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Overview of Wilms’ Tumor
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Wilms’ tumor is a type of kidney cancer that typically occurs in young children. It is responsible for 95% of all malignant kidney tumors in patients under the age of 15 years old. Wilms’ tumor can occur in one kidney (unilateral) or in both kidneys (bilateral) and can spread throughout the rest of the body. There are about 650 new cases diagnosed each year in the United States with the average age of diagnosis being 2 to 5 years of age.
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Overview of Wilms’ Tumor. Wilms’ tumor is a type of kidney cancer that typically occurs in young children. It is responsible for 95% of all malignant kidney tumors in patients under the age of 15 years old. Wilms’ tumor can occur in one kidney (unilateral) or in both kidneys (bilateral) and can spread throughout the rest of the body. There are about 650 new cases diagnosed each year in the United States with the average age of diagnosis being 2 to 5 years of age.
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Symptoms of Wilms’ Tumor
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Young children with Wilms’ tumor often show no signs or symptoms. The first sign that is often seen in patients with Wilms’ tumor is a large lump in the abdomen, also known as a mass, and can be associated with abdominal pain and swelling. Most parents may not notice the mass until it is large enough to be felt when bathing or dressing the child. Other symptoms are more common in older children and may include pain, anemia, fever, blood in the urine, nausea or vomiting or both, constipation, loss of appetite, shortness of breath and high blood pressure. There may be severe abdominal pain if the tumor ruptures or bleeds.Staging
There are 5 stages of Wilms’ Tumor:Stage I indicates that the tumor stayed in the kidney without spreading outside the renal capsule showing no vascular invasion. This is the most common stage of Wilms’ tumor accounting for 40% of all Wilms’ tumors.Stage II is when the tumor is confined to the kidney but involves the capsule around the kidney or the collecting system of the kidney. The tumor is still surgically removable since it is centralized to the kidney. This stage accounts for 20% of Wilms’ tumors.Stage III indicates that the tumor has spread beyond the kidney. The margins of resection may contain tumor cells; the cancer may have spread to regional lymph nodes near the kidney or along the aorta or inferior vena cava. In addition, tumor that is spilled from the mass, either by biopsy or tumor rupture is also included in stage III.Stage IV tumors are those that have spread through the vascular system. The tumor has spread through the blood to organs such as the lungs, liver, or rarely brain or bones. These account for about 10-15% of all Wilms’ tumors.Stage V are those cases where both kidneys have tumors at the time of initial diagnosis. About 5-10% of all Wilms tumors are at this stage.
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Symptoms of Wilms’ Tumor. Young children with Wilms’ tumor often show no signs or symptoms. The first sign that is often seen in patients with Wilms’ tumor is a large lump in the abdomen, also known as a mass, and can be associated with abdominal pain and swelling. Most parents may not notice the mass until it is large enough to be felt when bathing or dressing the child. Other symptoms are more common in older children and may include pain, anemia, fever, blood in the urine, nausea or vomiting or both, constipation, loss of appetite, shortness of breath and high blood pressure. There may be severe abdominal pain if the tumor ruptures or bleeds.Staging
There are 5 stages of Wilms’ Tumor:Stage I indicates that the tumor stayed in the kidney without spreading outside the renal capsule showing no vascular invasion. This is the most common stage of Wilms’ tumor accounting for 40% of all Wilms’ tumors.Stage II is when the tumor is confined to the kidney but involves the capsule around the kidney or the collecting system of the kidney. The tumor is still surgically removable since it is centralized to the kidney. This stage accounts for 20% of Wilms’ tumors.Stage III indicates that the tumor has spread beyond the kidney. The margins of resection may contain tumor cells; the cancer may have spread to regional lymph nodes near the kidney or along the aorta or inferior vena cava. In addition, tumor that is spilled from the mass, either by biopsy or tumor rupture is also included in stage III.Stage IV tumors are those that have spread through the vascular system. The tumor has spread through the blood to organs such as the lungs, liver, or rarely brain or bones. These account for about 10-15% of all Wilms’ tumors.Stage V are those cases where both kidneys have tumors at the time of initial diagnosis. About 5-10% of all Wilms tumors are at this stage.
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Causes of Wilms’ Tumor
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Kidneys start developing as the fetus grows in the womb. At about 3 years of age kidney cells become mature but in children with Wilms’ tumor, not all kidney cells mature. These immature kidney cells begin to cluster into a mass that grows out of control leading to a tumor in the kidney.Changes (pathogenic variants or mutations) in several genes are known to cause Wilms’ tumor. The WT1 or WT2 genes on chromosome 11, WTX gene and the AMER1 gene on the X chromosome, as well as the CTNNB1 gene on chromosome 3 are genes that are deleted or altered in patients presenting with Wilms’ tumor. These genes signal cells for growth and cell division but variants in these genes can lead to overgrowth of certain body tissues. The reason for the changes in these genes is not known.Some children have an underlying condition that is associated with Wilms’ tumor. One of the syndromes that has been linked to Wilms’ tumor is WAGR syndrome. Approximately 50% of children with WAGR syndrome will develop Wilms’ tumor. WAGR syndrome is a disorder that affects many body systems such as the eyes, brain and the genitourinary system. One of the first effects seen with WAGR syndrome is on the eye. Many people have what’s called aniridia which is an absence in the colored part of the eye, the iris. This can reduce sharpness in vision and increase sensitivity to light. Although the effects in the genitals and urinary tract happen in both genders, it is more common in males. WAGR syndrome can also have a negative impact on the brain leading to intellectual disability. An affected person may have trouble processing, learning, and properly responding to information. (For more information on this condition, search for “WAGR” in the Rare Disease Database.)Other syndromes that increase the likelihood of getting Wilms’ tumor are Denys-Drash syndrome which is where the kidneys stop working in children at a very young age, Beckwith-Wiedemann syndrome where internal organs and limbs of children are enlarged, and Frasier syndrome where scar tissue forms within the small blood vessels in the kidney resulting in kidney failure. All related syndromes that increase the probability of a child getting Wilms’ tumor also have some alteration of the WT1 gene as well.There are other risk factors or possible reasons for an increased risk of getting Wilms’ tumor such as having a family history. A family history of Wilms’ tumor is sometimes associated with variants in other genes different from the ones listed above. These variants occur in genes on chromosomes 16q and 1p and if the child has loss of heterozygosity, or LOH, meaning a loss of one of two copies of a chromosomal region, then the patient will be at a much higher risk.
