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nord_1271_3
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Affects of Very Long Chain Acyl CoA Dehydrogenase Deficiency (LCAD)
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VLCADD was originally described in 1992 and is now recognized as having an incidence of 1:40,000 babies. The introduction of heel-stick tandem mass spectrometry for the early diagnosis of VLCAD in newborns has markedly increased the number of infants in which the disorder is detected.
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Affects of Very Long Chain Acyl CoA Dehydrogenase Deficiency (LCAD). VLCADD was originally described in 1992 and is now recognized as having an incidence of 1:40,000 babies. The introduction of heel-stick tandem mass spectrometry for the early diagnosis of VLCAD in newborns has markedly increased the number of infants in which the disorder is detected.
| 1,271 |
Very Long Chain Acyl CoA Dehydrogenase Deficiency (LCAD)
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nord_1271_4
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Related disorders of Very Long Chain Acyl CoA Dehydrogenase Deficiency (LCAD)
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Symptoms of the following disorders may be similar to those of VLCADD. Comparisons may be useful for a differential diagnosis:There are several other genes involved in long chain fatty acid oxidation that overlap the symptoms seen in VLCADD. These include long chain acyl-CoA dehydrogenase or complete mitochondrial trifunctional protein deficiency, carnitinepalmitoyl transferase 1 and 2 deficiency, and carnitine-acylcarnitine translocase deficiency. All are inherited in an autosomal fashion.Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is considered the most common of the fatty acid oxidation disorders. It is characterized by deficiency of an enzyme that acts on medium-chain length fatty acids. During infancy or early childhood, affected individuals typically begin to experience acute, recurrent episodes provoked by prolonged fasting. Episodes may be characterized by elevated acid levels in blood and body tissues (metabolic acidosis), hypoketotic hypoglycemia, vomiting, lethargy, coma, and/or cardiorespiratory arrest. Additional findings may include fatty infiltration of the liver, secondary carnitine deficiency, elevated levels of certain organic acids in the urine, and other abnormalities. MCAD deficiency is inherited as an autosomal recessive trait. (For more information on this disorder, choose “medium chain” or “MCAD” as your search term in the Rare Disease Database.)Glutaricaciduria II (GA II) is a metabolic disorder characterized by deficiency of either of two enzymes that allow recycling of the acyl-CoA dehydrogenases (electron transfer flavoprotein or electron transfer flavoprotein dehydrogenase), or those involved in uptake of riboflavin into cells or metabolism into flavin adenine dinucleotide. Symptoms and findings may be variable, with decreased disease severity appearing to correlate with increased age at symptom onset. In the neonatal period, associated abnormalities may include metabolic acidosis, hypoglycemia, elevated levels of multiple organic acids in the urine, an unusual odor of “sweaty feet,” poor muscle tone (hypotonia), enlargement of the liver (hepatomegaly), cardiomyopathy, and coma. In some of these cases, affected infants may also have facial abnormalities and multiple cysts in the kidneys. Later-onset disease may be associated with fasting-induced episodes characterized by hypoketotic hypoglycemia, metabolic acidosis, lethargy, coma, secondary carnitine deficiency, and/or other associated abnormalities. Glutaricaciduria II is inherited in an autosomal recessive pattern. (For more information on this disorder, choose “glutaricaciduria II” as your search term in the Rare Disease Database.)Reye syndrome is a rare disorder that predominantly affects children from approximately age four to 12 years. In some cases, Reye syndrome has initially been suspected in infants or children with fatty acid oxidation disorders, including VLCADD. Reye syndrome is primarily characterized by rapid accumulation of fat in the liver and sudden inflammation and swelling of the brain (acute encephalopathy). Associated symptoms and findings may include the sudden onset of severe, persistent vomiting; elevated levels of certain liver enzymes in the blood (hepatic transaminases); severe disorientation; episodes of uncontrolled electrical disturbances in the brain (seizures); and coma. The condition’s cause is unknown. However, there appears to be an association between the onset of Reye syndrome and the use of aspirin-containing medications (salicylates) in children or adolescents with certain viral illnesses, particularly upper respiratory tract infections (e.g., influenza B) or, in some cases, chickenpox (varicella). Due to the potential association between the use of aspirin-containing agents and the development of Reye syndrome, it is advised that such medications be avoided for infants, children, adolescents, and young adults affected by viral infections such as influenza or chickenpox. (For further information, use “Reye” as your search term in the Rare Disease Database.)
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Related disorders of Very Long Chain Acyl CoA Dehydrogenase Deficiency (LCAD). Symptoms of the following disorders may be similar to those of VLCADD. Comparisons may be useful for a differential diagnosis:There are several other genes involved in long chain fatty acid oxidation that overlap the symptoms seen in VLCADD. These include long chain acyl-CoA dehydrogenase or complete mitochondrial trifunctional protein deficiency, carnitinepalmitoyl transferase 1 and 2 deficiency, and carnitine-acylcarnitine translocase deficiency. All are inherited in an autosomal fashion.Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is considered the most common of the fatty acid oxidation disorders. It is characterized by deficiency of an enzyme that acts on medium-chain length fatty acids. During infancy or early childhood, affected individuals typically begin to experience acute, recurrent episodes provoked by prolonged fasting. Episodes may be characterized by elevated acid levels in blood and body tissues (metabolic acidosis), hypoketotic hypoglycemia, vomiting, lethargy, coma, and/or cardiorespiratory arrest. Additional findings may include fatty infiltration of the liver, secondary carnitine deficiency, elevated levels of certain organic acids in the urine, and other abnormalities. MCAD deficiency is inherited as an autosomal recessive trait. (For more information on this disorder, choose “medium chain” or “MCAD” as your search term in the Rare Disease Database.)Glutaricaciduria II (GA II) is a metabolic disorder characterized by deficiency of either of two enzymes that allow recycling of the acyl-CoA dehydrogenases (electron transfer flavoprotein or electron transfer flavoprotein dehydrogenase), or those involved in uptake of riboflavin into cells or metabolism into flavin adenine dinucleotide. Symptoms and findings may be variable, with decreased disease severity appearing to correlate with increased age at symptom onset. In the neonatal period, associated abnormalities may include metabolic acidosis, hypoglycemia, elevated levels of multiple organic acids in the urine, an unusual odor of “sweaty feet,” poor muscle tone (hypotonia), enlargement of the liver (hepatomegaly), cardiomyopathy, and coma. In some of these cases, affected infants may also have facial abnormalities and multiple cysts in the kidneys. Later-onset disease may be associated with fasting-induced episodes characterized by hypoketotic hypoglycemia, metabolic acidosis, lethargy, coma, secondary carnitine deficiency, and/or other associated abnormalities. Glutaricaciduria II is inherited in an autosomal recessive pattern. (For more information on this disorder, choose “glutaricaciduria II” as your search term in the Rare Disease Database.)Reye syndrome is a rare disorder that predominantly affects children from approximately age four to 12 years. In some cases, Reye syndrome has initially been suspected in infants or children with fatty acid oxidation disorders, including VLCADD. Reye syndrome is primarily characterized by rapid accumulation of fat in the liver and sudden inflammation and swelling of the brain (acute encephalopathy). Associated symptoms and findings may include the sudden onset of severe, persistent vomiting; elevated levels of certain liver enzymes in the blood (hepatic transaminases); severe disorientation; episodes of uncontrolled electrical disturbances in the brain (seizures); and coma. The condition’s cause is unknown. However, there appears to be an association between the onset of Reye syndrome and the use of aspirin-containing medications (salicylates) in children or adolescents with certain viral illnesses, particularly upper respiratory tract infections (e.g., influenza B) or, in some cases, chickenpox (varicella). Due to the potential association between the use of aspirin-containing agents and the development of Reye syndrome, it is advised that such medications be avoided for infants, children, adolescents, and young adults affected by viral infections such as influenza or chickenpox. (For further information, use “Reye” as your search term in the Rare Disease Database.)
| 1,271 |
Very Long Chain Acyl CoA Dehydrogenase Deficiency (LCAD)
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nord_1271_5
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Diagnosis of Very Long Chain Acyl CoA Dehydrogenase Deficiency (LCAD)
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VLCADD may be diagnosed based upon a thorough clinical evaluation; identification of characteristic findings (e.g., hypoketotic hypoglycemia, severe skeletal muscle weakness, heart enlargement); and the results of various specialized tests, including analysis conducted on various specimens, such as urine, blood, muscle, liver tissue, skin cells (cultured fibroblasts), and/or white blood cells (leukocytes). A thorough and complete family history is especially important in order to determine if there is an episode of sudden infant death (SID) in the family’s past. One estimate is that prior to the advent of newborn screening VLCAD deficiency was responsible for up to 5% of all SIDS deaths.In individuals with the disorder, urine organic acid analysis typically reveals reduced or absent ketone bodies and elevated levels of certain dicarboxylic acids (i.e., dicarboxylic aciduria, e.g., increased C6-C10, C12-C14 dicarboxylic acids). In some cases, there may be increased blood levels of the enzyme creatine phosphokinase (CPK) and the abnormal presence of myoglobin in the urine (myoglobinuria).Removal (biopsy) and microscopic evaluation of small samples of liver tissue may also reveal fatty infiltration and structural changes of mitochondria, though this is not necessary for clinical diagnosis. In addition, abnormal enlargement of the heart (cardiomegaly) associated with cardiomyopathy may be apparent upon chest x-ray examination.Prenatal diagnosis is available by enzyme measurement of either cultured cells or cells obtained from the amniotic fluid or during chorionic villus sampling (CVS). (With amniocentesis, a sample of fluid that surrounds the developing fetus is removed and analyzed, while CVS involves the removal of tissue samples from a portion of the placenta.)
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Diagnosis of Very Long Chain Acyl CoA Dehydrogenase Deficiency (LCAD). VLCADD may be diagnosed based upon a thorough clinical evaluation; identification of characteristic findings (e.g., hypoketotic hypoglycemia, severe skeletal muscle weakness, heart enlargement); and the results of various specialized tests, including analysis conducted on various specimens, such as urine, blood, muscle, liver tissue, skin cells (cultured fibroblasts), and/or white blood cells (leukocytes). A thorough and complete family history is especially important in order to determine if there is an episode of sudden infant death (SID) in the family’s past. One estimate is that prior to the advent of newborn screening VLCAD deficiency was responsible for up to 5% of all SIDS deaths.In individuals with the disorder, urine organic acid analysis typically reveals reduced or absent ketone bodies and elevated levels of certain dicarboxylic acids (i.e., dicarboxylic aciduria, e.g., increased C6-C10, C12-C14 dicarboxylic acids). In some cases, there may be increased blood levels of the enzyme creatine phosphokinase (CPK) and the abnormal presence of myoglobin in the urine (myoglobinuria).Removal (biopsy) and microscopic evaluation of small samples of liver tissue may also reveal fatty infiltration and structural changes of mitochondria, though this is not necessary for clinical diagnosis. In addition, abnormal enlargement of the heart (cardiomegaly) associated with cardiomyopathy may be apparent upon chest x-ray examination.Prenatal diagnosis is available by enzyme measurement of either cultured cells or cells obtained from the amniotic fluid or during chorionic villus sampling (CVS). (With amniocentesis, a sample of fluid that surrounds the developing fetus is removed and analyzed, while CVS involves the removal of tissue samples from a portion of the placenta.)
| 1,271 |
Very Long Chain Acyl CoA Dehydrogenase Deficiency (LCAD)
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nord_1271_6
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Therapies of Very Long Chain Acyl CoA Dehydrogenase Deficiency (LCAD)
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Treatment
Disease management and treatment are primarily directed toward preventing and controlling acute episodes. Newborns should not fast more than 4 hours (including at night) for the first 6 months of age. This can be increased gradually to 8 hours over the next 6 months of age, then 8-12 hours after age 3. Additional preventive measures include maintaining a low-fat, high-carbohydrate diet, with frequent feeding (i.e., to keep periods of fasting to a minimum). Additional recommendations include the use of low-fat nutritional supplements and medium-chain triglycerides (e.g., MCT oil). Supplementation with carnitine (Carnitor) is somewhat controversial and most metabolic physicians will wait until laboratory evidence of carnitine deficiency develops before prescribing it. Riboflavin, sometimes recommended in the past, does not seem to be beneficial.If hospitalized for an acute episode, treatment may require the prompt administration of intravenous glucose (10% dextrose) and additional supportive measures as necessary.Genetic counseling should be provided to the families of all affected individuals. In addition, as noted above, diagnostic testing of siblings is crucial to help detect and appropriately manage the condition. Other treatment for this disorder is symptomatic and supportive.
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Therapies of Very Long Chain Acyl CoA Dehydrogenase Deficiency (LCAD). Treatment
Disease management and treatment are primarily directed toward preventing and controlling acute episodes. Newborns should not fast more than 4 hours (including at night) for the first 6 months of age. This can be increased gradually to 8 hours over the next 6 months of age, then 8-12 hours after age 3. Additional preventive measures include maintaining a low-fat, high-carbohydrate diet, with frequent feeding (i.e., to keep periods of fasting to a minimum). Additional recommendations include the use of low-fat nutritional supplements and medium-chain triglycerides (e.g., MCT oil). Supplementation with carnitine (Carnitor) is somewhat controversial and most metabolic physicians will wait until laboratory evidence of carnitine deficiency develops before prescribing it. Riboflavin, sometimes recommended in the past, does not seem to be beneficial.If hospitalized for an acute episode, treatment may require the prompt administration of intravenous glucose (10% dextrose) and additional supportive measures as necessary.Genetic counseling should be provided to the families of all affected individuals. In addition, as noted above, diagnostic testing of siblings is crucial to help detect and appropriately manage the condition. Other treatment for this disorder is symptomatic and supportive.
| 1,271 |
Very Long Chain Acyl CoA Dehydrogenase Deficiency (LCAD)
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nord_1272_0
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Overview of Visual Snow Syndrome
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SummaryVisual snow is a neurological disorder characterized by a continuous visual disturbance that occupies the entire visual field and is described as tiny flickering dots that resemble the noise of a detuned analogue television. In addition to the static, or “snow”, affected individuals can experience additional visual symptoms such as visual images that persist or recur after the image has been removed (palinopsia); sensitivity to light (photophobia); visual effects originating from within the eye itself (entoptic phenomena) and impaired night vision (nyctalopia).The prevalence of visual snow in the general population is currently unknown. The average age of the visual snow population seems to be younger than for many other neurological disorders. This early onset, combined with a general lack of recognition by health care providers, suggest it is an uncommon problem.Research has been limited because of issues of case identification and diagnosis, the latter now largely addressed, and the limited size of any studied cohort. Initial functional brain imaging research suggests visual snow is a brain disorder.Visual snow is a chronic condition, sometimes highly disabling, uncommon condition that is in need of collaborative research and lateral thinking to make progress towards understanding, treatment and cure.IntroductionSince its first description (1), the introduction of the term visual snow (2) and its formal clinical definition less than five years ago (3), visual snow is now being recognized by physicians and scientists as a new entity in the neurological world. The first literature reports of visual snow mostly represented isolated clinical descriptions in the context of larger groups of patients affected by persistent visual disturbance, previously defined as “persistent positive visual phenomena” (1).Visual snow has been misdiagnosed in case series being mixed with persistent migraine aura, which has led to mechanistic confusion, diagnostic imprecision (4) and certainly the use of treatments that have not been useful (5). Visual snow has been considered to be the same condition as hallucinogen persisting perception disorder (HPPD) (6). Although it seems hallucinogens can trigger a similar disturbance (7), it is clear visual snow syndrome can be entirely independent of drug triggers. Lastly, many patients are told they simply are normal. Admixing these issues has delayed recognition of the syndrome.
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Overview of Visual Snow Syndrome. SummaryVisual snow is a neurological disorder characterized by a continuous visual disturbance that occupies the entire visual field and is described as tiny flickering dots that resemble the noise of a detuned analogue television. In addition to the static, or “snow”, affected individuals can experience additional visual symptoms such as visual images that persist or recur after the image has been removed (palinopsia); sensitivity to light (photophobia); visual effects originating from within the eye itself (entoptic phenomena) and impaired night vision (nyctalopia).The prevalence of visual snow in the general population is currently unknown. The average age of the visual snow population seems to be younger than for many other neurological disorders. This early onset, combined with a general lack of recognition by health care providers, suggest it is an uncommon problem.Research has been limited because of issues of case identification and diagnosis, the latter now largely addressed, and the limited size of any studied cohort. Initial functional brain imaging research suggests visual snow is a brain disorder.Visual snow is a chronic condition, sometimes highly disabling, uncommon condition that is in need of collaborative research and lateral thinking to make progress towards understanding, treatment and cure.IntroductionSince its first description (1), the introduction of the term visual snow (2) and its formal clinical definition less than five years ago (3), visual snow is now being recognized by physicians and scientists as a new entity in the neurological world. The first literature reports of visual snow mostly represented isolated clinical descriptions in the context of larger groups of patients affected by persistent visual disturbance, previously defined as “persistent positive visual phenomena” (1).Visual snow has been misdiagnosed in case series being mixed with persistent migraine aura, which has led to mechanistic confusion, diagnostic imprecision (4) and certainly the use of treatments that have not been useful (5). Visual snow has been considered to be the same condition as hallucinogen persisting perception disorder (HPPD) (6). Although it seems hallucinogens can trigger a similar disturbance (7), it is clear visual snow syndrome can be entirely independent of drug triggers. Lastly, many patients are told they simply are normal. Admixing these issues has delayed recognition of the syndrome.
| 1,272 |
Visual Snow Syndrome
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nord_1272_1
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Symptoms of Visual Snow Syndrome
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The main clinical feature of the syndrome described consistently by patients is an unremitting, positive visual phenomena, present in the entire visual field and characterized by uncountable tiny flickering dots interposed between the person’s vision and the background. This ‘static’ is typically black and white but can also be colored, flashing or transparent.In addition to the static, or snow, patients can experience additional visual symptoms of either direct neurological origin, such as palinopsia (either in the form of preserved images from stationary scenes or as visual trailing), photophobia and nyctalopia, or the entoptic phenomena. The latter constitutes a group of symptoms considered to arise from the optic apparatus, which in the case of visual snow is completely intact and undamaged. Entoptic phenomena that are found (either alone or in combination) in visual snow, are the blue field entoptic phenomenon, floaters (the perception of which is defined as myodesopsia), self-light of the eye and spontaneous photopsia.Up to 75% of individuals with visual snow report at least three of these four ancillary visual phenomena, which along with the static itself form the “visual snow syndrome” (3). It is important for researchers and clinicians to distinguish visual snow from other phenomena and to recognize the associated symptoms (8). Most of these can in fact be experienced by healthy individuals (especially in the case of floaters or retinal afterimages), or by patients with ophthalmological diseases; the key difference with visual snow is that they manifest in a recurring, debilitating and pervasive manner and in the context of a perfectly functional optic apparatus.
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Symptoms of Visual Snow Syndrome. The main clinical feature of the syndrome described consistently by patients is an unremitting, positive visual phenomena, present in the entire visual field and characterized by uncountable tiny flickering dots interposed between the person’s vision and the background. This ‘static’ is typically black and white but can also be colored, flashing or transparent.In addition to the static, or snow, patients can experience additional visual symptoms of either direct neurological origin, such as palinopsia (either in the form of preserved images from stationary scenes or as visual trailing), photophobia and nyctalopia, or the entoptic phenomena. The latter constitutes a group of symptoms considered to arise from the optic apparatus, which in the case of visual snow is completely intact and undamaged. Entoptic phenomena that are found (either alone or in combination) in visual snow, are the blue field entoptic phenomenon, floaters (the perception of which is defined as myodesopsia), self-light of the eye and spontaneous photopsia.Up to 75% of individuals with visual snow report at least three of these four ancillary visual phenomena, which along with the static itself form the “visual snow syndrome” (3). It is important for researchers and clinicians to distinguish visual snow from other phenomena and to recognize the associated symptoms (8). Most of these can in fact be experienced by healthy individuals (especially in the case of floaters or retinal afterimages), or by patients with ophthalmological diseases; the key difference with visual snow is that they manifest in a recurring, debilitating and pervasive manner and in the context of a perfectly functional optic apparatus.
| 1,272 |
Visual Snow Syndrome
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nord_1272_2
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Causes of Visual Snow Syndrome
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The causes of visual snow syndrome are currently unknown. Some key features of the syndrome however, point to a neurological disorder of visual processing in the brain cortex. This is mostly due to the characteristic of the chief symptom of the syndrome (i.e. the visual static) which is a whole-field visual disturbance; this makes a localization of the problem in the visual pathway or primary visual cortex extremely unlikely. Furthermore, additional symptoms such as palinopsia, which can be considered an inability to suppress the just-seen, and the enhanced entoptic phenomena in the context of normal ophthalmological tests, also point in the same direction of a central neurological disorder of the visual pathway, from causes yet to be determined.A neuroimaging study using [18F]-FDG PET seems to have confirmed these hypotheses. The study demonstrated, in patients affected by visual snow, a hypermetabolism of the lingual gyrus (9); this is an area of the visual cortex involved in several other conditions such as photophobia. The lingual gyrus is also a key element of complex physiological functions such as visual memory, perception of color and identification of facial expressions.
Visual cortical hyperexcitability (10, 11) and thalamo-cortical dysrhythmia (12) have also been hypothesized as possible causes for the pathophysiology underlying visual snow.Further studies on larger numbers of patients are needed to confirm these initial hypotheses.
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Causes of Visual Snow Syndrome. The causes of visual snow syndrome are currently unknown. Some key features of the syndrome however, point to a neurological disorder of visual processing in the brain cortex. This is mostly due to the characteristic of the chief symptom of the syndrome (i.e. the visual static) which is a whole-field visual disturbance; this makes a localization of the problem in the visual pathway or primary visual cortex extremely unlikely. Furthermore, additional symptoms such as palinopsia, which can be considered an inability to suppress the just-seen, and the enhanced entoptic phenomena in the context of normal ophthalmological tests, also point in the same direction of a central neurological disorder of the visual pathway, from causes yet to be determined.A neuroimaging study using [18F]-FDG PET seems to have confirmed these hypotheses. The study demonstrated, in patients affected by visual snow, a hypermetabolism of the lingual gyrus (9); this is an area of the visual cortex involved in several other conditions such as photophobia. The lingual gyrus is also a key element of complex physiological functions such as visual memory, perception of color and identification of facial expressions.
Visual cortical hyperexcitability (10, 11) and thalamo-cortical dysrhythmia (12) have also been hypothesized as possible causes for the pathophysiology underlying visual snow.Further studies on larger numbers of patients are needed to confirm these initial hypotheses.
| 1,272 |
Visual Snow Syndrome
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nord_1272_3
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Affects of Visual Snow Syndrome
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It is currently unknown how many patients suffer from visual snow worldwide. The available data tells us that there is possibly a higher prevalence of the disease in the male population and that the average age of affected subjects is relatively young (13).The onset of symptoms can be in very early life, with most people presenting symptoms for their entire lifetime. There is also a proportion of subjects who have a sudden and unpredictable onset of the disease; this occasionally, but not necessarily, follows an identifiable cause.
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Affects of Visual Snow Syndrome. It is currently unknown how many patients suffer from visual snow worldwide. The available data tells us that there is possibly a higher prevalence of the disease in the male population and that the average age of affected subjects is relatively young (13).The onset of symptoms can be in very early life, with most people presenting symptoms for their entire lifetime. There is also a proportion of subjects who have a sudden and unpredictable onset of the disease; this occasionally, but not necessarily, follows an identifiable cause.
| 1,272 |
Visual Snow Syndrome
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nord_1272_4
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Related disorders of Visual Snow Syndrome
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A disorder which has been strongly related to visual snow is tinnitus. Tinnitus is a common condition often referred to as a “ringing in the ears” and characterized by the perception or sensation of sound even though there is no identifiable external source for the sound. Tinnitus is extremely frequent in patients with visual snow, with up to three quarters of subjects reporting the symptom (14). This has led some researchers to hypothesize a possible relationship between the two conditions, which both possibly represent a similar dysfunction in sensory processing, respectively of the visual and auditory system in the brain. (For more information on this disorder, choose “Tinnitus” as your search term in the Rare Disease Database.)The differential diagnosis of visual snow includes prolonged migraine aura. The relationship between migraine and visual snow is a complex one; it has been in fact proven that migraine can aggravate the clinical presentation of the visual snow syndrome and that it has a higher prevalence in this disorder than in the general population (9).
Visual aura, on the other hand, does not alter the typical phenotype of visual snow, but also often occurs with the condition. These two disorders, however, should not be confused; it is important to remember their chief difference, which is the unremitting characteristic as well as the panfield visual disturbance in the case of visual snow, as opposed to a transient disorder which normally occupies only a specific area of the visual field in migraine aura.Visual snow should also be distinguished from hallucinogen persisting perception disorder (HPPD) (6, 15, 16). This disorder is characterized by a presence of sensory, and particularly visual, disturbances and shares with visual snow the characteristic of being continuous and sometimes unremitting. It is however necessarily associated with the consumption of hallucinogenic substances, which is certainly not a prerequisite of visual snow, as can be seen by the fact that the syndrome has been reported even in young children.
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Related disorders of Visual Snow Syndrome. A disorder which has been strongly related to visual snow is tinnitus. Tinnitus is a common condition often referred to as a “ringing in the ears” and characterized by the perception or sensation of sound even though there is no identifiable external source for the sound. Tinnitus is extremely frequent in patients with visual snow, with up to three quarters of subjects reporting the symptom (14). This has led some researchers to hypothesize a possible relationship between the two conditions, which both possibly represent a similar dysfunction in sensory processing, respectively of the visual and auditory system in the brain. (For more information on this disorder, choose “Tinnitus” as your search term in the Rare Disease Database.)The differential diagnosis of visual snow includes prolonged migraine aura. The relationship between migraine and visual snow is a complex one; it has been in fact proven that migraine can aggravate the clinical presentation of the visual snow syndrome and that it has a higher prevalence in this disorder than in the general population (9).
Visual aura, on the other hand, does not alter the typical phenotype of visual snow, but also often occurs with the condition. These two disorders, however, should not be confused; it is important to remember their chief difference, which is the unremitting characteristic as well as the panfield visual disturbance in the case of visual snow, as opposed to a transient disorder which normally occupies only a specific area of the visual field in migraine aura.Visual snow should also be distinguished from hallucinogen persisting perception disorder (HPPD) (6, 15, 16). This disorder is characterized by a presence of sensory, and particularly visual, disturbances and shares with visual snow the characteristic of being continuous and sometimes unremitting. It is however necessarily associated with the consumption of hallucinogenic substances, which is certainly not a prerequisite of visual snow, as can be seen by the fact that the syndrome has been reported even in young children.
| 1,272 |
Visual Snow Syndrome
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nord_1272_5
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Diagnosis of Visual Snow Syndrome
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Visual Snow is a clinical diagnosis that comes from the fulfillment of a set of criteria and the exclusion of secondary causes of similar visual disturbances, such as underlying ophthalmological and neurological diseases.
Following the systematic characterization of 78 patients with visual snow (3), these criteria have been delineated as follows:A. Visual snow: dynamic, continuous, tiny dots in the entire visual field lasting longer than 3 months (the dots are usually black/grey on white background and grey/white on black background; they can also be transparent, white flashing or colored).B. Presence of at least two additional visual symptoms of the four following categories:i. Palinopsia. At least one of the following: afterimages or trailing of moving objects (After images should be different from retinal afterimages, which occur only when staring at a high contrast image and are in complementary color).ii. Enhanced entoptic phenomena. At least one of the following: excessive floaters in both eyes, excessive blue field entoptic phenomenon, self-light of the eye, or spontaneous photopsia (Entoptic phenomena arise from the structure of the visual system itself. The blue field entoptic phenomenon is described as uncountable little grey/white/black dots or rings shooting over visual field in both eyes when looking at homogeneous bright surfaces, such as the blue sky; self-light of the eye is described as colored waves or clouds when closing the eyes in the dark; spontaneous photopsia is characterized by bright flashes of light).iii. Photophobia (sensitivity to light).iv. Nyctalopia (impaired night vision).C. Symptoms are not consistent with typical migraine visual aura (as defined by the International Headache Society in the International Classification of Headache Disorders- currently (17).D. Symptoms are not better explained by another disorder (Normal ophthalmology tests; not caused by previous intake of psychotropic drugs).
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Diagnosis of Visual Snow Syndrome. Visual Snow is a clinical diagnosis that comes from the fulfillment of a set of criteria and the exclusion of secondary causes of similar visual disturbances, such as underlying ophthalmological and neurological diseases.
Following the systematic characterization of 78 patients with visual snow (3), these criteria have been delineated as follows:A. Visual snow: dynamic, continuous, tiny dots in the entire visual field lasting longer than 3 months (the dots are usually black/grey on white background and grey/white on black background; they can also be transparent, white flashing or colored).B. Presence of at least two additional visual symptoms of the four following categories:i. Palinopsia. At least one of the following: afterimages or trailing of moving objects (After images should be different from retinal afterimages, which occur only when staring at a high contrast image and are in complementary color).ii. Enhanced entoptic phenomena. At least one of the following: excessive floaters in both eyes, excessive blue field entoptic phenomenon, self-light of the eye, or spontaneous photopsia (Entoptic phenomena arise from the structure of the visual system itself. The blue field entoptic phenomenon is described as uncountable little grey/white/black dots or rings shooting over visual field in both eyes when looking at homogeneous bright surfaces, such as the blue sky; self-light of the eye is described as colored waves or clouds when closing the eyes in the dark; spontaneous photopsia is characterized by bright flashes of light).iii. Photophobia (sensitivity to light).iv. Nyctalopia (impaired night vision).C. Symptoms are not consistent with typical migraine visual aura (as defined by the International Headache Society in the International Classification of Headache Disorders- currently (17).D. Symptoms are not better explained by another disorder (Normal ophthalmology tests; not caused by previous intake of psychotropic drugs).
| 1,272 |
Visual Snow Syndrome
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nord_1272_6
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Therapies of Visual Snow Syndrome
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Treatment
The lack of knowledge on the basic biology of the visual snow syndrome has caused a general deficiency of effective treatment strategies for most patients. No clinical and systematic trials have been performed to date, and all available data on treatment comes from single patients or case reports. The current evidence seems to show that commonly used medications such as migraine preventives, antidepressants or pain medication do not consistently improve or worsen visual snow. There have been single positive experiences with drugs such as lamotrigine (18), which need to be contemplated within their low level of evidence.
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Therapies of Visual Snow Syndrome. Treatment
The lack of knowledge on the basic biology of the visual snow syndrome has caused a general deficiency of effective treatment strategies for most patients. No clinical and systematic trials have been performed to date, and all available data on treatment comes from single patients or case reports. The current evidence seems to show that commonly used medications such as migraine preventives, antidepressants or pain medication do not consistently improve or worsen visual snow. There have been single positive experiences with drugs such as lamotrigine (18), which need to be contemplated within their low level of evidence.
| 1,272 |
Visual Snow Syndrome
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nord_1273_0
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Overview of Vitamin D Deficiency Rickets
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Vitamin-D deficiency rickets, a disorder that becomes apparent during infancy or childhood, is the result of insufficient amounts of vitamin D in the body. The deficiency of vitamin D may be caused by poor nutrition, a lack of exposure to the sun, or malabsorption syndromes in which the intestines do not adequately absorb nutrients from food. Vitamin D is needed for the metabolism of calcium and phosphorus in the body. Vitamin D affects how calcium is deposited in the bones; thus it is considered essential for proper bone development and growth. Major symptoms of vitamin D deficiency rickets include bone deformities and bone pain, slow growth, fractures and seizures. It can be efficiently treated with vitamin D supplementation and with additional calcium supplementation in some cases. This disorder is rare in developed countries but is not uncommon in certain areas of the world with predisposing factors such as poor sun-exposure, high altitude, and breastfeeding.
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Overview of Vitamin D Deficiency Rickets. Vitamin-D deficiency rickets, a disorder that becomes apparent during infancy or childhood, is the result of insufficient amounts of vitamin D in the body. The deficiency of vitamin D may be caused by poor nutrition, a lack of exposure to the sun, or malabsorption syndromes in which the intestines do not adequately absorb nutrients from food. Vitamin D is needed for the metabolism of calcium and phosphorus in the body. Vitamin D affects how calcium is deposited in the bones; thus it is considered essential for proper bone development and growth. Major symptoms of vitamin D deficiency rickets include bone deformities and bone pain, slow growth, fractures and seizures. It can be efficiently treated with vitamin D supplementation and with additional calcium supplementation in some cases. This disorder is rare in developed countries but is not uncommon in certain areas of the world with predisposing factors such as poor sun-exposure, high altitude, and breastfeeding.
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Symptoms of Vitamin D Deficiency Rickets
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Rickets typically manifests in infants and toddlers, but can also happen in older children. Symptoms of vitamin D deficiency rickets include restlessness, lack of sleep, slow growth, a delay in crawling, sitting or walking, soft skull bones (craniotabes), swelling of the skull (frontal bossing), bead-like nodules where the ribs and their cartilages join (rachitic rosary), and a delay in the closing of the skull bones. Aches, pains and enlarged bones are possible, along with swelling at the joints such as wrists and ankles. Untreated vitamin D deficiency rickets results in the ends of the long bones becoming enlarged and the legs becoming bowed or knock-kneed. Muscles can become weak and the chest may become deformed due to the pull of the diaphragm on the ribs that have been weakened by rickets (Harrison’s groove). Abnormal development and decay of teeth may also occur.In the more severe, untreated cases of this disorder, the bones may become fragile and fractures may easily occur. Muscle twitching and sharp bending of the wrist and ankle joints (tetany spasms) may also be present.Some children also develop heart disease (cardiomyopathy) that can be fatal. Occasionally, when there is too little calcium in the blood (hypocalcemia) due to the lack of vitamin D, intellectual disability and seizures (hypocalcemic seizures) may occur.
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Symptoms of Vitamin D Deficiency Rickets. Rickets typically manifests in infants and toddlers, but can also happen in older children. Symptoms of vitamin D deficiency rickets include restlessness, lack of sleep, slow growth, a delay in crawling, sitting or walking, soft skull bones (craniotabes), swelling of the skull (frontal bossing), bead-like nodules where the ribs and their cartilages join (rachitic rosary), and a delay in the closing of the skull bones. Aches, pains and enlarged bones are possible, along with swelling at the joints such as wrists and ankles. Untreated vitamin D deficiency rickets results in the ends of the long bones becoming enlarged and the legs becoming bowed or knock-kneed. Muscles can become weak and the chest may become deformed due to the pull of the diaphragm on the ribs that have been weakened by rickets (Harrison’s groove). Abnormal development and decay of teeth may also occur.In the more severe, untreated cases of this disorder, the bones may become fragile and fractures may easily occur. Muscle twitching and sharp bending of the wrist and ankle joints (tetany spasms) may also be present.Some children also develop heart disease (cardiomyopathy) that can be fatal. Occasionally, when there is too little calcium in the blood (hypocalcemia) due to the lack of vitamin D, intellectual disability and seizures (hypocalcemic seizures) may occur.
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Causes of Vitamin D Deficiency Rickets
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Vitamin D deficiency rickets can be caused by a lack of vitamin D in the diet, a lack of exposure to the sun, or malabsorption syndromes such as celiac disease, in which there is an inability of the intestines to adequately absorb nutrients from foods. Nursing mothers may have low levels of vitamin D and feed their baby with milk that is deficient in vitamin D. Vitamin D is required for the metabolism of calcium and phosphorus. Therefore, low levels of vitamin D in turn decrease calcium and/or phosphate levels in the body. This causes a delay in the formation of bone at sites where bone usually grows (delay in bone mineralization in the growth plate).In some cases, rickets can be initially caused by calcium deficiency alone (hypocalcemia) due to low dietary intake of calcium. Low levels of calcium increase vitamin D utilization and can deplete vitamin D levels, causing a combination of calcium deficiency and vitamin D deficiency or insufficiency rickets.
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Causes of Vitamin D Deficiency Rickets. Vitamin D deficiency rickets can be caused by a lack of vitamin D in the diet, a lack of exposure to the sun, or malabsorption syndromes such as celiac disease, in which there is an inability of the intestines to adequately absorb nutrients from foods. Nursing mothers may have low levels of vitamin D and feed their baby with milk that is deficient in vitamin D. Vitamin D is required for the metabolism of calcium and phosphorus. Therefore, low levels of vitamin D in turn decrease calcium and/or phosphate levels in the body. This causes a delay in the formation of bone at sites where bone usually grows (delay in bone mineralization in the growth plate).In some cases, rickets can be initially caused by calcium deficiency alone (hypocalcemia) due to low dietary intake of calcium. Low levels of calcium increase vitamin D utilization and can deplete vitamin D levels, causing a combination of calcium deficiency and vitamin D deficiency or insufficiency rickets.
