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nord_142_6 | Therapies of Banti’s Syndrome | TreatmentTreatment of Banti syndrome is dependent upon the cause. If a contributing factor such as arsenic or azathioprine is identified, the exposure should be stopped.The main clinical problem is bleeding from esophageal or gastric swollen blood vessels (varices). Active bleeding may be treated with vasoconstrictor drugs or other methods used to treat portal hypertension. Recurrent bleeding may require that blood flow be rerouted by a surgical shunt. An orphan drug for bleeding esophageal varices, Ethamolin, was approved by the U.S. Food and Drug Administration (FDA) in 1988. | Therapies of Banti’s Syndrome. TreatmentTreatment of Banti syndrome is dependent upon the cause. If a contributing factor such as arsenic or azathioprine is identified, the exposure should be stopped.The main clinical problem is bleeding from esophageal or gastric swollen blood vessels (varices). Active bleeding may be treated with vasoconstrictor drugs or other methods used to treat portal hypertension. Recurrent bleeding may require that blood flow be rerouted by a surgical shunt. An orphan drug for bleeding esophageal varices, Ethamolin, was approved by the U.S. Food and Drug Administration (FDA) in 1988. | 142 | Banti’s Syndrome |
nord_143_0 | Overview of Barakat Syndrome | First described by Barakat, et al in 1977, the Barakat syndrome, also known as HDR syndrome is a clinically variable (heterogeneous), rare genetic disorder characterized by the triad of hypoparathyroidism (decreased function of the parathyroid glands which are small endocrine glands in the neck whose main function is to maintain the body calcium level), sensorineural deafness and renal disease.Hypoparathyroidism occurs in about 93% of patients. Deafness is the most consistent feature of the syndrome occurring in about 96% of patients. It usually affects both ears and is characterized by early onset and moderate to severe sensorineural hearing loss. Renal disease occurs in about 72% of patients and includes congenital anomalies of the kidney and urinary tract (cystic, dysplastic, hypoplastic or aplastic kidneys, pelvicalyceal deformity, vesicoureteral reflux), blood in the urine (hematuria), increased protein excretion in the urine (proteinuria), nephrotic syndrome (kidney disorder resulting in loss of large amounts of protein in the urine), chronic kidney disease and others. Several additional features have been described; among others, congenital heart disease, facial and ocular abnormalities (retinitis pigmentosa, nystagmus, pseudopapilledema), basal ganglia calcifications, psoriasis, growth failure and cognitive disability. The likelihood of occurrence of each component increases with age, and by age 50 all patients will probably have all three components of the syndrome. | Overview of Barakat Syndrome. First described by Barakat, et al in 1977, the Barakat syndrome, also known as HDR syndrome is a clinically variable (heterogeneous), rare genetic disorder characterized by the triad of hypoparathyroidism (decreased function of the parathyroid glands which are small endocrine glands in the neck whose main function is to maintain the body calcium level), sensorineural deafness and renal disease.Hypoparathyroidism occurs in about 93% of patients. Deafness is the most consistent feature of the syndrome occurring in about 96% of patients. It usually affects both ears and is characterized by early onset and moderate to severe sensorineural hearing loss. Renal disease occurs in about 72% of patients and includes congenital anomalies of the kidney and urinary tract (cystic, dysplastic, hypoplastic or aplastic kidneys, pelvicalyceal deformity, vesicoureteral reflux), blood in the urine (hematuria), increased protein excretion in the urine (proteinuria), nephrotic syndrome (kidney disorder resulting in loss of large amounts of protein in the urine), chronic kidney disease and others. Several additional features have been described; among others, congenital heart disease, facial and ocular abnormalities (retinitis pigmentosa, nystagmus, pseudopapilledema), basal ganglia calcifications, psoriasis, growth failure and cognitive disability. The likelihood of occurrence of each component increases with age, and by age 50 all patients will probably have all three components of the syndrome. | 143 | Barakat Syndrome |
nord_143_1 | Symptoms of Barakat Syndrome | Since newborn hearing screening and prenatal ultrasonography are now performed routinely, deafness and congenital anomalies of the kidney and urinary tract have become the more common modes of presentation. Patients may also present with symptoms associated with low blood calcium (hypocalcemia) caused by malfunction of the parathyroid glands such as muscle weakness, tetany and convulsions, or signs of kidney disease such as proteinuria, hematuria and chronic kidney disease. Deafness may be a presenting symptom or may be found on a routine hearing test at any age. | Symptoms of Barakat Syndrome. Since newborn hearing screening and prenatal ultrasonography are now performed routinely, deafness and congenital anomalies of the kidney and urinary tract have become the more common modes of presentation. Patients may also present with symptoms associated with low blood calcium (hypocalcemia) caused by malfunction of the parathyroid glands such as muscle weakness, tetany and convulsions, or signs of kidney disease such as proteinuria, hematuria and chronic kidney disease. Deafness may be a presenting symptom or may be found on a routine hearing test at any age. | 143 | Barakat Syndrome |
nord_143_2 | Causes of Barakat Syndrome | Barakat syndrome is inherited in an autosomal dominant pattern. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a changed (mutated) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.In most patients, there is a deletion in chromosome 10p14 or heterogenous changes (mutations or pathogenic variants) in the GATA3 gene. The GATA3 gene belongs to a family of dual zinc-finger transcription factors involved in vertebrate embryonic development of the parathyroid glands, auditory system, kidney as well as the thymus and central nervous system. So far, 93 GATA3 pathogenic variants have been reported in the literature. Different variants in the GATA3 gene can result in different clinical presentations of the condition. | Causes of Barakat Syndrome. Barakat syndrome is inherited in an autosomal dominant pattern. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a changed (mutated) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.In most patients, there is a deletion in chromosome 10p14 or heterogenous changes (mutations or pathogenic variants) in the GATA3 gene. The GATA3 gene belongs to a family of dual zinc-finger transcription factors involved in vertebrate embryonic development of the parathyroid glands, auditory system, kidney as well as the thymus and central nervous system. So far, 93 GATA3 pathogenic variants have been reported in the literature. Different variants in the GATA3 gene can result in different clinical presentations of the condition. | 143 | Barakat Syndrome |
nord_143_3 | Affects of Barakat Syndrome | The exact prevalence is unknown, but the disease is considered to be rare. So far, about 200 patients have been reported in the literature worldwide. Clinical awareness of this syndrome will certainly increase the number of patients diagnosed and reported. There is equal prevalence across ethnic groups, genders and ages of diagnosis (from newborns to age 60 years). | Affects of Barakat Syndrome. The exact prevalence is unknown, but the disease is considered to be rare. So far, about 200 patients have been reported in the literature worldwide. Clinical awareness of this syndrome will certainly increase the number of patients diagnosed and reported. There is equal prevalence across ethnic groups, genders and ages of diagnosis (from newborns to age 60 years). | 143 | Barakat Syndrome |
nord_143_4 | Related disorders of Barakat Syndrome | Differential diagnoses of the syndrome include familial isolated hypoparathyroidism and chromosome 22q11.2 deletion syndrome. | Related disorders of Barakat Syndrome. Differential diagnoses of the syndrome include familial isolated hypoparathyroidism and chromosome 22q11.2 deletion syndrome. | 143 | Barakat Syndrome |
nord_143_5 | Diagnosis of Barakat Syndrome | The diagnosis of this syndrome is based on the clinical findings of hypoparathyroidism, deafness and renal disease. The following studies should be performed: parathormone (PTH) and calcium levels, hearing test, urinalysis, imaging studies of the kidneys and possibly a kidney biopsy in the presence of nephrotic syndrome, hematuria or proteinuria. Molecular genetic testing for mutations in the GATA3 gene may be performed in specialized genetic labs. The syndrome should be considered in infants who have been prenatally diagnosed with a chromosome 10p abnormality or congenital anomalies of the kidney and urinary tract. Siblings and family members should be studied for hypoparathyroidism, deafness and renal disease and offered GATA3 gene testing.The “HDR” triad has been found in around 65% of reported cases, while the others seem to have various combinations of hypoparathyroidism, deafness and renal disease. In view of these findings, Barakat et al (2018) suggested that the diagnosis of the syndrome is confirmed in patients who have the “HDR” triad or those who have two of the three findings and a positive family history. Patients with isolated deafness or renal disease and those who do not fit the above criteria need to have a GATA3 gene study to confirm the diagnosis. Pathogenic variants in the GATA3 gene have not been reported in association with isolated hypoparathyroidism. | Diagnosis of Barakat Syndrome. The diagnosis of this syndrome is based on the clinical findings of hypoparathyroidism, deafness and renal disease. The following studies should be performed: parathormone (PTH) and calcium levels, hearing test, urinalysis, imaging studies of the kidneys and possibly a kidney biopsy in the presence of nephrotic syndrome, hematuria or proteinuria. Molecular genetic testing for mutations in the GATA3 gene may be performed in specialized genetic labs. The syndrome should be considered in infants who have been prenatally diagnosed with a chromosome 10p abnormality or congenital anomalies of the kidney and urinary tract. Siblings and family members should be studied for hypoparathyroidism, deafness and renal disease and offered GATA3 gene testing.The “HDR” triad has been found in around 65% of reported cases, while the others seem to have various combinations of hypoparathyroidism, deafness and renal disease. In view of these findings, Barakat et al (2018) suggested that the diagnosis of the syndrome is confirmed in patients who have the “HDR” triad or those who have two of the three findings and a positive family history. Patients with isolated deafness or renal disease and those who do not fit the above criteria need to have a GATA3 gene study to confirm the diagnosis. Pathogenic variants in the GATA3 gene have not been reported in association with isolated hypoparathyroidism. | 143 | Barakat Syndrome |
nord_143_6 | Therapies of Barakat Syndrome | Treatment
Management of patients with this syndrome should be comprehensive and include genetic counseling. Treatment is essentially symptomatic and depends on the clinical findings and severity of the disease. Hypocalcemia is usually the most common problem requiring immediate attention. Treatment of hearing loss in children should be instituted as early as possible with hearing amplification, and if needed cochlear implantation to help their speech, language and social skills so they can reach their full potential. The treatment of kidney disease depends on the abnormality. Some minor abnormalities such as cysts or small kidneys need no treatment but require close observation. Certain kidney and urinary tract abnormalities might need medical or surgical treatment. Since prognosis depends on the nature and severity of the kidney disease, renal function should be carefully monitored. Chronic kidney disease should be diagnosed early and treated promptly to prevent or delay end-stage renal disease (ESRD). Renal transplantation has been performed successfully in patients with ESRD. Patients with minor kidney problems have normal life expectancy. | Therapies of Barakat Syndrome. Treatment
Management of patients with this syndrome should be comprehensive and include genetic counseling. Treatment is essentially symptomatic and depends on the clinical findings and severity of the disease. Hypocalcemia is usually the most common problem requiring immediate attention. Treatment of hearing loss in children should be instituted as early as possible with hearing amplification, and if needed cochlear implantation to help their speech, language and social skills so they can reach their full potential. The treatment of kidney disease depends on the abnormality. Some minor abnormalities such as cysts or small kidneys need no treatment but require close observation. Certain kidney and urinary tract abnormalities might need medical or surgical treatment. Since prognosis depends on the nature and severity of the kidney disease, renal function should be carefully monitored. Chronic kidney disease should be diagnosed early and treated promptly to prevent or delay end-stage renal disease (ESRD). Renal transplantation has been performed successfully in patients with ESRD. Patients with minor kidney problems have normal life expectancy. | 143 | Barakat Syndrome |
nord_144_0 | Overview of Bardet-Biedl Syndrome | SummaryBardet-Biedl syndrome (BBS) is a genetic condition that impacts multiple body systems. It is classically defined by six features. Patients with BBS can experience problems with obesity, specifically with fat deposition along the abdomen. They often also suffer from intellectual impairments. Commonly, the kidneys, eyes and function of the genitalia will be compromised. People with BBS may also be born with an extra digit on the hands. The severity of BBS varies greatly even among individuals within the same family. The symptoms discussed below are those generally seen with BBS. They may or may not be seen in any given person with the syndrome.IntroductionBardet-Biedl syndrome was historically termed Laurence-Moon-Biedl-Bardet syndrome by the physicians who described the first cases of the syndrome. It is now generally considered that Bardet-Biedl syndrome and Laurence-Moon syndrome (see Related Disorders) are distinct conditions. | Overview of Bardet-Biedl Syndrome. SummaryBardet-Biedl syndrome (BBS) is a genetic condition that impacts multiple body systems. It is classically defined by six features. Patients with BBS can experience problems with obesity, specifically with fat deposition along the abdomen. They often also suffer from intellectual impairments. Commonly, the kidneys, eyes and function of the genitalia will be compromised. People with BBS may also be born with an extra digit on the hands. The severity of BBS varies greatly even among individuals within the same family. The symptoms discussed below are those generally seen with BBS. They may or may not be seen in any given person with the syndrome.IntroductionBardet-Biedl syndrome was historically termed Laurence-Moon-Biedl-Bardet syndrome by the physicians who described the first cases of the syndrome. It is now generally considered that Bardet-Biedl syndrome and Laurence-Moon syndrome (see Related Disorders) are distinct conditions. | 144 | Bardet-Biedl Syndrome |
nord_144_1 | Symptoms of Bardet-Biedl Syndrome | The cardinal features of BBS are truncal obesity, intellectual impairment, renal anomalies, polydactyly, retinal degeneration and hypogenitalism. Each feature is discussed in detail below. The term ‘truncal obesity’ refers to a condition where fat is disproportionately distributed onto the abdomen and chest rather than the arms and legs. Individuals can be described as having an apple-shape body type. Weight is usually normal at birth but weight gain is quickly evident through the first year of life in as many as 90% of people with BBS. Diabetes mellitus (specifically, type II diabetes, non-insulin dependent) has been estimated to affect up to 45% of patients with BBS. Weight management problems may further complicate problems with the heart and blood vessels seen in patients with BBS. The heart functions as a pump for the blood, moving the blood through the vessels that bring it throughout the body. The heart relies on valves that keep the flow moving in the forward direction. With age, stiffening of the heart valves is completely normal. The stiffening is due to calcium laying down on the valves, and this process if described by the word “stenosis”. Patients with BBS may experience stenosis of their heart valves prematurely. They may also have defects of the heart’s muscular walls. The heart muscle is designed such that every motion is smoothly orchestrated. Defects in the heart muscle predispose people with BBS to heart beat abnormalities, referred to as “arrhythmias”. Most patients with BBS will experience the loss of a particular population of cells in the eye, specifically in the retina. The retina is part of the eye involved in detecting and decoding incoming images. Incoming light is focused onto the retina at the back of the eye. The retina is composed of cells called “rods and cones”. They translate incoming light into nerve impulses the brain can use. This gradual loss of the rod and cone cells on the retina is described as “dystrophy”. Symptoms associated with cone-rod dystrophy may not become apparent until 7 or 8 years of age when children begin to complain of an inability to see in dimly lit environments, such as a sidewalk lit only by streetlights. This “night blindness” may progress to variable degrees. In most people, the vision becomes progressively weaker through the first and second decades of life. Affected individuals often first lose peripheral vision, and see only what is directly in front of their focus point. They see in what is termed ‘tunnel vision’. Many affected individuals also eventually lose central vision and become legally blind, often by their mid-teens. In some people, the degeneration of the retina may follow a characteristic course, referred to as “retinitis pigmentosa”, (RP). RP begins with night blindness, followed by a loss of the ability to discriminate colors from one another, and finally to a progressive tunnel vision. (For more information, choose “Retinitis Pigmentosa” as your search term in the Rare Disease Database). Additional effects on the eye characteristic to individuals with BBS include: lazy eye (strabismus), clouding of the lens of the eyes (cataracts), and an increased pressure within the eyes that can result in damage to the optic nerve conducting signals to the brain (glaucoma).Of note, many people with BBS also have problems with smell. They have a decreased ability to sense smells due to a change in the size to a brain center called the “olfactory bulb”. This is a relatively a mild problem but may impact safety if people are unable to sense for example, a gas leak from the stove.People with BBS also experience an abnormality of the hands and feet. They may be born with an extra digit near the pinky or an extra toe near the fifth “little” toe. This finding occurs in approximately 70 percent of patients. Specifically, the presence of an extra toe is more common than that of an extra finger. In medical terminology, this is described as ‘postaxial polydactyly’. Fingers and toes may also show webbing, called “syndactyly”. Syndactyly is especially common between the second and third toes. Fingers and toes may occasionally be abnormally short in length. This characteristic is called “brachydactyly”. The feet may overall be short in length, of wide width and carry a flat arch.Another cardinal feature of BBS is a small size and poor function of the male gonads, termed “testicular hypogonadism”. This may manifest as a small penis, failure of the testes to descend into the scrotum (termed “cryptorchidism”) or a delay in the onset of puberty. Undescended testicles are a concern because they are associated with a greater risk for testicular cancer and should not be left unaddressed. Affected females may also have complex genital and urinary tract abnormalities. They may demonstrate an underdeveloped uterus, fallopian tubes, or ovaries. Menstruation cycles are often delayed from the average first age of onset and may also follow an irregular cycle. Problems with fertility arise in both men and women. Pregnant women with BBS should be followed closely by obstetricians that are well trained in dealing with high-risk pregnancies.Some individuals with BBS may develop anomalies of the structure and function of the kidneys. Renal defects are highly variable but generally result in an accumulation of urine in the kidneys that results in inappropriate pressures within the kidneys, leading to stretching of important structures. The dilation resulting from this fluid accumulation is called “hydronephrosis”. It can be monitored by medical imaging such as ultrasound, abdominal x-ray, etc. One common risk that accompanies hydronephrosis includes bacterial infection of the kidneys. The inflammation associated with infection of the kidneys is called “pyelonephritis”. These complications to renal functions can often predispose individuals with BBS to renal failure. Other manifestations of BBS include the development of a cysts and damage to the microscopic filtration unit of the kidney. Kidneys are responsible for filtering the blood and damage to the filtration systems manifest with urine that is dark red blood, possibly even foamy. In scenarios of kidney failure, patients may require dialysis and kidney transplantation. In the scenario that a patient requires kidney transplantation, the use of kidney-protective immunosuppressive medications have been associated with an extra increase in weight gain. This extra weight gain can further complicate any pre-existing diabetes.Mild-to-moderate learning difficulties are common in individuals with BBS. Often, learning disabilities are attributed to weakened cognitive capacity. Some individuals affected with BBS may have true learning disabilities due to dysfunction of brain development. However, it is important to be sure that suspected disabilities (eg: delayed speech or reading skills) are not due to underlying visual impairment. Neurological impairments may manifest in poor coordination, gross and fine motor skills, and social milestones (eg: ability to play complicated games with other children). Many patients report a significant degree of clumsiness and often walk with legs in a wide-based stance. Walking heel-to-toe may be difficult. Some individuals with BBS may also experience problems with their liver. The liver is responsible for many body processes. Among them, it produces a green-brown digestive fluid that the body needs to break food down properly. Specifically, the liver conducts bile through thin ducts that can develop dilation or stricture and leak digestive fluid into the liver, where it causes damage in the form of scarring. More rarely, problems with digestion may be due to Hirschsprung disease. Hirschsprung disease describes an absence of the nerves normally found in the colon that control the innate motion of the colon and move food along the tract.A subgroup of affected individuals may exhibit some distinct facial features. These features including deep-set, widely-spaced eyes with downward-slanting lid folds, a flat nasal bridge with nostrils that flare forward, and a long groove (philtrum) in the center of the upper lip. Individuals may have a high-arched palate, with fewer teeth than expected The teeth may have short roots and lie crowded within the mouth. | Symptoms of Bardet-Biedl Syndrome. The cardinal features of BBS are truncal obesity, intellectual impairment, renal anomalies, polydactyly, retinal degeneration and hypogenitalism. Each feature is discussed in detail below. The term ‘truncal obesity’ refers to a condition where fat is disproportionately distributed onto the abdomen and chest rather than the arms and legs. Individuals can be described as having an apple-shape body type. Weight is usually normal at birth but weight gain is quickly evident through the first year of life in as many as 90% of people with BBS. Diabetes mellitus (specifically, type II diabetes, non-insulin dependent) has been estimated to affect up to 45% of patients with BBS. Weight management problems may further complicate problems with the heart and blood vessels seen in patients with BBS. The heart functions as a pump for the blood, moving the blood through the vessels that bring it throughout the body. The heart relies on valves that keep the flow moving in the forward direction. With age, stiffening of the heart valves is completely normal. The stiffening is due to calcium laying down on the valves, and this process if described by the word “stenosis”. Patients with BBS may experience stenosis of their heart valves prematurely. They may also have defects of the heart’s muscular walls. The heart muscle is designed such that every motion is smoothly orchestrated. Defects in the heart muscle predispose people with BBS to heart beat abnormalities, referred to as “arrhythmias”. Most patients with BBS will experience the loss of a particular population of cells in the eye, specifically in the retina. The retina is part of the eye involved in detecting and decoding incoming images. Incoming light is focused onto the retina at the back of the eye. The retina is composed of cells called “rods and cones”. They translate incoming light into nerve impulses the brain can use. This gradual loss of the rod and cone cells on the retina is described as “dystrophy”. Symptoms associated with cone-rod dystrophy may not become apparent until 7 or 8 years of age when children begin to complain of an inability to see in dimly lit environments, such as a sidewalk lit only by streetlights. This “night blindness” may progress to variable degrees. In most people, the vision becomes progressively weaker through the first and second decades of life. Affected individuals often first lose peripheral vision, and see only what is directly in front of their focus point. They see in what is termed ‘tunnel vision’. Many affected individuals also eventually lose central vision and become legally blind, often by their mid-teens. In some people, the degeneration of the retina may follow a characteristic course, referred to as “retinitis pigmentosa”, (RP). RP begins with night blindness, followed by a loss of the ability to discriminate colors from one another, and finally to a progressive tunnel vision. (For more information, choose “Retinitis Pigmentosa” as your search term in the Rare Disease Database). Additional effects on the eye characteristic to individuals with BBS include: lazy eye (strabismus), clouding of the lens of the eyes (cataracts), and an increased pressure within the eyes that can result in damage to the optic nerve conducting signals to the brain (glaucoma).Of note, many people with BBS also have problems with smell. They have a decreased ability to sense smells due to a change in the size to a brain center called the “olfactory bulb”. This is a relatively a mild problem but may impact safety if people are unable to sense for example, a gas leak from the stove.People with BBS also experience an abnormality of the hands and feet. They may be born with an extra digit near the pinky or an extra toe near the fifth “little” toe. This finding occurs in approximately 70 percent of patients. Specifically, the presence of an extra toe is more common than that of an extra finger. In medical terminology, this is described as ‘postaxial polydactyly’. Fingers and toes may also show webbing, called “syndactyly”. Syndactyly is especially common between the second and third toes. Fingers and toes may occasionally be abnormally short in length. This characteristic is called “brachydactyly”. The feet may overall be short in length, of wide width and carry a flat arch.Another cardinal feature of BBS is a small size and poor function of the male gonads, termed “testicular hypogonadism”. This may manifest as a small penis, failure of the testes to descend into the scrotum (termed “cryptorchidism”) or a delay in the onset of puberty. Undescended testicles are a concern because they are associated with a greater risk for testicular cancer and should not be left unaddressed. Affected females may also have complex genital and urinary tract abnormalities. They may demonstrate an underdeveloped uterus, fallopian tubes, or ovaries. Menstruation cycles are often delayed from the average first age of onset and may also follow an irregular cycle. Problems with fertility arise in both men and women. Pregnant women with BBS should be followed closely by obstetricians that are well trained in dealing with high-risk pregnancies.Some individuals with BBS may develop anomalies of the structure and function of the kidneys. Renal defects are highly variable but generally result in an accumulation of urine in the kidneys that results in inappropriate pressures within the kidneys, leading to stretching of important structures. The dilation resulting from this fluid accumulation is called “hydronephrosis”. It can be monitored by medical imaging such as ultrasound, abdominal x-ray, etc. One common risk that accompanies hydronephrosis includes bacterial infection of the kidneys. The inflammation associated with infection of the kidneys is called “pyelonephritis”. These complications to renal functions can often predispose individuals with BBS to renal failure. Other manifestations of BBS include the development of a cysts and damage to the microscopic filtration unit of the kidney. Kidneys are responsible for filtering the blood and damage to the filtration systems manifest with urine that is dark red blood, possibly even foamy. In scenarios of kidney failure, patients may require dialysis and kidney transplantation. In the scenario that a patient requires kidney transplantation, the use of kidney-protective immunosuppressive medications have been associated with an extra increase in weight gain. This extra weight gain can further complicate any pre-existing diabetes.Mild-to-moderate learning difficulties are common in individuals with BBS. Often, learning disabilities are attributed to weakened cognitive capacity. Some individuals affected with BBS may have true learning disabilities due to dysfunction of brain development. However, it is important to be sure that suspected disabilities (eg: delayed speech or reading skills) are not due to underlying visual impairment. Neurological impairments may manifest in poor coordination, gross and fine motor skills, and social milestones (eg: ability to play complicated games with other children). Many patients report a significant degree of clumsiness and often walk with legs in a wide-based stance. Walking heel-to-toe may be difficult. Some individuals with BBS may also experience problems with their liver. The liver is responsible for many body processes. Among them, it produces a green-brown digestive fluid that the body needs to break food down properly. Specifically, the liver conducts bile through thin ducts that can develop dilation or stricture and leak digestive fluid into the liver, where it causes damage in the form of scarring. More rarely, problems with digestion may be due to Hirschsprung disease. Hirschsprung disease describes an absence of the nerves normally found in the colon that control the innate motion of the colon and move food along the tract.A subgroup of affected individuals may exhibit some distinct facial features. These features including deep-set, widely-spaced eyes with downward-slanting lid folds, a flat nasal bridge with nostrils that flare forward, and a long groove (philtrum) in the center of the upper lip. Individuals may have a high-arched palate, with fewer teeth than expected The teeth may have short roots and lie crowded within the mouth. | 144 | Bardet-Biedl Syndrome |
nord_144_2 | Causes of Bardet-Biedl Syndrome | BBS can be caused by changes (mutations) in more than 20 different genes. It is usually inherited as an autosomal recessive condition. Below you will find a more technical description of the genetic changes that underlie BBS and known clinical associations. There are many gene mutations that are known to lead to the development of BBS, some of which are below.BBS1, BBS2, ARL6 (BBS3), BBS4, BBS5, MKKS (BBS6), BBS7, TTC8 (BBS8), BBS9, BBS10, TRIM32 (BBS11), BBS12,MKS1 (BBS13), CEP290 (BBS14), WDPCP (BBS15),SDCCAG8 (BBS16), LZTFL1 (BBS17), BBIP1 (BBS18), IFT27 (BBS19), IFT72 (BBS20), and C8ORF37(BBS21). Despite the great number of genes already identified as being associated with BBS, gene mutations have not been identified in an estimated 20-30 percent of individuals with BBS.There is moreover no clear link between the different mutations identified and disease severity, but some trends have emerged. Patients with mutations in the BBS1 gene seem to have milder ophthalmologic involvement. In comparison, patients with mutations in the BBS2, BBS3 and BBS4 genes experience classic deterioration of their vision. Patients with mutations in the BBS10 gene generally have significantly increased tendency to obesity and insulin resistance.Human DNA is organized into genes that contain the instructions cells need to produce proteins. Proteins are the major building block of the human body. Mutations in different genes can result in dysfunctional proteins or insufficient amounts of protein. Most of the genes associated with BBS encode proteins called ‘cilia’ and related structures called ‘basal bodies’. Cilia are the tiny hair-like structures that cover different types of cells in the body. The basal bodies are architectural elements which anchor cilia to the cell. Cilia are classified as motile or immotile. Motile cilia help in the beating of fluids through the local environment (eg: protective mucus covering the nasal sinuses). Immotile cilia function as in sensory processes (eg: light-perceptive rod cells of the retina in the eye). Immotile cilia are also required for normal health and development of the body. In BBS, it appears that gene mutations generally affect immotile cilia.Certain symptoms associated with BBS can be attributed specifically to ciliary dysfunction. These features include the classic cone-rod dystrophy and renal abnormalities previously discussed, as well as less commonly seen, anosmia (inability to smell), hearing loss, and situs inversus. Situs inversus is the term used to describe the condition wherein the major body organs exist in a mirror image to the expected anatomy. Other symptoms associated with BBS cannot clearly be attributed to ciliary dysfunction and active research in this domain is on-going.BBS is usually inherited in an autosomal recessive pattern. Recessive genetic disorders manifest when an individual inherits two abnormal alleles (variants, one coming from the mother and one from the father) for a gene. If an individual receives one normal allele and one mutated allele (that is responsible for causing illness), the person will be a carrier for the disease, but usually will not present with symptoms. The risk for two carrier parents to both pass the altered gene and, therefore have an affected child, is 25% with each pregnancy. The risk to have a child who is a carrier for the illness like the parents, is 50% with each pregnancy. The chance for the couple to have a child who receives a set of normal alleles is 25%. With respect to autosomal traits, both males and females are equally affected by allele changes. Rarely, patients may have multiple mutations in multiple genes. For example, when there are two mutations in one gene and a third mutation in a separate gene, the individual is said to have BBS due to a “triallelic inheritance pattern”.Given that BBS manifests in physical features, it is possible to inquire about the status of some babies prenatally. In a family with a history of individuals affected with BBS, a prenatal ultrasound may help in identifying polydactyly discussed above or enlarged kidneys. These findings may raise clinical suspicion for BBS in the baby and help give families time to better plan for the future care of their child ahead of their birth. | Causes of Bardet-Biedl Syndrome. BBS can be caused by changes (mutations) in more than 20 different genes. It is usually inherited as an autosomal recessive condition. Below you will find a more technical description of the genetic changes that underlie BBS and known clinical associations. There are many gene mutations that are known to lead to the development of BBS, some of which are below.BBS1, BBS2, ARL6 (BBS3), BBS4, BBS5, MKKS (BBS6), BBS7, TTC8 (BBS8), BBS9, BBS10, TRIM32 (BBS11), BBS12,MKS1 (BBS13), CEP290 (BBS14), WDPCP (BBS15),SDCCAG8 (BBS16), LZTFL1 (BBS17), BBIP1 (BBS18), IFT27 (BBS19), IFT72 (BBS20), and C8ORF37(BBS21). Despite the great number of genes already identified as being associated with BBS, gene mutations have not been identified in an estimated 20-30 percent of individuals with BBS.There is moreover no clear link between the different mutations identified and disease severity, but some trends have emerged. Patients with mutations in the BBS1 gene seem to have milder ophthalmologic involvement. In comparison, patients with mutations in the BBS2, BBS3 and BBS4 genes experience classic deterioration of their vision. Patients with mutations in the BBS10 gene generally have significantly increased tendency to obesity and insulin resistance.Human DNA is organized into genes that contain the instructions cells need to produce proteins. Proteins are the major building block of the human body. Mutations in different genes can result in dysfunctional proteins or insufficient amounts of protein. Most of the genes associated with BBS encode proteins called ‘cilia’ and related structures called ‘basal bodies’. Cilia are the tiny hair-like structures that cover different types of cells in the body. The basal bodies are architectural elements which anchor cilia to the cell. Cilia are classified as motile or immotile. Motile cilia help in the beating of fluids through the local environment (eg: protective mucus covering the nasal sinuses). Immotile cilia function as in sensory processes (eg: light-perceptive rod cells of the retina in the eye). Immotile cilia are also required for normal health and development of the body. In BBS, it appears that gene mutations generally affect immotile cilia.Certain symptoms associated with BBS can be attributed specifically to ciliary dysfunction. These features include the classic cone-rod dystrophy and renal abnormalities previously discussed, as well as less commonly seen, anosmia (inability to smell), hearing loss, and situs inversus. Situs inversus is the term used to describe the condition wherein the major body organs exist in a mirror image to the expected anatomy. Other symptoms associated with BBS cannot clearly be attributed to ciliary dysfunction and active research in this domain is on-going.BBS is usually inherited in an autosomal recessive pattern. Recessive genetic disorders manifest when an individual inherits two abnormal alleles (variants, one coming from the mother and one from the father) for a gene. If an individual receives one normal allele and one mutated allele (that is responsible for causing illness), the person will be a carrier for the disease, but usually will not present with symptoms. The risk for two carrier parents to both pass the altered gene and, therefore have an affected child, is 25% with each pregnancy. The risk to have a child who is a carrier for the illness like the parents, is 50% with each pregnancy. The chance for the couple to have a child who receives a set of normal alleles is 25%. With respect to autosomal traits, both males and females are equally affected by allele changes. Rarely, patients may have multiple mutations in multiple genes. For example, when there are two mutations in one gene and a third mutation in a separate gene, the individual is said to have BBS due to a “triallelic inheritance pattern”.Given that BBS manifests in physical features, it is possible to inquire about the status of some babies prenatally. In a family with a history of individuals affected with BBS, a prenatal ultrasound may help in identifying polydactyly discussed above or enlarged kidneys. These findings may raise clinical suspicion for BBS in the baby and help give families time to better plan for the future care of their child ahead of their birth. | 144 | Bardet-Biedl Syndrome |
nord_144_3 | Affects of Bardet-Biedl Syndrome | BBS affects males and females in equal numbers. The prevalence is estimated to be 1 in 100,000 in the non-related (non-consanguineous) populations of Northern Europe and America. In Sweden, the prevalence is estimated to be 1 in 160,000. The disorder occurs with greater frequency in the Bedouin population of Kuwait (1 in 13,500) and in certain populations of Newfoundland (1 in 17,500). A specific mutation (K243lfsX15) in the BBS10 gene is particularly common in South Africa. | Affects of Bardet-Biedl Syndrome. BBS affects males and females in equal numbers. The prevalence is estimated to be 1 in 100,000 in the non-related (non-consanguineous) populations of Northern Europe and America. In Sweden, the prevalence is estimated to be 1 in 160,000. The disorder occurs with greater frequency in the Bedouin population of Kuwait (1 in 13,500) and in certain populations of Newfoundland (1 in 17,500). A specific mutation (K243lfsX15) in the BBS10 gene is particularly common in South Africa. | 144 | Bardet-Biedl Syndrome |
nord_144_4 | Related disorders of Bardet-Biedl Syndrome | The conditions below are ones which may clinically resemble BBS. The list below can be useful in establishing a differential diagnosis.Laurence-Moon syndrome (LMS)
LMS is a rare autosomal recessive condition defined by visual degeneration compounded with pituitary dysfunction. The pituitary gland serves to regulate the major chemicals that drive body processes, ranging from growth and metabolism to reproduction potential. LMS is characterized by childhood neurological problems including loss of control over movement. Loss of peripheral nerves, those outside of the brain and spinal cord, result in a stiffness-contraction of the limbs. Intellectual disabilities may be associated but are poorly defined. Like BBS, LMS is also seen at increased incidence in the Arab populations of Kuwait. Alstrom syndrome
Alstrom syndrome is a rare autosomal recessive disorder characterized by vision and hearing abnormalities, childhood obesity, diabetes mellitus, and slowly progressive kidney dysfunction. Specific features vary significantly from person to person. Initial symptoms usually include an insensitivity to light and series of rapid, involuntary eye movements described under the term, “nystagmus”. Additional features sometimes associated with Alstrom syndrome include dysfunction of heart muscle and the skin. Intelligence is not affected. (For more information on this disorder, choose “Alstrom” as your search term in the Rare Disease Database.)Meckel syndrome
Meckel syndrome, also known as Meckel-Gruber syndrome, is inherited as an autosomal recessive disorder. This rare condition is characterized by abnormalities affecting several organ systems of the body. Characteristic findings include protrusion of part of the brain and its surrounding membranes (meninges) through a defect in the back or front of the skull. This protrusion is described by the term, “encephalocele”. This condition, like BBS, may manifest with an extra finger or toe at birth, or multiple cysts on the kidneys. Additional findings that may mimic BBS include scarring-fibrosis of the liver and genital abnormalities. Patients most commonly have central nervous system abnormalities, and underdevelopment of the lungs. Mutations in certain Bardet-Biedl genes (i.e., BBS2, BBS4 and BBS6) have been detected in some individuals with Meckel syndrome, meaning that in such cases Bardet-Biedl syndrome and Meckel syndrome occur from different mutations of the same gene (allelic). (For more information on this disorder, choose “Meckel” as your search term in the Rare Disease Database.)McKusick-Kaufman syndrome (MKKS)
MKKS is inherited as an autosomal recessive trait. It is an extremely rare genetic disorder characterized by the presence of an extra finger near the pinky or an extra toe near the fifth toe (postaxial polydactyly), congenital heart defects, and, in females, a collection of watery fluid in the uterus and vagina called “hydrometrocolpos” that results in dilation of the organs. Additional symptoms include genitourinary abnormalities, underdeveloped lungs, gastrointestinal abnormalities, and kidney defects. The disorder occurs due to mutations of the MKKS gene. This gene is also known as the BBS6 gene and has been linked to BBS.Biemon II syndrome
Biemond II syndrome is inherited as an autosomal recessive trait. This syndrome is an extremely rare genetic disorder characterized by absence of tissue from the colored portion of the eye (iris coloboma), intellectual disability, obesity, genitourinary abnormalities, and an extra finger near the pinky or an extra toe near the fifth toe (postaxial polydactyly). Causal genes for this disorder have not yet been identified.Prader-Willi syndrome
Prader-Willi syndrome is a genetic disorder characterized by weak resting muscle strength (hypotonia), feeding difficulties, and failure to gain weight through infancy (failure to thrive). In later childhood, features of the disorder include short stature, genital abnormalities and an excessive appetite. Progressive obesity presents in most people with this condition because of a lack of feeling satisfied after completing a meal (satiety) that leads to overeating. All individuals with Prader-Willi syndrome have some degree of cognitive impairment that ranges from borderline normal with learning disabilities to severe intellectual disability. Behavior problems are common and can manifest as temper tantrums, obsessive/compulsive behavior, or skin picking. Prader-Willi syndrome occurs when the genes in a specific region of chromosome 15 do not function. The abnormal genes usually result from random errors in development, but are sometimes inherited. (For more information on this disorder, choose “Prader Willi” as your search term in the Rare Disease Database.) | Related disorders of Bardet-Biedl Syndrome. The conditions below are ones which may clinically resemble BBS. The list below can be useful in establishing a differential diagnosis.Laurence-Moon syndrome (LMS)
LMS is a rare autosomal recessive condition defined by visual degeneration compounded with pituitary dysfunction. The pituitary gland serves to regulate the major chemicals that drive body processes, ranging from growth and metabolism to reproduction potential. LMS is characterized by childhood neurological problems including loss of control over movement. Loss of peripheral nerves, those outside of the brain and spinal cord, result in a stiffness-contraction of the limbs. Intellectual disabilities may be associated but are poorly defined. Like BBS, LMS is also seen at increased incidence in the Arab populations of Kuwait. Alstrom syndrome
Alstrom syndrome is a rare autosomal recessive disorder characterized by vision and hearing abnormalities, childhood obesity, diabetes mellitus, and slowly progressive kidney dysfunction. Specific features vary significantly from person to person. Initial symptoms usually include an insensitivity to light and series of rapid, involuntary eye movements described under the term, “nystagmus”. Additional features sometimes associated with Alstrom syndrome include dysfunction of heart muscle and the skin. Intelligence is not affected. (For more information on this disorder, choose “Alstrom” as your search term in the Rare Disease Database.)Meckel syndrome
Meckel syndrome, also known as Meckel-Gruber syndrome, is inherited as an autosomal recessive disorder. This rare condition is characterized by abnormalities affecting several organ systems of the body. Characteristic findings include protrusion of part of the brain and its surrounding membranes (meninges) through a defect in the back or front of the skull. This protrusion is described by the term, “encephalocele”. This condition, like BBS, may manifest with an extra finger or toe at birth, or multiple cysts on the kidneys. Additional findings that may mimic BBS include scarring-fibrosis of the liver and genital abnormalities. Patients most commonly have central nervous system abnormalities, and underdevelopment of the lungs. Mutations in certain Bardet-Biedl genes (i.e., BBS2, BBS4 and BBS6) have been detected in some individuals with Meckel syndrome, meaning that in such cases Bardet-Biedl syndrome and Meckel syndrome occur from different mutations of the same gene (allelic). (For more information on this disorder, choose “Meckel” as your search term in the Rare Disease Database.)McKusick-Kaufman syndrome (MKKS)
MKKS is inherited as an autosomal recessive trait. It is an extremely rare genetic disorder characterized by the presence of an extra finger near the pinky or an extra toe near the fifth toe (postaxial polydactyly), congenital heart defects, and, in females, a collection of watery fluid in the uterus and vagina called “hydrometrocolpos” that results in dilation of the organs. Additional symptoms include genitourinary abnormalities, underdeveloped lungs, gastrointestinal abnormalities, and kidney defects. The disorder occurs due to mutations of the MKKS gene. This gene is also known as the BBS6 gene and has been linked to BBS.Biemon II syndrome
Biemond II syndrome is inherited as an autosomal recessive trait. This syndrome is an extremely rare genetic disorder characterized by absence of tissue from the colored portion of the eye (iris coloboma), intellectual disability, obesity, genitourinary abnormalities, and an extra finger near the pinky or an extra toe near the fifth toe (postaxial polydactyly). Causal genes for this disorder have not yet been identified.Prader-Willi syndrome
Prader-Willi syndrome is a genetic disorder characterized by weak resting muscle strength (hypotonia), feeding difficulties, and failure to gain weight through infancy (failure to thrive). In later childhood, features of the disorder include short stature, genital abnormalities and an excessive appetite. Progressive obesity presents in most people with this condition because of a lack of feeling satisfied after completing a meal (satiety) that leads to overeating. All individuals with Prader-Willi syndrome have some degree of cognitive impairment that ranges from borderline normal with learning disabilities to severe intellectual disability. Behavior problems are common and can manifest as temper tantrums, obsessive/compulsive behavior, or skin picking. Prader-Willi syndrome occurs when the genes in a specific region of chromosome 15 do not function. The abnormal genes usually result from random errors in development, but are sometimes inherited. (For more information on this disorder, choose “Prader Willi” as your search term in the Rare Disease Database.) | 144 | Bardet-Biedl Syndrome |
nord_144_5 | Diagnosis of Bardet-Biedl Syndrome | BBS is generally diagnosed based upon identification of characteristic findings described above (eg: visual problems due to retinal dystrophy, truncal obesity, post-axial polydactyly). As diagnosis is based on clinical findings and BBS is associated with variable expression of the classical features, some patients may not have a clear diagnosis for many years. Difficulties with diagnosis arise when a child demonstrates learning disabilities and problems with weight management but who was not born with any congenital abnormality. For these children, diagnosis may remain uncertain until they begin to manifest vision loss symptoms. Diagnosis of retinal disease may require consultation with an ophthalmologist and an examination including an electroretinogram (ERG). The ERG is a procedure that measures the electrical response of the retina to light stimulation. Genetic testing may help confirm the diagnosis for some patients (e.g., individuals with certain BBS1 and BBS10 gene mutations). However, such testing may not be covered by insurance and available only through research laboratories with a special interest in BBS. | Diagnosis of Bardet-Biedl Syndrome. BBS is generally diagnosed based upon identification of characteristic findings described above (eg: visual problems due to retinal dystrophy, truncal obesity, post-axial polydactyly). As diagnosis is based on clinical findings and BBS is associated with variable expression of the classical features, some patients may not have a clear diagnosis for many years. Difficulties with diagnosis arise when a child demonstrates learning disabilities and problems with weight management but who was not born with any congenital abnormality. For these children, diagnosis may remain uncertain until they begin to manifest vision loss symptoms. Diagnosis of retinal disease may require consultation with an ophthalmologist and an examination including an electroretinogram (ERG). The ERG is a procedure that measures the electrical response of the retina to light stimulation. Genetic testing may help confirm the diagnosis for some patients (e.g., individuals with certain BBS1 and BBS10 gene mutations). However, such testing may not be covered by insurance and available only through research laboratories with a special interest in BBS. | 144 | Bardet-Biedl Syndrome |