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Causes of Wilms’ Tumor. Kidneys start developing as the fetus grows in the womb. At about 3 years of age kidney cells become mature but in children with Wilms’ tumor, not all kidney cells mature. These immature kidney cells begin to cluster into a mass that grows out of control leading to a tumor in the kidney.Changes (pathogenic variants or mutations) in several genes are known to cause Wilms’ tumor. The WT1 or WT2 genes on chromosome 11, WTX gene and the AMER1 gene on the X chromosome, as well as the CTNNB1 gene on chromosome 3 are genes that are deleted or altered in patients presenting with Wilms’ tumor. These genes signal cells for growth and cell division but variants in these genes can lead to overgrowth of certain body tissues. The reason for the changes in these genes is not known.Some children have an underlying condition that is associated with Wilms’ tumor. One of the syndromes that has been linked to Wilms’ tumor is WAGR syndrome. Approximately 50% of children with WAGR syndrome will develop Wilms’ tumor. WAGR syndrome is a disorder that affects many body systems such as the eyes, brain and the genitourinary system. One of the first effects seen with WAGR syndrome is on the eye. Many people have what’s called aniridia which is an absence in the colored part of the eye, the iris. This can reduce sharpness in vision and increase sensitivity to light. Although the effects in the genitals and urinary tract happen in both genders, it is more common in males. WAGR syndrome can also have a negative impact on the brain leading to intellectual disability. An affected person may have trouble processing, learning, and properly responding to information. (For more information on this condition, search for “WAGR” in the Rare Disease Database.)Other syndromes that increase the likelihood of getting Wilms’ tumor are Denys-Drash syndrome which is where the kidneys stop working in children at a very young age, Beckwith-Wiedemann syndrome where internal organs and limbs of children are enlarged, and Frasier syndrome where scar tissue forms within the small blood vessels in the kidney resulting in kidney failure. All related syndromes that increase the probability of a child getting Wilms’ tumor also have some alteration of the WT1 gene as well.There are other risk factors or possible reasons for an increased risk of getting Wilms’ tumor such as having a family history. A family history of Wilms’ tumor is sometimes associated with variants in other genes different from the ones listed above. These variants occur in genes on chromosomes 16q and 1p and if the child has loss of heterozygosity, or LOH, meaning a loss of one of two copies of a chromosomal region, then the patient will be at a much higher risk.
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Affects of Wilms’ Tumor
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Wilms’ tumor is the most common pediatric kidney cancer, and the fourth most common pediatric cancer overall. Wilms’ tumor affects approximately 1 in 10,000 children with the median age of onset being 3.5 years. Girls are slightly more likely than boys to develop Wilms’ tumor and African Americans are also at a higher risk.
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Affects of Wilms’ Tumor. Wilms’ tumor is the most common pediatric kidney cancer, and the fourth most common pediatric cancer overall. Wilms’ tumor affects approximately 1 in 10,000 children with the median age of onset being 3.5 years. Girls are slightly more likely than boys to develop Wilms’ tumor and African Americans are also at a higher risk.
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Related disorders of Wilms’ Tumor
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Differential diagnosis is the process of differentiating between two or more conditions with similar signs or symptoms. Below are diseases that may impact the ability to appropriately diagnose Wilms’ tumor in a patient.Clear cell renal sarcoma and Wilms’ tumor may be hard to differentiate. Clear cell renal sarcoma is also a renal tumor that affects children; however, the tumor spreads (metastasizes) to bones and other organs.Malignant rhabdoid tumor is a rare childhood tumor that commonly starts in the kidneys but also can occur in other soft tissues or in the brain. The tumor is seen primarily in children before the age of 2. It is often widely metastatic at the time of initial presentation with an 80% mortality rate within one year of diagnosis.Congenital mesoblastic nephroma is another type of kidney tumor. It contains cancerous fibroblastic cells which are connective tissue cells that may spread to nearby tissue. It is usually found before birth by ultrasound or within the first 3 months of life.Renal cell carcinoma, which occurs because of gene variants and other risk factors, is a disease in which cancer cells form in tubules of the kidney. Renal cell carcinoma is more commonly seen in older children and adolescents.
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Related disorders of Wilms’ Tumor. Differential diagnosis is the process of differentiating between two or more conditions with similar signs or symptoms. Below are diseases that may impact the ability to appropriately diagnose Wilms’ tumor in a patient.Clear cell renal sarcoma and Wilms’ tumor may be hard to differentiate. Clear cell renal sarcoma is also a renal tumor that affects children; however, the tumor spreads (metastasizes) to bones and other organs.Malignant rhabdoid tumor is a rare childhood tumor that commonly starts in the kidneys but also can occur in other soft tissues or in the brain. The tumor is seen primarily in children before the age of 2. It is often widely metastatic at the time of initial presentation with an 80% mortality rate within one year of diagnosis.Congenital mesoblastic nephroma is another type of kidney tumor. It contains cancerous fibroblastic cells which are connective tissue cells that may spread to nearby tissue. It is usually found before birth by ultrasound or within the first 3 months of life.Renal cell carcinoma, which occurs because of gene variants and other risk factors, is a disease in which cancer cells form in tubules of the kidney. Renal cell carcinoma is more commonly seen in older children and adolescents.
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Diagnosis of Wilms’ Tumor
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To diagnose Wilms’ tumor the doctor will first take a full medical history of all past and present conditions, medications and family history. The doctor will then perform a physical examination. If the doctor is suspicious of Wilms’ tumor, he or she may obtain an ultrasound of the abdomen and/or kidneys to define where the mass is coming from.The next step is to obtain a CT scan, which stands for computed tomography. A CT scan of the abdomen and chest provides detailed cross-sectional images of parts of the patient’s body, such as the kidneys and lungs. In a CT scan, the patient must lie very still on their back for the scans to come out clear. It is helpful for checking whether a cancer has grown into nearby veins or has spread to organs beyond the kidney. A CT scan may be useful in identifying a clot or tumor extension into the renal vein. If the cancer has spread to other organs in the patient’s body, then it is known to have metastasized (stage IV).Another useful imaging test to diagnose Wilms’ tumor is a magnetic resonance imaging scan otherwise known as an MRI scan which uses no radiation but rather radio waves and strong magnets. An MRI shows the kidneys and abdominal organs well, but usually requires sedation in a young child, and is not good at looking for spread to the lung.Lab tests also might be done to check urine and blood samples if the doctor suspects a kidney problem.
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Diagnosis of Wilms’ Tumor. To diagnose Wilms’ tumor the doctor will first take a full medical history of all past and present conditions, medications and family history. The doctor will then perform a physical examination. If the doctor is suspicious of Wilms’ tumor, he or she may obtain an ultrasound of the abdomen and/or kidneys to define where the mass is coming from.The next step is to obtain a CT scan, which stands for computed tomography. A CT scan of the abdomen and chest provides detailed cross-sectional images of parts of the patient’s body, such as the kidneys and lungs. In a CT scan, the patient must lie very still on their back for the scans to come out clear. It is helpful for checking whether a cancer has grown into nearby veins or has spread to organs beyond the kidney. A CT scan may be useful in identifying a clot or tumor extension into the renal vein. If the cancer has spread to other organs in the patient’s body, then it is known to have metastasized (stage IV).Another useful imaging test to diagnose Wilms’ tumor is a magnetic resonance imaging scan otherwise known as an MRI scan which uses no radiation but rather radio waves and strong magnets. An MRI shows the kidneys and abdominal organs well, but usually requires sedation in a young child, and is not good at looking for spread to the lung.Lab tests also might be done to check urine and blood samples if the doctor suspects a kidney problem.
