of a growth spurt during the early teen years. Myocardial infarction and cancer are the most common causes of death, typically about age 48 years. Variants in the WRN gene are causative. Werner syndrome is inherited in an autosomal recessive pattern. As a result, affected individuals have unusually short stature and low weight even relative to height. Initial findings usually observed in the 20s include loss and graying of hair, hoarseness, and scleroderma-like skin changes. As the disease progresses, additional abnormalities include loss of the layer of fat beneath the skin; severe wasting (atrophy) of muscle tissue in certain areas of the body; and degenerative skin changes. Due to degenerative changes affecting the facial area, individuals with Werner syndrome may have unusually prominent eyes, a beaked or pinched nose and/or other characteristic facial abnormalities.Werner syndrome may also be characterized by development of a distinctive high-pitched voice, eye abnormalities, including premature clouding of the lenses of the eyes due to aging (bilateral senile cataracts) and certain endocrine defects, such as hypogonadism and diabetes mellitus. In addition, individuals with Werner syndrome can develop age-associated heart disease such as atherosclerosis. Patients are also at risk for developing cancers, particularly thyroid cancer and sarcomas (cancers of the supporting, connective or soft tissues). Progressive heart disease, diabetes, or malignancy may result in potentially life-threatening complications by approximately the fourth or fifth decade of life. (For further information, choose “Werner” as your search term in the Rare Disease Database.)Other diseases that have some clinical features in common with RTS include:Poikiloderma with neutropenia (PN, Navajo poikiloderma), which was first described in Navajo individuals but has now been described in other ethnicities as well. These patients also have poikiloderma, but the onset and pattern of spread of rash in individuals with PN differs from that seen in RTS. Individuals with PN have clinically significant neutropenia (low white blood counts) and can develop recurrent lung infections. They also have abnormally thickened nails. Radial ray defects and hair abnormalities are not generally seen. PN is caused by variants in the USB1 gene.Dyskeratosis congenita (DC) is a genetically and clinically heterogeneous disorder. Patients have overlapping features with RTS including abnormal skin pigmentation, nail dystrophy, sparse hair, dental and bone abnormalities and small stature. In addition, patients can have oral leukoplakia, pulmonary fibrosis and other findings, and they have an increased risk of developing cancer (leukemia, head and neck and anogenital cancers) and bone marrow failure (aplastic anemia, myelodysplastic syndrome). DC is caused by many different mutations in genes involved in telomere maintenance.Individuals with Kindler syndrome also display poikiloderma. They usually present with blisters at birth and after minor trauma and their skin is markedly photosensitive. They can also develop thickened plaques on the hands, feet, elbows and knees. Other features include esophageal and urethral strictures, and webbing of fingers and toes.
Fanconi anemia (FA) is an autosomal recessive condition that is characterized by a range of physical abnormalities. Among those that are shared with RTS include radial ray defects, small stature, abnormal skin pigmentation, hypogonadism and increased risk for cancer, most often hematologic malignancies and solid tumors of the head and neck, skin, GI tract, and genital tract. Variants in multiple different genes can result in FA.
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Diagnosis of Rothmund-Thomson Syndrome
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Rothmund-Thompson syndrome is diagnosed based on the onset, appearance and progression of the poikilodermatous rash. A diagnosis of RTS may be suspected if the rash is present but atypical and other physical characteristics associated with RTS are present. Molecular genetic testing for the RECQL4 gene is available to confirm the diagnosis, although in one-third of cases of RTS this test can be negative. Thus, a negative test does not rule out the diagnosis of RTS, but a positive test confirms the diagnosis.
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Diagnosis of Rothmund-Thomson Syndrome. Rothmund-Thompson syndrome is diagnosed based on the onset, appearance and progression of the poikilodermatous rash. A diagnosis of RTS may be suspected if the rash is present but atypical and other physical characteristics associated with RTS are present. Molecular genetic testing for the RECQL4 gene is available to confirm the diagnosis, although in one-third of cases of RTS this test can be negative. Thus, a negative test does not rule out the diagnosis of RTS, but a positive test confirms the diagnosis.