nord_144_6 | Therapies of Bardet-Biedl Syndrome | Treatment
The primary treatment goal for patients with BBS involves treating the specific symptoms affecting each individual. Early intervention for anticipated problems can ensure that people with BBS reach their greatest potential. As many body systems are involved, care often requires the coordinated effort of a team of specialists.Puberty is a stressful period in the life of any person. It is beneficial to individuals with BBS to seek the guidance of an experienced counselor. Patients with low hormone levels may be prescribed supplements under the guidance of an endocrinologist.Some of the physical abnormalities associated with BBS can be corrected with surgery, including extra digits, and some genitourinary abnormalities and congenital heart defects. Kidney transplantation may be appropriate later in life if severe kidney disease develops. Surgery is a point of particular concern for patients with BBS. General anesthesia requires a series of highly coordinated steps that rely on the anatomy of the airways. Some patients with BBS may have significant anatomical anomalies in the airways and this might result in increased difficulty holding the airway open during general anesthesia. If this is the case, anesthetic medications may be introduced in the form of direct nerve blocks to a region of the body with while the patient is breathing for themselves.As obesity is a common component to BBS, this is a particularly important factor to address. This feature manifests typically by an age of two-three years. An active lifestyle incorporating athletic hobbies can make a significant impact. Both diet and exercise programs are also highly recommended. Good diet management can prevent the weight-related problems that manifest in later life. Consulting with a primary care physician and a dietician can help in planning for adequate nutrition and prevention of excess weight gain. If problems with high cholesterol and diabetes exist, they are treated as in the general population. Bariatric surgery with gastric banding or sleeve surgery has been attempted only in very few patients with BBS. In those patients, surgery was associated with a weight loss of 25% maintained at 12 months after procedure. Long-term follow-up of these patients is being conducted to determine the possible role for bariatric surgery in patients with BBS.The eye problems are of central concern with BBS. The first symptom onset is usually that of night-blindness, typically seen around age 8-9 years of age. Vitamin A deficiency can exacerbate visual difficulties and age-appropriate vitamin and mineral supplements can help support best function. While there are currently no proven therapies available to cure the retinal dystrophy associated with BBS, care under the supervision of an ophthalmologist is critical. Ophthalmologists can help correct refractive errors (e.g., myopia/near-sightedness or hyperopia/far-sightedness) and low-visual acuity problems. Individuals with BBS should undergo regular ophthalmologic examinations and keep up with their changing prescription lenses. As visual impairment is a major hurdle to learning in the classroom, special services might be organized between a child’s physician and their school. In 2022, the U.S. Food and Drug Administration (FDA) approved setmelanotide (Imcivree) as a treatment option for chronic weight management in adult and pediatric patients 6 years and older with obesity due to BBS. Finally, as with any genetic condition, genetic counseling is recommended for affected individuals and their families. | Therapies of Bardet-Biedl Syndrome. Treatment
The primary treatment goal for patients with BBS involves treating the specific symptoms affecting each individual. Early intervention for anticipated problems can ensure that people with BBS reach their greatest potential. As many body systems are involved, care often requires the coordinated effort of a team of specialists.Puberty is a stressful period in the life of any person. It is beneficial to individuals with BBS to seek the guidance of an experienced counselor. Patients with low hormone levels may be prescribed supplements under the guidance of an endocrinologist.Some of the physical abnormalities associated with BBS can be corrected with surgery, including extra digits, and some genitourinary abnormalities and congenital heart defects. Kidney transplantation may be appropriate later in life if severe kidney disease develops. Surgery is a point of particular concern for patients with BBS. General anesthesia requires a series of highly coordinated steps that rely on the anatomy of the airways. Some patients with BBS may have significant anatomical anomalies in the airways and this might result in increased difficulty holding the airway open during general anesthesia. If this is the case, anesthetic medications may be introduced in the form of direct nerve blocks to a region of the body with while the patient is breathing for themselves.As obesity is a common component to BBS, this is a particularly important factor to address. This feature manifests typically by an age of two-three years. An active lifestyle incorporating athletic hobbies can make a significant impact. Both diet and exercise programs are also highly recommended. Good diet management can prevent the weight-related problems that manifest in later life. Consulting with a primary care physician and a dietician can help in planning for adequate nutrition and prevention of excess weight gain. If problems with high cholesterol and diabetes exist, they are treated as in the general population. Bariatric surgery with gastric banding or sleeve surgery has been attempted only in very few patients with BBS. In those patients, surgery was associated with a weight loss of 25% maintained at 12 months after procedure. Long-term follow-up of these patients is being conducted to determine the possible role for bariatric surgery in patients with BBS.The eye problems are of central concern with BBS. The first symptom onset is usually that of night-blindness, typically seen around age 8-9 years of age. Vitamin A deficiency can exacerbate visual difficulties and age-appropriate vitamin and mineral supplements can help support best function. While there are currently no proven therapies available to cure the retinal dystrophy associated with BBS, care under the supervision of an ophthalmologist is critical. Ophthalmologists can help correct refractive errors (e.g., myopia/near-sightedness or hyperopia/far-sightedness) and low-visual acuity problems. Individuals with BBS should undergo regular ophthalmologic examinations and keep up with their changing prescription lenses. As visual impairment is a major hurdle to learning in the classroom, special services might be organized between a child’s physician and their school. In 2022, the U.S. Food and Drug Administration (FDA) approved setmelanotide (Imcivree) as a treatment option for chronic weight management in adult and pediatric patients 6 years and older with obesity due to BBS. Finally, as with any genetic condition, genetic counseling is recommended for affected individuals and their families. | 144 | Bardet-Biedl Syndrome |
nord_145_0 | Overview of Barth Syndrome | SummaryBarth syndrome is a genetic condition that mainly affects males. Some of the symptoms of the condition include enlarged heart, low blood cell count, weakness of muscles, and fatigue. Additionally, there can be increased levels of chemicals like 3-methyglutaconic acid and 2-ethyl hydracrylic acid in the urine or blood. Barth syndrome is caused by changes (mutations) in the TAZ gene and has an X-linked inheritance pattern.Introduction In 1983, multiple boys from a Dutch family were reported with enlarged and weakened heart (dilated cardiomyopathy), low white blood cells (neutropenia) and fatigue and weakness of muscles (hypotonia). This condition was named Barth syndrome after Dr. Peter Barth and is also called X-linked endocardial fibroelastosis because of the shiny white appearance of the inner membrane of the heart muscle. In 1996, mutations in the TAZ gene were found to be the cause of Barth syndrome. | Overview of Barth Syndrome. SummaryBarth syndrome is a genetic condition that mainly affects males. Some of the symptoms of the condition include enlarged heart, low blood cell count, weakness of muscles, and fatigue. Additionally, there can be increased levels of chemicals like 3-methyglutaconic acid and 2-ethyl hydracrylic acid in the urine or blood. Barth syndrome is caused by changes (mutations) in the TAZ gene and has an X-linked inheritance pattern.Introduction In 1983, multiple boys from a Dutch family were reported with enlarged and weakened heart (dilated cardiomyopathy), low white blood cells (neutropenia) and fatigue and weakness of muscles (hypotonia). This condition was named Barth syndrome after Dr. Peter Barth and is also called X-linked endocardial fibroelastosis because of the shiny white appearance of the inner membrane of the heart muscle. In 1996, mutations in the TAZ gene were found to be the cause of Barth syndrome. | 145 | Barth Syndrome |
nord_145_1 | Symptoms of Barth Syndrome | Barth syndrome is mainly found in early infancy or childhood. However, in some patients, symptoms appear in adulthood. Symptoms can present differently and can vary from one person to another. Males with Barth syndrome could have various heart problems like dilated cardiomyopathy, hypertrophic cardiomyopathy, endocardial fibroelastosis and left ventricular non-compaction. Dilated cardiomyopathy is when the left ventricle muscle becomes enlarged and weak which decreases the heart’s ability to pump blood. In some people with Barth syndrome, the heart muscles become very thick making it difficult to pump blood (hypertrophic cardiomyopathy). Sometimes, this thickening may be due to the build-up of connective tissues and elastin fibres (endocardial fibroelastosis). In other patients, the left ventricles do not develop properly (left ventricular noncompaction) so instead of the muscle being smooth, it becomes thick and spongy making it difficult to pump blood. These heart findings are almost always present before the age of 5. Sometimes the heart problems can be seen on an ultrasound exam in the last trimester in pregnancy. In addition to structural differences to the heart, in some adolescents and young adults, there could be an irregular heartbeat identified (arrhythmia). The heart problems might lead to decrease in blood circulation from in the body and to the lungs (heart failure). Symptoms of heart failure may include shortness of breath, tiredness and nausea, but the symptoms depend on the child and other factors. People with Barth syndrome have a low level of white blood cells (neutropenia). The white blood cells in our body help us fight infections. Due to neutropenia, people have mouth ulcers, pneumonia or blood infections. Males with Barth syndrome have weak muscles (hypotonia) especially in the hands and feet. Due to the hypotonia, children take longer to develop gross motor skills like crawling, sitting or walking. Due to the heart issues and weak muscles, these boys do not tolerate exercise well. Males with the condition have growth delay during childhood, but there is a significant growth spurt in puberty. Other symptoms include curvature of the spine (scoliosis) and delayed bone age.Males with Barth syndrome have distinct facial features. They have a round face with prominent chin and full cheeks. The ears are large, and they have deep set eyes. The facial features become less noticeable with age. The striking feature in adolescence and adulthood is the fat distribution in the hips, thighs and chest. People diagnosed with the condition have some form of learning disability. They have age appropriate reading skills and vocabulary. However, they may need extra help with mathematics. Their first words or forming sentences can be delayed in comparison to other people. They have delay in developing skills like reading a map, recognizing shapes and finding objects in a picture. The boys have feeding difficulties. The Barth syndrome registry data suggest that a third of males with this condition would need a tube put through the nose or directly to the stomach for feeding. Boys with this condition are picky eaters. Salty, cheesy and spicy food are some of the foods they prefer. In addition to the cardiomyopathy, neutropenia and growth delay, people with this condition have increased levels of biochemical markers. Increased levels of 3-methyglutaconic acid and 2-ethyl hydracrylic acid in the urine or blood is the common marker used to reach a diagnosis. However, there have been no symptoms associated with the increased levels of these chemicals. | Symptoms of Barth Syndrome. Barth syndrome is mainly found in early infancy or childhood. However, in some patients, symptoms appear in adulthood. Symptoms can present differently and can vary from one person to another. Males with Barth syndrome could have various heart problems like dilated cardiomyopathy, hypertrophic cardiomyopathy, endocardial fibroelastosis and left ventricular non-compaction. Dilated cardiomyopathy is when the left ventricle muscle becomes enlarged and weak which decreases the heart’s ability to pump blood. In some people with Barth syndrome, the heart muscles become very thick making it difficult to pump blood (hypertrophic cardiomyopathy). Sometimes, this thickening may be due to the build-up of connective tissues and elastin fibres (endocardial fibroelastosis). In other patients, the left ventricles do not develop properly (left ventricular noncompaction) so instead of the muscle being smooth, it becomes thick and spongy making it difficult to pump blood. These heart findings are almost always present before the age of 5. Sometimes the heart problems can be seen on an ultrasound exam in the last trimester in pregnancy. In addition to structural differences to the heart, in some adolescents and young adults, there could be an irregular heartbeat identified (arrhythmia). The heart problems might lead to decrease in blood circulation from in the body and to the lungs (heart failure). Symptoms of heart failure may include shortness of breath, tiredness and nausea, but the symptoms depend on the child and other factors. People with Barth syndrome have a low level of white blood cells (neutropenia). The white blood cells in our body help us fight infections. Due to neutropenia, people have mouth ulcers, pneumonia or blood infections. Males with Barth syndrome have weak muscles (hypotonia) especially in the hands and feet. Due to the hypotonia, children take longer to develop gross motor skills like crawling, sitting or walking. Due to the heart issues and weak muscles, these boys do not tolerate exercise well. Males with the condition have growth delay during childhood, but there is a significant growth spurt in puberty. Other symptoms include curvature of the spine (scoliosis) and delayed bone age.Males with Barth syndrome have distinct facial features. They have a round face with prominent chin and full cheeks. The ears are large, and they have deep set eyes. The facial features become less noticeable with age. The striking feature in adolescence and adulthood is the fat distribution in the hips, thighs and chest. People diagnosed with the condition have some form of learning disability. They have age appropriate reading skills and vocabulary. However, they may need extra help with mathematics. Their first words or forming sentences can be delayed in comparison to other people. They have delay in developing skills like reading a map, recognizing shapes and finding objects in a picture. The boys have feeding difficulties. The Barth syndrome registry data suggest that a third of males with this condition would need a tube put through the nose or directly to the stomach for feeding. Boys with this condition are picky eaters. Salty, cheesy and spicy food are some of the foods they prefer. In addition to the cardiomyopathy, neutropenia and growth delay, people with this condition have increased levels of biochemical markers. Increased levels of 3-methyglutaconic acid and 2-ethyl hydracrylic acid in the urine or blood is the common marker used to reach a diagnosis. However, there have been no symptoms associated with the increased levels of these chemicals. | 145 | Barth Syndrome |
nord_145_2 | Causes of Barth Syndrome | Barth syndrome is caused by mutations in the TAZ gene. The TAZ gene produces a protein called tafazzin. Tafazzin helps in altering a fat called cardiolipin. Cardiolipin is present in the inner membrane of structures called mitochondria. Mitochondria are structures in the cell which helps in making energy. Loss of tafazzin protein mainly affects energy requiring organs like heart and skeletal muscles. However, more research is required to understand how the loss of tafazzin leads to cardiomyopathy and neutropenia.
Barth syndrome is inherited in an X-linked manner. X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and manifest mostly in males. Females that have an abnormal gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the abnormal gene. No females who are carriers for Barth syndrome have reported any symptoms.
Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains an abnormal gene, he will develop the disease.Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son. If a male with an X-linked disorder can reproduce, he will pass the non-working gene to all his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. | Causes of Barth Syndrome. Barth syndrome is caused by mutations in the TAZ gene. The TAZ gene produces a protein called tafazzin. Tafazzin helps in altering a fat called cardiolipin. Cardiolipin is present in the inner membrane of structures called mitochondria. Mitochondria are structures in the cell which helps in making energy. Loss of tafazzin protein mainly affects energy requiring organs like heart and skeletal muscles. However, more research is required to understand how the loss of tafazzin leads to cardiomyopathy and neutropenia.
Barth syndrome is inherited in an X-linked manner. X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and manifest mostly in males. Females that have an abnormal gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the abnormal gene. No females who are carriers for Barth syndrome have reported any symptoms.
Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains an abnormal gene, he will develop the disease.Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son. If a male with an X-linked disorder can reproduce, he will pass the non-working gene to all his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. | 145 | Barth Syndrome |
nord_145_3 | Affects of Barth Syndrome | Barth syndrome affects all ethnic groups. The incidence of Barth syndrome is estimated to be 1 in 300,000 to 1 in 400,00 in United States. As of 2013, there have been 151 patients reported in the medical literature. | Affects of Barth Syndrome. Barth syndrome affects all ethnic groups. The incidence of Barth syndrome is estimated to be 1 in 300,000 to 1 in 400,00 in United States. As of 2013, there have been 151 patients reported in the medical literature. | 145 | Barth Syndrome |
nord_145_4 | Related disorders of Barth Syndrome | Researchers have seen that mutations in the TAZ gene causes a wide range of symptoms. There have been patients reported with several heart conditions like dilated cardiomyopathy, noncompaction of left ventricle and endocardial fibroelastosis but without other Barth syndrome symptoms like low white blood count, growth delay and increased biochemical levels of 3-methyglutaconic acid and 2-ethyl hydracrylic acid. Dilated cardiomyopathy with ataxia is a genetic disorder caused by mutations in the DNAJC19 gene. This condition is seen in early infancy or childhood and symptoms include imbalance in walking, arrhythmia which may lead to fainting, genital problems and anemia. People with this condition have increased levels of 3-methylglutaconic acid in the urine. Due to the similarities in the heart issues and elevated biochemical levels, this condition is considered as a differential diagnosis for Barth syndrome. However, other characteristics like the genital abnormalities and balance issues help diagnose this condition. Dilated cardiomyopathy with ataxia is inherited in an autosomal recessive pattern. Familial dilated cardiomyopathy has also been described in adolescents and adults in several families in which the condition appears to be inherited in an X-linked manner. Some females who carry a copy of a mutated gene for the condition may develop symptoms. In these patients, cardiac disease occurred without neutropenia or biochemical abnormalities associated with Barth syndrome (e.g., 3-methylglutaconic aciduria). In some affected families, the condition has been shown to result from mutations in the dystrophin gene that is thought to play a role in maintaining the structure of heart and skeletal muscle units. Various mutations of the dystrophin gene have also been identified in males with Duchenne or Becker muscular dystrophy. For further information on these disorders, please use “Duchenne” or “Becker” as your search term in the Rare Disease Database.) Several forms of familial dilated cardiomyopathy have also been reported that have been shown to result from mutations of various genes transmitted in an autosomal dominant or autosomal recessive pattern.Endocardial fibroelastosis may also occur as a primary condition that appears to be transmitted in an X-linked recessive pattern. Investigators have reported several families in which affected members, primarily infants and children, have developed diffuse, patchy thickening of the endocardium (innermost layer of the heart), primarily of the left ventricle, due to overgrowth (proliferation) of elastic and fibrous tissues. Associated findings may include symptoms of heart failure in the first months or years of life. Some researchers question whether X-linked endocardial fibroelastosis is a distinct disease entity, indicating that it may in fact represent a variant of Barth syndrome. However, very few families with apparently isolated, X-linked endocardial fibroelastosis have been tested for mutations in the TAZ gene.Acute viral cardiomyopathy is a heart condition characterized by sudden (acute) inflammation of heart muscle (myocarditis) due to viral infections. Initial symptoms may include a sudden onset of fever and flu-like symptoms. In addition, myocardial inflammation causes weakening of the heart muscle, leading to (dilated cardiomyopathy and heart failure. Associated findings may include fatigue, shortness of breath, arrhythmias, and other findings, leading to potentially life-threatening complications without appropriate treatment. Viral cardiomyopathy has often been the diagnosis given to children with Barth syndrome before recognition of other abnormalities, such as neutropenia or 3-methylglutaconic aciduria, led to the correct diagnosis.There are additional disorders of mitochondrial metabolism that may be associated with certain symptoms and findings like those seen in Barth syndrome, such as cardiomyopathy, neuromuscular abnormalities, delayed growth, and/or elevated urinary levels of 3-methylglutaconic acid. However, evidence suggests that such disorders may not be associated with other findings characteristic of Barth syndrome (e.g., neutropenia)–and/or may have other, distinctive features, such as additional biochemical findings, severe neurological symptoms, and/or other abnormalities. | Related disorders of Barth Syndrome. Researchers have seen that mutations in the TAZ gene causes a wide range of symptoms. There have been patients reported with several heart conditions like dilated cardiomyopathy, noncompaction of left ventricle and endocardial fibroelastosis but without other Barth syndrome symptoms like low white blood count, growth delay and increased biochemical levels of 3-methyglutaconic acid and 2-ethyl hydracrylic acid. Dilated cardiomyopathy with ataxia is a genetic disorder caused by mutations in the DNAJC19 gene. This condition is seen in early infancy or childhood and symptoms include imbalance in walking, arrhythmia which may lead to fainting, genital problems and anemia. People with this condition have increased levels of 3-methylglutaconic acid in the urine. Due to the similarities in the heart issues and elevated biochemical levels, this condition is considered as a differential diagnosis for Barth syndrome. However, other characteristics like the genital abnormalities and balance issues help diagnose this condition. Dilated cardiomyopathy with ataxia is inherited in an autosomal recessive pattern. Familial dilated cardiomyopathy has also been described in adolescents and adults in several families in which the condition appears to be inherited in an X-linked manner. Some females who carry a copy of a mutated gene for the condition may develop symptoms. In these patients, cardiac disease occurred without neutropenia or biochemical abnormalities associated with Barth syndrome (e.g., 3-methylglutaconic aciduria). In some affected families, the condition has been shown to result from mutations in the dystrophin gene that is thought to play a role in maintaining the structure of heart and skeletal muscle units. Various mutations of the dystrophin gene have also been identified in males with Duchenne or Becker muscular dystrophy. For further information on these disorders, please use “Duchenne” or “Becker” as your search term in the Rare Disease Database.) Several forms of familial dilated cardiomyopathy have also been reported that have been shown to result from mutations of various genes transmitted in an autosomal dominant or autosomal recessive pattern.Endocardial fibroelastosis may also occur as a primary condition that appears to be transmitted in an X-linked recessive pattern. Investigators have reported several families in which affected members, primarily infants and children, have developed diffuse, patchy thickening of the endocardium (innermost layer of the heart), primarily of the left ventricle, due to overgrowth (proliferation) of elastic and fibrous tissues. Associated findings may include symptoms of heart failure in the first months or years of life. Some researchers question whether X-linked endocardial fibroelastosis is a distinct disease entity, indicating that it may in fact represent a variant of Barth syndrome. However, very few families with apparently isolated, X-linked endocardial fibroelastosis have been tested for mutations in the TAZ gene.Acute viral cardiomyopathy is a heart condition characterized by sudden (acute) inflammation of heart muscle (myocarditis) due to viral infections. Initial symptoms may include a sudden onset of fever and flu-like symptoms. In addition, myocardial inflammation causes weakening of the heart muscle, leading to (dilated cardiomyopathy and heart failure. Associated findings may include fatigue, shortness of breath, arrhythmias, and other findings, leading to potentially life-threatening complications without appropriate treatment. Viral cardiomyopathy has often been the diagnosis given to children with Barth syndrome before recognition of other abnormalities, such as neutropenia or 3-methylglutaconic aciduria, led to the correct diagnosis.There are additional disorders of mitochondrial metabolism that may be associated with certain symptoms and findings like those seen in Barth syndrome, such as cardiomyopathy, neuromuscular abnormalities, delayed growth, and/or elevated urinary levels of 3-methylglutaconic acid. However, evidence suggests that such disorders may not be associated with other findings characteristic of Barth syndrome (e.g., neutropenia)–and/or may have other, distinctive features, such as additional biochemical findings, severe neurological symptoms, and/or other abnormalities. | 145 | Barth Syndrome |
nord_145_5 | Diagnosis of Barth Syndrome | Barth syndrome is usually diagnosed during infancy or early childhood, but has been diagnosed later in some patients. Diagnosis is based upon clinical evaluation, identification of characteristic physical findings, a complete patient and family history, and a variety of specialized tests.
Consider Barth syndrome if someone has:Multiple pregnancy losses involving a male fetus have been observed in some families with Barth syndrome.Molecular genetic testing for mutations in the TAZ gene confirms the diagnosis of Barth syndrome. The TAZ gene testing can be done individually or as a part of a multigene panel.Clinical testing and workupAs a part of routine follow up, growth and height of the children are monitored regularly. Annual cardiac follow up using ECG, echocardiogram and Holter monitor is considered. | Diagnosis of Barth Syndrome. Barth syndrome is usually diagnosed during infancy or early childhood, but has been diagnosed later in some patients. Diagnosis is based upon clinical evaluation, identification of characteristic physical findings, a complete patient and family history, and a variety of specialized tests.
Consider Barth syndrome if someone has:Multiple pregnancy losses involving a male fetus have been observed in some families with Barth syndrome.Molecular genetic testing for mutations in the TAZ gene confirms the diagnosis of Barth syndrome. The TAZ gene testing can be done individually or as a part of a multigene panel.Clinical testing and workupAs a part of routine follow up, growth and height of the children are monitored regularly. Annual cardiac follow up using ECG, echocardiogram and Holter monitor is considered. | 145 | Barth Syndrome |
nord_145_6 | Therapies of Barth Syndrome | TreatmentThe treatment of Barth syndrome is for specific symptoms. Such treatments may need the efforts of a team of medical professionals, such as pediatricians; physicians who specialize in childhood heart disease (pediatric cardiologists); specialists in the study of the blood and blood-forming tissues (hematologists); specialists in the treatment of bacterial infections, physical therapists; occupational therapists; and/or other health care professionals.Heart failure and/or bacterial infections are the threats to a patient with Barth syndrome. This is one of the main reasons for a reduced life expectancy. Standard heart failure medications like beta blockers, ACE inhibitors and digoxin are used. This helps in improving the heart function and reduces symptoms of heart failure. Aspirin is used for reducing clot formation. Heart transplant is considered when there is severe heart failure. The heart functioning tends to improve after infancy, so heart transplant should be carefully considered. For affected people with confirmed neutropenia, complications due to bacterial infection can be prevented by monitoring and starting early therapy of suspected infections with antibiotics. For example, antibiotics may be provided as a preventive (prophylactic) therapy during neutropenia to prevent the onset of infection. Giving uncooked cornstarch before bedtime is recommended to prevent muscle loss. Early intervention like physical therapy is recommended for increasing muscle tone and helps children to attain various developmental milestones. Genetic counseling is recommended for affected individuals and their families. Other treatment for this disorder is symptomatic and supportive. | Therapies of Barth Syndrome. TreatmentThe treatment of Barth syndrome is for specific symptoms. Such treatments may need the efforts of a team of medical professionals, such as pediatricians; physicians who specialize in childhood heart disease (pediatric cardiologists); specialists in the study of the blood and blood-forming tissues (hematologists); specialists in the treatment of bacterial infections, physical therapists; occupational therapists; and/or other health care professionals.Heart failure and/or bacterial infections are the threats to a patient with Barth syndrome. This is one of the main reasons for a reduced life expectancy. Standard heart failure medications like beta blockers, ACE inhibitors and digoxin are used. This helps in improving the heart function and reduces symptoms of heart failure. Aspirin is used for reducing clot formation. Heart transplant is considered when there is severe heart failure. The heart functioning tends to improve after infancy, so heart transplant should be carefully considered. For affected people with confirmed neutropenia, complications due to bacterial infection can be prevented by monitoring and starting early therapy of suspected infections with antibiotics. For example, antibiotics may be provided as a preventive (prophylactic) therapy during neutropenia to prevent the onset of infection. Giving uncooked cornstarch before bedtime is recommended to prevent muscle loss. Early intervention like physical therapy is recommended for increasing muscle tone and helps children to attain various developmental milestones. Genetic counseling is recommended for affected individuals and their families. Other treatment for this disorder is symptomatic and supportive. | 145 | Barth Syndrome |
nord_146_0 | Overview of Bartonellosis | SummaryBartonellosis is a group of emerging infectious diseases caused by bacteria belonging to the Bartonella genus. Bartonella includes at least 22 named species of bacteria that are mainly transmitted by carriers (vectors), including fleas, lice, or sandflies. Both domestic and wild animals can be infected with Bartonella species (Bartonella spp) by these vectors. Among the Bartonella spp, at least 14 have been implicated in diseases that can be transmitted from animals to people (zoonotic disease). Of these zoonotic species, several may be transmitted to humans by companion animals (dogs and cats), typically through a bite or scratch.Human diseases that have been identified to be caused by one of the Bartonella spp bacteria include cat scratch disease (Bartonella henselae), Carrion’s disease (Bartonella bacilliformis), and trench fever (Bartonella quintana). Bartonella spp have also been associated with diseases of the skin (bacillary angiomatosis), liver (peliosis hepatis), heart (endocarditis), eyes (neuroretinis), blood (bacteremia), and brain (encephalitis). Bartonella infection does not always cause overt illness. A number of studies have detected clinically healthy people that have tested positive (seropositive) for Bartonella but have no known history of typical Bartonella symptoms. Those who do become ill usually develop mild disease that tends to end without treatment (self-limiting). However, Bartonella can cause severe infection in some people. Immunocompromised patients, such as those undergoing immunosuppressive treatments for cancer, organ transplant patients, and people with HIV/AIDS, are more likely to develop severe, life-threatening disease.IntroductionIn 1909, Dr. Alberto Barton discovered the organism that became named Bartonella bacilliformis. Diseases caused by Bartonella spp occur all over the United States and in all major regions of the world, with higher prevalence occurring in areas that harbor insect carriers (arthropod vectors). | Overview of Bartonellosis. SummaryBartonellosis is a group of emerging infectious diseases caused by bacteria belonging to the Bartonella genus. Bartonella includes at least 22 named species of bacteria that are mainly transmitted by carriers (vectors), including fleas, lice, or sandflies. Both domestic and wild animals can be infected with Bartonella species (Bartonella spp) by these vectors. Among the Bartonella spp, at least 14 have been implicated in diseases that can be transmitted from animals to people (zoonotic disease). Of these zoonotic species, several may be transmitted to humans by companion animals (dogs and cats), typically through a bite or scratch.Human diseases that have been identified to be caused by one of the Bartonella spp bacteria include cat scratch disease (Bartonella henselae), Carrion’s disease (Bartonella bacilliformis), and trench fever (Bartonella quintana). Bartonella spp have also been associated with diseases of the skin (bacillary angiomatosis), liver (peliosis hepatis), heart (endocarditis), eyes (neuroretinis), blood (bacteremia), and brain (encephalitis). Bartonella infection does not always cause overt illness. A number of studies have detected clinically healthy people that have tested positive (seropositive) for Bartonella but have no known history of typical Bartonella symptoms. Those who do become ill usually develop mild disease that tends to end without treatment (self-limiting). However, Bartonella can cause severe infection in some people. Immunocompromised patients, such as those undergoing immunosuppressive treatments for cancer, organ transplant patients, and people with HIV/AIDS, are more likely to develop severe, life-threatening disease.IntroductionIn 1909, Dr. Alberto Barton discovered the organism that became named Bartonella bacilliformis. Diseases caused by Bartonella spp occur all over the United States and in all major regions of the world, with higher prevalence occurring in areas that harbor insect carriers (arthropod vectors). | 146 | Bartonellosis |
nord_146_1 | Symptoms of Bartonellosis | Diseases in humans that have been identified to be caused by one of the Bartonella spp include cat scratch disease, Carrion’s disease, and trench fever.Cat scratch disease (CSD):CSD, caused by Bartonella henselae (B. henselae), is an infectious disease with symptoms that can vary from mild to severe. Although in most patients the disease resolves spontaneously within 2-4 months without treatment, in people with severe cases and/or patients with a suppressed immune system, such as HIV/AIDS, antibiotic treatment is recommended.The major symptoms of cat scratch disease may not appear for several days or weeks after exposure. A red spot (macule) may appear on the skin at the site of infection, and may become raised (papule) 3 to 10 days after exposure. The papule is painless and does not itch. It may become filled with fluid (vesicle), then crust over and heal with a scar similar to those left by chicken pox. The papule persists for 1 to 3 weeks, but may go unnoticed or be attributed to an injury.Within 1-3 weeks, swelling of lymph nodes (lymphadenopathy) develops in a single node or group of regional nodes near the site of the bite or scratch. Swollen lymph nodes frequently occur under arms, on the neck, or in the groin regions. These nodes usually become very tender and the surface of the skin may appear red and feel hot to the touch. Pus may develop in the involved lymph nodes (suppuration) and become fluctuant. Lymphadenopathy remains regional and typically resolves within 2-4 months but may last up to 6-12 months.Other symptoms of cat-scratch disease may include achiness and overall discomfort (malaise), fatigue, headache, and in some patients, fever. Less common symptoms include loss of appetite, sore throat, and weight loss. In some cases chills, backache, and/or abdominal pain have been reported.Rare complications of Bartonella henselae infection more typically occur in people with immunocompromised conditions, such as those undergoing immunosuppressive treatments for cancer, organ transplant patients, and people with HIV/AIDS, although they are being increasingly reported in immunocompetent people, too. Increasingly these atypical manifestations have been reported in patients without the typical symptoms of CSD. Children in particular appear to develop inflammation in the liver (granulomatous hepatitis) or spleen (splenitis) and bone infection (osteomyelitis). Other atypical manifestations of CSD include bacillary angiomatosis, encephalopathy (inflammation of the brain), neuroretinitis (inflammation of the retina and optic nerve of the eye),, Parinaud’s oculolandular syndrome (conjunctivitis), and endocarditis (infection of the heart valve),Bacillary angiomatosis, caused by B. quintana or B. henselae, is a skin disorder that is characterized by reddish, elevated lesions that are often surrounded by a scaly ring and bleed easily. The condition may spread to produce a more widespread systemic disorder that can involve bone, liver, spleen, lymph nodes, the gastrointestinal and respiratory tracts, and bone marrow. Bacillary angiomatosis has occasionally been reported in immunocompetent patients.Bacillary peliosis, a form of peliosis hepatis, is a vascular condition caused by B. henselae. It is characterized by presence of blood-filled cavities in the liver.Parinaud’s oculoglandular syndrome, which affects the eye, presents in approximately 5% of patients with CSD. Symptoms include red, irritated, and painful eye (similar to conjunctivitis or “pink eye”), fever, general ill-feeling, and swelling of nearby lymph glands, often in front of the ear (preauricular lymphadenopathy).Neurologic complications occur in approximately 2% of infected patients, with encephalopathy being the most common presentation. Symptoms generally occur 2 to 3 weeks after the onset of lymphadenopathy, although some patients have been known to present with neurological symptoms without a CSD history. Greater than 90% of these patients have complete, spontaneous recovery with no negative after-effects.Other rare symptoms of bartonellosis may include swelling of the largest salivary gland (parotid gland), cardiac manifestation with inflammation of the lining of the heart and its valves (endocarditis), renal inflammation (glomerulonephritis), granulomatous inflammation of the liver (hepatitis), splenitis, and/or abscesses of the spleen. In very rare cases, bartonellosis has been associated with atypical pneumonia, an inflammatory reaction to infection characterized by bumps on the lower legs (erythema nodosum), and/or a skin discoloration associated with a decreased blood platelet count (thrombocytopenia purpura).Carrion’s disease:Carrion’s disease, caused by Bartonella bacilliformis (B. bacilliformis), is a rare infectious disease that was originally thought to occur only in the Peruvian Andes. Other South American countries have more recently been included. New cases of the disease have been found in individuals who have traveled to other parts of the world.In most affected individuals, Carrion’s disease is characterized by two well-defined stages: a sudden, acute phase known as Oroya fever and a chronic, benign skin (cutaneous) eruption consisting of raised, reddish-purple nodules known as verruga peruana (Peruvian warts). The first stage usually develops about three to 12 weeks following exposure to the B. bacilliformis bacterium.Oroya fever may be characterized by a sudden onset of high fever, profuse sweating, severe headache, chills, weakness, and paleness of the skin. In addition, in many affected individuals, mental changes may develop, including confusion and disorientation or a coma. Such abnormalities occur in association with rapidly developing reduced levels of red blood cells (erythrocytes) due to bacterial invasion and destruction of these cells (hemolytic anemia). The first phase of the disease is very similar to malaria.Additional associated findings may include abdominal pain, severe muscle aches (myalgia) and arthralgia, lymphadenopathy, inflammation of the brain and its protective membranes (meningoencephalitis), seizures, and/or other abnormalities. In addition, some affected individuals may develop chest pain due to insufficient oxygen supply to heart muscle (angina), thrombocytopenia, labored breathing (dyspnea), impaired digestive and liver function, and/or other abnormalities. Such findings are thought to result from severe hemolytic anemia and the abnormal formation of blood clots within small blood vessels (microvascular thrombosis), leading to an insufficient supply of oxygen to tissues (ischemia), impaired functioning of organs, and potentially life-threatening complications.In addition, in some patients, the acute stage of Carrion’s disease may be complicated by and increased in severity due to the presence of other infections, such as salmonellosis or malaria (i.e., intercurrent infections). (For more on salmonellosis, see below. For further information on malaria, please choose “malaria” as your search term in the Rare Disease Database.)In its mildest form, Carrion’s disease may not be noted until the development of characteristic skin lesions (verruga peruana). In such instances, it may have a gradual onset and initially be characterized by a fever that may be present for less than a week and be unrecognized as a manifestation of Carrion’s disease.In those affected by Oroya fever, the period of recovery is typically associated with gradually reduced fever and disappearance of the bacterium as seen on microscopic examination of small blood specimens. However, some individuals remain persistently infected for years; blood smear examination, although the historical standard diagnostic testin Peru, is a very insensitive test. Furthermore, some affected individuals may temporarily have an increased susceptibility to certain, subsequent infections, such as with Salmonella bacteria (salmonellosis). Infection with certain strains of Salmonella bacteria may cause high fever, abdominal pain, bloody diarrhea, nausea, vomiting, rash, and/or other symptoms and findings. In addition, in some cases, without appropriate antibacterial therapy, B. bacilliformis may remain present in the blood (bacteremia) for months to years without apparent symptoms (asymptomatic), potentially resulting in continued spread of the disease to others (i.e., as a “reservoir” or an ongoing source of infectious disease). Reports suggest that relapses or recurrences of Oroya fever are rare. According to experts, recurrence of fever after initial improvement of symptoms is considered suggestive of a secondary infection.Following resolution of the acute stage of infection (Oroya fever), untreated individuals typically develop distinctive skin lesions within weeks or months. This second stage is known as verruga peruana. As noted above, verruga peruana may develop in individuals who have or have not had previous symptoms of Oroya fever.Verruga peruana is typically characterized by reddish, purple skin lesions occurring in a series of outbreaks that may develop in one area as they heal in another and recur in certain sites. The lesions may initially be minute, eventually become nodular and range from about 0.2 to 4 centimeters in diameter, and potentially bleed, ulcerate, or become pus-containing blisters (pustules). Although they typically erupt on exposed skin, such as on the face, arms, and legs, they may also sometimes develop within mucous membranes and internal organs. In untreated individuals, verruga peruana may persist over a period of months to years.Trench fever:Trench fever, caused by Bartonella quintana (B. quintana), shows symptoms within a few days or up to five weeks following exposure to the bacterium. Affected individuals may develop sudden fever, chills, weakness, headache, dizziness, leg and back pain, and/or other abnormalities. Initial fever may last about four to five days and may recur one or several times, with each episode lasting about five days. Additional findings may include a temporary skin rash consisting of flat (macular) or raised (papular) lesions, and/or enlargement of the liver or spleen (hepatomegaly or splenomegaly). Trench fever is usually a self-limiting disease, although relapses and chronic bacteremic states are well known. A severe form of B. quintana infection has also been reported in immunocompromised individuals, such as in association with AIDS. | Symptoms of Bartonellosis. Diseases in humans that have been identified to be caused by one of the Bartonella spp include cat scratch disease, Carrion’s disease, and trench fever.Cat scratch disease (CSD):CSD, caused by Bartonella henselae (B. henselae), is an infectious disease with symptoms that can vary from mild to severe. Although in most patients the disease resolves spontaneously within 2-4 months without treatment, in people with severe cases and/or patients with a suppressed immune system, such as HIV/AIDS, antibiotic treatment is recommended.The major symptoms of cat scratch disease may not appear for several days or weeks after exposure. A red spot (macule) may appear on the skin at the site of infection, and may become raised (papule) 3 to 10 days after exposure. The papule is painless and does not itch. It may become filled with fluid (vesicle), then crust over and heal with a scar similar to those left by chicken pox. The papule persists for 1 to 3 weeks, but may go unnoticed or be attributed to an injury.Within 1-3 weeks, swelling of lymph nodes (lymphadenopathy) develops in a single node or group of regional nodes near the site of the bite or scratch. Swollen lymph nodes frequently occur under arms, on the neck, or in the groin regions. These nodes usually become very tender and the surface of the skin may appear red and feel hot to the touch. Pus may develop in the involved lymph nodes (suppuration) and become fluctuant. Lymphadenopathy remains regional and typically resolves within 2-4 months but may last up to 6-12 months.Other symptoms of cat-scratch disease may include achiness and overall discomfort (malaise), fatigue, headache, and in some patients, fever. Less common symptoms include loss of appetite, sore throat, and weight loss. In some cases chills, backache, and/or abdominal pain have been reported.Rare complications of Bartonella henselae infection more typically occur in people with immunocompromised conditions, such as those undergoing immunosuppressive treatments for cancer, organ transplant patients, and people with HIV/AIDS, although they are being increasingly reported in immunocompetent people, too. Increasingly these atypical manifestations have been reported in patients without the typical symptoms of CSD. Children in particular appear to develop inflammation in the liver (granulomatous hepatitis) or spleen (splenitis) and bone infection (osteomyelitis). Other atypical manifestations of CSD include bacillary angiomatosis, encephalopathy (inflammation of the brain), neuroretinitis (inflammation of the retina and optic nerve of the eye),, Parinaud’s oculolandular syndrome (conjunctivitis), and endocarditis (infection of the heart valve),Bacillary angiomatosis, caused by B. quintana or B. henselae, is a skin disorder that is characterized by reddish, elevated lesions that are often surrounded by a scaly ring and bleed easily. The condition may spread to produce a more widespread systemic disorder that can involve bone, liver, spleen, lymph nodes, the gastrointestinal and respiratory tracts, and bone marrow. Bacillary angiomatosis has occasionally been reported in immunocompetent patients.Bacillary peliosis, a form of peliosis hepatis, is a vascular condition caused by B. henselae. It is characterized by presence of blood-filled cavities in the liver.Parinaud’s oculoglandular syndrome, which affects the eye, presents in approximately 5% of patients with CSD. Symptoms include red, irritated, and painful eye (similar to conjunctivitis or “pink eye”), fever, general ill-feeling, and swelling of nearby lymph glands, often in front of the ear (preauricular lymphadenopathy).Neurologic complications occur in approximately 2% of infected patients, with encephalopathy being the most common presentation. Symptoms generally occur 2 to 3 weeks after the onset of lymphadenopathy, although some patients have been known to present with neurological symptoms without a CSD history. Greater than 90% of these patients have complete, spontaneous recovery with no negative after-effects.Other rare symptoms of bartonellosis may include swelling of the largest salivary gland (parotid gland), cardiac manifestation with inflammation of the lining of the heart and its valves (endocarditis), renal inflammation (glomerulonephritis), granulomatous inflammation of the liver (hepatitis), splenitis, and/or abscesses of the spleen. In very rare cases, bartonellosis has been associated with atypical pneumonia, an inflammatory reaction to infection characterized by bumps on the lower legs (erythema nodosum), and/or a skin discoloration associated with a decreased blood platelet count (thrombocytopenia purpura).Carrion’s disease:Carrion’s disease, caused by Bartonella bacilliformis (B. bacilliformis), is a rare infectious disease that was originally thought to occur only in the Peruvian Andes. Other South American countries have more recently been included. New cases of the disease have been found in individuals who have traveled to other parts of the world.In most affected individuals, Carrion’s disease is characterized by two well-defined stages: a sudden, acute phase known as Oroya fever and a chronic, benign skin (cutaneous) eruption consisting of raised, reddish-purple nodules known as verruga peruana (Peruvian warts). The first stage usually develops about three to 12 weeks following exposure to the B. bacilliformis bacterium.Oroya fever may be characterized by a sudden onset of high fever, profuse sweating, severe headache, chills, weakness, and paleness of the skin. In addition, in many affected individuals, mental changes may develop, including confusion and disorientation or a coma. Such abnormalities occur in association with rapidly developing reduced levels of red blood cells (erythrocytes) due to bacterial invasion and destruction of these cells (hemolytic anemia). The first phase of the disease is very similar to malaria.Additional associated findings may include abdominal pain, severe muscle aches (myalgia) and arthralgia, lymphadenopathy, inflammation of the brain and its protective membranes (meningoencephalitis), seizures, and/or other abnormalities. In addition, some affected individuals may develop chest pain due to insufficient oxygen supply to heart muscle (angina), thrombocytopenia, labored breathing (dyspnea), impaired digestive and liver function, and/or other abnormalities. Such findings are thought to result from severe hemolytic anemia and the abnormal formation of blood clots within small blood vessels (microvascular thrombosis), leading to an insufficient supply of oxygen to tissues (ischemia), impaired functioning of organs, and potentially life-threatening complications.In addition, in some patients, the acute stage of Carrion’s disease may be complicated by and increased in severity due to the presence of other infections, such as salmonellosis or malaria (i.e., intercurrent infections). (For more on salmonellosis, see below. For further information on malaria, please choose “malaria” as your search term in the Rare Disease Database.)In its mildest form, Carrion’s disease may not be noted until the development of characteristic skin lesions (verruga peruana). In such instances, it may have a gradual onset and initially be characterized by a fever that may be present for less than a week and be unrecognized as a manifestation of Carrion’s disease.In those affected by Oroya fever, the period of recovery is typically associated with gradually reduced fever and disappearance of the bacterium as seen on microscopic examination of small blood specimens. However, some individuals remain persistently infected for years; blood smear examination, although the historical standard diagnostic testin Peru, is a very insensitive test. Furthermore, some affected individuals may temporarily have an increased susceptibility to certain, subsequent infections, such as with Salmonella bacteria (salmonellosis). Infection with certain strains of Salmonella bacteria may cause high fever, abdominal pain, bloody diarrhea, nausea, vomiting, rash, and/or other symptoms and findings. In addition, in some cases, without appropriate antibacterial therapy, B. bacilliformis may remain present in the blood (bacteremia) for months to years without apparent symptoms (asymptomatic), potentially resulting in continued spread of the disease to others (i.e., as a “reservoir” or an ongoing source of infectious disease). Reports suggest that relapses or recurrences of Oroya fever are rare. According to experts, recurrence of fever after initial improvement of symptoms is considered suggestive of a secondary infection.Following resolution of the acute stage of infection (Oroya fever), untreated individuals typically develop distinctive skin lesions within weeks or months. This second stage is known as verruga peruana. As noted above, verruga peruana may develop in individuals who have or have not had previous symptoms of Oroya fever.Verruga peruana is typically characterized by reddish, purple skin lesions occurring in a series of outbreaks that may develop in one area as they heal in another and recur in certain sites. The lesions may initially be minute, eventually become nodular and range from about 0.2 to 4 centimeters in diameter, and potentially bleed, ulcerate, or become pus-containing blisters (pustules). Although they typically erupt on exposed skin, such as on the face, arms, and legs, they may also sometimes develop within mucous membranes and internal organs. In untreated individuals, verruga peruana may persist over a period of months to years.Trench fever:Trench fever, caused by Bartonella quintana (B. quintana), shows symptoms within a few days or up to five weeks following exposure to the bacterium. Affected individuals may develop sudden fever, chills, weakness, headache, dizziness, leg and back pain, and/or other abnormalities. Initial fever may last about four to five days and may recur one or several times, with each episode lasting about five days. Additional findings may include a temporary skin rash consisting of flat (macular) or raised (papular) lesions, and/or enlargement of the liver or spleen (hepatomegaly or splenomegaly). Trench fever is usually a self-limiting disease, although relapses and chronic bacteremic states are well known. A severe form of B. quintana infection has also been reported in immunocompromised individuals, such as in association with AIDS. | 146 | Bartonellosis |