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Therapies of Wilms’ Tumor
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Staging and Treatment
Therapy depends on the stage of the tumor as well as if the patient has a family history of Wilms’ tumor. The most common treatment for Wilms’ tumor is unilateral nephrectomy which is the surgical removal of the affected kidney, and regional lymph node sampling. Chemotherapy drugs such as vincristine, dactinomycin, doxorubicin, cyclophosphamide, etoposide and carboplatin are used; however, vincristine and dactinomycin are used for lower stage (I and II) disease. Depending on the severity of the disease, a combination of these drugs may be used for aggressive treatment. Radiation after surgery may also be required depending on tumor histology and extent of spread.Following recovery after surgical resection of the tumor, patients start treatment with systemic chemotherapy based upon stage and pathology. However, if the tumor is found to have LOH of both chromosomes 1p and 16q, or 1q gain, more aggressive therapy may be indicated.Stage IV of the disease is considered to be metastatic, meaning the cancer has spread throughout the patient’s body, most often to the lungs. Systemic therapy and radiation therapy to the lungs is dependent upon treatment response of the metastases to the lungs. Children with bilateral Wilms’ tumor will be given doxorubicin, vincristine and dactinomycin prior to surgery in order to shrink the tumor and preserve as much renal tissue as possible.With increasing new therapies such as chemotherapy the survival rate for Wilms’ tumor in the United States over 5 years is excellent at 92%.
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Therapies of Wilms’ Tumor. Staging and Treatment
Therapy depends on the stage of the tumor as well as if the patient has a family history of Wilms’ tumor. The most common treatment for Wilms’ tumor is unilateral nephrectomy which is the surgical removal of the affected kidney, and regional lymph node sampling. Chemotherapy drugs such as vincristine, dactinomycin, doxorubicin, cyclophosphamide, etoposide and carboplatin are used; however, vincristine and dactinomycin are used for lower stage (I and II) disease. Depending on the severity of the disease, a combination of these drugs may be used for aggressive treatment. Radiation after surgery may also be required depending on tumor histology and extent of spread.Following recovery after surgical resection of the tumor, patients start treatment with systemic chemotherapy based upon stage and pathology. However, if the tumor is found to have LOH of both chromosomes 1p and 16q, or 1q gain, more aggressive therapy may be indicated.Stage IV of the disease is considered to be metastatic, meaning the cancer has spread throughout the patient’s body, most often to the lungs. Systemic therapy and radiation therapy to the lungs is dependent upon treatment response of the metastases to the lungs. Children with bilateral Wilms’ tumor will be given doxorubicin, vincristine and dactinomycin prior to surgery in order to shrink the tumor and preserve as much renal tissue as possible.With increasing new therapies such as chemotherapy the survival rate for Wilms’ tumor in the United States over 5 years is excellent at 92%.
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Overview of Wilson Disease
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Wilson disease is a rare genetic disorder characterized by excess copper stored in various body tissues, particularly the liver, brain, and corneas of the eyes. The disease is progressive and, if left untreated, it may cause liver (hepatic) disease, central nervous system dysfunction, and death. Early diagnosis and treatment may prevent serious long-term disability and life threatening complications. Treatment is aimed at reducing the amount of copper that has accumulated in the body and maintaining normal copper levels thereafter.
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Overview of Wilson Disease. Wilson disease is a rare genetic disorder characterized by excess copper stored in various body tissues, particularly the liver, brain, and corneas of the eyes. The disease is progressive and, if left untreated, it may cause liver (hepatic) disease, central nervous system dysfunction, and death. Early diagnosis and treatment may prevent serious long-term disability and life threatening complications. Treatment is aimed at reducing the amount of copper that has accumulated in the body and maintaining normal copper levels thereafter.
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Symptoms of Wilson Disease
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Wilson disease is a rare genetic disorder beginning with liver dysfunction where damage begins by six years of age, but usually presents clinically in teenage years or early twenties. Common signs of associated liver disease include a yellow discoloration (jaundice) of the skin, mucous membranes and the membranes (sclera) that line the eye, swelling (edema) of the legs and abdomen (ascites) due to abnormal retention of fluid, presence of abnormal blood vessels in the esophagus that may bleed (esophageal varices), a tendency for bruising and prolonged bleeding, and excessive tiredness (fatigue). Some individuals with Wilson disease may have only abnormalities of liver function test and may show no other symptoms until many years later.A minority of affected individuals may experience severe liver failure. This happens most frequently in people with Wilson’s disease during adolescence and more commonly in women. These individuals may rapidly develop signs and symptoms of liver disease, often associated with anemia due to breakdown of red blood cells (hemolysis) and mental confusion. In these young patients, the characteristic rusty-brown deposits in the corneas of the eyes (Kayser-Fleischer rings) may not yet be present.In some patients, liver disease does not reveal itself, and the patient develops neurologic (brain-related) symptoms. Common neurological symptoms of Wilson disease that may appear and progress with time include tremor, involuntary movements, difficulty swallowing (dysphagia), difficulty speaking and poor articulation (dysarthria), lack of coordination, spasticity, dystonic postures, and muscle rigidity. Almost all affected individuals with the neurological symptoms of Wilson’s disease have Kayser-Fleischer rings in their eyes that can be identified by an ophthalmologist.The psychiatric manifestations of Wilson disease may vary widely from patient to patient. These symptoms may be confused with other disorders ranging from depression to schizophrenia, and are often misdiagnosed as substance abuse. Changes in personality or behavior may occur. Most affected individuals with psychiatric symptoms also have neurologic symptoms concurrently or will develop them within about three years and Kayser-Fleischer rings in the corneas of their eyes. In young females, menstruation may not begin or ceases, until disease is treated. This is due to general disturbances in hormone metabolism due to the liver disease caused by Wilson’s disease. Menstrual irregularity, loss of menstruation (ammenorrhea), miscarriages and infertility are also common.Other signs and symptoms of Wilson disease may include kidney stones and renal tubular damage, premature arthritis, and other joint and bone involvement including thinning of the bones (osteoporosis) and the appearance of bony outgrowths (osteophytes) at large joints. There may also be reduced spinal and extremity joint spaces.
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Symptoms of Wilson Disease. Wilson disease is a rare genetic disorder beginning with liver dysfunction where damage begins by six years of age, but usually presents clinically in teenage years or early twenties. Common signs of associated liver disease include a yellow discoloration (jaundice) of the skin, mucous membranes and the membranes (sclera) that line the eye, swelling (edema) of the legs and abdomen (ascites) due to abnormal retention of fluid, presence of abnormal blood vessels in the esophagus that may bleed (esophageal varices), a tendency for bruising and prolonged bleeding, and excessive tiredness (fatigue). Some individuals with Wilson disease may have only abnormalities of liver function test and may show no other symptoms until many years later.A minority of affected individuals may experience severe liver failure. This happens most frequently in people with Wilson’s disease during adolescence and more commonly in women. These individuals may rapidly develop signs and symptoms of liver disease, often associated with anemia due to breakdown of red blood cells (hemolysis) and mental confusion. In these young patients, the characteristic rusty-brown deposits in the corneas of the eyes (Kayser-Fleischer rings) may not yet be present.In some patients, liver disease does not reveal itself, and the patient develops neurologic (brain-related) symptoms. Common neurological symptoms of Wilson disease that may appear and progress with time include tremor, involuntary movements, difficulty swallowing (dysphagia), difficulty speaking and poor articulation (dysarthria), lack of coordination, spasticity, dystonic postures, and muscle rigidity. Almost all affected individuals with the neurological symptoms of Wilson’s disease have Kayser-Fleischer rings in their eyes that can be identified by an ophthalmologist.The psychiatric manifestations of Wilson disease may vary widely from patient to patient. These symptoms may be confused with other disorders ranging from depression to schizophrenia, and are often misdiagnosed as substance abuse. Changes in personality or behavior may occur. Most affected individuals with psychiatric symptoms also have neurologic symptoms concurrently or will develop them within about three years and Kayser-Fleischer rings in the corneas of their eyes. In young females, menstruation may not begin or ceases, until disease is treated. This is due to general disturbances in hormone metabolism due to the liver disease caused by Wilson’s disease. Menstrual irregularity, loss of menstruation (ammenorrhea), miscarriages and infertility are also common.Other signs and symptoms of Wilson disease may include kidney stones and renal tubular damage, premature arthritis, and other joint and bone involvement including thinning of the bones (osteoporosis) and the appearance of bony outgrowths (osteophytes) at large joints. There may also be reduced spinal and extremity joint spaces.