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Therapies of Rothmund-Thomson Syndrome
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The treatment of Rothmund-Thomson syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, physicians who specialize in the diagnosis and treatment of disorders of the skin (dermatologists), doctors who specialize in genetic disorders (geneticists), eye specialists (ophthalmologists), specialists who diagnose and treat bone disorders (orthopedists), dental specialists and/or other health care professionals may need to plan an affected child’s management systematically and comprehensively.Specific therapies for the treatment of RTS are symptomatic and supportive. Special measures may be recommended to protect affected individuals from sun exposure (e.g., use of topical sunscreens, sunglasses, etc.). Because patients are prone to developing skin cancer (e.g., squamous, or basal cell carcinomas), physicians may closely monitor affected skin areas to ensure prompt detection and treatment of skin malignancies.In addition, because some individuals with RTS are more prone to developing certain non-skin related malignancies (e.g., osteosarcoma) than the general population, physicians may closely monitor affected individuals to ensure early detection and prompt, appropriate treatment. Baseline skeletal surveys are recommended since these patients often have underlying skeletal defects that need to be distinguished from any new pathologic lesions. Effective therapies for osteosarcoma and other cancers are currently available, and it appears that some patients with RTS can tolerate these therapies similar to cancer patients in the general population. Other patients may require dose reductions based on individual tolerance to specific chemotherapy agents.RTS patients may be at risk for osteoporosis and bone fractures. Monitoring with DXA scans may be warranted and some patients may benefit from bone supplements.Because serious visual impairment or loss may result from cataracts, infants and children with RTS should be closely monitored by pediatricians and ophthalmologists to ensure immediate detection of cataracts and prompt, appropriate treatment. Surgical removal of opacified lenses can be performed to prevent serious visual impairment or loss.Dental abnormalities potentially occurring in association with RTS may be treated through surgery, use of dentures and other artificial devices (prosthetics), and/or other supportive techniques.Pulsed dye laser has been used for the cosmetic management of the telangiectatic component of the rash.Genetic counseling is recommended for affected individuals and their families. Other treatment for this disorder is symptomatic and supportive.
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Therapies of Rothmund-Thomson Syndrome. The treatment of Rothmund-Thomson syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, physicians who specialize in the diagnosis and treatment of disorders of the skin (dermatologists), doctors who specialize in genetic disorders (geneticists), eye specialists (ophthalmologists), specialists who diagnose and treat bone disorders (orthopedists), dental specialists and/or other health care professionals may need to plan an affected child’s management systematically and comprehensively.Specific therapies for the treatment of RTS are symptomatic and supportive. Special measures may be recommended to protect affected individuals from sun exposure (e.g., use of topical sunscreens, sunglasses, etc.). Because patients are prone to developing skin cancer (e.g., squamous, or basal cell carcinomas), physicians may closely monitor affected skin areas to ensure prompt detection and treatment of skin malignancies.In addition, because some individuals with RTS are more prone to developing certain non-skin related malignancies (e.g., osteosarcoma) than the general population, physicians may closely monitor affected individuals to ensure early detection and prompt, appropriate treatment. Baseline skeletal surveys are recommended since these patients often have underlying skeletal defects that need to be distinguished from any new pathologic lesions. Effective therapies for osteosarcoma and other cancers are currently available, and it appears that some patients with RTS can tolerate these therapies similar to cancer patients in the general population. Other patients may require dose reductions based on individual tolerance to specific chemotherapy agents.RTS patients may be at risk for osteoporosis and bone fractures. Monitoring with DXA scans may be warranted and some patients may benefit from bone supplements.Because serious visual impairment or loss may result from cataracts, infants and children with RTS should be closely monitored by pediatricians and ophthalmologists to ensure immediate detection of cataracts and prompt, appropriate treatment. Surgical removal of opacified lenses can be performed to prevent serious visual impairment or loss.Dental abnormalities potentially occurring in association with RTS may be treated through surgery, use of dentures and other artificial devices (prosthetics), and/or other supportive techniques.Pulsed dye laser has been used for the cosmetic management of the telangiectatic component of the rash.Genetic counseling is recommended for affected individuals and their families. Other treatment for this disorder is symptomatic and supportive.
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Overview of Roussy Lévy Syndrome
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Roussy-Lévy Syndrome, also known as hereditary areflexic dystasia, is a rare genetic neuromuscular disorder that typically becomes apparent during early childhood. The disorder is characterized by incoordination, poor judgment of movements (sensory ataxia), and absence of reflexes (areflexia) of the lower legs and, eventually, the hands; weakness and degeneration (atrophy) of muscles of the lower legs; abnormally high arches of the feet with increased extension of the toes (pes cavus or “clawfoot”); and tremors of the hands. Many affected individuals also have an abnormal front-to-back and sideways curvature of the spine (kyphoscoliosis). In individuals with Roussy-Lévy Syndrome, there is a failed communication of certain nerve signals to muscles of the lower legs (denervation). Roussy-Levy Syndrome is inherited as an autosomal dominant genetic trait.