nord_146_2 | Causes of Bartonellosis | Bartonella bacteria invade red blood cells (erythrocytes) and the lining of the blood vessels (endothelial cells), where the organism proliferates. Inside the erythrocytes, it is protected from the host’s primary and secondary immune response, thus explaining bacterial persistence that can occur in some cases.Cat scratch disease:Cat scratch disease is caused by the B. henselae bacterium. Most cases follow a lick, scratch, or bite from a cat or kitten when the bacterium is present on the cat’s claws or oral cavity. Fleas transmit the bacteria between cats. Some case reports have suggested transmission may occur from cat fleas directly to humans, but this has not yet been proven. Cat-to-cat and person-to-person transmission has not been documented. There have also been reports of the disease following the scratch or bite of dogs in 5% of cases.A feline infected with B. henselae is a common occurrence. Up to half of domestic cats have antibodies to B. henselae, which indicates that they have been previously exposed to these bacteria. Because cats are infected with B. henselae by fleas, preventing flea exposure will reduce B. henselae infection in cats and kittens and thereby prevent human infection. Kittens under 12 months of age are much more likely to transmit the disease than adult cats. Outdoor cats and cats infested with fleas are also more likely to show antibodies (test seropositive) to B. henselae. Animals that are carrying the disease are not ill, and will not exhibit any symptoms. Not every person exposed to the carrier animal will develop cat scratch disease, and in most cases the symptoms are temporary (transient) and mild.Carrion’s disease:B. bacilliformis is the etiologic agent of Carrion’s disease or Oroya fever (acute phase of infection) and verruga peruana or Peruvian warts (chronic phase of infection). The bacterium is primarily carried and transmitted by the night-biting sand fly known as Lutzomyia (formerly Phlebotomus).The B. bacilliformis bacterium enters the bloodstream via the bite of the sand fly, enabling the bacterium to attach to the surface of erythrocytes. Bacterial invasion and reproduction leads to abnormal fragility and premature destruction of many erythrocytes in the bloodstream (hemolysis). This results in abnormally decreased red blood cell levels and reduced concentrations of hemoglobin, the oxygen-carrying component of the blood (hemolytic anemia). In addition, the bacterium may invade cells lining small blood vessels (capillary endothelial cells), potentially leading to blockage of normal blood flow (vascular occlusion). Severe hemolytic anemia and the abnormal formation of blood clots within small blood vessels may potentially lead to life-threatening complications without prompt appropriate treatment.With developing immunity, levels of the bacterium markedly decrease in the blood. However, without appropriate antibiotic therapy, asymptomatic low-grade bacteremia may persist for months or years in some cases.Following the symptom-free (latent) period, most untreated individuals develop the distinctive skin lesions characteristic of verruga peruana. The nodular lesions consist of newly formed blood vessels (neovascular proliferation) infiltrated by certain white blood cells that play an important role in fighting and destroying invading microorganisms (e.g., lymphocytes, macrophages).Trench fever:Trench fever is caused by infection with B. quintana most likely transmitted by the human body louse (Pediculus humanus) and is commonly found in homeless, alcoholic, and poverty-stricken populations where poor sanitation and poor hygiene often occurs. Other diseases that have been identified to be caused by B. quintana include bacillary angiomatosis (angioproliferative lesions), bacteremia, and endocarditis. Human endocarditis has now been associated with at least nine different Bartonella spp.Bartonella vinsonii subsp. berkhoffii has been isolated from immunocompetent patients with endocarditis, arthritis, neurological disease and vasoproliferative neoplasia. Dogs and wild canines (foxes, coyotes, wolves), which are the primary reservoir hosts, are the suspected reservoir hosts for this bacterium, and ticks are the suspected vectors, but this has not been scientifically proven.Most infections in immunocompromised patients are caused by B. henselae and B. quintana. Unlike immunocompetent individuals who usually develop milder diseases such as cat scratch disease and trench fever, immunocompromised patients, including HIV/AIDS and posttransplant patients, are more likely to develop more severe, potentially life-threatening disease. | Causes of Bartonellosis. Bartonella bacteria invade red blood cells (erythrocytes) and the lining of the blood vessels (endothelial cells), where the organism proliferates. Inside the erythrocytes, it is protected from the host’s primary and secondary immune response, thus explaining bacterial persistence that can occur in some cases.Cat scratch disease:Cat scratch disease is caused by the B. henselae bacterium. Most cases follow a lick, scratch, or bite from a cat or kitten when the bacterium is present on the cat’s claws or oral cavity. Fleas transmit the bacteria between cats. Some case reports have suggested transmission may occur from cat fleas directly to humans, but this has not yet been proven. Cat-to-cat and person-to-person transmission has not been documented. There have also been reports of the disease following the scratch or bite of dogs in 5% of cases.A feline infected with B. henselae is a common occurrence. Up to half of domestic cats have antibodies to B. henselae, which indicates that they have been previously exposed to these bacteria. Because cats are infected with B. henselae by fleas, preventing flea exposure will reduce B. henselae infection in cats and kittens and thereby prevent human infection. Kittens under 12 months of age are much more likely to transmit the disease than adult cats. Outdoor cats and cats infested with fleas are also more likely to show antibodies (test seropositive) to B. henselae. Animals that are carrying the disease are not ill, and will not exhibit any symptoms. Not every person exposed to the carrier animal will develop cat scratch disease, and in most cases the symptoms are temporary (transient) and mild.Carrion’s disease:B. bacilliformis is the etiologic agent of Carrion’s disease or Oroya fever (acute phase of infection) and verruga peruana or Peruvian warts (chronic phase of infection). The bacterium is primarily carried and transmitted by the night-biting sand fly known as Lutzomyia (formerly Phlebotomus).The B. bacilliformis bacterium enters the bloodstream via the bite of the sand fly, enabling the bacterium to attach to the surface of erythrocytes. Bacterial invasion and reproduction leads to abnormal fragility and premature destruction of many erythrocytes in the bloodstream (hemolysis). This results in abnormally decreased red blood cell levels and reduced concentrations of hemoglobin, the oxygen-carrying component of the blood (hemolytic anemia). In addition, the bacterium may invade cells lining small blood vessels (capillary endothelial cells), potentially leading to blockage of normal blood flow (vascular occlusion). Severe hemolytic anemia and the abnormal formation of blood clots within small blood vessels may potentially lead to life-threatening complications without prompt appropriate treatment.With developing immunity, levels of the bacterium markedly decrease in the blood. However, without appropriate antibiotic therapy, asymptomatic low-grade bacteremia may persist for months or years in some cases.Following the symptom-free (latent) period, most untreated individuals develop the distinctive skin lesions characteristic of verruga peruana. The nodular lesions consist of newly formed blood vessels (neovascular proliferation) infiltrated by certain white blood cells that play an important role in fighting and destroying invading microorganisms (e.g., lymphocytes, macrophages).Trench fever:Trench fever is caused by infection with B. quintana most likely transmitted by the human body louse (Pediculus humanus) and is commonly found in homeless, alcoholic, and poverty-stricken populations where poor sanitation and poor hygiene often occurs. Other diseases that have been identified to be caused by B. quintana include bacillary angiomatosis (angioproliferative lesions), bacteremia, and endocarditis. Human endocarditis has now been associated with at least nine different Bartonella spp.Bartonella vinsonii subsp. berkhoffii has been isolated from immunocompetent patients with endocarditis, arthritis, neurological disease and vasoproliferative neoplasia. Dogs and wild canines (foxes, coyotes, wolves), which are the primary reservoir hosts, are the suspected reservoir hosts for this bacterium, and ticks are the suspected vectors, but this has not been scientifically proven.Most infections in immunocompromised patients are caused by B. henselae and B. quintana. Unlike immunocompetent individuals who usually develop milder diseases such as cat scratch disease and trench fever, immunocompromised patients, including HIV/AIDS and posttransplant patients, are more likely to develop more severe, potentially life-threatening disease. | 146 | Bartonellosis |
nord_146_3 | Affects of Bartonellosis | Cat scratch disease caused by B. henselae infection occurs in approximately 1 per 10,000 persons. Cat-scratch disease has been shown in some studies to occur more frequently in males than females with a ratio of 3:2. However, other studies have shown equal rates between males and females. One hypothesis to explain a greater incidence among males than females is the tendency toward rougher play with cats and consequently an increased risk of bites and scratches. A database analysis in 2016 showed 33% of patients with CSD were 14 years of age or younger. Cases of CSD occur throughout the United States and worldwide, with the incidence greater in regions with higher temperatures and humidity, which supports heavy flea populations. In the United States, the majority of cases occur between the months of July and January. One study in 2016 concluded that incidence of CSD in the United States is higher in the South and lower in the West.Carrion’s disease has, until recently, been restricted in its geographic distribution to the Andes Mountains regions of the South American countries of Colombia, Peru, and Ecuador at elevations of 1000-3000 meters because of the habitat of the sand fly Lutzomyia. Cases elsewhere in the world are found in travelers, who presumably acquired their infections while visiting one of these countries. Oroya fever was first recognized in the nineteenth century as the cause of acute fever and highly fatal, hemolytic anemia in railroad workers in Peru. Reports suggest that the chronic skin (cutaneous) stage was described earlier.The common bacterial cause of Oroya fever and verruga peruana was confirmed by a Peruvian medical student, Daniel Carrion, in 1885, when he succumbed to acute hemolytic anemia after injecting himself with blood from a verruga peruana skin lesion. The spectrum of B. bacilliformis infection as manifested in Oroya fever and verruga peruana has since been named “Carrion’s Disease.”Trench fever was first described during World War I when it affected nearly one million soldiers. B. quintana has caused geographically widespread disease, although little data exists regarding incidence among specific populations. Though the true incidence of contemporary (urban) trench fever is unknown, one study of patients in a downtown Seattle clinic for disadvantaged patients found 20% had antibodies to Bartonella spp., though most of these patients were asymptomatic. | Affects of Bartonellosis. Cat scratch disease caused by B. henselae infection occurs in approximately 1 per 10,000 persons. Cat-scratch disease has been shown in some studies to occur more frequently in males than females with a ratio of 3:2. However, other studies have shown equal rates between males and females. One hypothesis to explain a greater incidence among males than females is the tendency toward rougher play with cats and consequently an increased risk of bites and scratches. A database analysis in 2016 showed 33% of patients with CSD were 14 years of age or younger. Cases of CSD occur throughout the United States and worldwide, with the incidence greater in regions with higher temperatures and humidity, which supports heavy flea populations. In the United States, the majority of cases occur between the months of July and January. One study in 2016 concluded that incidence of CSD in the United States is higher in the South and lower in the West.Carrion’s disease has, until recently, been restricted in its geographic distribution to the Andes Mountains regions of the South American countries of Colombia, Peru, and Ecuador at elevations of 1000-3000 meters because of the habitat of the sand fly Lutzomyia. Cases elsewhere in the world are found in travelers, who presumably acquired their infections while visiting one of these countries. Oroya fever was first recognized in the nineteenth century as the cause of acute fever and highly fatal, hemolytic anemia in railroad workers in Peru. Reports suggest that the chronic skin (cutaneous) stage was described earlier.The common bacterial cause of Oroya fever and verruga peruana was confirmed by a Peruvian medical student, Daniel Carrion, in 1885, when he succumbed to acute hemolytic anemia after injecting himself with blood from a verruga peruana skin lesion. The spectrum of B. bacilliformis infection as manifested in Oroya fever and verruga peruana has since been named “Carrion’s Disease.”Trench fever was first described during World War I when it affected nearly one million soldiers. B. quintana has caused geographically widespread disease, although little data exists regarding incidence among specific populations. Though the true incidence of contemporary (urban) trench fever is unknown, one study of patients in a downtown Seattle clinic for disadvantaged patients found 20% had antibodies to Bartonella spp., though most of these patients were asymptomatic. | 146 | Bartonellosis |
nord_146_4 | Related disorders of Bartonellosis | Certain features of the following disorders may be similar to those of bartonellosis:Adenitis (Bacterial, Fungal, Pyogenic, and Tuberculous) is an inflammatory disease characterized by lymphadenopathy. Differential diagnosis may be accomplished through skin testing and/or microscopic examination of the involved lymph nodes.Atypical mycobacterial infections are caused by nontuberculous mycobacteria, but can be very difficult to distinguish from tuberculosis. Lymphadenopathy is caused by nontuberculous mycobacteria, surgical removal and examination (biopsy) of involved tissue may be necessary for diagnosis.Brucellosis is an infection of livestock that can be transmitted to humans. It is caused by different species of the bacteria Brucella. Initial infection may result in an acute flu-like illness, or may evolve over months. Untreated cases may take months to resolve, and some cases become chronic. Symptoms may include a gradual onset of fever, weakness, headache, joint pain, and/or night sweats. Other symptoms may include lymphadenopathy, splenomegaly, and/or hepatomegaly. (For more information on this disorder, choose “Brucellosis” as your search term in the Rare Disease Database.)Lymphogranuloma venereum is a sexually transmitted infection characterized by a primary skin lesion at the site of infection. This lesion may be a raised bump (papule) that heals spontaneously or may go unnoticed. This is followed by lymphadenopathy on one or both sides of the body. The site of the first infection or lesion will determine the region affected.Lymphomas are growths (tumors) of the lymphoid tissue. These tumors are divided into two types, Hodgkin’s and non-Hodgkin’s lymphoma. Symptoms will depend upon the type and location of the tumor. Symptoms may include lymphadenopathy, hoarseness, a high- pitched respiratory sound when inhaling (stridor), and/or difficulty in swallowing (dysphagia).Sarcoidosis is a rare disorder which affects many body systems. It is characterized by small round lesions (tubercles) of granulated tissue. Symptoms may vary depending on the severity of the disease and how much of the body is affected. Symptoms of sarcoidosis depend on the site of involvement and may be absent, slight, or severe. Lymphadenopathy is common. Both enlarged and normal-sized lymph nodes may contain the characteristic sarcoid tubercles. (For more information on this disorder, choose “Sarcoidosis” as your search term in the Rare Disease Database.)Kaposi’s sarcoma is a cancerous tumor that often appears as bluish-red or purple bump on the skin and is often associated with AIDS.Pyogenic granulomas are small, reddish bumps on the skin whose exact cause is unknown but often appear on the hands, arms or face following injury.Hemangioma is a benign tumor made up of blood vessels that typically occurs as a purplish or reddish slightly elevated area of skin.Lyme disease is a tick-borne infection. The most common initial symptom is an expanding flat or slightly raised red spot skin lesion (“bull’s eye” rash known as erythema migrans) that develops at the site of the bite of a tick. Within days or weeks after infection, flu-like symptoms can develop. Later manifestations may include arthritis, the central nervous system, or cardiac involvement. | Related disorders of Bartonellosis. Certain features of the following disorders may be similar to those of bartonellosis:Adenitis (Bacterial, Fungal, Pyogenic, and Tuberculous) is an inflammatory disease characterized by lymphadenopathy. Differential diagnosis may be accomplished through skin testing and/or microscopic examination of the involved lymph nodes.Atypical mycobacterial infections are caused by nontuberculous mycobacteria, but can be very difficult to distinguish from tuberculosis. Lymphadenopathy is caused by nontuberculous mycobacteria, surgical removal and examination (biopsy) of involved tissue may be necessary for diagnosis.Brucellosis is an infection of livestock that can be transmitted to humans. It is caused by different species of the bacteria Brucella. Initial infection may result in an acute flu-like illness, or may evolve over months. Untreated cases may take months to resolve, and some cases become chronic. Symptoms may include a gradual onset of fever, weakness, headache, joint pain, and/or night sweats. Other symptoms may include lymphadenopathy, splenomegaly, and/or hepatomegaly. (For more information on this disorder, choose “Brucellosis” as your search term in the Rare Disease Database.)Lymphogranuloma venereum is a sexually transmitted infection characterized by a primary skin lesion at the site of infection. This lesion may be a raised bump (papule) that heals spontaneously or may go unnoticed. This is followed by lymphadenopathy on one or both sides of the body. The site of the first infection or lesion will determine the region affected.Lymphomas are growths (tumors) of the lymphoid tissue. These tumors are divided into two types, Hodgkin’s and non-Hodgkin’s lymphoma. Symptoms will depend upon the type and location of the tumor. Symptoms may include lymphadenopathy, hoarseness, a high- pitched respiratory sound when inhaling (stridor), and/or difficulty in swallowing (dysphagia).Sarcoidosis is a rare disorder which affects many body systems. It is characterized by small round lesions (tubercles) of granulated tissue. Symptoms may vary depending on the severity of the disease and how much of the body is affected. Symptoms of sarcoidosis depend on the site of involvement and may be absent, slight, or severe. Lymphadenopathy is common. Both enlarged and normal-sized lymph nodes may contain the characteristic sarcoid tubercles. (For more information on this disorder, choose “Sarcoidosis” as your search term in the Rare Disease Database.)Kaposi’s sarcoma is a cancerous tumor that often appears as bluish-red or purple bump on the skin and is often associated with AIDS.Pyogenic granulomas are small, reddish bumps on the skin whose exact cause is unknown but often appear on the hands, arms or face following injury.Hemangioma is a benign tumor made up of blood vessels that typically occurs as a purplish or reddish slightly elevated area of skin.Lyme disease is a tick-borne infection. The most common initial symptom is an expanding flat or slightly raised red spot skin lesion (“bull’s eye” rash known as erythema migrans) that develops at the site of the bite of a tick. Within days or weeks after infection, flu-like symptoms can develop. Later manifestations may include arthritis, the central nervous system, or cardiac involvement. | 146 | Bartonellosis |
nord_146_5 | Diagnosis of Bartonellosis | Most cases of CSD can be diagnosed by the individual's symptoms and history, such as the development of papules or pustules after vector exposure or a cat scratch or bite. Development of swollen lymph nodes and fever further reinforce a clinical diagnosis. Blood (serological) testing is available to confirm the diagnosis. PCR and culture tests may also be used in certain cases. Carrion's disease may be diagnosed based upon thorough clinical evaluation, detection of characteristic symptoms and physical findings, a complete patient history, including information concerning recent travel to regions where Carrion's disease is known to occur; and specialized laboratory tests. For example, during the acute stage, the bacterium may easily be seen within red blood cells on blood smears. With this diagnostic test, a drop of blood is smeared on a slide, stained with special dyes to make blood cells more visible, and examined under a microscope. During the chronic, cutaneous stage, the bacterium may be isolated from skin lesions. Blood smears are typically negative during this second stage. However, the bacterium may be cultured from the blood and grown under controlled conditions in the laboratory, enabling identification of the causative microorganism. In some cases, other laboratory studies may be used to help diagnose Carrion's disease.Serological testing is used to diagnose trench fever. However, it is difficult to diagnose in the laboratory, especially with blood cultures, since results are often negative even when infection is present and growth often takes 20-40 days.Clinical Testing and Work-UpBartonella infection can be difficult to diagnose. Serological testing is the most cost-effective diagnostic tool in laboratory detection of bartonellosis when positive results are found. However, as previously discussed, false negatives can occur, leading to undiagnosed, untreated patients when further testing is not performed. Detection of IgG and IgM antibodies in blood serum to Bartonella henselae by Indirect Immunofluorescence Assays (IFA) is an accurate way to identify CSD. Microscopic examination of Giemsa-stained blood smears is used to detect B. bacilliformis in patients who may have Carrion’s disease. Other Bartonella species are visible only with silver stains (Warthin-Starry, Steiner, Dieterle), although they sometimes resist staining or are present in such low numbers as to not be detectable.A polymerase chain reaction (PCR) test is a molecular technique used to detect specific genetic material in blood. Because of the serological cross-reactivity between Bartonella species and other bacteria, PCR analysis of tissue and body fluid is the most specific diagnostic test, especially in identifying distinct genotypes among Bartonella species.Intradermal skin testing, using hypersensitivity reaction to B. henselae antigen, is a test that is no longer used as more accurate testing is now available. Stains of biopsied tissue from lymph nodes examined microscopically may show small curved Gram-negative rods characteristic of B. henselae, but this staining method is not a definitive diagnosis of CSD. PCR of lymph nodes and other tissues, when used in conjunction with DNA sequencing, allows for diagnostic confirmation of Bartonella spp. and strains.Complications involving the liver and/or spleen are now identified more frequently with the use of improved serologic, PCR and diagnostic imaging tests. Abdominal imaging is an important diagnostic tool for patients with suspected hepatosplenic disease and who present with prolonged fever. | Diagnosis of Bartonellosis. Most cases of CSD can be diagnosed by the individual's symptoms and history, such as the development of papules or pustules after vector exposure or a cat scratch or bite. Development of swollen lymph nodes and fever further reinforce a clinical diagnosis. Blood (serological) testing is available to confirm the diagnosis. PCR and culture tests may also be used in certain cases. Carrion's disease may be diagnosed based upon thorough clinical evaluation, detection of characteristic symptoms and physical findings, a complete patient history, including information concerning recent travel to regions where Carrion's disease is known to occur; and specialized laboratory tests. For example, during the acute stage, the bacterium may easily be seen within red blood cells on blood smears. With this diagnostic test, a drop of blood is smeared on a slide, stained with special dyes to make blood cells more visible, and examined under a microscope. During the chronic, cutaneous stage, the bacterium may be isolated from skin lesions. Blood smears are typically negative during this second stage. However, the bacterium may be cultured from the blood and grown under controlled conditions in the laboratory, enabling identification of the causative microorganism. In some cases, other laboratory studies may be used to help diagnose Carrion's disease.Serological testing is used to diagnose trench fever. However, it is difficult to diagnose in the laboratory, especially with blood cultures, since results are often negative even when infection is present and growth often takes 20-40 days.Clinical Testing and Work-UpBartonella infection can be difficult to diagnose. Serological testing is the most cost-effective diagnostic tool in laboratory detection of bartonellosis when positive results are found. However, as previously discussed, false negatives can occur, leading to undiagnosed, untreated patients when further testing is not performed. Detection of IgG and IgM antibodies in blood serum to Bartonella henselae by Indirect Immunofluorescence Assays (IFA) is an accurate way to identify CSD. Microscopic examination of Giemsa-stained blood smears is used to detect B. bacilliformis in patients who may have Carrion’s disease. Other Bartonella species are visible only with silver stains (Warthin-Starry, Steiner, Dieterle), although they sometimes resist staining or are present in such low numbers as to not be detectable.A polymerase chain reaction (PCR) test is a molecular technique used to detect specific genetic material in blood. Because of the serological cross-reactivity between Bartonella species and other bacteria, PCR analysis of tissue and body fluid is the most specific diagnostic test, especially in identifying distinct genotypes among Bartonella species.Intradermal skin testing, using hypersensitivity reaction to B. henselae antigen, is a test that is no longer used as more accurate testing is now available. Stains of biopsied tissue from lymph nodes examined microscopically may show small curved Gram-negative rods characteristic of B. henselae, but this staining method is not a definitive diagnosis of CSD. PCR of lymph nodes and other tissues, when used in conjunction with DNA sequencing, allows for diagnostic confirmation of Bartonella spp. and strains.Complications involving the liver and/or spleen are now identified more frequently with the use of improved serologic, PCR and diagnostic imaging tests. Abdominal imaging is an important diagnostic tool for patients with suspected hepatosplenic disease and who present with prolonged fever. | 146 | Bartonellosis |
nord_146_6 | Therapies of Bartonellosis | Treatment
Cat scratch disease typically subsides without any treatment, usually within 2 to 4 months. Therapy is symptomatic and supportive. Antipyretics (fever reducers) and analgesics may be administered as needed. Local heat may be applied to the involved lymph nodes.Cat scratch disease usually has a very good prognosis, with no long-term health effects. If the affected lymph node produces pus (suppurates) and becomes large and/or painful, it may be necessary to drain the node. Draining the pus through a needle (aspiration) is preferred over making an incision. Usually one aspiration is sufficient to relieve discomfort.Antibiotics may be considered for severe or systemic disease. Faster reduction of lymph node size has been demonstrated with a 5-day course of azithromycin. Other antibiotics that have been considered effective include rifampin, ciprofloxacin, gentamicin, and trimethoprim/sulfamethoxazole. Bartonella henselae is generally resistant to penicillin, amoxicillin, and nafcillin. Doxycycline and rifampin in combination are the preferred medications for treating neuroretinitis. Effective antibiotic therapy for the complication of endocarditis should include an aminoglycoside prescribed for a minimum of 2 weeks followed by doxycycline or ceftriaxone for 6 weeks.The treatment of choice for Oroya fever is administration of the antibiotic chloramphenicol (due to frequent, intercurrent infection with Salmonella). Ciprofloxacin has also been recommended. Antibiotic therapy may rapidly treat acute febrile illness associated with Oroya fever. Blood transfusions may be required to treat severe anemia. For antibiotic treatment of verruga peruana, rifampin and streptomycin are typically recommended. Other treatment for this disorder is symptomatic and supportive.Carrion's disease may be prevented by avoiding the sandflies that transmit the bacterium to humans. Insect repellents, bed nets, and long-acting insecticides can help prevent exposure to these insects.Tetracycline-group antibiotics (doxycycline, tetracycline) are commonly used to treat trench fever. Uncomplicated disease responds to doxycycline and gentamicin. Chloramphenicol is an alternative medication recommended when tetracycline usage is undesirable, such as in severe liver malfunction, kidney deficiency, in children under nine years and pregnant women. Macrolides and ceftriaxone have also been effective. A longer duration of treatment is recommended for immunocompromised patients and when the liver or other organs are involved. In patients with AIDS and bacillary angiomatosis, the primary choices of antibiotics are erythromycin or doxycycline. Doxycycline combined with rifampin is effective in patients with severe disease. An extended treatment if often required in these cases.Though the course of the disease can be far more severe and potentially life-threatening for immunocompromised patients, these patients typically experience full resolution of disease with appropriate antibiotic use and management of complications. The response of immunocompromised patients to antibiotics is significantly more dramatic than immunocompetent patients. Some researchers believe that less virulent strains tend to infect immunocompromised patients and are perhaps more antibiotic responsive. | Therapies of Bartonellosis. Treatment
Cat scratch disease typically subsides without any treatment, usually within 2 to 4 months. Therapy is symptomatic and supportive. Antipyretics (fever reducers) and analgesics may be administered as needed. Local heat may be applied to the involved lymph nodes.Cat scratch disease usually has a very good prognosis, with no long-term health effects. If the affected lymph node produces pus (suppurates) and becomes large and/or painful, it may be necessary to drain the node. Draining the pus through a needle (aspiration) is preferred over making an incision. Usually one aspiration is sufficient to relieve discomfort.Antibiotics may be considered for severe or systemic disease. Faster reduction of lymph node size has been demonstrated with a 5-day course of azithromycin. Other antibiotics that have been considered effective include rifampin, ciprofloxacin, gentamicin, and trimethoprim/sulfamethoxazole. Bartonella henselae is generally resistant to penicillin, amoxicillin, and nafcillin. Doxycycline and rifampin in combination are the preferred medications for treating neuroretinitis. Effective antibiotic therapy for the complication of endocarditis should include an aminoglycoside prescribed for a minimum of 2 weeks followed by doxycycline or ceftriaxone for 6 weeks.The treatment of choice for Oroya fever is administration of the antibiotic chloramphenicol (due to frequent, intercurrent infection with Salmonella). Ciprofloxacin has also been recommended. Antibiotic therapy may rapidly treat acute febrile illness associated with Oroya fever. Blood transfusions may be required to treat severe anemia. For antibiotic treatment of verruga peruana, rifampin and streptomycin are typically recommended. Other treatment for this disorder is symptomatic and supportive.Carrion's disease may be prevented by avoiding the sandflies that transmit the bacterium to humans. Insect repellents, bed nets, and long-acting insecticides can help prevent exposure to these insects.Tetracycline-group antibiotics (doxycycline, tetracycline) are commonly used to treat trench fever. Uncomplicated disease responds to doxycycline and gentamicin. Chloramphenicol is an alternative medication recommended when tetracycline usage is undesirable, such as in severe liver malfunction, kidney deficiency, in children under nine years and pregnant women. Macrolides and ceftriaxone have also been effective. A longer duration of treatment is recommended for immunocompromised patients and when the liver or other organs are involved. In patients with AIDS and bacillary angiomatosis, the primary choices of antibiotics are erythromycin or doxycycline. Doxycycline combined with rifampin is effective in patients with severe disease. An extended treatment if often required in these cases.Though the course of the disease can be far more severe and potentially life-threatening for immunocompromised patients, these patients typically experience full resolution of disease with appropriate antibiotic use and management of complications. The response of immunocompromised patients to antibiotics is significantly more dramatic than immunocompetent patients. Some researchers believe that less virulent strains tend to infect immunocompromised patients and are perhaps more antibiotic responsive. | 146 | Bartonellosis |
nord_147_0 | Overview of Bartter Syndrome | Summary Bartter syndrome is a general term for a group of rare genetic disorders in which there are specific defects in kidney function. These defects impair the kidney’s ability to reabsorb salt and cause imbalances in various electrolyte and fluid concentrations in the body. The electrolytes affected are primarily mineral salts such as potassium, calcium, magnesium, sodium, and chloride. The symptoms and severity of Bartter syndrome vary from one person to another and can range from mild to severe. Age of onset of overt symptoms can range from before birth to adulthood. Bartter syndrome is caused by alterations (mutations) in one of several different genes. Treatment is aimed at correcting the electrolyte imbalances through the use of supplements and certain medications such as nonsteroidal anti-inflammatories (NSAIDs) and diuretics. IntroductionBartter syndrome was first described in the medical literature in the 1960s by Dr. Frederic Bartter. Through the years, different terminology has been used to describe these disorders. Some researchers classify these disorders based on their clinical appearance, while others classify them based on the underlying mutated gene. The different terminology and classification systems can be confusing. Bartter syndrome can be variably classified as a renal tubulopathy (because certain small tubes within the kidneys are affected), a salt-wasting disorder (because affected individuals excrete excess amounts of salt), a salt-losing tubulopathy, and a channelopathy (because the ion channels in the kidneys are affected). Although Bartter syndrome can be broken down into subtypes based on the underlying gene or symptomatology, considerable overlap of symptoms and disease presentation exists among the subtypes and Bartter syndrome may be best thought of as spectrum of disease caused by several different gene mutations. The most common classification system for these disorders is based upon the underlying genetic mutation as listed above. The term antenatal (before birth) Bartter syndrome refers to those cases who present before birth and is typically associated with types 1, 2, 4a and 4b. These disorders were sometimes also called hyperprostaglandin E syndromes because they are associated with elevated levels of compounds known as prostaglandins, which act as signaling molecules in our body. Bartter syndrome type 3 is sometimes also referred to as classic Bartter syndrome. Gitelman syndrome, which has considerable clinical overlap with Bartter syndrome, especially type 3, is sometimes grouped with the Bartter syndromes. NORD has a separate report on Gitelman syndrome. | Overview of Bartter Syndrome. Summary Bartter syndrome is a general term for a group of rare genetic disorders in which there are specific defects in kidney function. These defects impair the kidney’s ability to reabsorb salt and cause imbalances in various electrolyte and fluid concentrations in the body. The electrolytes affected are primarily mineral salts such as potassium, calcium, magnesium, sodium, and chloride. The symptoms and severity of Bartter syndrome vary from one person to another and can range from mild to severe. Age of onset of overt symptoms can range from before birth to adulthood. Bartter syndrome is caused by alterations (mutations) in one of several different genes. Treatment is aimed at correcting the electrolyte imbalances through the use of supplements and certain medications such as nonsteroidal anti-inflammatories (NSAIDs) and diuretics. IntroductionBartter syndrome was first described in the medical literature in the 1960s by Dr. Frederic Bartter. Through the years, different terminology has been used to describe these disorders. Some researchers classify these disorders based on their clinical appearance, while others classify them based on the underlying mutated gene. The different terminology and classification systems can be confusing. Bartter syndrome can be variably classified as a renal tubulopathy (because certain small tubes within the kidneys are affected), a salt-wasting disorder (because affected individuals excrete excess amounts of salt), a salt-losing tubulopathy, and a channelopathy (because the ion channels in the kidneys are affected). Although Bartter syndrome can be broken down into subtypes based on the underlying gene or symptomatology, considerable overlap of symptoms and disease presentation exists among the subtypes and Bartter syndrome may be best thought of as spectrum of disease caused by several different gene mutations. The most common classification system for these disorders is based upon the underlying genetic mutation as listed above. The term antenatal (before birth) Bartter syndrome refers to those cases who present before birth and is typically associated with types 1, 2, 4a and 4b. These disorders were sometimes also called hyperprostaglandin E syndromes because they are associated with elevated levels of compounds known as prostaglandins, which act as signaling molecules in our body. Bartter syndrome type 3 is sometimes also referred to as classic Bartter syndrome. Gitelman syndrome, which has considerable clinical overlap with Bartter syndrome, especially type 3, is sometimes grouped with the Bartter syndromes. NORD has a separate report on Gitelman syndrome. | 147 | Bartter Syndrome |
nord_147_1 | Symptoms of Bartter Syndrome | The age of onset, severity and specific symptoms associated with Bartter syndrome can vary greatly from one person to another, even among individuals who have the same subtype. Some individuals may have mild cases; others may experience severe, potentially life-threatening complications, at birth.Generally, Bartter syndromes types 1, 2, 4a, and 4b are associated with an early (before birth) age of onset and more severe symptoms. Bartter syndrome type 3 can also present before birth, but usually with milder symptoms (see below) and many patients with this subtype present in infancy or early childhood with growth problems. However, this is not a universal, absolute rule and exceptions exist. Therefore, affected individuals may not have all of the symptoms discussed below and certain symptoms, which are more prevalent with one subtype of Bartter syndrome, can occur in another subtype. It is important to note that every case is unique and will follow its own course.Most medical sources will use specific terminology to describe the electrolyte imbalances that characterize the Bartter syndromes. These terms refer to findings on laboratory tests rather than specific symptoms. Such terms include low levels of potassium in the blood (hypokalemia), low levels of chloride in the blood (hypochloremia), excess alkaline levels in the body (metabolic alkalosis), high levels of renin in the blood (hyperreninemia), and high levels of aldosterone in the blood (hyperaldosteronemia).Symptoms can vary substantially. Some affected individuals may only have mild symptoms. Common symptoms include muscle weakness, cramping, spasms and fatigue. Excessive thirst (polydipsia), excessive urination (polyuria), and the need to urinate at night (nocturia) may also occur. Despite excessive fluid intake, frequent urination can lead to dehydration. Some children may crave salt. Additional symptoms that may occur include constipation, vomiting, elevated body temperature, lethargy, and a general feeling of poor health.
As children grow older, their growth rate may be below what would be expected based upon their age and gender (growth retardation). If left untreated, affected individuals may be shorter than would be expected as adults (short stature). Some children may experience delays in the reaching developmental milestones (developmental delays).The signs and symptoms of the antenatal Bartter syndromes, also known as Bartter syndromes 1 and 2 and Bartter syndromes 4a and 4b, can be seen before birth (antenatal period). Abnormal kidney function in utero can lead to excessive urine production and an abnormal buildup of amniotic fluid around the developing fetus (polyhydramnios). Birth is often premature. In the newborn period, affected infants may experience excessive urination (polyuria) and life-threatening episodes of fever and dehydration. Vomiting and diarrhea may also occur.
A special form is Bartter type 5: it manifests with excess amniotic fluid (polyhydramnios), that is typically severe leading to premature birth. In some instances, prematurity is so early that the baby is not viable outside the mother’s womb. Yet, within weeks of being born all the kidney symptoms of high urine output and electrolyte loss resolve spontaneously without any need for treatment. The gene underlying this condition is on the X-chromosome, so Bartter syndrome type 5 occurs predominantly in boys.Some affected infants may have characteristic facial features including a triangularly-shaped face, prominent forehead, large eyes, prominent, pointed ears, and a “pouting” expression because of drooping of the corners of the mouth. In some cases, these distinctive features may be absent or so mild as to go unnoticed. Affected infants may fail to grow and gain weight as would be expected based upon age and gender (failure to thrive). Growth delays and growth retardation may be seen as affected children age, and final adult height may be shorter than would otherwise be expected (short stature).In some individuals who experience significant electrolyte imbalances, severe complications, such as irregular heartbeats (cardiac arrhythmias) or muscle weakness (paralysis) may develop. Although rare, if untreated, these cardiac arrhythmias can potentially progress to cause sudden cardiac arrest and potentially sudden death.
Patients with Bartter syndromes type 1 and 2 typically have elevated levels of calcium in the urine which can lead to the deposition of calcium in the kidney (nephrocalcinosis). In mild cases, there may not be any associated symptoms or minor symptoms including blood in the urine, vomiting, or fever. Affected individuals may pass stones made up of calcium. Calcium buildup (calcification) in the kidneys may eventually affect kidney function.In Bartter syndrome types 4A and 4B, affected infants cannot hear from birth due to an impaired ability of the auditory nerves to transmit sensory input to the brain (congenital sensorineural deafness). In some cases, cognitive and motor development is also affected and affected children may experience delays in reaching certain developmental milestones. This is likely related to the degree of prematurity. | Symptoms of Bartter Syndrome. The age of onset, severity and specific symptoms associated with Bartter syndrome can vary greatly from one person to another, even among individuals who have the same subtype. Some individuals may have mild cases; others may experience severe, potentially life-threatening complications, at birth.Generally, Bartter syndromes types 1, 2, 4a, and 4b are associated with an early (before birth) age of onset and more severe symptoms. Bartter syndrome type 3 can also present before birth, but usually with milder symptoms (see below) and many patients with this subtype present in infancy or early childhood with growth problems. However, this is not a universal, absolute rule and exceptions exist. Therefore, affected individuals may not have all of the symptoms discussed below and certain symptoms, which are more prevalent with one subtype of Bartter syndrome, can occur in another subtype. It is important to note that every case is unique and will follow its own course.Most medical sources will use specific terminology to describe the electrolyte imbalances that characterize the Bartter syndromes. These terms refer to findings on laboratory tests rather than specific symptoms. Such terms include low levels of potassium in the blood (hypokalemia), low levels of chloride in the blood (hypochloremia), excess alkaline levels in the body (metabolic alkalosis), high levels of renin in the blood (hyperreninemia), and high levels of aldosterone in the blood (hyperaldosteronemia).Symptoms can vary substantially. Some affected individuals may only have mild symptoms. Common symptoms include muscle weakness, cramping, spasms and fatigue. Excessive thirst (polydipsia), excessive urination (polyuria), and the need to urinate at night (nocturia) may also occur. Despite excessive fluid intake, frequent urination can lead to dehydration. Some children may crave salt. Additional symptoms that may occur include constipation, vomiting, elevated body temperature, lethargy, and a general feeling of poor health.
As children grow older, their growth rate may be below what would be expected based upon their age and gender (growth retardation). If left untreated, affected individuals may be shorter than would be expected as adults (short stature). Some children may experience delays in the reaching developmental milestones (developmental delays).The signs and symptoms of the antenatal Bartter syndromes, also known as Bartter syndromes 1 and 2 and Bartter syndromes 4a and 4b, can be seen before birth (antenatal period). Abnormal kidney function in utero can lead to excessive urine production and an abnormal buildup of amniotic fluid around the developing fetus (polyhydramnios). Birth is often premature. In the newborn period, affected infants may experience excessive urination (polyuria) and life-threatening episodes of fever and dehydration. Vomiting and diarrhea may also occur.
A special form is Bartter type 5: it manifests with excess amniotic fluid (polyhydramnios), that is typically severe leading to premature birth. In some instances, prematurity is so early that the baby is not viable outside the mother’s womb. Yet, within weeks of being born all the kidney symptoms of high urine output and electrolyte loss resolve spontaneously without any need for treatment. The gene underlying this condition is on the X-chromosome, so Bartter syndrome type 5 occurs predominantly in boys.Some affected infants may have characteristic facial features including a triangularly-shaped face, prominent forehead, large eyes, prominent, pointed ears, and a “pouting” expression because of drooping of the corners of the mouth. In some cases, these distinctive features may be absent or so mild as to go unnoticed. Affected infants may fail to grow and gain weight as would be expected based upon age and gender (failure to thrive). Growth delays and growth retardation may be seen as affected children age, and final adult height may be shorter than would otherwise be expected (short stature).In some individuals who experience significant electrolyte imbalances, severe complications, such as irregular heartbeats (cardiac arrhythmias) or muscle weakness (paralysis) may develop. Although rare, if untreated, these cardiac arrhythmias can potentially progress to cause sudden cardiac arrest and potentially sudden death.