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Causes of Wilson Disease
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Wilson disease is inherited as an autosomal recessive trait. Genetic diseases are determined by two genes, one received from the father and one from the mother.Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. Researchers have determined that Wilson disease is caused by disruption or changes (mutations) of the ATP7B gene, which plays an important role in the movement of excess copper from the liver to the bile to eventually be excreted from the body through the intestines. More than 300 different mutations of the ATP7B gene have been identified.
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Causes of Wilson Disease. Wilson disease is inherited as an autosomal recessive trait. Genetic diseases are determined by two genes, one received from the father and one from the mother.Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. Researchers have determined that Wilson disease is caused by disruption or changes (mutations) of the ATP7B gene, which plays an important role in the movement of excess copper from the liver to the bile to eventually be excreted from the body through the intestines. More than 300 different mutations of the ATP7B gene have been identified.
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Affects of Wilson Disease
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Wilson disease is a rare disorder that affects males and females in equal numbers. The disease is found in all races and ethnic groups. Although estimates vary, it is believed that Wilson’s disease occurs in approximately one in 30,000 to 40,000 people worldwide. Approximately one in 90 people may be carriers of the disease gene. Although only about 2,000-3,000 cases have been diagnosed in the United States, other affected individuals may be misdiagnosed with other neurological, liver or psychiatric disorders. According to one estimate, there may actually be 9,000 people affected by Wilson’s disease in the United States.
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Affects of Wilson Disease. Wilson disease is a rare disorder that affects males and females in equal numbers. The disease is found in all races and ethnic groups. Although estimates vary, it is believed that Wilson’s disease occurs in approximately one in 30,000 to 40,000 people worldwide. Approximately one in 90 people may be carriers of the disease gene. Although only about 2,000-3,000 cases have been diagnosed in the United States, other affected individuals may be misdiagnosed with other neurological, liver or psychiatric disorders. According to one estimate, there may actually be 9,000 people affected by Wilson’s disease in the United States.
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Related disorders of Wilson Disease
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Symptoms of the following disorders can be similar to those of Wilson disease. Comparisons may be useful for a differential diagnosis:If the patient presents with mild liver disease, the most common mistaken diagnosis is viral hepatitis. Viral antigen and copper studies should differentiate. If cirrhosis is well established and the patient drinks alcohol, an incorrect diagnosis of alcoholic cirrhosis is often made. Copper studies should differentiate. If the patient presents with tremor, an incorrect diagnosis of essential tremor, or early Parkinson’s disease may be made. Again copper studies should differentiate. If psychiatric symptoms are pronounced, an incorrect diagnosis of substance abuse may be made. Again, copper studies should differentiate.Other disorders which are occasionally mistaken for Wilson’s are as follows:Sydenham chorea is an acute, usually self-limited disorder that occurs after about 5 to 10 percent of cases of rheumatic fever. The disorder typically begins with jerky, uncontrollable, non-repetitive muscle movements on one or both sides of the body. Patients develop rapid, involuntary movements that can affect the manner or style of walking, arm movements and speech. Clumsiness and facial grimacing are common. (For more information on this disorder choose “Sydenham Chorea” as your search term in the Rare Disease Database.)Primary biliary cholangitis is a chronic, progressive disease of the liver thought to be related to abnormalities in the immune system. The initial symptoms of this disorder usually include persistent, generalized itching, dark urine, pale stools and jaundice. Eventually, excessive amounts of copper accumulate in the liver and fibrous or granular hardening occurs in the soft tissue of the liver. (For more information on this disorder, choose “primary biliary cholangitis” as your search term in the Rare Disease Database.)Heavy metal poisoning is generally caused by industrial exposure to a variety of toxins such as copper, aluminum, arsenic or mercury. Depending of the type and duration of exposure, the injury may occur in the lungs, nervous system, the skin or digestive system. The symptoms of the poisoning vary according to the type of metal that was involved in the overexposure. These include headache, nausea, dizziness, painful joints and muscles, delirium, seizures and a wide range of other symptoms. (For more information on these disorders, choose “heavy metal poisoning” as your search term in the Rare Disease Database.)Neuroacanthocytosis is a very rare genetic disorder of the neuromuscular and blood systems. Abnormal blood cells (acanthocytosis) are produced and there is a wasting away (atrophy) of muscles. The major symptom of this disorder is uncontrolled rapid muscular movements (amyotrophic chorea). Initially there are subtle involuntary movements (tics) of the face, mouth, and tongue. These slowly progress to severe, uncontrolled, rapid motions (chorea) of the trunk and limbs. Approximately 50 percent of people with Levine-Critchley syndrome have seizures. (For more information on this disorder, please choose “neuroacanthocytosis” as your search term in the Rare Disease Database.)Huntington’s disease (Huntington’s chorea) is an inherited, progressively degenerative neurological disorder. Initially there are personality changes and rapid jerky muscle movements that are involuntary. In time speech and memory become impaired and involuntary muscle movements become more frequent and pronounced. As Huntington’s disease progresses there is a further loss of cognitive abilities and dementia. The symptoms of this disorder usually begin during adulthood generally after the age of forty. (For more information on this disorder choose “Huntington” as your search term in the Rare Disease Database.)Tourette syndrome is a neurologic movement disorder that is characterized by repetitive motor and vocal tics. The first symptoms usually occur during childhood are rapid eye blinking or facial grimaces. Symptoms may also include involuntary movements of the extremities, shoulders, face and voluntary muscles. Some people with Tourette syndrome may vocalize involuntarily; these may be inarticulate sounds or words. Tourette syndrome is not a progressive or degenerative disorder; symptoms tend to be variable and follow a chronic waxing and waning course. Onset usually occurs before the age of 16. (For more information on this disorder, choose “Tourette” as your search term in the Rare Disease Database.)Cerebral palsy is a neuromuscular disorder that is the result of an injury to the brain during early development or at birth. The major symptom of this disorder is a lack of muscle control and coordination. Cerebral palsy is not a progressive disorder. Generally infants may exhibit developmental delays during the first or second year and may have muscle weakness and abnormal muscle tone. The coordination and speech difficulties associated with Wilson’s disease can resemble the symptoms of cerebral palsy. (For more information on this disorder, choose “cerebral palsy” as your search term in the Rare Disease Database.)