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Overview of Roussy Lévy Syndrome. Roussy-Lévy Syndrome, also known as hereditary areflexic dystasia, is a rare genetic neuromuscular disorder that typically becomes apparent during early childhood. The disorder is characterized by incoordination, poor judgment of movements (sensory ataxia), and absence of reflexes (areflexia) of the lower legs and, eventually, the hands; weakness and degeneration (atrophy) of muscles of the lower legs; abnormally high arches of the feet with increased extension of the toes (pes cavus or “clawfoot”); and tremors of the hands. Many affected individuals also have an abnormal front-to-back and sideways curvature of the spine (kyphoscoliosis). In individuals with Roussy-Lévy Syndrome, there is a failed communication of certain nerve signals to muscles of the lower legs (denervation). Roussy-Levy Syndrome is inherited as an autosomal dominant genetic trait.
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Symptoms of Roussy Lévy Syndrome
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Symptoms of Roussy-Lévy Syndrome are similar to other hereditary motor sensory neuropathies in that there is weakness and atrophy of the leg muscles with some loss of feeling. People with this syndrome have difficulty walking and a lack of reflexes and deformity of the foot or feet (pes cavus). Roussy-Lévy differs, however, from other hereditary motor sensory neuropathies because of the very early onset of the disorder during childhood and its slowly progressive course. Roussy-Lévy also has as one of its characteristics a slight tremor in the hands.
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Symptoms of Roussy Lévy Syndrome. Symptoms of Roussy-Lévy Syndrome are similar to other hereditary motor sensory neuropathies in that there is weakness and atrophy of the leg muscles with some loss of feeling. People with this syndrome have difficulty walking and a lack of reflexes and deformity of the foot or feet (pes cavus). Roussy-Lévy differs, however, from other hereditary motor sensory neuropathies because of the very early onset of the disorder during childhood and its slowly progressive course. Roussy-Lévy also has as one of its characteristics a slight tremor in the hands.
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Causes of Roussy Lévy Syndrome
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Roussy-Lévy is inherited through autosomal dominant genetic transmission. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother. In dominant disorders, a single copy of the disease gene (received from either the mother or father) will be expressed “dominating” the other normal gene and resulting in the appearance of the disease. The risk of transmitting the disorder from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child. Scientific evidence published in 1998 indicated that Rousy Lévy Syndrome appears to be a form of Charcot Marie Tooth Disease because it is caused by a partial duplication of the same gene that causes CMT (17p11.2). (For more information, choose “CMT” as your search term in the Rare Disease Database.)
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Causes of Roussy Lévy Syndrome. Roussy-Lévy is inherited through autosomal dominant genetic transmission. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother. In dominant disorders, a single copy of the disease gene (received from either the mother or father) will be expressed “dominating” the other normal gene and resulting in the appearance of the disease. The risk of transmitting the disorder from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child. Scientific evidence published in 1998 indicated that Rousy Lévy Syndrome appears to be a form of Charcot Marie Tooth Disease because it is caused by a partial duplication of the same gene that causes CMT (17p11.2). (For more information, choose “CMT” as your search term in the Rare Disease Database.)
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Affects of Roussy Lévy Syndrome
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Roussy-Lévy is a rare disorder that affects both sexes in equal numbers. Onset is during early childhood.
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Affects of Roussy Lévy Syndrome. Roussy-Lévy is a rare disorder that affects both sexes in equal numbers. Onset is during early childhood.
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Related disorders of Roussy Lévy Syndrome
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Symptoms of the following disorders can be similar to those of Roussy-Lévy Syndrome. Comparisons may be useful for a differential diagnosis:Charcot-Marie-Tooth Disease is an hereditary neurological disorder. It is characterized by weakness and atrophy of the legs and disappearance of the fatty shield surrounding the nerves. The most incapacitating initial symptom is “foot drop”. The disorder has a gradual progression usually beginning in middle childhood through age 30. Symptoms of CMT may arrest spontaneously or it may continue to progress slowly. Patients may remain active for years. (For more information on this disorder, choose “Charcot-Marie-Tooth” as your search term in the Rare Disease Database.)Dejerine-Sottas Disease is a hereditary neurological disorder which progressively affects mobility. It tends to begin suddenly, usually between ten and thirty years of age. Tingling, prickling or burning sensations are usually the initial symptoms. Weakness is commonly first noticed in the muscles of the back of the legs. This then spreads to the front leg muscles. Pain, loss of heat sensitivity, absence of reflexes and atrophy of leg muscles are further symptoms of Dejerine-Sottas Disease. (For more information on this disorder, choose “Dejerine-Sottas” as your search term in the Rare Disease Database.)Hereditary Sensory Radicular Neuropathy is a dominant hereditary disorder characterized initially by pain and loss of heat sensation in the feet and lower legs. Later the patient may have attacks of sharp pains throughout the body and weakness in the legs along with ulcers of the feet. (For more information on this disorder, choose “Hereditary Sensory Radicular Neuropathy” as your search term in the Rare Disease Database.)Refsum Syndrome is a rare recessive hereditary disorder of fat metabolism which is characterized by peripheral neuropathy, impaired muscle coordination (ataxia), eye problems, deafness, and bone and skin changes. It is associated with marked accumulation of phytanic acid in the blood plasma and tissues. The disorder may be due to the absence of phytanic acid hydroxylase, an enzyme needed for the metabolism of phytanic acid. (For more information on this disorder, choose “Refsum Syndrome” as your search term in the Rare Disease Database.)Friedreich's Ataxia is a hereditary syndrome characterized by slow degenerative changes of the spinal cord and the brain. Dysfunction of the central nervous system affects coordination of the muscles in the limbs. Speech can be affected and numbness or weakness of the arms and legs develops. This syndrome is the most common of the many different forms of hereditary ataxia and usually begins in childhood or during teenage years. It produces an unsteady gait, staggering, and lurching or trembling when standing or walking. In time tremors may occur in the hands or arms. (For more information on this disorder, choose “Friedreich's Ataxia” as your search term in the Rare Disease Database.)