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Affects of Vitamin D Deficiency Rickets
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Vitamin D deficiency rickets affects males and females equally. Even though it can affect older children, rickets mostly affects infants and preschool children and can be present at birth (congenital) in babies born to a woman with low levels of vitamin D. Nutritional rickets is more common in babies that are breastfed for more than a year, as many women of child-bearing age have low levels of vitamin D and breastmilk is low in vitamin D. This is especially the case for veiled women, as they tend to have low sun exposure. Rickets is also more common in children with darker skin, as they absorb less vitamin D from sunlight, and also in immigrants, refugees, and prematurely born babies.Rickets is more common in regions of Asia where there is pollution and a lack of sunlight and/or low intake of meat due to a vegetarian diet. The Middle East is a region where Vitamin D deficiency rickets is prevalent due to lack of exposure to the sun because of cultural practices (purdah). Rickets is also more common in Africa, partly because people tend to have darker skin, which reduces vitamin D absorption.
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Affects of Vitamin D Deficiency Rickets. Vitamin D deficiency rickets affects males and females equally. Even though it can affect older children, rickets mostly affects infants and preschool children and can be present at birth (congenital) in babies born to a woman with low levels of vitamin D. Nutritional rickets is more common in babies that are breastfed for more than a year, as many women of child-bearing age have low levels of vitamin D and breastmilk is low in vitamin D. This is especially the case for veiled women, as they tend to have low sun exposure. Rickets is also more common in children with darker skin, as they absorb less vitamin D from sunlight, and also in immigrants, refugees, and prematurely born babies.Rickets is more common in regions of Asia where there is pollution and a lack of sunlight and/or low intake of meat due to a vegetarian diet. The Middle East is a region where Vitamin D deficiency rickets is prevalent due to lack of exposure to the sun because of cultural practices (purdah). Rickets is also more common in Africa, partly because people tend to have darker skin, which reduces vitamin D absorption.
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Related disorders of Vitamin D Deficiency Rickets
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Symptoms and clinical features of the following disorders can be similar to those of vitamin D deficiency rickets. This includes other types of rickets and other diseases that can affect bone health. Comparisons may be useful for a differential diagnosis:Pseudovitamin D deficiency rickets (vitamin D dependent rickets, type I) is characterized by skeletal changes and weakness similar to severe vitamin D deficiency. This disorder is caused by abnormal vitamin D metabolism and is inherited in an autosomal recessive pattern. This type of rickets often begins earlier than hypophosphatemic rickets (see below for more details). Blood levels of calcium are severely diminished in patients with vitamin D dependent rickets. Amino acids become lost in the urine due to abnormal kidney function. Intermittent muscle cramps may occur. Convulsions and abnormalities of the spine and pelvis may also develop.Hypophosphatemic rickets can be due to sporadic gene mutations or due to the PHEX mutation causing X–linked hypophosphatemic rickets, the most common inherited form of hypophosphataemic rickets. This is a rare genetic form of rickets characterized by impaired reabsorption of phosphate from the renal tubules. Major symptoms of this disorder include skeletal changes, weakness and slow growth. Cases affecting females are usually less severe than those affecting males. Another rare acquired form of hypophosphatemic rickets is associated with a benign tumor and referred to as tumour-induced osteomalacia. (For more information on this disorder choose “hypophosphatemic rickets” as your search term in the Rare Disease Database.)Fanconi’s syndrome is a rare disorder characterized by kidney dysfunction and hypophosphatemic rickets that shows bone abnormalities similar to those of vitamin D deficiency rickets. Excess amounts of phosphate, amino acids, glucose, and uric acid are eliminated in the urine. This disorder may be acquired through various causes or inherited as an autosomal recessive disorder. It can also be associated with Lowe’s syndrome, a disorder linked to the X chromosome. Bone symptoms include rickets in children and softening of the bones (osteomalacia) in adults. Fanconi’s syndrome may be associated with a variety of inherited metabolic disorders such as cystinosis, Lowe’s syndrome, a form of tyrosinemia, hereditary fructose intolerance, Wilson’s disease, galactosemia and glycogen storage disorders. (For more information on this disorder, choose “Fanconi” as your search term in the Rare Disease Database.)Lowe’s syndrome is a rare inherited, metabolic disorder characterized by eye abnormalities such as congenital cataracts and glaucoma, bone malformations caused by vitamin D resistant rickets, intellectual disability and impairment of kidney function. This disorder affects only males and is most common in those with fair coloring. Lowe’s syndrome follows an X-linked pattern of inheritance. (For more information on this disorder choose “Lowe” as your search term in the Rare Disease Database.)Osteomalacia is a disorder characterized by a gradual softening and bending of the bones. Pain may occur in various degrees of severity. Softening occurs because solid bones have failed to form properly (calcify) due to the lack of vitamin D or a kidney dysfunction. This disorder is more common in females than males, and often begins during pregnancy. It can exist alone or in association with other disorders.Osteopetrosis is marked by increased bone density due to a defect in bone reabsorption by cells called osteoclasts. This leads to accumulation of bone with defective architecture, making them brittle and susceptible to fracture. In some cases, this is also accompanied by skeletal abnormalities. Although symptoms may not initially be apparent in people with mild forms of this disorder, trivial injuries may cause bone fractures due to bone fragility. Osteopetrosis can also cause calcium and phosphorus imbalance, leading to a disease called osteopetrorickets. (For more information on this disorder choose “Osteopetrosis” as your search term in the Rare Disease Database.)
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Related disorders of Vitamin D Deficiency Rickets. Symptoms and clinical features of the following disorders can be similar to those of vitamin D deficiency rickets. This includes other types of rickets and other diseases that can affect bone health. Comparisons may be useful for a differential diagnosis:Pseudovitamin D deficiency rickets (vitamin D dependent rickets, type I) is characterized by skeletal changes and weakness similar to severe vitamin D deficiency. This disorder is caused by abnormal vitamin D metabolism and is inherited in an autosomal recessive pattern. This type of rickets often begins earlier than hypophosphatemic rickets (see below for more details). Blood levels of calcium are severely diminished in patients with vitamin D dependent rickets. Amino acids become lost in the urine due to abnormal kidney function. Intermittent muscle cramps may occur. Convulsions and abnormalities of the spine and pelvis may also develop.Hypophosphatemic rickets can be due to sporadic gene mutations or due to the PHEX mutation causing X–linked hypophosphatemic rickets, the most common inherited form of hypophosphataemic rickets. This is a rare genetic form of rickets characterized by impaired reabsorption of phosphate from the renal tubules. Major symptoms of this disorder include skeletal changes, weakness and slow growth. Cases affecting females are usually less severe than those affecting males. Another rare acquired form of hypophosphatemic rickets is associated with a benign tumor and referred to as tumour-induced osteomalacia. (For more information on this disorder choose “hypophosphatemic rickets” as your search term in the Rare Disease Database.)Fanconi’s syndrome is a rare disorder characterized by kidney dysfunction and hypophosphatemic rickets that shows bone abnormalities similar to those of vitamin D deficiency rickets. Excess amounts of phosphate, amino acids, glucose, and uric acid are eliminated in the urine. This disorder may be acquired through various causes or inherited as an autosomal recessive disorder. It can also be associated with Lowe’s syndrome, a disorder linked to the X chromosome. Bone symptoms include rickets in children and softening of the bones (osteomalacia) in adults. Fanconi’s syndrome may be associated with a variety of inherited metabolic disorders such as cystinosis, Lowe’s syndrome, a form of tyrosinemia, hereditary fructose intolerance, Wilson’s disease, galactosemia and glycogen storage disorders. (For more information on this disorder, choose “Fanconi” as your search term in the Rare Disease Database.)Lowe’s syndrome is a rare inherited, metabolic disorder characterized by eye abnormalities such as congenital cataracts and glaucoma, bone malformations caused by vitamin D resistant rickets, intellectual disability and impairment of kidney function. This disorder affects only males and is most common in those with fair coloring. Lowe’s syndrome follows an X-linked pattern of inheritance. (For more information on this disorder choose “Lowe” as your search term in the Rare Disease Database.)Osteomalacia is a disorder characterized by a gradual softening and bending of the bones. Pain may occur in various degrees of severity. Softening occurs because solid bones have failed to form properly (calcify) due to the lack of vitamin D or a kidney dysfunction. This disorder is more common in females than males, and often begins during pregnancy. It can exist alone or in association with other disorders.Osteopetrosis is marked by increased bone density due to a defect in bone reabsorption by cells called osteoclasts. This leads to accumulation of bone with defective architecture, making them brittle and susceptible to fracture. In some cases, this is also accompanied by skeletal abnormalities. Although symptoms may not initially be apparent in people with mild forms of this disorder, trivial injuries may cause bone fractures due to bone fragility. Osteopetrosis can also cause calcium and phosphorus imbalance, leading to a disease called osteopetrorickets. (For more information on this disorder choose “Osteopetrosis” as your search term in the Rare Disease Database.)
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Diagnosis of Vitamin D Deficiency Rickets
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In children, the suspected joints are X-rayed and characteristic changes in the bones may be detected. Blood tests might also reveal high levels of parathyroid hormone (PTH) and alkaline phosphatase (ALP), and low levels of calcium, phosphorus and 25(OH)D (a marker for vitamin D levels).
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Diagnosis of Vitamin D Deficiency Rickets. In children, the suspected joints are X-rayed and characteristic changes in the bones may be detected. Blood tests might also reveal high levels of parathyroid hormone (PTH) and alkaline phosphatase (ALP), and low levels of calcium, phosphorus and 25(OH)D (a marker for vitamin D levels).
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Therapies of Vitamin D Deficiency Rickets
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Treatment
Treatment of vitamin D deficiency rickets is accomplished with doses of vitamin D given daily until the bone disease is cured. The dose of vitamin D can then be reduced to the daily recommended requirements. Adequate dietary calcium intake also has to be ensured.In cases where vitamin D deficiency is caused by calcium deficiency, calcium supplementation for at least six months can cure rickets and promote bone healing.In more severe cases of vitamin D deficiency rickets when cramps, seizures, muscle twitching and sharp bending of the ankle and wrist joints (tetany) is present, the treatment with vitamin D is supplemented with intravenous calcium gluconate. In some instances, surgery may be required to correct the severe bowing or knock-knee deformities of the legs. Vitamin D deficiency rickets can be prevented by providing a normal balanced diet to infants and children, assuming that they are exposed to adequate amounts of sun. Fortification of food such as milk with vitamin D and vitamin D supplementation in pregnant women can also prevent rickets.
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Therapies of Vitamin D Deficiency Rickets. Treatment
Treatment of vitamin D deficiency rickets is accomplished with doses of vitamin D given daily until the bone disease is cured. The dose of vitamin D can then be reduced to the daily recommended requirements. Adequate dietary calcium intake also has to be ensured.In cases where vitamin D deficiency is caused by calcium deficiency, calcium supplementation for at least six months can cure rickets and promote bone healing.In more severe cases of vitamin D deficiency rickets when cramps, seizures, muscle twitching and sharp bending of the ankle and wrist joints (tetany) is present, the treatment with vitamin D is supplemented with intravenous calcium gluconate. In some instances, surgery may be required to correct the severe bowing or knock-knee deformities of the legs. Vitamin D deficiency rickets can be prevented by providing a normal balanced diet to infants and children, assuming that they are exposed to adequate amounts of sun. Fortification of food such as milk with vitamin D and vitamin D supplementation in pregnant women can also prevent rickets.
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Overview of Vogt-Koyanagi-Harada Disease
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Vogt-Koyanagi-Harada disease is a rare disorder of unknown origin that affects many body systems, including as the eyes, ears, skin, and the covering of the brain and spinal cord (the meninges). The most noticeable symptom is a rapid loss of vision. There may also be neurological signs such as severe headache, vertigo, nausea, and drowsiness. Loss of hearing, and loss of hair (alopecia) and skin color may occur along, with whitening (loss of pigmentation) of the hair and eyelashes (poliosis).
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Overview of Vogt-Koyanagi-Harada Disease. Vogt-Koyanagi-Harada disease is a rare disorder of unknown origin that affects many body systems, including as the eyes, ears, skin, and the covering of the brain and spinal cord (the meninges). The most noticeable symptom is a rapid loss of vision. There may also be neurological signs such as severe headache, vertigo, nausea, and drowsiness. Loss of hearing, and loss of hair (alopecia) and skin color may occur along, with whitening (loss of pigmentation) of the hair and eyelashes (poliosis).
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Symptoms of Vogt-Koyanagi-Harada Disease
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Vogt-Koyanagi-Harada disease is initially characterized by headaches, very deep pain in the eyes, dizziness (vertigo), and nausea. These symptoms are usually followed in a few weeks by eye inflammation (uveitis) and blurring of vision. This may occur in both eyes at the same time or in one eye first and, a few days later, in the other. The retina may detach and hearing loss may become apparent. The chronic stage follows in a few weeks. This stage is characterized by changes in the eyes and skin. The changes in the eyes may include loss of color in the layer of the eye filled with blood vessels that nourish the retina (choroid), as well as the development of small yellow nodules in parts of the retina. Skin changes may include the development of smooth, white patches in the skin caused by the loss of pigment-producing cells (vitiligo). These white patches are usually distributed over the head, eyelids and torso. The chronic stage can last for several months to several years. In many individuals, treatment improves sight and hearing. However, there may be some permanent problems, including vision and hearing deficits, and hair loss with associated loss of color of the hair, eyelashes, and skin. Lasting visual effects may include the development of secondary glaucoma and cataracts.
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Symptoms of Vogt-Koyanagi-Harada Disease. Vogt-Koyanagi-Harada disease is initially characterized by headaches, very deep pain in the eyes, dizziness (vertigo), and nausea. These symptoms are usually followed in a few weeks by eye inflammation (uveitis) and blurring of vision. This may occur in both eyes at the same time or in one eye first and, a few days later, in the other. The retina may detach and hearing loss may become apparent. The chronic stage follows in a few weeks. This stage is characterized by changes in the eyes and skin. The changes in the eyes may include loss of color in the layer of the eye filled with blood vessels that nourish the retina (choroid), as well as the development of small yellow nodules in parts of the retina. Skin changes may include the development of smooth, white patches in the skin caused by the loss of pigment-producing cells (vitiligo). These white patches are usually distributed over the head, eyelids and torso. The chronic stage can last for several months to several years. In many individuals, treatment improves sight and hearing. However, there may be some permanent problems, including vision and hearing deficits, and hair loss with associated loss of color of the hair, eyelashes, and skin. Lasting visual effects may include the development of secondary glaucoma and cataracts.
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Causes of Vogt-Koyanagi-Harada Disease
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The exact cause of Vogt-Koyanagi-Harada disease is unknown. It is thought by researchers to be an immune response to the human leukocyte antigen (HLA). These are genetic markers located on chromosome 6 that react specifically with a particular antibody. This genetic defect may predispose persons who carry this antigen to develop Vogt-Koyanagi-Harada disease. Autoimmune disorders are caused when the body's natural defenses (antibodies, lymphocytes, etc.) against invading organisms suddenly begin to attack perfectly healthy tissue. Some researchers also think that there may be a genetic predisposition for the disease since it has occurred in a brother and sister and in a set of twins. 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.
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Causes of Vogt-Koyanagi-Harada Disease. The exact cause of Vogt-Koyanagi-Harada disease is unknown. It is thought by researchers to be an immune response to the human leukocyte antigen (HLA). These are genetic markers located on chromosome 6 that react specifically with a particular antibody. This genetic defect may predispose persons who carry this antigen to develop Vogt-Koyanagi-Harada disease. Autoimmune disorders are caused when the body's natural defenses (antibodies, lymphocytes, etc.) against invading organisms suddenly begin to attack perfectly healthy tissue. Some researchers also think that there may be a genetic predisposition for the disease since it has occurred in a brother and sister and in a set of twins. 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.
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Affects of Vogt-Koyanagi-Harada Disease
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Vogt-Koyanagi-Harada disease is a rare disease that affects males and females in equal numbers. The disorder is more prevalent in Asian, Hispanic and Native American populations than in people who trace their ancestry to northern Europe. Onset typically occurs at around 30 or 40 years of age, but cases have been reported among children as young as four years old.
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Affects of Vogt-Koyanagi-Harada Disease. Vogt-Koyanagi-Harada disease is a rare disease that affects males and females in equal numbers. The disorder is more prevalent in Asian, Hispanic and Native American populations than in people who trace their ancestry to northern Europe. Onset typically occurs at around 30 or 40 years of age, but cases have been reported among children as young as four years old.
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Related disorders of Vogt-Koyanagi-Harada Disease
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Symptoms of the following disorders can be similar to those of Vogt-Koyanagi-Harada disease or may occur in conjunction with Vogt-Koyanagi-Harada disease. Alopecia is unpredictable hair loss due to an unknown cause. Regrowth of hair may or may not occur. Hair loss is usually confined to the head and face, although the entire body may be involved. (For more information on this disorder, choose “Alopecia” as your search term in the Rare Disease Database.) Vitiligo is characterized by spots on the skin with decreased pigmentation. These areas are usually sharply demarcated with increased coloring (hyperpigmentation) on the borders, and are often symmetrical in shape. The face, neck, hands, abdomen, and thighs are most often affected. The hair and skin in the area are usually white. The white areas are prone to sunburn and should be protected from sunlight. (For more information on this disorder, choose “Vitiligo” as your search term in the Rare Disease Database.) Glaucoma may occur as a secondary characteristic of VKH disease. It is characterized by increased pressure within the eye. If left untreated the increased pressure may affect the lens and optic nerve of the eye, resulting in eventual blindness. Some symptoms for people to be aware of are: blurred vision, rainbow colored halos around lights, and loss of side vision resulting in “tunnel vision.”
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Related disorders of Vogt-Koyanagi-Harada Disease. Symptoms of the following disorders can be similar to those of Vogt-Koyanagi-Harada disease or may occur in conjunction with Vogt-Koyanagi-Harada disease. Alopecia is unpredictable hair loss due to an unknown cause. Regrowth of hair may or may not occur. Hair loss is usually confined to the head and face, although the entire body may be involved. (For more information on this disorder, choose “Alopecia” as your search term in the Rare Disease Database.) Vitiligo is characterized by spots on the skin with decreased pigmentation. These areas are usually sharply demarcated with increased coloring (hyperpigmentation) on the borders, and are often symmetrical in shape. The face, neck, hands, abdomen, and thighs are most often affected. The hair and skin in the area are usually white. The white areas are prone to sunburn and should be protected from sunlight. (For more information on this disorder, choose “Vitiligo” as your search term in the Rare Disease Database.) Glaucoma may occur as a secondary characteristic of VKH disease. It is characterized by increased pressure within the eye. If left untreated the increased pressure may affect the lens and optic nerve of the eye, resulting in eventual blindness. Some symptoms for people to be aware of are: blurred vision, rainbow colored halos around lights, and loss of side vision resulting in “tunnel vision.”
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Diagnosis of Vogt-Koyanagi-Harada Disease
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The diagnostic criteria for VKH disease includes inflammation of both eyes, no evidence of another ocular disease causing the inflammation, and no history of trauma or ocular surgery. An international group of experts has established three categories of disease:a. Complete VKH disease: diffuse choroiditis involving both eyes that may include serous retinal detachments. Inflammation of the iris and ciliary body may develop in some patients. The complete form of the disease includes neurologic signs such as ringing in the ears (tinnitus), neck stiffness, and/or cells in the cerebrospinal fluid (pleocytosis) as well as dermatological signs such as white patches on the arms or torso, sudden loss of hair (alopecia), or loss of color of the hair, eyelashes or eyelids (poliosis)b. Incomplete VKH disease: similar eye disease as patients with complete VKH disease but do not have both neurologic and dermatological signs. Patients must have either the neurologic manifestations or dermatological signs.c. Probable VKH disease: similar eye disease as patients with complete VKH disease but without neurologic and dermatological signs.
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Diagnosis of Vogt-Koyanagi-Harada Disease. The diagnostic criteria for VKH disease includes inflammation of both eyes, no evidence of another ocular disease causing the inflammation, and no history of trauma or ocular surgery. An international group of experts has established three categories of disease:a. Complete VKH disease: diffuse choroiditis involving both eyes that may include serous retinal detachments. Inflammation of the iris and ciliary body may develop in some patients. The complete form of the disease includes neurologic signs such as ringing in the ears (tinnitus), neck stiffness, and/or cells in the cerebrospinal fluid (pleocytosis) as well as dermatological signs such as white patches on the arms or torso, sudden loss of hair (alopecia), or loss of color of the hair, eyelashes or eyelids (poliosis)b. Incomplete VKH disease: similar eye disease as patients with complete VKH disease but do not have both neurologic and dermatological signs. Patients must have either the neurologic manifestations or dermatological signs.c. Probable VKH disease: similar eye disease as patients with complete VKH disease but without neurologic and dermatological signs.
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Therapies of Vogt-Koyanagi-Harada Disease
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TreatmentStandard treatment of Vogt-Koyanagi-Harada disease is the use of high-dose systemic steroid drugs initially and often followed by immunosuppressive therapy. Testing used by an ophthalmologist or neurologist to determine if this disease is present include a spinal tap, x-ray of the blood vessels after the injection of dye (angiography), and ultrasound. Other treatment is symptomatic and supportive.
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Therapies of Vogt-Koyanagi-Harada Disease. TreatmentStandard treatment of Vogt-Koyanagi-Harada disease is the use of high-dose systemic steroid drugs initially and often followed by immunosuppressive therapy. Testing used by an ophthalmologist or neurologist to determine if this disease is present include a spinal tap, x-ray of the blood vessels after the injection of dye (angiography), and ultrasound. Other treatment is symptomatic and supportive.
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Overview of Von Hippel-Lindau Disease
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SummaryVHL or von Hippel-Lindau disease is an autosomal dominant genetic condition resulting from a deletion or mutation in the VHL gene. VHL disease effects 1 in 36,000 people (10,000 cases in the U.S and 200,000 cases worldwide) and 20% of patients are first-in-family or de novo cases. The mean age of onset of 26 years and 97% of people with a VHL gene mutation have symptoms by the age of 65. VHL disease affects males and females and all ethnic groups equally, and occurs in all parts of the world.
People who have VHL disease may experience tumors and/or cysts in up to ten parts of the body, including the brain, spine, eyes, kidneys, pancreas, adrenal glands, inner ears, reproductive tract, liver and lung:Most of these VHL tumors are benign, but that does not mean they are problem-free. In fact, benign VHL tumors can still be very serious. As they grow in size, these tumors and the associated cysts can cause an increased pressure on the structure around them. This pressure can create symptoms including severe pain or worse.VHL disease is different in every patient, even within the same family. Since it is impossible to predict exactly how and when the disease will present for each person, it is very important to check regularly for possible VHL manifestations throughout a person’s lifetime.Currently, a drug (pharmacological) treatment is not available; surgical removal is the method of treatment. An organ sparing approach is the best approach for reducing irreparable damage while minimalizing the need for organ removal. For this reason, Active Surveillance Guidelines were developed to make sure VHL tumors can be found and managed appropriately. With careful monitoring, early detection, and appropriate treatment, the most harmful consequences of this gene mutation can be greatly reduced, or in some people, completely prevented.IntroductionBecause VHL disease can cause malignant tumors, it is considered one of a group of familial cancer risk factors, which are transmitted genetically. The objective is to find tumors early, watch for signs that a tumor is growing, and remove or disable the tumor before it invades other tissues. Benign tumors may also need treatment or removal if their growth causes symptoms.
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Overview of Von Hippel-Lindau Disease. SummaryVHL or von Hippel-Lindau disease is an autosomal dominant genetic condition resulting from a deletion or mutation in the VHL gene. VHL disease effects 1 in 36,000 people (10,000 cases in the U.S and 200,000 cases worldwide) and 20% of patients are first-in-family or de novo cases. The mean age of onset of 26 years and 97% of people with a VHL gene mutation have symptoms by the age of 65. VHL disease affects males and females and all ethnic groups equally, and occurs in all parts of the world.
People who have VHL disease may experience tumors and/or cysts in up to ten parts of the body, including the brain, spine, eyes, kidneys, pancreas, adrenal glands, inner ears, reproductive tract, liver and lung:Most of these VHL tumors are benign, but that does not mean they are problem-free. In fact, benign VHL tumors can still be very serious. As they grow in size, these tumors and the associated cysts can cause an increased pressure on the structure around them. This pressure can create symptoms including severe pain or worse.VHL disease is different in every patient, even within the same family. Since it is impossible to predict exactly how and when the disease will present for each person, it is very important to check regularly for possible VHL manifestations throughout a person’s lifetime.Currently, a drug (pharmacological) treatment is not available; surgical removal is the method of treatment. An organ sparing approach is the best approach for reducing irreparable damage while minimalizing the need for organ removal. For this reason, Active Surveillance Guidelines were developed to make sure VHL tumors can be found and managed appropriately. With careful monitoring, early detection, and appropriate treatment, the most harmful consequences of this gene mutation can be greatly reduced, or in some people, completely prevented.IntroductionBecause VHL disease can cause malignant tumors, it is considered one of a group of familial cancer risk factors, which are transmitted genetically. The objective is to find tumors early, watch for signs that a tumor is growing, and remove or disable the tumor before it invades other tissues. Benign tumors may also need treatment or removal if their growth causes symptoms.
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Symptoms of Von Hippel-Lindau Disease
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VHL disease does not have a single primary symptom. This is in part because it does not occur exclusively in one organ of the body. It also does not always occur in a particular age group. The condition is hereditary, but the presentation of the disease can be very different between individuals, despite the same genetic mutation. In addition, the appearance and severity of VHL lesions are so different between people that many members of the same family may have only some relatively harmless issue, while others may have a serious illness.Age of onset varies from family to family and from individual to individual. Pheochromocytomas (adrenal tumors) are very common in some families, while clear cell renal cell carcinomas (kidney tumors) are more common in other families.The most common symptom of VHL is hemangioblastomas. These are benign tumors occurring in the brain, spinal cord, and retina. Hemangioblastomas are benign. In the brain or spinal cord, the hemangioblastoma may, in some cases, be contained within a cyst or fluid-filled sac. The hemangioblastomas, or surrounding cysts may press on nerve or brain tissue and cause symptoms such as headaches, balance problems when walking, or weakness of arms and legs. In the eyes, blood or fluid leakage from hemangioblastomas can interfere with vision. Early detection, careful monitoring of the eyes and prompt treatment are very important to maintain healthy vision.Early signs of adrenal tumors may be high blood pressure, panic attacks, or heavy sweating. Early signs of pancreatic cysts and tumors may include digestive complaints like bloating, or disturbance of bowel and bladder function. Some of these tumors are benign, while others may become cancerous. Kidney tumors and cysts (clear cell renal cell carcinoma) may lead to reduced kidney function, but there are usually no symptoms in the early stages. Kidney tumors will metastasize, if not removed, when they reach approximately 3 cm in diameter.VHL may also cause a benign tumor in the inner ear called an endolymphatic sac tumor. If not removed, this tumor can lead to hearing loss in the affected ear as well as balance problems. Less common manifestations of VHL include benign reproductive tract tumors in both men and women. These tumors, however, can lead to impregnation problems or becoming pregnantTumors in the liver and lungs are considered non-problematic.
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Symptoms of Von Hippel-Lindau Disease. VHL disease does not have a single primary symptom. This is in part because it does not occur exclusively in one organ of the body. It also does not always occur in a particular age group. The condition is hereditary, but the presentation of the disease can be very different between individuals, despite the same genetic mutation. In addition, the appearance and severity of VHL lesions are so different between people that many members of the same family may have only some relatively harmless issue, while others may have a serious illness.Age of onset varies from family to family and from individual to individual. Pheochromocytomas (adrenal tumors) are very common in some families, while clear cell renal cell carcinomas (kidney tumors) are more common in other families.The most common symptom of VHL is hemangioblastomas. These are benign tumors occurring in the brain, spinal cord, and retina. Hemangioblastomas are benign. In the brain or spinal cord, the hemangioblastoma may, in some cases, be contained within a cyst or fluid-filled sac. The hemangioblastomas, or surrounding cysts may press on nerve or brain tissue and cause symptoms such as headaches, balance problems when walking, or weakness of arms and legs. In the eyes, blood or fluid leakage from hemangioblastomas can interfere with vision. Early detection, careful monitoring of the eyes and prompt treatment are very important to maintain healthy vision.Early signs of adrenal tumors may be high blood pressure, panic attacks, or heavy sweating. Early signs of pancreatic cysts and tumors may include digestive complaints like bloating, or disturbance of bowel and bladder function. Some of these tumors are benign, while others may become cancerous. Kidney tumors and cysts (clear cell renal cell carcinoma) may lead to reduced kidney function, but there are usually no symptoms in the early stages. Kidney tumors will metastasize, if not removed, when they reach approximately 3 cm in diameter.VHL may also cause a benign tumor in the inner ear called an endolymphatic sac tumor. If not removed, this tumor can lead to hearing loss in the affected ear as well as balance problems. Less common manifestations of VHL include benign reproductive tract tumors in both men and women. These tumors, however, can lead to impregnation problems or becoming pregnantTumors in the liver and lungs are considered non-problematic.
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Causes of Von Hippel-Lindau Disease
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VHL disease is an autosomal dominant disorder resulting from a deletion or mutation in the VHL gene located on the short arm of chromosome 3. Each child of a person with VHL is at 50% risk of inheriting the altered copy of the gene.The normal VHL gene acts as a tumor-suppressor gene, with the function of preventing the formation of tumors. The gene acts as the key regulator of cellular hypoxia signaling via its product, the VHL protein (pVHL). pVHL through the HIF (hypoxia-inducible factor) complex, is indirectly responsible for enhanced levels of growth factors including vascular endothelial factor, platelet derived growth factor, and transforming growth factor alpha.In the case of a non-functioning gene such as in VHL disease, regulation of the HIF complex does not occur. The result is increased levels of the various growth factors allowing for increased blood vessel growth (angiogenesis) and the formation of tumors. This is the same process involved in other more common cancers, such as kidney, breast, pancreas, adrenal cancers. Researchers believe that intervening in growth factor and/or HIF activity will prove to be an effective treatment for VHL and other forms of cancer.
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Causes of Von Hippel-Lindau Disease. VHL disease is an autosomal dominant disorder resulting from a deletion or mutation in the VHL gene located on the short arm of chromosome 3. Each child of a person with VHL is at 50% risk of inheriting the altered copy of the gene.The normal VHL gene acts as a tumor-suppressor gene, with the function of preventing the formation of tumors. The gene acts as the key regulator of cellular hypoxia signaling via its product, the VHL protein (pVHL). pVHL through the HIF (hypoxia-inducible factor) complex, is indirectly responsible for enhanced levels of growth factors including vascular endothelial factor, platelet derived growth factor, and transforming growth factor alpha.In the case of a non-functioning gene such as in VHL disease, regulation of the HIF complex does not occur. The result is increased levels of the various growth factors allowing for increased blood vessel growth (angiogenesis) and the formation of tumors. This is the same process involved in other more common cancers, such as kidney, breast, pancreas, adrenal cancers. Researchers believe that intervening in growth factor and/or HIF activity will prove to be an effective treatment for VHL and other forms of cancer.
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Affects of Von Hippel-Lindau Disease
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VHL is a familial genetic condition, however, 20% of all patients are first-in-family or de novo cases. The incidence is 1 in 36,000 births, affecting males and females and all ethnic groups equally, and occurring in all parts of the world.
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Affects of Von Hippel-Lindau Disease. VHL is a familial genetic condition, however, 20% of all patients are first-in-family or de novo cases. The incidence is 1 in 36,000 births, affecting males and females and all ethnic groups equally, and occurring in all parts of the world.
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Related disorders of Von Hippel-Lindau Disease
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VHL is a complicated disease, which causes tumors to grow in 10 different parts of the body: kidneys, adrenals, pancreas, brain, spine, retina, inner ears, reproductive tract, liver, and lungs. Because of the multi-organ involvement, the symptoms and manifestations of VHL overlap with a wide range of diseases. These include the following:
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Related disorders of Von Hippel-Lindau Disease. VHL is a complicated disease, which causes tumors to grow in 10 different parts of the body: kidneys, adrenals, pancreas, brain, spine, retina, inner ears, reproductive tract, liver, and lungs. Because of the multi-organ involvement, the symptoms and manifestations of VHL overlap with a wide range of diseases. These include the following:
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Diagnosis of Von Hippel-Lindau Disease
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Anyone with a parent with VHL and most people with a brother or sister with VHL are at a 50% chance of having VHL disease. Anyone with an aunt, uncle, cousin, or grandparent with VHL may also be at risk. The only way to determine for sure that someone does not have an altered VHL gene is through DNA testing. A clinical diagnosis can also be made when a person exhibits a tumor specific to VHL.Once a VHL diagnosis has been made, it is important to begin surveillance testing early before any symptoms occur. Most VHL lesions are much easier to treat when they are small. A number of possible complications of VHL do not present with symptoms until the problem has developed to a critical level. Treatment may only be able to stop symptoms that have occurred; it is not always possible to reverse the changes and go back to normal.
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Diagnosis of Von Hippel-Lindau Disease. Anyone with a parent with VHL and most people with a brother or sister with VHL are at a 50% chance of having VHL disease. Anyone with an aunt, uncle, cousin, or grandparent with VHL may also be at risk. The only way to determine for sure that someone does not have an altered VHL gene is through DNA testing. A clinical diagnosis can also be made when a person exhibits a tumor specific to VHL.Once a VHL diagnosis has been made, it is important to begin surveillance testing early before any symptoms occur. Most VHL lesions are much easier to treat when they are small. A number of possible complications of VHL do not present with symptoms until the problem has developed to a critical level. Treatment may only be able to stop symptoms that have occurred; it is not always possible to reverse the changes and go back to normal.
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Therapies of Von Hippel-Lindau Disease
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A universal treatment recommendation does not exist. Treatment options can only be determined by careful evaluation of the individual patient’s total situation—symptoms, test results, imaging studies, and general physical condition. The following are offered as general guidelines for possible treatment therapies.Brain and Spinal Hemangioblastomas
Symptoms related to hemangioblastomas in the brain and spinal cord depend on tumor location, size, and the presence of associated swelling or cysts. Symptomatic lesions grow more rapidly than asymptomatic lesions. Cysts often cause more symptoms than the tumor itself. Once the lesion has been removed, the cyst will collapse. If any portion of the tumor is left in place, the cyst will re-fill. Small hemangioblastomas, which are not symptomatic and are not associated with a cyst, have sometimes been treated with stereotactic radiosurgery, but this is more preventative than a treatment, and long-term results seem to show only marginal benefit. In addition, during the recovery period symptoms may not be reduced.Pancreatic Neuroendocrine Tumors
Careful analysis is required to differentiate between serous cystadenomas and pancreatic neuroendocrine tumors (pancreatic NETs). Cysts and cystadenomas generally do not require treatment. Pancreatic NETs should be rated on size, behavior, and specific genetic mutation.Renal Cell Carcinoma
VHL kidney tumors are often found when they are very small in size and at very early stages of development. A strategy for ensuring that an individual will have a sufficient functioning kidney throughout his or her lifetime begins with careful monitoring and choosing to operate only when tumor size or rapid growth rate suggest the tumor may gain metastatic potential (at approximately 3 cm). The technique of kidney-sparing surgery is widely used in this setting. Radio frequency ablation (RFA) or cryosurgery (cryotherapy) may be considered, especially for smaller tumors at earlier stages. Care must be taken not to injure adjacent structures and to limit scarring which may complicate subsequent surgeries.Retinal Hemangioblastomas
Small peripheral lesions can be successfully treated with little to no loss of vision using laser. Larger lesions often require cryotherapy. If the hemangioblastoma is on the optic disc, there are few treatment options that will successfully preserve vision.Pheochromocytomas
Surgical removal is performed after adequate blocking with medication, and laparoscopic partial adrenalectomy is preferred. Vital signs are carefully monitored for at least a week following surgery while the body readjusts to its “new normal.” Special caution is warranted during surgical procedures of any type and during pregnancy and delivery. Even pheochromocytomas that do not appear to be active or causing symptoms should be considered for removal, ideally prior to pregnancy or non-emergency surgery.Endolymphatic Sac Tumors (ELSTs)
Patients who have a tumor or hemorrhage visible on MRI but who can still hear require surgery to prevent a worsening of their condition. Deaf patients with evidence on imaging of a tumor should undergo surgery if other neurological symptoms are present in order to prevent worsening of balance problems. Not all ELSTs are visible with imaging; some are only found during surgery.In 2021, belzutifan (Welireg) was approved for adult patients with von Hippel-Lindau disease who require therapy for associated renal cell carcinoma, central nervous system hemangioblastomas or pancreatic neuroendocrine tumors not requiring immediate surgery.