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Related disorders of Wilson Disease. Symptoms of the following disorders can be similar to those of Wilson disease. Comparisons may be useful for a differential diagnosis:If the patient presents with mild liver disease, the most common mistaken diagnosis is viral hepatitis. Viral antigen and copper studies should differentiate. If cirrhosis is well established and the patient drinks alcohol, an incorrect diagnosis of alcoholic cirrhosis is often made. Copper studies should differentiate. If the patient presents with tremor, an incorrect diagnosis of essential tremor, or early Parkinson’s disease may be made. Again copper studies should differentiate. If psychiatric symptoms are pronounced, an incorrect diagnosis of substance abuse may be made. Again, copper studies should differentiate.Other disorders which are occasionally mistaken for Wilson’s are as follows:Sydenham chorea is an acute, usually self-limited disorder that occurs after about 5 to 10 percent of cases of rheumatic fever. The disorder typically begins with jerky, uncontrollable, non-repetitive muscle movements on one or both sides of the body. Patients develop rapid, involuntary movements that can affect the manner or style of walking, arm movements and speech. Clumsiness and facial grimacing are common. (For more information on this disorder choose “Sydenham Chorea” as your search term in the Rare Disease Database.)Primary biliary cholangitis is a chronic, progressive disease of the liver thought to be related to abnormalities in the immune system. The initial symptoms of this disorder usually include persistent, generalized itching, dark urine, pale stools and jaundice. Eventually, excessive amounts of copper accumulate in the liver and fibrous or granular hardening occurs in the soft tissue of the liver. (For more information on this disorder, choose “primary biliary cholangitis” as your search term in the Rare Disease Database.)Heavy metal poisoning is generally caused by industrial exposure to a variety of toxins such as copper, aluminum, arsenic or mercury. Depending of the type and duration of exposure, the injury may occur in the lungs, nervous system, the skin or digestive system. The symptoms of the poisoning vary according to the type of metal that was involved in the overexposure. These include headache, nausea, dizziness, painful joints and muscles, delirium, seizures and a wide range of other symptoms. (For more information on these disorders, choose “heavy metal poisoning” as your search term in the Rare Disease Database.)Neuroacanthocytosis is a very rare genetic disorder of the neuromuscular and blood systems. Abnormal blood cells (acanthocytosis) are produced and there is a wasting away (atrophy) of muscles. The major symptom of this disorder is uncontrolled rapid muscular movements (amyotrophic chorea). Initially there are subtle involuntary movements (tics) of the face, mouth, and tongue. These slowly progress to severe, uncontrolled, rapid motions (chorea) of the trunk and limbs. Approximately 50 percent of people with Levine-Critchley syndrome have seizures. (For more information on this disorder, please choose “neuroacanthocytosis” as your search term in the Rare Disease Database.)Huntington’s disease (Huntington’s chorea) is an inherited, progressively degenerative neurological disorder. Initially there are personality changes and rapid jerky muscle movements that are involuntary. In time speech and memory become impaired and involuntary muscle movements become more frequent and pronounced. As Huntington’s disease progresses there is a further loss of cognitive abilities and dementia. The symptoms of this disorder usually begin during adulthood generally after the age of forty. (For more information on this disorder choose “Huntington” as your search term in the Rare Disease Database.)Tourette syndrome is a neurologic movement disorder that is characterized by repetitive motor and vocal tics. The first symptoms usually occur during childhood are rapid eye blinking or facial grimaces. Symptoms may also include involuntary movements of the extremities, shoulders, face and voluntary muscles. Some people with Tourette syndrome may vocalize involuntarily; these may be inarticulate sounds or words. Tourette syndrome is not a progressive or degenerative disorder; symptoms tend to be variable and follow a chronic waxing and waning course. Onset usually occurs before the age of 16. (For more information on this disorder, choose “Tourette” as your search term in the Rare Disease Database.)Cerebral palsy is a neuromuscular disorder that is the result of an injury to the brain during early development or at birth. The major symptom of this disorder is a lack of muscle control and coordination. Cerebral palsy is not a progressive disorder. Generally infants may exhibit developmental delays during the first or second year and may have muscle weakness and abnormal muscle tone. The coordination and speech difficulties associated with Wilson’s disease can resemble the symptoms of cerebral palsy. (For more information on this disorder, choose “cerebral palsy” as your search term in the Rare Disease Database.)
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Diagnosis of Wilson Disease
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Wilson disease may be diagnosed based upon a thorough clinical evaluation, a complete patient history, and specialized tests. Such tests may include slit-lamp examination of the eyes that reveals the presence of Kayser-Fleischer rings; tests of the fluid portion of the blood (serum) that demonstrate low levels of ceruloplasmin, a copper protein; and tests that reveal abnormally high levels of copper excreted in the urine. In some patients, a liver biopsy for copper analysis may be necessary to confirm a diagnosis of Wilson disease. Molecular genetic studies that use DNA from blood cells to search for patterns of differences or similarities, a procedure called haplotype analysis may establish whether a full sibling of an affected patient has Wilson disease, is a carrier of the Wilson disease gene, or is not a carrier. This analysis is available for family members of individuals identified as having Wilson disease. DNA analysis may also be used for diagnosing affected patients. In over half of patients, DNA analysis will reveal mutations that cause Wilson’s disease. It is important to diagnose Wilson disease as early as possible. Permanent neurologic dysfunction and serious liver disease may be avoided with early diagnosis and treatment.
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Diagnosis of Wilson Disease. Wilson disease may be diagnosed based upon a thorough clinical evaluation, a complete patient history, and specialized tests. Such tests may include slit-lamp examination of the eyes that reveals the presence of Kayser-Fleischer rings; tests of the fluid portion of the blood (serum) that demonstrate low levels of ceruloplasmin, a copper protein; and tests that reveal abnormally high levels of copper excreted in the urine. In some patients, a liver biopsy for copper analysis may be necessary to confirm a diagnosis of Wilson disease. Molecular genetic studies that use DNA from blood cells to search for patterns of differences or similarities, a procedure called haplotype analysis may establish whether a full sibling of an affected patient has Wilson disease, is a carrier of the Wilson disease gene, or is not a carrier. This analysis is available for family members of individuals identified as having Wilson disease. DNA analysis may also be used for diagnosing affected patients. In over half of patients, DNA analysis will reveal mutations that cause Wilson’s disease. It is important to diagnose Wilson disease as early as possible. Permanent neurologic dysfunction and serious liver disease may be avoided with early diagnosis and treatment.
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Therapies of Wilson Disease
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TreatmentTreatment for Wilson disease is life-long and aimed at lowering copper levels to nontoxic levels, and at preventing the progression of the disease and trying to reverse any signs and symptoms that have appeared because of copper accumulation in the body. Treatment may be divided into three parts: first, treatment of symptomatic patients, second, maintenance therapy after copper has been reduced in affected tissues, and third, in asymptomatic patients, maintenance therapy may be used from the beginning.Treatment for Wilson disease includes three types of medications. First those that remove (chelate) copper from the body by urinary excretion such as penicillamine (Cuprimine) and trientine dihydrochloride (Syprine), second, zinc salts to prevent the gut from absorbing copper from the diet, and third, tetrathiomolybdate which both prevents absorbing copper and binds up toxic copper in the blood making it nontoxic.