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Related disorders of Roussy Lévy Syndrome. Symptoms of the following disorders can be similar to those of Roussy-Lévy Syndrome. Comparisons may be useful for a differential diagnosis:Charcot-Marie-Tooth Disease is an hereditary neurological disorder. It is characterized by weakness and atrophy of the legs and disappearance of the fatty shield surrounding the nerves. The most incapacitating initial symptom is “foot drop”. The disorder has a gradual progression usually beginning in middle childhood through age 30. Symptoms of CMT may arrest spontaneously or it may continue to progress slowly. Patients may remain active for years. (For more information on this disorder, choose “Charcot-Marie-Tooth” as your search term in the Rare Disease Database.)Dejerine-Sottas Disease is a hereditary neurological disorder which progressively affects mobility. It tends to begin suddenly, usually between ten and thirty years of age. Tingling, prickling or burning sensations are usually the initial symptoms. Weakness is commonly first noticed in the muscles of the back of the legs. This then spreads to the front leg muscles. Pain, loss of heat sensitivity, absence of reflexes and atrophy of leg muscles are further symptoms of Dejerine-Sottas Disease. (For more information on this disorder, choose “Dejerine-Sottas” as your search term in the Rare Disease Database.)Hereditary Sensory Radicular Neuropathy is a dominant hereditary disorder characterized initially by pain and loss of heat sensation in the feet and lower legs. Later the patient may have attacks of sharp pains throughout the body and weakness in the legs along with ulcers of the feet. (For more information on this disorder, choose “Hereditary Sensory Radicular Neuropathy” as your search term in the Rare Disease Database.)Refsum Syndrome is a rare recessive hereditary disorder of fat metabolism which is characterized by peripheral neuropathy, impaired muscle coordination (ataxia), eye problems, deafness, and bone and skin changes. It is associated with marked accumulation of phytanic acid in the blood plasma and tissues. The disorder may be due to the absence of phytanic acid hydroxylase, an enzyme needed for the metabolism of phytanic acid. (For more information on this disorder, choose “Refsum Syndrome” as your search term in the Rare Disease Database.)Friedreich's Ataxia is a hereditary syndrome characterized by slow degenerative changes of the spinal cord and the brain. Dysfunction of the central nervous system affects coordination of the muscles in the limbs. Speech can be affected and numbness or weakness of the arms and legs develops. This syndrome is the most common of the many different forms of hereditary ataxia and usually begins in childhood or during teenage years. It produces an unsteady gait, staggering, and lurching or trembling when standing or walking. In time tremors may occur in the hands or arms. (For more information on this disorder, choose “Friedreich's Ataxia” as your search term in the Rare Disease Database.)
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Diagnosis of Roussy Lévy Syndrome
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Diagnosis of Roussy Lévy Syndrome.
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nord_1083_6
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Therapies of Roussy Lévy Syndrome
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Treatment of Roussy-Lévy Syndrome may include use of braces for the foot deformity or orthopedic surgery on the feet to correct the imbalance of the affected muscles. Genetic counseling may be of benefit to patients and their families. Other treatment is symptomatic and supportive.