Patients with Bartter syndromes type 1 and 2 typically have elevated levels of calcium in the urine which can lead to the deposition of calcium in the kidney (nephrocalcinosis). In mild cases, there may not be any associated symptoms or minor symptoms including blood in the urine, vomiting, or fever. Affected individuals may pass stones made up of calcium. Calcium buildup (calcification) in the kidneys may eventually affect kidney function.In Bartter syndrome types 4A and 4B, affected infants cannot hear from birth due to an impaired ability of the auditory nerves to transmit sensory input to the brain (congenital sensorineural deafness). In some cases, cognitive and motor development is also affected and affected children may experience delays in reaching certain developmental milestones. This is likely related to the degree of prematurity. | 147 | Bartter Syndrome |
nord_147_2 | Causes of Bartter Syndrome | Bartter syndromes are caused by recessive mutations in the SLC12A1 gene (type 1), the KCNJ1 gene (type 2), the CLCNKB gene (type 3), the BSND gene (type 4A), or both the CLCNKA and CLCNKB genes (type 4B). Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body. Bartter syndrome is inherited in an autosomal recessive manner, except for type 5, which is inherited in an X-linked recessive matter.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 abnormal copies of a gene, one from each parent. If an individual inherits one normal copy and one copy 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.This is however different for the X-linked Bartter syndrome type 5, as a boy only has one X-chromosome, which he inherits from the mother. If the mother is a carrier for a mutation in MAGED2, then there is a 50% risk that she passes this on to her children. If she passes it on to a daughter, then she will be a carrier, as well, as a daughter also inherits a normal copy of MAGED2 on the X-chromosome she receives from the father. But if she passes it on to a boy, then he will be affected, as he does not have a second normal copy, for he receives the Y-chromosome from the father. Very rarely, girls who are carriers can also have disease manifestations, but it is typically much milder than in boys.Most of the genes involved in Bartter syndrome produce (encode) proteins that are required for the proper function of the kidneys. One of the different functions of the kidney is maintaining a specific volume and composition of body fluids through the reabsorption of salts and minerals that conduct electrical impulses in the body (electrolytes). Electrolytes are necessary for various functions in the body including nerve firing, muscle contraction, energy generation, and most major biochemical reactions in the body. The kidneys maintain electrolyte balance by filtering the blood. Hair-sized structures called nephrons are the basic functional units of the kidneys and there are roughly a million of these in our kidneys. Each nephron consists of a glomerulus and a renal tubule. The glomeruli filter the blood and in an adult create a primary urine volume of about 100 ml/min (or roughly 150litres per day). This is called the glomerular filtration rate (GFR). The renal tubule then reabsorbs most of this filtrate, including electrolytes such as sodium, chloride and potassium back into the blood to ensure that not too much is lost through the urine. The renal tubule contains four main segments known as the proximal convoluted tube, the loop of Henle, the distal convoluted tube (DCT), and the collecting duct. Bartter syndrome is primarily a disorder in the loop of Henle, but the distal convoluted tubule can also be affected in some subtypes.The loop of Henle accounts for a significant percentage of the salt and mineral reabsorption in the body. It also plays a role in urine concentration. The DCT plays a lesser role in salt reabsorption and also has a role in functions necessary to maintain chemical balance in the body (e.g. potassium secretion). When one segment of the distal nephron does not function properly, others try to compensate. An important segment for compensation is the collecting duct, where especially the sodium that has not been reabsorbed upstream is taken up, but this occurs in exchange for potassium and acid. It is this compensation that generates the typical electrolyte abnormalities of Bartter syndrome, the low potassium and the alkalosis (lack of acid).Mutations in the genes involved in Bartter syndrome result in abnormal functioning of the ion channels or proteins involved in the transport of electrolytes back into the bloodstream. This abnormal functioning prevents sodium and chloride (salt) from being reabsorbed from the urine. This causes too much salt and water to be expelled from the body through the urine. In turn, either directly or indirectly, other electrolytes such as potassium, magnesium, and calcium are also affected. Thus, the proper balance of electrolytes in the body is disrupted, and it is this balance which is critical for the normal functioning of our body. These imbalances ultimately lead to the various symptoms of the Bartter syndromes. | Causes of Bartter Syndrome. Bartter syndromes are caused by recessive mutations in the SLC12A1 gene (type 1), the KCNJ1 gene (type 2), the CLCNKB gene (type 3), the BSND gene (type 4A), or both the CLCNKA and CLCNKB genes (type 4B). Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body. Bartter syndrome is inherited in an autosomal recessive manner, except for type 5, which is inherited in an X-linked recessive matter.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 abnormal copies of a gene, one from each parent. If an individual inherits one normal copy and one copy 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.This is however different for the X-linked Bartter syndrome type 5, as a boy only has one X-chromosome, which he inherits from the mother. If the mother is a carrier for a mutation in MAGED2, then there is a 50% risk that she passes this on to her children. If she passes it on to a daughter, then she will be a carrier, as well, as a daughter also inherits a normal copy of MAGED2 on the X-chromosome she receives from the father. But if she passes it on to a boy, then he will be affected, as he does not have a second normal copy, for he receives the Y-chromosome from the father. Very rarely, girls who are carriers can also have disease manifestations, but it is typically much milder than in boys.Most of the genes involved in Bartter syndrome produce (encode) proteins that are required for the proper function of the kidneys. One of the different functions of the kidney is maintaining a specific volume and composition of body fluids through the reabsorption of salts and minerals that conduct electrical impulses in the body (electrolytes). Electrolytes are necessary for various functions in the body including nerve firing, muscle contraction, energy generation, and most major biochemical reactions in the body. The kidneys maintain electrolyte balance by filtering the blood. Hair-sized structures called nephrons are the basic functional units of the kidneys and there are roughly a million of these in our kidneys. Each nephron consists of a glomerulus and a renal tubule. The glomeruli filter the blood and in an adult create a primary urine volume of about 100 ml/min (or roughly 150litres per day). This is called the glomerular filtration rate (GFR). The renal tubule then reabsorbs most of this filtrate, including electrolytes such as sodium, chloride and potassium back into the blood to ensure that not too much is lost through the urine. The renal tubule contains four main segments known as the proximal convoluted tube, the loop of Henle, the distal convoluted tube (DCT), and the collecting duct. Bartter syndrome is primarily a disorder in the loop of Henle, but the distal convoluted tubule can also be affected in some subtypes.The loop of Henle accounts for a significant percentage of the salt and mineral reabsorption in the body. It also plays a role in urine concentration. The DCT plays a lesser role in salt reabsorption and also has a role in functions necessary to maintain chemical balance in the body (e.g. potassium secretion). When one segment of the distal nephron does not function properly, others try to compensate. An important segment for compensation is the collecting duct, where especially the sodium that has not been reabsorbed upstream is taken up, but this occurs in exchange for potassium and acid. It is this compensation that generates the typical electrolyte abnormalities of Bartter syndrome, the low potassium and the alkalosis (lack of acid).Mutations in the genes involved in Bartter syndrome result in abnormal functioning of the ion channels or proteins involved in the transport of electrolytes back into the bloodstream. This abnormal functioning prevents sodium and chloride (salt) from being reabsorbed from the urine. This causes too much salt and water to be expelled from the body through the urine. In turn, either directly or indirectly, other electrolytes such as potassium, magnesium, and calcium are also affected. Thus, the proper balance of electrolytes in the body is disrupted, and it is this balance which is critical for the normal functioning of our body. These imbalances ultimately lead to the various symptoms of the Bartter syndromes. | 147 | Bartter Syndrome |
nord_147_3 | Affects of Bartter Syndrome | The Bartter syndromes affect males and females in equal numbers. They are estimated to affect approximately one in 100,000 people in the general population. However, many cases go undiagnosed or misdiagnosed, making it difficult to determine the true frequency in the general population. Bartter syndromes can occur in individuals of any race or ethnic background. | Affects of Bartter Syndrome. The Bartter syndromes affect males and females in equal numbers. They are estimated to affect approximately one in 100,000 people in the general population. However, many cases go undiagnosed or misdiagnosed, making it difficult to determine the true frequency in the general population. Bartter syndromes can occur in individuals of any race or ethnic background. | 147 | Bartter Syndrome |
nord_147_4 | Related disorders of Bartter Syndrome | Symptoms of the following disorders can be similar to those of the Bartter syndromes. Comparisons may be useful for a differential diagnosis.Gitelman syndrome usually becomes apparent anywhere from late childhood (usually over the age of six) to adulthood. Muscle weakness, spasms, and cramps may be more common in Gitelman syndrome than the Bartter syndromes. Affected individuals may experience episodes of fatigue and muscle weakness, muscle aches, cramps and spasms. Gitelman syndrome is caused by alterations in the SLC12A3 gene and is inherited in an autosomal recessive manner. (For more information on this disorder, choose “Gitelman” as your search term in the Rare Disease Database.)EAST syndrome is an extremely rare genetic disorder, first described in the medical literature in 2009. The disorder is characterized by seizures, hearing loss from birth (congenital sensorineural deafness), impaired coordination of voluntary movements (ataxia) so that a person’s movements are unsteady or wobbly, and impairment in a specific part of the kidney (renal salt-losing tubulopathy). The underlying defect in EAST syndrome causing salt and electrolyte imbalances is similar to that seen in Gitelman syndrome. EAST syndrome is caused by mutations in the KCNJ10 gene and is inherited in an autosomal recessive manner. EAST is an acronym that stands for epilepsy, ataxia, sensorineural deafness, and tubulopathy. Pseudo-Bartter syndrome is a general term that refers to certain conditions that cause similar symptoms and signs of Bartter syndrome, but in which there is no inherited renal tubular dysfunction. It is also due to salt losses and reasons for these include the use of certain diuretics, conditions in which frequent vomiting occurs including bulimia and cyclic vomiting syndrome, and the abuse of laxatives. Some individuals with cystic fibrosis may exhibit symptoms similar to those seen in Bartter syndrome, particularly young children with cystic fibrosis who have specific risk factors (i.e. severe respiratory or pancreatic disease, gastrointestinal losses, or warm weather).Autosomal dominant hypocalcemia type 1 (also called familial hypocalcemia) can sometimes look like Bartter syndrome. Hypocalcemia is the medical term for low levels of calcium in the blood. Symptoms and severity vary from one person to another. Generally, affected individuals may experience a mild form of Bartter syndrome with onset usually in young adulthood characterized by excessive need to urinate (polyuria), muscle weakness, muscle cramps, spasms, and tetany. Affected individuals may experience low levels of parathyroid levels (hypoparathyroidism), seizures, and sensations of numbness or tingling on the skin (paresthesia). Some affected individuals may develop excess levels of calcium in the kidney (nephrocalcinosis) and kidney stones. This condition is inherited in an autosomal dominant manner. | Related disorders of Bartter Syndrome. Symptoms of the following disorders can be similar to those of the Bartter syndromes. Comparisons may be useful for a differential diagnosis.Gitelman syndrome usually becomes apparent anywhere from late childhood (usually over the age of six) to adulthood. Muscle weakness, spasms, and cramps may be more common in Gitelman syndrome than the Bartter syndromes. Affected individuals may experience episodes of fatigue and muscle weakness, muscle aches, cramps and spasms. Gitelman syndrome is caused by alterations in the SLC12A3 gene and is inherited in an autosomal recessive manner. (For more information on this disorder, choose “Gitelman” as your search term in the Rare Disease Database.)EAST syndrome is an extremely rare genetic disorder, first described in the medical literature in 2009. The disorder is characterized by seizures, hearing loss from birth (congenital sensorineural deafness), impaired coordination of voluntary movements (ataxia) so that a person’s movements are unsteady or wobbly, and impairment in a specific part of the kidney (renal salt-losing tubulopathy). The underlying defect in EAST syndrome causing salt and electrolyte imbalances is similar to that seen in Gitelman syndrome. EAST syndrome is caused by mutations in the KCNJ10 gene and is inherited in an autosomal recessive manner. EAST is an acronym that stands for epilepsy, ataxia, sensorineural deafness, and tubulopathy. Pseudo-Bartter syndrome is a general term that refers to certain conditions that cause similar symptoms and signs of Bartter syndrome, but in which there is no inherited renal tubular dysfunction. It is also due to salt losses and reasons for these include the use of certain diuretics, conditions in which frequent vomiting occurs including bulimia and cyclic vomiting syndrome, and the abuse of laxatives. Some individuals with cystic fibrosis may exhibit symptoms similar to those seen in Bartter syndrome, particularly young children with cystic fibrosis who have specific risk factors (i.e. severe respiratory or pancreatic disease, gastrointestinal losses, or warm weather).Autosomal dominant hypocalcemia type 1 (also called familial hypocalcemia) can sometimes look like Bartter syndrome. Hypocalcemia is the medical term for low levels of calcium in the blood. Symptoms and severity vary from one person to another. Generally, affected individuals may experience a mild form of Bartter syndrome with onset usually in young adulthood characterized by excessive need to urinate (polyuria), muscle weakness, muscle cramps, spasms, and tetany. Affected individuals may experience low levels of parathyroid levels (hypoparathyroidism), seizures, and sensations of numbness or tingling on the skin (paresthesia). Some affected individuals may develop excess levels of calcium in the kidney (nephrocalcinosis) and kidney stones. This condition is inherited in an autosomal dominant manner. | 147 | Bartter Syndrome |
nord_147_5 | Diagnosis of Bartter Syndrome | A diagnosis of one of the Bartter syndromes is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests.Clinical Testing and WorkupLaboratory tests that are used to diagnose these disorders include blood tests to determine serum electrolyte levels, specifically potassium, chloride, bicarbonate, magnesium, renin, and aldosterone levels and urine tests to determine the presence of prostaglandin E2 and urine electrolytes, including sodium, chloride, potassium, calcium and magnesium.The antenatal subtypes of Bartter syndrome can be diagnosed before birth (prenatally) when polyhydramnios is detected without the presence of associated congenital malformations, and elevated levels of chloride and aldosterone are detected in the amniotic fluid.Molecular genetic testing can confirm a diagnosis. Molecular genetic testing can detect mutations in specific genes known to cause the Bartter syndromes, but is only available as a diagnostic service at specialized laboratories. | Diagnosis of Bartter Syndrome. A diagnosis of one of the Bartter syndromes is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests.Clinical Testing and WorkupLaboratory tests that are used to diagnose these disorders include blood tests to determine serum electrolyte levels, specifically potassium, chloride, bicarbonate, magnesium, renin, and aldosterone levels and urine tests to determine the presence of prostaglandin E2 and urine electrolytes, including sodium, chloride, potassium, calcium and magnesium.The antenatal subtypes of Bartter syndrome can be diagnosed before birth (prenatally) when polyhydramnios is detected without the presence of associated congenital malformations, and elevated levels of chloride and aldosterone are detected in the amniotic fluid.Molecular genetic testing can confirm a diagnosis. Molecular genetic testing can detect mutations in specific genes known to cause the Bartter syndromes, but is only available as a diagnostic service at specialized laboratories. | 147 | Bartter Syndrome |
nord_147_6 | Therapies of Bartter Syndrome | TreatmentThe treatment of the Bartter syndromes is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians or general internists, kidney specialists (nephrologists or pediatric nephrologists) and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well.There is no cure for these disorders, which require lifelong administration of certain supplements and medications. The mainstay of treatment is restoring the proper balance of fluids and electrolytes in the body. This typically includes sodium and potassium chloride supplementation to help correct electrolyte imbalances. Potassium chloride supplementation is preferred to other forms of potassium salts because of the corresponding chloride deficiencies. Some infants with severe, life-threatening loop disorders (antenatal Bartter syndromes) may require intravenous salt and water replacement. Because the elevated levels of prostaglandins aggravate the polyuria and electrolyte abnormalities, treatment typically includes a drug that decreases the production of these such as indomethacin, ibuprofen or celecoxib. These drugs are also called nonsteroidal anti-inflammatory drug (NSAID). Indomethacin has generally been used and shown to be effective in individuals with Bartter syndromes, but can have severe side effects, especially in premature babies with regards to perforation in the intestinal tract, especially the stomach. If used, it is recommended to do so in combination with a stomach acid blocker. Newer forms of NSAID, such as celecoxib (also called “COX2 inhibitors”) have a much lower risk of these intestinal side effects and have also been shown to be effective in Bartter syndrome, but there is less experience in their use. With increasing age, Bartter syndrome tends to get easier to manage and control. The most difficult period is usually the first year(s) of life. As there is also concern that long-term use of NSIAD may affect kidney function, these medications often get reduced or weaned off over the years.Some affected individuals may receive medications known as potassium-sparing diuretics such as spironolactone or amiloride. These drugs increase the excretion of sodium in urine, but retain potassium and acid thereby improving low potassium levels in the blood (hypokalemia) and alkalosis. Yet, because they worsen the loss of sodium, they risk low blood pressure and potentially even collapse (hypovolemic shock) and it is usually recommended to take these together with adequate sodium chloride supplementation.Drugs that inhibit or block the renin-aldosterone-angiotensin system (RAAS inhibitors) have been used to treat individuals with Bartter syndromes in addition to other therapies (adjunct therapy). RAAS inhibitors include aldosterone antagonists, angiotensin II receptor blockers, and angiotensin-converting enzyme (ACE) inhibitors. These drugs can prevent the secretion of aldosterone from the adrenal glands and counteract the effects of renin on the kidneys, thereby reducing potassium and acid loss. But, like the potassium-sparing diuretics, they may dangerously lower blood pressure, which may already be low in individuals with Bartter syndromes, and can potentially impact kidney and cardiovascular function. Thus, their use should be carefully considered and monitored and the drugs must be stopped, if the patient has additional salt losses, e.g. from diarrhea and/or vomiting.Successful use of growth hormone therapy has been reported in some cases for the treatment of growth retardation and short stature potentially associated with Bartter syndrome.Especially in Bartter syndrome type 3, magnesium supplementation may be used to treat muscle spasms or tetany.Adequate salt and water intake is necessary. Affected individuals typically have a large appetite for salt due to salt cravings and should be encouraged to indulge in salty foods. Affected individuals may also be encouraged to eat foods that are high in potassium.Cochlear implants can be used to treat deafness associated with Bartter syndromes type 4A and 4B.In stressful situations, blood electrolytes can change rapidly, require prompt intravenous treatment. Stressful situations can include surgical procedures, trauma, and the presence of another type of disease or infection (intercurrent disease). | Therapies of Bartter Syndrome. TreatmentThe treatment of the Bartter syndromes is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians or general internists, kidney specialists (nephrologists or pediatric nephrologists) and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well.There is no cure for these disorders, which require lifelong administration of certain supplements and medications. The mainstay of treatment is restoring the proper balance of fluids and electrolytes in the body. This typically includes sodium and potassium chloride supplementation to help correct electrolyte imbalances. Potassium chloride supplementation is preferred to other forms of potassium salts because of the corresponding chloride deficiencies. Some infants with severe, life-threatening loop disorders (antenatal Bartter syndromes) may require intravenous salt and water replacement. Because the elevated levels of prostaglandins aggravate the polyuria and electrolyte abnormalities, treatment typically includes a drug that decreases the production of these such as indomethacin, ibuprofen or celecoxib. These drugs are also called nonsteroidal anti-inflammatory drug (NSAID). Indomethacin has generally been used and shown to be effective in individuals with Bartter syndromes, but can have severe side effects, especially in premature babies with regards to perforation in the intestinal tract, especially the stomach. If used, it is recommended to do so in combination with a stomach acid blocker. Newer forms of NSAID, such as celecoxib (also called “COX2 inhibitors”) have a much lower risk of these intestinal side effects and have also been shown to be effective in Bartter syndrome, but there is less experience in their use. With increasing age, Bartter syndrome tends to get easier to manage and control. The most difficult period is usually the first year(s) of life. As there is also concern that long-term use of NSIAD may affect kidney function, these medications often get reduced or weaned off over the years.Some affected individuals may receive medications known as potassium-sparing diuretics such as spironolactone or amiloride. These drugs increase the excretion of sodium in urine, but retain potassium and acid thereby improving low potassium levels in the blood (hypokalemia) and alkalosis. Yet, because they worsen the loss of sodium, they risk low blood pressure and potentially even collapse (hypovolemic shock) and it is usually recommended to take these together with adequate sodium chloride supplementation.Drugs that inhibit or block the renin-aldosterone-angiotensin system (RAAS inhibitors) have been used to treat individuals with Bartter syndromes in addition to other therapies (adjunct therapy). RAAS inhibitors include aldosterone antagonists, angiotensin II receptor blockers, and angiotensin-converting enzyme (ACE) inhibitors. These drugs can prevent the secretion of aldosterone from the adrenal glands and counteract the effects of renin on the kidneys, thereby reducing potassium and acid loss. But, like the potassium-sparing diuretics, they may dangerously lower blood pressure, which may already be low in individuals with Bartter syndromes, and can potentially impact kidney and cardiovascular function. Thus, their use should be carefully considered and monitored and the drugs must be stopped, if the patient has additional salt losses, e.g. from diarrhea and/or vomiting.Successful use of growth hormone therapy has been reported in some cases for the treatment of growth retardation and short stature potentially associated with Bartter syndrome.Especially in Bartter syndrome type 3, magnesium supplementation may be used to treat muscle spasms or tetany.Adequate salt and water intake is necessary. Affected individuals typically have a large appetite for salt due to salt cravings and should be encouraged to indulge in salty foods. Affected individuals may also be encouraged to eat foods that are high in potassium.Cochlear implants can be used to treat deafness associated with Bartter syndromes type 4A and 4B.In stressful situations, blood electrolytes can change rapidly, require prompt intravenous treatment. Stressful situations can include surgical procedures, trauma, and the presence of another type of disease or infection (intercurrent disease). | 147 | Bartter Syndrome |
nord_148_0 | Overview of Beckwith-Wiedemann Syndrome | Beckwith-Wiedemann syndrome (BWS) is the most common overgrowth and cancer predisposition disorder. BWS is caused by changes on chromosome 11p15.5 and is characterized by a wide spectrum of symptoms and physical findings that vary in range and severity from person to person. Associated features include a large tongue (macroglossia), abdominal wall abnormalities (omphalocele, umbilical hernia or diastasis recti), abnormal enlargement of one side or structure of the body (lateralized overgrowth) resulting in unequal (asymmetric) growth, an increased risk of developing certain childhood cancers, most commonly Wilms tumor (kidney tumor) and hepatoblastoma (liver tumor) and low blood sugar levels in the first few days of life (neonatal hypoglycemia) or beyond leading to persistent low blood sugars (hyperinsulinism). BWS may also be associated with above-average birth weight (large for gestational age), increased growth after birth (macrosomia), enlargement of certain internal organs (organomegaly), distinctive grooves in the ear lobes (ear creases and ear pits), and a characteristic facial appearance.Beckwith-Wiedemann syndrome has been recently reclassified as Beckwith-Wiedemann spectrum as the clinical presentation can vary from patient to patient. Approximately 80% of people with BWS have chromosome changes that appear to occur randomly (sporadically). Familial transmission (inherited forms) occurs in about 5-10% of patients with BWS. About 14% of patients with BWS have an unknown cause for diagnosis. BWS affects at least one in 10,340 live births. Researchers have determined that BWS results from various abnormalities affecting the normal, proper expression of certain genes that control growth within a specific region of chromosome 11 (BWS critical region). | Overview of Beckwith-Wiedemann Syndrome. Beckwith-Wiedemann syndrome (BWS) is the most common overgrowth and cancer predisposition disorder. BWS is caused by changes on chromosome 11p15.5 and is characterized by a wide spectrum of symptoms and physical findings that vary in range and severity from person to person. Associated features include a large tongue (macroglossia), abdominal wall abnormalities (omphalocele, umbilical hernia or diastasis recti), abnormal enlargement of one side or structure of the body (lateralized overgrowth) resulting in unequal (asymmetric) growth, an increased risk of developing certain childhood cancers, most commonly Wilms tumor (kidney tumor) and hepatoblastoma (liver tumor) and low blood sugar levels in the first few days of life (neonatal hypoglycemia) or beyond leading to persistent low blood sugars (hyperinsulinism). BWS may also be associated with above-average birth weight (large for gestational age), increased growth after birth (macrosomia), enlargement of certain internal organs (organomegaly), distinctive grooves in the ear lobes (ear creases and ear pits), and a characteristic facial appearance.Beckwith-Wiedemann syndrome has been recently reclassified as Beckwith-Wiedemann spectrum as the clinical presentation can vary from patient to patient. Approximately 80% of people with BWS have chromosome changes that appear to occur randomly (sporadically). Familial transmission (inherited forms) occurs in about 5-10% of patients with BWS. About 14% of patients with BWS have an unknown cause for diagnosis. BWS affects at least one in 10,340 live births. Researchers have determined that BWS results from various abnormalities affecting the normal, proper expression of certain genes that control growth within a specific region of chromosome 11 (BWS critical region). | 148 | Beckwith-Wiedemann Syndrome |
nord_148_1 | Symptoms of Beckwith-Wiedemann Syndrome | The characteristic features of BWS vary greatly from person to person, which can make clinical diagnosis based on physical exam findings and molecular diagnosis based on genetic testing challenging. Sometimes, the clinical and molecular diagnoses do not match because clinically the patients may not have many obvious physical features of BWS even if they have changes in the BWS critical region based on genetic testing. Some individuals may appear mildly affected while others appear more significantly affected. Affected individuals may not have all the symptoms listed. The range of clinical features due to changes on chromosome 11p15.5 has been redefined as the Beckwith-Wiedemann spectrum.Some infants with BWS are born prematurely, but still have an excessive birth weight (large for gestational age). Over half of infants with BWS are above the 97th percentile in weight for gestational age. Overgrowth can continue throughout childhood (macrosomia). Abnormal enlargement of one side or structure of the body (lateralized overgrowth) may occur, resulting in asymmetric growth. Lateralized overgrowth or isolated lateralized overgrowth (ILO) is a new term used to describe what was previously called hemihypertrophy or hemihyperplasia. ILO is defined as asymmetric overgrowth of the body. ILO is not limited to one side of the body, and it does not specify what part or tissue is displaying overgrowth. For example, a patient may have a larger left arm and a larger right leg.Abdominal wall abnormalities can include an omphalocele (also known as exomphalos), in which part of an infant’s intestines and other abdominal organs are outside of the body because of an opening in the belly button. The intestines and other organs are covered by a thin membrane. Less severe abdominal abnormalities can include protrusion of part of the intestines through an abnormal opening in the muscular wall of the abdomen near the umbilical cord (umbilical hernia), or weakness and separation of the left and right muscles of the abdominal wall (diastasis recti). Additionally, the internal organs of affected individuals can become abnormally enlarged (organomegaly). Any or all of the following organs may be affected: liver, spleen, pancreas, kidneys or adrenal glands.Some newborns with BWS may have low blood sugar (neonatal hypoglycemia or hyperinsulinism) due to overgrowth and excessive secretion of the hormone insulin by the pancreas. Insulin helps regulate blood glucose levels by promoting the movement of glucose into cells. Most infants with neonatal hypoglycemia associated with BWS have mild and transient symptoms that resolve without treatment. However, without proper detection and appropriate treatment, neurological complications may result. Congenital hyperinsulinism is the most common cause for persistent and severe low blood sugar.Patients with BWS may have an enlarged tongue (macroglossia), which can cause difficulties in speaking, feeding and breathing. In addition to macroglossia, BWS may be characterized by other differences of the skull and facial (craniofacial) region. Such features may include distinctive slit-like grooves or creases in the ear lobes and dimples on the back of the ears (ear creases or pits). Some infants may have flat, pale red or reddish-purple facial marks at birth, most commonly on the eyelids and forehead, which consist of abnormal clusters of small blood vessels (facial nevus simplex). Such marks typically become less apparent during the first year of life. In patients with lateralized overgrowth, one side of the face may appear larger than the other. Some patients may have improper contact of the teeth of the upper and lower jaws (malocclusion) and abnormal protrusion of the lower jaw (mandibular prognathism), features that may occur secondary to macroglossia.A variety of kidney (renal) abnormalities can occur in individuals with BWS, including abnormally large kidneys (nephromegaly), improper development of the innermost tissues of the kidney (renal medullary dysplasia) and the formation of calcium deposits in the kidney (nephrocalcinosis), which could potentially impair kidney function. Additional abnormalities include duplication of the series of tubes and ducts through which the kidneys reabsorb water and sodium (duplicated collecting system), widening of some of the small tubes and collecting ducts (medullary sponge kidney) and the presence of small pouches (diverticula) on the kidneys. Kidney stones have been reported to occur in adolescents and adults with BWS.Patients with BWS may have an increased risk of developing certain childhood cancers. Embryonal cancers occur in approximately 8% of patients with BWS. The most common types of tumors are Wilms tumor (a kidney tumor) and hepatoblastoma (a liver tumor). Neuroblastoma (a nerve cell tumor), rhabdomyosarcoma (a soft tissue tumor) and adrenal carcinoma (an adrenal gland tumor) have been reported more rarely. The overall tumor risk is highest during the first two years of life.Many clinical features of BWS become less evident with increasing age and many adults experience normal growth and appearance. Neurological (brain) development appears to be unaffected in BWS, unless associated with prolonged, untreated neonatal hypoglycemia, extreme prematurity, or a chromosomal duplication. Adult patients may present with medical issues related to these clinical features, and some have required surgery in early childhood. Most features in adults with BWS, such as renal issues and back pain, are consequences of pediatric issues. However, more research is needed to determine the relationship between features of adults with BWS and pediatric symptoms. | Symptoms of Beckwith-Wiedemann Syndrome. The characteristic features of BWS vary greatly from person to person, which can make clinical diagnosis based on physical exam findings and molecular diagnosis based on genetic testing challenging. Sometimes, the clinical and molecular diagnoses do not match because clinically the patients may not have many obvious physical features of BWS even if they have changes in the BWS critical region based on genetic testing. Some individuals may appear mildly affected while others appear more significantly affected. Affected individuals may not have all the symptoms listed. The range of clinical features due to changes on chromosome 11p15.5 has been redefined as the Beckwith-Wiedemann spectrum.Some infants with BWS are born prematurely, but still have an excessive birth weight (large for gestational age). Over half of infants with BWS are above the 97th percentile in weight for gestational age. Overgrowth can continue throughout childhood (macrosomia). Abnormal enlargement of one side or structure of the body (lateralized overgrowth) may occur, resulting in asymmetric growth. Lateralized overgrowth or isolated lateralized overgrowth (ILO) is a new term used to describe what was previously called hemihypertrophy or hemihyperplasia. ILO is defined as asymmetric overgrowth of the body. ILO is not limited to one side of the body, and it does not specify what part or tissue is displaying overgrowth. For example, a patient may have a larger left arm and a larger right leg.Abdominal wall abnormalities can include an omphalocele (also known as exomphalos), in which part of an infant’s intestines and other abdominal organs are outside of the body because of an opening in the belly button. The intestines and other organs are covered by a thin membrane. Less severe abdominal abnormalities can include protrusion of part of the intestines through an abnormal opening in the muscular wall of the abdomen near the umbilical cord (umbilical hernia), or weakness and separation of the left and right muscles of the abdominal wall (diastasis recti). Additionally, the internal organs of affected individuals can become abnormally enlarged (organomegaly). Any or all of the following organs may be affected: liver, spleen, pancreas, kidneys or adrenal glands.Some newborns with BWS may have low blood sugar (neonatal hypoglycemia or hyperinsulinism) due to overgrowth and excessive secretion of the hormone insulin by the pancreas. Insulin helps regulate blood glucose levels by promoting the movement of glucose into cells. Most infants with neonatal hypoglycemia associated with BWS have mild and transient symptoms that resolve without treatment. However, without proper detection and appropriate treatment, neurological complications may result. Congenital hyperinsulinism is the most common cause for persistent and severe low blood sugar.Patients with BWS may have an enlarged tongue (macroglossia), which can cause difficulties in speaking, feeding and breathing. In addition to macroglossia, BWS may be characterized by other differences of the skull and facial (craniofacial) region. Such features may include distinctive slit-like grooves or creases in the ear lobes and dimples on the back of the ears (ear creases or pits). Some infants may have flat, pale red or reddish-purple facial marks at birth, most commonly on the eyelids and forehead, which consist of abnormal clusters of small blood vessels (facial nevus simplex). Such marks typically become less apparent during the first year of life. In patients with lateralized overgrowth, one side of the face may appear larger than the other. Some patients may have improper contact of the teeth of the upper and lower jaws (malocclusion) and abnormal protrusion of the lower jaw (mandibular prognathism), features that may occur secondary to macroglossia.A variety of kidney (renal) abnormalities can occur in individuals with BWS, including abnormally large kidneys (nephromegaly), improper development of the innermost tissues of the kidney (renal medullary dysplasia) and the formation of calcium deposits in the kidney (nephrocalcinosis), which could potentially impair kidney function. Additional abnormalities include duplication of the series of tubes and ducts through which the kidneys reabsorb water and sodium (duplicated collecting system), widening of some of the small tubes and collecting ducts (medullary sponge kidney) and the presence of small pouches (diverticula) on the kidneys. Kidney stones have been reported to occur in adolescents and adults with BWS.Patients with BWS may have an increased risk of developing certain childhood cancers. Embryonal cancers occur in approximately 8% of patients with BWS. The most common types of tumors are Wilms tumor (a kidney tumor) and hepatoblastoma (a liver tumor). Neuroblastoma (a nerve cell tumor), rhabdomyosarcoma (a soft tissue tumor) and adrenal carcinoma (an adrenal gland tumor) have been reported more rarely. The overall tumor risk is highest during the first two years of life.Many clinical features of BWS become less evident with increasing age and many adults experience normal growth and appearance. Neurological (brain) development appears to be unaffected in BWS, unless associated with prolonged, untreated neonatal hypoglycemia, extreme prematurity, or a chromosomal duplication. Adult patients may present with medical issues related to these clinical features, and some have required surgery in early childhood. Most features in adults with BWS, such as renal issues and back pain, are consequences of pediatric issues. However, more research is needed to determine the relationship between features of adults with BWS and pediatric symptoms. | 148 | Beckwith-Wiedemann Syndrome |
nord_148_2 | Causes of Beckwith-Wiedemann Syndrome | Genetics is the study of genes whereas epigenetics is the study of how those genes are turned on or off (gene expression). BWS results from various abnormalities affecting the proper expression of genes that control growth within a specific region of chromosome 11(11p15.5). This region is referred to as the BWS critical region.Approximately 80% of people with BWS have no family history of this syndrome. For these people, BWS is usually caused by epigenetic changes that appear to occur randomly (sporadically). More rarely, BWS is caused by genetic changes that are passed down from a parent (inherited). Approximately 5-10% of patients have BWS due to a family history of the syndrome. About 14% of patients with BWS have an unknown cause for diagnosis.Everyone has two copies of every gene, one received from the father, and one received from the mother. In most people, both genes are “turned on” or active. However, some genes are “turned off” or preferentially silenced based upon which parent that gene came from (a process known as genomic imprinting). Genomic imprinting is controlled by marks on the DNA called methylation. Proper genomic imprinting is necessary for normal development and defective imprinting on chromosome 11 can lead to BWS. Several genes that control growth on chromosome 11 are imprinted, which means that the gene is only active from the mother’s chromosome or the father’s chromosome but not both.Imprinted genes tend to be clustered or grouped together. Chromosome 11p15.5 has two imprinting cluster regions known as imprinting centers 1 and 2 (IC1 and IC2). Several specific imprinted genes are located in these regions. The improper imprinting of these two regions leads to the improper expression of the genes located within the regions, playing a role in the development of BWS. These genes include H19 (a gene that signals not to grow), IGF2 (insulin-like growth factor II), KCNQ10T1 (LIT1) and CDKN1C (p57[KIP2]) (a gene that signals not to grow).H19 is a long noncoding RNA thought to play a role in inhibiting growth. IGF2 is a growth factor. KCNQ10T1 is a noncoding RNA and CDKN1C is a cell cycle regulator and tumor suppressor. Researchers believe that the paternally expressed genes promote growth and that the maternally expressed genes act as tumor suppressor genes or inhibit growth. Normally, H19 and CDKN1C are expressed from the maternal chromosome and IGF2 and KCNQ1OT1 are expressed from the paternal chromosome. Improper methylation in the BWS critical region can lead to an imbalance of the “grow” and “don’t grow” signals, leading to overgrowth.Gain of methylation (hypermethylation) at imprinting center 1 (IC1 GOM) occurs in about 5% of patients with BWS. This leads to decreased H19 expression and increased IGF2 expression.Imprinting center 2 (IC2) is associated with KvDMR, a chemical switch found on the KCNQ1 gene. Loss of methylation (hypomethylation) at KvDMR of imprinting center 2 (IC2 LOM) occurs in about 50% of people with BWS. This leads to increased KCNQ10T1 (long QT intronic transcript 1 [LIT1]) expression and decreased CDKN1C expression.Imprinting errors may also be caused by a chromosomal abnormality known as uniparental disomy (UPD). UPD occurs when a person receives both copies of a chromosome (or part of a chromosome) from one parent instead of receiving one copy from each parent. Approximately 20% of people with BWS have UPD. In BWS, both copies of chromosome 11 are received from the father (paternal uniparental disomy (pUPD)). As a result, there are too many active paternally expressed genes (IGF2) in this region and not enough maternally expressed genes (H19, CDKN1C). Uniparental paternal disomy occurs after fertilization, and therefore the risk of recurrence is extremely low.Mosaic genome-wide paternal uniparental isodisomy (GWpUPD) occurs in about 10% of BWS due to pUPD (approximately 2% of all patients with BWS). In the case of GWpUPD, every chromosome is inherited from the father in the cells that carries the abnormality, instead of just chromosome 11 as in pUPD. GWpUPD is associated with a greater tumor risk. The severity of GWpUPD varies according to the number of cells affected and where the affected cells are located within the patient.Changes (variants or mutations) of the CDKN1C gene have been detected in some individuals with BWS. The loss of proper expression or “underexpression” of the gene is thought to play an important role in causing the disorder. Approximately 5% of people with BWS are found to have variants of the CDKN1C gene. The variant is inherited in an autosomal dominant pattern, which means that only one copy of the changed gene is needed for the disorder to occur. However, CDKN1C is normally only maternally expressed, and therefore, children will only be affected (i.e., have BWS) if the variant is passed from the mother. Approximately 40% of individuals with a family history of BWS have variants of the CDKN1C gene. Variants in CDKN1C can also occur randomly without the mother carrying the variant (de novo). Patients with BWS due to CDKN1C changes have a 50% risk of passing the variant to their children.Research has shown that small deletions (microdeletions) affecting imprinting center 1 (IC1) of chromosome 11p15.5 may be the cause of familial BWS in some people. Approximately 1-2% of patients with BWS have deletions involving 11p15.5. Microdeletions of the KCNQ10T1 (LIT1) gene have also been identified in some people with BWS. These microdeletions appear to cause BWS when inherited maternally; when inherited paternally, the disorder does not develop. Small duplications (microduplications), affecting imprinting center 1 (IC1) of chromosome 11p15.5 inherited from the father can also cause BWS. These microduplications can also occur randomly (de novo).Approximately 2-4% of cases of BWS are due to various chromosomal abnormalities involving the 11p15.5 chromosomal region. This includes chromosomal inversions or rearrangements (translocations) or the presence of extra chromosomal material (duplications).Phenotype genotype correlation
Researchers are investigating if specific causes of BWS are associated with specific symptoms (genotype-phenotype correlation). Research indicates that omphalocele and macroglossia are more common in individuals with defects of IC2 or a variant in the CDKN1C gene. Patients with pUPD are at a greater risk for lateralized overgrowth and hyperinsulinism. Individuals with defects of IC1 or pUPD appear to be at a greater risk of developing an associated tumor such as Wilms tumor. Patients with pUPD also have a greater risk of developing a liver tumor (hepatoblastoma). The different molecular types of BWS each carry a different tumor risk. More research is necessary to determine how the specific causes of BWS correlate with the various symptoms of the disorder. | Causes of Beckwith-Wiedemann Syndrome. Genetics is the study of genes whereas epigenetics is the study of how those genes are turned on or off (gene expression). BWS results from various abnormalities affecting the proper expression of genes that control growth within a specific region of chromosome 11(11p15.5). This region is referred to as the BWS critical region.Approximately 80% of people with BWS have no family history of this syndrome. For these people, BWS is usually caused by epigenetic changes that appear to occur randomly (sporadically). More rarely, BWS is caused by genetic changes that are passed down from a parent (inherited). Approximately 5-10% of patients have BWS due to a family history of the syndrome. About 14% of patients with BWS have an unknown cause for diagnosis.Everyone has two copies of every gene, one received from the father, and one received from the mother. In most people, both genes are “turned on” or active. However, some genes are “turned off” or preferentially silenced based upon which parent that gene came from (a process known as genomic imprinting). Genomic imprinting is controlled by marks on the DNA called methylation. Proper genomic imprinting is necessary for normal development and defective imprinting on chromosome 11 can lead to BWS. Several genes that control growth on chromosome 11 are imprinted, which means that the gene is only active from the mother’s chromosome or the father’s chromosome but not both.Imprinted genes tend to be clustered or grouped together. Chromosome 11p15.5 has two imprinting cluster regions known as imprinting centers 1 and 2 (IC1 and IC2). Several specific imprinted genes are located in these regions. The improper imprinting of these two regions leads to the improper expression of the genes located within the regions, playing a role in the development of BWS. These genes include H19 (a gene that signals not to grow), IGF2 (insulin-like growth factor II), KCNQ10T1 (LIT1) and CDKN1C (p57[KIP2]) (a gene that signals not to grow).H19 is a long noncoding RNA thought to play a role in inhibiting growth. IGF2 is a growth factor. KCNQ10T1 is a noncoding RNA and CDKN1C is a cell cycle regulator and tumor suppressor. Researchers believe that the paternally expressed genes promote growth and that the maternally expressed genes act as tumor suppressor genes or inhibit growth. Normally, H19 and CDKN1C are expressed from the maternal chromosome and IGF2 and KCNQ1OT1 are expressed from the paternal chromosome. Improper methylation in the BWS critical region can lead to an imbalance of the “grow” and “don’t grow” signals, leading to overgrowth.Gain of methylation (hypermethylation) at imprinting center 1 (IC1 GOM) occurs in about 5% of patients with BWS. This leads to decreased H19 expression and increased IGF2 expression.Imprinting center 2 (IC2) is associated with KvDMR, a chemical switch found on the KCNQ1 gene. Loss of methylation (hypomethylation) at KvDMR of imprinting center 2 (IC2 LOM) occurs in about 50% of people with BWS. This leads to increased KCNQ10T1 (long QT intronic transcript 1 [LIT1]) expression and decreased CDKN1C expression.Imprinting errors may also be caused by a chromosomal abnormality known as uniparental disomy (UPD). UPD occurs when a person receives both copies of a chromosome (or part of a chromosome) from one parent instead of receiving one copy from each parent. Approximately 20% of people with BWS have UPD. In BWS, both copies of chromosome 11 are received from the father (paternal uniparental disomy (pUPD)). As a result, there are too many active paternally expressed genes (IGF2) in this region and not enough maternally expressed genes (H19, CDKN1C). Uniparental paternal disomy occurs after fertilization, and therefore the risk of recurrence is extremely low.Mosaic genome-wide paternal uniparental isodisomy (GWpUPD) occurs in about 10% of BWS due to pUPD (approximately 2% of all patients with BWS). In the case of GWpUPD, every chromosome is inherited from the father in the cells that carries the abnormality, instead of just chromosome 11 as in pUPD. GWpUPD is associated with a greater tumor risk. The severity of GWpUPD varies according to the number of cells affected and where the affected cells are located within the patient.Changes (variants or mutations) of the CDKN1C gene have been detected in some individuals with BWS. The loss of proper expression or “underexpression” of the gene is thought to play an important role in causing the disorder. Approximately 5% of people with BWS are found to have variants of the CDKN1C gene. The variant is inherited in an autosomal dominant pattern, which means that only one copy of the changed gene is needed for the disorder to occur. However, CDKN1C is normally only maternally expressed, and therefore, children will only be affected (i.e., have BWS) if the variant is passed from the mother. Approximately 40% of individuals with a family history of BWS have variants of the CDKN1C gene. Variants in CDKN1C can also occur randomly without the mother carrying the variant (de novo). Patients with BWS due to CDKN1C changes have a 50% risk of passing the variant to their children.Research has shown that small deletions (microdeletions) affecting imprinting center 1 (IC1) of chromosome 11p15.5 may be the cause of familial BWS in some people. Approximately 1-2% of patients with BWS have deletions involving 11p15.5. Microdeletions of the KCNQ10T1 (LIT1) gene have also been identified in some people with BWS. These microdeletions appear to cause BWS when inherited maternally; when inherited paternally, the disorder does not develop. Small duplications (microduplications), affecting imprinting center 1 (IC1) of chromosome 11p15.5 inherited from the father can also cause BWS. These microduplications can also occur randomly (de novo).Approximately 2-4% of cases of BWS are due to various chromosomal abnormalities involving the 11p15.5 chromosomal region. This includes chromosomal inversions or rearrangements (translocations) or the presence of extra chromosomal material (duplications).Phenotype genotype correlation