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Therapies of Von Hippel-Lindau Disease. A universal treatment recommendation does not exist. Treatment options can only be determined by careful evaluation of the individual patient’s total situation—symptoms, test results, imaging studies, and general physical condition. The following are offered as general guidelines for possible treatment therapies.Brain and Spinal Hemangioblastomas
Symptoms related to hemangioblastomas in the brain and spinal cord depend on tumor location, size, and the presence of associated swelling or cysts. Symptomatic lesions grow more rapidly than asymptomatic lesions. Cysts often cause more symptoms than the tumor itself. Once the lesion has been removed, the cyst will collapse. If any portion of the tumor is left in place, the cyst will re-fill. Small hemangioblastomas, which are not symptomatic and are not associated with a cyst, have sometimes been treated with stereotactic radiosurgery, but this is more preventative than a treatment, and long-term results seem to show only marginal benefit. In addition, during the recovery period symptoms may not be reduced.Pancreatic Neuroendocrine Tumors
Careful analysis is required to differentiate between serous cystadenomas and pancreatic neuroendocrine tumors (pancreatic NETs). Cysts and cystadenomas generally do not require treatment. Pancreatic NETs should be rated on size, behavior, and specific genetic mutation.Renal Cell Carcinoma
VHL kidney tumors are often found when they are very small in size and at very early stages of development. A strategy for ensuring that an individual will have a sufficient functioning kidney throughout his or her lifetime begins with careful monitoring and choosing to operate only when tumor size or rapid growth rate suggest the tumor may gain metastatic potential (at approximately 3 cm). The technique of kidney-sparing surgery is widely used in this setting. Radio frequency ablation (RFA) or cryosurgery (cryotherapy) may be considered, especially for smaller tumors at earlier stages. Care must be taken not to injure adjacent structures and to limit scarring which may complicate subsequent surgeries.Retinal Hemangioblastomas
Small peripheral lesions can be successfully treated with little to no loss of vision using laser. Larger lesions often require cryotherapy. If the hemangioblastoma is on the optic disc, there are few treatment options that will successfully preserve vision.Pheochromocytomas
Surgical removal is performed after adequate blocking with medication, and laparoscopic partial adrenalectomy is preferred. Vital signs are carefully monitored for at least a week following surgery while the body readjusts to its “new normal.” Special caution is warranted during surgical procedures of any type and during pregnancy and delivery. Even pheochromocytomas that do not appear to be active or causing symptoms should be considered for removal, ideally prior to pregnancy or non-emergency surgery.Endolymphatic Sac Tumors (ELSTs)
Patients who have a tumor or hemorrhage visible on MRI but who can still hear require surgery to prevent a worsening of their condition. Deaf patients with evidence on imaging of a tumor should undergo surgery if other neurological symptoms are present in order to prevent worsening of balance problems. Not all ELSTs are visible with imaging; some are only found during surgery.In 2021, belzutifan (Welireg) was approved for adult patients with von Hippel-Lindau disease who require therapy for associated renal cell carcinoma, central nervous system hemangioblastomas or pancreatic neuroendocrine tumors not requiring immediate surgery.
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Overview of Waardenburg Syndrome
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Waardenburg syndrome is a genetic disorder that may be evident at birth (congenital). The range and severity of associated symptoms and findings may vary greatly from case to case. However, primary features often include distinctive facial abnormalities; unusually diminished coloration (pigmentation) of the hair, the skin, and/or the iris of both eyes (irides); and/or congenital deafness. More specifically, some affected individuals may have an unusually wide nasal bridge due to sideways (lateral) displacement of the inner angles (canthi) of the eyes (dystopia canthorum). In addition, pigmentary abnormalities may include a white lock of hair growing above the forehead (white forelock); premature graying or whitening of the hair; differences in the coloration of the two irides or in different regions of the same iris (heterochromia irides); and/or patchy, abnormally light (depigmented) regions of skin (leukoderma). Some affected individuals may also have hearing impairment due to abnormalities of the inner ear (sensorineural deafness).Researchers have described different types of Waardenburg syndrome (WS), based upon associated symptoms and specific genetic findings. For example, Waardenburg syndrome type I (WS1) is characteristically associated with sideways displacement of the inner angles of the eyes (i.e., dystopia canthorum), yet type II (WS2) is not associated with this feature. In addition, WS1 and WS2 are known to be caused by alterations (mutations) of different genes. Another form, known as type III (WS3), has been described in which characteristic facial, eye (ocular), and hearing (auditory) abnormalities may be associated with distinctive malformations of the arms and hands (upper limbs). A fourth form, known as WS4 or Waardenburg-Hirschsprung disease, may be characterized by primary features of WS in association with Hirschsprung disease. The latter is a digestive (gastrointestinal) disorder in which there is absence of groups of specialized nerve cell bodies within a region of the smooth (involuntary) muscle wall of the large intestine.In most cases, Waardenburg syndrome is transmitted as an autosomal dominant trait. A number of different disease genes have been identified that may cause Waardenburg syndrome in certain individuals or families (kindreds).
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Overview of Waardenburg Syndrome. Waardenburg syndrome is a genetic disorder that may be evident at birth (congenital). The range and severity of associated symptoms and findings may vary greatly from case to case. However, primary features often include distinctive facial abnormalities; unusually diminished coloration (pigmentation) of the hair, the skin, and/or the iris of both eyes (irides); and/or congenital deafness. More specifically, some affected individuals may have an unusually wide nasal bridge due to sideways (lateral) displacement of the inner angles (canthi) of the eyes (dystopia canthorum). In addition, pigmentary abnormalities may include a white lock of hair growing above the forehead (white forelock); premature graying or whitening of the hair; differences in the coloration of the two irides or in different regions of the same iris (heterochromia irides); and/or patchy, abnormally light (depigmented) regions of skin (leukoderma). Some affected individuals may also have hearing impairment due to abnormalities of the inner ear (sensorineural deafness).Researchers have described different types of Waardenburg syndrome (WS), based upon associated symptoms and specific genetic findings. For example, Waardenburg syndrome type I (WS1) is characteristically associated with sideways displacement of the inner angles of the eyes (i.e., dystopia canthorum), yet type II (WS2) is not associated with this feature. In addition, WS1 and WS2 are known to be caused by alterations (mutations) of different genes. Another form, known as type III (WS3), has been described in which characteristic facial, eye (ocular), and hearing (auditory) abnormalities may be associated with distinctive malformations of the arms and hands (upper limbs). A fourth form, known as WS4 or Waardenburg-Hirschsprung disease, may be characterized by primary features of WS in association with Hirschsprung disease. The latter is a digestive (gastrointestinal) disorder in which there is absence of groups of specialized nerve cell bodies within a region of the smooth (involuntary) muscle wall of the large intestine.In most cases, Waardenburg syndrome is transmitted as an autosomal dominant trait. A number of different disease genes have been identified that may cause Waardenburg syndrome in certain individuals or families (kindreds).
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Symptoms of Waardenburg Syndrome
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Primary features of Waardenburg syndrome (WS) may include distinctive facial abnormalities; unusually diminished pigmentation (hypopigmentation) of the hair, the skin, and/or the irides or the iris of both eyes (partial albinism); and/or deafness that is present at birth (congenital). However, as mentioned earlier, associated symptoms and findings may be extremely variable, including among affected members of the same family (kindred). For example, while some affected individuals may have only one characteristic feature, others may have several abnormalities associated with the disorder.In some individuals with WS, there is abnormal sideways (lateral) displacement of the inner angles (canthi) of the eyes formed by the junction of the upper and lower eyelids (dystopia canthorum). In addition, the condition may be associated with unusually low (inferior) openings to the tear (lacrimal) ducts and an increased susceptibility to infections of the lacrimal sacs (dacryocystitis). (Each inner canthus opens into a small space that contains the opening to a lacrimal duct.) Due to dystopia canthorum, affected individuals may have an abnormally wide, high nasal bridge and underdeveloped nasal “wings” (hypoplastic nasal alae), resulting in narrow nostrils. In addition, in some cases, the eyebrows may be unusually bushy and/or may grow together (synophrys). Rarely, affected individuals also have widely spaced eyes (ocular hypertelorism). As mentioned previously, researchers have described different forms of WS based upon certain symptoms and specific genetic findings. WS type II (WS2) is distinguished from WS type I (WS1) by the absence of dystopia canthorum.In some individuals with WS, additional facial abnormalities may be present. These may include an unusually rounded nasal tip that may be slightly upturned; abnormal “smoothness” of the vertical groove of the upper lip (philtrum); full lips; and/or mild protrusion of the lower jaw (mandibular prognathism). There have also been a few reports in which the disorder has been associated with incomplete closure of the roof of the mouth (cleft palate) and/or an abnormal groove in the upper lip (cleft lip).WS is often associated with pigmentary abnormalities due to deficiency of the pigment melanin. Some with the disorder have a white forelock (poliosis) at birth that tends to disappear with age or patches of white hair other than a forelock. (There have also been cases in which a black rather than a white forelock is present.) The eyebrows, eyelashes, and scalp hair may become prematurely gray or white (beginning as early as mid-childhood, adolescence, or early adulthood). In addition, some affected individuals have irregular patchy skin regions that lack pigmentation (leukoderma or vitiligo), particularly on the face and arms. WS may also be associated with underdevelopment (hypoplasia) of the connective tissue fibers that comprise most of the colored region (iris) of both eyes (irides). As a result, affected individuals may have unusually pale blue eyes or differences in the pigmentation of the two irides or within different areas of the same iris (heterochromia irides). For example, the iris of one eye may be blue while the other has a different color or one or both irides may seem unusually “mottled” in appearance. Some reports suggest that heterochromia irides may be more frequent in WS2 while the presence of a white forelock and depigmented skin patches are more common in those with WS1.Some individuals with WS are also affected by congenital deafness. Such hearing impairment appears to result from abnormalities or absence of the organ of Corti, a structure within the hollow, coiled passage of the inner ear (cochlea). The organ of Corti contains minute hair cells that convert sound vibrations into nerve impulses, which are then transmitted via the auditory nerve (vestibulocochlear nerve) to the brain. Abnormalities of the organ of Corti may prevent the transmission of such nerve impulses, resulting in hearing impairment (known as sensorineural or cochlear deafness). In most affected individuals with WS, congenital sensorineural deafness affects both ears (bilateral). However, in rare cases, only one side may be affected (unilateral). Evidence suggests that congenital sensorineural deafness is more frequently associated with WS2 than WS1.In some cases, characteristic facial, eye (ocular), and hearing (auditory) features of WS may occur in association with bilateral malformations of the arms and hands (upper limbs). This form of the disorder, which has been described as a severe presentation of WS1, is sometimes referred to as WS type III (WS3), Klein-Waardenburg syndrome, or Waardenburg syndrome with upper limb anomalies. Bilateral defects may include underdevelopment (hypoplasia) and abnormal shortness of the upper limbs; abnormal bending of certain joints of the fingers in fixed positions (flexion contractures); fusion of wrist (carpal) bones; and/or webbing or fusion (syndactyly) of certain fingers. In some cases, other skeletal abnormalities may be present, such as abnormal elevation of the shoulder blades (Sprengel deformity).A fourth form of WS has also been described in which primary features of WS occur in association with Hirschsprung disease. This form of the disorder may be referred to as WS4, Waardenburg-Shah syndrome, or Waardenburg-Hirschsprung disease. Hirschsprung disease (also known as aganglionic megacolon) is a gastrointestinal (GI) disorder characterized by absence of certain nerve cell bodies (ganglia) in the smooth muscle wall within a region of the large intestine (i.e., colon). As a result, there is absence or impairment of the involuntary, rhythmic contractions that propel food through the GI tract (peristalsis). Associated symptoms and findings may include an abnormal accumulation of feces within the colon; widening of the colon above the affected segment (megacolon); abdominal bloating (distension); vomiting; lack of appetite (anorexia); failure to grow and gain weight at the expected rate (failure to thrive); and/or other abnormalities.Rare cases of WS4 have been described in which affected individuals have also had neurologic symptoms due to abnormalities of the brain and spinal cord (central nervous system). In such instances, additional findings have included growth restriction; abnormally diminished muscle tone (hypotonia); flexion or extension of certain joints in various fixed postures (arthrogryposis); and/or other abnormalities.
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Symptoms of Waardenburg Syndrome. Primary features of Waardenburg syndrome (WS) may include distinctive facial abnormalities; unusually diminished pigmentation (hypopigmentation) of the hair, the skin, and/or the irides or the iris of both eyes (partial albinism); and/or deafness that is present at birth (congenital). However, as mentioned earlier, associated symptoms and findings may be extremely variable, including among affected members of the same family (kindred). For example, while some affected individuals may have only one characteristic feature, others may have several abnormalities associated with the disorder.In some individuals with WS, there is abnormal sideways (lateral) displacement of the inner angles (canthi) of the eyes formed by the junction of the upper and lower eyelids (dystopia canthorum). In addition, the condition may be associated with unusually low (inferior) openings to the tear (lacrimal) ducts and an increased susceptibility to infections of the lacrimal sacs (dacryocystitis). (Each inner canthus opens into a small space that contains the opening to a lacrimal duct.) Due to dystopia canthorum, affected individuals may have an abnormally wide, high nasal bridge and underdeveloped nasal “wings” (hypoplastic nasal alae), resulting in narrow nostrils. In addition, in some cases, the eyebrows may be unusually bushy and/or may grow together (synophrys). Rarely, affected individuals also have widely spaced eyes (ocular hypertelorism). As mentioned previously, researchers have described different forms of WS based upon certain symptoms and specific genetic findings. WS type II (WS2) is distinguished from WS type I (WS1) by the absence of dystopia canthorum.In some individuals with WS, additional facial abnormalities may be present. These may include an unusually rounded nasal tip that may be slightly upturned; abnormal “smoothness” of the vertical groove of the upper lip (philtrum); full lips; and/or mild protrusion of the lower jaw (mandibular prognathism). There have also been a few reports in which the disorder has been associated with incomplete closure of the roof of the mouth (cleft palate) and/or an abnormal groove in the upper lip (cleft lip).WS is often associated with pigmentary abnormalities due to deficiency of the pigment melanin. Some with the disorder have a white forelock (poliosis) at birth that tends to disappear with age or patches of white hair other than a forelock. (There have also been cases in which a black rather than a white forelock is present.) The eyebrows, eyelashes, and scalp hair may become prematurely gray or white (beginning as early as mid-childhood, adolescence, or early adulthood). In addition, some affected individuals have irregular patchy skin regions that lack pigmentation (leukoderma or vitiligo), particularly on the face and arms. WS may also be associated with underdevelopment (hypoplasia) of the connective tissue fibers that comprise most of the colored region (iris) of both eyes (irides). As a result, affected individuals may have unusually pale blue eyes or differences in the pigmentation of the two irides or within different areas of the same iris (heterochromia irides). For example, the iris of one eye may be blue while the other has a different color or one or both irides may seem unusually “mottled” in appearance. Some reports suggest that heterochromia irides may be more frequent in WS2 while the presence of a white forelock and depigmented skin patches are more common in those with WS1.Some individuals with WS are also affected by congenital deafness. Such hearing impairment appears to result from abnormalities or absence of the organ of Corti, a structure within the hollow, coiled passage of the inner ear (cochlea). The organ of Corti contains minute hair cells that convert sound vibrations into nerve impulses, which are then transmitted via the auditory nerve (vestibulocochlear nerve) to the brain. Abnormalities of the organ of Corti may prevent the transmission of such nerve impulses, resulting in hearing impairment (known as sensorineural or cochlear deafness). In most affected individuals with WS, congenital sensorineural deafness affects both ears (bilateral). However, in rare cases, only one side may be affected (unilateral). Evidence suggests that congenital sensorineural deafness is more frequently associated with WS2 than WS1.In some cases, characteristic facial, eye (ocular), and hearing (auditory) features of WS may occur in association with bilateral malformations of the arms and hands (upper limbs). This form of the disorder, which has been described as a severe presentation of WS1, is sometimes referred to as WS type III (WS3), Klein-Waardenburg syndrome, or Waardenburg syndrome with upper limb anomalies. Bilateral defects may include underdevelopment (hypoplasia) and abnormal shortness of the upper limbs; abnormal bending of certain joints of the fingers in fixed positions (flexion contractures); fusion of wrist (carpal) bones; and/or webbing or fusion (syndactyly) of certain fingers. In some cases, other skeletal abnormalities may be present, such as abnormal elevation of the shoulder blades (Sprengel deformity).A fourth form of WS has also been described in which primary features of WS occur in association with Hirschsprung disease. This form of the disorder may be referred to as WS4, Waardenburg-Shah syndrome, or Waardenburg-Hirschsprung disease. Hirschsprung disease (also known as aganglionic megacolon) is a gastrointestinal (GI) disorder characterized by absence of certain nerve cell bodies (ganglia) in the smooth muscle wall within a region of the large intestine (i.e., colon). As a result, there is absence or impairment of the involuntary, rhythmic contractions that propel food through the GI tract (peristalsis). Associated symptoms and findings may include an abnormal accumulation of feces within the colon; widening of the colon above the affected segment (megacolon); abdominal bloating (distension); vomiting; lack of appetite (anorexia); failure to grow and gain weight at the expected rate (failure to thrive); and/or other abnormalities.Rare cases of WS4 have been described in which affected individuals have also had neurologic symptoms due to abnormalities of the brain and spinal cord (central nervous system). In such instances, additional findings have included growth restriction; abnormally diminished muscle tone (hypotonia); flexion or extension of certain joints in various fixed postures (arthrogryposis); and/or other abnormalities.
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Causes of Waardenburg Syndrome
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In most cases, Waardenburg syndrome type I (WS1) and type II (WS2) are inherited as autosomal dominant traits with variable penetrance and expressivity. Some cases of Waardenburg syndrome type III (WS3) and type IV (WS4) appear to have an autosomal recessive pattern of inheritance. Mutations in the EDN3, EDNRB, MITF, PAX3 and SOX10 genes cause Waardenburg syndrome.In dominant disorders, a single copy of the disease gene (received from either the mother or father) will be expressed “dominating” the other normal gene, potentially resulting in the appearance of the disease. The risk of transmitting the disease gene from parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child. In autosomal dominant disorders with variable penetrance and expressivity, manifestations of the disorder may not be present in all those who inherit the altered (mutated) gene for the disease. In those who do develop symptoms, the specific characteristics that are manifested may vary greatly in range and severity from case to case.In some individuals with WS1 or WS2, there may be no apparent family history of the disorder. In such cases, researchers indicate that the disorder may sometimes result from new genetic changes (mutations) that occur spontaneously (sporadically) for unknown reasons. (In other instances, an apparent lack of a positive family history may be due to incomplete penetrance and/or variable expressivity as discussed above.) Evidence suggests that new (sporadic) mutations for WS1 may be associated with advanced age of the father (advanced paternal age).Researchers have located a gene responsible for WS1–known as the “PAX3” gene–on the long arm (q) of chromosome 2 (2q35). Multiple specific mutations of the PAX3 gene have been identified in different individuals and families (kindreds) affected by WS1. Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q.” Chromosomes are further subdivided into bands that are numbered. Therefore, “chromosome 2q35” refers to band 35 on the long arm of chromosome 2.The function of the PAX3 gene remains unknown. However, some researchers suggest that PAX3 helps to regulate the functioning of another gene (known as “MITF”) that has been implicated in some cases of WS2.In some families with WS2, researchers have determined that the disorder results from mutations of a gene designated “MITF” (for “microphthalmia-associated transcription factor”) on chromosome 3 (3p14.1-p12.3). WS2 due to MITF gene mutations is known as “WS2A.” However, in other families, genetic analysis has demonstrated that WS2 does not result from mutations of the MITF gene. Thus, researchers indicate that there is at least one other genetic form of WS2, which they have designated “WS2B.” SOX10 mutations and deletions are also responsible for WS2.The MITF gene is thought to regulate the production of a protein that plays an essential role in the development of certain pigment (melanin)-producing cells known as melanocytes. Absence or impaired functioning of melanocytes affects pigmentation of the eyes, skin, and hair and has been shown to affect hearing function of the cochlea of the inner ear. Thus, investigators indicate that mutations of the MITF gene may result in abnormalities of melanocyte development, leading to the reduced pigmentation (hypopigmentation) and hearing loss potentially associated with WS2. As mentioned above, evidence suggests that the MITF gene is regulated by the PAX3 gene. Therefore, researchers indicate that mutations of the PAX3 gene may cause failed regulation of the MITF gene, potentially leading to the pigmentary and hearing abnormalities also seen in WS1.As with WS1, Waardenburg syndrome type III (WS3) may result from certain mutations of the PAX3 gene that may be inherited as an autosomal dominant trait or occur sporadically. In addition, some investigators suggest that WS3 may sometimes result from mutations of the PAX3 gene of both chromosomes (homozygosity). For example, in a large family (kindred) in which several members were affected by WS1, one child was diagnosed with severe WS3. The parents, who were closely related by blood (consanguineous), were both affected by mild WS1. Evidence suggested that siblings with WS1 inherited one mutated copy of the PAX3 gene (heterozygosity) from one parent, whereas the child with WS3 inherited mutated copies of the PAX3 gene from both parents. In other individuals with WS3, the disorder has been shown to result from deletion of the PAX3 gene and adjacent genes on chromosome 2.Waardenburg syndrome type IV (WS4), also known as Waardenburg-Hirschsprung disease, has been shown to result from mutations of several different genes that have also been implicated in causing some isolated cases of Hirschsprung disease. These include the EDNRB gene (mapped to chromosome 13q22), the EDN3 gene (chromosome 20q13.2-q13.3), or the SOX10 gene (chromosome 22q13).Researchers have identified mutations of the EDNRB gene or the EDN3 gene on both chromosomes (homozygosity) in some individuals with WS4, whereas single mutations of these genes (i.e., heterozygosity) may result in Hirschsprung disease alone. Therefore, researchers indicate that WS4 due to mutation of the EDNRB or EDN3 gene may be inherited as an autosomal recessive trait. In recessive disorders, the condition does not appear unless a person inherits the same defective gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy.In contrast, evidence suggests that a single mutated copy of the SOX10 gene may result in WS4. Thus, WS4 due to mutation of the SOX10 gene may be inherited as an autosomal dominant trait or may appear to occur sporadically due to new gene mutations. Together with the PAX3 gene, the SOX10 gene is thought to play some role in activating expression of the MITF gene. As mentioned above, mutations of the PAX3 gene have been identified in individuals with WS1 and WS3. MITF gene mutations have been implicated in some cases of WS2 (i.e., WS2A). Thus, researchers suggest that mutations leading to alterations in the interaction between the PAX3, MITF, and SOX10 genes may result in the pigmentary and hearing abnormalities seen in the Waardenburg syndromes. In addition, because some individuals with WS4 due to SOX10 mutations have had Hirschsprung disease as well as certain abnormalities of the central nervous system (CNS), the SOX10 gene is also thought to play some role in the early development of the autonomic nervous system and the CNS, particularly glial cells. The autonomic nervous system helps to regulate involuntary functions of the body. Glial cells are connective tissue cells of the CNS that hold together and protect certain nerve cells (neurons).
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Causes of Waardenburg Syndrome. In most cases, Waardenburg syndrome type I (WS1) and type II (WS2) are inherited as autosomal dominant traits with variable penetrance and expressivity. Some cases of Waardenburg syndrome type III (WS3) and type IV (WS4) appear to have an autosomal recessive pattern of inheritance. Mutations in the EDN3, EDNRB, MITF, PAX3 and SOX10 genes cause Waardenburg syndrome.In dominant disorders, a single copy of the disease gene (received from either the mother or father) will be expressed “dominating” the other normal gene, potentially resulting in the appearance of the disease. The risk of transmitting the disease gene from parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child. In autosomal dominant disorders with variable penetrance and expressivity, manifestations of the disorder may not be present in all those who inherit the altered (mutated) gene for the disease. In those who do develop symptoms, the specific characteristics that are manifested may vary greatly in range and severity from case to case.In some individuals with WS1 or WS2, there may be no apparent family history of the disorder. In such cases, researchers indicate that the disorder may sometimes result from new genetic changes (mutations) that occur spontaneously (sporadically) for unknown reasons. (In other instances, an apparent lack of a positive family history may be due to incomplete penetrance and/or variable expressivity as discussed above.) Evidence suggests that new (sporadic) mutations for WS1 may be associated with advanced age of the father (advanced paternal age).Researchers have located a gene responsible for WS1–known as the “PAX3” gene–on the long arm (q) of chromosome 2 (2q35). Multiple specific mutations of the PAX3 gene have been identified in different individuals and families (kindreds) affected by WS1. Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q.” Chromosomes are further subdivided into bands that are numbered. Therefore, “chromosome 2q35” refers to band 35 on the long arm of chromosome 2.The function of the PAX3 gene remains unknown. However, some researchers suggest that PAX3 helps to regulate the functioning of another gene (known as “MITF”) that has been implicated in some cases of WS2.In some families with WS2, researchers have determined that the disorder results from mutations of a gene designated “MITF” (for “microphthalmia-associated transcription factor”) on chromosome 3 (3p14.1-p12.3). WS2 due to MITF gene mutations is known as “WS2A.” However, in other families, genetic analysis has demonstrated that WS2 does not result from mutations of the MITF gene. Thus, researchers indicate that there is at least one other genetic form of WS2, which they have designated “WS2B.” SOX10 mutations and deletions are also responsible for WS2.The MITF gene is thought to regulate the production of a protein that plays an essential role in the development of certain pigment (melanin)-producing cells known as melanocytes. Absence or impaired functioning of melanocytes affects pigmentation of the eyes, skin, and hair and has been shown to affect hearing function of the cochlea of the inner ear. Thus, investigators indicate that mutations of the MITF gene may result in abnormalities of melanocyte development, leading to the reduced pigmentation (hypopigmentation) and hearing loss potentially associated with WS2. As mentioned above, evidence suggests that the MITF gene is regulated by the PAX3 gene. Therefore, researchers indicate that mutations of the PAX3 gene may cause failed regulation of the MITF gene, potentially leading to the pigmentary and hearing abnormalities also seen in WS1.As with WS1, Waardenburg syndrome type III (WS3) may result from certain mutations of the PAX3 gene that may be inherited as an autosomal dominant trait or occur sporadically. In addition, some investigators suggest that WS3 may sometimes result from mutations of the PAX3 gene of both chromosomes (homozygosity). For example, in a large family (kindred) in which several members were affected by WS1, one child was diagnosed with severe WS3. The parents, who were closely related by blood (consanguineous), were both affected by mild WS1. Evidence suggested that siblings with WS1 inherited one mutated copy of the PAX3 gene (heterozygosity) from one parent, whereas the child with WS3 inherited mutated copies of the PAX3 gene from both parents. In other individuals with WS3, the disorder has been shown to result from deletion of the PAX3 gene and adjacent genes on chromosome 2.Waardenburg syndrome type IV (WS4), also known as Waardenburg-Hirschsprung disease, has been shown to result from mutations of several different genes that have also been implicated in causing some isolated cases of Hirschsprung disease. These include the EDNRB gene (mapped to chromosome 13q22), the EDN3 gene (chromosome 20q13.2-q13.3), or the SOX10 gene (chromosome 22q13).Researchers have identified mutations of the EDNRB gene or the EDN3 gene on both chromosomes (homozygosity) in some individuals with WS4, whereas single mutations of these genes (i.e., heterozygosity) may result in Hirschsprung disease alone. Therefore, researchers indicate that WS4 due to mutation of the EDNRB or EDN3 gene may be inherited as an autosomal recessive trait. In recessive disorders, the condition does not appear unless a person inherits the same defective gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy.In contrast, evidence suggests that a single mutated copy of the SOX10 gene may result in WS4. Thus, WS4 due to mutation of the SOX10 gene may be inherited as an autosomal dominant trait or may appear to occur sporadically due to new gene mutations. Together with the PAX3 gene, the SOX10 gene is thought to play some role in activating expression of the MITF gene. As mentioned above, mutations of the PAX3 gene have been identified in individuals with WS1 and WS3. MITF gene mutations have been implicated in some cases of WS2 (i.e., WS2A). Thus, researchers suggest that mutations leading to alterations in the interaction between the PAX3, MITF, and SOX10 genes may result in the pigmentary and hearing abnormalities seen in the Waardenburg syndromes. In addition, because some individuals with WS4 due to SOX10 mutations have had Hirschsprung disease as well as certain abnormalities of the central nervous system (CNS), the SOX10 gene is also thought to play some role in the early development of the autonomic nervous system and the CNS, particularly glial cells. The autonomic nervous system helps to regulate involuntary functions of the body. Glial cells are connective tissue cells of the CNS that hold together and protect certain nerve cells (neurons).
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Affects of Waardenburg Syndrome
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Waardenburg syndrome (WS) is named after the investigator (PJ Waardenburg) who first precisely described the disorder in 1951. At least 1,400 cases have since been recorded in the medical literature. Evidence suggests that WS may have a frequency of approximately one in 40,000 births and account for about two to five percent of cases of congenital deafness. The disorder appears to affect males and females relatively equally.
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Affects of Waardenburg Syndrome. Waardenburg syndrome (WS) is named after the investigator (PJ Waardenburg) who first precisely described the disorder in 1951. At least 1,400 cases have since been recorded in the medical literature. Evidence suggests that WS may have a frequency of approximately one in 40,000 births and account for about two to five percent of cases of congenital deafness. The disorder appears to affect males and females relatively equally.
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Related disorders of Waardenburg Syndrome
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Symptoms of the following disorders may be similar to those of Waardenburg syndrome (WS). Comparisons may be useful for a differential diagnosis:There are a number of disorders that may be characterized by certain features similar to those seen in WS. For example, according to researchers, such disorders may include familial cases of partial albinism and deafness; familial cases of vitiligo and congenital sensorineural deafness; or a condition known as Vogt-Koyanagi-Harada syndrome. The latter may be characterized by inflammatory conditions of the eyes; vitiligo; whitening of the eyebrows, eyelashes, and scalp hair (poliosis); hair loss (alopecia); a condition in which certain sounds may cause discomfort (dysacusis); and/or other symptoms and findings. In addition, some congenital disorders may also be associated with sideways displacement of the inner angles of the eyes (dystopia canthorum); widely spaced eyes (ocular hypertelorism); narrow nostrils; unusually bushy eyebrows that may grow together (synophrys); hearing impairment; upper limb malformations; digestive abnormalities; and/or other features potentially associated with WS. However, such disorders are often characterized by additional, distinctive symptoms, physical findings, or other features that may help to distinguish them from WS. (For more information on these disorders, choose the exact disease name in question as your search term in the Rare Disease Database.)
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Related disorders of Waardenburg Syndrome. Symptoms of the following disorders may be similar to those of Waardenburg syndrome (WS). Comparisons may be useful for a differential diagnosis:There are a number of disorders that may be characterized by certain features similar to those seen in WS. For example, according to researchers, such disorders may include familial cases of partial albinism and deafness; familial cases of vitiligo and congenital sensorineural deafness; or a condition known as Vogt-Koyanagi-Harada syndrome. The latter may be characterized by inflammatory conditions of the eyes; vitiligo; whitening of the eyebrows, eyelashes, and scalp hair (poliosis); hair loss (alopecia); a condition in which certain sounds may cause discomfort (dysacusis); and/or other symptoms and findings. In addition, some congenital disorders may also be associated with sideways displacement of the inner angles of the eyes (dystopia canthorum); widely spaced eyes (ocular hypertelorism); narrow nostrils; unusually bushy eyebrows that may grow together (synophrys); hearing impairment; upper limb malformations; digestive abnormalities; and/or other features potentially associated with WS. However, such disorders are often characterized by additional, distinctive symptoms, physical findings, or other features that may help to distinguish them from WS. (For more information on these disorders, choose the exact disease name in question as your search term in the Rare Disease Database.)
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Diagnosis of Waardenburg Syndrome
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Waardenburg syndrome (WS) may be diagnosed at birth or early childhood (or, in some cases, at a later age) based upon a thorough clinical evaluation, identification of characteristic physical findings, a complete patient and family history, and various specialized studies. For example, in those with suspected WS, diagnostic evaluation may include use of a caliper to measure the distances between the inner angles of the eyes (inner canthi), the outer angles of the eyes (outer canthi), and the pupils (interpupillary distances). (A caliper is an instrument with two hinged, movable, curved arms used to measure thickness or diameter.) Researchers indicate that obtaining and evaluating a composite of these measurements (i.e., using a predefined biometric index known as the “W-index”) may sometimes be helpful in confirming the presence or absence of dystopia canthorum, a finding that may suggest WS1.Additional diagnostic studies may be conducted to help detect or characterize certain abnormalities potentially associated with WS. Such studies may include examination with an illuminated microscope to visualize internal structures of the eyes (slit-lamp examination); specialized hearing (auditory) tests; and/or advanced imaging techniques, such as to evaluate inner ear abnormalities, skeletal defects (e.g., seen in WS3), Hirschsprung disease (e.g., seen in WS4), etc. For example, researchers indicate that computed tomography (CT) scanning may help to characterize inner ear defects responsible for congenital sensorineural deafness. (During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of internal structures.) In selected cases, diagnostic evaluation may also include the removal (biopsy) and microscopic examination of certain tissue samples, such as rectal biopsies to help confirm Hirschsprung disease. In some instances, additional diagnostic studies may also be recommended.
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Diagnosis of Waardenburg Syndrome. Waardenburg syndrome (WS) may be diagnosed at birth or early childhood (or, in some cases, at a later age) based upon a thorough clinical evaluation, identification of characteristic physical findings, a complete patient and family history, and various specialized studies. For example, in those with suspected WS, diagnostic evaluation may include use of a caliper to measure the distances between the inner angles of the eyes (inner canthi), the outer angles of the eyes (outer canthi), and the pupils (interpupillary distances). (A caliper is an instrument with two hinged, movable, curved arms used to measure thickness or diameter.) Researchers indicate that obtaining and evaluating a composite of these measurements (i.e., using a predefined biometric index known as the “W-index”) may sometimes be helpful in confirming the presence or absence of dystopia canthorum, a finding that may suggest WS1.Additional diagnostic studies may be conducted to help detect or characterize certain abnormalities potentially associated with WS. Such studies may include examination with an illuminated microscope to visualize internal structures of the eyes (slit-lamp examination); specialized hearing (auditory) tests; and/or advanced imaging techniques, such as to evaluate inner ear abnormalities, skeletal defects (e.g., seen in WS3), Hirschsprung disease (e.g., seen in WS4), etc. For example, researchers indicate that computed tomography (CT) scanning may help to characterize inner ear defects responsible for congenital sensorineural deafness. (During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of internal structures.) In selected cases, diagnostic evaluation may also include the removal (biopsy) and microscopic examination of certain tissue samples, such as rectal biopsies to help confirm Hirschsprung disease. In some instances, additional diagnostic studies may also be recommended.