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Therapies of Roussy Lévy Syndrome. Treatment of Roussy-Lévy Syndrome may include use of braces for the foot deformity or orthopedic surgery on the feet to correct the imbalance of the affected muscles. Genetic counseling may be of benefit to patients and their families. Other treatment is symptomatic and supportive.
| 1,083 |
Roussy Lévy Syndrome
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nord_1084_0
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Overview of Rubella
|
Rubella is a viral infection characterized by fever, headache, swollen lymph nodes, aching joints, and a distinctive red rash. Although it is sometimes called German measles or three-day measles, it is not caused by the same virus that causes measles. Rubella is generally mild in children and more severe but not life-threatening in adults. However, if a pregnant woman is infected with rubella, it can cause serious problems for the unborn child. In the United States, most children receive the measles-mumps-rubella (MMR) vaccine, and therefore the disease has become uncommon. In March 2005, health officials announced that rubella has been eliminated from the United States. However, it is still important for Americans to vaccinate their children, and women who are pregnant or might get pregnant still need to be sure they are immune, because the disease exists elsewhere. According to the Centers for Disease Control and Prevention (CDC), nine rubella cases were reported in the United States in 2004, and all of them originated in other countries.
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Overview of Rubella. Rubella is a viral infection characterized by fever, headache, swollen lymph nodes, aching joints, and a distinctive red rash. Although it is sometimes called German measles or three-day measles, it is not caused by the same virus that causes measles. Rubella is generally mild in children and more severe but not life-threatening in adults. However, if a pregnant woman is infected with rubella, it can cause serious problems for the unborn child. In the United States, most children receive the measles-mumps-rubella (MMR) vaccine, and therefore the disease has become uncommon. In March 2005, health officials announced that rubella has been eliminated from the United States. However, it is still important for Americans to vaccinate their children, and women who are pregnant or might get pregnant still need to be sure they are immune, because the disease exists elsewhere. According to the Centers for Disease Control and Prevention (CDC), nine rubella cases were reported in the United States in 2004, and all of them originated in other countries.
| 1,084 |
Rubella
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nord_1084_1
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Symptoms of Rubella
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Rubella is predominantly a childhood disease, although it also occurs among adolescents and adults. It has a 14- to 21-day incubation period and a 1- to 5-day preliminary phase in children. The preliminary phase may be minimal or absent in adolescents and adults. Tender swelling of the glands in the back of the head, the neck and behind the ears is characteristic. The typical rash appears days after onset of these symptoms.The rubella rash is similar to that of measles, but it is usually less extensive and disappears more quickly. It begins on the face and neck and quickly spreads to the trunk and the extremities. At the onset of the eruption, a flush similar to that of scarlet fever may appear, particularly on the face. The rash usually lasts about three days. It may disappear before this time, and rarely there is no rash at all. A slight fever usually occurs with the rash. Other symptoms such as headache, loss of appetite, sore throat and general malaise, are more common in adults and teenagers than in children.After-effects of rubella are rare among children, although there have been cases of joint pain (arthralgia), sleeping sickness and blood clotting problems. Adult women who contract rubella are often left with chronic joint pains. Encephalitis is a rare complication that has occurred during extensive outbreaks of rubella among young adults serving in the armed services. Transient pain in the testes is also a frequent complaint in adult males with rubella.Congenital rubella syndrome is the name applied to the disease that affects the unborn child when a pregnant woman becomes infected with rubella. This is most dangerous to the fetus during the first six months of pregnancy. Congenital rubella syndrome can lead to miscarriage, stillbirth, and birth defects that include cataracts, deafness, mental retardation, and cardiac anomalies.
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Symptoms of Rubella. Rubella is predominantly a childhood disease, although it also occurs among adolescents and adults. It has a 14- to 21-day incubation period and a 1- to 5-day preliminary phase in children. The preliminary phase may be minimal or absent in adolescents and adults. Tender swelling of the glands in the back of the head, the neck and behind the ears is characteristic. The typical rash appears days after onset of these symptoms.The rubella rash is similar to that of measles, but it is usually less extensive and disappears more quickly. It begins on the face and neck and quickly spreads to the trunk and the extremities. At the onset of the eruption, a flush similar to that of scarlet fever may appear, particularly on the face. The rash usually lasts about three days. It may disappear before this time, and rarely there is no rash at all. A slight fever usually occurs with the rash. Other symptoms such as headache, loss of appetite, sore throat and general malaise, are more common in adults and teenagers than in children.After-effects of rubella are rare among children, although there have been cases of joint pain (arthralgia), sleeping sickness and blood clotting problems. Adult women who contract rubella are often left with chronic joint pains. Encephalitis is a rare complication that has occurred during extensive outbreaks of rubella among young adults serving in the armed services. Transient pain in the testes is also a frequent complaint in adult males with rubella.Congenital rubella syndrome is the name applied to the disease that affects the unborn child when a pregnant woman becomes infected with rubella. This is most dangerous to the fetus during the first six months of pregnancy. Congenital rubella syndrome can lead to miscarriage, stillbirth, and birth defects that include cataracts, deafness, mental retardation, and cardiac anomalies.