Researchers are investigating if specific causes of BWS are associated with specific symptoms (genotype-phenotype correlation). Research indicates that omphalocele and macroglossia are more common in individuals with defects of IC2 or a variant in the CDKN1C gene. Patients with pUPD are at a greater risk for lateralized overgrowth and hyperinsulinism. Individuals with defects of IC1 or pUPD appear to be at a greater risk of developing an associated tumor such as Wilms tumor. Patients with pUPD also have a greater risk of developing a liver tumor (hepatoblastoma). The different molecular types of BWS each carry a different tumor risk. More research is necessary to determine how the specific causes of BWS correlate with the various symptoms of the disorder. | 148 | Beckwith-Wiedemann Syndrome |
nord_148_3 | Affects of Beckwith-Wiedemann Syndrome | BWS affects males and females in equal numbers. It is estimated to occur in 1 in 10,340 individuals in the general population. Because people who are mildly affected may go undiagnosed, it is difficult to determine the true frequency of BWS in the general population.There is no specific increased risk for BWS within specific race/ethnicity populations, although the clinical presentations may vary between groups.Research suggests that patients conceived with assistive reproductive technology (ART) such as in vitro fertilization (IVF) and/or intracytoplasmic sperm injection (ICSI) may be at a greater risk of developing disorders resulting from genomic imprinting (such as BWS) than the general population. A recent study revealed a tenfold increased risk for BWS in patients conceived via ART, with a prevalence of one in 1,126 patients. Most patients with BWS who are conceived through ART have BWS due to IC2 LOM. More research is necessary to determine the exact relationship between such technologies and the development of BWS.Studies have also shown that the frequency of twin pregnancies is more common in the BWS population than in the general population. However, twins with BWS tend to present with varying levels of severity making it challenging for physicians to diagnose twins with BWS. | Affects of Beckwith-Wiedemann Syndrome. BWS affects males and females in equal numbers. It is estimated to occur in 1 in 10,340 individuals in the general population. Because people who are mildly affected may go undiagnosed, it is difficult to determine the true frequency of BWS in the general population.There is no specific increased risk for BWS within specific race/ethnicity populations, although the clinical presentations may vary between groups.Research suggests that patients conceived with assistive reproductive technology (ART) such as in vitro fertilization (IVF) and/or intracytoplasmic sperm injection (ICSI) may be at a greater risk of developing disorders resulting from genomic imprinting (such as BWS) than the general population. A recent study revealed a tenfold increased risk for BWS in patients conceived via ART, with a prevalence of one in 1,126 patients. Most patients with BWS who are conceived through ART have BWS due to IC2 LOM. More research is necessary to determine the exact relationship between such technologies and the development of BWS.Studies have also shown that the frequency of twin pregnancies is more common in the BWS population than in the general population. However, twins with BWS tend to present with varying levels of severity making it challenging for physicians to diagnose twins with BWS. | 148 | Beckwith-Wiedemann Syndrome |
nord_148_4 | Related disorders of Beckwith-Wiedemann Syndrome | Symptoms of the following disorders can be similar to those of BWS. Comparisons may be useful for a differential diagnosis:Simpson-Golabi-Behmel syndrome is an X-linked recessive genetic disorder due to mutations in the GPC3 or GPC4 genes. Simpson-Golabi-Behmel syndrome is characterized by overgrowth before and after birth (macrosomia); a particular facial appearance including widely spaced eyes (hypertelorism), coarse facial features, large mouth (macrostomia), large head (macrocephaly), large tongue (macroglossia), and mild to severe intellectual disability. (For more information on this disorder, choose “Simpson dysmorphia” as your search term in the Rare Disease Database.)Perlman syndrome is an extremely rare recessive genetic disorder due to variants in the DIS3L2 gene. Perlman syndrome is characterized by overgrowth before and after birth (macrosomia), distinctive facial features, enlarged internal organs (organomegaly), the presence of fragments (rests) of embryonic tissue in the kidney (nephroblastomatosis) and a predisposition to developing Wilms tumor.Sotos syndrome is a rare genetic disorder due to sporadic variants of the NSD1 gene. Sotos syndrome is an autosomal dominant disorder, meaning only one copy of the NSD1 gene variant is necessary for a person to be affected. Sotos syndrome is characterized by excessive growth both before and after birth (prenatally and postnatally). Newborns typically demonstrate advanced bone growth, large hands and/or feet and characteristic facial features. Characteristic facial differences may include a large head (macrocephaly) that may appear elongated (dolichocephalic) with a prominent forehead (frontal bossing); widely spaced eyes (ocular hypertelorism); downwardly slanting eyelid folds (palpebral fissures), a highly arched roof of the mouth (palate), protrusion of the lower jaw (prognathism) and/or a pointed chin. Affected infants and patients may also have developmental abnormalities including delays in reaching developmental milestones (e.g., sitting, crawling, and walking), delays in coordination of muscular and mental activity (psychomotor delays), and delays in language skills. (For more information on this disorder, choose “Sotos” as your search term in the Rare Disease Database.)Weaver syndrome, also known as Weaver-Smith syndrome, is an extremely rare autosomal dominant disorder due to variants in the EZH2 gene. Weaver syndrome is characterized by accelerated growth. Facial features of an affected patient can include a high broad forehead, a round face, widely spaced eyes (ocular hypertelorism) and a small jaw. Patients often have increased muscle tone (hypertonia) and joint problems. (For more information on this disorder, choose “Weaver” as your search term in the Rare Disease Database.) | Related disorders of Beckwith-Wiedemann Syndrome. Symptoms of the following disorders can be similar to those of BWS. Comparisons may be useful for a differential diagnosis:Simpson-Golabi-Behmel syndrome is an X-linked recessive genetic disorder due to mutations in the GPC3 or GPC4 genes. Simpson-Golabi-Behmel syndrome is characterized by overgrowth before and after birth (macrosomia); a particular facial appearance including widely spaced eyes (hypertelorism), coarse facial features, large mouth (macrostomia), large head (macrocephaly), large tongue (macroglossia), and mild to severe intellectual disability. (For more information on this disorder, choose “Simpson dysmorphia” as your search term in the Rare Disease Database.)Perlman syndrome is an extremely rare recessive genetic disorder due to variants in the DIS3L2 gene. Perlman syndrome is characterized by overgrowth before and after birth (macrosomia), distinctive facial features, enlarged internal organs (organomegaly), the presence of fragments (rests) of embryonic tissue in the kidney (nephroblastomatosis) and a predisposition to developing Wilms tumor.Sotos syndrome is a rare genetic disorder due to sporadic variants of the NSD1 gene. Sotos syndrome is an autosomal dominant disorder, meaning only one copy of the NSD1 gene variant is necessary for a person to be affected. Sotos syndrome is characterized by excessive growth both before and after birth (prenatally and postnatally). Newborns typically demonstrate advanced bone growth, large hands and/or feet and characteristic facial features. Characteristic facial differences may include a large head (macrocephaly) that may appear elongated (dolichocephalic) with a prominent forehead (frontal bossing); widely spaced eyes (ocular hypertelorism); downwardly slanting eyelid folds (palpebral fissures), a highly arched roof of the mouth (palate), protrusion of the lower jaw (prognathism) and/or a pointed chin. Affected infants and patients may also have developmental abnormalities including delays in reaching developmental milestones (e.g., sitting, crawling, and walking), delays in coordination of muscular and mental activity (psychomotor delays), and delays in language skills. (For more information on this disorder, choose “Sotos” as your search term in the Rare Disease Database.)Weaver syndrome, also known as Weaver-Smith syndrome, is an extremely rare autosomal dominant disorder due to variants in the EZH2 gene. Weaver syndrome is characterized by accelerated growth. Facial features of an affected patient can include a high broad forehead, a round face, widely spaced eyes (ocular hypertelorism) and a small jaw. Patients often have increased muscle tone (hypertonia) and joint problems. (For more information on this disorder, choose “Weaver” as your search term in the Rare Disease Database.) | 148 | Beckwith-Wiedemann Syndrome |
nord_148_5 | Diagnosis of Beckwith-Wiedemann Syndrome | Patients with BWS can be diagnosed both before and after birth (prenatally and postnatally) either by physical evaluation (clinical diagnosis) and/or genetic testing (molecular diagnosis).In some cases, certain procedures may be performed before birth (prenatally) to detect BWS. For example, ultrasound imaging may allow assessment of organ size and overall size of the developing fetus and potentially reveal other findings that may be suggestive of BWS. Features that can be detected by prenatal imaging include increased amniotic fluid surrounding the fetus (polyhydramnios), an enlarged placenta, omphalocele, enlarged abdominal circumference, nephromegaly, macroglossia and/or other abnormalities. The most common prenatally detected feature that leads to a higher clinical suspicion of BWS is an omphalocele. If BWS is suspected, prenatal testing is available.BWS may be diagnosed or confirmed shortly after birth based on a thorough clinical evaluation, detection of characteristic physical findings (e.g., increased weight and length, macroglossia, abdominal wall defects) and genetic testing of the BWS critical region.BWS spectrum can be further divided into three subcategories: classic or typical BWS, atypical BWS and isolated lateralized overgrowth. A patient who presents with physical features and who appears more affected is thought to present with classic or typical BWS. A patient with fewer isolated features, such as neonatal hyperinsulinism or an embryonal tumor, is thought to present with “atypical” BWS. Finally, some patients may present with only isolated lateralized overgrowth.A BWS consensus scoring system has been established to help with the clinical diagnosis of BWS and to determine the need for molecular testing. Features that will more likely lead to a diagnosis of BWS are termed “cardinal features” (including macroglossia, omphalocele, lateralized overgrowth, multiple Wilms tumors, hyperinsulinism and specific pathology findings including adrenal cytomegaly (enlargement of the cells in the adrenal gland) and placental mesenchymal dysplasia (enlargement of cells in the placenta). As such, cardinal features are given two points each in the scoring system. Features that are seen in BWS but are also present in the general population are termed “suggestive features” (including large birth weight, macrosomia, facial nevus simplex, polyhydramnios or large placenta, ear creases or pits, hypoglycemia, embryonal tumors such as single Wilms tumors or hepatoblastomas, nephromegaly or hepatomegaly, umbilical hernia and diastasis recti). Suggestive features are given one point each. A total of four or more points, two of which should be due to a cardinal feature, is consistent with a clinical diagnosis of BWS. A total of two or more points indicates the need for molecular testing, especially if a cardinal feature is present.Genetic testing looks for changes in the BWS critical region. This includes looking at the methylation marks (11p15.5 methylation analysis) on the DNA followed by looking at the number of copies of the imprinting control regions (11p15.5 copy number analysis) that are present in that region (normally there should be two copies). This will detect if there are deletions or duplications of the region. Additionally, if previous testing is normal, CDKN1C sequencing is performed to detect any changes in the CDKN1C gene. Additional testing that looks at all the chromosomes is recommended for patients determined to have UPD based on the methylation analysis. A chromosome microarray or a single nucleotide polymorphism (SNP) array is used to detect the extent of the region of UPD.Not every patient with a clinical diagnosis of BWS will have a diagnosis that is confirmed by molecular testing. This is because most of the genetic and epigenetic changes that cause BWS are not present in every cell. This is termed “mosaicism.” For this reason, testing multiple tissues can increase the likelihood of finding the cause of BWS. Negative testing on blood, for example, may not necessarily exclude a diagnosis. A recent study demonstrated that testing multiple tissues increased the likelihood of a molecular diagnosis from 70% to 82%. | Diagnosis of Beckwith-Wiedemann Syndrome. Patients with BWS can be diagnosed both before and after birth (prenatally and postnatally) either by physical evaluation (clinical diagnosis) and/or genetic testing (molecular diagnosis).In some cases, certain procedures may be performed before birth (prenatally) to detect BWS. For example, ultrasound imaging may allow assessment of organ size and overall size of the developing fetus and potentially reveal other findings that may be suggestive of BWS. Features that can be detected by prenatal imaging include increased amniotic fluid surrounding the fetus (polyhydramnios), an enlarged placenta, omphalocele, enlarged abdominal circumference, nephromegaly, macroglossia and/or other abnormalities. The most common prenatally detected feature that leads to a higher clinical suspicion of BWS is an omphalocele. If BWS is suspected, prenatal testing is available.BWS may be diagnosed or confirmed shortly after birth based on a thorough clinical evaluation, detection of characteristic physical findings (e.g., increased weight and length, macroglossia, abdominal wall defects) and genetic testing of the BWS critical region.BWS spectrum can be further divided into three subcategories: classic or typical BWS, atypical BWS and isolated lateralized overgrowth. A patient who presents with physical features and who appears more affected is thought to present with classic or typical BWS. A patient with fewer isolated features, such as neonatal hyperinsulinism or an embryonal tumor, is thought to present with “atypical” BWS. Finally, some patients may present with only isolated lateralized overgrowth.A BWS consensus scoring system has been established to help with the clinical diagnosis of BWS and to determine the need for molecular testing. Features that will more likely lead to a diagnosis of BWS are termed “cardinal features” (including macroglossia, omphalocele, lateralized overgrowth, multiple Wilms tumors, hyperinsulinism and specific pathology findings including adrenal cytomegaly (enlargement of the cells in the adrenal gland) and placental mesenchymal dysplasia (enlargement of cells in the placenta). As such, cardinal features are given two points each in the scoring system. Features that are seen in BWS but are also present in the general population are termed “suggestive features” (including large birth weight, macrosomia, facial nevus simplex, polyhydramnios or large placenta, ear creases or pits, hypoglycemia, embryonal tumors such as single Wilms tumors or hepatoblastomas, nephromegaly or hepatomegaly, umbilical hernia and diastasis recti). Suggestive features are given one point each. A total of four or more points, two of which should be due to a cardinal feature, is consistent with a clinical diagnosis of BWS. A total of two or more points indicates the need for molecular testing, especially if a cardinal feature is present.Genetic testing looks for changes in the BWS critical region. This includes looking at the methylation marks (11p15.5 methylation analysis) on the DNA followed by looking at the number of copies of the imprinting control regions (11p15.5 copy number analysis) that are present in that region (normally there should be two copies). This will detect if there are deletions or duplications of the region. Additionally, if previous testing is normal, CDKN1C sequencing is performed to detect any changes in the CDKN1C gene. Additional testing that looks at all the chromosomes is recommended for patients determined to have UPD based on the methylation analysis. A chromosome microarray or a single nucleotide polymorphism (SNP) array is used to detect the extent of the region of UPD.Not every patient with a clinical diagnosis of BWS will have a diagnosis that is confirmed by molecular testing. This is because most of the genetic and epigenetic changes that cause BWS are not present in every cell. This is termed “mosaicism.” For this reason, testing multiple tissues can increase the likelihood of finding the cause of BWS. Negative testing on blood, for example, may not necessarily exclude a diagnosis. A recent study demonstrated that testing multiple tissues increased the likelihood of a molecular diagnosis from 70% to 82%. | 148 | Beckwith-Wiedemann Syndrome |
nord_148_6 | Therapies of Beckwith-Wiedemann Syndrome | Treatment
The treatment of BWS is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Geneticists, pediatricians, plastic surgeons, endocrinologists, nephrologists (kidney specialists), orthodontists (dental specialists), pulmonologists (lung specialists), speech pathologists, pediatric oncologists and other healthcare professionals may need to plan an affected child’s treatment systematically and comprehensively.In newborns with BWS, regular monitoring of blood glucose levels should be performed to ensure prompt detection and treatment of hypoglycemia in the immediate neonatal period. Although neonatal hypoglycemia is usually mild and temporary, its early detection and treatment is essential in preventing associated neurologic complications. Treatment measures may include the administration of intravenous glucose, frequent feedings, certain medications (e.g., diazoxide or octreotide) and/or surgical intervention in some cases.In many infants with umbilical hernia, the defect may spontaneously disappear by the age of approximately one year. Surgery is usually not required unless an umbilical hernia becomes progressively larger, does not spontaneously resolve (e.g., by about three or four years of age) and/or is associated with certain complications. However, in newborns with an omphalocele, surgical repair of the defect is typically required shortly after birth.Like other features associated with BWS, macroglossia can vary in severity. Patients with macroglossia are at an increased risk for obstructive sleep apnea, feeding difficulties, speech difficulties and potential jaw development issues. Patients with macroglossia require the support of a multidisciplinary team. They should undergo feeding evaluation and sleep studies in addition to consultations with plastic surgeons and pulmonologists if needed. Feeding difficulties caused by macroglossia may require the support of feeding specialists or dieticians. Treatment may include the use of specialized nipples or the temporary insertion of a nasogastric tube. Speech difficulties may require the support of speech therapy. A pulmonologist can evaluate the degree to which macroglossia affects a patient’s breathing and sleeping. A sleep study may be used to assess obstructive sleep apnea, airway obstruction, airway resistance, severe desaturation, sleep disordered breathing and snoring. Continuous positive airway pressure (CPAP) is a method used to support children with obstructive sleep apnea. Some patients may undergo tongue reduction surgery with the goal of improving breathing, feeding and jaw or dental malformations due to macroglossia. Patients with macroglossia should be followed closely by a multidisciplinary team.Regular orthopedic evaluation is recommended for patients with lateralized overgrowth and an associated leg length difference. Some patients with significant lateralized overgrowth of the limbs may require shoe lifts and, in other patients, surgical correction may be needed.Infants and patients with BWS should undergo regular abdominal and renal ultrasounds, and measurement of serum alpha-fetoprotein levels as recommended to ensure early detection and treatment of certain malignancies that may occur in association with BWS (e.g., Wilms tumor, hepatoblastoma).Alpha-fetoprotein (AFP) is a protein produced by the liver. AFP levels typically decline during infancy; however, AFP may be abnormally elevated in blood if certain tumors are present (hepatoblastoma). The trend in AFP levels over time should be followed in patients with BWS and normal AFP values for children with BWS are available to aid in interpretation of results. There have been recent discussions regarding the utility of AFP screening in young children. While some suggest that the invasiveness of a regular blood draw may be stressful for many families, AFP has proven to be a useful early indicator for hepatoblastoma.According to the United States-based guidelines, screening is recommended for all patients with a clinical or molecular diagnosis of BWS by AFP analysis and a full abdominal ultrasound every three months until the 4th birthday (to screen for hepatoblastoma and Wilms tumor) followed by renal ultrasounds every 3 months until 7th birthday (to screen for Wilms tumor). Additional screening by urine analysis and chest x-rays for neuroblastoma is recommended for patients with CDKN1C variants. Also, screening for patients with BWS due to GWpUPD may extend beyond the 7th birthday.If a tumor develops in association with BWS, the appropriate treatment measures vary depending on the specific tumor present, the stage and/or extent of disease and/or other factors. Treatment methods may include surgery (for example, nephron-sparing kidney resection in the case of a Wilms tumor), use of certain anticancer drugs (chemotherapy), radiation therapy and/or other measures. (For more information on Wilms tumor, choose “Wilms” as your search term in the Rare Disease Database.)Patients with cardiac, gastrointestinal and renal abnormalities may require certain medications, surgery or other medical interventions. These patients should be referred to appropriate specialists. Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.Late-onset complications with BWS may require continued follow-up in adulthood. More research is needed to understand the features and associated treatments for adults with BWS. | Therapies of Beckwith-Wiedemann Syndrome. Treatment
The treatment of BWS is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Geneticists, pediatricians, plastic surgeons, endocrinologists, nephrologists (kidney specialists), orthodontists (dental specialists), pulmonologists (lung specialists), speech pathologists, pediatric oncologists and other healthcare professionals may need to plan an affected child’s treatment systematically and comprehensively.In newborns with BWS, regular monitoring of blood glucose levels should be performed to ensure prompt detection and treatment of hypoglycemia in the immediate neonatal period. Although neonatal hypoglycemia is usually mild and temporary, its early detection and treatment is essential in preventing associated neurologic complications. Treatment measures may include the administration of intravenous glucose, frequent feedings, certain medications (e.g., diazoxide or octreotide) and/or surgical intervention in some cases.In many infants with umbilical hernia, the defect may spontaneously disappear by the age of approximately one year. Surgery is usually not required unless an umbilical hernia becomes progressively larger, does not spontaneously resolve (e.g., by about three or four years of age) and/or is associated with certain complications. However, in newborns with an omphalocele, surgical repair of the defect is typically required shortly after birth.Like other features associated with BWS, macroglossia can vary in severity. Patients with macroglossia are at an increased risk for obstructive sleep apnea, feeding difficulties, speech difficulties and potential jaw development issues. Patients with macroglossia require the support of a multidisciplinary team. They should undergo feeding evaluation and sleep studies in addition to consultations with plastic surgeons and pulmonologists if needed. Feeding difficulties caused by macroglossia may require the support of feeding specialists or dieticians. Treatment may include the use of specialized nipples or the temporary insertion of a nasogastric tube. Speech difficulties may require the support of speech therapy. A pulmonologist can evaluate the degree to which macroglossia affects a patient’s breathing and sleeping. A sleep study may be used to assess obstructive sleep apnea, airway obstruction, airway resistance, severe desaturation, sleep disordered breathing and snoring. Continuous positive airway pressure (CPAP) is a method used to support children with obstructive sleep apnea. Some patients may undergo tongue reduction surgery with the goal of improving breathing, feeding and jaw or dental malformations due to macroglossia. Patients with macroglossia should be followed closely by a multidisciplinary team.Regular orthopedic evaluation is recommended for patients with lateralized overgrowth and an associated leg length difference. Some patients with significant lateralized overgrowth of the limbs may require shoe lifts and, in other patients, surgical correction may be needed.Infants and patients with BWS should undergo regular abdominal and renal ultrasounds, and measurement of serum alpha-fetoprotein levels as recommended to ensure early detection and treatment of certain malignancies that may occur in association with BWS (e.g., Wilms tumor, hepatoblastoma).Alpha-fetoprotein (AFP) is a protein produced by the liver. AFP levels typically decline during infancy; however, AFP may be abnormally elevated in blood if certain tumors are present (hepatoblastoma). The trend in AFP levels over time should be followed in patients with BWS and normal AFP values for children with BWS are available to aid in interpretation of results. There have been recent discussions regarding the utility of AFP screening in young children. While some suggest that the invasiveness of a regular blood draw may be stressful for many families, AFP has proven to be a useful early indicator for hepatoblastoma.According to the United States-based guidelines, screening is recommended for all patients with a clinical or molecular diagnosis of BWS by AFP analysis and a full abdominal ultrasound every three months until the 4th birthday (to screen for hepatoblastoma and Wilms tumor) followed by renal ultrasounds every 3 months until 7th birthday (to screen for Wilms tumor). Additional screening by urine analysis and chest x-rays for neuroblastoma is recommended for patients with CDKN1C variants. Also, screening for patients with BWS due to GWpUPD may extend beyond the 7th birthday.If a tumor develops in association with BWS, the appropriate treatment measures vary depending on the specific tumor present, the stage and/or extent of disease and/or other factors. Treatment methods may include surgery (for example, nephron-sparing kidney resection in the case of a Wilms tumor), use of certain anticancer drugs (chemotherapy), radiation therapy and/or other measures. (For more information on Wilms tumor, choose “Wilms” as your search term in the Rare Disease Database.)Patients with cardiac, gastrointestinal and renal abnormalities may require certain medications, surgery or other medical interventions. These patients should be referred to appropriate specialists. Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.Late-onset complications with BWS may require continued follow-up in adulthood. More research is needed to understand the features and associated treatments for adults with BWS. | 148 | Beckwith-Wiedemann Syndrome |
nord_149_0 | Overview of Behçet’s Syndrome | Behçet’s syndrome is a rare multisystem inflammatory disorder characterized by ulcers affecting the mouth and genitals, various skin lesions and abnormalities affecting the eyes. Symptoms include mucous membrane lesions of the mouth (canker sores) and genitals (ulcers) that tend to disappear and recur spontaneously. Inflammation of the eyes (anterior uveitis, posterior uveitis, or panuveitis) also affects individuals with Behçet’s syndrome. Additional systems of the body may also be affected including the joints, blood vessels, central nervous system and/or digestive tract. The exact cause of Behçet’s syndrome is unknown. | Overview of Behçet’s Syndrome. Behçet’s syndrome is a rare multisystem inflammatory disorder characterized by ulcers affecting the mouth and genitals, various skin lesions and abnormalities affecting the eyes. Symptoms include mucous membrane lesions of the mouth (canker sores) and genitals (ulcers) that tend to disappear and recur spontaneously. Inflammation of the eyes (anterior uveitis, posterior uveitis, or panuveitis) also affects individuals with Behçet’s syndrome. Additional systems of the body may also be affected including the joints, blood vessels, central nervous system and/or digestive tract. The exact cause of Behçet’s syndrome is unknown. | 149 | Behçet’s Syndrome |
nord_149_1 | Symptoms of Behçet’s Syndrome | The earliest symptom of Behçet’s syndrome is usually painful canker sores on the mucous membranes that line the mouth (aphthous stomatitis). The sores are usually round or oval with reddish (erythematous) borders that may occur anywhere within the mouth. They may be shallow or deep and may appear as a single lesion or a cluster of multiple lesions. The sores typically heal within a few days, up to a week or more, without scarring, but frequently recur. They may precede other symptoms of Behçet’s syndrome by several years. Sometimes similar sores may appear on the genitals, specifically the scrotum and shaft of the penis in males and the vulva in females. The sores are also round and painful but may be larger and deeper than those affecting the mouth. These sores also recur, but unlike oral lesions, may tend to scar.Behçet’s syndrome may also affect the eyes. Symptoms may include inflammation of the back of the eye (posterior uveitis) and inflammation of the front of the eye (anterior uveitis or iridocyclitis). Inflammation of the iris accompanied by pain, tearing (lacrimation) and the accumulation of pus (hypopyon iritis) may also occur. The retina may become inflamed resulting in blurred vision, abnormal sensitivity to light (photophobia) and/or, inflammation of the thin membranous layer of blood vessels behind the retina (chorioretinitis). Although the lesions that cause inflammation in various parts of the eyes may resolve, repeated recurrences may result in the partial loss of vision (decreased visual acuity) or complete blindness if the disease is uncontrolled. In some cases, eye abnormalities may be the first symptom of Behçet’s syndrome. In other cases, they may not develop until several years later.Individuals with Behçet’s syndrome may also exhibit the formation of small, pus-filled growths on the skin (pustules). Some affected individuals, especially females, may develop lesions that resemble those of erythema nodosum, a skin disorder characterized by the formation of tender, reddish, inflammatory nodules on the front of the legs. These nodules disappear on their own (spontaneously) sometimes leaving faint scars or discoloration (pigmentation). Some individuals with Behçet’s syndrome may develop small eruptions that resemble acne (acneiform eruptions) and/or inflammation that mistakenly appear to affect the hair follicles on the skin (pseudofolliculitis).In approximately 50 percent of cases of Behçet’s syndrome, affected individuals experience pain (arthralgia) and swelling in various joints of the body (polyarthritis). This may occur before, during, or after the onset of the other symptoms associated with Behçet’s syndrome. Pain, which can range from mild to severe, typically affects the joints of the knees, wrists, elbows and ankles, and may become chronic. Lasting damage to affected joints is extremely rare.Individuals with Behçet’s syndrome may also have recurring ulcers in the digestive tract. Symptoms vary from mild abdominal discomfort to severe inflammation of the large intestine and rectum accompanied by diarrhea or bleeding.Approximately 10%-20% of individuals with Behçet’s syndrome also have involvement of the central nervous system. These symptoms usually appear months or years after the initial symptoms of Behçet’s syndrome. Recurring attacks of inflammation involving the brain (parenchymal Neuro-Behçet) or the membranes that surround the brain or spinal cord (meningitis or meningoencephalitis) can result in neurological damage. Symptoms may include headache, the inability to coordinate voluntary movement (cerebellar ataxia), impaired muscle movements of the face and throat (pseudobulbar palsies), stroke and/or rarely, seizures.Behçet’s syndrome causes inflammation of the blood vessels (vasculitis). Involvement of small vessels is thought to drive many of the problems that the disorder causes. In some instances, inflammation of the large veins, particularly those in the legs may occur along with the formation of blood clots (thrombophlebitis). The walls of an involved artery may bulge forming a sac (aneurysm). In very rare cases, blood clots from the veins travel to the lungs (pulmonary emboli) resulting in episodes of chest pain, coughing, difficult or labored breathing (dyspnea) and coughing up blood (hemoptysis).Unlike most diseases which are classified as vasculitis, involvement of the kidneys or peripheral nerves is very rare.It is especially important to identify Behçet’s disease when there is ocular, central nervous system or large blood vessel involvement as manifestations are usually the most serious. | Symptoms of Behçet’s Syndrome. The earliest symptom of Behçet’s syndrome is usually painful canker sores on the mucous membranes that line the mouth (aphthous stomatitis). The sores are usually round or oval with reddish (erythematous) borders that may occur anywhere within the mouth. They may be shallow or deep and may appear as a single lesion or a cluster of multiple lesions. The sores typically heal within a few days, up to a week or more, without scarring, but frequently recur. They may precede other symptoms of Behçet’s syndrome by several years. Sometimes similar sores may appear on the genitals, specifically the scrotum and shaft of the penis in males and the vulva in females. The sores are also round and painful but may be larger and deeper than those affecting the mouth. These sores also recur, but unlike oral lesions, may tend to scar.Behçet’s syndrome may also affect the eyes. Symptoms may include inflammation of the back of the eye (posterior uveitis) and inflammation of the front of the eye (anterior uveitis or iridocyclitis). Inflammation of the iris accompanied by pain, tearing (lacrimation) and the accumulation of pus (hypopyon iritis) may also occur. The retina may become inflamed resulting in blurred vision, abnormal sensitivity to light (photophobia) and/or, inflammation of the thin membranous layer of blood vessels behind the retina (chorioretinitis). Although the lesions that cause inflammation in various parts of the eyes may resolve, repeated recurrences may result in the partial loss of vision (decreased visual acuity) or complete blindness if the disease is uncontrolled. In some cases, eye abnormalities may be the first symptom of Behçet’s syndrome. In other cases, they may not develop until several years later.Individuals with Behçet’s syndrome may also exhibit the formation of small, pus-filled growths on the skin (pustules). Some affected individuals, especially females, may develop lesions that resemble those of erythema nodosum, a skin disorder characterized by the formation of tender, reddish, inflammatory nodules on the front of the legs. These nodules disappear on their own (spontaneously) sometimes leaving faint scars or discoloration (pigmentation). Some individuals with Behçet’s syndrome may develop small eruptions that resemble acne (acneiform eruptions) and/or inflammation that mistakenly appear to affect the hair follicles on the skin (pseudofolliculitis).In approximately 50 percent of cases of Behçet’s syndrome, affected individuals experience pain (arthralgia) and swelling in various joints of the body (polyarthritis). This may occur before, during, or after the onset of the other symptoms associated with Behçet’s syndrome. Pain, which can range from mild to severe, typically affects the joints of the knees, wrists, elbows and ankles, and may become chronic. Lasting damage to affected joints is extremely rare.Individuals with Behçet’s syndrome may also have recurring ulcers in the digestive tract. Symptoms vary from mild abdominal discomfort to severe inflammation of the large intestine and rectum accompanied by diarrhea or bleeding.Approximately 10%-20% of individuals with Behçet’s syndrome also have involvement of the central nervous system. These symptoms usually appear months or years after the initial symptoms of Behçet’s syndrome. Recurring attacks of inflammation involving the brain (parenchymal Neuro-Behçet) or the membranes that surround the brain or spinal cord (meningitis or meningoencephalitis) can result in neurological damage. Symptoms may include headache, the inability to coordinate voluntary movement (cerebellar ataxia), impaired muscle movements of the face and throat (pseudobulbar palsies), stroke and/or rarely, seizures.Behçet’s syndrome causes inflammation of the blood vessels (vasculitis). Involvement of small vessels is thought to drive many of the problems that the disorder causes. In some instances, inflammation of the large veins, particularly those in the legs may occur along with the formation of blood clots (thrombophlebitis). The walls of an involved artery may bulge forming a sac (aneurysm). In very rare cases, blood clots from the veins travel to the lungs (pulmonary emboli) resulting in episodes of chest pain, coughing, difficult or labored breathing (dyspnea) and coughing up blood (hemoptysis).Unlike most diseases which are classified as vasculitis, involvement of the kidneys or peripheral nerves is very rare.It is especially important to identify Behçet’s disease when there is ocular, central nervous system or large blood vessel involvement as manifestations are usually the most serious. | 149 | Behçet’s Syndrome |
nord_149_2 | Causes of Behçet’s Syndrome | The exact cause of Behçet’s syndrome is not known. Studies suggest that some people may have a genetic predisposition to the condition. A genetic predisposition means that a person may carry a gene for a disease, but it may not be expressed unless something in the environment triggers the disease. Researchers have demonstrated that certain individuals with Behçet’s syndrome, especially those of Middle Eastern and Asian descent, have an increased frequency of certain human leukocyte antigens (HLAs) in the blood. Individuals with Behçet’s syndrome are more likely to have HLA-B51 than the general population. The possible role of HLA-B51 in predisposing individuals to Behçet’s syndrome and its overall association with the disorder is unknown. Other genetic markers and their role in the development of Behçet’s disease are being studied. Viral or bacterial infections have also been suggested as a possible cause for the disorder. Still another theory is that the disease is an auto-inflammatory disorder in which the body loses the ability to appropriately regulate and control inflammation.Autoimmune disorders are caused when the body’s natural defenses against “foreign” or invading organisms (e.g., antibodies) begin to attack healthy tissue for unknown reasons. While investigation is ongoing, no autoantibodies to date have been identified to suggest that Behçet’s syndrome is an autoimmune disease. | Causes of Behçet’s Syndrome. The exact cause of Behçet’s syndrome is not known. Studies suggest that some people may have a genetic predisposition to the condition. A genetic predisposition means that a person may carry a gene for a disease, but it may not be expressed unless something in the environment triggers the disease. Researchers have demonstrated that certain individuals with Behçet’s syndrome, especially those of Middle Eastern and Asian descent, have an increased frequency of certain human leukocyte antigens (HLAs) in the blood. Individuals with Behçet’s syndrome are more likely to have HLA-B51 than the general population. The possible role of HLA-B51 in predisposing individuals to Behçet’s syndrome and its overall association with the disorder is unknown. Other genetic markers and their role in the development of Behçet’s disease are being studied. Viral or bacterial infections have also been suggested as a possible cause for the disorder. Still another theory is that the disease is an auto-inflammatory disorder in which the body loses the ability to appropriately regulate and control inflammation.Autoimmune disorders are caused when the body’s natural defenses against “foreign” or invading organisms (e.g., antibodies) begin to attack healthy tissue for unknown reasons. While investigation is ongoing, no autoantibodies to date have been identified to suggest that Behçet’s syndrome is an autoimmune disease. | 149 | Behçet’s Syndrome |
nord_149_3 | Affects of Behçet’s Syndrome | Behçet’s syndrome is a rare disorder in the United States and Western Europe. It occurs most frequently in the Middle East and Asia, along ancient trading routes between the Mediterranean basin and eastern Asia, known as the Silk Road. Turkey has the highest prevalence rate (80-370 cases per 100,000); Japan, Korea, China, Iran, and Saudi Arabia also have high prevalence rates. The disorder is the leading cause of blindness in Japan. The age of onset is typically between 30 and 40 years.In the United States and Australia, this syndrome is more common in women than men, and the symptoms tend to be less severe. Men may be more commonly affected in Middle Eastern countries and usually have more severe disease. Central nervous system involvement is more common among native populations of northern Europe and the United States. | Affects of Behçet’s Syndrome. Behçet’s syndrome is a rare disorder in the United States and Western Europe. It occurs most frequently in the Middle East and Asia, along ancient trading routes between the Mediterranean basin and eastern Asia, known as the Silk Road. Turkey has the highest prevalence rate (80-370 cases per 100,000); Japan, Korea, China, Iran, and Saudi Arabia also have high prevalence rates. The disorder is the leading cause of blindness in Japan. The age of onset is typically between 30 and 40 years.In the United States and Australia, this syndrome is more common in women than men, and the symptoms tend to be less severe. Men may be more commonly affected in Middle Eastern countries and usually have more severe disease. Central nervous system involvement is more common among native populations of northern Europe and the United States. | 149 | Behçet’s Syndrome |
nord_149_4 | Related disorders of Behçet’s Syndrome | Symptoms of the following disorders can be similar to those of Behçet’s syndrome. Comparisons may be useful for a differential diagnosis:Reactive arthritis, previously known as Reiter’s syndrome, is a rare infectious disorder characterized by arthritis, inflammation of the urinary tract (non-gonococcal urethritis), and inflammation of the membranes that line the eyes (conjunctivitis). Lesions may also appear on the skin and mucous membranes. The symptoms may not all appear at once. There may be spontaneous remissions and recurrences. Symptoms may include pus in the urine, swollen painful joints and ulcers in the mouth. Occasionally the iris of the eyes may become inflamed (iritis). This disorder can be transmitted through sexual contact. (For more information on this disorder, choose “reactive arthritis” as your search term in the Rare Disease Database.)Stevens-Johnson syndrome is a rare skin disorder characterized by large bullous lesions on the skin and mucous membranes of the mouth, throat, nose, eyes and genitals. The lesions are typically painful. Inflammation of the membranes that line the eyes (conjunctivitis) may also occur and be accompanied by a discharge. This can lead to scarring of the cornea and loss of vision. Some people may experience fever and fatigue. (For more information on this disorder, choose “Stevens-Johnson” as your search term in the Rare Disease Database.)Sweet syndrome is a rare skin disorder characterized by painful red eruptions usually on the arms, face, neck, and legs. Major symptoms of Sweet syndrome are tender or painful skin eruptions and general feeling of discomfort (malaise). Skin lesions usually occur on the arms, but also on the face, neck, legs and occasionally the thighs and trunk. The lesions may be up to an inch in diameter. They are usually bluish-red, irregular, flat or raised, sharply outlined, circular and/or hardened, with a rounded edge. Scarring is usually absent. Remission may occur after a few weeks, but recurrences are possible. On rare occasions, the female genital tract (vagina and uterus) may be involved. The exact cause of this disorder is not known. (For more information on this disorder, choose “Sweet” as your search term in the Rare Disease Database.) | Related disorders of Behçet’s Syndrome. Symptoms of the following disorders can be similar to those of Behçet’s syndrome. Comparisons may be useful for a differential diagnosis:Reactive arthritis, previously known as Reiter’s syndrome, is a rare infectious disorder characterized by arthritis, inflammation of the urinary tract (non-gonococcal urethritis), and inflammation of the membranes that line the eyes (conjunctivitis). Lesions may also appear on the skin and mucous membranes. The symptoms may not all appear at once. There may be spontaneous remissions and recurrences. Symptoms may include pus in the urine, swollen painful joints and ulcers in the mouth. Occasionally the iris of the eyes may become inflamed (iritis). This disorder can be transmitted through sexual contact. (For more information on this disorder, choose “reactive arthritis” as your search term in the Rare Disease Database.)Stevens-Johnson syndrome is a rare skin disorder characterized by large bullous lesions on the skin and mucous membranes of the mouth, throat, nose, eyes and genitals. The lesions are typically painful. Inflammation of the membranes that line the eyes (conjunctivitis) may also occur and be accompanied by a discharge. This can lead to scarring of the cornea and loss of vision. Some people may experience fever and fatigue. (For more information on this disorder, choose “Stevens-Johnson” as your search term in the Rare Disease Database.)Sweet syndrome is a rare skin disorder characterized by painful red eruptions usually on the arms, face, neck, and legs. Major symptoms of Sweet syndrome are tender or painful skin eruptions and general feeling of discomfort (malaise). Skin lesions usually occur on the arms, but also on the face, neck, legs and occasionally the thighs and trunk. The lesions may be up to an inch in diameter. They are usually bluish-red, irregular, flat or raised, sharply outlined, circular and/or hardened, with a rounded edge. Scarring is usually absent. Remission may occur after a few weeks, but recurrences are possible. On rare occasions, the female genital tract (vagina and uterus) may be involved. The exact cause of this disorder is not known. (For more information on this disorder, choose “Sweet” as your search term in the Rare Disease Database.) | 149 | Behçet’s Syndrome |
nord_149_5 | Diagnosis of Behçet’s Syndrome | The diagnosis of Behçet’s syndrome is made based on the clinical judgment of a physician. Criteria have been accepted, based upon the identification of recurrent oral ulcerations (aphthous stomatitis) that occur along with at least two of the following: eye lesions, skin lesions, recurrent genital ulcerations and a positive pathergy test. During a pathergy test, a physician pricks an individual with a sterile needle. A positive outcome occurs if a reddish spot (nodule or pustule) forms 48 hours after the prick. However, these criteria have been formed so that patients might be included in clinical studies (“classification criteria”) and are not really “diagnostic” criteria. | Diagnosis of Behçet’s Syndrome. The diagnosis of Behçet’s syndrome is made based on the clinical judgment of a physician. Criteria have been accepted, based upon the identification of recurrent oral ulcerations (aphthous stomatitis) that occur along with at least two of the following: eye lesions, skin lesions, recurrent genital ulcerations and a positive pathergy test. During a pathergy test, a physician pricks an individual with a sterile needle. A positive outcome occurs if a reddish spot (nodule or pustule) forms 48 hours after the prick. However, these criteria have been formed so that patients might be included in clinical studies (“classification criteria”) and are not really “diagnostic” criteria. | 149 | Behçet’s Syndrome |
nord_149_6 | Therapies of Behçet’s Syndrome | Treatment
The treatment of Behçet’s syndrome is directed toward the specific symptoms that are apparent in each individual. Specific therapies for Behçet’s syndrome are symptomatic and supportive. Severity of the condition as well as the patient’s age and sex may all affect treatment decisions. Spontaneous remission over time is common for individuals with Behçet’s syndrome.Oral and genital ulcerations may be treated with topical application of corticosteroid-containing preparations to the affected areas to assist in aborting developing attacks. Mouthwash containing a local anesthetic such as lidocaine or diphenhydramine may temporarily relieve pain. For recurrent attacks, colchicine can be effective in preventing recurring attacks of oral and genital ulcers. Apremilast is now FDA approved for the treatment of recurrent oral ulcerations in patients with Behçet’s. More aggressive therapies such as azathioprine, thalidomide, interferon-alpha and anti-TNF agents may be considered.Individuals who have arthritis associated with Behçet’s may respond to nonsteroidal anti-inflammatory drugs (NSAIDs) and colchicine. Treatment with azathioprine and anti-TNF agents can be used for more aggressive or refractory disease.Identification of eye inflammation requires close collaboration with an ophthalmologist as treatment is based on the location of eye inflammation and severity. Treatment may include eye drops containing corticosteroids to relieve pain. For more aggressive or refractory disease, oral corticosteroids combined with an immunosuppressant drug such as azathioprine or anti-TNF are used to control the progression of eye disease.Sulfasalazine, azathioprine, and corticosteroids may be administered to treat inflammatory bowel disease and gastrointestinal lesions associated with Behçet’s. Central nervous system and vascular abnormalities may be treated with corticosteroids as well, often in conjunction with immunosuppressive agents. In patients with clotting of major blood vessels, systemic anticoagulants and immunosuppressants should be considered.Inflammation of the joints, skin, and/or mucous membranes or other organs may be reduced with oral corticosteroid drugs. However, corticosteroids do not prevent recurring episodes of symptoms and may not reduce damage when used alone. Therefore, immunosuppressive agents such as azathioprine, methotrexate, cyclosporine or chlorambucil may be employed for improved control of inflammation and organ protection. Experience is evolving with the use of interferon-alpha and with agents which inhibit tumor necrosis factor (TNF) in the treatment of Behçet’s disease. | Therapies of Behçet’s Syndrome. Treatment