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Therapies of Waardenburg Syndrome
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TreatmentThe treatment of WS is directed toward the specific symptoms that are apparent in each individual. Such treatment may require the coordinated efforts of a team of medical professionals, such as physicians who specialize in skin disorders (dermatologists); eye specialists (ophthalmologists); hearing specialists; physicians who diagnose and treat disorders of the skeleton, joints, muscles, and related tissues (orthopedists); physicians who specialize in diseases of the digestive tract (gastroenterologists); speech-language pathologists; physical therapists; and/or other health care professionals.Early recognition of sensorineural deafness may play an important role in ensuring prompt intervention and appropriate supportive management. In some instances, physicians may recommend treatment with a cochlear implant, a device in which electrodes implanted in the inner ear stimulate the auditory nerve to send impulses to the brain. In addition, early, special instruction may be recommended to assist in the development of speech and certain methods (e.g., sign language, lip reading, the use of communication devices, etc.) that may aid communication.Because individuals with pigmentary abnormalities of the skin may be prone to sunburns and a risk of skin cancer, physicians may recommend avoiding direct sunlight, using sunscreen with a high sun protection factor (SPF), wearing sunglasses and coverings that help to protect against the sun (e.g., hats, long sleeves, pants, etc.), and following other appropriate measures. For those with diminished pigmentation of the irides, lateral displacement of the inner angles of the eyes (dystopia canthorum), and/or other associated ocular abnormalities, ophthalmologists may also recommend certain supportive measures. These may include the use of specially tinted glasses or contact lenses (e.g., to help reduce possible sensitivity to light), measures to help prevent or treat infection, or other preventive or therapeutic steps.In individuals with upper limb abnormalities, treatment may include physical therapy and various orthopedic techniques, potentially including surgical measures. In addition, surgery may sometimes be recommended to help treat other abnormalities that may be associated with the disorder. The specific surgical procedures performed will depend upon the severity and location of the anatomical abnormalities, their associated symptoms, and other factors.For example, for affected individuals with Hirschsprung disease, treatment may require removal of the affected intestinal region and surgical “rejoining” of healthy intestinal areas. In some instances, before surgical correction of the condition, treatment may require the creation of an artificial outlet for the colon through an opening in the abdominal wall (i.e., a temporary colostomy).Additional supportive services that may be beneficial for some affected individuals include special education and/or other medical, social, or occupational services. Genetic counseling will also be of benefit for affected individuals and their families. Other treatment for this disorder is symptomatic and supportive.
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Therapies of Waardenburg Syndrome. TreatmentThe treatment of WS is directed toward the specific symptoms that are apparent in each individual. Such treatment may require the coordinated efforts of a team of medical professionals, such as physicians who specialize in skin disorders (dermatologists); eye specialists (ophthalmologists); hearing specialists; physicians who diagnose and treat disorders of the skeleton, joints, muscles, and related tissues (orthopedists); physicians who specialize in diseases of the digestive tract (gastroenterologists); speech-language pathologists; physical therapists; and/or other health care professionals.Early recognition of sensorineural deafness may play an important role in ensuring prompt intervention and appropriate supportive management. In some instances, physicians may recommend treatment with a cochlear implant, a device in which electrodes implanted in the inner ear stimulate the auditory nerve to send impulses to the brain. In addition, early, special instruction may be recommended to assist in the development of speech and certain methods (e.g., sign language, lip reading, the use of communication devices, etc.) that may aid communication.Because individuals with pigmentary abnormalities of the skin may be prone to sunburns and a risk of skin cancer, physicians may recommend avoiding direct sunlight, using sunscreen with a high sun protection factor (SPF), wearing sunglasses and coverings that help to protect against the sun (e.g., hats, long sleeves, pants, etc.), and following other appropriate measures. For those with diminished pigmentation of the irides, lateral displacement of the inner angles of the eyes (dystopia canthorum), and/or other associated ocular abnormalities, ophthalmologists may also recommend certain supportive measures. These may include the use of specially tinted glasses or contact lenses (e.g., to help reduce possible sensitivity to light), measures to help prevent or treat infection, or other preventive or therapeutic steps.In individuals with upper limb abnormalities, treatment may include physical therapy and various orthopedic techniques, potentially including surgical measures. In addition, surgery may sometimes be recommended to help treat other abnormalities that may be associated with the disorder. The specific surgical procedures performed will depend upon the severity and location of the anatomical abnormalities, their associated symptoms, and other factors.For example, for affected individuals with Hirschsprung disease, treatment may require removal of the affected intestinal region and surgical “rejoining” of healthy intestinal areas. In some instances, before surgical correction of the condition, treatment may require the creation of an artificial outlet for the colon through an opening in the abdominal wall (i.e., a temporary colostomy).Additional supportive services that may be beneficial for some affected individuals include special education and/or other medical, social, or occupational services. Genetic counseling will also be of benefit for affected individuals and their families. Other treatment for this disorder is symptomatic and supportive.
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Overview of WAGR Syndrome/11p Deletion Syndrome
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WAGR syndrome/11p deletion syndrome is a rare genetic syndrome in which there is a predisposition to several conditions, including certain malignancies, distinctive eye abnormalities, and/or intellectual disability. “WAGR” is an acronym for the characteristic abnormalities associated with the syndrome. The acronym stands for (W)ilms' Tumor, the most common form of kidney cancer in children; (A)niridia, partial or complete absence of the colored region of the eye(s) (iris or irides); (G) Genitourinary abnormalities, such as undescended testicles or hypospadias in males, or internal genital or urinary anomalies in females; and Mental (R)etardation (intellectual disability). A combination of two or more of these conditions is usually present in most individuals with WAGR syndrome/11p deletion syndrome. The clinical picture varies, depending upon the combination of associated abnormalities.WAGR syndrome/11p deletion syndrome is caused by defects (mutations) of adjacent genes on a region of chromosome 11 (11p13). In most cases, such genetic changes (e.g., deletions at band 11p13) occur spontaneously during early embryonic development (de novo) for unknown reasons (sporadic). In very rare cases, the mutation may be inherited as the result of a rearrangement of parts of two chromosomes, which causes the loss of some genetic material (translocation) or other heritable genetic abnormality. The presence of more than one type of chromosomal makeup within an individual (mosaic deletion) resulting in WAGR syndrome/11p deletion syndrome has also been reported.Since 1964, the names given to this disorder have changed frequently as variations in the combination of clinical symptoms present and the range of genetic abnormalities associated with it have been discovered. The term “WAGR syndrome” is now being replaced by “11p deletion syndrome” to more accurately reflect current knowledge about the disorder and to allow for consistent clinical diagnosis and genetic classification in the future.
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Overview of WAGR Syndrome/11p Deletion Syndrome. WAGR syndrome/11p deletion syndrome is a rare genetic syndrome in which there is a predisposition to several conditions, including certain malignancies, distinctive eye abnormalities, and/or intellectual disability. “WAGR” is an acronym for the characteristic abnormalities associated with the syndrome. The acronym stands for (W)ilms' Tumor, the most common form of kidney cancer in children; (A)niridia, partial or complete absence of the colored region of the eye(s) (iris or irides); (G) Genitourinary abnormalities, such as undescended testicles or hypospadias in males, or internal genital or urinary anomalies in females; and Mental (R)etardation (intellectual disability). A combination of two or more of these conditions is usually present in most individuals with WAGR syndrome/11p deletion syndrome. The clinical picture varies, depending upon the combination of associated abnormalities.WAGR syndrome/11p deletion syndrome is caused by defects (mutations) of adjacent genes on a region of chromosome 11 (11p13). In most cases, such genetic changes (e.g., deletions at band 11p13) occur spontaneously during early embryonic development (de novo) for unknown reasons (sporadic). In very rare cases, the mutation may be inherited as the result of a rearrangement of parts of two chromosomes, which causes the loss of some genetic material (translocation) or other heritable genetic abnormality. The presence of more than one type of chromosomal makeup within an individual (mosaic deletion) resulting in WAGR syndrome/11p deletion syndrome has also been reported.Since 1964, the names given to this disorder have changed frequently as variations in the combination of clinical symptoms present and the range of genetic abnormalities associated with it have been discovered. The term “WAGR syndrome” is now being replaced by “11p deletion syndrome” to more accurately reflect current knowledge about the disorder and to allow for consistent clinical diagnosis and genetic classification in the future.
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Symptoms of WAGR Syndrome/11p Deletion Syndrome
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WAGR syndrome/11p deletion syndrome is defined as a genetic syndrome in which there is a predisposition to Wilms' tumor; aniridia; abnormalities of the reproductive and urinary tracts (genitourinary); and intellectual disability. The specific symptoms that occur depend upon the combination of disorders present.Wilms' tumor (nephroblastoma) is the most common form of kidney cancer in early childhood. It occurs in approximately one half of all cases of WAGR syndrome/11p deletion syndrome. In the early stages of Wilms' tumor, there are usually no symptoms. The first signs of the disease may include blood in the urine (hematuria), low-grade fever, loss of appetite, paleness, weight loss, fatigue and lack of energy (lethargy), and swelling of the abdomen. In the later stages, slight pain may occur at intervals (intermittent), or pain may be sudden and sharp. (For more information on this disorder, choose “Wilms' tumor” as your search term in the Rare Disease Database.) Abnormally persistent clusters of embryonal cells within the kidneys (nephrogenic rests) are not uncommon in children with WAGR syndrome/11p deletion syndrome. This tissue is noticeable on ultrasound examination, and is sometimes difficult to distinguish from Wilms' tumor. It is thought that nephrogenic rests, or clusters of rests (nephroblastomatosis), may give rise to Wilms' tumor in some cases.In infants with aniridia that is associated with WAGR syndrome/11p deletion syndrome, the irises fail to develop normally before birth (prenatally). This results in the partial or complete absence of the round, colored (pigmented) portion of the eye (iris). Aniridia is almost always present in individuals with WAGR syndrome/11p deletion syndrome; however, at least four cases of WAGR syndrome/11p deletion syndrome have been confirmed without aniridia. In almost all cases, aniridia occurs in combination with other disorders of the eye. These accompanying disorders may include clouding of the lens of the eye (cataract); rapid, involuntary movements of the eye (nystagmus); and/or partial or complete loss of vision due to abnormally high pressure of the fluid in the eye (glaucoma). Progressive scarring and opacity of the cornea (aniridic keratopathy, also called corneal pannus) is common in adolescents and adults with aniridia, but may also occur in children. (For more information on these disorders, choose “Aniridia” and “Cataracts” as your search terms in the Rare Disease Database.)In the medical literature, the “G” in the acronym WAGR refers to “Genitourinary abnormalities,” “ambiguous Genitalia,” or “Gonadoblastoma.” Gonadoblastoma, a cancer of the cells that form the testes in males or the ovaries in females (gonads), occurs exclusively in people with defective development of the gonads (gonadal dysgenesis), as is the case in some infants with WAGR syndrome/11p deletion syndrome. Although gonadoblastoma is not always manifested in WAGR syndrome/11p deletion syndrome, it is important to be aware of the genetic predisposition for this potentially serious disorder so that appropriate steps can be taken. (See the “Standard Therapies” section of this report for more information.)Other abnormalities of the reproductive and urinary tracts (genitourinary) may be present in many children with WAGR syndrome/11p deletion syndrome. In males, these may include the failure of one or both testes to descend into the scrotum (cryptorchidism) and placement of the urinary opening (meatus) on the underside of the penis (hypospadias). In females, these abnormalities may include underdeveloped (streak) ovaries, and malformations of the uterus, fallopian tubes, or vagina. These abnormalities may also include duplicate ureters or horseshoe kidney.In addition, individuals with WAGR syndrome/11p deletion syndrome may have the gonads of one sex and external genitalia resembling that of the opposite sex (ambiguous genitalia), making their sexual assignment (i.e., male or female) uncertain (pseudohermaphroditism).Intellectual disability is common in children with WAGR syndrome/11p deletion syndrome. However, the severity of the impairment varies greatly from case to case, ranging from severe to mild intellectual disability (IQ of 20 to 70) ). Some children with WAGR syndrome/11p deletion syndrome may have normal intelligence (IQ at or above 100).A variety of behavioral and psychiatric disorders have been reported in WAGR syndrome/11p deletion syndrome. These include autism spectrum disorders, attention-deficit disorder (with or without hyperactivity), obsessive-compulsive disorder, other anxiety disorders, and depression.Although hearing is usually normal in people with WAGR syndrome/11p deletion syndrome, many individuals have difficulty with the way the brain processes auditory information, particularly with recognizing and interpreting the sounds involved with speech (auditory processing disorder).Metabolic abnormalities present in some individuals with WAGR syndrome/11p deletion syndrome may include early-onset overweight (obesity), and high serum cholesterol (hyperlipidemia). Some individuals with WAGR syndrome/11p deletion syndrome have a combination of conditions including insulin resistance, high blood pressure, and high serum cholesterol which can increase the risk for coronary artery disease, stroke, and type 2 diabetes (metabolic syndrome).Chronic kidney failure occurs in approximately 60% of individuals with WAGR syndrome/11p deletion syndrome, most often after age 12. This failure is usually the result of Focal Segmental Glomerulosclerosis (FSGS) a disorder which results in scarring of the filtering tubes of the kidneys. Chronic kidney failure may occur in an individual with WAGR syndrome/11p deletion syndrome regardless of their history of Wilms tumor.Frequent, recurrent upper respiratory infections, ear and sinus infections, asthma, and pneumonia are common in WAGR syndrome/11p deletion syndrome, particularly in young children with the disorder. Delayed loss of primary teeth and severely crowded or uneven teeth (dental malocclusion) are also common. A temporary suspension of breathing occurring repeatedly during sleep (sleep apnea) may occur in both children and adults with WAGR syndrome/11p deletion syndrome.Abnormalities of muscle tone or strength (hypertonia/hypotonia) are common in WAGR syndrome/11p deletion syndrome, particularly during infancy and early childhood. Seizure disorder (epilepsy) has been reported frequently and chronic inflammation of the pancreas (pancreatitis) has also been reported.In rare cases, other symptoms of WAGR syndrome/11p deletion syndrome which may be present at birth (congenital) may include: defects of the heart or kidneys, partial or complete absence of the structure which connects the two hemispheres of the brain (agenesis of the corpus callosum) a weak area of the abdomen which allows part of the intestines to push through (inguinal hernia) an abnormal opening in the diaphragm which allows part of the abdominal organs to migrate into the chest cavity (diaphragmatic hernia) extra fingers or toes (polydactyly) webbing or fusing of fingers or toes (syndactyly) absence or closure of ducts which drain bile from the liver (biliary atresia) weakness or floppiness of the walls of the windpipe (tracheomalacia) and hearing impairment.In rare cases, other symptoms of WAGR syndrome/11p deletion syndrome which may develop or be diagnosed after birth may include: an abnormal enlargement of a part of the body (hemihypertrophy), growth retardation, communication disorders, inability of the brain to integrate information received from the body's five sensory systems (sensory integration disorder) feeding/swallowing disorders, gastroesophageal reflux, multiple bony lumps or spurs on the bones (multiple exostoses) and curvature of the spine (scoliosis).The disorders most commonly associated with WAGR syndrome/11p deletion syndrome (Wilms' tumor, aniridia, genitourinary abnormalities, and intellectual disability) as well as those listed above may appear together or in a variety of combinations. In the medical literature, these various groupings (disorder subdivisions) have been referred to as distinct disorders including “Aniridia-Wilms' Tumor Association” (AWTA); “Aniridia-ambiguous Genitalia-mental Retardation” (AGR triad); or “Aniridia- Wilms' Tumor-Gonadoblastoma.” While all individuals with WAGR syndrome/11p deletion syndrome will be found to have deletions in chromosome 11p13, great variation in the size and nature of these deletions is possible among individuals. These variations in missing genetic material are thought to account for the differences in symptoms and manifestations of the disorder.
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Symptoms of WAGR Syndrome/11p Deletion Syndrome. WAGR syndrome/11p deletion syndrome is defined as a genetic syndrome in which there is a predisposition to Wilms' tumor; aniridia; abnormalities of the reproductive and urinary tracts (genitourinary); and intellectual disability. The specific symptoms that occur depend upon the combination of disorders present.Wilms' tumor (nephroblastoma) is the most common form of kidney cancer in early childhood. It occurs in approximately one half of all cases of WAGR syndrome/11p deletion syndrome. In the early stages of Wilms' tumor, there are usually no symptoms. The first signs of the disease may include blood in the urine (hematuria), low-grade fever, loss of appetite, paleness, weight loss, fatigue and lack of energy (lethargy), and swelling of the abdomen. In the later stages, slight pain may occur at intervals (intermittent), or pain may be sudden and sharp. (For more information on this disorder, choose “Wilms' tumor” as your search term in the Rare Disease Database.) Abnormally persistent clusters of embryonal cells within the kidneys (nephrogenic rests) are not uncommon in children with WAGR syndrome/11p deletion syndrome. This tissue is noticeable on ultrasound examination, and is sometimes difficult to distinguish from Wilms' tumor. It is thought that nephrogenic rests, or clusters of rests (nephroblastomatosis), may give rise to Wilms' tumor in some cases.In infants with aniridia that is associated with WAGR syndrome/11p deletion syndrome, the irises fail to develop normally before birth (prenatally). This results in the partial or complete absence of the round, colored (pigmented) portion of the eye (iris). Aniridia is almost always present in individuals with WAGR syndrome/11p deletion syndrome; however, at least four cases of WAGR syndrome/11p deletion syndrome have been confirmed without aniridia. In almost all cases, aniridia occurs in combination with other disorders of the eye. These accompanying disorders may include clouding of the lens of the eye (cataract); rapid, involuntary movements of the eye (nystagmus); and/or partial or complete loss of vision due to abnormally high pressure of the fluid in the eye (glaucoma). Progressive scarring and opacity of the cornea (aniridic keratopathy, also called corneal pannus) is common in adolescents and adults with aniridia, but may also occur in children. (For more information on these disorders, choose “Aniridia” and “Cataracts” as your search terms in the Rare Disease Database.)In the medical literature, the “G” in the acronym WAGR refers to “Genitourinary abnormalities,” “ambiguous Genitalia,” or “Gonadoblastoma.” Gonadoblastoma, a cancer of the cells that form the testes in males or the ovaries in females (gonads), occurs exclusively in people with defective development of the gonads (gonadal dysgenesis), as is the case in some infants with WAGR syndrome/11p deletion syndrome. Although gonadoblastoma is not always manifested in WAGR syndrome/11p deletion syndrome, it is important to be aware of the genetic predisposition for this potentially serious disorder so that appropriate steps can be taken. (See the “Standard Therapies” section of this report for more information.)Other abnormalities of the reproductive and urinary tracts (genitourinary) may be present in many children with WAGR syndrome/11p deletion syndrome. In males, these may include the failure of one or both testes to descend into the scrotum (cryptorchidism) and placement of the urinary opening (meatus) on the underside of the penis (hypospadias). In females, these abnormalities may include underdeveloped (streak) ovaries, and malformations of the uterus, fallopian tubes, or vagina. These abnormalities may also include duplicate ureters or horseshoe kidney.In addition, individuals with WAGR syndrome/11p deletion syndrome may have the gonads of one sex and external genitalia resembling that of the opposite sex (ambiguous genitalia), making their sexual assignment (i.e., male or female) uncertain (pseudohermaphroditism).Intellectual disability is common in children with WAGR syndrome/11p deletion syndrome. However, the severity of the impairment varies greatly from case to case, ranging from severe to mild intellectual disability (IQ of 20 to 70) ). Some children with WAGR syndrome/11p deletion syndrome may have normal intelligence (IQ at or above 100).A variety of behavioral and psychiatric disorders have been reported in WAGR syndrome/11p deletion syndrome. These include autism spectrum disorders, attention-deficit disorder (with or without hyperactivity), obsessive-compulsive disorder, other anxiety disorders, and depression.Although hearing is usually normal in people with WAGR syndrome/11p deletion syndrome, many individuals have difficulty with the way the brain processes auditory information, particularly with recognizing and interpreting the sounds involved with speech (auditory processing disorder).Metabolic abnormalities present in some individuals with WAGR syndrome/11p deletion syndrome may include early-onset overweight (obesity), and high serum cholesterol (hyperlipidemia). Some individuals with WAGR syndrome/11p deletion syndrome have a combination of conditions including insulin resistance, high blood pressure, and high serum cholesterol which can increase the risk for coronary artery disease, stroke, and type 2 diabetes (metabolic syndrome).Chronic kidney failure occurs in approximately 60% of individuals with WAGR syndrome/11p deletion syndrome, most often after age 12. This failure is usually the result of Focal Segmental Glomerulosclerosis (FSGS) a disorder which results in scarring of the filtering tubes of the kidneys. Chronic kidney failure may occur in an individual with WAGR syndrome/11p deletion syndrome regardless of their history of Wilms tumor.Frequent, recurrent upper respiratory infections, ear and sinus infections, asthma, and pneumonia are common in WAGR syndrome/11p deletion syndrome, particularly in young children with the disorder. Delayed loss of primary teeth and severely crowded or uneven teeth (dental malocclusion) are also common. A temporary suspension of breathing occurring repeatedly during sleep (sleep apnea) may occur in both children and adults with WAGR syndrome/11p deletion syndrome.Abnormalities of muscle tone or strength (hypertonia/hypotonia) are common in WAGR syndrome/11p deletion syndrome, particularly during infancy and early childhood. Seizure disorder (epilepsy) has been reported frequently and chronic inflammation of the pancreas (pancreatitis) has also been reported.In rare cases, other symptoms of WAGR syndrome/11p deletion syndrome which may be present at birth (congenital) may include: defects of the heart or kidneys, partial or complete absence of the structure which connects the two hemispheres of the brain (agenesis of the corpus callosum) a weak area of the abdomen which allows part of the intestines to push through (inguinal hernia) an abnormal opening in the diaphragm which allows part of the abdominal organs to migrate into the chest cavity (diaphragmatic hernia) extra fingers or toes (polydactyly) webbing or fusing of fingers or toes (syndactyly) absence or closure of ducts which drain bile from the liver (biliary atresia) weakness or floppiness of the walls of the windpipe (tracheomalacia) and hearing impairment.In rare cases, other symptoms of WAGR syndrome/11p deletion syndrome which may develop or be diagnosed after birth may include: an abnormal enlargement of a part of the body (hemihypertrophy), growth retardation, communication disorders, inability of the brain to integrate information received from the body's five sensory systems (sensory integration disorder) feeding/swallowing disorders, gastroesophageal reflux, multiple bony lumps or spurs on the bones (multiple exostoses) and curvature of the spine (scoliosis).The disorders most commonly associated with WAGR syndrome/11p deletion syndrome (Wilms' tumor, aniridia, genitourinary abnormalities, and intellectual disability) as well as those listed above may appear together or in a variety of combinations. In the medical literature, these various groupings (disorder subdivisions) have been referred to as distinct disorders including “Aniridia-Wilms' Tumor Association” (AWTA); “Aniridia-ambiguous Genitalia-mental Retardation” (AGR triad); or “Aniridia- Wilms' Tumor-Gonadoblastoma.” While all individuals with WAGR syndrome/11p deletion syndrome will be found to have deletions in chromosome 11p13, great variation in the size and nature of these deletions is possible among individuals. These variations in missing genetic material are thought to account for the differences in symptoms and manifestations of the disorder.
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Causes of WAGR Syndrome/11p Deletion Syndrome
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WAGR syndrome/11p deletion syndrome is known as a “contiguous gene syndrome”, meaning that it is caused by defects (mutations) of adjacent genes on a particular chromosome. In many affected individuals, the syndrome is thought to result from deletion of one copy of chromosome 11 at band p13 (monosomy). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q”. Chromosomes are further subdivided into bands that are numbered.In most individuals with WAGR syndrome/11p deletion syndrome, deletion of the short arm of chromosome 11 at band p13 occurs spontaneously during early embryonic development (de novo) for unknown reasons (sporadic). The size and nature of the chromosomal deletion and the specific genes affected determine the symptoms and findings associated with the disorder. For example, deletions (or other defects) of certain adjacent genes within the 11p13 chromosomal region are thought to result in Wilms' tumor (WT1 gene), aniridia (PAX6 gene), and possibly mental retardation. In addition, some researchers suggest that another gene closely located to the WT1 gene (designated as the GUD gene for genital dysplasia) may result in abnormalities of genitourinary development. However, others indicate that the genitourinary abnormalities seen in WAGR syndrome/11p deletion syndrome may actually be caused by deletion or other defects of the Wilms' Tumor (WT1) gene, suggesting that WT1 gene mutations may be manifested in more than one way (pleiotropy).Some documented cases of WAGR syndrome/11p deletion syndrome have been caused by complex chromosomal rearrangements that occur sporadically during early embryonic development (de novo). In these rearrangements, segments of chromosome 11 may break off and move to another chromosomal location. Many researchers believe that, in many WAGR syndrome/11p deletion syndrome cases caused by de novo rearrangements, parts of chromosomes other than chromosome 11 may have also switched locations.In a few documented cases of WAGR syndrome/11p deletion syndrome, one of the parents has a balanced translocation or other chromosomal abnormality. A translocation is balanced if pieces of two or more chromosomes break off and trade places, creating an altered but balanced set of chromosomes. Because a person with a balanced translocation has all the necessary genetic material for normal development, balanced translocations usually do not affect the carrier. However, they are associated with a higher risk of abnormal chromosomal development in the carrier's offspring. Mosaic deletions, in which more than one type of chromosomal makeup is present in an individual, have also been reported.
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Causes of WAGR Syndrome/11p Deletion Syndrome. WAGR syndrome/11p deletion syndrome is known as a “contiguous gene syndrome”, meaning that it is caused by defects (mutations) of adjacent genes on a particular chromosome. In many affected individuals, the syndrome is thought to result from deletion of one copy of chromosome 11 at band p13 (monosomy). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q”. Chromosomes are further subdivided into bands that are numbered.In most individuals with WAGR syndrome/11p deletion syndrome, deletion of the short arm of chromosome 11 at band p13 occurs spontaneously during early embryonic development (de novo) for unknown reasons (sporadic). The size and nature of the chromosomal deletion and the specific genes affected determine the symptoms and findings associated with the disorder. For example, deletions (or other defects) of certain adjacent genes within the 11p13 chromosomal region are thought to result in Wilms' tumor (WT1 gene), aniridia (PAX6 gene), and possibly mental retardation. In addition, some researchers suggest that another gene closely located to the WT1 gene (designated as the GUD gene for genital dysplasia) may result in abnormalities of genitourinary development. However, others indicate that the genitourinary abnormalities seen in WAGR syndrome/11p deletion syndrome may actually be caused by deletion or other defects of the Wilms' Tumor (WT1) gene, suggesting that WT1 gene mutations may be manifested in more than one way (pleiotropy).Some documented cases of WAGR syndrome/11p deletion syndrome have been caused by complex chromosomal rearrangements that occur sporadically during early embryonic development (de novo). In these rearrangements, segments of chromosome 11 may break off and move to another chromosomal location. Many researchers believe that, in many WAGR syndrome/11p deletion syndrome cases caused by de novo rearrangements, parts of chromosomes other than chromosome 11 may have also switched locations.In a few documented cases of WAGR syndrome/11p deletion syndrome, one of the parents has a balanced translocation or other chromosomal abnormality. A translocation is balanced if pieces of two or more chromosomes break off and trade places, creating an altered but balanced set of chromosomes. Because a person with a balanced translocation has all the necessary genetic material for normal development, balanced translocations usually do not affect the carrier. However, they are associated with a higher risk of abnormal chromosomal development in the carrier's offspring. Mosaic deletions, in which more than one type of chromosomal makeup is present in an individual, have also been reported.
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Affects of WAGR Syndrome/11p Deletion Syndrome
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WAGR syndrome/11p deletion syndrome is a rare genetic disorder that is thought to affect males more frequently than females. Because some affected individuals have external genitalia that strongly resembles that of the opposite sex, incorrect sex identification may occur initially
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Affects of WAGR Syndrome/11p Deletion Syndrome. WAGR syndrome/11p deletion syndrome is a rare genetic disorder that is thought to affect males more frequently than females. Because some affected individuals have external genitalia that strongly resembles that of the opposite sex, incorrect sex identification may occur initially
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Related disorders of WAGR Syndrome/11p Deletion Syndrome
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Symptoms of the following disorders can be similar to those of WAGR syndrome/11p deletion syndrome. Comparisons may be useful for a differential diagnosis:Drash syndrome is a very rare disorder that usually appears early in life. It is characterized by the combination of abnormal kidney function (nephropathy); Wilms' Tumor; and the presence of the gonads of one sex and external genitalia resembling that of the other, making the individual's sexual assignment (i.e., male or female) uncertain (pseudohermaphroditism). Some individuals may have the incomplete form of Drash syndrome, which consists of abnormal kidney function with either genital abnormalities (pseudohermaphroditism) or Wilms' tumor. Drash syndrome is caused by a point mutation (a type of mutation which causes the replacement of a single base nucleotide with another nucleotide) in the WT1 gene. Drash syndrome typically occurs for no apparent reason (sporadically). However, in rare cases, it may be inherited as an autosomal dominant genetic trait. (For more information on this disorder, choose “Drash” as your search term in the Rare Disease Database.)Frasier syndrome is a very rare disorder characterized by kidney failure; defective development of the gonads (gonadal dysgenesis), such as underdeveloped ovaries (streak gonads); cancer of the cells that form the ovaries or testes (gonadoblastoma); and pseudohermaphroditism. Researchers have reported that some individuals who were thought to have Drash syndrome actually had what is now designated as Frasier syndrome. Frasier syndrome is caused by a point mutation (a type of mutation which causes the replacement of a single base nucleotide with another nucleotide) in the WT1 gene, which is thought to occur for no apparent reason (sporadic).Potocki-Shaffer syndrome is a very rare disorder characterized by multiple bony lumps or spurs on the bones (multiple exostoses) and abnormally large openings in the skull (enlarged parietal foramina). Intellectual disability, malformations of the face (dysmorphism) and premature closure of the fibrous joints between the bones of the skull (craniosynostosis) may also be associated. Potocki-Shaffer syndrome is the result of a genetic deletion at 11p11.2, which is thought to occur for no apparent reason (sporadic). There have been several documented cases of individuals with overlap of Potocki-Shaffer syndrome and WAGR syndrome/11p deletion syndrome.Beckwith Wiedemann syndrome (BWS) The cardinal features of this disorder are bulging of the eyes (exomphalos), an enlarged tongue (macroglossia) and excessive secretion of growth hormone (gigantism) in the newborn. These features, together with omphalocele or other umbilical abnormalities, permit recognition of the disorder at birth. Because many of the affected infants have very low blood sugar (hypoglycemia) in the first days of life, anticipation of this complication can prevent serious neurologic consequences. Enlargement of the abdominal organs (visceromegaly), enlargement of cells within the outer layer of the adrenal gland (adrenocortical cytomegaly), and abnormal growth or development (dysplasia) of the renal medulla are conspicuous features. BWS patients are at increased risk of developing specific tumors. These include Adrenal carcinoma, nephroblastoma (Wilms tumor), hepatoblastoma, and rhabdomyosarcoma. BWS syndrome is caused by mutation in the chromosome 11p15.5 region. Most cases occur for no apparent reason (sporadic).
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Related disorders of WAGR Syndrome/11p Deletion Syndrome. Symptoms of the following disorders can be similar to those of WAGR syndrome/11p deletion syndrome. Comparisons may be useful for a differential diagnosis:Drash syndrome is a very rare disorder that usually appears early in life. It is characterized by the combination of abnormal kidney function (nephropathy); Wilms' Tumor; and the presence of the gonads of one sex and external genitalia resembling that of the other, making the individual's sexual assignment (i.e., male or female) uncertain (pseudohermaphroditism). Some individuals may have the incomplete form of Drash syndrome, which consists of abnormal kidney function with either genital abnormalities (pseudohermaphroditism) or Wilms' tumor. Drash syndrome is caused by a point mutation (a type of mutation which causes the replacement of a single base nucleotide with another nucleotide) in the WT1 gene. Drash syndrome typically occurs for no apparent reason (sporadically). However, in rare cases, it may be inherited as an autosomal dominant genetic trait. (For more information on this disorder, choose “Drash” as your search term in the Rare Disease Database.)Frasier syndrome is a very rare disorder characterized by kidney failure; defective development of the gonads (gonadal dysgenesis), such as underdeveloped ovaries (streak gonads); cancer of the cells that form the ovaries or testes (gonadoblastoma); and pseudohermaphroditism. Researchers have reported that some individuals who were thought to have Drash syndrome actually had what is now designated as Frasier syndrome. Frasier syndrome is caused by a point mutation (a type of mutation which causes the replacement of a single base nucleotide with another nucleotide) in the WT1 gene, which is thought to occur for no apparent reason (sporadic).Potocki-Shaffer syndrome is a very rare disorder characterized by multiple bony lumps or spurs on the bones (multiple exostoses) and abnormally large openings in the skull (enlarged parietal foramina). Intellectual disability, malformations of the face (dysmorphism) and premature closure of the fibrous joints between the bones of the skull (craniosynostosis) may also be associated. Potocki-Shaffer syndrome is the result of a genetic deletion at 11p11.2, which is thought to occur for no apparent reason (sporadic). There have been several documented cases of individuals with overlap of Potocki-Shaffer syndrome and WAGR syndrome/11p deletion syndrome.Beckwith Wiedemann syndrome (BWS) The cardinal features of this disorder are bulging of the eyes (exomphalos), an enlarged tongue (macroglossia) and excessive secretion of growth hormone (gigantism) in the newborn. These features, together with omphalocele or other umbilical abnormalities, permit recognition of the disorder at birth. Because many of the affected infants have very low blood sugar (hypoglycemia) in the first days of life, anticipation of this complication can prevent serious neurologic consequences. Enlargement of the abdominal organs (visceromegaly), enlargement of cells within the outer layer of the adrenal gland (adrenocortical cytomegaly), and abnormal growth or development (dysplasia) of the renal medulla are conspicuous features. BWS patients are at increased risk of developing specific tumors. These include Adrenal carcinoma, nephroblastoma (Wilms tumor), hepatoblastoma, and rhabdomyosarcoma. BWS syndrome is caused by mutation in the chromosome 11p15.5 region. Most cases occur for no apparent reason (sporadic).
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Diagnosis of WAGR Syndrome/11p Deletion Syndrome
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Diagnosis of WAGR Syndrome/11p Deletion Syndrome.