| 1,084 |
Rubella
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nord_1084_2
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Causes of Rubella
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Rubella is caused by a virus and is spread by airborne droplet clusters or by close contact with an infected person. A patient can transmit the disease from 1 week before onset of the rash until 1 week after it fades. Congenitally infected infants are potentially infectious for a few months after birth. Rubella is apparently less contagious than measles, and many persons are not infected during childhood. As a result, 10% to 15% of young adult women are susceptible if they have not been vaccinated against the disorder. Many cases are misdiagnosed or go unnoticed.Before the rubella vaccine was developed, epidemics occurred at regular intervals during the spring. Major epidemics occur at about 6- to 9-year intervals. Once a person has been infected by rubella, immunity appears to be lifelong.
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Causes of Rubella. Rubella is caused by a virus and is spread by airborne droplet clusters or by close contact with an infected person. A patient can transmit the disease from 1 week before onset of the rash until 1 week after it fades. Congenitally infected infants are potentially infectious for a few months after birth. Rubella is apparently less contagious than measles, and many persons are not infected during childhood. As a result, 10% to 15% of young adult women are susceptible if they have not been vaccinated against the disorder. Many cases are misdiagnosed or go unnoticed.Before the rubella vaccine was developed, epidemics occurred at regular intervals during the spring. Major epidemics occur at about 6- to 9-year intervals. Once a person has been infected by rubella, immunity appears to be lifelong.
| 1,084 |
Rubella
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nord_1084_3
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Affects of Rubella
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Rubella affects males and females in equal numbers. During 1964 and 1965, according to the CDC, a rubella epidemic in the United States caused an estimated 12.5 million cases of rubella and 20,000 cases of congenital rubella syndrome, which led to more than 11,600 babies born deaf, 11,250 fetal deaths, 2,100 neonatal deaths, 3,580 babies born blind, and 1,800 babies born mentally retarded. Since 1969, the rubella virus has been included in the measles, mumps, and rubella (MMR) vaccine routinely given to babies and young children.
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Affects of Rubella. Rubella affects males and females in equal numbers. During 1964 and 1965, according to the CDC, a rubella epidemic in the United States caused an estimated 12.5 million cases of rubella and 20,000 cases of congenital rubella syndrome, which led to more than 11,600 babies born deaf, 11,250 fetal deaths, 2,100 neonatal deaths, 3,580 babies born blind, and 1,800 babies born mentally retarded. Since 1969, the rubella virus has been included in the measles, mumps, and rubella (MMR) vaccine routinely given to babies and young children.
| 1,084 |
Rubella
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nord_1084_4
|
Related disorders of Rubella
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Symptoms of the following disorders can be similar to those of rubella. Comparisons may be useful for a differential diagnosis:Allergic contact dermatitis is an itchy skin condition caused by an allergic reaction to material in contact with the skin. It arises some hours after the skin has come into contact with the responsible substance, and gradually goes away over a period of days. Contact allergy usually is the result of the allergen on the skin rather than from internal sources or food. The first contact usually does not result in allergy; often the person has been able to touch the material for many years without adverse reaction.Cytomegalovirus, or CMV, is found in all geographic regions and among all socioeconomic groups. By age 40, it infects between 50% and 85% of adults in the United States. CMV is also the virus most frequently transmitted to a developing fetus before birth. CMV infection is more widespread in poor countries and among poor people. Healthy individuals who acquire CMV after birth present with few symptoms and no long-term health consequences. Some people with symptoms experience a mononucleosis-like syndrome with prolonged fever and a mild hepatitis. Once a person becomes infected, the virus remains alive, but usually dormant within that person's body for life. Recurrent disease rarely occurs unless the person's immune system is suppressed due to therapeutic drugs or disease. Herpesvirus 6 infection (HHV-6) is another very widespread disease that is thought to be present in 90-95% of the human population, and in virtually all geographic areas. Primary HHV-6 infection takes place by age 2 and usually presents as an unremarkable illness with fever. The peak age of infection is 6-9 months. Infection lasts for an average of 6 days. Rubella is clinically differentiated from measles by the milder rash that disappears faster and by the absence of the small, irregular, bright red spots (Koplik's spots) on the mucous membranes inside the cheeks and on the tongue, as well as the aversion to light and a cough. A patient with measles appear to be sicker, and the illness lasts longer than is the case with rubella.