The treatment of Behçet’s syndrome is directed toward the specific symptoms that are apparent in each individual. Specific therapies for Behçet’s syndrome are symptomatic and supportive. Severity of the condition as well as the patient’s age and sex may all affect treatment decisions. Spontaneous remission over time is common for individuals with Behçet’s syndrome.Oral and genital ulcerations may be treated with topical application of corticosteroid-containing preparations to the affected areas to assist in aborting developing attacks. Mouthwash containing a local anesthetic such as lidocaine or diphenhydramine may temporarily relieve pain. For recurrent attacks, colchicine can be effective in preventing recurring attacks of oral and genital ulcers. Apremilast is now FDA approved for the treatment of recurrent oral ulcerations in patients with Behçet’s. More aggressive therapies such as azathioprine, thalidomide, interferon-alpha and anti-TNF agents may be considered.Individuals who have arthritis associated with Behçet’s may respond to nonsteroidal anti-inflammatory drugs (NSAIDs) and colchicine. Treatment with azathioprine and anti-TNF agents can be used for more aggressive or refractory disease.Identification of eye inflammation requires close collaboration with an ophthalmologist as treatment is based on the location of eye inflammation and severity. Treatment may include eye drops containing corticosteroids to relieve pain. For more aggressive or refractory disease, oral corticosteroids combined with an immunosuppressant drug such as azathioprine or anti-TNF are used to control the progression of eye disease.Sulfasalazine, azathioprine, and corticosteroids may be administered to treat inflammatory bowel disease and gastrointestinal lesions associated with Behçet’s. Central nervous system and vascular abnormalities may be treated with corticosteroids as well, often in conjunction with immunosuppressive agents. In patients with clotting of major blood vessels, systemic anticoagulants and immunosuppressants should be considered.Inflammation of the joints, skin, and/or mucous membranes or other organs may be reduced with oral corticosteroid drugs. However, corticosteroids do not prevent recurring episodes of symptoms and may not reduce damage when used alone. Therefore, immunosuppressive agents such as azathioprine, methotrexate, cyclosporine or chlorambucil may be employed for improved control of inflammation and organ protection. Experience is evolving with the use of interferon-alpha and with agents which inhibit tumor necrosis factor (TNF) in the treatment of Behçet’s disease. | 149 | Behçet’s Syndrome |
nord_150_0 | Overview of Bejel | Bejel is an infectious disease that is rare in the United States but common in certain parts of the world. The infection is very similar to syphilis but is not sexually transmitted. Most frequently, transmission is by means of non-sexual skin contact or by common use of eating and drinking utensils. The organism that causes bejel belongs to the same family as the bacterium that causes syphilis, pinta and yaws and is known as treponema. Treponemas are spiral-shaped bacteria (spirochetes). Also known as endemic syphilis, bejel is characterized by lesions of the skin and bones that begin in the mouth and progress in gradual stages. The late stages are the most severe.Bejel is very common in dry, hot climates especially in the countries of the eastern Mediterranean region and in Saharan West Africa. | Overview of Bejel. Bejel is an infectious disease that is rare in the United States but common in certain parts of the world. The infection is very similar to syphilis but is not sexually transmitted. Most frequently, transmission is by means of non-sexual skin contact or by common use of eating and drinking utensils. The organism that causes bejel belongs to the same family as the bacterium that causes syphilis, pinta and yaws and is known as treponema. Treponemas are spiral-shaped bacteria (spirochetes). Also known as endemic syphilis, bejel is characterized by lesions of the skin and bones that begin in the mouth and progress in gradual stages. The late stages are the most severe.Bejel is very common in dry, hot climates especially in the countries of the eastern Mediterranean region and in Saharan West Africa. | 150 | Bejel |
nord_150_1 | Symptoms of Bejel | At the outset, children with bejel have patchy, slimy, ulcerations (lesions) on the mucous membranes, particularly in or near the mouth. Later, blisters appear on the back, arms, and legs. Further disease progression is indicated by infections of the bones, especially those of the legs. In these later stages, soft, gummy lumps (gummas) appear on the roof of the mouth and in the nasal passages. Other symptoms may include swollen glands or lymph nodes (lymph-adenopathy), and/or skin ulcerations under the arms or around the rectum and groin. | Symptoms of Bejel. At the outset, children with bejel have patchy, slimy, ulcerations (lesions) on the mucous membranes, particularly in or near the mouth. Later, blisters appear on the back, arms, and legs. Further disease progression is indicated by infections of the bones, especially those of the legs. In these later stages, soft, gummy lumps (gummas) appear on the roof of the mouth and in the nasal passages. Other symptoms may include swollen glands or lymph nodes (lymph-adenopathy), and/or skin ulcerations under the arms or around the rectum and groin. | 150 | Bejel |
nord_150_2 | Causes of Bejel | Bejel is a rare infectious disease caused by a spiral-shaped bacterium (spirochete), known as Treponema pallidum endemicum. Under a microscope, T. p. endemicum is virtually indistinguishable from Treponema pallidum, the bacterium that causes syphilis. The disease is not sexually transmitted. | Causes of Bejel. Bejel is a rare infectious disease caused by a spiral-shaped bacterium (spirochete), known as Treponema pallidum endemicum. Under a microscope, T. p. endemicum is virtually indistinguishable from Treponema pallidum, the bacterium that causes syphilis. The disease is not sexually transmitted. | 150 | Bejel |
nord_150_3 | Affects of Bejel | In the USA, bejel remains a rare disorder. It was brought to the USA via immigration of families from countries in which it is common (endemic), or by Americans who may have contracted the disease while in a hot, dry country. Bejel exhibits no preferences or propensities as to gender or race. Children living in unsanitary conditions are most often affected. About 25% of cases involve children of six years or younger; about 55% involve children and adolescents of age 16 years or younger, while about 20% involve persons of adult age, especially those who are closely involved with children. | Affects of Bejel. In the USA, bejel remains a rare disorder. It was brought to the USA via immigration of families from countries in which it is common (endemic), or by Americans who may have contracted the disease while in a hot, dry country. Bejel exhibits no preferences or propensities as to gender or race. Children living in unsanitary conditions are most often affected. About 25% of cases involve children of six years or younger; about 55% involve children and adolescents of age 16 years or younger, while about 20% involve persons of adult age, especially those who are closely involved with children. | 150 | Bejel |
nord_150_4 | Related disorders of Bejel | Symptoms of the following disorders can be similar to those of Bejel. Comparisons may be useful for a differential diagnosis:Acquired syphilis is a chronic infectious disease caused by the bacteria Treponema pallidum. It is transmitted by direct contact with an infected individual, usually through sexual intercourse. When left untreated, the symptoms of syphilis progress (i.e., primary, secondary, and latent stages). Eventually any tissue or organ in the body may be affected. Early symptoms include lesions (chancres) of the skin, anus, vagina, or the moist surfaces of the mouth. The symptoms may remain dormant for years. (For more information on this disorder, choose “Syphilis” as your search term in the Rare Disease Database.)Pinta is a rare infectious tropical disease affecting the skin that is caused by the bacterium Treponema Carateum, which is transmitted by direct, nonsexual contact. Pinta progresses through three distinct stages, which are characterized by various skin lesions and discoloration. Other organ systems are not affected. Exposed areas of the skin such as the face and extremities are most often affected. (For more information on this disorder, choose “Pinta” as your search term in the Rare Disease Database.)Yaws is an infectious tropical disease caused by the spirochete (spiral shaped) bacterium known as Treponema pertenue. The disease presents in three stages of which the first and second are easily treated. The third, however, may involve complex changes to the bones in many parts of the body. The first stage is characterized by the appearance of small, painless bumps on the skin that group together and grow until they resemble a strawberry. The skin may break open, forming an ulcer. The second stage (usually starting several weeks or months after the first) presents with a crispy, crunchy rash that may cover arms, legs, buttocks and/or face. If the bottoms of the feet are involved, walking is painful and the stage is known as “crab yaws.” Stage 3 yaws involves the long bones, joints, and/or skin. Yaws is very common in tropical areas of the world but rare in the United States. It is not a sexually transmitted disease. (For more information on this disorder, choose “yaws” as your search term in the Rare Disease Database.) | Related disorders of Bejel. Symptoms of the following disorders can be similar to those of Bejel. Comparisons may be useful for a differential diagnosis:Acquired syphilis is a chronic infectious disease caused by the bacteria Treponema pallidum. It is transmitted by direct contact with an infected individual, usually through sexual intercourse. When left untreated, the symptoms of syphilis progress (i.e., primary, secondary, and latent stages). Eventually any tissue or organ in the body may be affected. Early symptoms include lesions (chancres) of the skin, anus, vagina, or the moist surfaces of the mouth. The symptoms may remain dormant for years. (For more information on this disorder, choose “Syphilis” as your search term in the Rare Disease Database.)Pinta is a rare infectious tropical disease affecting the skin that is caused by the bacterium Treponema Carateum, which is transmitted by direct, nonsexual contact. Pinta progresses through three distinct stages, which are characterized by various skin lesions and discoloration. Other organ systems are not affected. Exposed areas of the skin such as the face and extremities are most often affected. (For more information on this disorder, choose “Pinta” as your search term in the Rare Disease Database.)Yaws is an infectious tropical disease caused by the spirochete (spiral shaped) bacterium known as Treponema pertenue. The disease presents in three stages of which the first and second are easily treated. The third, however, may involve complex changes to the bones in many parts of the body. The first stage is characterized by the appearance of small, painless bumps on the skin that group together and grow until they resemble a strawberry. The skin may break open, forming an ulcer. The second stage (usually starting several weeks or months after the first) presents with a crispy, crunchy rash that may cover arms, legs, buttocks and/or face. If the bottoms of the feet are involved, walking is painful and the stage is known as “crab yaws.” Stage 3 yaws involves the long bones, joints, and/or skin. Yaws is very common in tropical areas of the world but rare in the United States. It is not a sexually transmitted disease. (For more information on this disorder, choose “yaws” as your search term in the Rare Disease Database.) | 150 | Bejel |
nord_150_5 | Diagnosis of Bejel | The diagnosis of bejel is based on the geographic history of the patient as well as laboratory testing of material from the lesions (darkfield examination). The responsible bacterium is readily identifiable on sight in a microscope as a treponema. Samples of the fluid that surrounds the lesions yield a positive VDRL (Venereal Disease Research Laboratory) and FTA-ABS (fluorescent treponemal antibody-absorption) test. However, additional history may be required to differentiate bejel from venereal syphilis. | Diagnosis of Bejel. The diagnosis of bejel is based on the geographic history of the patient as well as laboratory testing of material from the lesions (darkfield examination). The responsible bacterium is readily identifiable on sight in a microscope as a treponema. Samples of the fluid that surrounds the lesions yield a positive VDRL (Venereal Disease Research Laboratory) and FTA-ABS (fluorescent treponemal antibody-absorption) test. However, additional history may be required to differentiate bejel from venereal syphilis. | 150 | Bejel |
nord_150_6 | Therapies of Bejel | TreatmentThe standard treatment for bejel is the antimicrobial drug benzathine penicillin G. Those individuals who are allergic to penicillin may be given doxycycline or tetracycline. The lesions caused by this disease typically heal after treatment. However, scarring may be permanent. | Therapies of Bejel. TreatmentThe standard treatment for bejel is the antimicrobial drug benzathine penicillin G. Those individuals who are allergic to penicillin may be given doxycycline or tetracycline. The lesions caused by this disease typically heal after treatment. However, scarring may be permanent. | 150 | Bejel |
nord_151_0 | Overview of Bell’s Palsy | Bell’s palsy is a non-progressive neurological disorder of the facial nerve (7th cranial nerve). This disorder is characterized by the sudden onset of facial paralysis that may be preceded by a slight fever, pain behind the ear on the affected side and weakness on one side of the face. Paralysis results from decreased blood supply (ischemia) and/or compression of the 7th cranial nerve. The exact cause of Bell’s palsy is not known. Viral (e.g., herpes zoster virus) and immune disorders are frequently suggested as a cause for this disorder. There may also be an inherited tendency toward developing Bell’s palsy. | Overview of Bell’s Palsy. Bell’s palsy is a non-progressive neurological disorder of the facial nerve (7th cranial nerve). This disorder is characterized by the sudden onset of facial paralysis that may be preceded by a slight fever, pain behind the ear on the affected side and weakness on one side of the face. Paralysis results from decreased blood supply (ischemia) and/or compression of the 7th cranial nerve. The exact cause of Bell’s palsy is not known. Viral (e.g., herpes zoster virus) and immune disorders are frequently suggested as a cause for this disorder. There may also be an inherited tendency toward developing Bell’s palsy. | 151 | Bell’s Palsy |
nord_151_1 | Symptoms of Bell’s Palsy | The early symptoms of Bell’s palsy may include a slight fever, pain behind the ear and weakness on one side of the face. The symptoms may begin suddenly and progress rapidly over several hours and sometimes follow a period of stress or reduced immunity. The whole side of the face is affected.In most cases of Bell’s palsy, only facial muscle weakness occurs, and the facial paralysis is temporary. Most cases resolve in two to three weeks. Approximately 80% of cases resolve within three months. However, some cases persist. In severe cases of Bell’s palsy, the facial muscles on the affected side are completely paralyzed, causing that side of the face to become smooth, expressionless and immobile. Often the opening between the upper and lower eyelids (palpebral fissure) is enlarged and remains open during sleep. This may result in the inability to close the eye on the affected side. People with Bell’s palsy may not have a corneal reflex, which means that the eye on the affected side does not close when the cornea is touched.If the compressed region of the facial nerve is higher than certain facial nerve branches, there may be a decrease in saliva and/or tear production. Some people with Bell’s palsy experience a loss of the sense of taste on one side of the mouth, drooling and an increased sensitivity to sound (hyperacusis) on the affected side of the head. In some cases, an affected individual’s response to a pinprick behind the ear is also decreased.Recovery from Bell’s palsy depends on the extent and severity of damage to the 7th cranial nerve. If facial paralysis is only partial, complete recovery can be expected. The affected muscles usually regain their original function within one to two months. If, as recovery proceeds, the nerve fibers regrow to muscles other than the ones they originally supplied, there may be voluntary muscle movements of the face accompanied by involuntary contractions of other facial muscles (synkinesia). Crocodile tears (tears not brought on by emotion) associated with facial muscular contractions occasionally develop in the aftermath of Bell’s palsy, particularly when eating. | Symptoms of Bell’s Palsy. The early symptoms of Bell’s palsy may include a slight fever, pain behind the ear and weakness on one side of the face. The symptoms may begin suddenly and progress rapidly over several hours and sometimes follow a period of stress or reduced immunity. The whole side of the face is affected.In most cases of Bell’s palsy, only facial muscle weakness occurs, and the facial paralysis is temporary. Most cases resolve in two to three weeks. Approximately 80% of cases resolve within three months. However, some cases persist. In severe cases of Bell’s palsy, the facial muscles on the affected side are completely paralyzed, causing that side of the face to become smooth, expressionless and immobile. Often the opening between the upper and lower eyelids (palpebral fissure) is enlarged and remains open during sleep. This may result in the inability to close the eye on the affected side. People with Bell’s palsy may not have a corneal reflex, which means that the eye on the affected side does not close when the cornea is touched.If the compressed region of the facial nerve is higher than certain facial nerve branches, there may be a decrease in saliva and/or tear production. Some people with Bell’s palsy experience a loss of the sense of taste on one side of the mouth, drooling and an increased sensitivity to sound (hyperacusis) on the affected side of the head. In some cases, an affected individual’s response to a pinprick behind the ear is also decreased.Recovery from Bell’s palsy depends on the extent and severity of damage to the 7th cranial nerve. If facial paralysis is only partial, complete recovery can be expected. The affected muscles usually regain their original function within one to two months. If, as recovery proceeds, the nerve fibers regrow to muscles other than the ones they originally supplied, there may be voluntary muscle movements of the face accompanied by involuntary contractions of other facial muscles (synkinesia). Crocodile tears (tears not brought on by emotion) associated with facial muscular contractions occasionally develop in the aftermath of Bell’s palsy, particularly when eating. | 151 | Bell’s Palsy |
nord_151_2 | Causes of Bell’s Palsy | The exact cause of Bell’s palsy is not known. Viral and immune disorders are often suggested as a cause for this disorder. There may also be an inherited tendency toward developing Bell’s palsy. Symptoms develop due to deficiency of blood supply and pressure on the 7th cranial nerve as a result of nerve swelling. | Causes of Bell’s Palsy. The exact cause of Bell’s palsy is not known. Viral and immune disorders are often suggested as a cause for this disorder. There may also be an inherited tendency toward developing Bell’s palsy. Symptoms develop due to deficiency of blood supply and pressure on the 7th cranial nerve as a result of nerve swelling. | 151 | Bell’s Palsy |
nord_151_3 | Affects of Bell’s Palsy | Bell’s palsy affects males and females in equal numbers. It is estimated that 25-35 per 100,000 people in the United States are affected with Bell’s palsy. Approximately 40,000 individuals are diagnosed with Bell’s palsy in the United States each year.Elderly individuals are more likely to develop Bell’s palsy than children, but the disorder may affect individuals of any age. Pregnant women or individuals with diabetes or upper respiratory ailments are affected more often than the general population | Affects of Bell’s Palsy. Bell’s palsy affects males and females in equal numbers. It is estimated that 25-35 per 100,000 people in the United States are affected with Bell’s palsy. Approximately 40,000 individuals are diagnosed with Bell’s palsy in the United States each year.Elderly individuals are more likely to develop Bell’s palsy than children, but the disorder may affect individuals of any age. Pregnant women or individuals with diabetes or upper respiratory ailments are affected more often than the general population | 151 | Bell’s Palsy |
nord_151_4 | Related disorders of Bell’s Palsy | Symptoms of the following disorders can be similar to those of Bell’s palsy. Comparisons may be useful for a differential diagnosis:Ramsay Hunt syndrome is a rare neurological disorder that typically affects adults over 60 years of age. The disorder is characterized by facial weakness or paralysis of the facial nerve and a rash affecting the ear or mouth. Symptoms are usually on one side of the face. Ringing in the ears (tinnitus) and hearing loss may also be present. Ramsay Hunt syndrome is caused by the varicella zoster virus (VZV), the same virus that causes chickenpox in children and shingles (herpes zoster) in adults. In Ramsay Hunt syndrome, previously inactive (dormant) varicella-zoster virus is reactivated and spreads to affect the facial nerve. (For more information in this disorder, choose “Ramsay-Hunt syndrome” as your search term on the Rare Disease Database.)Acoustic neuroma, also known as vestibular schwannoma, is a rare benign (non-cancerous) growth that develops on the 8th cranial nerve. This nerve runs from the inner ear to the brain and is responsible for hearing and balance. Although there is no standard or typical pattern of symptom development, hearing loss in one ear is the initial symptom in approximately 90% of affected individuals. Additional findings include ringing in the ears (tinnitus) and dizziness or imbalance. The symptoms of an acoustic neuroma occur from the tumor pressing against the 8th cranial nerve and disrupting its ability to transmit nerve signals to the brain. The exact cause of acoustic neuroma is unknown. (For more information in this disorder, choose “acoustic neuroma” as your search term on the Rare Disease Database.)Myasthenia gravis is a neuromuscular disorder primarily characterized by muscle weakness and muscle fatigue. The disorder usually becomes apparent during adulthood, but symptom onset may occur at any age. The condition may be restricted to certain muscle groups, particularly those of the eyes (ocular myasthenia), or may become more generalized (generalized myasthenia gravis), involving multiple muscle groups. Most individuals with myasthenia gravis develop weakness and drooping of the eyelids (ptosis); weakness of eye muscles, resulting in double vision (diplopia); and excessive muscle fatigue following activity. Additional features can include weakness of facial muscles; impaired speech (dysarthria); difficulties chewing and swallowing (dysphagia) and weakness of the upper arms and legs (proximal limb weakness). In addition, about 10% of patients develop potentially life-threatening complications due to severe involvement of muscles used during breathing (myasthenic crisis). Myasthenia gravis results from an abnormal immune reaction in which the body’s natural immune defenses (i.e., antibodies) inappropriately attack and gradually injure certain receptors in muscles that receive nerve impulses (antibody-mediated autoimmune response). (For more information on this disorder, choose “myasthenia gravis” as your search term in the Rare Disease Database.)Partial facial palsy can occur when only one or several branches of the facial nerve are compressed or damaged rather than the entire nerve. This can follow trauma to the face including lacerations and compression injuries. | Related disorders of Bell’s Palsy. Symptoms of the following disorders can be similar to those of Bell’s palsy. Comparisons may be useful for a differential diagnosis:Ramsay Hunt syndrome is a rare neurological disorder that typically affects adults over 60 years of age. The disorder is characterized by facial weakness or paralysis of the facial nerve and a rash affecting the ear or mouth. Symptoms are usually on one side of the face. Ringing in the ears (tinnitus) and hearing loss may also be present. Ramsay Hunt syndrome is caused by the varicella zoster virus (VZV), the same virus that causes chickenpox in children and shingles (herpes zoster) in adults. In Ramsay Hunt syndrome, previously inactive (dormant) varicella-zoster virus is reactivated and spreads to affect the facial nerve. (For more information in this disorder, choose “Ramsay-Hunt syndrome” as your search term on the Rare Disease Database.)Acoustic neuroma, also known as vestibular schwannoma, is a rare benign (non-cancerous) growth that develops on the 8th cranial nerve. This nerve runs from the inner ear to the brain and is responsible for hearing and balance. Although there is no standard or typical pattern of symptom development, hearing loss in one ear is the initial symptom in approximately 90% of affected individuals. Additional findings include ringing in the ears (tinnitus) and dizziness or imbalance. The symptoms of an acoustic neuroma occur from the tumor pressing against the 8th cranial nerve and disrupting its ability to transmit nerve signals to the brain. The exact cause of acoustic neuroma is unknown. (For more information in this disorder, choose “acoustic neuroma” as your search term on the Rare Disease Database.)Myasthenia gravis is a neuromuscular disorder primarily characterized by muscle weakness and muscle fatigue. The disorder usually becomes apparent during adulthood, but symptom onset may occur at any age. The condition may be restricted to certain muscle groups, particularly those of the eyes (ocular myasthenia), or may become more generalized (generalized myasthenia gravis), involving multiple muscle groups. Most individuals with myasthenia gravis develop weakness and drooping of the eyelids (ptosis); weakness of eye muscles, resulting in double vision (diplopia); and excessive muscle fatigue following activity. Additional features can include weakness of facial muscles; impaired speech (dysarthria); difficulties chewing and swallowing (dysphagia) and weakness of the upper arms and legs (proximal limb weakness). In addition, about 10% of patients develop potentially life-threatening complications due to severe involvement of muscles used during breathing (myasthenic crisis). Myasthenia gravis results from an abnormal immune reaction in which the body’s natural immune defenses (i.e., antibodies) inappropriately attack and gradually injure certain receptors in muscles that receive nerve impulses (antibody-mediated autoimmune response). (For more information on this disorder, choose “myasthenia gravis” as your search term in the Rare Disease Database.)Partial facial palsy can occur when only one or several branches of the facial nerve are compressed or damaged rather than the entire nerve. This can follow trauma to the face including lacerations and compression injuries. | 151 | Bell’s Palsy |
nord_151_5 | Diagnosis of Bell’s Palsy | A preliminary diagnosis may be made by the physician upon looking at the patient's face and noticing the difficulty the patient has in moving the facial muscles. Electromyography, a test that measures the electrical conductivity of the nerve, may be used to confirm the diagnosis and to measure the extent of the nerve damage.Patients often worry that they have suffered a stroke. Stroke can cause facial weakness but following a stroke most people are still able to move their forehead and eye, whereas after facial palsy the forehead and eye areas are unable to move. | Diagnosis of Bell’s Palsy. A preliminary diagnosis may be made by the physician upon looking at the patient's face and noticing the difficulty the patient has in moving the facial muscles. Electromyography, a test that measures the electrical conductivity of the nerve, may be used to confirm the diagnosis and to measure the extent of the nerve damage.Patients often worry that they have suffered a stroke. Stroke can cause facial weakness but following a stroke most people are still able to move their forehead and eye, whereas after facial palsy the forehead and eye areas are unable to move. | 151 | Bell’s Palsy |
nord_151_6 | Therapies of Bell’s Palsy | TreatmentMost people with Bell's palsy recover fully without treatment. Massage can maintain the mobility of the facial muscles and prevent the loss of muscle function as the nerve recovers. Treatment with oral corticosteroid drugs such as prednisone has been more successful than surgical attempts to widen the facial canal. Steroids must be given within the first 72 hours of onset of facial palsy to have optimal benefit. It is best to avoid exercise while the face is flaccid as this can cause overactivity of the face following recovery and worsen synkinesis.Preservative free eye drops and/or eye ointment, taping, and eyeglasses or goggles may help to protect the exposed eye of people with Bell's palsy if they cannot close the eye. In extremely severe cases, partial or total surgical closure (tarsorrhaphy) or chemical closure (with botulinum toxin) of the eyelid on the affected side may protect the eye from permanent damage. In those rare cases when Bell's palsy has caused permanent paralysis of one side of the face, the peripheral facial nerve can be surgically connected to adjacent cranial nerves to allow some eventual return of muscle function. If the paralysis has continued for more than two years, the existing facial muscles may not be able to recover, in which case surgery may be used to transfer muscles from other parts of the body to restore function such as smiling.Patients with long-term complications such as synkinesis may benefit from specialist facial therapy including muscle release, relaxation retraining and neuromuscular retraining as well as adjunctive treatments such as botulinum toxin to reduce problematic muscle overactivity. There are also surgical options to reduce synkinesis and improve function if conservative options are unsuccessful. Patients with long term complications often benefit from counseling and support groups to reduce anxiety and social isolation. | Therapies of Bell’s Palsy. TreatmentMost people with Bell's palsy recover fully without treatment. Massage can maintain the mobility of the facial muscles and prevent the loss of muscle function as the nerve recovers. Treatment with oral corticosteroid drugs such as prednisone has been more successful than surgical attempts to widen the facial canal. Steroids must be given within the first 72 hours of onset of facial palsy to have optimal benefit. It is best to avoid exercise while the face is flaccid as this can cause overactivity of the face following recovery and worsen synkinesis.Preservative free eye drops and/or eye ointment, taping, and eyeglasses or goggles may help to protect the exposed eye of people with Bell's palsy if they cannot close the eye. In extremely severe cases, partial or total surgical closure (tarsorrhaphy) or chemical closure (with botulinum toxin) of the eyelid on the affected side may protect the eye from permanent damage. In those rare cases when Bell's palsy has caused permanent paralysis of one side of the face, the peripheral facial nerve can be surgically connected to adjacent cranial nerves to allow some eventual return of muscle function. If the paralysis has continued for more than two years, the existing facial muscles may not be able to recover, in which case surgery may be used to transfer muscles from other parts of the body to restore function such as smiling.Patients with long-term complications such as synkinesis may benefit from specialist facial therapy including muscle release, relaxation retraining and neuromuscular retraining as well as adjunctive treatments such as botulinum toxin to reduce problematic muscle overactivity. There are also surgical options to reduce synkinesis and improve function if conservative options are unsuccessful. Patients with long term complications often benefit from counseling and support groups to reduce anxiety and social isolation. | 151 | Bell’s Palsy |
nord_152_0 | Overview of Benign Essential Blepharospasm | SummaryBenign essential blepharospasm (BEB) is a rare neurological disorder in which affected individuals experience involuntary muscle spasms and contractions of the muscles around the eyes. These spasms come and go (intermittent). Symptoms may begin as eye twitching and blinking and there may be symptoms of eye irritation. Eventually, BEB causes involuntary closure of the eyes. The exact cause of BEB is unknown. The disorder is one of a group of disorders collectively known as adult-onset focal dystonia.IntroductionDystonia is a group of movement disorders that vary in their symptoms, causes, progression and treatments. This group of neurological conditions is generally characterized by involuntary muscle contractions that force the body into abnormal, sometimes painful, movements and positions (postures). | Overview of Benign Essential Blepharospasm. SummaryBenign essential blepharospasm (BEB) is a rare neurological disorder in which affected individuals experience involuntary muscle spasms and contractions of the muscles around the eyes. These spasms come and go (intermittent). Symptoms may begin as eye twitching and blinking and there may be symptoms of eye irritation. Eventually, BEB causes involuntary closure of the eyes. The exact cause of BEB is unknown. The disorder is one of a group of disorders collectively known as adult-onset focal dystonia.IntroductionDystonia is a group of movement disorders that vary in their symptoms, causes, progression and treatments. This group of neurological conditions is generally characterized by involuntary muscle contractions that force the body into abnormal, sometimes painful, movements and positions (postures). | 152 | Benign Essential Blepharospasm |
nord_152_1 | Symptoms of Benign Essential Blepharospasm | In the early stages, benign essential blepharospasm is characterized by frequent or forced blinking and eye irritation that is often worsened by certain stimuli including bright lights, fatigue, emotional tension and environmental factors such as wind or air pollution. BEB virtually always affects both eyes (bilateral).The frequency of muscle spasms and contractions may increase causing involuntary narrowing of the opening between the eyelids or closure of the eyelids. It may become progressively harder for affected individuals to keep their eyes open. In severe cases, the spasms may intensify to the point where the eyelids are closed several hours at a time. Although an individual’s vision remains unaffected, prolonged closure of the eyelids may cause a person to become functionally blind.BEB may occur in association with dystonia of the lower part of the face, mouth or jaw. In these cases, BEB may be associated with jaw clenching, grimacing or tongue protrusion. This is called Meige syndrome or cranial dystonia. BEB may also be associated with abnormally dry eyes.In most patients, spasms and contractions occur during the daytime and disappear while the individual is sleeping, only to recur the next day. Symptoms of BEB may be temporarily alleviated by a variety of activities including singing, laughing, yawning and chewing.Other activities may worsen symptoms. Such activities include reading, walking, watching television, exposure to bright lights and driving. Stress may also worsen symptoms. | Symptoms of Benign Essential Blepharospasm. In the early stages, benign essential blepharospasm is characterized by frequent or forced blinking and eye irritation that is often worsened by certain stimuli including bright lights, fatigue, emotional tension and environmental factors such as wind or air pollution. BEB virtually always affects both eyes (bilateral).The frequency of muscle spasms and contractions may increase causing involuntary narrowing of the opening between the eyelids or closure of the eyelids. It may become progressively harder for affected individuals to keep their eyes open. In severe cases, the spasms may intensify to the point where the eyelids are closed several hours at a time. Although an individual’s vision remains unaffected, prolonged closure of the eyelids may cause a person to become functionally blind.BEB may occur in association with dystonia of the lower part of the face, mouth or jaw. In these cases, BEB may be associated with jaw clenching, grimacing or tongue protrusion. This is called Meige syndrome or cranial dystonia. BEB may also be associated with abnormally dry eyes.In most patients, spasms and contractions occur during the daytime and disappear while the individual is sleeping, only to recur the next day. Symptoms of BEB may be temporarily alleviated by a variety of activities including singing, laughing, yawning and chewing.Other activities may worsen symptoms. Such activities include reading, walking, watching television, exposure to bright lights and driving. Stress may also worsen symptoms. | 152 | Benign Essential Blepharospasm |
nord_152_2 | Causes of Benign Essential Blepharospasm | The cause of benign essential blepharospasm is unknown. Researchers speculate that the cause of BEB may be multifactorial (e.g., caused by the interaction of certain genetic and environmental factors).Malfunctioning of a region of the brain known as the basal ganglia may play a role in the development of BEB. The basal ganglia are structures composed of nerve cells located deep in the brain. The basal ganglia are involved in the regulation of motor and learning functions. The exact problem(s) associated with the basal ganglia in individuals with BEB is unknown.In some cases, BEB runs in families. More study is required to determine the exact role genetics plays in the development of BEB.Some affected individuals may have a history of local eye disease such as eye trauma. However, no proven relationship between local eye disease and the development of BEB has been established. In most affected individuals, BEB develops spontaneously with no known precipitating factor.Blepharospasm may also occur secondary to other disorders such as tardive dyskinesia or generalized dystonia, Wilson disease and various parkinsonian syndromes. Blepharospasm may also occur secondary to the use of certain drugs, specifically the drugs used to treat Parkinson’s disease. | Causes of Benign Essential Blepharospasm. The cause of benign essential blepharospasm is unknown. Researchers speculate that the cause of BEB may be multifactorial (e.g., caused by the interaction of certain genetic and environmental factors).Malfunctioning of a region of the brain known as the basal ganglia may play a role in the development of BEB. The basal ganglia are structures composed of nerve cells located deep in the brain. The basal ganglia are involved in the regulation of motor and learning functions. The exact problem(s) associated with the basal ganglia in individuals with BEB is unknown.In some cases, BEB runs in families. More study is required to determine the exact role genetics plays in the development of BEB.Some affected individuals may have a history of local eye disease such as eye trauma. However, no proven relationship between local eye disease and the development of BEB has been established. In most affected individuals, BEB develops spontaneously with no known precipitating factor.Blepharospasm may also occur secondary to other disorders such as tardive dyskinesia or generalized dystonia, Wilson disease and various parkinsonian syndromes. Blepharospasm may also occur secondary to the use of certain drugs, specifically the drugs used to treat Parkinson’s disease. | 152 | Benign Essential Blepharospasm |
nord_152_3 | Affects of Benign Essential Blepharospasm | Benign essential blepharospasm affects women more often than men. The average age of onset is 56.It is estimated that approximately 2,000 individuals are diagnosed with new cases of BEB each year in the United States. The prevalence of BEB in the general population is approximately 5 per 100,000 individuals. | Affects of Benign Essential Blepharospasm. Benign essential blepharospasm affects women more often than men. The average age of onset is 56.It is estimated that approximately 2,000 individuals are diagnosed with new cases of BEB each year in the United States. The prevalence of BEB in the general population is approximately 5 per 100,000 individuals. | 152 | Benign Essential Blepharospasm |
nord_152_4 | Related disorders of Benign Essential Blepharospasm | Symptoms of the following disorders can be similar to those of benign essential blepharospasm. Comparisons may be useful for a differential diagnosis:Meige syndrome (cranial dystonia), is a rare neurological disorder that is characterized by spasms of all the muscles of the face, including the tongue and jaw. People in late middle age are most often affected. Just as in blepharospasm, involuntary eyelid closure may result from spasms of the muscles around the eyes. (For more information on this disorder, choose “Meige syndrome” as your search term in the Rare Disease Database.)Bell’s palsy is a nonprogressive neurological disorder of one of the facial nerves (7th cranial nerve). This disorder is characterized by the sudden onset of facial paralysis only on one side that may be preceded by a slight fever, pain behind the ear on the affected side or a stiff neck. The exact cause of Bell’s palsy is not known, but viral (e.g., herpes zoster virus) and immune disorders are frequently implicated as a cause for this disorder. There may also be an inherited tendency toward developing Bell’s palsy. (For more information on this disorder, choose “Bell’s palsy” as your search term in the Rare Disease Database.)Dystonia is a group of neurological movement disorders characterized by involuntary muscle contractions. Dystonia may be focal (affecting an isolated body part), segmental (affecting adjacent body areas or generalized (affecting many major muscle groups simultaneously). Dystonia may result in abnormal, sometimes painful movements or postures. When dystonia is generalized, it may include blepharospasm. There are many different causes for dystonia. Genetic as well as non-genetic factors contribute to all forms of dystonia. (For more information on this disorder, choose “dystonia” as your search term in the Rare Disease Database.)Hemifacial spasm, which is characterized by spasmodic contractions on one side of the face, is not a form of dystonia. The initial symptom of hemifacial spasm may be twitching of one eyelid that eventually results in brief forced closure of the eyelid. Hemifacial spasm may be caused by pressure on or irritation of the facial nerve. Hemifacial spasm is only rarely bilateral, and when it is, the spasms are not synchronous on the two sides of the face. | Related disorders of Benign Essential Blepharospasm. Symptoms of the following disorders can be similar to those of benign essential blepharospasm. Comparisons may be useful for a differential diagnosis:Meige syndrome (cranial dystonia), is a rare neurological disorder that is characterized by spasms of all the muscles of the face, including the tongue and jaw. People in late middle age are most often affected. Just as in blepharospasm, involuntary eyelid closure may result from spasms of the muscles around the eyes. (For more information on this disorder, choose “Meige syndrome” as your search term in the Rare Disease Database.)Bell’s palsy is a nonprogressive neurological disorder of one of the facial nerves (7th cranial nerve). This disorder is characterized by the sudden onset of facial paralysis only on one side that may be preceded by a slight fever, pain behind the ear on the affected side or a stiff neck. The exact cause of Bell’s palsy is not known, but viral (e.g., herpes zoster virus) and immune disorders are frequently implicated as a cause for this disorder. There may also be an inherited tendency toward developing Bell’s palsy. (For more information on this disorder, choose “Bell’s palsy” as your search term in the Rare Disease Database.)Dystonia is a group of neurological movement disorders characterized by involuntary muscle contractions. Dystonia may be focal (affecting an isolated body part), segmental (affecting adjacent body areas or generalized (affecting many major muscle groups simultaneously). Dystonia may result in abnormal, sometimes painful movements or postures. When dystonia is generalized, it may include blepharospasm. There are many different causes for dystonia. Genetic as well as non-genetic factors contribute to all forms of dystonia. (For more information on this disorder, choose “dystonia” as your search term in the Rare Disease Database.)Hemifacial spasm, which is characterized by spasmodic contractions on one side of the face, is not a form of dystonia. The initial symptom of hemifacial spasm may be twitching of one eyelid that eventually results in brief forced closure of the eyelid. Hemifacial spasm may be caused by pressure on or irritation of the facial nerve. Hemifacial spasm is only rarely bilateral, and when it is, the spasms are not synchronous on the two sides of the face. | 152 | Benign Essential Blepharospasm |
nord_152_5 | Diagnosis of Benign Essential Blepharospasm | No laboratory tests exist to make a definitive diagnosis of benign essential blepharospasm. A diagnosis is made based upon a thorough clinical evaluation, a detailed patient history and identification of characteristic symptoms. | Diagnosis of Benign Essential Blepharospasm. No laboratory tests exist to make a definitive diagnosis of benign essential blepharospasm. A diagnosis is made based upon a thorough clinical evaluation, a detailed patient history and identification of characteristic symptoms. | 152 | Benign Essential Blepharospasm |
nord_152_6 | Therapies of Benign Essential Blepharospasm | Treatment
Treatment of BEB consists of oral drug therapy, focal injections of botulinum toxin (four different brands are available in the USA) or surgery to remove eyelid muscle, used alone or in conjunction with the botulinum toxin injections.Approximately one-third of affected individuals are treated with oral medications (drug therapy) specifically anticholinergic drugs and with dopamine depleters such as tetrabenazine. The results of these drug treatments are usually moderate or unsatisfactory and often temporary. Additional drugs that have been used to treat BEB include clonazepam, trihexyphenidyl, diazepam and baclofen.Botulinum toxin has been approved by the Food and Drug Administration (FDA) as a treatment for blepharospasm and has become the primary form of treatment. The technique of injecting small amounts of botulinum toxin into the orbicularis oculi weakens these muscles for approximately three months, after which time the procedure must be repeated. Botulinum toxin injections have been helpful for many individuals with blepharospasm, but some people do not respond well. Botox and Xeomin are type A botulinum toxin products that are FDA approved for the treatment of blepharospasm.Two surgical approaches are in use in patients in which drug therapy does not work. In a procedure called a protractor myectomy, the eyelid muscles themselves are removed either partially or completely.In the past a procedure known as a neurectomy was performed to treat individuals with BEB. However, the complication rate is much higher than with a myectomy and this procedure is rarely used anymore. In a neurectomy, sections are taken off the branches of the facial nerve leading to the orbicularis oculi. Paralysis of the entire upper face may result, but the nerve branches tend to regenerate after a period of months or years. | Therapies of Benign Essential Blepharospasm. Treatment
Treatment of BEB consists of oral drug therapy, focal injections of botulinum toxin (four different brands are available in the USA) or surgery to remove eyelid muscle, used alone or in conjunction with the botulinum toxin injections.Approximately one-third of affected individuals are treated with oral medications (drug therapy) specifically anticholinergic drugs and with dopamine depleters such as tetrabenazine. The results of these drug treatments are usually moderate or unsatisfactory and often temporary. Additional drugs that have been used to treat BEB include clonazepam, trihexyphenidyl, diazepam and baclofen.Botulinum toxin has been approved by the Food and Drug Administration (FDA) as a treatment for blepharospasm and has become the primary form of treatment. The technique of injecting small amounts of botulinum toxin into the orbicularis oculi weakens these muscles for approximately three months, after which time the procedure must be repeated. Botulinum toxin injections have been helpful for many individuals with blepharospasm, but some people do not respond well. Botox and Xeomin are type A botulinum toxin products that are FDA approved for the treatment of blepharospasm.Two surgical approaches are in use in patients in which drug therapy does not work. In a procedure called a protractor myectomy, the eyelid muscles themselves are removed either partially or completely.In the past a procedure known as a neurectomy was performed to treat individuals with BEB. However, the complication rate is much higher than with a myectomy and this procedure is rarely used anymore. In a neurectomy, sections are taken off the branches of the facial nerve leading to the orbicularis oculi. Paralysis of the entire upper face may result, but the nerve branches tend to regenerate after a period of months or years. | 152 | Benign Essential Blepharospasm |