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Therapies of WAGR Syndrome/11p Deletion Syndrome
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WAGR syndrome/11p deletion syndrome can be diagnosed at birth, based upon a clinical evaluation, characteristic physical findings, and chromosomal studies (high-resolution karyotyping and molecular cytogenetic tests). In many cases, the partial or complete absence of the iris of the eye (aniridia) may be the only physical feature associated with WAGR Syndrome/11p deletion syndrome that is obvious at birth. In other cases, genitourinary abnormalities associated with the syndrome may also be apparent.If a child has aniridia, chromosomal studies are necessary to determine whether the child has a genetic predisposition for the disorders associated with WAGR syndrome/11p deletion syndrome.Treatment of WAGR syndrome/11p deletion syndrome is directed toward the specific symptoms that are apparent in each individual.Wilms' Tumor:Wilms' tumor will occur in approximately 50% of children with WAGR syndrome/11p deletion syndrome whose deletion encompasses the WT1 gene. The onset of Wilms' tumor in these children is most often between the ages of 1 and 3. The majority of cases of Wilms' tumor have been detected by age 8, but rare cases have occurred in individuals with WAGR syndrome/11p deletion syndrome as late as age 25. Surveillance for the development of Wilms'. tumor in children with WAGR syndrome/11p deletion syndrome should begin at birth or as soon as WAGR syndrome/11p deletion syndrome is suspected. This surveillance consists of abdominal ultrasound every 3 months until at least age 8. In addition, feeling the abdomen for signs of swelling or masses (palpation) may be done by both the pediatrician and, with instruction, the parents. (For more information on the symptoms associated with Wilms' tumor, refer to the "Symptoms" section of this report.)Wilms' tumor can often be treated successfully depending on the stage of the tumor at detection. Treatment programs may combine surgical techniques (including kidney removal), radiation therapy, and chemotherapy. The chemotherapy regimen currently preferred to treat Wilms' tumor consists of the drugs dactinomycin and vincristine, which may be combined with doxorubicin. Cyclophosphamide may also be used with this drug regimen to treat tumors that have not responded to the first line of chemotherapy. Other regimens sometimes used to treat Wilms' tumor include a combination of the drugs cisplatin and etoposide or a regimen that combines ifosfamide and mesna. Abnormally persistent clusters of embryonal cells within the kidneys (nephrogenic rests or nephroblastomatosis) are thought to be precursors of Wilms' tumor in some cases. Serial abdominal ultrasound may be used to monitor this tissue for changes which indicate malignancy (cancer), and surgery or chemotherapy is sometimes indicated if changes are noted.Aniridia:The treatment of aniridia is usually directed at preserving vision. Drugs or surgery may be helpful for glaucoma and/or cataracts. Individuals with aniridia often lack limbal cells, which serve to regenerate the cornea. For this reason, care should be taken to prevent injury to the corneas. Contact lenses should be avoided if possible, and when needed, preservative-free ocular lubricants and antibiotics should be used. In the past, cornea transplants typically failed in persons with aniridia, but simultaneous treatment with corneal limbal stem cells has been found to significantly increase the success rate.. An artificial cornea (Boston Keratoprosthesis) and several types of artificial iris implants are currently in clinical trials.Gonadoblastoma and Genitourinary Abnormalities:Children with WAGR Syndrome/11p deletion syndrome should be regularly evaluated to detect abnormal development of the ovaries (streak gonads) or testes. Surgical removal of abnormal gonads (gonadectomy) may be indicated to prevent the occurrence of gonadoblastoma. In cases when gonadoblastoma is actually present, surgery to remove the gonad(s) with the tumor is performed. If one gonad is cancer-free, it still may be removed since it may be at risk for developing gonadoblastoma. Individuals who have had both gonads removed are given hormone treatment to help them develop sexual characteristics that are usually manifested during puberty. Because hormone therapy may cause secondary uterine cancer to develop, the uterus may be surgically removed (if one is present) when the gonadectomy is initially performed.In males with WAGR syndrome/11p deletion syndrome, one or both testes may fail to descend into the scrotum (cryptorchidism). If a testis does not properly descend into the scrotum on its own before the child is 1 year of age, hormone treatment may be given. If this treatment is not successful, surgery may be performed to move the undescended testis into the scrotum and attach it in a fixed position so it will not retract (orchiopexy).Males with cryptorchidism may also have the urinary opening on the underside of the penis (hypospadias). When hypospadias is identified in infants, routine removal of the penis's foreskin (circumcision) soon after birth should not be performed. The foreskin can be essential in aiding surgical repair later in life. Surgical correction is performed as necessary for cosmetic, reproductive, and/or psychological purposes and/or to correct problems with urination. Surgical correction is usually performed before the child is 1 year of age.In females with WAGR syndrome/11p deletion syndrome, the ovaries may be small, or may not have developed properly (streak ovaries). Abnormal ovaries may or may not function well enough to produce adequate levels of hormones for the development of puberty and for menstruation. If abnormal ovaries are detected, surveillance for the development of gonadoblastoma is necessary. Pelvic ultrasound or MRI (magnetic resonance imaging) may be used.Individuals with WAGR syndrome/11p deletion syndrome may have the gonads of one sex and external genitalia resembling that of the opposite sex (ambiguous genitalia), making their sexual assignment (i.e., male or female) uncertain (pseudohermaphroditism). Surgery may be performed to correct some abnormalities of the external genitalia, and hormone treatment may be instituted.Intellectual Disability:The intellectual capacity of individuals with WAGR syndrome/11p deletion syndrome may range from severe impairment (IQ of 35 or lower) to mild impairment (IQ of 70 ) to intelligence that is within normal limits (IQ of approximately 100). Most individuals with WAGR syndrome/11p deletion syndrome fall into the range of mild to moderate impairment (IQ of 35 to 70) Children with WAGR syndrome/11p deletion syndrome should be referred for Early Intervention services soon after birth or diagnosis. Physical, Occupational, and Speech therapies, as well as Special Education services can maximize normal development and can ensure that appropriate steps are taken to help affected individuals reach their potential.Kidney (Renal) Failure:The renal failure associated with WAGR syndrome/11p deletion syndrome often causes high blood pressure (hypertension) high blood cholesterol (hyperlipidemia) and the leakage of protein from the blood into the urine (proteinuria). Treatment consists of medications called "ACE" (angiotensin converting enzyme) inhibitors, or "ARBs" (angiotensin II receptor blockers). If given early in the course of kidney failure, these drugs may help maintain blood pressure within a normal range, reduce the loss of protein through the blood, and may prolong the function of the kidney(s). Some individuals with WAGR Ssyndrome/11p deletion syndrome and renal failure may require kidney transplant.Genetic counseling is important for individuals with WAGR Ssyndrome/11p deletion syndrome and for their families. Chromosomal studies are necessary to determine parents' risk for WAGRsyndrome/11p deletion syndrome in subsequent children. Ongoing genetic counseling will also allow for up-to-date genetic testing and for the provision of information regarding new treatments and therapies.
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Therapies of WAGR Syndrome/11p Deletion Syndrome. WAGR syndrome/11p deletion syndrome can be diagnosed at birth, based upon a clinical evaluation, characteristic physical findings, and chromosomal studies (high-resolution karyotyping and molecular cytogenetic tests). In many cases, the partial or complete absence of the iris of the eye (aniridia) may be the only physical feature associated with WAGR Syndrome/11p deletion syndrome that is obvious at birth. In other cases, genitourinary abnormalities associated with the syndrome may also be apparent.If a child has aniridia, chromosomal studies are necessary to determine whether the child has a genetic predisposition for the disorders associated with WAGR syndrome/11p deletion syndrome.Treatment of WAGR syndrome/11p deletion syndrome is directed toward the specific symptoms that are apparent in each individual.Wilms' Tumor:Wilms' tumor will occur in approximately 50% of children with WAGR syndrome/11p deletion syndrome whose deletion encompasses the WT1 gene. The onset of Wilms' tumor in these children is most often between the ages of 1 and 3. The majority of cases of Wilms' tumor have been detected by age 8, but rare cases have occurred in individuals with WAGR syndrome/11p deletion syndrome as late as age 25. Surveillance for the development of Wilms'. tumor in children with WAGR syndrome/11p deletion syndrome should begin at birth or as soon as WAGR syndrome/11p deletion syndrome is suspected. This surveillance consists of abdominal ultrasound every 3 months until at least age 8. In addition, feeling the abdomen for signs of swelling or masses (palpation) may be done by both the pediatrician and, with instruction, the parents. (For more information on the symptoms associated with Wilms' tumor, refer to the "Symptoms" section of this report.)Wilms' tumor can often be treated successfully depending on the stage of the tumor at detection. Treatment programs may combine surgical techniques (including kidney removal), radiation therapy, and chemotherapy. The chemotherapy regimen currently preferred to treat Wilms' tumor consists of the drugs dactinomycin and vincristine, which may be combined with doxorubicin. Cyclophosphamide may also be used with this drug regimen to treat tumors that have not responded to the first line of chemotherapy. Other regimens sometimes used to treat Wilms' tumor include a combination of the drugs cisplatin and etoposide or a regimen that combines ifosfamide and mesna. Abnormally persistent clusters of embryonal cells within the kidneys (nephrogenic rests or nephroblastomatosis) are thought to be precursors of Wilms' tumor in some cases. Serial abdominal ultrasound may be used to monitor this tissue for changes which indicate malignancy (cancer), and surgery or chemotherapy is sometimes indicated if changes are noted.Aniridia:The treatment of aniridia is usually directed at preserving vision. Drugs or surgery may be helpful for glaucoma and/or cataracts. Individuals with aniridia often lack limbal cells, which serve to regenerate the cornea. For this reason, care should be taken to prevent injury to the corneas. Contact lenses should be avoided if possible, and when needed, preservative-free ocular lubricants and antibiotics should be used. In the past, cornea transplants typically failed in persons with aniridia, but simultaneous treatment with corneal limbal stem cells has been found to significantly increase the success rate.. An artificial cornea (Boston Keratoprosthesis) and several types of artificial iris implants are currently in clinical trials.Gonadoblastoma and Genitourinary Abnormalities:Children with WAGR Syndrome/11p deletion syndrome should be regularly evaluated to detect abnormal development of the ovaries (streak gonads) or testes. Surgical removal of abnormal gonads (gonadectomy) may be indicated to prevent the occurrence of gonadoblastoma. In cases when gonadoblastoma is actually present, surgery to remove the gonad(s) with the tumor is performed. If one gonad is cancer-free, it still may be removed since it may be at risk for developing gonadoblastoma. Individuals who have had both gonads removed are given hormone treatment to help them develop sexual characteristics that are usually manifested during puberty. Because hormone therapy may cause secondary uterine cancer to develop, the uterus may be surgically removed (if one is present) when the gonadectomy is initially performed.In males with WAGR syndrome/11p deletion syndrome, one or both testes may fail to descend into the scrotum (cryptorchidism). If a testis does not properly descend into the scrotum on its own before the child is 1 year of age, hormone treatment may be given. If this treatment is not successful, surgery may be performed to move the undescended testis into the scrotum and attach it in a fixed position so it will not retract (orchiopexy).Males with cryptorchidism may also have the urinary opening on the underside of the penis (hypospadias). When hypospadias is identified in infants, routine removal of the penis's foreskin (circumcision) soon after birth should not be performed. The foreskin can be essential in aiding surgical repair later in life. Surgical correction is performed as necessary for cosmetic, reproductive, and/or psychological purposes and/or to correct problems with urination. Surgical correction is usually performed before the child is 1 year of age.In females with WAGR syndrome/11p deletion syndrome, the ovaries may be small, or may not have developed properly (streak ovaries). Abnormal ovaries may or may not function well enough to produce adequate levels of hormones for the development of puberty and for menstruation. If abnormal ovaries are detected, surveillance for the development of gonadoblastoma is necessary. Pelvic ultrasound or MRI (magnetic resonance imaging) may be used.Individuals with WAGR syndrome/11p deletion syndrome may have the gonads of one sex and external genitalia resembling that of the opposite sex (ambiguous genitalia), making their sexual assignment (i.e., male or female) uncertain (pseudohermaphroditism). Surgery may be performed to correct some abnormalities of the external genitalia, and hormone treatment may be instituted.Intellectual Disability:The intellectual capacity of individuals with WAGR syndrome/11p deletion syndrome may range from severe impairment (IQ of 35 or lower) to mild impairment (IQ of 70 ) to intelligence that is within normal limits (IQ of approximately 100). Most individuals with WAGR syndrome/11p deletion syndrome fall into the range of mild to moderate impairment (IQ of 35 to 70) Children with WAGR syndrome/11p deletion syndrome should be referred for Early Intervention services soon after birth or diagnosis. Physical, Occupational, and Speech therapies, as well as Special Education services can maximize normal development and can ensure that appropriate steps are taken to help affected individuals reach their potential.Kidney (Renal) Failure:The renal failure associated with WAGR syndrome/11p deletion syndrome often causes high blood pressure (hypertension) high blood cholesterol (hyperlipidemia) and the leakage of protein from the blood into the urine (proteinuria). Treatment consists of medications called "ACE" (angiotensin converting enzyme) inhibitors, or "ARBs" (angiotensin II receptor blockers). If given early in the course of kidney failure, these drugs may help maintain blood pressure within a normal range, reduce the loss of protein through the blood, and may prolong the function of the kidney(s). Some individuals with WAGR Ssyndrome/11p deletion syndrome and renal failure may require kidney transplant.Genetic counseling is important for individuals with WAGR Ssyndrome/11p deletion syndrome and for their families. Chromosomal studies are necessary to determine parents' risk for WAGRsyndrome/11p deletion syndrome in subsequent children. Ongoing genetic counseling will also allow for up-to-date genetic testing and for the provision of information regarding new treatments and therapies.
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Overview of Waldenström Macroglobulinemia
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Waldenström macroglobulinemia (WMG) is a malignant disorder of the bone marrow and lymphatic tissues, a type of lymphoma and characterized by the presence of abnormally large numbers of a particular kind of white blood cell known as B lymphocytes. As these cells accumulate in the body, excessive quantities of an antibody protein known as IgM are produced. Large amounts of IgM cause the blood to become thick (hyperviscosity) and affects the flow of blood through the smaller blood vessels, leading to some of the symptoms of the disorder. Small blood vessels may tear leading to bleeding in the nose, gums, or retina.
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Overview of Waldenström Macroglobulinemia. Waldenström macroglobulinemia (WMG) is a malignant disorder of the bone marrow and lymphatic tissues, a type of lymphoma and characterized by the presence of abnormally large numbers of a particular kind of white blood cell known as B lymphocytes. As these cells accumulate in the body, excessive quantities of an antibody protein known as IgM are produced. Large amounts of IgM cause the blood to become thick (hyperviscosity) and affects the flow of blood through the smaller blood vessels, leading to some of the symptoms of the disorder. Small blood vessels may tear leading to bleeding in the nose, gums, or retina.
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Symptoms of Waldenström Macroglobulinemia
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Symptoms of Waldenström macroglobulinemia usually begin gradually. Common symptoms are fatigue and loss of energy due to anemia. Bleeding from the nose and gums may also occur, and tingling in the fingers and toes is often seen (peripheral neuropathy). Examination may also reveal enlarged liver, spleen or lymph nodes. Blurring or vision impairment may also occur due to changes in blood flow through the blood vessels that serve the retina. The symptoms are quite variable depending on the effect of the thickened (viscous) blood on the organ involved.
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Symptoms of Waldenström Macroglobulinemia. Symptoms of Waldenström macroglobulinemia usually begin gradually. Common symptoms are fatigue and loss of energy due to anemia. Bleeding from the nose and gums may also occur, and tingling in the fingers and toes is often seen (peripheral neuropathy). Examination may also reveal enlarged liver, spleen or lymph nodes. Blurring or vision impairment may also occur due to changes in blood flow through the blood vessels that serve the retina. The symptoms are quite variable depending on the effect of the thickened (viscous) blood on the organ involved.
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Causes of Waldenström Macroglobulinemia
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The cause of Waldenström macroglobulinemia is unknown. There is evidence of occurrence within families, but such occurrence is uncommon.
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Causes of Waldenström Macroglobulinemia. The cause of Waldenström macroglobulinemia is unknown. There is evidence of occurrence within families, but such occurrence is uncommon.
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Affects of Waldenström Macroglobulinemia
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Waldenström macroglobulinemia is a very rare disorder affecting about 1 in 3.4 million American men and about half that number of American women. The incidence of WMG is estimated to be about 5 per 1,000,000 people over the age of 50. The median age at diagnosis is 67. However, patients have been diagnosed in their twenties. This disorder is considerably less common among people of African descent.
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Affects of Waldenström Macroglobulinemia. Waldenström macroglobulinemia is a very rare disorder affecting about 1 in 3.4 million American men and about half that number of American women. The incidence of WMG is estimated to be about 5 per 1,000,000 people over the age of 50. The median age at diagnosis is 67. However, patients have been diagnosed in their twenties. This disorder is considerably less common among people of African descent.
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Related disorders of Waldenström Macroglobulinemia
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The disease is classified as a lymphoma and also has characteristics in common with chronic lymphocytic leukemia and multiple myeloma.Multiple myeloma is characterized by excessive growth (neoplastic proliferation) of plasma cells. Plasma cells are produced in the marrow and eventually enter the blood stream. They are a key component of the immune system and secrete a substance known as M-protein, a type of antibody. Antibodies, also known as immunoglobulins, are produced by the body to combat invading microorganisms, toxins or other foreign substances. Overproduction of plasma cells in affected individuals results in abnormally high levels of M proteins in the body. In addition, excessive plasma cells may eventually mass together to form a tumor, known as a plasmacytoma, in various sites of the body, especially the bone marrow.Chronic lymphocytic leukemia is the most common type of leukemia in people over 50 years of age. It is characterized by fatigue, weight loss, repeated infections and enlarged lymph nodes. Small, well-separated, movable, hard nodes usually occur. The number of lymph cells in the peripheral blood and bone marrow is elevated. In the advanced stages of the disease, bone marrow failure is common, resulting in an abnormally low red blood cell count (anemia) and lack of blood platelets (thrombocytopenia).
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Related disorders of Waldenström Macroglobulinemia. The disease is classified as a lymphoma and also has characteristics in common with chronic lymphocytic leukemia and multiple myeloma.Multiple myeloma is characterized by excessive growth (neoplastic proliferation) of plasma cells. Plasma cells are produced in the marrow and eventually enter the blood stream. They are a key component of the immune system and secrete a substance known as M-protein, a type of antibody. Antibodies, also known as immunoglobulins, are produced by the body to combat invading microorganisms, toxins or other foreign substances. Overproduction of plasma cells in affected individuals results in abnormally high levels of M proteins in the body. In addition, excessive plasma cells may eventually mass together to form a tumor, known as a plasmacytoma, in various sites of the body, especially the bone marrow.Chronic lymphocytic leukemia is the most common type of leukemia in people over 50 years of age. It is characterized by fatigue, weight loss, repeated infections and enlarged lymph nodes. Small, well-separated, movable, hard nodes usually occur. The number of lymph cells in the peripheral blood and bone marrow is elevated. In the advanced stages of the disease, bone marrow failure is common, resulting in an abnormally low red blood cell count (anemia) and lack of blood platelets (thrombocytopenia).
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Diagnosis of Waldenström Macroglobulinemia
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When patients show symptoms of an enlarged spleen and liver combined with bleeding of the retina, WMG is reasonably suspected. The results of a complete blood count (CBC) usually show low red blood cell counts as well as low platelet counts. In such circumstances, electrophoresis (analysis of the blood proteins) of serum samples will show a peak reading for IgM. The most common finding preceding the diagnosis is unexplained anemia.
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Diagnosis of Waldenström Macroglobulinemia. When patients show symptoms of an enlarged spleen and liver combined with bleeding of the retina, WMG is reasonably suspected. The results of a complete blood count (CBC) usually show low red blood cell counts as well as low platelet counts. In such circumstances, electrophoresis (analysis of the blood proteins) of serum samples will show a peak reading for IgM. The most common finding preceding the diagnosis is unexplained anemia.
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Therapies of Waldenström Macroglobulinemia
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TreatmentWith asymptomatic patients, a period of watchful waiting is considered the preferred course. To reduce the blood thickness, plasmapheresis, a method of blood exchange which filters out much of the IgM protein, has been shown to be effective in preventing complications of hyperviscosity. The blood cells are separated from the liquid component (serum or plasma). The heavy IgM molecules that cause the trouble are discarded with the liquid fraction of the exchange. The blood is “reconstituted” by adding previously donated plasma or a plasma substitute. If the disorder progresses, red blood cell transfusions and/or platelet infusions may be necessary.Traditional chemotherapeutic agents, particularly chlorambucil (Leukeran), cyclophosphamide (Cytoxan) and/or melphalan (Alkeran) either as single agents or in combination with others, have been used in the management of this disease for over 40 years but are not commonly used today. The monoclonal antibody, rituximab, has been found to be effective. Ongoing research is examining combinations of these drugs. Many new therapies have been introduced in the past few years and including bortezomib, Ixazomib, carfilzomib, bendamustine ibrutinib, zanubrutinib and acalbrutinib. The U.S. Food and Drug Administration (FDA) has approved the use of ibrutinib and zanubrutinib for Waldenstrom macroglobulinemia.Most people with Waldenström macroglobulinemia have a specific change (mutation) in the MYD88 gene and 30-40% of affected people have a mutation in the CXCR4 gene. These mutations occur in the Waldenstrom cells only and are not inherited. There is some evidence that patients with a CXCR4 mutation are more severely affected and do not respond as well to treatment.
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Therapies of Waldenström Macroglobulinemia. TreatmentWith asymptomatic patients, a period of watchful waiting is considered the preferred course. To reduce the blood thickness, plasmapheresis, a method of blood exchange which filters out much of the IgM protein, has been shown to be effective in preventing complications of hyperviscosity. The blood cells are separated from the liquid component (serum or plasma). The heavy IgM molecules that cause the trouble are discarded with the liquid fraction of the exchange. The blood is “reconstituted” by adding previously donated plasma or a plasma substitute. If the disorder progresses, red blood cell transfusions and/or platelet infusions may be necessary.Traditional chemotherapeutic agents, particularly chlorambucil (Leukeran), cyclophosphamide (Cytoxan) and/or melphalan (Alkeran) either as single agents or in combination with others, have been used in the management of this disease for over 40 years but are not commonly used today. The monoclonal antibody, rituximab, has been found to be effective. Ongoing research is examining combinations of these drugs. Many new therapies have been introduced in the past few years and including bortezomib, Ixazomib, carfilzomib, bendamustine ibrutinib, zanubrutinib and acalbrutinib. The U.S. Food and Drug Administration (FDA) has approved the use of ibrutinib and zanubrutinib for Waldenstrom macroglobulinemia.Most people with Waldenström macroglobulinemia have a specific change (mutation) in the MYD88 gene and 30-40% of affected people have a mutation in the CXCR4 gene. These mutations occur in the Waldenstrom cells only and are not inherited. There is some evidence that patients with a CXCR4 mutation are more severely affected and do not respond as well to treatment.
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Overview of Walker Warburg Syndrome
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SummaryWalker-Warburg syndrome (WWS) is a rare inherited disorder that affects the development of the muscles, brain and eyes. WWS is characterized by (1) congenital muscular dystrophy (progressive degeneration and weakness of the voluntary muscles) (2) lissencephaly (a smooth appearance of the surface of the brain due to lack of normal folding pattern) and hydrocephalus (buildup of fluid in the brain), often with malformations of other brain structures including the cerebellum and brain stem and (3) various developmental abnormalities of the eye. The specific symptoms and severity can vary greatly from person to person. WWS is inherited as an autosomal recessive condition, meaning an individual inherits two abnormal copies of a gene, one from each parent. However, genetic testing does not identify a genetic cause in all individuals with a diagnosis of WWS.IntroductionWWS belongs to a group of disorders known as the congenital muscular dystrophies (CMD). CMD is a general term for a group of over 30 genetic muscle disorders that cause hypotonia (low muscle tone) and atrophy (progressive muscle weakness) at birth or during infancy. These disorders affect different muscles and have different ages of onset, severity and inheritance patterns. One specific subtype of CMD is known as the dystroglycanopathies, which are caused by disruptions or changes (mutations) in one of the genes involved in the modification of a protein called α-dystroglycan described in the Causes section below. WWS is the most severe dystroglycanopathy and often leads to death in infancy, with most children not surviving past age three.
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Overview of Walker Warburg Syndrome. SummaryWalker-Warburg syndrome (WWS) is a rare inherited disorder that affects the development of the muscles, brain and eyes. WWS is characterized by (1) congenital muscular dystrophy (progressive degeneration and weakness of the voluntary muscles) (2) lissencephaly (a smooth appearance of the surface of the brain due to lack of normal folding pattern) and hydrocephalus (buildup of fluid in the brain), often with malformations of other brain structures including the cerebellum and brain stem and (3) various developmental abnormalities of the eye. The specific symptoms and severity can vary greatly from person to person. WWS is inherited as an autosomal recessive condition, meaning an individual inherits two abnormal copies of a gene, one from each parent. However, genetic testing does not identify a genetic cause in all individuals with a diagnosis of WWS.IntroductionWWS belongs to a group of disorders known as the congenital muscular dystrophies (CMD). CMD is a general term for a group of over 30 genetic muscle disorders that cause hypotonia (low muscle tone) and atrophy (progressive muscle weakness) at birth or during infancy. These disorders affect different muscles and have different ages of onset, severity and inheritance patterns. One specific subtype of CMD is known as the dystroglycanopathies, which are caused by disruptions or changes (mutations) in one of the genes involved in the modification of a protein called α-dystroglycan described in the Causes section below. WWS is the most severe dystroglycanopathy and often leads to death in infancy, with most children not surviving past age three.
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Symptoms of Walker Warburg Syndrome
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The main symptoms of WWS are muscular dystrophy (progressive degeneration and weakness of the voluntary muscles) and abnormalities of the brain and eyes. Symptoms of WWS are congenital (present at birth), and some of the brain abnormalities can be detected by prenatal ultrasound and/or fetal MRI in the later stages of pregnancy.Individuals with WWS have congenital muscular dystrophy, or a weakening and loss of muscle at birth. Muscular dystrophy causes affected infants to have severe hypotonia (low muscle tone), muscle weakness, and atrophy (wasting away) which typically get worse over time. Some affected individuals develop contractures (abnormally fixed joints) that occur when thickening and shortening of tissue, such as muscle fibers, deform and restrict movement of an affected area.Affected infants usually have a variety of serious brain findings, including type II lissencephaly (smooth brain), hydrocephalus (enlarged ventricles) and malformations in the back of the brain. Type II lissencephaly is also called cobblestone lissencephaly because the surface of the brain has a cobblestone appearance due to the collection of clumps of neurons (brain cells) at the surface. (For more information on this, choose “Lissencephaly” as your search term in the Rare Disease Database.) Hydrocephalus, which is characterized by having too much cerebrospinal fluid in the ventricles of the brain causing an enlargement, can be quite severe and lead to an abnormally large head. Malformations of the back portions of the brain can include hypoplasia (underdevelopment) of the cerebellum and brainstem. The cerebellum helps coordinate voluntary muscle movements, while the brainstem helps control basic functions such as breathing, salivation and heart rate. These posterior malformations can involve an abnormally enlarged space at the back of the brain, sometimes referred to as Dandy-Walker malformation. In some individuals with WWS, there is an encephalocele, which is a protrusion of part of the brain through the skull bone. Individuals with WWS may also have absence of the corpus callosum, which is the band of white matter that normally connects the two brain hemispheres.The combined brain and muscle abnormalities lead to significant delays in reaching developmental milestones (e.g., sitting up, grabbing objects, crawling, talking) and can be so severe as to cause difficulties in breathing and swallowing. Children born with WWS display intellectual disability and often have seizures.The eye abnormalities associated with WWS vary widely from person to person and can include any of the following: microphthalmia (abnormally small eyes), optic nerve hypoplasia (absent or underdeveloped optic nerves), retinal dysplasia (malformation of the retina which could cause the retina to become detached) and malformations of the fluid-filled space within the eyes behind the cornea and in front of the iris. Additional eye symptoms can include cataracts, coloboma (a cleft or loss of tissue of the retina or iris), buphthalmos (large and protruding eyes) or glaucoma (increased pressure within the eyes). Most of these abnormalities lead to partial or complete blindness.Occasionally, additional symptoms in different body systems can also be present. In some affected children, genitourinary abnormalities can occur, causing urinary tract blockage and kidney pelvic dilation (hydronephrosis) or failure of the testes to descend into the scrotum in males (cryptorchidism). Some affected children have other features, such as low-set or prominent ears, cleft lip or palate or cochlear hypoplasia (inner ear malformation).
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Symptoms of Walker Warburg Syndrome. The main symptoms of WWS are muscular dystrophy (progressive degeneration and weakness of the voluntary muscles) and abnormalities of the brain and eyes. Symptoms of WWS are congenital (present at birth), and some of the brain abnormalities can be detected by prenatal ultrasound and/or fetal MRI in the later stages of pregnancy.Individuals with WWS have congenital muscular dystrophy, or a weakening and loss of muscle at birth. Muscular dystrophy causes affected infants to have severe hypotonia (low muscle tone), muscle weakness, and atrophy (wasting away) which typically get worse over time. Some affected individuals develop contractures (abnormally fixed joints) that occur when thickening and shortening of tissue, such as muscle fibers, deform and restrict movement of an affected area.Affected infants usually have a variety of serious brain findings, including type II lissencephaly (smooth brain), hydrocephalus (enlarged ventricles) and malformations in the back of the brain. Type II lissencephaly is also called cobblestone lissencephaly because the surface of the brain has a cobblestone appearance due to the collection of clumps of neurons (brain cells) at the surface. (For more information on this, choose “Lissencephaly” as your search term in the Rare Disease Database.) Hydrocephalus, which is characterized by having too much cerebrospinal fluid in the ventricles of the brain causing an enlargement, can be quite severe and lead to an abnormally large head. Malformations of the back portions of the brain can include hypoplasia (underdevelopment) of the cerebellum and brainstem. The cerebellum helps coordinate voluntary muscle movements, while the brainstem helps control basic functions such as breathing, salivation and heart rate. These posterior malformations can involve an abnormally enlarged space at the back of the brain, sometimes referred to as Dandy-Walker malformation. In some individuals with WWS, there is an encephalocele, which is a protrusion of part of the brain through the skull bone. Individuals with WWS may also have absence of the corpus callosum, which is the band of white matter that normally connects the two brain hemispheres.The combined brain and muscle abnormalities lead to significant delays in reaching developmental milestones (e.g., sitting up, grabbing objects, crawling, talking) and can be so severe as to cause difficulties in breathing and swallowing. Children born with WWS display intellectual disability and often have seizures.The eye abnormalities associated with WWS vary widely from person to person and can include any of the following: microphthalmia (abnormally small eyes), optic nerve hypoplasia (absent or underdeveloped optic nerves), retinal dysplasia (malformation of the retina which could cause the retina to become detached) and malformations of the fluid-filled space within the eyes behind the cornea and in front of the iris. Additional eye symptoms can include cataracts, coloboma (a cleft or loss of tissue of the retina or iris), buphthalmos (large and protruding eyes) or glaucoma (increased pressure within the eyes). Most of these abnormalities lead to partial or complete blindness.Occasionally, additional symptoms in different body systems can also be present. In some affected children, genitourinary abnormalities can occur, causing urinary tract blockage and kidney pelvic dilation (hydronephrosis) or failure of the testes to descend into the scrotum in males (cryptorchidism). Some affected children have other features, such as low-set or prominent ears, cleft lip or palate or cochlear hypoplasia (inner ear malformation).
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Causes of Walker Warburg Syndrome
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WWS is due to abnormally functioning or non-working genes that are important in muscle, brain and eye development. It is inherited in an autosomal recessive manner and occurs in an individual who inherits two abnormal copies of a gene, one from each parent. An individual that has one normally functioning copy of the gene and one non-working copy of the gene is a carrier for WWS but usually does not have any symptoms. The risk for two carrier parents who have children together to both pass on the abnormal or non-working gene and therefore have an affected child is 25%, or 1 in 4, with each pregnancy. The risk for these parents to have a child who is a carrier only (unaffected) is 50%, or 1 in 2, with each pregnancy. Their chance to have a child with two normally functioning copies of the gene (unaffected and not a carrier) is 25%, 1 in 4, with each pregnancy. These risks are the same for male and female offspring.WWS results when certain genes involved in the development and function of the muscle, brain and eyes are not working properly. These WWS-associated genes are required for making proteins that are involved in a process known as glycosylation, which is the adding of sugar molecules to other proteins such that they can function correctly. The genes involved with WWS are required for the proper glycosylation of a protein called α-dystroglycan, as discussed in the Introduction. α-dystroglycan normally functions to stabilize muscle cells and aid in the migration of nerve cells in the brain during development. When these WWS-associated genes are unable to make proteins that normally glycosylate α-dystroglycan, it can lead to issues in the development of the muscle, brain and eyes that are seen in individuals affected by WWS and related dystroglycanopathies. WWS has been associated with at least 14 different genes that are responsible for making proteins involved in the glycosylation process described above. Listed alphabetically below are the genes identified thus far and the proteins they produce.•B3GALNT2: Beta-1,3-N-acetylgalactosaminyltransferase 2 protein
•B4GAT1 or B3GNT1: Beta-1,4-glucuronyltransferase 1 protein
•DAG1: Dystrophin-associated glycoprotein 1
•FKRP: Fukutin-related protein
•FKTN: Fukutin protein*
•GMPPB: GDP-mannose pyrophosphorylase B protein
•ISPD: Isoprenoid synthase domain-containing protein
•LARGE: Acetylglucosaminyltransferase-like protein
•POMT1: O-mannosyltransferase 1 protein
•POMT2: O-mannosyltransferase 2 protein
•POMGNT1: O-mannose beta-1,2-N-acetylglucosaminyltransferase protein
•POMGNT2 or GTDC2: O-mannose beta-1,4-N-acetylglucosaminyltransferase 2 protein
•POMK or SGK196: Protein-O-mannose kinase
•TMEM5: Transmembrane protein 5*FKTN mutations are associated with several other conditions. Recent advances in genetic research and testing, such as whole genome and whole exome sequencing, have determined that these genes are associated with WWS. The discovery of these genes and the characterization of symptoms they cause when not functioning properly has demonstrated variability in the clinical presentation of WWS in affected individuals. Although the 14 above-mentioned genes have been identified as causes of WWS, they explain only half of known WWS cases, and changes in all these genes can also cause less severe forms of muscular dystrophy. Because of this, genetic testing may not be able to identify a genetic cause of WWS in every individual or family. It is also likely that more genes associated with WWS, and related conditions will be discovered in the future, which could introduce additional variability to the spectrum of WWS.
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Causes of Walker Warburg Syndrome. WWS is due to abnormally functioning or non-working genes that are important in muscle, brain and eye development. It is inherited in an autosomal recessive manner and occurs in an individual who inherits two abnormal copies of a gene, one from each parent. An individual that has one normally functioning copy of the gene and one non-working copy of the gene is a carrier for WWS but usually does not have any symptoms. The risk for two carrier parents who have children together to both pass on the abnormal or non-working gene and therefore have an affected child is 25%, or 1 in 4, with each pregnancy. The risk for these parents to have a child who is a carrier only (unaffected) is 50%, or 1 in 2, with each pregnancy. Their chance to have a child with two normally functioning copies of the gene (unaffected and not a carrier) is 25%, 1 in 4, with each pregnancy. These risks are the same for male and female offspring.WWS results when certain genes involved in the development and function of the muscle, brain and eyes are not working properly. These WWS-associated genes are required for making proteins that are involved in a process known as glycosylation, which is the adding of sugar molecules to other proteins such that they can function correctly. The genes involved with WWS are required for the proper glycosylation of a protein called α-dystroglycan, as discussed in the Introduction. α-dystroglycan normally functions to stabilize muscle cells and aid in the migration of nerve cells in the brain during development. When these WWS-associated genes are unable to make proteins that normally glycosylate α-dystroglycan, it can lead to issues in the development of the muscle, brain and eyes that are seen in individuals affected by WWS and related dystroglycanopathies. WWS has been associated with at least 14 different genes that are responsible for making proteins involved in the glycosylation process described above. Listed alphabetically below are the genes identified thus far and the proteins they produce.•B3GALNT2: Beta-1,3-N-acetylgalactosaminyltransferase 2 protein
•B4GAT1 or B3GNT1: Beta-1,4-glucuronyltransferase 1 protein
•DAG1: Dystrophin-associated glycoprotein 1
•FKRP: Fukutin-related protein
•FKTN: Fukutin protein*
•GMPPB: GDP-mannose pyrophosphorylase B protein
•ISPD: Isoprenoid synthase domain-containing protein
•LARGE: Acetylglucosaminyltransferase-like protein
•POMT1: O-mannosyltransferase 1 protein
•POMT2: O-mannosyltransferase 2 protein
•POMGNT1: O-mannose beta-1,2-N-acetylglucosaminyltransferase protein
•POMGNT2 or GTDC2: O-mannose beta-1,4-N-acetylglucosaminyltransferase 2 protein
•POMK or SGK196: Protein-O-mannose kinase
•TMEM5: Transmembrane protein 5*FKTN mutations are associated with several other conditions. Recent advances in genetic research and testing, such as whole genome and whole exome sequencing, have determined that these genes are associated with WWS. The discovery of these genes and the characterization of symptoms they cause when not functioning properly has demonstrated variability in the clinical presentation of WWS in affected individuals. Although the 14 above-mentioned genes have been identified as causes of WWS, they explain only half of known WWS cases, and changes in all these genes can also cause less severe forms of muscular dystrophy. Because of this, genetic testing may not be able to identify a genetic cause of WWS in every individual or family. It is also likely that more genes associated with WWS, and related conditions will be discovered in the future, which could introduce additional variability to the spectrum of WWS.
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Affects of Walker Warburg Syndrome
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WWS has been reported worldwide and affects males and females in equal numbers. The incidence is unknown but is estimated to be about 1 in 100,000.
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Affects of Walker Warburg Syndrome. WWS has been reported worldwide and affects males and females in equal numbers. The incidence is unknown but is estimated to be about 1 in 100,000.
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Related disorders of Walker Warburg Syndrome
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Symptoms of several disorders can show overlap with WWS. As noted earlier, congenital muscular dystrophy (CMD) is a general term for a group of muscle diseases that includes several different conditions. The severity, specific symptoms and progression of these disorders vary greatly. CMDs related to WWS can present with milder brain abnormalities, such as cerebellar cysts or intellectual disability without brain malformations. Two specific forms of CMD, Fukuyama CMD and muscle-eye-brain disease (MEB), have symptoms similar to WWS, but are generally less severe. Some forms of CMD may not involve any malformations of the central nervous system. Almost all known forms of CMD are inherited as autosomal recessive conditions. (For more information on these disorders, choose “congenital muscular dystrophy” as your search term in the Rare Disease Database.) Type II lissencephaly can be seen on its own, without muscular dystrophy, but its genetic causes are unknown in those cases. It is unclear whether isolated type II lissencephaly is related to WWS. Type I lissencephaly appears to be a distinct condition and is described under the term “Lissencephaly” in the Rare Disease Database.