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Related disorders of Rubella. Symptoms of the following disorders can be similar to those of rubella. Comparisons may be useful for a differential diagnosis:Allergic contact dermatitis is an itchy skin condition caused by an allergic reaction to material in contact with the skin. It arises some hours after the skin has come into contact with the responsible substance, and gradually goes away over a period of days. Contact allergy usually is the result of the allergen on the skin rather than from internal sources or food. The first contact usually does not result in allergy; often the person has been able to touch the material for many years without adverse reaction.Cytomegalovirus, or CMV, is found in all geographic regions and among all socioeconomic groups. By age 40, it infects between 50% and 85% of adults in the United States. CMV is also the virus most frequently transmitted to a developing fetus before birth. CMV infection is more widespread in poor countries and among poor people. Healthy individuals who acquire CMV after birth present with few symptoms and no long-term health consequences. Some people with symptoms experience a mononucleosis-like syndrome with prolonged fever and a mild hepatitis. Once a person becomes infected, the virus remains alive, but usually dormant within that person's body for life. Recurrent disease rarely occurs unless the person's immune system is suppressed due to therapeutic drugs or disease. Herpesvirus 6 infection (HHV-6) is another very widespread disease that is thought to be present in 90-95% of the human population, and in virtually all geographic areas. Primary HHV-6 infection takes place by age 2 and usually presents as an unremarkable illness with fever. The peak age of infection is 6-9 months. Infection lasts for an average of 6 days. Rubella is clinically differentiated from measles by the milder rash that disappears faster and by the absence of the small, irregular, bright red spots (Koplik's spots) on the mucous membranes inside the cheeks and on the tongue, as well as the aversion to light and a cough. A patient with measles appear to be sicker, and the illness lasts longer than is the case with rubella.
| 1,084 |
Rubella
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nord_1084_5
|
Diagnosis of Rubella
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Since the rubella rash is so much like rashes caused by other viruses, the definitive diagnosis is made on the basis of blood tests for the presence of the virus.
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Diagnosis of Rubella. Since the rubella rash is so much like rashes caused by other viruses, the definitive diagnosis is made on the basis of blood tests for the presence of the virus.
| 1,084 |
Rubella
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nord_1084_6
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Therapies of Rubella
|
TreatmentThere is no specific treatment for rubella, so prevention (through vaccination) is important. Women of childbearing age who are not immune should be immunized. Conception should be prevented afterward until the overseeing physician says that it is safe. Women who become pregnant and have not had rubella or been immunized, or are not certain whether they have, should contact their physicians promptly.
|
Therapies of Rubella. TreatmentThere is no specific treatment for rubella, so prevention (through vaccination) is important. Women of childbearing age who are not immune should be immunized. Conception should be prevented afterward until the overseeing physician says that it is safe. Women who become pregnant and have not had rubella or been immunized, or are not certain whether they have, should contact their physicians promptly.
| 1,084 |
Rubella
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nord_1085_0
|
Overview of Rubella, Congenital
|
Congenital rubella is a syndrome that occurs when a fetus has been infected with the rubella virus while in the uterus. It is primarily characterized by abnormalities of the heart and nervous system, the eyes and the ears. The fetus is most vulnerable to the virus during the first three months of pregnancy, although pregnant women are advised to avoid exposure to rubella virus at all times. Women who contract rubella during pregnancy have a high risk of having a baby with congenital rubella.
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Overview of Rubella, Congenital. Congenital rubella is a syndrome that occurs when a fetus has been infected with the rubella virus while in the uterus. It is primarily characterized by abnormalities of the heart and nervous system, the eyes and the ears. The fetus is most vulnerable to the virus during the first three months of pregnancy, although pregnant women are advised to avoid exposure to rubella virus at all times. Women who contract rubella during pregnancy have a high risk of having a baby with congenital rubella.
| 1,085 |
Rubella, Congenital
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nord_1085_1
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Symptoms of Rubella, Congenital
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Classic congenital rubella syndrome symptoms include a combination of heart, eye and hearing defects, although infection and damage can occur in almost every organ system. Of the abnormalities most likely to be present at birth, cardiovascular defects are most common, such as underdevelopment (hypoplasia) of the pulmonary artery and the failure of a duct connecting the pulmonary artery and aorta (patent ductus arteriosus) to close. Low birth weight, inflammation of the bones (osteitis), enlarged liver and spleen (hepatosplenomegaly), disease of the retina (retinopathy), and cataracts of the crystalline lens of the eye also occur frequently. Brain infection (encephalitis), an abnormally small head (microcephaly), swollen lymph glands (adenopathy), inflammation of the lungs (pneumonitis), jaundice, reduced number of blood platelets (thrombocytopenia), pinpoint purplish red spots due to bleeding in the skin (petechiae) or purpura, and anemia may also occur in babies with this syndrome.Congenital rubella syndrome can be viewed as a chronic infection that may produce progressive damage. Central nervous system abnormalities such as hearing loss, mental retardation, behavior problems and slowness in muscular development, are frequent and significant clinical problems.Most patients who are symptomatic, and many of those who lack signs of infection at birth, will develop some degree of hearing loss or psychomotor damage during early childhood.