Patients who present symptomatically with mild to moderate liver failure can be effectively treated with a combination of trientine and zinc for 4-6 months, and then go on maintenance therapy with zinc or trientine alone. A second choice would be penicillamine and zinc, but penicillamine has more side effects than zinc. Patients with severe liver failure may require liver transplantation. Patients who present neurologically can best be treated with tetrathiomolybdate, but it is not commercially available as yet. The second choice is zinc alone. Zinc is rather slow acting but doesn’t cause the drug catalyzed worsening so common with trientine and penicillamine. Trientine and penicillamine are poor choices to treat neurologically presenting patients because of the high frequency of neurological worsening, from which many patients never recover.Zinc Acetate (Galzin) has been approved for the maintenance treatment for patients.For affected individuals without symptoms (asymptomatic) or for individuals initially treated with chelating agents, zinc acetate (Galzin manufactured by the Gate division of Teva Pharmaceuticals) is used to prevent copper absorption from the gut. Zinc therapy is often preferred in children and pregnant women because of limited side effects. For some patients intolerant of zinc due to gastric irritation, maintenance therapy with trientine may be preferable.Monitoring of chronic drug therapy includes follow-up physical examinations, measurement of copper (and zinc for those on zinc therapy) in 24-hour urine collection, blood tests to determine the amount of copper not bound to ceruloplasmin (free copper), periodic measurement of liver functions, and blood counts. For those on chelating agents, periodic urinalysis should also be done to look for the presence of cells or protein in the urine. Repeat liver biopsies are usually not necessary to follow the progress of drug therapy.Discontinuation of medication for Wilson disease may cause rapid build-up of copper and life threatening events. It is important that patients taking zinc acetate use the prescription version of this drug (Galzin) because nutritional supplements may not be bioequivalent and may be ineffective.Liver transplantation may be lifesaving for individuals presenting with severe liver failure.
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Therapies of Wilson Disease. TreatmentTreatment for Wilson disease is life-long and aimed at lowering copper levels to nontoxic levels, and at preventing the progression of the disease and trying to reverse any signs and symptoms that have appeared because of copper accumulation in the body. Treatment may be divided into three parts: first, treatment of symptomatic patients, second, maintenance therapy after copper has been reduced in affected tissues, and third, in asymptomatic patients, maintenance therapy may be used from the beginning.Treatment for Wilson disease includes three types of medications. First those that remove (chelate) copper from the body by urinary excretion such as penicillamine (Cuprimine) and trientine dihydrochloride (Syprine), second, zinc salts to prevent the gut from absorbing copper from the diet, and third, tetrathiomolybdate which both prevents absorbing copper and binds up toxic copper in the blood making it nontoxic.
Patients who present symptomatically with mild to moderate liver failure can be effectively treated with a combination of trientine and zinc for 4-6 months, and then go on maintenance therapy with zinc or trientine alone. A second choice would be penicillamine and zinc, but penicillamine has more side effects than zinc. Patients with severe liver failure may require liver transplantation. Patients who present neurologically can best be treated with tetrathiomolybdate, but it is not commercially available as yet. The second choice is zinc alone. Zinc is rather slow acting but doesn’t cause the drug catalyzed worsening so common with trientine and penicillamine. Trientine and penicillamine are poor choices to treat neurologically presenting patients because of the high frequency of neurological worsening, from which many patients never recover.Zinc Acetate (Galzin) has been approved for the maintenance treatment for patients.For affected individuals without symptoms (asymptomatic) or for individuals initially treated with chelating agents, zinc acetate (Galzin manufactured by the Gate division of Teva Pharmaceuticals) is used to prevent copper absorption from the gut. Zinc therapy is often preferred in children and pregnant women because of limited side effects. For some patients intolerant of zinc due to gastric irritation, maintenance therapy with trientine may be preferable.Monitoring of chronic drug therapy includes follow-up physical examinations, measurement of copper (and zinc for those on zinc therapy) in 24-hour urine collection, blood tests to determine the amount of copper not bound to ceruloplasmin (free copper), periodic measurement of liver functions, and blood counts. For those on chelating agents, periodic urinalysis should also be done to look for the presence of cells or protein in the urine. Repeat liver biopsies are usually not necessary to follow the progress of drug therapy.Discontinuation of medication for Wilson disease may cause rapid build-up of copper and life threatening events. It is important that patients taking zinc acetate use the prescription version of this drug (Galzin) because nutritional supplements may not be bioequivalent and may be ineffective.Liver transplantation may be lifesaving for individuals presenting with severe liver failure.
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Overview of Winchester Syndrome
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Winchester syndrome is an extremely rare congenital connective tissue and bone disorder. Winchester syndrome is characterized most frequently by short stature, wearing down of bone and tissue, dark skin patches, and coarse facial features. The main feature of this syndrome is short stature due to changes in the vertebrae of the backbone and long bones of the limbs that get worse over time (degenerative). Other symptoms commonly include arthritis-like symptoms, loss of bone tissue (osteolysis), reduced bone density (osteoporosis), nodules under the skin (subcutaneous), coarse facial features, and abnormalities of the eyes and teeth. The most commonly affected joints are those of the hands, feet, knees, shoulders, elbow, and hip. Winchester syndrome is caused by changes (mutations) in either the MMP14 or MMP2 gene and is inherited in a recessive manner.
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Overview of Winchester Syndrome. Winchester syndrome is an extremely rare congenital connective tissue and bone disorder. Winchester syndrome is characterized most frequently by short stature, wearing down of bone and tissue, dark skin patches, and coarse facial features. The main feature of this syndrome is short stature due to changes in the vertebrae of the backbone and long bones of the limbs that get worse over time (degenerative). Other symptoms commonly include arthritis-like symptoms, loss of bone tissue (osteolysis), reduced bone density (osteoporosis), nodules under the skin (subcutaneous), coarse facial features, and abnormalities of the eyes and teeth. The most commonly affected joints are those of the hands, feet, knees, shoulders, elbow, and hip. Winchester syndrome is caused by changes (mutations) in either the MMP14 or MMP2 gene and is inherited in a recessive manner.
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Symptoms of Winchester Syndrome
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The primary signs of Winchester syndrome are skeletal changes that involve thinning or weakening of the bone (multifocal osteoporosis), loss of bone tissue (progressive osteolysis), low bone mineral density (osteopenia) and joint issues (arthropathy) which encompass degenerative changes in the hands, feet, elbows, shoulders, knees, hips and spine. Due to loss of bone tissue and density, fractures may be more prevalent. Age of onset varies from 3 months to 22 years. Typically, the syndrome becomes apparent around the age of two years. The beginning signs of this syndrome are osteolysis particularly of the hands and feet which causes pain and limited movement. The accumulation of these skeletal abnormalities leads to short stature in the affected individual.In addition to skeletal alterations, other symptoms include coarse facial features, congenital heart defects, cloudy covering of the cornea (corneal opacities), and skin findings. Coarse facial features can include a large head; flat, broad nose with a fleshy tip; large lips; large tongue (macroglossia); and irregularly spaced teeth or extra teeth. Patients also present with large, inflamed gums, also known as hypertrophic gums. About one third of those affected with Winchester syndrome are born with a heart defect; these heart defects may include transposition of the great arteries, atrial septal defect, ventricular septal defect, bicuspid valves, or mitral valve prolapse. There should be ongoing surveillance of the heart through EKG (electrocardiogram) as heart murmurs may occur. Clouding of the cornea may be observed in those affected with this syndrome and can cause vision problems or vision loss. Lastly, skin findings include thickened hyperpigmentation such as thick and darkened patches of skin and/or over growth of hair on the skin (hirsutism). Most individuals with Winchester syndrome have normal intelligence.