nord_153_0 | Overview of Benign Paroxysmal Positional Vertigo | SummaryBenign paroxysmal position vertigo (BPPV) is a disorder characterized by brief, recurrent bouts of vertigo. Vertigo is a sensation of spinning, whirling or turning. Individuals often feel as if the room is moving or spinning and they can lose their balance and have difficulty standing or walking. During the vertigo spells, affected individuals often have abnormal eye movements as well (nystagmus). BPPV is most often triggered by changes in head position. The severity of the disorder varies. In some people, it only causes mild symptoms, while in others it can potentially cause more severe, even debilitating symptoms. BPPV may disappear but sometimes it persists recurrently for many months. Most affected individuals can be easily and effectively treated by non-invasive methods such as canalith (or canalolith) repositioning maneuvers. However, BPPV may recur even after effectively treated. BPPV is believed to be caused by the displacement of small calcium carbonate crystals within the inner ear. These tiny crystals originate from the gravity and acceleration sensing structures and become inappropriately located in one of three semicircular canals, which are tiny, interconnected, looped tubes that serve to detect movements of the head and play a role in helping the body maintain balance. The exact, underlying cause of this displacement is not always known (idiopathic). Recurrences are possible because additional calcium can become dislodged. The treatment maneuvers move the calcium particles back to the main vestibule, the chamber from which they originated. This stops the vertigo. However, the maneuvers do not prevent the shedding of additional calcium crystals in the future.IntroductionBPPV has been identified as a clinical entity since the late 1800s. The term benign means that the disorder is not progressive and is not considered serious. Although labeled benign, BPPV can disrupt a person's daily activities and affect quality of life. The term paroxysmal means that episodes arise suddenly and often unpredictably. The term positional means the disorder is contingent on a change of the position of the head. BPPV is one of the most common causes of vertigo. | Overview of Benign Paroxysmal Positional Vertigo. SummaryBenign paroxysmal position vertigo (BPPV) is a disorder characterized by brief, recurrent bouts of vertigo. Vertigo is a sensation of spinning, whirling or turning. Individuals often feel as if the room is moving or spinning and they can lose their balance and have difficulty standing or walking. During the vertigo spells, affected individuals often have abnormal eye movements as well (nystagmus). BPPV is most often triggered by changes in head position. The severity of the disorder varies. In some people, it only causes mild symptoms, while in others it can potentially cause more severe, even debilitating symptoms. BPPV may disappear but sometimes it persists recurrently for many months. Most affected individuals can be easily and effectively treated by non-invasive methods such as canalith (or canalolith) repositioning maneuvers. However, BPPV may recur even after effectively treated. BPPV is believed to be caused by the displacement of small calcium carbonate crystals within the inner ear. These tiny crystals originate from the gravity and acceleration sensing structures and become inappropriately located in one of three semicircular canals, which are tiny, interconnected, looped tubes that serve to detect movements of the head and play a role in helping the body maintain balance. The exact, underlying cause of this displacement is not always known (idiopathic). Recurrences are possible because additional calcium can become dislodged. The treatment maneuvers move the calcium particles back to the main vestibule, the chamber from which they originated. This stops the vertigo. However, the maneuvers do not prevent the shedding of additional calcium crystals in the future.IntroductionBPPV has been identified as a clinical entity since the late 1800s. The term benign means that the disorder is not progressive and is not considered serious. Although labeled benign, BPPV can disrupt a person's daily activities and affect quality of life. The term paroxysmal means that episodes arise suddenly and often unpredictably. The term positional means the disorder is contingent on a change of the position of the head. BPPV is one of the most common causes of vertigo. | 153 | Benign Paroxysmal Positional Vertigo |
nord_153_1 | Symptoms of Benign Paroxysmal Positional Vertigo | The onset of an episode of BPPV is usually sudden following changes in head position. Often, ordinary movements such as turning over on one’s side, lying down, looking up, stooping or bending over can cause an episode. The severity of the disorder can vary greatly from one person to another. Factors that may affect the severity include the speed of head movement, the volume of calcium crystals that are moved, and a person’s innate sensitivity to motion. For some people, only a slight positional change of the head can cause symptoms. In such cases, this extreme sensitivity can cause near frequent sensations of tilting or dizziness. In other individuals, the disorder may only produce mild symptoms despite a rapid change of head position. In some affected individuals, symptoms may only be caused by very precise, specific movements. The duration of symptoms of BPPV may also vary and can potentially persist recurrently for days, weeks, or months or become recurrent over many years.Vertigo in individuals with BPPV usually lasts less than 30 seconds. Vertigo can lead to unsteadiness and a loss of balance. Additional symptoms can develop including lightheadedness, dizziness, nausea, vomiting, and blurred vision. Nausea or a feeling of queasiness can persist for a short time even after the sensation of vertigo has passed.A common associated finding with BPPV is nystagmus, an eye movement disorder characterized by rapid, involuntary movements of the eye. The eyes may be described as jumping or twitching in certain directions. Nystagmus associated with BPPV is fatigable meaning that if one repeats the position change that induced the original vertigo and nystagmus, after time nystagmus lessens in severity.The type of nystagmus, defined by the direction of the abnormal eye movements, depends upon which of the three semicircular canals of the inner ear is involved. The three canals are known as the posterior, horizontal (lateral) and anterior (superior) canals. Thus BPPV can be classified as posterior canal BPPV, horizontal canal BPPV or anterior canal BPPV based on the specific canal involved. Most cases of BPPV involve the posterior canal which accounts for around 80% of cases. | Symptoms of Benign Paroxysmal Positional Vertigo. The onset of an episode of BPPV is usually sudden following changes in head position. Often, ordinary movements such as turning over on one’s side, lying down, looking up, stooping or bending over can cause an episode. The severity of the disorder can vary greatly from one person to another. Factors that may affect the severity include the speed of head movement, the volume of calcium crystals that are moved, and a person’s innate sensitivity to motion. For some people, only a slight positional change of the head can cause symptoms. In such cases, this extreme sensitivity can cause near frequent sensations of tilting or dizziness. In other individuals, the disorder may only produce mild symptoms despite a rapid change of head position. In some affected individuals, symptoms may only be caused by very precise, specific movements. The duration of symptoms of BPPV may also vary and can potentially persist recurrently for days, weeks, or months or become recurrent over many years.Vertigo in individuals with BPPV usually lasts less than 30 seconds. Vertigo can lead to unsteadiness and a loss of balance. Additional symptoms can develop including lightheadedness, dizziness, nausea, vomiting, and blurred vision. Nausea or a feeling of queasiness can persist for a short time even after the sensation of vertigo has passed.A common associated finding with BPPV is nystagmus, an eye movement disorder characterized by rapid, involuntary movements of the eye. The eyes may be described as jumping or twitching in certain directions. Nystagmus associated with BPPV is fatigable meaning that if one repeats the position change that induced the original vertigo and nystagmus, after time nystagmus lessens in severity.The type of nystagmus, defined by the direction of the abnormal eye movements, depends upon which of the three semicircular canals of the inner ear is involved. The three canals are known as the posterior, horizontal (lateral) and anterior (superior) canals. Thus BPPV can be classified as posterior canal BPPV, horizontal canal BPPV or anterior canal BPPV based on the specific canal involved. Most cases of BPPV involve the posterior canal which accounts for around 80% of cases. | 153 | Benign Paroxysmal Positional Vertigo |
nord_153_2 | Causes of Benign Paroxysmal Positional Vertigo | In some patients, the exact underlying cause of BPPV is unknown. Researchers believe that most cases of BPPV are caused by abnormalities affecting the inner ear. The inner ear contains the cochlea, which converts sound pressure from the outer ear into nerve impulses that are sent to the brain via the auditory canal. The inner ear also contains a vestibular apparatus for balance that includes of the semicircular canals. Fluid moves through these canals enabling the brain to detect turning movements of the head.Two additional structures found in the inner ear are the utricle and saccule (otolith organs). The utricle and saccule are fluid-filled sacs or cavities that detect acceleration movements of the head including gravity. The utricle and saccule contain small calcium carbonate crystals. For unknown reasons, in individuals with BPPV these crystals may partially erode and small pieces of the crystals fall off and end up in one of the adjoining semicircular canals. Within the canals, these crystals may stimulate specialized sensing organ of the inner ear tubes that is called the cupula. This results in the body being sensitive to certain head position changes that normally would not cause dizziness. Basically, the brain is sent powerful asymmetric nerve signals that resemble the kind of asymmetry associated with spinning. This gives a patient the same sensation that would occur with spinning.Two specific theories proposed in regard to the underlying cause of BPPV are the canalithiasis and cupulolithiasis theories. These proposed mechanisms are not mutually exclusive and there is scientific evidence that both occur, but that canalithiasis is more common than cupulolithiasis. Canalithiasis refers to calcium crystals that are freely mobile within the semicircular canals and, whenever the head changes position, these crystals move through the canal. As these crystals move, they are believed to drag the fluid within the canals, known as endolymph, behind them. As the endolymph moves through the canals, it stimulates the hair cells of the cupula causing vertigo and nystagmus. When the head is not moving, the crystals (and therefore the endolymph) do not move as well. Consequently, there is no stimulation of the cupula and no associated vertigo or nystagmus. It is believed that these crystals eventually dissolve or fall back into the vestibule (the cavity at the entrance to one of the canals). Canalithiasis appears to best explain most cases of BPPV.Cupulolithiasis refers to crystals that have become stuck or attached to the cupula in one of the three semicircular canals, usually the posterior canal. BPPV caused by cupulolithiasis is believed to account for the more persistent cases of BPPV that do not respond as well to positioning treatments.Neither the canalithiasis nor the cupulolithiasis theories address why the crystals become dislodged. There are many different theories as to what conditions can cause crystals to become dislodged and enter the semicircular canals. Such conditions include head trauma, surgery, chronic middle ear infections (otitis media), a severe cold or infection or vestibular neuritis. There are some possible associations with osteoporosis.Additional factors that may predispose individuals to BPPV include alcoholism, inactivity, age, and certain central nervous system disorders. In many cases, no such precipitating cause can be identified. | Causes of Benign Paroxysmal Positional Vertigo. In some patients, the exact underlying cause of BPPV is unknown. Researchers believe that most cases of BPPV are caused by abnormalities affecting the inner ear. The inner ear contains the cochlea, which converts sound pressure from the outer ear into nerve impulses that are sent to the brain via the auditory canal. The inner ear also contains a vestibular apparatus for balance that includes of the semicircular canals. Fluid moves through these canals enabling the brain to detect turning movements of the head.Two additional structures found in the inner ear are the utricle and saccule (otolith organs). The utricle and saccule are fluid-filled sacs or cavities that detect acceleration movements of the head including gravity. The utricle and saccule contain small calcium carbonate crystals. For unknown reasons, in individuals with BPPV these crystals may partially erode and small pieces of the crystals fall off and end up in one of the adjoining semicircular canals. Within the canals, these crystals may stimulate specialized sensing organ of the inner ear tubes that is called the cupula. This results in the body being sensitive to certain head position changes that normally would not cause dizziness. Basically, the brain is sent powerful asymmetric nerve signals that resemble the kind of asymmetry associated with spinning. This gives a patient the same sensation that would occur with spinning.Two specific theories proposed in regard to the underlying cause of BPPV are the canalithiasis and cupulolithiasis theories. These proposed mechanisms are not mutually exclusive and there is scientific evidence that both occur, but that canalithiasis is more common than cupulolithiasis. Canalithiasis refers to calcium crystals that are freely mobile within the semicircular canals and, whenever the head changes position, these crystals move through the canal. As these crystals move, they are believed to drag the fluid within the canals, known as endolymph, behind them. As the endolymph moves through the canals, it stimulates the hair cells of the cupula causing vertigo and nystagmus. When the head is not moving, the crystals (and therefore the endolymph) do not move as well. Consequently, there is no stimulation of the cupula and no associated vertigo or nystagmus. It is believed that these crystals eventually dissolve or fall back into the vestibule (the cavity at the entrance to one of the canals). Canalithiasis appears to best explain most cases of BPPV.Cupulolithiasis refers to crystals that have become stuck or attached to the cupula in one of the three semicircular canals, usually the posterior canal. BPPV caused by cupulolithiasis is believed to account for the more persistent cases of BPPV that do not respond as well to positioning treatments.Neither the canalithiasis nor the cupulolithiasis theories address why the crystals become dislodged. There are many different theories as to what conditions can cause crystals to become dislodged and enter the semicircular canals. Such conditions include head trauma, surgery, chronic middle ear infections (otitis media), a severe cold or infection or vestibular neuritis. There are some possible associations with osteoporosis.Additional factors that may predispose individuals to BPPV include alcoholism, inactivity, age, and certain central nervous system disorders. In many cases, no such precipitating cause can be identified. | 153 | Benign Paroxysmal Positional Vertigo |
nord_153_3 | Affects of Benign Paroxysmal Positional Vertigo | The lifetime prevalence of BPPV is about 2.4% and other estimates range from 10-64 per 100,000 people in the general population. However, many physicians believe that the disorder is often misdiagnosed and that the true frequency may be higher. BPPV most often affects older adults with a peak age of onset in the sixth decade. The disorder may affect individuals of any age, but is quite uncommon in those under 20 years of age. Women are believed to be affected at least twice as often as men. | Affects of Benign Paroxysmal Positional Vertigo. The lifetime prevalence of BPPV is about 2.4% and other estimates range from 10-64 per 100,000 people in the general population. However, many physicians believe that the disorder is often misdiagnosed and that the true frequency may be higher. BPPV most often affects older adults with a peak age of onset in the sixth decade. The disorder may affect individuals of any age, but is quite uncommon in those under 20 years of age. Women are believed to be affected at least twice as often as men. | 153 | Benign Paroxysmal Positional Vertigo |
nord_153_4 | Related disorders of Benign Paroxysmal Positional Vertigo | Symptoms of the following disorders can be similar to those of BBPV. Comparisons may be useful for a differential diagnosis.Ménière's disease is a disorder characterized by recurrent vertigo, unilateral hearing loss and ringing sounds in the affected ear (tinnitus). It is associated with swelling (dilation) of the membranous labyrinth (endolymphatic hydrops) in the ear. The attacks of vertigo in Meniere’s disease appear suddenly and usually last 2-6 hours. Vertigo consists of the sensation that the room or objects are rotating around an affected individual. The dizziness often subsides gradually. The attacks may be of vertigo are often associated with nausea and vomiting. Affected individuals may have a recurrent feeling of fullness or pressure in the affected ear, and hearing tends to fluctuate. Over the years, hearing may progressively worsen. Tinnitus often develops on the affected side and may be more intense before or during an attack of vertigo. Usually, one ear is affected, but both ears are involved in 10 to 15 percent of individuals with Meniere’s disease. (For more information on this disorder, choose “Ménière's” as your search term in the Rare Disease Database.)Labyrinthitis is a disorder characterized by inflammation and swelling of the inner ear. The membranous labyrinth is the series of interconnected tubes and cavities within the inner ear. Labyrinthitis is an inflammatory condition, probably caused by one of many possible viruses and leads to vertigo that is evoked by head movements. Vertigo can result in loss of balance. Nausea and vomiting may also occur. Hearing loss in the affected ear is typical. Labyrinthitis is usually caused by viral infection and much less commonly by bacterial infection.Vestibular neuritis is very similar to labyrinthitis except that hearing is unaffected. Like labyrinthitis, it is usually caused viral infection of the vestibular nerve of the ear. Since some viral infections may cause patchy inflammation of the vestibular nerve and labyrinth, some have proposed the term neurolabyrinthitis be used to include both labyrinthitis and vestibular neuritis. The vestibular nerve carries information from the inner ear to the brain regarding head movement. There are two vestibular nerve branches and when either one is affected by an infection it leads to imbalance and vertigo. Vestibular neuritis may follow a viral upper respiratory tract infection.An acoustic neuroma, also known as a vestibular schwannoma, is a rare benign (non-cancerous) growth that develops on the eighth cranial nerve. This nerve runs from the inner ear to the brain and is responsible for hearing and balance (equilibrium). There is no standard or typical pattern of symptom development, although hearing loss in one ear (unilateral) is the initial symptom in approximately 90 percent of cases. Additional findings include ringing in the ears (tinnitus) and dizziness. The symptoms of an acoustic neuroma occur from the tumor pressing against the eighth cranial nerve and disrupting its ability to transmit nerve signals to the brain. An acoustic neuroma is not cancerous (malignant); it does not spread to other parts of the body. The reason an acoustic neuroma forms is unknown. (For more information on this disorder, choose “acoustic neuroma” as your search term in the Rare Disease Database.)There are additional disorders or conditions that can cause vertigo including migraines, head trauma, and reduced blood flow in the brain as might be caused by stroke, cerebellar hemorrhage or other similar conditions. Mal de Debarquement syndrome, a rare and poorly understood disorder, is characterized by a rocking sensation and/or imbalance that persist for an excessive length of time after a boating excursion or cruise of at least a few days duration, or less commonly after an airplane flight or other motion experience. | Related disorders of Benign Paroxysmal Positional Vertigo. Symptoms of the following disorders can be similar to those of BBPV. Comparisons may be useful for a differential diagnosis.Ménière's disease is a disorder characterized by recurrent vertigo, unilateral hearing loss and ringing sounds in the affected ear (tinnitus). It is associated with swelling (dilation) of the membranous labyrinth (endolymphatic hydrops) in the ear. The attacks of vertigo in Meniere’s disease appear suddenly and usually last 2-6 hours. Vertigo consists of the sensation that the room or objects are rotating around an affected individual. The dizziness often subsides gradually. The attacks may be of vertigo are often associated with nausea and vomiting. Affected individuals may have a recurrent feeling of fullness or pressure in the affected ear, and hearing tends to fluctuate. Over the years, hearing may progressively worsen. Tinnitus often develops on the affected side and may be more intense before or during an attack of vertigo. Usually, one ear is affected, but both ears are involved in 10 to 15 percent of individuals with Meniere’s disease. (For more information on this disorder, choose “Ménière's” as your search term in the Rare Disease Database.)Labyrinthitis is a disorder characterized by inflammation and swelling of the inner ear. The membranous labyrinth is the series of interconnected tubes and cavities within the inner ear. Labyrinthitis is an inflammatory condition, probably caused by one of many possible viruses and leads to vertigo that is evoked by head movements. Vertigo can result in loss of balance. Nausea and vomiting may also occur. Hearing loss in the affected ear is typical. Labyrinthitis is usually caused by viral infection and much less commonly by bacterial infection.Vestibular neuritis is very similar to labyrinthitis except that hearing is unaffected. Like labyrinthitis, it is usually caused viral infection of the vestibular nerve of the ear. Since some viral infections may cause patchy inflammation of the vestibular nerve and labyrinth, some have proposed the term neurolabyrinthitis be used to include both labyrinthitis and vestibular neuritis. The vestibular nerve carries information from the inner ear to the brain regarding head movement. There are two vestibular nerve branches and when either one is affected by an infection it leads to imbalance and vertigo. Vestibular neuritis may follow a viral upper respiratory tract infection.An acoustic neuroma, also known as a vestibular schwannoma, is a rare benign (non-cancerous) growth that develops on the eighth cranial nerve. This nerve runs from the inner ear to the brain and is responsible for hearing and balance (equilibrium). There is no standard or typical pattern of symptom development, although hearing loss in one ear (unilateral) is the initial symptom in approximately 90 percent of cases. Additional findings include ringing in the ears (tinnitus) and dizziness. The symptoms of an acoustic neuroma occur from the tumor pressing against the eighth cranial nerve and disrupting its ability to transmit nerve signals to the brain. An acoustic neuroma is not cancerous (malignant); it does not spread to other parts of the body. The reason an acoustic neuroma forms is unknown. (For more information on this disorder, choose “acoustic neuroma” as your search term in the Rare Disease Database.)There are additional disorders or conditions that can cause vertigo including migraines, head trauma, and reduced blood flow in the brain as might be caused by stroke, cerebellar hemorrhage or other similar conditions. Mal de Debarquement syndrome, a rare and poorly understood disorder, is characterized by a rocking sensation and/or imbalance that persist for an excessive length of time after a boating excursion or cruise of at least a few days duration, or less commonly after an airplane flight or other motion experience. | 153 | Benign Paroxysmal Positional Vertigo |
nord_153_5 | Diagnosis of Benign Paroxysmal Positional Vertigo | A diagnosis of BPPV is based upon identification of characteristic symptoms, a detailed patient history and a thorough clinical evaluation. Affected individuals usually have a history of episodes of vertigo.Clinical Testing and Work-Up
Affected individuals will undergo a Dix-Hallpike test. During this test, an affected individual sits down, with legs extended, on an examination table. The doctor will rotate the head approximately 30 to 45 degrees and then help the person quickly lie on his or her back (supine position). In individuals with BPPV, this will prompt a characteristic episode of nystagmus and/or vertigo. The timing and appearance of the eye movements will help a physician determine the cause of vertigo. The Dix-Hallpike test can differentiate vertigo caused by a problem in the brain from vertigo caused by a problem in the inner ear. The specific pattern of nystagmus will tell a physician which of the three semicircular canals of the inner ear is involved in an individual case.When the diagnosis is in doubt, affected individuals may undergo a test such as magnetic resonance imaging (MRI) to rule out other conditions. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues such as in the brain or ear.In some cases, a physician may use a test called a videonystagmography (VNG) or videonystagmography (VNG), which records the voluntary and involuntary movements of the eyes. During this exam, electrodes are placed around the eyes (ENG) or goggles with cameras are placed over the eyes (VNG). Both techniques record eye movements following different stimuli such as staring at a light, moving the head to different positions, and stimulating the inner ear and nearby tissue, usually by cold or warm water (or air). The information can then be analyzed by a computer and this can determine if there is a disturbance in the normal functioning of the inner ear balance. | Diagnosis of Benign Paroxysmal Positional Vertigo. A diagnosis of BPPV is based upon identification of characteristic symptoms, a detailed patient history and a thorough clinical evaluation. Affected individuals usually have a history of episodes of vertigo.Clinical Testing and Work-Up
Affected individuals will undergo a Dix-Hallpike test. During this test, an affected individual sits down, with legs extended, on an examination table. The doctor will rotate the head approximately 30 to 45 degrees and then help the person quickly lie on his or her back (supine position). In individuals with BPPV, this will prompt a characteristic episode of nystagmus and/or vertigo. The timing and appearance of the eye movements will help a physician determine the cause of vertigo. The Dix-Hallpike test can differentiate vertigo caused by a problem in the brain from vertigo caused by a problem in the inner ear. The specific pattern of nystagmus will tell a physician which of the three semicircular canals of the inner ear is involved in an individual case.When the diagnosis is in doubt, affected individuals may undergo a test such as magnetic resonance imaging (MRI) to rule out other conditions. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues such as in the brain or ear.In some cases, a physician may use a test called a videonystagmography (VNG) or videonystagmography (VNG), which records the voluntary and involuntary movements of the eyes. During this exam, electrodes are placed around the eyes (ENG) or goggles with cameras are placed over the eyes (VNG). Both techniques record eye movements following different stimuli such as staring at a light, moving the head to different positions, and stimulating the inner ear and nearby tissue, usually by cold or warm water (or air). The information can then be analyzed by a computer and this can determine if there is a disturbance in the normal functioning of the inner ear balance. | 153 | Benign Paroxysmal Positional Vertigo |
nord_153_6 | Therapies of Benign Paroxysmal Positional Vertigo | Treatment
Individuals with BPPV may be treated with canalith repositioning maneuvers, in which the head is put through a series of specific movements designed to shift the crystals (otoliths) out of the semicircular canals and back into the vestibule. Once the crystals are back in the vestibule, they are usually reabsorbed in a matter of days. The maneuvers may need to be repeated. Different maneuvers are required depending upon which of the three semicircular canals is involved. Canalith repositioning maneuvers are often highly effective in treating BPPV, although the condition can recur often within one year. Canalith repositioning maneuvers are initially performed at a physician’s office, but affected individuals may be taught the maneuvers in to order to perform them at home. During therapy, crystals may occasionally move from one semicircular canal to another, which is referred to as canal switch.The Epley maneuver is a common canalith repositioning maneuver. The Epley maneuver is a five position cycle that is repeated until no signs of nystagmus are observed. Patients are placed in a sitting position on an examination table with their head turned 45 degrees toward the affected ear. Patients are then tilted back onto the table with their head hanging off the end. The head is then slowly rotated toward the unaffected ear. Patients are then rolled onto their side and the head is rotated back toward the affected ear. The patient is then brought back to a sitting position. Canalith repositioning maneuvers like the Epley maneuver are relatively simple, noninvasive and effective therapy for individuals with BPPV. Treatment for right sided typical BPPV can be viewed on YouTube at: http://www.youtube.com/watch?v=ZqokxZRbJfw . Other canal repositioning maneuvers used to treat individuals with BPPV include the Semont liberatory maneuver and for the less common horizontal canal variant of BPPV, the Lempert or Gufoni maneuver. These maneuvers may have slight variations as well and some of these treatments may be viewed on YouTube at: http://www.youtube.com/watch?v=hq-IQWSrAtM.Some affected individuals may be referred for vestibular rehabilitation therapy (VRT). VRT is the use of specific exercises that are designed to compensate for inner ear deficiencies. While this technique may coincidentally improve BPPV, it is really intended to promote adaptation by the brain to loss of balance function related to inner ear on one side. A physical or occupational therapist will develop a treatment plan tailored to an individual based upon a thorough examination. Basically, affected individuals will perform a series of exercises or postures that over time will lessen their symptoms. Initially, the exercises may temporarily worsen symptoms. However, if affected individuals persist with their instructions, VRT often leads to a decrease in symptom severity or complete disappearance of symptoms. In some cases, no other therapy is necessary.Some individuals with BPPV may opt for watchful waiting, meaning not treating the condition and waiting for symptoms to spontaneously resolve. This is the best option for those with recent cervical spine fractures that must remain immobilized while healing, for example. For most people, however, there seems little point in waiting to be treated since treatment is so quick and easy. Furthermore, symptom resolution can take weeks or months in some individuals.Some affected individuals may receive vestibular suppressant medications (e.g., meclizine or diazepam) that may help relieve certain symptoms of BPPV such as the spinning sensation or nausea. However, drug therapy for BPPV itself is generally ineffective and usually not recommended because canalith repositioning maneuvers are so effective.In rare cases, individuals with BPPV may be treated with surgery. The frequency of surgery as a treatment for BPPV has dropped in recent years. Surgery for BPPV is reserved for individuals who fail to respond to less invasive treatment options and for whom symptoms are recurrent and problematic (intractable BPPV). The most common procedure used is plugging (occluding) the posterior semicircular canal in order to prevent crystals from causing deflection and stimulation of the cupula. Canal plugging is used more often in the rare cases that require surgical intervention. Surgical therapy is not considered for BPPV except as a last resort. | Therapies of Benign Paroxysmal Positional Vertigo. Treatment
Individuals with BPPV may be treated with canalith repositioning maneuvers, in which the head is put through a series of specific movements designed to shift the crystals (otoliths) out of the semicircular canals and back into the vestibule. Once the crystals are back in the vestibule, they are usually reabsorbed in a matter of days. The maneuvers may need to be repeated. Different maneuvers are required depending upon which of the three semicircular canals is involved. Canalith repositioning maneuvers are often highly effective in treating BPPV, although the condition can recur often within one year. Canalith repositioning maneuvers are initially performed at a physician’s office, but affected individuals may be taught the maneuvers in to order to perform them at home. During therapy, crystals may occasionally move from one semicircular canal to another, which is referred to as canal switch.The Epley maneuver is a common canalith repositioning maneuver. The Epley maneuver is a five position cycle that is repeated until no signs of nystagmus are observed. Patients are placed in a sitting position on an examination table with their head turned 45 degrees toward the affected ear. Patients are then tilted back onto the table with their head hanging off the end. The head is then slowly rotated toward the unaffected ear. Patients are then rolled onto their side and the head is rotated back toward the affected ear. The patient is then brought back to a sitting position. Canalith repositioning maneuvers like the Epley maneuver are relatively simple, noninvasive and effective therapy for individuals with BPPV. Treatment for right sided typical BPPV can be viewed on YouTube at: http://www.youtube.com/watch?v=ZqokxZRbJfw . Other canal repositioning maneuvers used to treat individuals with BPPV include the Semont liberatory maneuver and for the less common horizontal canal variant of BPPV, the Lempert or Gufoni maneuver. These maneuvers may have slight variations as well and some of these treatments may be viewed on YouTube at: http://www.youtube.com/watch?v=hq-IQWSrAtM.Some affected individuals may be referred for vestibular rehabilitation therapy (VRT). VRT is the use of specific exercises that are designed to compensate for inner ear deficiencies. While this technique may coincidentally improve BPPV, it is really intended to promote adaptation by the brain to loss of balance function related to inner ear on one side. A physical or occupational therapist will develop a treatment plan tailored to an individual based upon a thorough examination. Basically, affected individuals will perform a series of exercises or postures that over time will lessen their symptoms. Initially, the exercises may temporarily worsen symptoms. However, if affected individuals persist with their instructions, VRT often leads to a decrease in symptom severity or complete disappearance of symptoms. In some cases, no other therapy is necessary.Some individuals with BPPV may opt for watchful waiting, meaning not treating the condition and waiting for symptoms to spontaneously resolve. This is the best option for those with recent cervical spine fractures that must remain immobilized while healing, for example. For most people, however, there seems little point in waiting to be treated since treatment is so quick and easy. Furthermore, symptom resolution can take weeks or months in some individuals.Some affected individuals may receive vestibular suppressant medications (e.g., meclizine or diazepam) that may help relieve certain symptoms of BPPV such as the spinning sensation or nausea. However, drug therapy for BPPV itself is generally ineffective and usually not recommended because canalith repositioning maneuvers are so effective.In rare cases, individuals with BPPV may be treated with surgery. The frequency of surgery as a treatment for BPPV has dropped in recent years. Surgery for BPPV is reserved for individuals who fail to respond to less invasive treatment options and for whom symptoms are recurrent and problematic (intractable BPPV). The most common procedure used is plugging (occluding) the posterior semicircular canal in order to prevent crystals from causing deflection and stimulation of the cupula. Canal plugging is used more often in the rare cases that require surgical intervention. Surgical therapy is not considered for BPPV except as a last resort. | 153 | Benign Paroxysmal Positional Vertigo |
nord_154_0 | Overview of Bernard-Soulier Syndrome | Bernard-Soulier syndrome (BSS) is a rare inherited disorder of blood clotting (coagulation) characterized by unusually large platelets, low platelet count (thrombocytopenia) and prolonged bleeding time (difficulty in clotting). Affected individuals tend to bleed excessively and bruise easily. Most cases of Bernard-Soulier syndrome are inherited in an autosomal recessive genetic pattern. | Overview of Bernard-Soulier Syndrome. Bernard-Soulier syndrome (BSS) is a rare inherited disorder of blood clotting (coagulation) characterized by unusually large platelets, low platelet count (thrombocytopenia) and prolonged bleeding time (difficulty in clotting). Affected individuals tend to bleed excessively and bruise easily. Most cases of Bernard-Soulier syndrome are inherited in an autosomal recessive genetic pattern. | 154 | Bernard-Soulier Syndrome |
nord_154_1 | Symptoms of Bernard-Soulier Syndrome | The symptoms of Bernard-Soulier syndrome, which are typically apparent at birth and continue throughout life, may include the tendency to bleed excessively from cuts and other injuries, nosebleeds (epistaxis), and/or an unusually heavy menstrual flow in women. Some babies and children with BSS have no symptoms and the disorder does not present until adult life. People with this disease also bruise easily and the bruises tend to linger. Bleeding from very small blood vessels under the skin (subcutaneous) may cause small or widespread areas of small red or purple colored spots (purpura or petechiae). | Symptoms of Bernard-Soulier Syndrome. The symptoms of Bernard-Soulier syndrome, which are typically apparent at birth and continue throughout life, may include the tendency to bleed excessively from cuts and other injuries, nosebleeds (epistaxis), and/or an unusually heavy menstrual flow in women. Some babies and children with BSS have no symptoms and the disorder does not present until adult life. People with this disease also bruise easily and the bruises tend to linger. Bleeding from very small blood vessels under the skin (subcutaneous) may cause small or widespread areas of small red or purple colored spots (purpura or petechiae). | 154 | Bernard-Soulier Syndrome |
nord_154_2 | Causes of Bernard-Soulier Syndrome | BSS is a genetic disorder that affects the ability of the platelets in the circulating blood to bind with a damaged blood vessel and hence to clot blood. These platelets are missing an essential protein called the glycoprotein Ib-IX-V complex (GPIb). The Gp1b complex is composed of 4 protein subunits that bind closely together (GP1b-alpha, GP1b-beta, GP9 and GP5). BSS is caused by mutations in one of the Gp1b complex genes- so far mutations have been found in BP1b-alpha, Gp1b-beta and GP9 but no mutations have been found in GP5. Normally the GP1b complex sticks out of the platelet’s surface and binds with another protein found in the circulating blood called von Willebrand factor. If one of these proteins is missing or abnormal, they cannot bind correctly to begin the clotting process and excessive bleeding results.Bernard-Soulier syndrome is usually inherited in an autosomal recessive genetic pattern. Recessive genetic disorders occur when an individual inherits an abnormal gene from each parent. If an individual receives one normal gene and one abnormal gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the abnormal gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. | Causes of Bernard-Soulier Syndrome. BSS is a genetic disorder that affects the ability of the platelets in the circulating blood to bind with a damaged blood vessel and hence to clot blood. These platelets are missing an essential protein called the glycoprotein Ib-IX-V complex (GPIb). The Gp1b complex is composed of 4 protein subunits that bind closely together (GP1b-alpha, GP1b-beta, GP9 and GP5). BSS is caused by mutations in one of the Gp1b complex genes- so far mutations have been found in BP1b-alpha, Gp1b-beta and GP9 but no mutations have been found in GP5. Normally the GP1b complex sticks out of the platelet’s surface and binds with another protein found in the circulating blood called von Willebrand factor. If one of these proteins is missing or abnormal, they cannot bind correctly to begin the clotting process and excessive bleeding results.Bernard-Soulier syndrome is usually inherited in an autosomal recessive genetic pattern. Recessive genetic disorders occur when an individual inherits an abnormal gene from each parent. If an individual receives one normal gene and one abnormal gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the abnormal gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. | 154 | Bernard-Soulier Syndrome |
nord_154_3 | Affects of Bernard-Soulier Syndrome | Bernard-Soulier syndrome is a rare bleeding disorder that affects males and females in equal numbers. Recent estimates suggest that Bernard Soulier syndrome affects 1 in a million people. More than 200 cases have been reported worldwide. | Affects of Bernard-Soulier Syndrome. Bernard-Soulier syndrome is a rare bleeding disorder that affects males and females in equal numbers. Recent estimates suggest that Bernard Soulier syndrome affects 1 in a million people. More than 200 cases have been reported worldwide. | 154 | Bernard-Soulier Syndrome |
nord_154_4 | Related disorders of Bernard-Soulier Syndrome | Symptoms of the following disorders can be similar to those of Bernard-Soulier syndrome. Comparisons may be useful for a differential diagnosis:May-Hegglin anomaly is a rare inherited disorder of blood platelets and certain white blood cells characterized by abnormally large platelets. Some people with this disorder have symptoms from birth while others are without symptoms for life. Symptoms may include nosebleeds, purple colored spots on the skin (purpura), excessive bleeding from the mouth during dental work, and/or headaches. Some people with May-Hegglin anomaly may experience muscular weakness on one side of the body because of abnormal bleeding inside the brain (intracranial hemorrhage). (For more information on this disorder, choose “May Hegglin” as your search term in the Rare Disease Database.) May Hegglin does not usually cause bleeding in newborn babies unlike BSS.Hemophilia is a rare inherited blood clotting (coagulation) disorder caused by inactive or deficient blood proteins (usually factor VIII). Factor VIII is one of several proteins that facilitate blood clotting. Hemophilia is found in males almost exclusively and can be classified as mild, moderate, or severe depending upon the percentage of clotting factor present in a person’s blood. The most serious symptom of hemophilia is uncontrolled internal bleeding that may begin spontaneously without any apparent cause. Internal bleeding may cause permanent damage to the joints and muscles. People with hemophilia bleed for a longer period of time than people who have the normal percentage of active clotting factors in their blood. Bruises and trauma can trigger episodes of serious internal bleeding in males with this disorder. (For more information on this disorder, choose “Hemophilia” as your search term in the Rare Disease Database.)Thrombasthenia of Glanzmann and Naegeli is a rare inherited blood clotting (coagulation) disorder characterized by impaired function of the specialized red blood cells (platelets) that are essential for proper blood clotting. Symptoms may include abnormal bleeding, and/or hemorrhage, easy bruising, bleeding from the gums, nosebleeds (epistaxis), and/or large red or purple colored spots on the skin (purpura). The symptoms of Thrombasthenia of Glanzmann and Naegeli are not progressive and may improve with age. (For more information on this disorder, choose “Thrombasthenia” as your search term in the Rare Disease Database.)Von Willebrand disease is a rare inherited blood clotting (coagulation) disorder that varies widely in its effects. Most people have relatively mild diseaseand are not diagnosed until they are adults. A small number start to have problems during infancy or early childhood, such as prolonged bleeding and an abnormally slow blood clotting time. Symptoms may include bleeding from the gastrointestinal tract, nosebleeds, bleeding from the gums, and/or easy bruising. People with this disorder may also bleed easily after injury, childbirth, and/or surgery. These symptoms occur because of a deficiency of factor VIII and the von Willebrand factor. (For more information on this disorder, choose “von Willebrand” as your search term in the Rare Disease Database.)Storage pool disease (SPD) is a rare inherited disorder of blood platelets characterized by clotting dysfunction due to the platelets’ inability to store certain clotting factors. Symptoms occur mostly in women and may include mild bleeding, nosebleeds, and/or slightly heavier than normal menstrual periods. People with Storage pool disease may also have abnormally low levels of blood platelets (thrombocytopenia).Platelet disorders are also associated with congenital conditions such as Wiskott-Aldrich syndrome, Down syndrome, and thrombocytopenia with absent radius syndrome. For more information on these disorders choose “Wiskott- Aldrich,” “Down Syndrome,” and “Thrombocytopenia with Absent Radius,” as your search terms in the Rare Disease Database.) | Related disorders of Bernard-Soulier Syndrome. Symptoms of the following disorders can be similar to those of Bernard-Soulier syndrome. Comparisons may be useful for a differential diagnosis:May-Hegglin anomaly is a rare inherited disorder of blood platelets and certain white blood cells characterized by abnormally large platelets. Some people with this disorder have symptoms from birth while others are without symptoms for life. Symptoms may include nosebleeds, purple colored spots on the skin (purpura), excessive bleeding from the mouth during dental work, and/or headaches. Some people with May-Hegglin anomaly may experience muscular weakness on one side of the body because of abnormal bleeding inside the brain (intracranial hemorrhage). (For more information on this disorder, choose “May Hegglin” as your search term in the Rare Disease Database.) May Hegglin does not usually cause bleeding in newborn babies unlike BSS.Hemophilia is a rare inherited blood clotting (coagulation) disorder caused by inactive or deficient blood proteins (usually factor VIII). Factor VIII is one of several proteins that facilitate blood clotting. Hemophilia is found in males almost exclusively and can be classified as mild, moderate, or severe depending upon the percentage of clotting factor present in a person’s blood. The most serious symptom of hemophilia is uncontrolled internal bleeding that may begin spontaneously without any apparent cause. Internal bleeding may cause permanent damage to the joints and muscles. People with hemophilia bleed for a longer period of time than people who have the normal percentage of active clotting factors in their blood. Bruises and trauma can trigger episodes of serious internal bleeding in males with this disorder. (For more information on this disorder, choose “Hemophilia” as your search term in the Rare Disease Database.)Thrombasthenia of Glanzmann and Naegeli is a rare inherited blood clotting (coagulation) disorder characterized by impaired function of the specialized red blood cells (platelets) that are essential for proper blood clotting. Symptoms may include abnormal bleeding, and/or hemorrhage, easy bruising, bleeding from the gums, nosebleeds (epistaxis), and/or large red or purple colored spots on the skin (purpura). The symptoms of Thrombasthenia of Glanzmann and Naegeli are not progressive and may improve with age. (For more information on this disorder, choose “Thrombasthenia” as your search term in the Rare Disease Database.)Von Willebrand disease is a rare inherited blood clotting (coagulation) disorder that varies widely in its effects. Most people have relatively mild diseaseand are not diagnosed until they are adults. A small number start to have problems during infancy or early childhood, such as prolonged bleeding and an abnormally slow blood clotting time. Symptoms may include bleeding from the gastrointestinal tract, nosebleeds, bleeding from the gums, and/or easy bruising. People with this disorder may also bleed easily after injury, childbirth, and/or surgery. These symptoms occur because of a deficiency of factor VIII and the von Willebrand factor. (For more information on this disorder, choose “von Willebrand” as your search term in the Rare Disease Database.)Storage pool disease (SPD) is a rare inherited disorder of blood platelets characterized by clotting dysfunction due to the platelets’ inability to store certain clotting factors. Symptoms occur mostly in women and may include mild bleeding, nosebleeds, and/or slightly heavier than normal menstrual periods. People with Storage pool disease may also have abnormally low levels of blood platelets (thrombocytopenia).Platelet disorders are also associated with congenital conditions such as Wiskott-Aldrich syndrome, Down syndrome, and thrombocytopenia with absent radius syndrome. For more information on these disorders choose “Wiskott- Aldrich,” “Down Syndrome,” and “Thrombocytopenia with Absent Radius,” as your search terms in the Rare Disease Database.) | 154 | Bernard-Soulier Syndrome |
nord_154_5 | Diagnosis of Bernard-Soulier Syndrome | The diagnosis of Bernard-Soulier syndrome is made by a combination of blood testing to reveal whether platelets are at abnormally low levels (thrombocytopenia), microscopic examination to determine the presence of abnormally large platelets and irregularly shaped platelets, and a test called ‘flow cytometry, which is able to measure the level of expression of the missing protein ion the outside of platelets affected by Bernard-Soulier syndrome. In recent years, most families are offered molecular genetic testing to identify which gene carries the mutations. | Diagnosis of Bernard-Soulier Syndrome. The diagnosis of Bernard-Soulier syndrome is made by a combination of blood testing to reveal whether platelets are at abnormally low levels (thrombocytopenia), microscopic examination to determine the presence of abnormally large platelets and irregularly shaped platelets, and a test called ‘flow cytometry, which is able to measure the level of expression of the missing protein ion the outside of platelets affected by Bernard-Soulier syndrome. In recent years, most families are offered molecular genetic testing to identify which gene carries the mutations. | 154 | Bernard-Soulier Syndrome |
nord_154_6 | Therapies of Bernard-Soulier Syndrome | Treatment
Platelet transfusion is used to treat Bernard-Soulier syndrome when surgery is necessary or when there is a risk for life-threatening hemorrhage. Some patients with Bernard-Soulier syndrome become resistant (refractory) to platelet transfusions because they develop antibodies against the GPIb protein- to reduce this risk it is now recommended that specially selected platelet transfusions (from HLA-matched single donors) should be used. Where HLA-matched platelets are not available, leucocyte-depleted platelets can be used (these are platelet transfusions from which contaminating white blood cells-leucocytes- have been removed). People with this disorder should not take aspirin or other related drugs because these medications affect the blood’s ability to clot (platelet aggregation). It is suggested that acetaminophen, which is present in medications such as Tylenol, is used for the relief of mild pain. Antifibrinolytic agents (drugs which delay the breakdown of blood clots) are often useful to help reduce bleeding after minor surgery (eg dental surgery) or for prolonged nosebleeds. The most commonly used antifibrinolytic drug is tranexamic acid (also known as epsilon aminocaproic acid).Genetic counseling is recommended for people with Bernard-Soulier syndrome and their families. Other treatment is symptomatic and supportive. | Therapies of Bernard-Soulier Syndrome. Treatment