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Symptoms of Rubella, Congenital. Classic congenital rubella syndrome symptoms include a combination of heart, eye and hearing defects, although infection and damage can occur in almost every organ system. Of the abnormalities most likely to be present at birth, cardiovascular defects are most common, such as underdevelopment (hypoplasia) of the pulmonary artery and the failure of a duct connecting the pulmonary artery and aorta (patent ductus arteriosus) to close. Low birth weight, inflammation of the bones (osteitis), enlarged liver and spleen (hepatosplenomegaly), disease of the retina (retinopathy), and cataracts of the crystalline lens of the eye also occur frequently. Brain infection (encephalitis), an abnormally small head (microcephaly), swollen lymph glands (adenopathy), inflammation of the lungs (pneumonitis), jaundice, reduced number of blood platelets (thrombocytopenia), pinpoint purplish red spots due to bleeding in the skin (petechiae) or purpura, and anemia may also occur in babies with this syndrome.Congenital rubella syndrome can be viewed as a chronic infection that may produce progressive damage. Central nervous system abnormalities such as hearing loss, mental retardation, behavior problems and slowness in muscular development, are frequent and significant clinical problems.Most patients who are symptomatic, and many of those who lack signs of infection at birth, will develop some degree of hearing loss or psychomotor damage during early childhood.
| 1,085 |
Rubella, Congenital
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nord_1085_2
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Causes of Rubella, Congenital
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Congenital rubella can affect a fetus when a pregnant woman who is not immune to the virus contracts rubella (German Measles). The baby may also be affected if the mother contracts rubella immediately before conception. The fetus is most vulnerable during the first three months (first trimester) of a pregnancy.
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Causes of Rubella, Congenital. Congenital rubella can affect a fetus when a pregnant woman who is not immune to the virus contracts rubella (German Measles). The baby may also be affected if the mother contracts rubella immediately before conception. The fetus is most vulnerable during the first three months (first trimester) of a pregnancy.
| 1,085 |
Rubella, Congenital
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nord_1085_3
|
Affects of Rubella, Congenital
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Congenital rubella is found in newborns and infants of mothers who were infected with rubella immediately before or during the early months of pregnancy. The frequency of congenital rubella thus depends upon the number of women of childbearing age who are susceptible to the virus, and the frequency of rubella infection in the community. Before the development of rubella virus vaccine, epidemics of rubella and congenital rubella occurred about every six to nine years. During epidemic years, congenital rubella infection was found (using serologic testing to identify nonsymptomatic cases) in as many as 2% of newborns; the rate of its presence at other times (the endemic rate) is 0.1%. Widespread use of rubella vaccine in the United States has eliminated epidemics, but the endemic rate of congenital infection appears to be about the same.Both the chance of transmission of rubella to the fetus during pregnancy and the consequences of the infection to the unborn baby are related to the stage of development of the fetus at the time of maternal infection. Maternal infection during the first 8 weeks of pregnancy results in an infection rate in the fetus of about 85%. Subsequently, the rate of transmission drops sharply so that the risk of fetal infection is 50% when the mother is infected during the 12th week of pregnancy, 15% during weeks 13 to 20, and approaching zero after the 20th week of pregnancy.
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Affects of Rubella, Congenital. Congenital rubella is found in newborns and infants of mothers who were infected with rubella immediately before or during the early months of pregnancy. The frequency of congenital rubella thus depends upon the number of women of childbearing age who are susceptible to the virus, and the frequency of rubella infection in the community. Before the development of rubella virus vaccine, epidemics of rubella and congenital rubella occurred about every six to nine years. During epidemic years, congenital rubella infection was found (using serologic testing to identify nonsymptomatic cases) in as many as 2% of newborns; the rate of its presence at other times (the endemic rate) is 0.1%. Widespread use of rubella vaccine in the United States has eliminated epidemics, but the endemic rate of congenital infection appears to be about the same.Both the chance of transmission of rubella to the fetus during pregnancy and the consequences of the infection to the unborn baby are related to the stage of development of the fetus at the time of maternal infection. Maternal infection during the first 8 weeks of pregnancy results in an infection rate in the fetus of about 85%. Subsequently, the rate of transmission drops sharply so that the risk of fetal infection is 50% when the mother is infected during the 12th week of pregnancy, 15% during weeks 13 to 20, and approaching zero after the 20th week of pregnancy.
| 1,085 |
Rubella, Congenital
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nord_1085_4
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Related disorders of Rubella, Congenital
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Related disorders of Rubella, Congenital.
| 1,085 |
Rubella, Congenital
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