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Related disorders of Walker Warburg Syndrome. Symptoms of several disorders can show overlap with WWS. As noted earlier, congenital muscular dystrophy (CMD) is a general term for a group of muscle diseases that includes several different conditions. The severity, specific symptoms and progression of these disorders vary greatly. CMDs related to WWS can present with milder brain abnormalities, such as cerebellar cysts or intellectual disability without brain malformations. Two specific forms of CMD, Fukuyama CMD and muscle-eye-brain disease (MEB), have symptoms similar to WWS, but are generally less severe. Some forms of CMD may not involve any malformations of the central nervous system. Almost all known forms of CMD are inherited as autosomal recessive conditions. (For more information on these disorders, choose “congenital muscular dystrophy” as your search term in the Rare Disease Database.) Type II lissencephaly can be seen on its own, without muscular dystrophy, but its genetic causes are unknown in those cases. It is unclear whether isolated type II lissencephaly is related to WWS. Type I lissencephaly appears to be a distinct condition and is described under the term “Lissencephaly” in the Rare Disease Database.
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Diagnosis of Walker Warburg Syndrome
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A diagnosis of WWS is based upon the identification of characteristic features, a thorough clinical evaluation and a variety of specialized tests. A diagnosis can be confirmed through molecular genetic testing. A diagnosis can be suspected via routine ultrasound and/or fetal MRI during the late stages of pregnancy and confirmed at or shortly after birth. During the pregnancy, imaging can suggest WWS when there is type II lissencephaly (smooth brain), cerebellum abnormalities and other early changes in the brain and eye. Additional tests shortly after birth are necessary to establish a clinical diagnosis of WWS. Identification of the brain findings can be done with magnetic resonance imaging (MRI), which provides detailed pictures of the brain. However, the enlarged ventricles that often accompany a diagnosis of WWS can also be detected by ultrasound and computed tomography (CT) of the head. A biopsy (surgical removal and microscopic examination) of affected muscle tissue might be needed to reveal characteristic changes in muscle fibers. A blood test for creatine kinase (CK) levels is also commonly done, as CK measurement is used to detect muscle damage. The detection of elevated CK levels can confirm that muscle is damaged or inflamed but cannot confirm a diagnosis of WWS specifically. A careful eye exam can also identify the characteristic eye findings of WWS described in the Signs & Symptoms section. Molecular genetic testing can be performed to identify specific genetic mutations and can be used to confirm a clinical diagnosis of WWS. Genetic confirmation occurs when two mutations are identified in a gene known to be associated with WWS. If the individual is of Ashkenazi Jewish descent, the FKTN gene may be tested first because there is a specific mutation in this gene that is common within this population. However, a more comprehensive genetic test would be most helpful because there is significant overlap of symptoms caused by mutations in the 14 genes linked to WWS. It is possible to test for all genes known to be associated with WWS or congenital muscular dystrophies (CMD) at the same time with a multiple gene panel test. Additionally, exome sequencing can be performed to look at all genes that are known to provide instructions for making proteins. Each test has benefits and limitations that should be discussed with a genetic counselor. The 14 genes identified to cause for WWS explain only about half of all known cases of WWS. Therefore, genetic testing could come back negative, and an individual can still have a clinical diagnosis of WWS. In these patients, additional genetic testing could be considered periodically over time to include newly identified genes linked to WWS. Genetic counseling can help families understand autosomal recessive inheritance, the current and ever-changing state of genetic testing for WWS, what the results from genetic testing mean and the impact of this information on the members of the family. Psychosocial support may also be beneficial for the entire family.
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Diagnosis of Walker Warburg Syndrome. A diagnosis of WWS is based upon the identification of characteristic features, a thorough clinical evaluation and a variety of specialized tests. A diagnosis can be confirmed through molecular genetic testing. A diagnosis can be suspected via routine ultrasound and/or fetal MRI during the late stages of pregnancy and confirmed at or shortly after birth. During the pregnancy, imaging can suggest WWS when there is type II lissencephaly (smooth brain), cerebellum abnormalities and other early changes in the brain and eye. Additional tests shortly after birth are necessary to establish a clinical diagnosis of WWS. Identification of the brain findings can be done with magnetic resonance imaging (MRI), which provides detailed pictures of the brain. However, the enlarged ventricles that often accompany a diagnosis of WWS can also be detected by ultrasound and computed tomography (CT) of the head. A biopsy (surgical removal and microscopic examination) of affected muscle tissue might be needed to reveal characteristic changes in muscle fibers. A blood test for creatine kinase (CK) levels is also commonly done, as CK measurement is used to detect muscle damage. The detection of elevated CK levels can confirm that muscle is damaged or inflamed but cannot confirm a diagnosis of WWS specifically. A careful eye exam can also identify the characteristic eye findings of WWS described in the Signs & Symptoms section. Molecular genetic testing can be performed to identify specific genetic mutations and can be used to confirm a clinical diagnosis of WWS. Genetic confirmation occurs when two mutations are identified in a gene known to be associated with WWS. If the individual is of Ashkenazi Jewish descent, the FKTN gene may be tested first because there is a specific mutation in this gene that is common within this population. However, a more comprehensive genetic test would be most helpful because there is significant overlap of symptoms caused by mutations in the 14 genes linked to WWS. It is possible to test for all genes known to be associated with WWS or congenital muscular dystrophies (CMD) at the same time with a multiple gene panel test. Additionally, exome sequencing can be performed to look at all genes that are known to provide instructions for making proteins. Each test has benefits and limitations that should be discussed with a genetic counselor. The 14 genes identified to cause for WWS explain only about half of all known cases of WWS. Therefore, genetic testing could come back negative, and an individual can still have a clinical diagnosis of WWS. In these patients, additional genetic testing could be considered periodically over time to include newly identified genes linked to WWS. Genetic counseling can help families understand autosomal recessive inheritance, the current and ever-changing state of genetic testing for WWS, what the results from genetic testing mean and the impact of this information on the members of the family. Psychosocial support may also be beneficial for the entire family.
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Therapies of Walker Warburg Syndrome
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Treatment
There is no cure for WWS at this time and treatment is individualized based on specific symptoms. Medical management can require the coordinated efforts of a team of specialists including pediatricians, geneticists/genetic counselors, orthopedic surgeons, neurologists, ophthalmologists, and other health care professionals to systematically and comprehensively plan an affected child’s treatment.Treatments might include anti-seizure medication, surgery for hydrocephalus, such as the placement of shunts to drain excess cerebrospinal fluid and reduce pressure in the brain, and physical therapy to improve muscle strength and prevent contractures. Some children might need a gastric tube to assist with feeding. Other symptomatic and supportive treatments could also be necessary. Due to the severe brain and muscle abnormalities, life expectancy is reduced with almost all affected children not surviving past age three.
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Therapies of Walker Warburg Syndrome. Treatment
There is no cure for WWS at this time and treatment is individualized based on specific symptoms. Medical management can require the coordinated efforts of a team of specialists including pediatricians, geneticists/genetic counselors, orthopedic surgeons, neurologists, ophthalmologists, and other health care professionals to systematically and comprehensively plan an affected child’s treatment.Treatments might include anti-seizure medication, surgery for hydrocephalus, such as the placement of shunts to drain excess cerebrospinal fluid and reduce pressure in the brain, and physical therapy to improve muscle strength and prevent contractures. Some children might need a gastric tube to assist with feeding. Other symptomatic and supportive treatments could also be necessary. Due to the severe brain and muscle abnormalities, life expectancy is reduced with almost all affected children not surviving past age three.
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Overview of Wandering Spleen
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Congenital wandering spleen is a very rare, randomly distributed birth defect characterized by the absence or weakness of one or more of the ligaments that hold the spleen in its normal position in the upper left abdomen. The disorder is not genetic in origin. Instead of ligaments, the spleen is attached by a stalk-like tissue supplied with blood vessels (vascular pedicle). If the pedicle is twisted in the course of the movement of the spleen, the blood supply may be interrupted or blocked (ischemia) to the point of severe damage to the blood vessels (infarction). Because there is little or nothing to hold it in place the spleen “wanders” in the lower abdomen or pelvis where it may be mistaken for an unidentified abdominal mass.The spleen is a small organ located in the upper left portion of the abdomen. The spleen removes or filters out unnecessary or foreign material, breaks down and eliminates worn out blood cells, and produces white blood cells, which aid the body in fighting infection. Symptoms of wandering spleen are typically those associated with an abnormally large size of the spleen (splenomegaly) or the unusual position of the spleen in the abdomen. Enlargement is most often the result of twisting (torsion) of the splenic arteries and veins or, in some cases, the formation of a blood clot (infarct) in the spleen.“Acquired” wandering spleen may occur during adulthood due to injuries or other underlying conditions that may weaken the ligaments that hold the spleen in its normal position (e.g., connective tissue disease or pregnancy).
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Overview of Wandering Spleen. Congenital wandering spleen is a very rare, randomly distributed birth defect characterized by the absence or weakness of one or more of the ligaments that hold the spleen in its normal position in the upper left abdomen. The disorder is not genetic in origin. Instead of ligaments, the spleen is attached by a stalk-like tissue supplied with blood vessels (vascular pedicle). If the pedicle is twisted in the course of the movement of the spleen, the blood supply may be interrupted or blocked (ischemia) to the point of severe damage to the blood vessels (infarction). Because there is little or nothing to hold it in place the spleen “wanders” in the lower abdomen or pelvis where it may be mistaken for an unidentified abdominal mass.The spleen is a small organ located in the upper left portion of the abdomen. The spleen removes or filters out unnecessary or foreign material, breaks down and eliminates worn out blood cells, and produces white blood cells, which aid the body in fighting infection. Symptoms of wandering spleen are typically those associated with an abnormally large size of the spleen (splenomegaly) or the unusual position of the spleen in the abdomen. Enlargement is most often the result of twisting (torsion) of the splenic arteries and veins or, in some cases, the formation of a blood clot (infarct) in the spleen.“Acquired” wandering spleen may occur during adulthood due to injuries or other underlying conditions that may weaken the ligaments that hold the spleen in its normal position (e.g., connective tissue disease or pregnancy).
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Symptoms of Wandering Spleen
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Some children with wandering spleen may have no symptoms (asymptomatic), while others may experience acute or chronic abdominal pain. In most cases, episodes of pain may be related to the spontaneous twisting and untwisting of the mobile spleen (torsion and detorsion) or of the blood vessels serving the spleen. Infants with wandering spleen may attempt to relieve pain by stretching. Other symptoms may include a bulging abdominal mass, constipation, bloating, nausea, vomiting, frequent difficult urination, and/or menstrual problems in women.In some cases, the spleen may lack proper blood supply due to the twisting of the splenic arteries. In these cases, symptoms may include abdominal pain, abnormal enlargement of the spleen (splenomegaly), bleeding into the abdomen (infarct), the accumulation of fibrous tissue in the spleen (fibrosis), and/or decay of splenic tissue (necrosis). In severe cases, blood flow into the spleen is diminished and the spleen may become greatly enlarged, as it accumulates (sequesters) blood elements such as platelets and red blood cells. Resulting symptoms may include fatigue, weakness, blood in the stools, anemia, bloody vomit (hematemesis), and/or an abnormally low level of blood platelets (thrombocytopenia).In adulthood, wandering spleen most often causes abdominal pain or present as an abdominal mass that does not cause symptoms (asymptomatic).
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Symptoms of Wandering Spleen. Some children with wandering spleen may have no symptoms (asymptomatic), while others may experience acute or chronic abdominal pain. In most cases, episodes of pain may be related to the spontaneous twisting and untwisting of the mobile spleen (torsion and detorsion) or of the blood vessels serving the spleen. Infants with wandering spleen may attempt to relieve pain by stretching. Other symptoms may include a bulging abdominal mass, constipation, bloating, nausea, vomiting, frequent difficult urination, and/or menstrual problems in women.In some cases, the spleen may lack proper blood supply due to the twisting of the splenic arteries. In these cases, symptoms may include abdominal pain, abnormal enlargement of the spleen (splenomegaly), bleeding into the abdomen (infarct), the accumulation of fibrous tissue in the spleen (fibrosis), and/or decay of splenic tissue (necrosis). In severe cases, blood flow into the spleen is diminished and the spleen may become greatly enlarged, as it accumulates (sequesters) blood elements such as platelets and red blood cells. Resulting symptoms may include fatigue, weakness, blood in the stools, anemia, bloody vomit (hematemesis), and/or an abnormally low level of blood platelets (thrombocytopenia).In adulthood, wandering spleen most often causes abdominal pain or present as an abdominal mass that does not cause symptoms (asymptomatic).
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Causes of Wandering Spleen
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The exact cause of wandering spleen is not known. Researchers suspect that multiple factors play a role in the development of the disorder (multifactorial). Babies may be born with a wandering spleen that may be the result of a defect in a certain area of the developing embryo (mesogastrium dorsum). This is the area of the embryo that gives rise to the ligaments that normally hold the spleen in the upper left abdomen. Affected children may be missing one or all of these ligaments, or, if present, the ligaments are not positioned properly. Symptoms usually develop due to the abnormal position of the spleen in the lower abdomen or because of the abnormal enlargement of the spleen (splenomegaly).Wandering spleen may occur during adulthood because of accident or injury, another underlying disorder (e.g., connective tissue disease), or the abnormal relaxation (laxity) of the ligaments caused by pregnancy.
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Causes of Wandering Spleen. The exact cause of wandering spleen is not known. Researchers suspect that multiple factors play a role in the development of the disorder (multifactorial). Babies may be born with a wandering spleen that may be the result of a defect in a certain area of the developing embryo (mesogastrium dorsum). This is the area of the embryo that gives rise to the ligaments that normally hold the spleen in the upper left abdomen. Affected children may be missing one or all of these ligaments, or, if present, the ligaments are not positioned properly. Symptoms usually develop due to the abnormal position of the spleen in the lower abdomen or because of the abnormal enlargement of the spleen (splenomegaly).Wandering spleen may occur during adulthood because of accident or injury, another underlying disorder (e.g., connective tissue disease), or the abnormal relaxation (laxity) of the ligaments caused by pregnancy.
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Affects of Wandering Spleen
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Wandering spleen, whether it is a condition with which a baby is born (congenital form) or is the result of multiple births in women or some sort of accident that may affect men and women (acquired form), is an extremely rare disorder. Fewer than 500 cases of wandering spleen have been reported in the medical literature. The incidence of wandering spleen is unknown and, because the condition may be underdiagnosed, is difficult to determine. It usually reported between the ages of 20 and 40 years with sex ratios of 7 females to 1 male. Most women are of reproductive age at the time of presentation. Children make up about a third of all cases, with 30 percent under 10 years of age. Among such children, the male-female ratio is 1:1.As noted, acquired wandering spleen is acquired usually during adulthood, and it affects females many times more frequently than males. This is probably due to the relaxation (laxity) of the splenic ligaments during the childbearing years. Pregnancy is thought to contribute to the laxity, which increases the frequency of acquired wandering spleen among women who have had children.
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Affects of Wandering Spleen. Wandering spleen, whether it is a condition with which a baby is born (congenital form) or is the result of multiple births in women or some sort of accident that may affect men and women (acquired form), is an extremely rare disorder. Fewer than 500 cases of wandering spleen have been reported in the medical literature. The incidence of wandering spleen is unknown and, because the condition may be underdiagnosed, is difficult to determine. It usually reported between the ages of 20 and 40 years with sex ratios of 7 females to 1 male. Most women are of reproductive age at the time of presentation. Children make up about a third of all cases, with 30 percent under 10 years of age. Among such children, the male-female ratio is 1:1.As noted, acquired wandering spleen is acquired usually during adulthood, and it affects females many times more frequently than males. This is probably due to the relaxation (laxity) of the splenic ligaments during the childbearing years. Pregnancy is thought to contribute to the laxity, which increases the frequency of acquired wandering spleen among women who have had children.
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Related disorders of Wandering Spleen
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Symptoms of the following disorders can be similar to those of wandering spleen. Comparisons may be useful for a differential diagnosis:Peritonitis is a common disease characterized by the inflammation of the membrane that lines the abdominal wall (peritoneum). It may be caused by bacteria or other infectious organisms that enter the abdomen through a wound or hole (perforation) in one of the abdominal organs (e.g., ruptured appendix). Symptoms may include abdominal pain and rigidity, enlargement of the abdomen, vomiting, decreased bowel function, nausea, and/or an abnormally rapid heartbeat (tachycardia). If not treated, late symptoms may include chills, fever, rapid breathing, and/or shock.Appendicitis is a common disease characterized by the acute inflammation of the appendix. If left untreated, the appendix may burst and cause peritonitis. The most common symptoms of appendicitis include pain in the lower right abdomen, vomiting, fever, and/or abdominal tenderness and rigidity. Treatment involves the prompt surgical removal of the appendix.Diverticulitis is a common digestive disorder characterized by inflammation of one or more of the sacs (diverticula) that can form due to protrusion of the inner lining of the colon through its intestinal wall. The major symptom of diverticulitis is pain near the groin in the lower part of the abdomen. Other symptoms may include pain when urinating, constipation, diarrhea or other changes in bowel movements, fever, and/or rectal bleeding. (For more information on this disorder, choose “Diverticulitis” as your search term in the Rare Disease Database.)Intestinal obstruction is a common condition characterized by the blockage of the intestines and a lack of intestinal motility. This results in the failure of waste (feces) to pass through intestines and be eliminated. The most common causes of intestinal obstruction are adhesions from previous surgery, impacted stools, a narrowing of the bowel because of an inflammatory bowel disease, and/or the presence of a tumor. Symptoms may include a swollen abdomen, severe abdominal pain, nausea and vomiting, and/or constipation.Cholecystitis is a common disease characterized by inflammation of the gall bladder. This disease, which is usually caused by the presence of gallstones, can be acute or chronic. Symptoms may include ongoing or episodic severe abdominal pain, chills, nausea and vomiting, indigestion, heartburn, gassiness, fever, and/or pain in the chest, shoulder, and back. There may also be some discomfort after eating, an intolerance to fatty foods, and/or a yellowish discoloration of the skin. (For more information on this disorder, choose “Cholecystitis” as your search term in the Rare Disease Database.)Other common diseases may also have symptoms that are similar to those of wandering spleen. These include pyelonephritis, hiatal hernia, hepatitis, gastric ulcer, gastroenteritis, and/or pancreatitis.The following disorders may be associated with Wandering Spleen as secondary characteristics. Comparisons are not necessary for a differential diagnosis:Thrombocytopenia is a condition characterized by abnormally low levels of platelets in the circulating blood. When the spleen becomes enlarged, platelets or other blood elements may be “captured” (sequestered) in the spleen. Symptoms of thrombocytopenia may include excessive bleeding, the tendency to bruise easily, nosebleeds, and/or abnormally heavy menstrual flow in women. If an enlarged spleen (splenomegaly)is not detected in the abdomen, then some people with wandering spleen may be misdiagnosed with other blood disorders that involve low circulating platelets (i.e., autoimmune thrombocytopenia purpura).Prune belly syndrome is a rare congenital disorder characterized by underdevelopment of the abdominal muscles. The syndrome is associated with a number of intestinal and urogenital abnormalities. Often, the attachments of the muscles to the bones are present, but the muscles are small in size and thickness. Children with prune belly syndrome typically have abnormally large abdomens and the skin may appear loose or lax. The chest may also have a horizontal depression (Harrison groove) or may be very narrow (pigeon breast). Some children with pune belly syndrome may have wandering spleen because of the underdevelopment of the ligaments that normally anchor the spleen in the upper left abdomen. (For more information on this disorder, choose “Prune Belly” as your search term in the Rare Disease Database.)Other conditions that have been associated with wandering spleen include the absence or abnormal enlargement of a kidney, infectious mononucleosis, malaria, sickle cell anemia, and Hodgkin's disease. (For more information on these disorders, choose “Malaria,” “Sickle Cell,” and “Hodgkin” as your search terms in the Rare Disease Database or use “splenomegaly” as your search term to find other diseases that include an enlarged spleen.)
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Related disorders of Wandering Spleen. Symptoms of the following disorders can be similar to those of wandering spleen. Comparisons may be useful for a differential diagnosis:Peritonitis is a common disease characterized by the inflammation of the membrane that lines the abdominal wall (peritoneum). It may be caused by bacteria or other infectious organisms that enter the abdomen through a wound or hole (perforation) in one of the abdominal organs (e.g., ruptured appendix). Symptoms may include abdominal pain and rigidity, enlargement of the abdomen, vomiting, decreased bowel function, nausea, and/or an abnormally rapid heartbeat (tachycardia). If not treated, late symptoms may include chills, fever, rapid breathing, and/or shock.Appendicitis is a common disease characterized by the acute inflammation of the appendix. If left untreated, the appendix may burst and cause peritonitis. The most common symptoms of appendicitis include pain in the lower right abdomen, vomiting, fever, and/or abdominal tenderness and rigidity. Treatment involves the prompt surgical removal of the appendix.Diverticulitis is a common digestive disorder characterized by inflammation of one or more of the sacs (diverticula) that can form due to protrusion of the inner lining of the colon through its intestinal wall. The major symptom of diverticulitis is pain near the groin in the lower part of the abdomen. Other symptoms may include pain when urinating, constipation, diarrhea or other changes in bowel movements, fever, and/or rectal bleeding. (For more information on this disorder, choose “Diverticulitis” as your search term in the Rare Disease Database.)Intestinal obstruction is a common condition characterized by the blockage of the intestines and a lack of intestinal motility. This results in the failure of waste (feces) to pass through intestines and be eliminated. The most common causes of intestinal obstruction are adhesions from previous surgery, impacted stools, a narrowing of the bowel because of an inflammatory bowel disease, and/or the presence of a tumor. Symptoms may include a swollen abdomen, severe abdominal pain, nausea and vomiting, and/or constipation.Cholecystitis is a common disease characterized by inflammation of the gall bladder. This disease, which is usually caused by the presence of gallstones, can be acute or chronic. Symptoms may include ongoing or episodic severe abdominal pain, chills, nausea and vomiting, indigestion, heartburn, gassiness, fever, and/or pain in the chest, shoulder, and back. There may also be some discomfort after eating, an intolerance to fatty foods, and/or a yellowish discoloration of the skin. (For more information on this disorder, choose “Cholecystitis” as your search term in the Rare Disease Database.)Other common diseases may also have symptoms that are similar to those of wandering spleen. These include pyelonephritis, hiatal hernia, hepatitis, gastric ulcer, gastroenteritis, and/or pancreatitis.The following disorders may be associated with Wandering Spleen as secondary characteristics. Comparisons are not necessary for a differential diagnosis:Thrombocytopenia is a condition characterized by abnormally low levels of platelets in the circulating blood. When the spleen becomes enlarged, platelets or other blood elements may be “captured” (sequestered) in the spleen. Symptoms of thrombocytopenia may include excessive bleeding, the tendency to bruise easily, nosebleeds, and/or abnormally heavy menstrual flow in women. If an enlarged spleen (splenomegaly)is not detected in the abdomen, then some people with wandering spleen may be misdiagnosed with other blood disorders that involve low circulating platelets (i.e., autoimmune thrombocytopenia purpura).Prune belly syndrome is a rare congenital disorder characterized by underdevelopment of the abdominal muscles. The syndrome is associated with a number of intestinal and urogenital abnormalities. Often, the attachments of the muscles to the bones are present, but the muscles are small in size and thickness. Children with prune belly syndrome typically have abnormally large abdomens and the skin may appear loose or lax. The chest may also have a horizontal depression (Harrison groove) or may be very narrow (pigeon breast). Some children with pune belly syndrome may have wandering spleen because of the underdevelopment of the ligaments that normally anchor the spleen in the upper left abdomen. (For more information on this disorder, choose “Prune Belly” as your search term in the Rare Disease Database.)Other conditions that have been associated with wandering spleen include the absence or abnormal enlargement of a kidney, infectious mononucleosis, malaria, sickle cell anemia, and Hodgkin's disease. (For more information on these disorders, choose “Malaria,” “Sickle Cell,” and “Hodgkin” as your search terms in the Rare Disease Database or use “splenomegaly” as your search term to find other diseases that include an enlarged spleen.)
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Diagnosis of Wandering Spleen
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The diagnosis of wanderin. spleen is suspected when the pain associated with an abdominal mass can be relieved by moving it toward the upper left quadrant of the abdomen, the normal position of the spleen. Wandering spleen may be confirmed by specialized examinations such as ultrasonography and CT scan that enable the physician to view the structure, size, and placement of the spleen within the abdomen or pelvis. Specialized ultrasound tests (i.e., Doppler studies) may show impaired blood flow in and out of the spleen. Radioisotopic scanning (technetium 99 sulfur colloid scan), another imaging test, allows the physician to determine how well the liver and spleen are functioning. Low spleen function (functional asplenia) may suggest that the organ is damaged as a result of arterial obstruction (infarct).
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Diagnosis of Wandering Spleen. The diagnosis of wanderin. spleen is suspected when the pain associated with an abdominal mass can be relieved by moving it toward the upper left quadrant of the abdomen, the normal position of the spleen. Wandering spleen may be confirmed by specialized examinations such as ultrasonography and CT scan that enable the physician to view the structure, size, and placement of the spleen within the abdomen or pelvis. Specialized ultrasound tests (i.e., Doppler studies) may show impaired blood flow in and out of the spleen. Radioisotopic scanning (technetium 99 sulfur colloid scan), another imaging test, allows the physician to determine how well the liver and spleen are functioning. Low spleen function (functional asplenia) may suggest that the organ is damaged as a result of arterial obstruction (infarct).
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Therapies of Wandering Spleen
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TreatmentThe treatment of wandering spleen depends on the severity of symptoms and a thorough evaluation to determine the size, location, and functional status of the spleen. Since the spleen helps to maintain the proper function of the blood and immune system, most treatments are aimed at conserving the spleen and maximizing its function. However, since a person can live reasonably well without a spleen, surgical removal is considered.The most conservative approach to the treatment of wandering spleen includes watchful waiting while observing splenic function and/or enlargement. Prevention of injury by avoiding contact sports or other activities that might threaten the spleen is also a part of the conservative approach.For children with congenital wandering spleen who are experiencing episodes of torsion and acute pain, the treatment of choice may be surgery that anchors the spleen back in the proper position in the upper left abdomen (splenopexy). In many cases, the spleen can be preserved and the risk of torsion and infarct is reduced. Preservation of the spleen is preferred to removal through surgery because absence of the spleen can make a person vulnerable to certain infections.If wandering spleen causes chronic abdominal pain, abnormal enlargement of the spleen, and/or deficiencies of one or more necessary blood elements (i.e., thrombocytopenic hypersplenism), the treatment of choice is usually surgery to remove the spleen (splenectomy). Acute abdominal pain associated with wandering spleen is considered a surgical emergency and may require immediate splenectomy.The potential complications of complete removal of the spleen (splenectomy) may include postsplenectomy infection syndrome, which includes life-threatening bacterial infections (sepsis). People who have had a splenectomy are at higher lifetime risk for serious infections than the general population. Immunizations to boost immunity against haemophilus influenzae B, streptococcus pneumoniae, seisseria meningitis, and other contagious diseases are usually administered before the splenectomy is performed. All people who have had a splenectomy must be observed carefully in case of fever or other symptoms of infection. Antibiotics may be prescribed to help prevent infectious disease (prophylaxis), especially in children under the age of 2 years.
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Therapies of Wandering Spleen. TreatmentThe treatment of wandering spleen depends on the severity of symptoms and a thorough evaluation to determine the size, location, and functional status of the spleen. Since the spleen helps to maintain the proper function of the blood and immune system, most treatments are aimed at conserving the spleen and maximizing its function. However, since a person can live reasonably well without a spleen, surgical removal is considered.The most conservative approach to the treatment of wandering spleen includes watchful waiting while observing splenic function and/or enlargement. Prevention of injury by avoiding contact sports or other activities that might threaten the spleen is also a part of the conservative approach.For children with congenital wandering spleen who are experiencing episodes of torsion and acute pain, the treatment of choice may be surgery that anchors the spleen back in the proper position in the upper left abdomen (splenopexy). In many cases, the spleen can be preserved and the risk of torsion and infarct is reduced. Preservation of the spleen is preferred to removal through surgery because absence of the spleen can make a person vulnerable to certain infections.If wandering spleen causes chronic abdominal pain, abnormal enlargement of the spleen, and/or deficiencies of one or more necessary blood elements (i.e., thrombocytopenic hypersplenism), the treatment of choice is usually surgery to remove the spleen (splenectomy). Acute abdominal pain associated with wandering spleen is considered a surgical emergency and may require immediate splenectomy.The potential complications of complete removal of the spleen (splenectomy) may include postsplenectomy infection syndrome, which includes life-threatening bacterial infections (sepsis). People who have had a splenectomy are at higher lifetime risk for serious infections than the general population. Immunizations to boost immunity against haemophilus influenzae B, streptococcus pneumoniae, seisseria meningitis, and other contagious diseases are usually administered before the splenectomy is performed. All people who have had a splenectomy must be observed carefully in case of fever or other symptoms of infection. Antibiotics may be prescribed to help prevent infectious disease (prophylaxis), especially in children under the age of 2 years.
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Wandering Spleen
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Overview of Warburg Micro Syndrome
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SummaryWarburg Micro syndrome (WARBM) is a rare autosomal recessive genetic disorder. It is primarily characterized by problems with the eyes and with the growth and development of the brain, resulting in neurodevelopmental delay. Affected children have severe intellectual disability, and they experience delays in reaching, or fail to reach, normal developmental milestones. They may also have microcephaly, a condition that indicates that the head circumference is significantly smaller than would be expected based upon an infant’s age and gender. Most children exhibit underdevelopment and reduced activity of the testes or ovaries (hypothalamic hypogonadism), and in some children with WARBM1 there is a peripheral neuropathy leading to lower limb spasticity and/or cardiomyopathy. Changes in one of at least four different genes, RAB3GAP1 (WARBM1 on 2q21.3), RAB3GAP2 (WARBM2 on 1q41), RAB18 (WARBM3 on 10p12), or TCB1D20 (WARBM4 on 20p13), causes this disorder, and Warburg Micro syndrome is inherited in an autosomal recessive manner. The 4 different types are clinically indistinguishable from each other, so molecular testing is required to distinguish between them. In 1993 Warburg used the term MICRO syndrome to describe an autosomal recessive syndrome comprising microcephaly, microcornea, congenital cataract, mental retardation, Optic atrophy, and hypogenitalism. This disorder is part of a spectrum of disease that includes Martsolf syndrome at the mild end, and changes in RAB3GAP2 have been linked to Martsolf syndrome.
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Overview of Warburg Micro Syndrome. SummaryWarburg Micro syndrome (WARBM) is a rare autosomal recessive genetic disorder. It is primarily characterized by problems with the eyes and with the growth and development of the brain, resulting in neurodevelopmental delay. Affected children have severe intellectual disability, and they experience delays in reaching, or fail to reach, normal developmental milestones. They may also have microcephaly, a condition that indicates that the head circumference is significantly smaller than would be expected based upon an infant’s age and gender. Most children exhibit underdevelopment and reduced activity of the testes or ovaries (hypothalamic hypogonadism), and in some children with WARBM1 there is a peripheral neuropathy leading to lower limb spasticity and/or cardiomyopathy. Changes in one of at least four different genes, RAB3GAP1 (WARBM1 on 2q21.3), RAB3GAP2 (WARBM2 on 1q41), RAB18 (WARBM3 on 10p12), or TCB1D20 (WARBM4 on 20p13), causes this disorder, and Warburg Micro syndrome is inherited in an autosomal recessive manner. The 4 different types are clinically indistinguishable from each other, so molecular testing is required to distinguish between them. In 1993 Warburg used the term MICRO syndrome to describe an autosomal recessive syndrome comprising microcephaly, microcornea, congenital cataract, mental retardation, Optic atrophy, and hypogenitalism. This disorder is part of a spectrum of disease that includes Martsolf syndrome at the mild end, and changes in RAB3GAP2 have been linked to Martsolf syndrome.
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Symptoms of Warburg Micro Syndrome
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With over 100 published families, researchers have been able to establish a clear syndrome with characteristic or “core” symptoms, characterized by microcephaly, microphthalmia, microcornea, congenital cataracts, corpus callosum hypoplasia, intellectual disability, and hypogonadism. RAB3GAP1 encodes the catalytic subunit of a GTPase activator protein and guanine exchange factor for Rab3 and Rab18 respectively. Rab proteins are involved in membrane trafficking in the endoplasmic reticulum, axonal transport, autophagy and synaptic transmission. The Rab3 protein family is also involved in regulated exocytosis of neurotransmitters and hormones, and Rab18 functions in organelle tethering and autophagy. Rab18 is a critical regulator of neuronal migration and morphogenesis, and Rab18 is a physiological substrate of TBC1D20. It is important to note that affected individuals may not have all of the symptoms discussed below. Every child is unique. Parents should talk to their children’s physicians and medical team about their specific case, associated symptoms and overall prognosis.Children with Warburg Micro syndrome have problems with vision and their eyes. This includes abnormally small eyes (microphthalmia) and abnormally small corneas. The corneas are the clear (transparent) outer layer of the eyes. Some infants have clouding of the lenses of the eyes at birth (congenital cataracts). Cataracts usually affect both eyes. Degeneration of the optic nerve can also occur (optic atrophy). The optic nerve is the main nerve of the eyes that carries impulses from the eyes to the brain to form images. An affected individual’s vision is usually very poor due to optic atrophy and damage to the part of the brain that controls vision (cortical visual impairment). Some children may develop glaucoma, a condition characterized by increased pressure within the eyes. Affected children may also have atonic pupils. Atonic pupils are abnormally large, irregularly-shaped pupils that react poorly to light. Normally, the pupil gets smaller (constricts) in the presence of light or when focusing on nearby objects. The pupil normally opens wider (dilates) in dim light or darkness, when focusing on far away objects, or when a person is excited. Affected children have intellectual disability that is often severe. They may fail to reach developmental milestones on time (developmental delays). Some children will be unable to sit independently, walk or talk. Some children will eventually display autistic features. Although less common, seizures can also occur. There are several abnormalities of brain development associated with Warburg Micro syndrome. These include underdevelopment of the ‘bridge’ that connects the right and left halves (cerebral hemispheres) of the brain (hypoplasia of the corpus callosum), shrinkage of the brain (cortical atrophy), progressive shrinkage of the area of brain that controls coordination and balance (cerebellar atrophy), and polymicrogyria, a condition in which there are too many folds in the brain, and the folds are abnormally small. Some infants may experience a delay in the formation of the myelin sheath (delayed myelination). The myelin sheath covers and protects nerve fibers, acts as an insulator, and increases the speed of transmission of nerve signals. These brain findings may differ from one child to another. Affected infants exhibit growth failure and may have diminished muscle tone (hypotonia) so that they appear floppy. As they get older, they may have increased muscle tone and stiffness (spasticity), particularly in the legs. Spasticity can lead to the development of contractures, in which a joint become fixed in a bent or straightened position. Contractures can partially or completely restrict the movement of the affected joint. Eventually the arms become involved. Progressive muscle weakness will develop and affected individuals may not be able to move their arms and legs (quadriplegia). Most children will exhibit underdevelopment and reduced activity of the testes or ovaries (hypothalamic hypogonadism). Affected boys may have a small penis, underdeveloped scrotums, and their testes may fail to descend into the scrotum (cryptorchidism). Affected girls may have underdevelopment of the clitoris and labia minora, and an abnormally small opening that leads to the vagina (small introitus). In girls, hypogonadism can be mild and may go unnoticed. Some infants and children with Warburg Micro syndrome may have distinctive facial features including a narrow mouth, a wide bridge of the nose, and deep-set eyes. Additional symptoms have been reported including abnormal front-to-back and/or sideways curving of the spine (kyphoscoliosis) and excessive hair growth (hypertrichosis).