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Symptoms of Winchester Syndrome. The primary signs of Winchester syndrome are skeletal changes that involve thinning or weakening of the bone (multifocal osteoporosis), loss of bone tissue (progressive osteolysis), low bone mineral density (osteopenia) and joint issues (arthropathy) which encompass degenerative changes in the hands, feet, elbows, shoulders, knees, hips and spine. Due to loss of bone tissue and density, fractures may be more prevalent. Age of onset varies from 3 months to 22 years. Typically, the syndrome becomes apparent around the age of two years. The beginning signs of this syndrome are osteolysis particularly of the hands and feet which causes pain and limited movement. The accumulation of these skeletal abnormalities leads to short stature in the affected individual.In addition to skeletal alterations, other symptoms include coarse facial features, congenital heart defects, cloudy covering of the cornea (corneal opacities), and skin findings. Coarse facial features can include a large head; flat, broad nose with a fleshy tip; large lips; large tongue (macroglossia); and irregularly spaced teeth or extra teeth. Patients also present with large, inflamed gums, also known as hypertrophic gums. About one third of those affected with Winchester syndrome are born with a heart defect; these heart defects may include transposition of the great arteries, atrial septal defect, ventricular septal defect, bicuspid valves, or mitral valve prolapse. There should be ongoing surveillance of the heart through EKG (electrocardiogram) as heart murmurs may occur. Clouding of the cornea may be observed in those affected with this syndrome and can cause vision problems or vision loss. Lastly, skin findings include thickened hyperpigmentation such as thick and darkened patches of skin and/or over growth of hair on the skin (hirsutism). Most individuals with Winchester syndrome have normal intelligence.
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Causes of Winchester Syndrome
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Winchester syndrome is associated with mutations in matrix metallopeptidase genes (MMP14 or MMP2). These genes code for proteins that breakdown the extracellular matrix, the protein framework that provides structural support for cells in tissues. The breakdown of the extracellular matrix is a normal process in tissue remodeling and when disturbed, may lead to disease processes such as arthritis. Loss in activity of either the MMP2 or MMP14 gene results in a spectrum of skeletal abnormalities with osteolysis. However, it is still being investigated whether or not these genes act alone in causing disease. In all known individuals affected with Winchester syndrome, two copies of the gene are altered, leading to disease. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body. In the case of Winchester syndrome, the parts of the body that are affected the most are the bones and skin.Winchester syndrome is an extremely rare disorder inherited in a recessive manner. This means that two non-working copies of the gene must be present in order for symptoms to occur. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.All individuals carry a few changes in genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same altered genes, which increases the risk to have children with a recessive genetic disorder.
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Causes of Winchester Syndrome. Winchester syndrome is associated with mutations in matrix metallopeptidase genes (MMP14 or MMP2). These genes code for proteins that breakdown the extracellular matrix, the protein framework that provides structural support for cells in tissues. The breakdown of the extracellular matrix is a normal process in tissue remodeling and when disturbed, may lead to disease processes such as arthritis. Loss in activity of either the MMP2 or MMP14 gene results in a spectrum of skeletal abnormalities with osteolysis. However, it is still being investigated whether or not these genes act alone in causing disease. In all known individuals affected with Winchester syndrome, two copies of the gene are altered, leading to disease. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body. In the case of Winchester syndrome, the parts of the body that are affected the most are the bones and skin.Winchester syndrome is an extremely rare disorder inherited in a recessive manner. This means that two non-working copies of the gene must be present in order for symptoms to occur. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.All individuals carry a few changes in genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same altered genes, which increases the risk to have children with a recessive genetic disorder.
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Affects of Winchester Syndrome
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Since the original description of this syndrome in 1969, only about a dozen affected individuals have been described in the medical literature. Those identified with the syndrome to date have included individuals of Mexican, Puerto Rican, and Iranian descent. More recently, multiple affected individuals of South Asian (India and Pakistan) and East Asian (Korean and Japanese) ancestry have been reported. Between 1969-2001, only 12 affected individuals with Winchester syndrome were reported worldwide. It appears that Winchester is more common in females than males with a female to male ratio of 3:1 (nine females, three males). Additional affected individuals may be undiagnosed or misdiagnosed.
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Affects of Winchester Syndrome. Since the original description of this syndrome in 1969, only about a dozen affected individuals have been described in the medical literature. Those identified with the syndrome to date have included individuals of Mexican, Puerto Rican, and Iranian descent. More recently, multiple affected individuals of South Asian (India and Pakistan) and East Asian (Korean and Japanese) ancestry have been reported. Between 1969-2001, only 12 affected individuals with Winchester syndrome were reported worldwide. It appears that Winchester is more common in females than males with a female to male ratio of 3:1 (nine females, three males). Additional affected individuals may be undiagnosed or misdiagnosed.
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Related disorders of Winchester Syndrome
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The following disorders may be associated with Winchester syndrome. Winchester syndrome may appear in conjunction with or as a result of the following disorders:Multicentric osteolysis, nodulosis, and arthropathy (MONA): MONA is an inherited disease characterized by a loss of bone tissue (osteolysis) in the hands and feet. This osteolysis commonly spreads to other areas of the body, causing joint problems in elbows, shoulders, knees, hips, and the spine. Patients with MONA usually have low bone mineral density (osteopenia) and tinning of the bones (osteoporosis). These bone abnormalities lead to short stature. Individuals with MONA develop subcutaneous nodules and may have skin findings, such as dark, thick, and leathery skin patches. Coarse facial features and corneal opacity are key indicators of MONA. It is unknown whether MONA is a part of Winchester syndrome or if they are separate disorders caused by different gene mutations. Further research is needed to make this distinction. However, it is possible for a person to be diagnosed with both MONA and Winchester syndrome.Juvenile rheumatoid arthritis (JRA): Juvenile rheumatoid arthritis is characterized by inflammation of one or more joints (arthritis) that persists for six weeks or more in a child age 16 years or younger. The arthritis results in swelling, stiffness, limited range of motion, tenderness or pain, and/or abnormal warmth of affected joints. Associated symptoms and findings may vary, depending upon the form of the disease present. JRA is differentiated from Winchester syndrome by a faster rate of red blood cells falling to a bottom of a test tube (erythrocyte sedimentation rate), a positive rheumatoid factor test, the presence of rheumatoid nodules, the pattern of bone destruction, and painful inflammation around the joints. Idiopathic multicentric osteolysis (IMO): IMO is a rare skeletal disorder that presents as early as the first year of life. The carpal and tarsal bones are most often affected with inflammation. Frequent recurrence of inflammation causes crippling deformities of the limbs. Individuals with IMO typically have characteristic facial features that include a slender nose, jutting out of the lower jaw (maxillary hypoplasia), and undersized jaw (micrognathia). IMO is thought to be inherited in an autosomal dominant manner; however autosomal recessive inheritance has also been suggested.A number of additional conditions may also be characterized by certain joint symptoms, skeletal findings, and other features similar to those associated with Winchester syndrome. Such disorders are typically associated with additional, characteristic features that may help to differentiate them from Winchester syndrome.