Platelet transfusion is used to treat Bernard-Soulier syndrome when surgery is necessary or when there is a risk for life-threatening hemorrhage. Some patients with Bernard-Soulier syndrome become resistant (refractory) to platelet transfusions because they develop antibodies against the GPIb protein- to reduce this risk it is now recommended that specially selected platelet transfusions (from HLA-matched single donors) should be used. Where HLA-matched platelets are not available, leucocyte-depleted platelets can be used (these are platelet transfusions from which contaminating white blood cells-leucocytes- have been removed). People with this disorder should not take aspirin or other related drugs because these medications affect the blood’s ability to clot (platelet aggregation). It is suggested that acetaminophen, which is present in medications such as Tylenol, is used for the relief of mild pain. Antifibrinolytic agents (drugs which delay the breakdown of blood clots) are often useful to help reduce bleeding after minor surgery (eg dental surgery) or for prolonged nosebleeds. The most commonly used antifibrinolytic drug is tranexamic acid (also known as epsilon aminocaproic acid).Genetic counseling is recommended for people with Bernard-Soulier syndrome and their families. Other treatment is symptomatic and supportive. | 154 | Bernard-Soulier Syndrome |
nord_155_0 | Overview of Berylliosis | Berylliosis is a form of metal poisoning caused by inhalation of beryllium dusts, vapors, or its compounds or implantation of the substance in the skin. The toxic effects of beryllium most commonly occur due to occupational exposure. Beryllium is a metallic element used in many industries, including electronics, high-technology ceramics, metals extraction, and dental alloy preparation.There are two forms of beryllium-induced lung disease, acute and chronic. Acute berylliosis has a sudden, rapid onset and is characterized by severe inflammation of the lungs (pneumonitis), coughing, increasing breathlessness (dyspnea), and other associated symptoms and findings. In addition, in some individuals, the skin or the eyes may be affected. The more common, chronic form of the disease develops more slowly and, in some cases, may not become apparent for many years after initial beryllium exposure. Chronic berylliosis is characterized by the abnormal formation of inflammatory masses or nodules (granulomas) within certain tissues and organs and widespread scarring and thickening of deep lung tissues (interstitial pulmonary fibrosis). Although granuloma development primarily affects the lungs, it may also occur within other bodily tissues and organs, such as the skin and underlying (subcutaneous) tissues or the liver. In individuals with chronic berylliosis, associated symptoms and findings often include dry coughing, fatigue, weight loss, chest pain, and increasing shortness of breath. | Overview of Berylliosis. Berylliosis is a form of metal poisoning caused by inhalation of beryllium dusts, vapors, or its compounds or implantation of the substance in the skin. The toxic effects of beryllium most commonly occur due to occupational exposure. Beryllium is a metallic element used in many industries, including electronics, high-technology ceramics, metals extraction, and dental alloy preparation.There are two forms of beryllium-induced lung disease, acute and chronic. Acute berylliosis has a sudden, rapid onset and is characterized by severe inflammation of the lungs (pneumonitis), coughing, increasing breathlessness (dyspnea), and other associated symptoms and findings. In addition, in some individuals, the skin or the eyes may be affected. The more common, chronic form of the disease develops more slowly and, in some cases, may not become apparent for many years after initial beryllium exposure. Chronic berylliosis is characterized by the abnormal formation of inflammatory masses or nodules (granulomas) within certain tissues and organs and widespread scarring and thickening of deep lung tissues (interstitial pulmonary fibrosis). Although granuloma development primarily affects the lungs, it may also occur within other bodily tissues and organs, such as the skin and underlying (subcutaneous) tissues or the liver. In individuals with chronic berylliosis, associated symptoms and findings often include dry coughing, fatigue, weight loss, chest pain, and increasing shortness of breath. | 155 | Berylliosis |
nord_155_1 | Symptoms of Berylliosis | Acute berylliosis is a rare condition that develops suddenly due to exposure to beryllium. The condition is primarily characterized by severe inflammation of the lungs (pneumonitis). Associated symptoms typically include an abrupt onset of coughing, and difficulties breathing (dyspnea). Some affected individuals may also develop a sore throat (pharyngitis); inflammation of the mucous membranes of the nose (rhinitis) and associated nasal discharge; and inflammation of the windpipe and air passages of the lungs (tracheobronchitis). In addition, in some cases, other areas of the body may be affected, such as the skin or eyes. Although most individuals with acute berylliosis have a complete recovery with no residual effects, potentially life-threatening complications may result without prompt, appropriate treatment. The severity of the condition may depend upon the duration of beryllium exposure, the concentration of the irritant, and/or other factors.Chronic berylliosis is a systemic disease in which there is an abnormally exaggerated immune response (hypersensitivity) to beryllium. The onset of symptoms after initial beryllium exposure may be extremely variable, ranging from a few months to years or even decades. In those with chronic berylliosis, abnormal inflammatory nodules (granulomas) form in the lungs and, in some cases, within other bodily tissues. These may include the lymph nodes, liver, skin and underlying (subcutaneous) tissues, and/or other organs and tissues. Chronic berylliosis is also characterized by widespread scarring and thickening of deep lung tissues (interstitial pulmonary fibrosis). Symptoms and findings associated with the disorder may include dry coughing; increasing shortness of breath (dyspnea); chest pain; fatigue; fever; night sweats; lack of appetite (anorexia); weight loss; and enlargement of lymph nodes. Some may also develop reddened patches or small raised spots on the skin. As the disease progresses, affected individuals may have increasingly severe lung damage, resulting in labored breathing with the slightest exertion; liver damage; and potentially life-threatening complications. | Symptoms of Berylliosis. Acute berylliosis is a rare condition that develops suddenly due to exposure to beryllium. The condition is primarily characterized by severe inflammation of the lungs (pneumonitis). Associated symptoms typically include an abrupt onset of coughing, and difficulties breathing (dyspnea). Some affected individuals may also develop a sore throat (pharyngitis); inflammation of the mucous membranes of the nose (rhinitis) and associated nasal discharge; and inflammation of the windpipe and air passages of the lungs (tracheobronchitis). In addition, in some cases, other areas of the body may be affected, such as the skin or eyes. Although most individuals with acute berylliosis have a complete recovery with no residual effects, potentially life-threatening complications may result without prompt, appropriate treatment. The severity of the condition may depend upon the duration of beryllium exposure, the concentration of the irritant, and/or other factors.Chronic berylliosis is a systemic disease in which there is an abnormally exaggerated immune response (hypersensitivity) to beryllium. The onset of symptoms after initial beryllium exposure may be extremely variable, ranging from a few months to years or even decades. In those with chronic berylliosis, abnormal inflammatory nodules (granulomas) form in the lungs and, in some cases, within other bodily tissues. These may include the lymph nodes, liver, skin and underlying (subcutaneous) tissues, and/or other organs and tissues. Chronic berylliosis is also characterized by widespread scarring and thickening of deep lung tissues (interstitial pulmonary fibrosis). Symptoms and findings associated with the disorder may include dry coughing; increasing shortness of breath (dyspnea); chest pain; fatigue; fever; night sweats; lack of appetite (anorexia); weight loss; and enlargement of lymph nodes. Some may also develop reddened patches or small raised spots on the skin. As the disease progresses, affected individuals may have increasingly severe lung damage, resulting in labored breathing with the slightest exertion; liver damage; and potentially life-threatening complications. | 155 | Berylliosis |
nord_155_2 | Causes of Berylliosis | Berylliosis is caused by inhalation of beryllium dusts, fumes, or its compounds or entrance of the substance through the skin. Beryllium is a natural metallic chemical element that forms strong, lightweight alloys with various metals. (Alloys are formed by the fusion of two or more metals.) Due to such properties, beryllium has numerous industrial uses including aerospace, electronic, and nuclear components; high-technology ceramics; and dental alloys. In addition, prior to the 1950s, beryllium was often used in the manufacture of fluorescent lights. The risk of beryllium exposure occurs in any setting in which beryllium or its compounds may become airborne in the form of vapors, fumes, small particles, or dust.Chronic berylliosis, also known as chronic beryllium disease (CBD), is a progressive, systemic disease caused by an abnormally exaggerated immune response (delayed-type hypersensitivity reaction) in individuals who have become “sensitized” or allergic to beryllium (sensitizing antigen). (The immune system is responsible for defending the body against foreign agents, such as toxins and invading microorganisms, including bacteria and viruses.) Sensitization to beryllium may develop rapidly or several years after initial beryllium exposure, resulting in an increased risk of chronic berylliosis.In those who develop CBD, inappropriately heightened immune reactions result in an abnormal activation of certain white blood cells (macrophages and lymphocytes). The function of macrophages is to surround and destroy foreign particles (phagocytosis). Lymphocyte proliferation in affected tissues results in the formation of the inflammatory masses or nodules (granulomas) characteristically associated with CBD. The granulomas that are formed due to these processes may affect the normal structure and functioning of affected organ(s). For example, granulomas may develop around beryllium particles that are present in the walls of tiny air sacs within the lungs (alveoli), resulting in or contributing to increasing difficulties breathing. (The alveoli contain minute blood vessels [capillaries] that enable the absorption of oxygen into the blood.)According to reports in the medical literature, a relatively small percentage of employees exposed to beryllium (i.e., one to six percent) ultimately develop CBD. Researchers suggest that specific genetic variations may be associated with sensitization to beryllium and increased suspectibility to CBD. For example, in all individuals, certain genetic variations (i.e., of the major histocompatibility complex [MHC]) result in the production of specific “human leukocyte antigens” or HLAs. HLAs are proteins that stimulate the production of certain antibodies in response to foreign agents. Because the specific structures of HLAs are partially genetically determined, they may take a variety of forms. The results of genetic analysis demonstrate that most individuals with CBD have specific variations (alleles) of one of the major histocompatibility genes (HLA-DPB1 gene alleles with glutamate 69 marker). Researchers suggest that such genetic variations may result in increased susceptibility to CBD in beryllium-exposed individuals. | Causes of Berylliosis. Berylliosis is caused by inhalation of beryllium dusts, fumes, or its compounds or entrance of the substance through the skin. Beryllium is a natural metallic chemical element that forms strong, lightweight alloys with various metals. (Alloys are formed by the fusion of two or more metals.) Due to such properties, beryllium has numerous industrial uses including aerospace, electronic, and nuclear components; high-technology ceramics; and dental alloys. In addition, prior to the 1950s, beryllium was often used in the manufacture of fluorescent lights. The risk of beryllium exposure occurs in any setting in which beryllium or its compounds may become airborne in the form of vapors, fumes, small particles, or dust.Chronic berylliosis, also known as chronic beryllium disease (CBD), is a progressive, systemic disease caused by an abnormally exaggerated immune response (delayed-type hypersensitivity reaction) in individuals who have become “sensitized” or allergic to beryllium (sensitizing antigen). (The immune system is responsible for defending the body against foreign agents, such as toxins and invading microorganisms, including bacteria and viruses.) Sensitization to beryllium may develop rapidly or several years after initial beryllium exposure, resulting in an increased risk of chronic berylliosis.In those who develop CBD, inappropriately heightened immune reactions result in an abnormal activation of certain white blood cells (macrophages and lymphocytes). The function of macrophages is to surround and destroy foreign particles (phagocytosis). Lymphocyte proliferation in affected tissues results in the formation of the inflammatory masses or nodules (granulomas) characteristically associated with CBD. The granulomas that are formed due to these processes may affect the normal structure and functioning of affected organ(s). For example, granulomas may develop around beryllium particles that are present in the walls of tiny air sacs within the lungs (alveoli), resulting in or contributing to increasing difficulties breathing. (The alveoli contain minute blood vessels [capillaries] that enable the absorption of oxygen into the blood.)According to reports in the medical literature, a relatively small percentage of employees exposed to beryllium (i.e., one to six percent) ultimately develop CBD. Researchers suggest that specific genetic variations may be associated with sensitization to beryllium and increased suspectibility to CBD. For example, in all individuals, certain genetic variations (i.e., of the major histocompatibility complex [MHC]) result in the production of specific “human leukocyte antigens” or HLAs. HLAs are proteins that stimulate the production of certain antibodies in response to foreign agents. Because the specific structures of HLAs are partially genetically determined, they may take a variety of forms. The results of genetic analysis demonstrate that most individuals with CBD have specific variations (alleles) of one of the major histocompatibility genes (HLA-DPB1 gene alleles with glutamate 69 marker). Researchers suggest that such genetic variations may result in increased susceptibility to CBD in beryllium-exposed individuals. | 155 | Berylliosis |
nord_155_3 | Affects of Berylliosis | The toxic effects of beryllium most commonly affect individuals who work in occupational settings in which beryllium or its components may become airborne. As discussed above, beryllium is used in numerous industries, including electronics, high-technology ceramics, dental alloy preparation, and metals extraction.According to reports in the medical literature, the incidence of acute berylliosis is now rare due to the introduction of protective measures designed to reduce occupational exposure to beryllium. However, chronic beryllium disease (CBD) continues to occur at about the same rate as when the condition was originally reported in the 1940s. Approximately one to six percent of beryllium-exposed employees develop CBD. In addition, there is increasing evidence that even limited exposure to low concentrations of beryllium may lead to CBD in some individuals with increased susceptibility. For example, research indicates that some employees who work outside of beryllium work zones, such as clerical staff, have developed CBD. There have also been reports of the disorder in family members who were exposed to beryllium dust from an employee's clothing and in individuals who reside in the vicinity of beryllium refineries. | Affects of Berylliosis. The toxic effects of beryllium most commonly affect individuals who work in occupational settings in which beryllium or its components may become airborne. As discussed above, beryllium is used in numerous industries, including electronics, high-technology ceramics, dental alloy preparation, and metals extraction.According to reports in the medical literature, the incidence of acute berylliosis is now rare due to the introduction of protective measures designed to reduce occupational exposure to beryllium. However, chronic beryllium disease (CBD) continues to occur at about the same rate as when the condition was originally reported in the 1940s. Approximately one to six percent of beryllium-exposed employees develop CBD. In addition, there is increasing evidence that even limited exposure to low concentrations of beryllium may lead to CBD in some individuals with increased susceptibility. For example, research indicates that some employees who work outside of beryllium work zones, such as clerical staff, have developed CBD. There have also been reports of the disorder in family members who were exposed to beryllium dust from an employee's clothing and in individuals who reside in the vicinity of beryllium refineries. | 155 | Berylliosis |
nord_155_4 | Related disorders of Berylliosis | Symptoms of the following disorders may be similar to those of berylliosis. Comparisons may be useful for a differential diagnosis:Sarcoidosis is a multisystem disorder characterized by the abnormal formation of inflammatory masses or nodules (granulomas) consisting of granular white blood cells in certain organs of the body. The granulomas that are formed are thought to affect the normal structure of and, potentially, the normal functioning of the affected organs, causing symptoms associated with the particular body systems in question. In individuals with sarcoidosis, such granuloma formation most commonly affects the lungs. However, in many cases, the upper respiratory system, lymph nodes, skin, or eyes may also be involved. In addition, in some individuals, other organs may be affected, including the liver, bone marrow, spleen, musculoskeletal system, heart, salivary glands, or nervous system (i.e., central or peripheral nervous system). The range and severity of symptoms associated with sarcoidosis vary greatly, depending upon the specific organs involved and the degree of such involvement. In some cases, the symptoms of sarcoidosis may begin suddenly (acute), sometimes severely, and subside in a relatively short period (self limited). Acute sarcoidosis is often characterized by fatigue, fever, generalized muscle aches, difficulty breathing (dyspnea), joint pain, swollen glands, skin eruptions, eye irregularities, or other symptoms. In the subacute form, affected individuals may experience no symptoms (asymptomatic), even with organ involvement. In chronic sarcoidosis, symptoms may appear slowly and subtly and may persist or recur over a long period. Initial symptoms of chronic sarcoidosis may include difficulty breathing, dry cough, limited airflow, and other respiratory abnormalities. Symptoms associated with other organ involvement may follow. The exact cause of sarcoidosis is unknown. However, possible infectious, environmental, genetic, and immunological factors are under investigation as potential causes of the disorder. (For more information, choose “sarcoidosis” as your search term in the Rare Disease Database.)In some cases, exposure to other hard metals, such as chromium, titanium dioxide, or cobalt, may result in symptoms and findings that may be similar to those associated with berylliosis. For example, such exposure may result in chronic inflammation of the lungs (pneumonitis) in association with widespread scarring and thickening of deep lung tissues (interstitial pulmonary fibrosis). Associated symptoms may include coughing, chest pain, and increasing difficulties breathing. | Related disorders of Berylliosis. Symptoms of the following disorders may be similar to those of berylliosis. Comparisons may be useful for a differential diagnosis:Sarcoidosis is a multisystem disorder characterized by the abnormal formation of inflammatory masses or nodules (granulomas) consisting of granular white blood cells in certain organs of the body. The granulomas that are formed are thought to affect the normal structure of and, potentially, the normal functioning of the affected organs, causing symptoms associated with the particular body systems in question. In individuals with sarcoidosis, such granuloma formation most commonly affects the lungs. However, in many cases, the upper respiratory system, lymph nodes, skin, or eyes may also be involved. In addition, in some individuals, other organs may be affected, including the liver, bone marrow, spleen, musculoskeletal system, heart, salivary glands, or nervous system (i.e., central or peripheral nervous system). The range and severity of symptoms associated with sarcoidosis vary greatly, depending upon the specific organs involved and the degree of such involvement. In some cases, the symptoms of sarcoidosis may begin suddenly (acute), sometimes severely, and subside in a relatively short period (self limited). Acute sarcoidosis is often characterized by fatigue, fever, generalized muscle aches, difficulty breathing (dyspnea), joint pain, swollen glands, skin eruptions, eye irregularities, or other symptoms. In the subacute form, affected individuals may experience no symptoms (asymptomatic), even with organ involvement. In chronic sarcoidosis, symptoms may appear slowly and subtly and may persist or recur over a long period. Initial symptoms of chronic sarcoidosis may include difficulty breathing, dry cough, limited airflow, and other respiratory abnormalities. Symptoms associated with other organ involvement may follow. The exact cause of sarcoidosis is unknown. However, possible infectious, environmental, genetic, and immunological factors are under investigation as potential causes of the disorder. (For more information, choose “sarcoidosis” as your search term in the Rare Disease Database.)In some cases, exposure to other hard metals, such as chromium, titanium dioxide, or cobalt, may result in symptoms and findings that may be similar to those associated with berylliosis. For example, such exposure may result in chronic inflammation of the lungs (pneumonitis) in association with widespread scarring and thickening of deep lung tissues (interstitial pulmonary fibrosis). Associated symptoms may include coughing, chest pain, and increasing difficulties breathing. | 155 | Berylliosis |
nord_155_5 | Diagnosis of Berylliosis | Individuals with an unexplained cough, difficulties breathing, fatigue, weight loss, and/or rash should inform their physicians concerning any past beryllium exposure. Berylliosis may be diagnosed based upon a thorough clinical evaluation, detection of characteristic physical findings, a complete patient history, and specialized testing. During examination with a stethoscope, abnormal lung sounds may be heard. In addition, a series of procedures may be performed to evaluate the function of the lungs (pulmonary function tests) and chest x-rays are typically conducted. Although imaging studies may be abnormal, the changes are usually similar to those seen in individuals with other lung disorders, such as sarcoidosis. In many patients with CBD, imaging studies may even be normal at the time of their initial presentation. Diagnostic assessment may include the surgical removal (biopsy) and microscopic examination of lung tissue. In those with chronic berylliosis, lung biopsy typically reveals granuloma development (a finding that is also associated with sarcoidosis).Diagnostic assessment may include additional, more specialized tests to help distinguish berylliosis from other lung disorders. For example, blood tests may be conducted to confirm sensitivity to beryllium (beryllium lymphocyte proliferation test [BeLPT]). When white blood cells (lymphocytes) from affected individuals are cultured in the presence of certain beryllium salts (in vitro), they begin to abnormally proliferate, demonstrating a positive immune reaction associated with beryllium sensitivity or chronic berylliosis. In some cases, the BeLPT may also be conducted on cells and fluid obtained from the tiny air sacs (alveoli) and airways (bronchioles) of the lungs (bronchoalveolar lavage).Some workplaces have implemented voluntary screening programs using BeLPT blood tests to identify employees with beryllium sensitivity. The goal of such testing is to identify those who may have an increased risk of developing CBD and to reassign such workers away from high-exposure work areas. Evidence suggests that approximately 45 percent of those with positive BeLPT results for beryllium sensitivity go on to develop CBD. However, there is a great deal of controversy concerning the use of such workplace screening, since current tests are not yet considered highly specific predictors of disease. Therefore, many suggest that the implementation of such screening programs may raise ethical issues including concerns about privacy, potential genetic discrimination issues, and whether effective preventive steps or treatments will be available for individuals with positive results. A number of research teams are working on developing more specific diagnostic tests (such as potential genetic analysis) that may more reliably identify employees who are risk for developing CBD. | Diagnosis of Berylliosis. Individuals with an unexplained cough, difficulties breathing, fatigue, weight loss, and/or rash should inform their physicians concerning any past beryllium exposure. Berylliosis may be diagnosed based upon a thorough clinical evaluation, detection of characteristic physical findings, a complete patient history, and specialized testing. During examination with a stethoscope, abnormal lung sounds may be heard. In addition, a series of procedures may be performed to evaluate the function of the lungs (pulmonary function tests) and chest x-rays are typically conducted. Although imaging studies may be abnormal, the changes are usually similar to those seen in individuals with other lung disorders, such as sarcoidosis. In many patients with CBD, imaging studies may even be normal at the time of their initial presentation. Diagnostic assessment may include the surgical removal (biopsy) and microscopic examination of lung tissue. In those with chronic berylliosis, lung biopsy typically reveals granuloma development (a finding that is also associated with sarcoidosis).Diagnostic assessment may include additional, more specialized tests to help distinguish berylliosis from other lung disorders. For example, blood tests may be conducted to confirm sensitivity to beryllium (beryllium lymphocyte proliferation test [BeLPT]). When white blood cells (lymphocytes) from affected individuals are cultured in the presence of certain beryllium salts (in vitro), they begin to abnormally proliferate, demonstrating a positive immune reaction associated with beryllium sensitivity or chronic berylliosis. In some cases, the BeLPT may also be conducted on cells and fluid obtained from the tiny air sacs (alveoli) and airways (bronchioles) of the lungs (bronchoalveolar lavage).Some workplaces have implemented voluntary screening programs using BeLPT blood tests to identify employees with beryllium sensitivity. The goal of such testing is to identify those who may have an increased risk of developing CBD and to reassign such workers away from high-exposure work areas. Evidence suggests that approximately 45 percent of those with positive BeLPT results for beryllium sensitivity go on to develop CBD. However, there is a great deal of controversy concerning the use of such workplace screening, since current tests are not yet considered highly specific predictors of disease. Therefore, many suggest that the implementation of such screening programs may raise ethical issues including concerns about privacy, potential genetic discrimination issues, and whether effective preventive steps or treatments will be available for individuals with positive results. A number of research teams are working on developing more specific diagnostic tests (such as potential genetic analysis) that may more reliably identify employees who are risk for developing CBD. | 155 | Berylliosis |
nord_155_6 | Therapies of Berylliosis | TreatmentAs discussed above, protective measures have been introduced to minimize beryllium exposure in the workplace. Employees should follow all workplace and safety guidelines and take any additional, appropriate steps to reduce their exposure to beryllium dust particles, fumes, and vapors. For example, it may be advised that, after completing their shifts, employees change out of their work clothing and shoes, shower, and change into street clothing. (This may help to reduce the risk of carrying residual beryllium to their vehicles and back to their residences [e.g., via their hands, clothing, and shoes].)The treatment of individuals with acute berylliosis may include therapy with corticosteroid drugs, breathing support (such as the use of ventilators), and/or other supportive measures. With prompt, appropriate treatment, most affected individuals have a complete recovery with no residual effects.If it is determined that individuals have become sensitized to beryllium yet have not developed chronic beryllium disease (CBD), treatment may not be required. However, such individuals should be regularly monitored by physicians to ensure early detection of CBD and prompt, appropriate treatment. Avoidance of further exposure to beryllium is recommended.There is currently no cure for CBD. Thus, prevention and early recognition of individuals at risk are crucial. In individuals diagnosed with chronic berylliosis, corticosteroid therapy, such as with the medication prednisone, may be prescribed. It is possible that such therapy may help to alleviate certain symptoms in some cases. Other treatment is symptomatic and supportive. | Therapies of Berylliosis. TreatmentAs discussed above, protective measures have been introduced to minimize beryllium exposure in the workplace. Employees should follow all workplace and safety guidelines and take any additional, appropriate steps to reduce their exposure to beryllium dust particles, fumes, and vapors. For example, it may be advised that, after completing their shifts, employees change out of their work clothing and shoes, shower, and change into street clothing. (This may help to reduce the risk of carrying residual beryllium to their vehicles and back to their residences [e.g., via their hands, clothing, and shoes].)The treatment of individuals with acute berylliosis may include therapy with corticosteroid drugs, breathing support (such as the use of ventilators), and/or other supportive measures. With prompt, appropriate treatment, most affected individuals have a complete recovery with no residual effects.If it is determined that individuals have become sensitized to beryllium yet have not developed chronic beryllium disease (CBD), treatment may not be required. However, such individuals should be regularly monitored by physicians to ensure early detection of CBD and prompt, appropriate treatment. Avoidance of further exposure to beryllium is recommended.There is currently no cure for CBD. Thus, prevention and early recognition of individuals at risk are crucial. In individuals diagnosed with chronic berylliosis, corticosteroid therapy, such as with the medication prednisone, may be prescribed. It is possible that such therapy may help to alleviate certain symptoms in some cases. Other treatment is symptomatic and supportive. | 155 | Berylliosis |
nord_156_0 | Overview of Best Vitelliform Macular Dystrophy | Best vitelliform macular dystrophy (BVMD) is a genetic form of macular degeneration (damage to a part of the eye called the macula) that occurs in about 1 in 10,000 individuals. The physical cause of BVMD is breakdown of the tissue in the retina called retinal pigment epithelium (RPE). The condition gets worse over time, starting with blurred central vision, and possibly leading to complete loss of central vision. Peripheral vision (vision from the sides of the eye) and the ability of the eye to adjust to dark are unaffected. The age of onset of BVMD can vary. Many individuals with BVMD have symptoms in childhood or early adulthood. BVMD is associated with a harmful genetic change (mutation) in the BEST1 gene. There is no cure for BVMD, although some treatments and medications exist that can minimize the damage caused by breakdown of the RPE including anti-VEGF therapy (medicine used to prevent growth of new blood vessels in the eye), laser photocoagulation (laser treatment used to destroy leaky blood vessels), and photodynamic therapy (a combination of medicine and laser treatment used to get rid of bad eye cells). | Overview of Best Vitelliform Macular Dystrophy. Best vitelliform macular dystrophy (BVMD) is a genetic form of macular degeneration (damage to a part of the eye called the macula) that occurs in about 1 in 10,000 individuals. The physical cause of BVMD is breakdown of the tissue in the retina called retinal pigment epithelium (RPE). The condition gets worse over time, starting with blurred central vision, and possibly leading to complete loss of central vision. Peripheral vision (vision from the sides of the eye) and the ability of the eye to adjust to dark are unaffected. The age of onset of BVMD can vary. Many individuals with BVMD have symptoms in childhood or early adulthood. BVMD is associated with a harmful genetic change (mutation) in the BEST1 gene. There is no cure for BVMD, although some treatments and medications exist that can minimize the damage caused by breakdown of the RPE including anti-VEGF therapy (medicine used to prevent growth of new blood vessels in the eye), laser photocoagulation (laser treatment used to destroy leaky blood vessels), and photodynamic therapy (a combination of medicine and laser treatment used to get rid of bad eye cells). | 156 | Best Vitelliform Macular Dystrophy |
nord_156_1 | Symptoms of Best Vitelliform Macular Dystrophy | BVMD has an average age of onset between age 5 and 10 but can vary from person to person. Affected individuals initially have normal vision and then experience blurred vision, reduced sharpness or clarity of vision or the appearance of objects that have a distorted shape (metamorphosia). BVMD affects central vision but usually not peripheral vision and varies in severity. Some people with the disorder do not notice a decline in vision and may be diagnosed in passing from a routine eye exam. Others experience significant loss of vision, which can occur because of the formation of blood vessels under the macula and retina (choroidal neovascularization). The degree of visual loss can be different in each eye. Most individuals with BVMD have one eye more severely affected than the other and can continue to perform daily tasks such as driving well into the later decades of life. | Symptoms of Best Vitelliform Macular Dystrophy. BVMD has an average age of onset between age 5 and 10 but can vary from person to person. Affected individuals initially have normal vision and then experience blurred vision, reduced sharpness or clarity of vision or the appearance of objects that have a distorted shape (metamorphosia). BVMD affects central vision but usually not peripheral vision and varies in severity. Some people with the disorder do not notice a decline in vision and may be diagnosed in passing from a routine eye exam. Others experience significant loss of vision, which can occur because of the formation of blood vessels under the macula and retina (choroidal neovascularization). The degree of visual loss can be different in each eye. Most individuals with BVMD have one eye more severely affected than the other and can continue to perform daily tasks such as driving well into the later decades of life. | 156 | Best Vitelliform Macular Dystrophy |
nord_156_2 | Causes of Best Vitelliform Macular Dystrophy | The macula is the region of the retina that contains the light-sensing cells necessary for central vision. Individuals with BVMD develop a yellowish material under the macula that resembles an egg yolk (vitelliform means yolk-like). This material eventually breaks up and spreads throughout the macula, leading to a reduction in central vision. Lipofuscin, a chemical made by the body, makes up this yolk-like material.BVMD is inherited as an autosomal dominant genetic condition and is usually associated with the mutations in the BEST1 gene. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent. It can also occur as a new gene change in the affected individual. Most individuals affected with BVMD have an affected parent. The chance 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.When working normally, the BEST1 gene acts as a gate to help move chemicals between cells in the retina. When this “gate” isn’t working properly, this can cause the build up of fluid and lipofuscin in the retinal tissue. Because BVMD is a progressive condition, there are different stages that are recognized.The BEST1 gene is one of two genes associated with this condition. This gene is linked to the early onset form of this condition typically presenting in late childhood or early adolescence. BVMD-like symptoms diagnosed after age 20 with no gene abnormality in the BEST1 gene may be associated with mutations in the PRPH2 gene which is linked to adult-onset BVMD. | Causes of Best Vitelliform Macular Dystrophy. The macula is the region of the retina that contains the light-sensing cells necessary for central vision. Individuals with BVMD develop a yellowish material under the macula that resembles an egg yolk (vitelliform means yolk-like). This material eventually breaks up and spreads throughout the macula, leading to a reduction in central vision. Lipofuscin, a chemical made by the body, makes up this yolk-like material.BVMD is inherited as an autosomal dominant genetic condition and is usually associated with the mutations in the BEST1 gene. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent. It can also occur as a new gene change in the affected individual. Most individuals affected with BVMD have an affected parent. The chance 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.When working normally, the BEST1 gene acts as a gate to help move chemicals between cells in the retina. When this “gate” isn’t working properly, this can cause the build up of fluid and lipofuscin in the retinal tissue. Because BVMD is a progressive condition, there are different stages that are recognized.The BEST1 gene is one of two genes associated with this condition. This gene is linked to the early onset form of this condition typically presenting in late childhood or early adolescence. BVMD-like symptoms diagnosed after age 20 with no gene abnormality in the BEST1 gene may be associated with mutations in the PRPH2 gene which is linked to adult-onset BVMD. | 156 | Best Vitelliform Macular Dystrophy |
nord_156_3 | Affects of Best Vitelliform Macular Dystrophy | BVMD is fairly common form of macular degeneration affecting about 1 in 10,000 individuals. Typical age of onset is between the ages of 5 and 10 but can occur earlier or later. BVMD occurs equally often in men and women. This condition has been diagnosed in individuals of European, African and Hispanic ancestry. | Affects of Best Vitelliform Macular Dystrophy. BVMD is fairly common form of macular degeneration affecting about 1 in 10,000 individuals. Typical age of onset is between the ages of 5 and 10 but can occur earlier or later. BVMD occurs equally often in men and women. This condition has been diagnosed in individuals of European, African and Hispanic ancestry. | 156 | Best Vitelliform Macular Dystrophy |
nord_156_4 | Related disorders of Best Vitelliform Macular Dystrophy | Symptoms of the following disorders can be similar to those of BVMD. Comparisons may be useful for a differential diagnosis:Adult vitelliform macular dystrophy is an autosomal dominant form of macular dystrophy that usually begins in middle age. A yolk-like mass is often present on the macula, but a special light test used to evaluate the function of the layer of cells between the retina and eye wall (retinal pigment epithelium) is usually normal. Some affected individuals have an abnormality in either the BEST1 or PRPH2 gene.Age-related macular degeneration is a common type of macular degeneration that usually occurs in people over 60 years of age.Autosomal recessive bestrophinopathy (ARB) is a form of macular degeneration inherited in an autosomal recessive fashion (both copies of the gene must be non-working in order to have the disease). The disease is caused by two non-working copies of the BEST1 gene. In this condition, the same yellowish material and fluid pocket in the retinal tissue can be found. Farsightedness and an abnormal EOG are common. In some people, multiple pockets of fluid can be seen in the retina, many of which are smaller than those seen in BVMD. | Related disorders of Best Vitelliform Macular Dystrophy. Symptoms of the following disorders can be similar to those of BVMD. Comparisons may be useful for a differential diagnosis:Adult vitelliform macular dystrophy is an autosomal dominant form of macular dystrophy that usually begins in middle age. A yolk-like mass is often present on the macula, but a special light test used to evaluate the function of the layer of cells between the retina and eye wall (retinal pigment epithelium) is usually normal. Some affected individuals have an abnormality in either the BEST1 or PRPH2 gene.Age-related macular degeneration is a common type of macular degeneration that usually occurs in people over 60 years of age.Autosomal recessive bestrophinopathy (ARB) is a form of macular degeneration inherited in an autosomal recessive fashion (both copies of the gene must be non-working in order to have the disease). The disease is caused by two non-working copies of the BEST1 gene. In this condition, the same yellowish material and fluid pocket in the retinal tissue can be found. Farsightedness and an abnormal EOG are common. In some people, multiple pockets of fluid can be seen in the retina, many of which are smaller than those seen in BVMD. | 156 | Best Vitelliform Macular Dystrophy |
nord_156_5 | Diagnosis of Best Vitelliform Macular Dystrophy | Best vitelliform macular dystrophy is diagnosed by the appearance of a yellow mass on the macula during an eye exam. There are different eye tests that can detect or lead to a suspicion of BVMD including a test called an electrooculogram (EOG) which can measure how well the eye responds to light. The test measures how well the eye responds to light by looking at how retina reacts to different amounts of light. A very low score on this test, indicated as a number called an Arden ratio, is a strong indicator for BVMD. Another test called a fundus exam can identify the yolk-like mass on the macula that is characteristic of BVMD.Other family members like siblings or parents with similar symptoms may help in diagnosing BVMD in an individual. Molecular genetic testing for the BEST1 gene is available to confirm the diagnosis. Sequencing of BEST1 (reading every letter of the gene from start to finish) can detect more than 96% of harmful genetic changes if there is a family history of BVMD. This means that only 4% of harmful changes in the BEST1 gene are not detected in an individual with BVMD. If there is no family history, sequencing can detect 50 – 70% of harmful genetic changes known to cause BVMD. | Diagnosis of Best Vitelliform Macular Dystrophy. Best vitelliform macular dystrophy is diagnosed by the appearance of a yellow mass on the macula during an eye exam. There are different eye tests that can detect or lead to a suspicion of BVMD including a test called an electrooculogram (EOG) which can measure how well the eye responds to light. The test measures how well the eye responds to light by looking at how retina reacts to different amounts of light. A very low score on this test, indicated as a number called an Arden ratio, is a strong indicator for BVMD. Another test called a fundus exam can identify the yolk-like mass on the macula that is characteristic of BVMD.Other family members like siblings or parents with similar symptoms may help in diagnosing BVMD in an individual. Molecular genetic testing for the BEST1 gene is available to confirm the diagnosis. Sequencing of BEST1 (reading every letter of the gene from start to finish) can detect more than 96% of harmful genetic changes if there is a family history of BVMD. This means that only 4% of harmful changes in the BEST1 gene are not detected in an individual with BVMD. If there is no family history, sequencing can detect 50 – 70% of harmful genetic changes known to cause BVMD. | 156 | Best Vitelliform Macular Dystrophy |
nord_156_6 | Therapies of Best Vitelliform Macular Dystrophy | Treatment
There is no cure for BVMD but there are treatment options available that can help reduce the effects of vision loss. For individuals with BVMD who have choroidal neovascularization, anti-VEGF therapy is available to help limit the formation of blood vessels in the macula. Affected individuals should have regular eye examinations to monitor the progression of the disease. Devices or aids to help with poor vision are beneficial for those who experience significant vision loss.If the eye lesions are large enough, sudden injury to the eye or head may lead to bursting of the lesions. People with BVMD should avoid strenuous exercise or high contact activity that may lead to head trauma. Genetic counseling is beneficial for affected individuals and their families. These specialists can provide information on the genetic causes of certain inherited conditions, counsel on the chance of genetic disease reoccurring in the family, discuss the availability of different genetic testing options, and provide resources related to genetic disease. | Therapies of Best Vitelliform Macular Dystrophy. Treatment
There is no cure for BVMD but there are treatment options available that can help reduce the effects of vision loss. For individuals with BVMD who have choroidal neovascularization, anti-VEGF therapy is available to help limit the formation of blood vessels in the macula. Affected individuals should have regular eye examinations to monitor the progression of the disease. Devices or aids to help with poor vision are beneficial for those who experience significant vision loss.If the eye lesions are large enough, sudden injury to the eye or head may lead to bursting of the lesions. People with BVMD should avoid strenuous exercise or high contact activity that may lead to head trauma. Genetic counseling is beneficial for affected individuals and their families. These specialists can provide information on the genetic causes of certain inherited conditions, counsel on the chance of genetic disease reoccurring in the family, discuss the availability of different genetic testing options, and provide resources related to genetic disease. | 156 | Best Vitelliform Macular Dystrophy |
nord_157_0 | Overview of Beta Thalassemia | Summary
Beta thalassemia is an inherited blood disorder characterized by reduced levels of functional hemoglobin. Hemoglobin is found in red blood cells; it is the red, iron-rich, oxygen-carrying pigment of the blood. A main function of red blood cells is to deliver oxygen throughout the body. Beta thalassemia has three main forms – minor, intermedia and major, which indicate the severity of the disease. Individuals with beta thalassemia minor usually do not have any symptoms (asymptomatic) and individuals often are unaware that they have the condition. Some individuals do experience very mild anemia. Individuals with beta thalassemia major have a severe expression of the disorder; they almost always require regular blood transfusions and lifelong, ongoing medical care.The symptoms of beta thalassemia intermedia are widely variable, and severity falls in the broad range between the two extremes of the major and minor forms. The characteristic finding of beta thalassemia is anemia, which is caused because red blood cells are abnormally small (microcytic), are not produced at the normal amounts and do not contain enough functional hemoglobin. Consequently, affected individuals do not receive enough oxygen-rich blood throughout the body. Affected individuals may experience classic symptoms of anemia including fatigue, weakness, shortness of breath, dizziness or headaches. Severe anemia can cause serious, even life-threatening complications if left untreated. Affected individuals are treated by regular blood transfusions. Because of repeated blood transfusions individuals with beta thalassemia may develop excess levels of iron in the body (iron overload). Iron overload can cause a variety of symptoms affecting multiple systems of the body but can be treated with medications. Beta thalassemia is caused by changes (variants or mutations) in the hemoglobin beta (HBB) gene. Individuals with beta thalassemia minor have a mutation in one HBB gene, while individuals with the intermediate and major forms have mutations in both HBB genes.Introduction
Thalassemia is a term for a group of disorders in which there is reduced levels of hemoglobin, decreased red blood cell production and anemia. There are two main forms – alpha thalassemia and beta thalassemia, each with various subtypes. Beta thalassemia minor, also known as beta thalassemia trait, is a common condition. Beta thalassemia major was first described in the medical literature in 1925 by an American physician – Thomas Cooley. Beta thalassemia major is also known as Cooley’s anemia. Today, the classic clinical picture of beta thalassemia major is rarely seen when treatment is initiated early and regularly for the condition. Because of the anemia and the need for transfusions, thalassemia is now described as either transfusion dependent thalassemia (TDT) or non-transfusion dependent thalassemia (NTDT) rather than minor, intermedia or major. | Overview of Beta Thalassemia. Summary
Beta thalassemia is an inherited blood disorder characterized by reduced levels of functional hemoglobin. Hemoglobin is found in red blood cells; it is the red, iron-rich, oxygen-carrying pigment of the blood. A main function of red blood cells is to deliver oxygen throughout the body. Beta thalassemia has three main forms – minor, intermedia and major, which indicate the severity of the disease. Individuals with beta thalassemia minor usually do not have any symptoms (asymptomatic) and individuals often are unaware that they have the condition. Some individuals do experience very mild anemia. Individuals with beta thalassemia major have a severe expression of the disorder; they almost always require regular blood transfusions and lifelong, ongoing medical care.The symptoms of beta thalassemia intermedia are widely variable, and severity falls in the broad range between the two extremes of the major and minor forms. The characteristic finding of beta thalassemia is anemia, which is caused because red blood cells are abnormally small (microcytic), are not produced at the normal amounts and do not contain enough functional hemoglobin. Consequently, affected individuals do not receive enough oxygen-rich blood throughout the body. Affected individuals may experience classic symptoms of anemia including fatigue, weakness, shortness of breath, dizziness or headaches. Severe anemia can cause serious, even life-threatening complications if left untreated. Affected individuals are treated by regular blood transfusions. Because of repeated blood transfusions individuals with beta thalassemia may develop excess levels of iron in the body (iron overload). Iron overload can cause a variety of symptoms affecting multiple systems of the body but can be treated with medications. Beta thalassemia is caused by changes (variants or mutations) in the hemoglobin beta (HBB) gene. Individuals with beta thalassemia minor have a mutation in one HBB gene, while individuals with the intermediate and major forms have mutations in both HBB genes.Introduction
Thalassemia is a term for a group of disorders in which there is reduced levels of hemoglobin, decreased red blood cell production and anemia. There are two main forms – alpha thalassemia and beta thalassemia, each with various subtypes. Beta thalassemia minor, also known as beta thalassemia trait, is a common condition. Beta thalassemia major was first described in the medical literature in 1925 by an American physician – Thomas Cooley. Beta thalassemia major is also known as Cooley’s anemia. Today, the classic clinical picture of beta thalassemia major is rarely seen when treatment is initiated early and regularly for the condition. Because of the anemia and the need for transfusions, thalassemia is now described as either transfusion dependent thalassemia (TDT) or non-transfusion dependent thalassemia (NTDT) rather than minor, intermedia or major. | 157 | Beta Thalassemia |
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