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Symptoms of Warburg Micro Syndrome. With over 100 published families, researchers have been able to establish a clear syndrome with characteristic or “core” symptoms, characterized by microcephaly, microphthalmia, microcornea, congenital cataracts, corpus callosum hypoplasia, intellectual disability, and hypogonadism. RAB3GAP1 encodes the catalytic subunit of a GTPase activator protein and guanine exchange factor for Rab3 and Rab18 respectively. Rab proteins are involved in membrane trafficking in the endoplasmic reticulum, axonal transport, autophagy and synaptic transmission. The Rab3 protein family is also involved in regulated exocytosis of neurotransmitters and hormones, and Rab18 functions in organelle tethering and autophagy. Rab18 is a critical regulator of neuronal migration and morphogenesis, and Rab18 is a physiological substrate of TBC1D20. It is important to note that affected individuals may not have all of the symptoms discussed below. Every child is unique. Parents should talk to their children’s physicians and medical team about their specific case, associated symptoms and overall prognosis.Children with Warburg Micro syndrome have problems with vision and their eyes. This includes abnormally small eyes (microphthalmia) and abnormally small corneas. The corneas are the clear (transparent) outer layer of the eyes. Some infants have clouding of the lenses of the eyes at birth (congenital cataracts). Cataracts usually affect both eyes. Degeneration of the optic nerve can also occur (optic atrophy). The optic nerve is the main nerve of the eyes that carries impulses from the eyes to the brain to form images. An affected individual’s vision is usually very poor due to optic atrophy and damage to the part of the brain that controls vision (cortical visual impairment). Some children may develop glaucoma, a condition characterized by increased pressure within the eyes. Affected children may also have atonic pupils. Atonic pupils are abnormally large, irregularly-shaped pupils that react poorly to light. Normally, the pupil gets smaller (constricts) in the presence of light or when focusing on nearby objects. The pupil normally opens wider (dilates) in dim light or darkness, when focusing on far away objects, or when a person is excited. Affected children have intellectual disability that is often severe. They may fail to reach developmental milestones on time (developmental delays). Some children will be unable to sit independently, walk or talk. Some children will eventually display autistic features. Although less common, seizures can also occur. There are several abnormalities of brain development associated with Warburg Micro syndrome. These include underdevelopment of the ‘bridge’ that connects the right and left halves (cerebral hemispheres) of the brain (hypoplasia of the corpus callosum), shrinkage of the brain (cortical atrophy), progressive shrinkage of the area of brain that controls coordination and balance (cerebellar atrophy), and polymicrogyria, a condition in which there are too many folds in the brain, and the folds are abnormally small. Some infants may experience a delay in the formation of the myelin sheath (delayed myelination). The myelin sheath covers and protects nerve fibers, acts as an insulator, and increases the speed of transmission of nerve signals. These brain findings may differ from one child to another. Affected infants exhibit growth failure and may have diminished muscle tone (hypotonia) so that they appear floppy. As they get older, they may have increased muscle tone and stiffness (spasticity), particularly in the legs. Spasticity can lead to the development of contractures, in which a joint become fixed in a bent or straightened position. Contractures can partially or completely restrict the movement of the affected joint. Eventually the arms become involved. Progressive muscle weakness will develop and affected individuals may not be able to move their arms and legs (quadriplegia). Most children will exhibit underdevelopment and reduced activity of the testes or ovaries (hypothalamic hypogonadism). Affected boys may have a small penis, underdeveloped scrotums, and their testes may fail to descend into the scrotum (cryptorchidism). Affected girls may have underdevelopment of the clitoris and labia minora, and an abnormally small opening that leads to the vagina (small introitus). In girls, hypogonadism can be mild and may go unnoticed. Some infants and children with Warburg Micro syndrome may have distinctive facial features including a narrow mouth, a wide bridge of the nose, and deep-set eyes. Additional symptoms have been reported including abnormal front-to-back and/or sideways curving of the spine (kyphoscoliosis) and excessive hair growth (hypertrichosis).
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Warburg Micro Syndrome
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Causes of Warburg Micro Syndrome
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Warburg Micro syndrome is caused by alterations (changes) in one of at least four different genes. The four genes known to be associated with this disorder are RAB18, RAB3GAP1, RAB3GAP2, and TBC1D20. In some people, no alternation in any of these genes has been found. This suggests that additional genes may cause this disorder. A SNP chromosomal microarray should also be done because some submicroscopic chromosomal deletions have similar symptoms, particularly deletion 1q43-44 and deletion 1p36.Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation occurs in a gene, 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, including the brain and the eyes.The genetic alterations that cause Warburg Micro syndrome are inherited in an autosomal recessive manner. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. All individuals carry 7-8 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
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Causes of Warburg Micro Syndrome. Warburg Micro syndrome is caused by alterations (changes) in one of at least four different genes. The four genes known to be associated with this disorder are RAB18, RAB3GAP1, RAB3GAP2, and TBC1D20. In some people, no alternation in any of these genes has been found. This suggests that additional genes may cause this disorder. A SNP chromosomal microarray should also be done because some submicroscopic chromosomal deletions have similar symptoms, particularly deletion 1q43-44 and deletion 1p36.Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation occurs in a gene, 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, including the brain and the eyes.The genetic alterations that cause Warburg Micro syndrome are inherited in an autosomal recessive manner. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. All individuals carry 7-8 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
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Warburg Micro Syndrome
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Affects of Warburg Micro Syndrome
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Warburg Micro syndrome is an extremely rare disorder. As with many rare disorders, the exact incidence or prevalence of this disorder is unknown. The disorder probably goes misdiagnosed or undiagnosed making it difficult to determine the true frequency in the general population. Fewer than 100 people with this disorder have been described in the medical literature.
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Affects of Warburg Micro Syndrome. Warburg Micro syndrome is an extremely rare disorder. As with many rare disorders, the exact incidence or prevalence of this disorder is unknown. The disorder probably goes misdiagnosed or undiagnosed making it difficult to determine the true frequency in the general population. Fewer than 100 people with this disorder have been described in the medical literature.
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Related disorders of Warburg Micro Syndrome
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Symptoms of the following disorders can be similar to those of Warburg Micro syndrome. Comparisons may be useful for a differential diagnosis.Martsolf syndrome is a rare genetic disorder characterized by bilateral congenital cataracts, abnormally small eyes (microphthalmia), intellectual disability, and hypogonadism. Some children may have microcephaly, a condition that indicates that the head circumference is significantly smaller than would be expected based upon an infant’s age and gender. Distinctive facial features can occur including a small jaw (micrognathia), underdevelopment of the upper jaw (maxillary hypoplasia), an abnormally short groove between the nose and the upper lip (short philtrum), and large ears. Some children have developed disease of the heart muscle (cardiomyopathy). Martsolf syndrome is caused by alterations in the RAB3GAP2 gene, one of the four genes associated with Warburg Micro syndrome. There is significant overlap between this disorder and Warburg Micro syndrome. Some researchers believe that these two disorders represent a spectrum of disease associated with the RAB3GAP2 gene. Martsolf syndrome is toward the milder end of this spectrum and Warburg Micro syndrome is on the severe end. Martsolf syndrome is inherited in an autosomal recessive manner. Cerebro-oculo-facial-skeletal (COFS) syndrome is a genetic degenerative disorder of the brain and spinal cord that begins before birth. The disorder is characterized by growth failure at birth and little or no neurological development, structural abnormalities of the eyes, and fixed bending of the spine and joints. Abnormalities of the skull, face, limbs and other parts of the body may also occur. Affected individuals may have congenital cataracts, small eyes (microphthalmia), and their head circumference may be smaller than would otherwise be expected (microcephaly). COFS syndrome is inherited as an autosomal recessive trait. Some researchers consider COFS to be part of the spectrum of disorders within Cockayne syndrome. (For more information on this disorder, choose “COFS” as your search term in the Rare Disease Database.)Cockayne syndrome is a rare genetic disorder. The severity and age of onset can vary greatly from one person to another. The disorder is characterized by microcephaly, an abnormal sensitivity to light (photophobia), growth deficiency, developmental delays and intellectual disability. Certain infants, sometimes classified as having Cockayne syndrome type II, have been reported and characterized by obvious growth failure at birth along with little or no neurological development after birth. Serious vision impairments (cataracts and other structural abnormalities of the eye) are usually present at birth. Early skeletal aberrations occur as well. It is likely that CS type II includes some patients previously diagnosed with cerebro-oculo-facial syndrome (COFS) due to the identification of a common genetic defect in these patients. Cockayne syndrome is inherited as an autosomal recessive trait. (For more information on this disorder, choose “Cockayne” as your search term in the Rare Disease Database.)There are a few very rare autosomal recessive disorders that have signs and symptoms similar to those seen in Warburg Micro syndrome. These disorders include congenital cataracts-facial dysmorphism-neuropathy (CCFDN) syndrome and CAMFAK syndrome. Smith-Lemli-Opitz syndrome may have similar symptoms, but these children usually also have multiple visceral abnormalities as well. It is important to rule out genomic disorders with a chromosomal microarray, such as 1p36 microdeletion syndrome or 1q43-44 microdeletion, since these conditions have similar features and can arise through a balanced parental translocation, thereby resulting in recurrent cases within a family.
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Related disorders of Warburg Micro Syndrome. Symptoms of the following disorders can be similar to those of Warburg Micro syndrome. Comparisons may be useful for a differential diagnosis.Martsolf syndrome is a rare genetic disorder characterized by bilateral congenital cataracts, abnormally small eyes (microphthalmia), intellectual disability, and hypogonadism. Some children may have microcephaly, a condition that indicates that the head circumference is significantly smaller than would be expected based upon an infant’s age and gender. Distinctive facial features can occur including a small jaw (micrognathia), underdevelopment of the upper jaw (maxillary hypoplasia), an abnormally short groove between the nose and the upper lip (short philtrum), and large ears. Some children have developed disease of the heart muscle (cardiomyopathy). Martsolf syndrome is caused by alterations in the RAB3GAP2 gene, one of the four genes associated with Warburg Micro syndrome. There is significant overlap between this disorder and Warburg Micro syndrome. Some researchers believe that these two disorders represent a spectrum of disease associated with the RAB3GAP2 gene. Martsolf syndrome is toward the milder end of this spectrum and Warburg Micro syndrome is on the severe end. Martsolf syndrome is inherited in an autosomal recessive manner. Cerebro-oculo-facial-skeletal (COFS) syndrome is a genetic degenerative disorder of the brain and spinal cord that begins before birth. The disorder is characterized by growth failure at birth and little or no neurological development, structural abnormalities of the eyes, and fixed bending of the spine and joints. Abnormalities of the skull, face, limbs and other parts of the body may also occur. Affected individuals may have congenital cataracts, small eyes (microphthalmia), and their head circumference may be smaller than would otherwise be expected (microcephaly). COFS syndrome is inherited as an autosomal recessive trait. Some researchers consider COFS to be part of the spectrum of disorders within Cockayne syndrome. (For more information on this disorder, choose “COFS” as your search term in the Rare Disease Database.)Cockayne syndrome is a rare genetic disorder. The severity and age of onset can vary greatly from one person to another. The disorder is characterized by microcephaly, an abnormal sensitivity to light (photophobia), growth deficiency, developmental delays and intellectual disability. Certain infants, sometimes classified as having Cockayne syndrome type II, have been reported and characterized by obvious growth failure at birth along with little or no neurological development after birth. Serious vision impairments (cataracts and other structural abnormalities of the eye) are usually present at birth. Early skeletal aberrations occur as well. It is likely that CS type II includes some patients previously diagnosed with cerebro-oculo-facial syndrome (COFS) due to the identification of a common genetic defect in these patients. Cockayne syndrome is inherited as an autosomal recessive trait. (For more information on this disorder, choose “Cockayne” as your search term in the Rare Disease Database.)There are a few very rare autosomal recessive disorders that have signs and symptoms similar to those seen in Warburg Micro syndrome. These disorders include congenital cataracts-facial dysmorphism-neuropathy (CCFDN) syndrome and CAMFAK syndrome. Smith-Lemli-Opitz syndrome may have similar symptoms, but these children usually also have multiple visceral abnormalities as well. It is important to rule out genomic disorders with a chromosomal microarray, such as 1p36 microdeletion syndrome or 1q43-44 microdeletion, since these conditions have similar features and can arise through a balanced parental translocation, thereby resulting in recurrent cases within a family.
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Diagnosis of Warburg Micro Syndrome
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A diagnosis of Warburg Micro syndrome is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. Key findings of this disorder (microcephaly, cataracts, and microcornea) can also occur because of congenital viral infections and chromosomal abnormalities. Initial tests should be done to rule out congenital viral infections and chromosomal abnormalities. Clinical Testing and Workup
A thorough eye (ophthalmological) examination is necessary in infants suspected of Warburg Micro syndrome. Such an exam can reveal characteristic changes in the eyes. Specialized imaging techniques can also be performed and may include magnetic resonance imaging (MRI). An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues including the brain and can reveal characteristic changes such as cortical malformations, polymicrogyria and hypoplasia of the corpus callosum.Molecular genetic testing via whole exome sequencing or whole genome sequencing can confirm a diagnosis of Warburg Micro syndrome. Molecular genetic testing can detect alterations in the specific genes known to cause the disorder, but is available only as a diagnostic service at specialized laboratories. Molecular diagnosis permits adequate genetic counseling and appropriate management for predicted complications such as adequate sex steroid supplementation therapy for hypogonadism, in addition to standard supportive therapies for developmental delay and visual dysfunction, therefore molecular studies are recommended for this rare condition.
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Diagnosis of Warburg Micro Syndrome. A diagnosis of Warburg Micro syndrome is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. Key findings of this disorder (microcephaly, cataracts, and microcornea) can also occur because of congenital viral infections and chromosomal abnormalities. Initial tests should be done to rule out congenital viral infections and chromosomal abnormalities. Clinical Testing and Workup
A thorough eye (ophthalmological) examination is necessary in infants suspected of Warburg Micro syndrome. Such an exam can reveal characteristic changes in the eyes. Specialized imaging techniques can also be performed and may include magnetic resonance imaging (MRI). An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues including the brain and can reveal characteristic changes such as cortical malformations, polymicrogyria and hypoplasia of the corpus callosum.Molecular genetic testing via whole exome sequencing or whole genome sequencing can confirm a diagnosis of Warburg Micro syndrome. Molecular genetic testing can detect alterations in the specific genes known to cause the disorder, but is available only as a diagnostic service at specialized laboratories. Molecular diagnosis permits adequate genetic counseling and appropriate management for predicted complications such as adequate sex steroid supplementation therapy for hypogonadism, in addition to standard supportive therapies for developmental delay and visual dysfunction, therefore molecular studies are recommended for this rare condition.
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Therapies of Warburg Micro Syndrome
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The treatment of Warburg Micro syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, pediatric neurologists, eye specialists (ophthalmologists), clinical geneticists, speech pathologists, physical therapists, psychologists, and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Genetic counseling is recommended for affected individuals and their families.Treatment options that may be used to treat individuals with Warburg Micro syndrome can be complex and varied. The specific treatment plan will need to be highly individualized. Decisions concerning the use of specific treatments should be made by physicians and other members of the health care team in careful consultation with an affected child’s parents or with an adult patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.Early developmental intervention is important to ensure that affected children reach their potential. Most affected children will benefit from occupational, physical and speech therapy. Various methods of rehabilitative and behavioral therapy may be beneficial. Additional medical, social and/or vocational services including special remedial education may be necessary. Psychosocial support for the entire family is essential as well.Additional treatment is symptomatic and supportive. Surgery may be performed to remove cataracts. However, vision remains poor despite successful cataract removal. Surgery may also be used to treat contractures. Medications that treat seizures (anticonvulsants) can be tried, but seizures may persist.
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Therapies of Warburg Micro Syndrome. The treatment of Warburg Micro syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, pediatric neurologists, eye specialists (ophthalmologists), clinical geneticists, speech pathologists, physical therapists, psychologists, and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Genetic counseling is recommended for affected individuals and their families.Treatment options that may be used to treat individuals with Warburg Micro syndrome can be complex and varied. The specific treatment plan will need to be highly individualized. Decisions concerning the use of specific treatments should be made by physicians and other members of the health care team in careful consultation with an affected child’s parents or with an adult patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.Early developmental intervention is important to ensure that affected children reach their potential. Most affected children will benefit from occupational, physical and speech therapy. Various methods of rehabilitative and behavioral therapy may be beneficial. Additional medical, social and/or vocational services including special remedial education may be necessary. Psychosocial support for the entire family is essential as well.Additional treatment is symptomatic and supportive. Surgery may be performed to remove cataracts. However, vision remains poor despite successful cataract removal. Surgery may also be used to treat contractures. Medications that treat seizures (anticonvulsants) can be tried, but seizures may persist.
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Overview of Warm Autoimmune Hemolytic Anemia
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Warm autoimmune hemolytic anemia (wAIHA) is an autoimmune disorder characterized by the premature destruction of healthy red blood cells (hemolysis). Autoimmune diseases occur when one’s own immune system attacks healthy tissue. In the case of wAIHA and other types of autoimmune hemolytic anemia, red blood cells are “tagged” by antibodies and are then destroyed by other types of immune cells. wAIHA is the most common type of autoimmune hemolytic anemia; it affects approximately 1 to 3 per 100,000 people every year and can occur at any age. The disease is termed “warm” because the antibodies are active and cause hemolysis at body temperature, which is not necessarily the case in other types of autoimmune hemolytic anemia. Normally, the red blood cells have a life span of approximately 120 days before they are destroyed by the spleen. In individuals with wAIHA, the red blood cells are destroyed prematurely and the rate of production of new cells in the bone marrow can no longer compensate for their loss. A decreased number of red blood cells (anemia) may cause fatigue, weakness, a pale skin color (pallor), dizziness, palpitations, and shortness of breath (dyspnea). Hemolysis leads to an increased release from the red blood cells of hemoglobin, a protein responsible for carrying oxygen in the blood. Degradation of hemoglobin into bilirubin can result in yellowing of the skin and whites of the eyes (jaundice). Hemoglobin can also pass in the urine and give it a dark brown color. The treatment of wAIHA is supportive and can also include corticosteroids and/or rituximab. Individuals that do not respond to usual treatment of have more severe disease might require drugs that suppress the immune system (immunosuppressive agents), blood transfusions, or surgical removal of the spleen (splenectomy).
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Overview of Warm Autoimmune Hemolytic Anemia. Warm autoimmune hemolytic anemia (wAIHA) is an autoimmune disorder characterized by the premature destruction of healthy red blood cells (hemolysis). Autoimmune diseases occur when one’s own immune system attacks healthy tissue. In the case of wAIHA and other types of autoimmune hemolytic anemia, red blood cells are “tagged” by antibodies and are then destroyed by other types of immune cells. wAIHA is the most common type of autoimmune hemolytic anemia; it affects approximately 1 to 3 per 100,000 people every year and can occur at any age. The disease is termed “warm” because the antibodies are active and cause hemolysis at body temperature, which is not necessarily the case in other types of autoimmune hemolytic anemia. Normally, the red blood cells have a life span of approximately 120 days before they are destroyed by the spleen. In individuals with wAIHA, the red blood cells are destroyed prematurely and the rate of production of new cells in the bone marrow can no longer compensate for their loss. A decreased number of red blood cells (anemia) may cause fatigue, weakness, a pale skin color (pallor), dizziness, palpitations, and shortness of breath (dyspnea). Hemolysis leads to an increased release from the red blood cells of hemoglobin, a protein responsible for carrying oxygen in the blood. Degradation of hemoglobin into bilirubin can result in yellowing of the skin and whites of the eyes (jaundice). Hemoglobin can also pass in the urine and give it a dark brown color. The treatment of wAIHA is supportive and can also include corticosteroids and/or rituximab. Individuals that do not respond to usual treatment of have more severe disease might require drugs that suppress the immune system (immunosuppressive agents), blood transfusions, or surgical removal of the spleen (splenectomy).
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Symptoms of Warm Autoimmune Hemolytic Anemia
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wAIHA can develop at any age, but the median age of onset is 52 years. This means that one half of affected individuals will be younger than 52 years of age when the disease begins and that the other half will be above this age. The symptoms of wAIHA usually develop slowly over a period of several weeks to months, but in some people can develop suddenly over a few days. Specific symptoms that occur may vary from one person to another and depend on the rate of onset, the degree of hemolysis, and the presence of an underlying disorder. Some individuals, especially those with a gradual onset of anemia, may not have any obvious symptoms (asymptomatic). Symptoms of anemia include paleness of the skin (pallor), fatigue, shortness of breath (dyspnea), dizziness and palpitations. In cases of brisk and severe hemolysis, chest pain, decreased alertness (lethargy), confusion, transient loss of consciousness (syncope), and deregulation of heart rate and blood pressure (hemodynamic instability) might occur. Hemolysis also leads to increased release of hemoglobin (an oxygen-carrying protein) in the blood and urine, which can result in darkly pigmented urine. Hemoglobin is degraded into a yellow compound called bilirubin, which can accumulate and lead to yellowing of the skin and whites of the eyes (jaundice). An enlarged spleen (splenomegaly) can also be seen. Splenomegaly may cause an affected individual to have a bloated or full feeling in the abdomen. wAIHA is also associated with an increased risk of blood clots in the veins (venous thromboembolism). These clots can notably develop in the legs (deep vein thrombosis) and have the potential to detach, circulate in the blood, and occlude the veins of the lungs (pulmonary embolism). Thromboembolisms typically occur in the weeks after diagnosis and are more common in patients with more severe hemolysis and in those that are treated with surgical removal of the spleen (splenectomy). Rarely, clots can form in the arteries feeding the heart (coronary arteries) and lead to a heart attack (myocardial infarction) or in the arteries of the brain (cerebral arteries) and lead to a stroke. Patients that require a splenectomy are also at a higher rate of developing infections. After being treated, 30% of patients will be cured, and the rest are at risk of developing recurrent episodes of hemolysis. The majority of people with wAIHA survive, although a mortality rate of about 5% is seen. Mortality is mainly attributed to thromboembolisms and infections, and the risk depends on many factors, notably the cause of wAIHA and the overall health of the affected individual.
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Symptoms of Warm Autoimmune Hemolytic Anemia. wAIHA can develop at any age, but the median age of onset is 52 years. This means that one half of affected individuals will be younger than 52 years of age when the disease begins and that the other half will be above this age. The symptoms of wAIHA usually develop slowly over a period of several weeks to months, but in some people can develop suddenly over a few days. Specific symptoms that occur may vary from one person to another and depend on the rate of onset, the degree of hemolysis, and the presence of an underlying disorder. Some individuals, especially those with a gradual onset of anemia, may not have any obvious symptoms (asymptomatic). Symptoms of anemia include paleness of the skin (pallor), fatigue, shortness of breath (dyspnea), dizziness and palpitations. In cases of brisk and severe hemolysis, chest pain, decreased alertness (lethargy), confusion, transient loss of consciousness (syncope), and deregulation of heart rate and blood pressure (hemodynamic instability) might occur. Hemolysis also leads to increased release of hemoglobin (an oxygen-carrying protein) in the blood and urine, which can result in darkly pigmented urine. Hemoglobin is degraded into a yellow compound called bilirubin, which can accumulate and lead to yellowing of the skin and whites of the eyes (jaundice). An enlarged spleen (splenomegaly) can also be seen. Splenomegaly may cause an affected individual to have a bloated or full feeling in the abdomen. wAIHA is also associated with an increased risk of blood clots in the veins (venous thromboembolism). These clots can notably develop in the legs (deep vein thrombosis) and have the potential to detach, circulate in the blood, and occlude the veins of the lungs (pulmonary embolism). Thromboembolisms typically occur in the weeks after diagnosis and are more common in patients with more severe hemolysis and in those that are treated with surgical removal of the spleen (splenectomy). Rarely, clots can form in the arteries feeding the heart (coronary arteries) and lead to a heart attack (myocardial infarction) or in the arteries of the brain (cerebral arteries) and lead to a stroke. Patients that require a splenectomy are also at a higher rate of developing infections. After being treated, 30% of patients will be cured, and the rest are at risk of developing recurrent episodes of hemolysis. The majority of people with wAIHA survive, although a mortality rate of about 5% is seen. Mortality is mainly attributed to thromboembolisms and infections, and the risk depends on many factors, notably the cause of wAIHA and the overall health of the affected individual.
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Causes of Warm Autoimmune Hemolytic Anemia
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wAIHA occurs when antibodies produced by the immune system bind to red blood cells and identify them as targets to be attacked. Most of the “tagged” red blood cells are transported to the spleen, where they are destroyed by different types of immune cells. Antibodies are specialized proteins that usually bind to invading organisms and lead to their destruction. There are five main classes of antibodies: IgA, IgD, IgE, IgG, and IgM. Most cases of wAIHA are due to IgG antibodies. Less often, IgM or IgA antibodies cause the disorder. When antibodies attack healthy tissue, they may be referred to as autoantibodies. In the case of wAIHA, these autoantibodies are active and can trigger hemolysis when they are at body temperature. The trigger leading to the development of autoantibodies against red blood cells is usually unknown. These cases may be referred to as primary or idiopathic wAIHA. The disorder may also have a clear trigger in the case of secondary wAIHA. The list of causes of secondary wAIHA is extensive but notably includes medications, autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis, deficiency of the immune system (immunodeficiency), leukemias and lymphomas, infections, and pregnancy. Identifying the cause of secondary wAIHA is important, as it might influence treatment and management of the underlying condition.
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Causes of Warm Autoimmune Hemolytic Anemia. wAIHA occurs when antibodies produced by the immune system bind to red blood cells and identify them as targets to be attacked. Most of the “tagged” red blood cells are transported to the spleen, where they are destroyed by different types of immune cells. Antibodies are specialized proteins that usually bind to invading organisms and lead to their destruction. There are five main classes of antibodies: IgA, IgD, IgE, IgG, and IgM. Most cases of wAIHA are due to IgG antibodies. Less often, IgM or IgA antibodies cause the disorder. When antibodies attack healthy tissue, they may be referred to as autoantibodies. In the case of wAIHA, these autoantibodies are active and can trigger hemolysis when they are at body temperature. The trigger leading to the development of autoantibodies against red blood cells is usually unknown. These cases may be referred to as primary or idiopathic wAIHA. The disorder may also have a clear trigger in the case of secondary wAIHA. The list of causes of secondary wAIHA is extensive but notably includes medications, autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis, deficiency of the immune system (immunodeficiency), leukemias and lymphomas, infections, and pregnancy. Identifying the cause of secondary wAIHA is important, as it might influence treatment and management of the underlying condition.
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Affects of Warm Autoimmune Hemolytic Anemia
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wAIHA affects 1 to 3 people per 100,000 each year in the general population. A total of about 1 in 8,000 individuals live with this condition. People of any age, including children, may develop wAIHA, but it is more common among adults, with a peak incidence between 50-70 years. The median age at onset is 52 years. It is possibly slightly more common in women compared to men. Secondary wAIHA is more common in people with predisposing conditions, such as those with lymphomas and leukemias or those with a disease affecting the immune system.
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Affects of Warm Autoimmune Hemolytic Anemia. wAIHA affects 1 to 3 people per 100,000 each year in the general population. A total of about 1 in 8,000 individuals live with this condition. People of any age, including children, may develop wAIHA, but it is more common among adults, with a peak incidence between 50-70 years. The median age at onset is 52 years. It is possibly slightly more common in women compared to men. Secondary wAIHA is more common in people with predisposing conditions, such as those with lymphomas and leukemias or those with a disease affecting the immune system.
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Related disorders of Warm Autoimmune Hemolytic Anemia
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Symptoms of the following disorders can be similar to those of wAIHA. Comparisons may be useful for a differential diagnosis.Cold agglutinin disease (CAD) is a type of autoimmune hemolytic anemia that typically becomes apparent at 50 to 60 years of age. Symptoms of cold agglutinin disease are similar to those seen in wAIHA, as hemolysis and anemia are also present. As the name indicates, the antibodies seen in cold agglutinin disease activate at temperatures lower than those of the body. Exposure to cold can also trigger coldness of the fingers and/or toes (digits) and uneven bluish or reddish discoloration of the skin of the digits, ankles, and wrists (acrocyanosis or Raynaud’s phenomenon). Although CAD is known to be an autoimmune disorder, its exact underlying cause is not fully understood. (For more information on this disorder, choose “cold agglutinin disease” as your search term in the Rare Disease Database.) Paroxysmal cold hemoglobinuria (PCH) is another type of cold-induced autoimmune hemolytic anemia. Its manifestations are similar to those seen in cold agglutinin disease. (For more information on this disorder, choose “paroxysmal cold hemoglobinuria” as your search term in the Rare Disease Database.)Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired stem cell disorder. The classic finding is hemolysis, resulting in repeated episodes of hemoglobin in the urine (hemoglobinuria). Individuals with hemoglobinuria may exhibit dark-colored or bloody urine. This finding is most prominent in the morning. In addition to hemolysis, individuals with PNH are also susceptible to developing repeated, potentially life-threatening blood clots (thromboses). Affected individuals also have some degree of underlying bone marrow dysfunction. Severe bone marrow dysfunction potentially results in low values of red blood cells, white blood cells and platelets (pancytopenia). The specific symptoms of PNH vary greatly and affected individuals usually do not exhibit all of the symptoms associated with the disorder. (For more information on this disorder, choose “paroxysmal nocturnal hemoglobinuria” as your search term in the Rare Disease Database.)Hereditary spherocytosis (HS) is an inherited disease that affects the structure of red blood cells. Characteristic symptoms of HS are those related to hemolysis and splenomegaly. Age of onset varies, but often occurs between 3 to 7 years of age. Symptoms can develop in infancy, but some people with HS have no symptoms or minor symptoms and are diagnosed later in life. Suspicion of HS is based on clinical features and a family history of HS or related symptoms. Surgical removal of the spleen (splenectomy) can be used to manage HS in the case of severe anemia. Other treatments include folate supplementation and blood transfusions. In contrast to wAIHA and other diseases described above, the hemolysis seen in HS is not autoimmune in origin, but rather the result of a structural defect of red blood cells. (For more information on this disorder, choose “hereditary spherocytosis” as your search term in the Rare Disease Database.)
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Related disorders of Warm Autoimmune Hemolytic Anemia. Symptoms of the following disorders can be similar to those of wAIHA. Comparisons may be useful for a differential diagnosis.Cold agglutinin disease (CAD) is a type of autoimmune hemolytic anemia that typically becomes apparent at 50 to 60 years of age. Symptoms of cold agglutinin disease are similar to those seen in wAIHA, as hemolysis and anemia are also present. As the name indicates, the antibodies seen in cold agglutinin disease activate at temperatures lower than those of the body. Exposure to cold can also trigger coldness of the fingers and/or toes (digits) and uneven bluish or reddish discoloration of the skin of the digits, ankles, and wrists (acrocyanosis or Raynaud’s phenomenon). Although CAD is known to be an autoimmune disorder, its exact underlying cause is not fully understood. (For more information on this disorder, choose “cold agglutinin disease” as your search term in the Rare Disease Database.) Paroxysmal cold hemoglobinuria (PCH) is another type of cold-induced autoimmune hemolytic anemia. Its manifestations are similar to those seen in cold agglutinin disease. (For more information on this disorder, choose “paroxysmal cold hemoglobinuria” as your search term in the Rare Disease Database.)Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired stem cell disorder. The classic finding is hemolysis, resulting in repeated episodes of hemoglobin in the urine (hemoglobinuria). Individuals with hemoglobinuria may exhibit dark-colored or bloody urine. This finding is most prominent in the morning. In addition to hemolysis, individuals with PNH are also susceptible to developing repeated, potentially life-threatening blood clots (thromboses). Affected individuals also have some degree of underlying bone marrow dysfunction. Severe bone marrow dysfunction potentially results in low values of red blood cells, white blood cells and platelets (pancytopenia). The specific symptoms of PNH vary greatly and affected individuals usually do not exhibit all of the symptoms associated with the disorder. (For more information on this disorder, choose “paroxysmal nocturnal hemoglobinuria” as your search term in the Rare Disease Database.)Hereditary spherocytosis (HS) is an inherited disease that affects the structure of red blood cells. Characteristic symptoms of HS are those related to hemolysis and splenomegaly. Age of onset varies, but often occurs between 3 to 7 years of age. Symptoms can develop in infancy, but some people with HS have no symptoms or minor symptoms and are diagnosed later in life. Suspicion of HS is based on clinical features and a family history of HS or related symptoms. Surgical removal of the spleen (splenectomy) can be used to manage HS in the case of severe anemia. Other treatments include folate supplementation and blood transfusions. In contrast to wAIHA and other diseases described above, the hemolysis seen in HS is not autoimmune in origin, but rather the result of a structural defect of red blood cells. (For more information on this disorder, choose “hereditary spherocytosis” as your search term in the Rare Disease Database.)
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Diagnosis of Warm Autoimmune Hemolytic Anemia
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A diagnosis of hemolytic anemia may be suspected based on a thorough clinical evaluation, a detailed patient history, identification of characteristic symptoms and a variety of tests such as blood tests that measure values of hemoglobin and the percentage of the total blood volume occupied by red blood cells (hematocrit). Blood tests may also show an elevated value of immature red blood cells (reticulocytes), which occurs when the body is forced to produce extra red blood cells to make up for those that are destroyed prematurely. Some individuals with hemolytic anemia have elevated values of bilirubin in the blood (hyperbilirubinemia). Hemolytic anemia also leads to increased values of lactate dehydrogenase (LDH) in the blood, as it is released from destroyed red blood cells. Haptoglobin is a hemoglobin scavenger that gets consumed when increased values of hemoglobin are released in the blood due to hemolysis. Haptoglobin values are therefore low in hemolytic anemia. When hemolytic anemia is suspected to be autoimmune in origin, specialized tests such as a Coombs test may be performed. This test is used to detect antibodies that act against red blood cells. A sample of blood is taken and then exposed to the Coombs reagent. A positive test is indicated when the red blood cells clump in the presence of the reagent. The autoantibodies seen in wAIHA are notable for being of the IgG subtype in most cases and being active at body temperature. Depending on the case, further testing might be performed to attempt to identify a cause of secondary wAIHA. In summary, the following sequence allows the diagnosis of wAIHA: 1) detection of anemia with increased reticulocyte counts, 2) determination that the anemia is caused by hemolysis, based on elevated bilirubin and LDH and low haptoglobin, 3) determination that wAIHA is the cause of hemolytic anemia with a Coombs test and 4) possible investigation for a secondary cause of wAIHA.
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Diagnosis of Warm Autoimmune Hemolytic Anemia. A diagnosis of hemolytic anemia may be suspected based on a thorough clinical evaluation, a detailed patient history, identification of characteristic symptoms and a variety of tests such as blood tests that measure values of hemoglobin and the percentage of the total blood volume occupied by red blood cells (hematocrit). Blood tests may also show an elevated value of immature red blood cells (reticulocytes), which occurs when the body is forced to produce extra red blood cells to make up for those that are destroyed prematurely. Some individuals with hemolytic anemia have elevated values of bilirubin in the blood (hyperbilirubinemia). Hemolytic anemia also leads to increased values of lactate dehydrogenase (LDH) in the blood, as it is released from destroyed red blood cells. Haptoglobin is a hemoglobin scavenger that gets consumed when increased values of hemoglobin are released in the blood due to hemolysis. Haptoglobin values are therefore low in hemolytic anemia. When hemolytic anemia is suspected to be autoimmune in origin, specialized tests such as a Coombs test may be performed. This test is used to detect antibodies that act against red blood cells. A sample of blood is taken and then exposed to the Coombs reagent. A positive test is indicated when the red blood cells clump in the presence of the reagent. The autoantibodies seen in wAIHA are notable for being of the IgG subtype in most cases and being active at body temperature. Depending on the case, further testing might be performed to attempt to identify a cause of secondary wAIHA. In summary, the following sequence allows the diagnosis of wAIHA: 1) detection of anemia with increased reticulocyte counts, 2) determination that the anemia is caused by hemolysis, based on elevated bilirubin and LDH and low haptoglobin, 3) determination that wAIHA is the cause of hemolytic anemia with a Coombs test and 4) possible investigation for a secondary cause of wAIHA.
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Therapies of Warm Autoimmune Hemolytic Anemia
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Treatment
The treatment of warm antibody hemolytic anemia is symptomatic and supportive. Affected individuals are usually treated with corticosteroid drugs such as prednisone and can usually be well controlled with proper treatment. A high-dose of these drugs may be recommended initially followed by a gradual reduction (tapering) of the dose over the next few weeks or months. Rituximab is an artificially-created antibody (monoclonal antibody) that targets certain white blood cells that create the antibodies which prematurely destroy red blood cells. Rituximab might be initiated alongside or instead of corticosteroids, or might be given if there is no response to initial treatment. It is sometimes combined with mycophenolate mofetil (MMF), a medication that suppresses the immune system (immunosuppressive agent). Individuals that do not respond to these medications might be given other immunosuppressive agents, such as azathioprine and cyclophosphamide. Another treatment option for patients that do not respond to treatment is surgical removal of the spleen (splenectomy). Splenectomy is also used for people with severe cases that require continual prednisone for control, as this medication is associated with numerous side effects if it is used for an extended period of time. In affected individuals with an underlying disorder, treatment of the disorder usually brings marked improvement of the anemia. Red blood cell transfusions may be necessary to maintain proper red blood cell values in people with severe cases. This supportive technique provides temporary relief, but does not treat the underlying cause of the disorder.
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Therapies of Warm Autoimmune Hemolytic Anemia. Treatment
The treatment of warm antibody hemolytic anemia is symptomatic and supportive. Affected individuals are usually treated with corticosteroid drugs such as prednisone and can usually be well controlled with proper treatment. A high-dose of these drugs may be recommended initially followed by a gradual reduction (tapering) of the dose over the next few weeks or months. Rituximab is an artificially-created antibody (monoclonal antibody) that targets certain white blood cells that create the antibodies which prematurely destroy red blood cells. Rituximab might be initiated alongside or instead of corticosteroids, or might be given if there is no response to initial treatment. It is sometimes combined with mycophenolate mofetil (MMF), a medication that suppresses the immune system (immunosuppressive agent). Individuals that do not respond to these medications might be given other immunosuppressive agents, such as azathioprine and cyclophosphamide. Another treatment option for patients that do not respond to treatment is surgical removal of the spleen (splenectomy). Splenectomy is also used for people with severe cases that require continual prednisone for control, as this medication is associated with numerous side effects if it is used for an extended period of time. In affected individuals with an underlying disorder, treatment of the disorder usually brings marked improvement of the anemia. Red blood cell transfusions may be necessary to maintain proper red blood cell values in people with severe cases. This supportive technique provides temporary relief, but does not treat the underlying cause of the disorder.
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Overview of WAS Related Disorders
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The WAS-related disorders are a spectrum of conditions affecting the immune system that are caused by mutations in the WAS gene. These disorders include Wiskott-Aldrich syndrome, X-linked thrombocytopenia and X-linked congenital neutropenia. The WAS gene abnormality results in a deficiency in the WASP protein that leads to a low platelet count (thrombocytopenia). WAS-related disorders usually present in infancy and are characterized by bloody diarrhea, recurrent infections, scaling, itchy, skin rashes (eczema), and the appearance of small purple spots on the skin (petechia). The development of Pneumocystis carinii pneumonia (PCP) and intracranial bleeding are possible early, life-threatening complications. Later potential complications include destruction of red blood cells (hemolytic anemia), arthritis, vasculitis and kidney and liver damage. Affected individuals have an increased risk of developing lymphomas, especially after exposure to Epstein-Barr virus. WAS-related disorders are extremely variable, even in individuals in the same family.
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Overview of WAS Related Disorders. The WAS-related disorders are a spectrum of conditions affecting the immune system that are caused by mutations in the WAS gene. These disorders include Wiskott-Aldrich syndrome, X-linked thrombocytopenia and X-linked congenital neutropenia. The WAS gene abnormality results in a deficiency in the WASP protein that leads to a low platelet count (thrombocytopenia). WAS-related disorders usually present in infancy and are characterized by bloody diarrhea, recurrent infections, scaling, itchy, skin rashes (eczema), and the appearance of small purple spots on the skin (petechia). The development of Pneumocystis carinii pneumonia (PCP) and intracranial bleeding are possible early, life-threatening complications. Later potential complications include destruction of red blood cells (hemolytic anemia), arthritis, vasculitis and kidney and liver damage. Affected individuals have an increased risk of developing lymphomas, especially after exposure to Epstein-Barr virus. WAS-related disorders are extremely variable, even in individuals in the same family.
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Symptoms of WAS Related Disorders
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The WAS-related disorders are a spectrum of conditions affecting the immune system that are caused by mutations in the WAS gene. These disorders include Wiskott-Aldrich syndrome, X-linked thrombocytopenia and X-linked congenital neutropenia.Symptoms of Wiskott Aldrich syndrome usually begin in infancy. The original description of this condition included a combination of three features: bloody diarrhea, abnormal bleeding episodes and/or small purple spots on the skin (petechia); scaling, itchy, skin rashes (eczema); recurrent ear infections. A low platelet count (thrombocytopenia), in association with small platelet size, is usually present at birth, but platelet counts may initially be near normal. Intracranial bleeding is a possible life-threatening complication of WAS. Eczema occurs in approximately 80% of affected individuals and can range from mild to severe. Boys with WAS have an increased risk for recurrent bacterial and viral infections. The development of Pneumocystis carinii pneumonia (PCP) is a possible life-threatening complication. Autoimmune disorders are common in those who survive and include destruction of red blood cells (hemolytic anemia), arthritis, vasculitis and kidney and liver damage. The risk for developing an autoimmune disorder increases with age. Boys with WAS have an increased risk of developing lymphomas, especially after exposure to Epstein-Barr virus. The lymphomas are often in unusual locations such as the brain, lung or gastrointestinal tract. Males with X-linked thrombocytopenia have thrombocytopenia without eczema or immune dysfunction It is not always possible to classify a patient as having XLT or WAS because of the overlap of clinical symptoms, variabilities in WAS protein expression and overlap of mutations in these disorders. X-linked congenital neutropenia is thought to be extremely rare and is characterized by recurrent bacterial infections, an abnormal decrease in the number of neutrophils (the most common type of white blood cells) in the blood, and abnormal development of bone marrow.
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Symptoms of WAS Related Disorders. The WAS-related disorders are a spectrum of conditions affecting the immune system that are caused by mutations in the WAS gene. These disorders include Wiskott-Aldrich syndrome, X-linked thrombocytopenia and X-linked congenital neutropenia.Symptoms of Wiskott Aldrich syndrome usually begin in infancy. The original description of this condition included a combination of three features: bloody diarrhea, abnormal bleeding episodes and/or small purple spots on the skin (petechia); scaling, itchy, skin rashes (eczema); recurrent ear infections. A low platelet count (thrombocytopenia), in association with small platelet size, is usually present at birth, but platelet counts may initially be near normal. Intracranial bleeding is a possible life-threatening complication of WAS. Eczema occurs in approximately 80% of affected individuals and can range from mild to severe. Boys with WAS have an increased risk for recurrent bacterial and viral infections. The development of Pneumocystis carinii pneumonia (PCP) is a possible life-threatening complication. Autoimmune disorders are common in those who survive and include destruction of red blood cells (hemolytic anemia), arthritis, vasculitis and kidney and liver damage. The risk for developing an autoimmune disorder increases with age. Boys with WAS have an increased risk of developing lymphomas, especially after exposure to Epstein-Barr virus. The lymphomas are often in unusual locations such as the brain, lung or gastrointestinal tract. Males with X-linked thrombocytopenia have thrombocytopenia without eczema or immune dysfunction It is not always possible to classify a patient as having XLT or WAS because of the overlap of clinical symptoms, variabilities in WAS protein expression and overlap of mutations in these disorders. X-linked congenital neutropenia is thought to be extremely rare and is characterized by recurrent bacterial infections, an abnormal decrease in the number of neutrophils (the most common type of white blood cells) in the blood, and abnormal development of bone marrow.
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Causes of WAS Related Disorders
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WAS-related disorders are X-linked recessive genetic diseases that occur almost exclusively in males. X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. WAS-related disorders are caused by a mutation in the WAS gene on the X chromosome that leads to a deficiency of the WASP protein. The WASP protein is important in the structure and function of most blood cells.Females have two X chromosomes but one of the X chromosomes is “turned off” and all of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder because it is usually the X chromosome with the abnormal gene that is “turned off”. A male has one X chromosome and if he inherits an X chromosome that contains a disease gene, he will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease, and a 25% chance to have an unaffected son.
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Causes of WAS Related Disorders. WAS-related disorders are X-linked recessive genetic diseases that occur almost exclusively in males. X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. WAS-related disorders are caused by a mutation in the WAS gene on the X chromosome that leads to a deficiency of the WASP protein. The WASP protein is important in the structure and function of most blood cells.Females have two X chromosomes but one of the X chromosomes is “turned off” and all of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder because it is usually the X chromosome with the abnormal gene that is “turned off”. A male has one X chromosome and if he inherits an X chromosome that contains a disease gene, he will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease, and a 25% chance to have an unaffected son.
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Affects of WAS Related Disorders
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The estimated prevalence of WAS-related disorders is 3/1,000,000 males. This condition has been described in many ethnic groups and in many countries.
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Affects of WAS Related Disorders. The estimated prevalence of WAS-related disorders is 3/1,000,000 males. This condition has been described in many ethnic groups and in many countries.
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Related disorders of WAS Related Disorders
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Symptoms of the following disorders may be similar to those of WAS-related disorders. Comparisons may be useful for a differential diagnosis:Human immunodeficiency (HIV) infection should always be ruled out in any individual presenting with PCP or severe immune dysfunction. Idiopathic thrombocytopenic purpura (ITP) is a rare autoimmune bleeding disorder characterized by the abnormally low levels of certain blood cells called platelets, creating a condition known as thrombocytopenia. Platelets are specialized blood cells that help prevent and stop bleeding by inducing clotting. In ITP, there is no readily apparent cause or underlying disease (idiopathic). The cells of the immune system, lymphocytes, produce anti-platelet antibodies that attach to the platelets. The presence of antibodies on platelets leads to their destruction in the spleen. The disorder is characterized by abnormal bleeding into the skin resulting in bruising, which is what the term purpura means. Bleeding from mucous membranes also occurs, and may subsequently result in low levels of circulating red blood cells (anemia). (For more information on this disorder, choose “ITP” as your search term in the Rare Disease Database.)In males who initially present with Pneumocystis Carinii pneumonia, SCID and XHM should be considered. Neither is typically associated with persistent thrombocytopenia.Severe Combined Immunodeficiency (SCID) is a group of rare congenital syndromes characterized by little if any immune responses. This results in frequent recurring infections. Cellular immune responses involve specialized white blood cells known as T lymphocytes which consist of “helper” and “killer cells.” These cells assist other white blood cells (B lymphocytes) to respond to infectious, foreign agents that invade the body (i.e., bacteria or viruses). The B lymphocytes maintain immunity by enabling the body to produce and preserve circulating antibodies. People with SCID are unusually susceptible to recurrent infections with bacteria, viruses, fungi, and other infectious agents that can be life threatening.There are several types of SCID. Each type of severe combined immune deficiency is caused by a different genetic defect, but the primary symptom is reduced or absent immune functions, and all types are hereditary. (For more information on this disorder, choose “SCID” as your search term in the Rare Disease Database.)Hyper-IgM Syndrome (HIM) is a rare genetic (primary) immunodeficiency disorder that is typically inherited as an X-linked recessive genetic trait. Symptoms and physical findings associated with the disorder usually become apparent in the first or second year of life. Hyper-IgM Syndrome may be characterized by recurrent bacterial infections of the upper and lower respiratory tract including the sinuses and/or the lungs (pneumonitis or pneumonia); the middle ear (otitis media); the membrane that lines the eyelids and the white portions (sclera) of the eyes (conjunctivitis); the skin (pyoderma); and/or, in some cases, other areas. Individuals with Hyper-IgM Syndrome are also susceptible to “opportunistic” infections, i.e., infections caused by microorganisms that usually do not cause disease in individuals with fully functioning immune systems (non-immunocompromised) or widespread (systemic) overwhelming disease by microorganisms that typically cause only localized, mild infections. In addition, individuals with Hyper-IgM syndrome are prone to certain autoimmune disorders affecting particular elements of the blood, such as neutropenia, a condition in which there is an abnormal decrease of certain white blood cells (neutrophils). Additional physical findings often associated with the disorder may include enlargement (hypertrophy) of the tonsils, enlargement of the liver and spleen (hepatosplenomegaly), chronic diarrhea and impaired absorption of nutrients by the intestinal tract (malabsorption), and/or other symptoms. (For more information on this disorder, choose “hyper IgM” as your search term in the Rare Disease Database.)
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Related disorders of WAS Related Disorders. Symptoms of the following disorders may be similar to those of WAS-related disorders. Comparisons may be useful for a differential diagnosis:Human immunodeficiency (HIV) infection should always be ruled out in any individual presenting with PCP or severe immune dysfunction. Idiopathic thrombocytopenic purpura (ITP) is a rare autoimmune bleeding disorder characterized by the abnormally low levels of certain blood cells called platelets, creating a condition known as thrombocytopenia. Platelets are specialized blood cells that help prevent and stop bleeding by inducing clotting. In ITP, there is no readily apparent cause or underlying disease (idiopathic). The cells of the immune system, lymphocytes, produce anti-platelet antibodies that attach to the platelets. The presence of antibodies on platelets leads to their destruction in the spleen. The disorder is characterized by abnormal bleeding into the skin resulting in bruising, which is what the term purpura means. Bleeding from mucous membranes also occurs, and may subsequently result in low levels of circulating red blood cells (anemia). (For more information on this disorder, choose “ITP” as your search term in the Rare Disease Database.)In males who initially present with Pneumocystis Carinii pneumonia, SCID and XHM should be considered. Neither is typically associated with persistent thrombocytopenia.Severe Combined Immunodeficiency (SCID) is a group of rare congenital syndromes characterized by little if any immune responses. This results in frequent recurring infections. Cellular immune responses involve specialized white blood cells known as T lymphocytes which consist of “helper” and “killer cells.” These cells assist other white blood cells (B lymphocytes) to respond to infectious, foreign agents that invade the body (i.e., bacteria or viruses). The B lymphocytes maintain immunity by enabling the body to produce and preserve circulating antibodies. People with SCID are unusually susceptible to recurrent infections with bacteria, viruses, fungi, and other infectious agents that can be life threatening.There are several types of SCID. Each type of severe combined immune deficiency is caused by a different genetic defect, but the primary symptom is reduced or absent immune functions, and all types are hereditary. (For more information on this disorder, choose “SCID” as your search term in the Rare Disease Database.)Hyper-IgM Syndrome (HIM) is a rare genetic (primary) immunodeficiency disorder that is typically inherited as an X-linked recessive genetic trait. Symptoms and physical findings associated with the disorder usually become apparent in the first or second year of life. Hyper-IgM Syndrome may be characterized by recurrent bacterial infections of the upper and lower respiratory tract including the sinuses and/or the lungs (pneumonitis or pneumonia); the middle ear (otitis media); the membrane that lines the eyelids and the white portions (sclera) of the eyes (conjunctivitis); the skin (pyoderma); and/or, in some cases, other areas. Individuals with Hyper-IgM Syndrome are also susceptible to “opportunistic” infections, i.e., infections caused by microorganisms that usually do not cause disease in individuals with fully functioning immune systems (non-immunocompromised) or widespread (systemic) overwhelming disease by microorganisms that typically cause only localized, mild infections. In addition, individuals with Hyper-IgM syndrome are prone to certain autoimmune disorders affecting particular elements of the blood, such as neutropenia, a condition in which there is an abnormal decrease of certain white blood cells (neutrophils). Additional physical findings often associated with the disorder may include enlargement (hypertrophy) of the tonsils, enlargement of the liver and spleen (hepatosplenomegaly), chronic diarrhea and impaired absorption of nutrients by the intestinal tract (malabsorption), and/or other symptoms. (For more information on this disorder, choose “hyper IgM” as your search term in the Rare Disease Database.)
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WAS Related Disorders
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Diagnosis of WAS Related Disorders
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A WAS-related disorder is suspected based on clinical features and laboratory testing. Testing shows a low platelet count and small platelet size, and sometimes shows abnormal levels of serum immunoglobulins: low IgM, elevated IgA and IgE, decreased absolute numbers of CD8+ T cells and decreased function of natural killer cells. Decreased or absent WASP protein in blood cells strengthens the diagnosis. Molecular genetic testing for the WAS gene is available to confirm the diagnosis.
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Diagnosis of WAS Related Disorders. A WAS-related disorder is suspected based on clinical features and laboratory testing. Testing shows a low platelet count and small platelet size, and sometimes shows abnormal levels of serum immunoglobulins: low IgM, elevated IgA and IgE, decreased absolute numbers of CD8+ T cells and decreased function of natural killer cells. Decreased or absent WASP protein in blood cells strengthens the diagnosis. Molecular genetic testing for the WAS gene is available to confirm the diagnosis.
| 1,283 |
WAS Related Disorders
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Therapies of WAS Related Disorders
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TreatmentThe only treatment currently available to cure WAS-related disorders is bone marrow transplant from an allogeneic donor. Allogeneic donors must have human leukocyte antigens (HLA) that match the recipient. Human leukocyte antigens (HLA), which are a form of "histocompatability antigens," are present within the body's tissues and function as an essential part of the immune system. The specific type of HLA within a person's tissues is inherited and is known as the person's "tissue type.". When tissues are transplanted, a donor's and a recipient's HLA tissue types influence the outcome of transplantation. For example, if a donor can be located whose HLA tissue types are very close to those of the recipient, the histocompatability antigens in the donor tissue may not be recognized as foreign and therefore may not be attacked by the recipient's immune system, improving the chances of successful transplantation. Siblings or other blood relatives are the most likely to have HLA types very similar to those of the recipient. Boys with WAS who receive bone marrow transplantation from a matched healthy sibling or closely matched unrelated donor have a greater than 85% chance of being cured if the procedure is performed before five years of age.Supportive care for WAS-related disorders includes prophylaxis against PCP and appropriate antimicrobial therapy for infections. intravenous immunoglobulin. routine childhood immunizations, and treating eczema with topical steroid therapy. Treatment of significant bleeding sometimes includes platelet transfusions. Splenectomy is no longer recommended as it increases the risk of late death following bone marrow transplantation.
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Therapies of WAS Related Disorders. TreatmentThe only treatment currently available to cure WAS-related disorders is bone marrow transplant from an allogeneic donor. Allogeneic donors must have human leukocyte antigens (HLA) that match the recipient. Human leukocyte antigens (HLA), which are a form of "histocompatability antigens," are present within the body's tissues and function as an essential part of the immune system. The specific type of HLA within a person's tissues is inherited and is known as the person's "tissue type.". When tissues are transplanted, a donor's and a recipient's HLA tissue types influence the outcome of transplantation. For example, if a donor can be located whose HLA tissue types are very close to those of the recipient, the histocompatability antigens in the donor tissue may not be recognized as foreign and therefore may not be attacked by the recipient's immune system, improving the chances of successful transplantation. Siblings or other blood relatives are the most likely to have HLA types very similar to those of the recipient. Boys with WAS who receive bone marrow transplantation from a matched healthy sibling or closely matched unrelated donor have a greater than 85% chance of being cured if the procedure is performed before five years of age.Supportive care for WAS-related disorders includes prophylaxis against PCP and appropriate antimicrobial therapy for infections. intravenous immunoglobulin. routine childhood immunizations, and treating eczema with topical steroid therapy. Treatment of significant bleeding sometimes includes platelet transfusions. Splenectomy is no longer recommended as it increases the risk of late death following bone marrow transplantation.
| 1,283 |
WAS Related Disorders
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nord_1284_0
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Overview of WDR26-Related Disorder
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SummaryWDR26-related disorder, also known as Skraban-Deardorff syndrome (SKDEAS), is a rare neurodevelopmental disorder caused by changes (variants or mutations) in the gene WDR26. Individuals with SKDEAS can present with a variety of symptoms that commonly include differences in development, seizures, low muscle tone, friendly personality and unique facial features. Most individuals have a new (de novo) change in the WDR26 gene that is not inherited. WDR26-related disorder follows an autosomal dominant inheritance pattern, meaning that someone with the condition has a 50% risk of passing the gene variant to each child. There is no specific treatment for the condition and management is based on an individual’s symptoms with particular focus on attainment of developmental milestones.
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Overview of WDR26-Related Disorder. SummaryWDR26-related disorder, also known as Skraban-Deardorff syndrome (SKDEAS), is a rare neurodevelopmental disorder caused by changes (variants or mutations) in the gene WDR26. Individuals with SKDEAS can present with a variety of symptoms that commonly include differences in development, seizures, low muscle tone, friendly personality and unique facial features. Most individuals have a new (de novo) change in the WDR26 gene that is not inherited. WDR26-related disorder follows an autosomal dominant inheritance pattern, meaning that someone with the condition has a 50% risk of passing the gene variant to each child. There is no specific treatment for the condition and management is based on an individual’s symptoms with particular focus on attainment of developmental milestones.
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WDR26-Related Disorder
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Symptoms of WDR26-Related Disorder
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The symptoms of WDR26-related disorder vary among individuals. Not every person with the syndrome exhibits all of the symptoms or exhibits them in the same way. Symptoms can include:Developmental delay and intellectual disability
• People with WDR26-related disorder have varying degrees of developmental delays and intellectual disabilities ranging from mild to severe.
• Speech delays are typical, particularly in expressive language.
• Delays in the development of motor skills including sitting and walking are common. Many individuals walk with a wide-based, spastic, stiff-legged gait.
• Some individuals have repetitive (stereotypical) movements and autistic features. Some have a formal diagnosis of autism spectrum disorder. Most are described as happy and socially engaging.Neurological differences
• All individuals in the initially reported group (Skraban et al, 2017) had a history of seizures. Since then, many individuals without epilepsy have been identified, but seizures still remain common. Some of the seizures were triggered by fever (febrile seizures); others were not. Some patients received treatment with antiepileptic medications, which typically brought the seizures under control.
• Minor structural brain malformations have been identified in some people.
• Decreased muscle tone (hypotonia) is common.Facial differences
• People with WDR26-related disorder typically share a set of subtle facial characteristics, though not every individual with the diagnosis exhibits all of them. These characteristics can include:
o prominent upper lip and upper jawbone
o wide mouth
o prominent gums
o widely spaced teeth
o mildly coarse facial features
o broad nasal tipOther health differences
• People with WDR26-related disorder can have a variety of other health issues. Some of these include:
o Feeding issues/poor growth
o Ophthalmologic (eye and vision) differences
o Structural heart differences
o Skeletal differences
o Cleft palate
o Genitourinary differences
o Recurrent infections
o Sleep issues
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Symptoms of WDR26-Related Disorder. The symptoms of WDR26-related disorder vary among individuals. Not every person with the syndrome exhibits all of the symptoms or exhibits them in the same way. Symptoms can include:Developmental delay and intellectual disability
• People with WDR26-related disorder have varying degrees of developmental delays and intellectual disabilities ranging from mild to severe.
• Speech delays are typical, particularly in expressive language.
• Delays in the development of motor skills including sitting and walking are common. Many individuals walk with a wide-based, spastic, stiff-legged gait.
• Some individuals have repetitive (stereotypical) movements and autistic features. Some have a formal diagnosis of autism spectrum disorder. Most are described as happy and socially engaging.Neurological differences
• All individuals in the initially reported group (Skraban et al, 2017) had a history of seizures. Since then, many individuals without epilepsy have been identified, but seizures still remain common. Some of the seizures were triggered by fever (febrile seizures); others were not. Some patients received treatment with antiepileptic medications, which typically brought the seizures under control.
• Minor structural brain malformations have been identified in some people.
• Decreased muscle tone (hypotonia) is common.Facial differences
• People with WDR26-related disorder typically share a set of subtle facial characteristics, though not every individual with the diagnosis exhibits all of them. These characteristics can include:
o prominent upper lip and upper jawbone
o wide mouth
o prominent gums
o widely spaced teeth
o mildly coarse facial features
o broad nasal tipOther health differences
• People with WDR26-related disorder can have a variety of other health issues. Some of these include:
o Feeding issues/poor growth
o Ophthalmologic (eye and vision) differences
o Structural heart differences
o Skeletal differences
o Cleft palate
o Genitourinary differences
o Recurrent infections
o Sleep issues
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WDR26-Related Disorder
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Causes of WDR26-Related Disorder
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WDR26-related disorder is caused by changes (variants or mutations) in the WDR26 gene. In the individuals identified to date, the vast majority are de novo WDR26 gene variants. This means that the variants are not inherited from either parent, but instead are random variants that occur in a parent’s single egg or sperm prior to conception or during early embryologic development. The variants are heterozygous, which means that only one of two copies of an individual’s WDR26 gene has the variant.
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Causes of WDR26-Related Disorder. WDR26-related disorder is caused by changes (variants or mutations) in the WDR26 gene. In the individuals identified to date, the vast majority are de novo WDR26 gene variants. This means that the variants are not inherited from either parent, but instead are random variants that occur in a parent’s single egg or sperm prior to conception or during early embryologic development. The variants are heterozygous, which means that only one of two copies of an individual’s WDR26 gene has the variant.
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WDR26-Related Disorder
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Affects of WDR26-Related Disorder
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The exact number of individuals WDR26-related disorder is unknown and this condition is likely underrecognized. It affects both males and females and has been identified in people from all over the world.
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Affects of WDR26-Related Disorder. The exact number of individuals WDR26-related disorder is unknown and this condition is likely underrecognized. It affects both males and females and has been identified in people from all over the world.
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WDR26-Related Disorder
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Related disorders of WDR26-Related Disorder
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WDR26-related disorder has overlapping features with many other neurodevelopmental disorders and seizure disorders.The gene WDR26 is located on chromosome 1q42. Some individuals have deletions of this region of chromosome 1 who also have deletions (missing copies) of other genes and this is called 1q41q42 microdeletion syndrome. These individuals have features that overlap with WRD26-related disorder but can also have more complex symptoms depending on the number of other genes they are missing. Missing a copy of the WDR26 gene is thought to be a big contributor to the symptoms in these individuals.Some features of Angelman syndrome are similar to WDR26-related disorder. These include developmental delays and seizures, both of which are typically more severe in Angelman syndrome. Children with both diagnoses can also be described as happy and can be unsteady walking, although these features are a little different between the two disorders. (More information about this condition is available in the Rare Disease Database.)
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Related disorders of WDR26-Related Disorder. WDR26-related disorder has overlapping features with many other neurodevelopmental disorders and seizure disorders.The gene WDR26 is located on chromosome 1q42. Some individuals have deletions of this region of chromosome 1 who also have deletions (missing copies) of other genes and this is called 1q41q42 microdeletion syndrome. These individuals have features that overlap with WRD26-related disorder but can also have more complex symptoms depending on the number of other genes they are missing. Missing a copy of the WDR26 gene is thought to be a big contributor to the symptoms in these individuals.Some features of Angelman syndrome are similar to WDR26-related disorder. These include developmental delays and seizures, both of which are typically more severe in Angelman syndrome. Children with both diagnoses can also be described as happy and can be unsteady walking, although these features are a little different between the two disorders. (More information about this condition is available in the Rare Disease Database.)
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WDR26-Related Disorder
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Diagnosis of WDR26-Related Disorder
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WDR26-related disorder may be suspected based on the signs and symptoms associated with the disorder. The diagnosis is confirmed with molecular genetic testing that shows a disease-causing variant in the WDR26 gene.
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Diagnosis of WDR26-Related Disorder. WDR26-related disorder may be suspected based on the signs and symptoms associated with the disorder. The diagnosis is confirmed with molecular genetic testing that shows a disease-causing variant in the WDR26 gene.
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WDR26-Related Disorder
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Therapies of WDR26-Related Disorder
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Currently, there is no specific treatment for WDR26-related disorder. Care focuses on the individual’s symptoms. The medical team typically includes a genetic specialist, a neurologist and a developmental pediatrician, with other specialists involved as symptoms warrant. Early therapy is encouraged (physical, occupational, speech therapy) to ensure that the child achieves to the best of their abilities. Applied Behavior Analysis (ABA) therapy has been beneficial for some individuals.
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Therapies of WDR26-Related Disorder. Currently, there is no specific treatment for WDR26-related disorder. Care focuses on the individual’s symptoms. The medical team typically includes a genetic specialist, a neurologist and a developmental pediatrician, with other specialists involved as symptoms warrant. Early therapy is encouraged (physical, occupational, speech therapy) to ensure that the child achieves to the best of their abilities. Applied Behavior Analysis (ABA) therapy has been beneficial for some individuals.
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WDR26-Related Disorder
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nord_1285_0
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Overview of Weaver Syndrome
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Weaver Syndrome (WS) is a genetic condition which causes fast growth. Children usually start having symptoms before birth (prenatal onset). The primary symptom is growth and bone development (maturation) that occurs faster than usual, so affected individuals are taller than average. Intellectual disability, loose muscles (hypotonia) of the core, and rigid muscles (hypertonia) of the limbs with poor coordination are also seen. Physical differences of the face and feet are common. Babies with this syndrome have a hoarse low-pitched cry.
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Overview of Weaver Syndrome. Weaver Syndrome (WS) is a genetic condition which causes fast growth. Children usually start having symptoms before birth (prenatal onset). The primary symptom is growth and bone development (maturation) that occurs faster than usual, so affected individuals are taller than average. Intellectual disability, loose muscles (hypotonia) of the core, and rigid muscles (hypertonia) of the limbs with poor coordination are also seen. Physical differences of the face and feet are common. Babies with this syndrome have a hoarse low-pitched cry.
| 1,285 |
Weaver Syndrome
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Symptoms of Weaver Syndrome
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The main symptom of WS is fast growth and bone development (maturation). Children with WS may be tall, they have a normal or high weight for their height. A large head size (macrocephaly) is also common. Some children with WS may not show symptoms until several months after birth. People with WS may have muscles that get more rigid over time (hypertonia), especially in the arms and legs. However, the muscles in their core may be looser (hypotonia). Due to their rigid muscles, individuals with WS may have poor coordination. Babies with this syndrome have a hoarse and low-pitched cry.People with WS may have eyes that are far apart (hypertelorism), extra skin over the inner corner of the eyes (epicanthal folds) or eyelids that slant down (down-slanting palpebral fissures). The back of the head (occiput) may be flat, the forehead wide and the ears larger than usual. The groove located above the upper lip and below the nose (philtrum) may be longer than average. People with WS may have a smaller jaw than normal (micrognathia). Other physical features can include thin hair, inverted nipples and loose skin.People with WS usually have wide thumbs. One or more fingers may be permanently bent (camptodactyly). Nails may be deep-set and thin. The pads of the fingertips are usually raised. People with WS may have differences of the feet. These may include misshapen toes (clinodactyly), a very high arch of the foot (pes cavus), a clubfoot or a twisted foot (metatarsus adductus). The clubfoot may have the sole of the foot turned inward and upward towards the heel (talipes equinovarus) or towards the toes (talipes calcaneovalgus). People with WS may not be able to fully extend their elbows or knees.Other symptoms associated with WS include varying levels of intellectual ability, from normal intelligence to severe intellectual disability. There also seems to be an increased chance for umbilical hernias and, more rarely, a type of brain cancer called neuroblastoma.
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Symptoms of Weaver Syndrome. The main symptom of WS is fast growth and bone development (maturation). Children with WS may be tall, they have a normal or high weight for their height. A large head size (macrocephaly) is also common. Some children with WS may not show symptoms until several months after birth. People with WS may have muscles that get more rigid over time (hypertonia), especially in the arms and legs. However, the muscles in their core may be looser (hypotonia). Due to their rigid muscles, individuals with WS may have poor coordination. Babies with this syndrome have a hoarse and low-pitched cry.People with WS may have eyes that are far apart (hypertelorism), extra skin over the inner corner of the eyes (epicanthal folds) or eyelids that slant down (down-slanting palpebral fissures). The back of the head (occiput) may be flat, the forehead wide and the ears larger than usual. The groove located above the upper lip and below the nose (philtrum) may be longer than average. People with WS may have a smaller jaw than normal (micrognathia). Other physical features can include thin hair, inverted nipples and loose skin.People with WS usually have wide thumbs. One or more fingers may be permanently bent (camptodactyly). Nails may be deep-set and thin. The pads of the fingertips are usually raised. People with WS may have differences of the feet. These may include misshapen toes (clinodactyly), a very high arch of the foot (pes cavus), a clubfoot or a twisted foot (metatarsus adductus). The clubfoot may have the sole of the foot turned inward and upward towards the heel (talipes equinovarus) or towards the toes (talipes calcaneovalgus). People with WS may not be able to fully extend their elbows or knees.Other symptoms associated with WS include varying levels of intellectual ability, from normal intelligence to severe intellectual disability. There also seems to be an increased chance for umbilical hernias and, more rarely, a type of brain cancer called neuroblastoma.
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Weaver Syndrome
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Causes of Weaver Syndrome
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WS is usually caused by harmful changes (mutations) in the EZH2 gene. These harmful changes cause the EZH2 gene to work incorrectly. The function of the EZH2 gene is to turn other genes on and off in a process called methylation. The EZH2 gene’s influence on the function of many other genes explains why WS affects many body systems. However, it is not known how these changes cause the specific symptoms of WS. Some people with WS do not have a mutation in the EZH2 gene.WS 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 condition. In about half of patients, the non-working gene is inherited from an affected parent. In the other half, it occurs as a new (de novo) change one of the EZH2 genes in the affected individual. The chance of passing the non-working gene from an affected parent to a child is 50% for each pregnancy. The chance is the same for males and females.
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Causes of Weaver Syndrome. WS is usually caused by harmful changes (mutations) in the EZH2 gene. These harmful changes cause the EZH2 gene to work incorrectly. The function of the EZH2 gene is to turn other genes on and off in a process called methylation. The EZH2 gene’s influence on the function of many other genes explains why WS affects many body systems. However, it is not known how these changes cause the specific symptoms of WS. Some people with WS do not have a mutation in the EZH2 gene.WS 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 condition. In about half of patients, the non-working gene is inherited from an affected parent. In the other half, it occurs as a new (de novo) change one of the EZH2 genes in the affected individual. The chance of passing the non-working gene from an affected parent to a child is 50% for each pregnancy. The chance is the same for males and females.
| 1,285 |
Weaver Syndrome
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nord_1285_3
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Affects of Weaver Syndrome
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WS is a very rare disorder – only about 50 affected individuals have been identified.
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Affects of Weaver Syndrome. WS is a very rare disorder – only about 50 affected individuals have been identified.
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Weaver Syndrome
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Related disorders of Weaver Syndrome
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Cohen-Gibson syndrome is considered a “Weaver-like” syndrome. It is marked by similar features as WS, but with other skeletal changes like a curved spine (scoliosis). Cohen-Gibson syndrome is an autosomal dominant genetic condition caused by changes in the EED gene.Imagawa-Matsumoto syndrome is also considered a “Weaver-like” syndrome. People with this condition have the same features as WS but may also have genital and urinary differences or breathing problems. Imagawa-Matsumoto syndrome is is an autosomal dominant genetic condition caused by changes in the SUZ12 gene.People with Marfan syndrome also have tall stature, scoliosis, and lax joints, but have some other defining features. These include eye and heart problems, chest wall differences, and normal intelligence. Marfan syndrome is an autosomal dominant genetic disorder caused by changes in the FBN1 gene. (For more information, choose “Marfan” as your search term in the Rare Disease Database.)Gigantism occurs before puberty and is caused by too much growth hormone. Gigantism causes extra growth during childhood. People with this condition have relatively normal body proportions and sexual development. Height sometimes reaches 7 or 8 feet. (For more information on disorders involving gigantism, choose “gigantism” as your search term in the Rare Disease Database.Sotos syndrome is a rare, autosomal dominant genetic disorder which causes too much growth during the first 4 to 5 years of life. Differences of the nervous system cause aggression, annoyance, clumsiness and intellectual disability. Sotos syndrome is caused by changes in the NSD1 gene. (For more information, choose “Sotos” as your search term in the Rare Disease Database.)
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Related disorders of Weaver Syndrome. Cohen-Gibson syndrome is considered a “Weaver-like” syndrome. It is marked by similar features as WS, but with other skeletal changes like a curved spine (scoliosis). Cohen-Gibson syndrome is an autosomal dominant genetic condition caused by changes in the EED gene.Imagawa-Matsumoto syndrome is also considered a “Weaver-like” syndrome. People with this condition have the same features as WS but may also have genital and urinary differences or breathing problems. Imagawa-Matsumoto syndrome is is an autosomal dominant genetic condition caused by changes in the SUZ12 gene.People with Marfan syndrome also have tall stature, scoliosis, and lax joints, but have some other defining features. These include eye and heart problems, chest wall differences, and normal intelligence. Marfan syndrome is an autosomal dominant genetic disorder caused by changes in the FBN1 gene. (For more information, choose “Marfan” as your search term in the Rare Disease Database.)Gigantism occurs before puberty and is caused by too much growth hormone. Gigantism causes extra growth during childhood. People with this condition have relatively normal body proportions and sexual development. Height sometimes reaches 7 or 8 feet. (For more information on disorders involving gigantism, choose “gigantism” as your search term in the Rare Disease Database.Sotos syndrome is a rare, autosomal dominant genetic disorder which causes too much growth during the first 4 to 5 years of life. Differences of the nervous system cause aggression, annoyance, clumsiness and intellectual disability. Sotos syndrome is caused by changes in the NSD1 gene. (For more information, choose “Sotos” as your search term in the Rare Disease Database.)
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Weaver Syndrome
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