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Related disorders of Winchester Syndrome. The following disorders may be associated with Winchester syndrome. Winchester syndrome may appear in conjunction with or as a result of the following disorders:Multicentric osteolysis, nodulosis, and arthropathy (MONA): MONA is an inherited disease characterized by a loss of bone tissue (osteolysis) in the hands and feet. This osteolysis commonly spreads to other areas of the body, causing joint problems in elbows, shoulders, knees, hips, and the spine. Patients with MONA usually have low bone mineral density (osteopenia) and tinning of the bones (osteoporosis). These bone abnormalities lead to short stature. Individuals with MONA develop subcutaneous nodules and may have skin findings, such as dark, thick, and leathery skin patches. Coarse facial features and corneal opacity are key indicators of MONA. It is unknown whether MONA is a part of Winchester syndrome or if they are separate disorders caused by different gene mutations. Further research is needed to make this distinction. However, it is possible for a person to be diagnosed with both MONA and Winchester syndrome.Juvenile rheumatoid arthritis (JRA): Juvenile rheumatoid arthritis is characterized by inflammation of one or more joints (arthritis) that persists for six weeks or more in a child age 16 years or younger. The arthritis results in swelling, stiffness, limited range of motion, tenderness or pain, and/or abnormal warmth of affected joints. Associated symptoms and findings may vary, depending upon the form of the disease present. JRA is differentiated from Winchester syndrome by a faster rate of red blood cells falling to a bottom of a test tube (erythrocyte sedimentation rate), a positive rheumatoid factor test, the presence of rheumatoid nodules, the pattern of bone destruction, and painful inflammation around the joints. Idiopathic multicentric osteolysis (IMO): IMO is a rare skeletal disorder that presents as early as the first year of life. The carpal and tarsal bones are most often affected with inflammation. Frequent recurrence of inflammation causes crippling deformities of the limbs. Individuals with IMO typically have characteristic facial features that include a slender nose, jutting out of the lower jaw (maxillary hypoplasia), and undersized jaw (micrognathia). IMO is thought to be inherited in an autosomal dominant manner; however autosomal recessive inheritance has also been suggested.A number of additional conditions may also be characterized by certain joint symptoms, skeletal findings, and other features similar to those associated with Winchester syndrome. Such disorders are typically associated with additional, characteristic features that may help to differentiate them from Winchester syndrome.
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Diagnosis of Winchester Syndrome
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A diagnosis of Winchester syndrome can be made in one of two ways. There are established clinical criteria and there is clinical genetic testing that can identify mutations in the MMP14 or MMP2 genes.Clinical Diagnostic CriteriaThe main clinical findings needed for a diagnosis of Winchester syndrome are the skeletal findings including osteoporosis, osteolysis, and degenerative changes in the vertebral, carpal, and tarsal bones. Skeletal findings need to be accompanied by two of the following symptoms: short stature, progressive fusion of the joints (contractures), corneal clouding (cataracts), thickened patches of skin (hyperpigmentation) or growth of hair on the skin (hirsutism), gum enlargement/hypertrophy, and coarse facial features.Clinical Testing and WorkupMolecular genetic testing can be used to confirm a diagnosis of Winchester syndrome. Molecular testing is capable of identifying genetic mistakes in the DNA code. There are currently two known genes that are associated with Winchester syndrome; MMP14 and MMP2. Molecular genetic testing of these two genes can confirm a diagnosis of Winchester syndrome.
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Diagnosis of Winchester Syndrome. A diagnosis of Winchester syndrome can be made in one of two ways. There are established clinical criteria and there is clinical genetic testing that can identify mutations in the MMP14 or MMP2 genes.Clinical Diagnostic CriteriaThe main clinical findings needed for a diagnosis of Winchester syndrome are the skeletal findings including osteoporosis, osteolysis, and degenerative changes in the vertebral, carpal, and tarsal bones. Skeletal findings need to be accompanied by two of the following symptoms: short stature, progressive fusion of the joints (contractures), corneal clouding (cataracts), thickened patches of skin (hyperpigmentation) or growth of hair on the skin (hirsutism), gum enlargement/hypertrophy, and coarse facial features.Clinical Testing and WorkupMolecular genetic testing can be used to confirm a diagnosis of Winchester syndrome. Molecular testing is capable of identifying genetic mistakes in the DNA code. There are currently two known genes that are associated with Winchester syndrome; MMP14 and MMP2. Molecular genetic testing of these two genes can confirm a diagnosis of Winchester syndrome.
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Therapies of Winchester Syndrome
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TreatmentAt this point in time, there is no effective cure for Winchester syndrome. Treatments involve supportive measures to lessen the effect of symptoms. Both physical therapy and analgesic therapy are important for individuals with Winchester syndrome. Physical therapy may aid in slowing down the onset of joint contractures, which will help prolong mobility. Surgical treatments involving joint contracture release may be available, but outcomes have been inconsistent. Analgesic therapy refers to therapy that involves drugs that assist in the relief of pain; this may include anti-inflammatories, skeletal muscle relaxants, and antibiotics. In addition to physical and analgesic therapies, physiotherapy and hydrotherapy may be beneficial for those experiencing movement difficulties. To support bone health, supplements of calcium and vitamin D may be incorporated on a daily basis. Recent studies have reported success with bisphosphonate treatments in individuals with inherited osteolysis like those affected with Winchester syndrome. Bisphosphonate therapy includes dosing of two drugs, pamidronate or soledronate, to aid in the prevention of loss of bone density. Early initiation of this therapy when symptoms first appear can provide a better quality of life for those with Winchester syndrome.Individuals with an initial diagnosis of Winchester syndrome should receive a complete skeletal survey, cardiac evaluation which includes an ultrasound of the heart (echocardiogram), and an eye examination. Referrals to an orthopedic surgeon, rheumatologist, physical therapist, clinical geneticist and/or genetic counselor are also necessary. After the initial diagnosis, individuals should receive annual check-ups by a rheumatologist and/or orthopedic surgeon for pain and joint assessment.
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Therapies of Winchester Syndrome. TreatmentAt this point in time, there is no effective cure for Winchester syndrome. Treatments involve supportive measures to lessen the effect of symptoms. Both physical therapy and analgesic therapy are important for individuals with Winchester syndrome. Physical therapy may aid in slowing down the onset of joint contractures, which will help prolong mobility. Surgical treatments involving joint contracture release may be available, but outcomes have been inconsistent. Analgesic therapy refers to therapy that involves drugs that assist in the relief of pain; this may include anti-inflammatories, skeletal muscle relaxants, and antibiotics. In addition to physical and analgesic therapies, physiotherapy and hydrotherapy may be beneficial for those experiencing movement difficulties. To support bone health, supplements of calcium and vitamin D may be incorporated on a daily basis. Recent studies have reported success with bisphosphonate treatments in individuals with inherited osteolysis like those affected with Winchester syndrome. Bisphosphonate therapy includes dosing of two drugs, pamidronate or soledronate, to aid in the prevention of loss of bone density. Early initiation of this therapy when symptoms first appear can provide a better quality of life for those with Winchester syndrome.Individuals with an initial diagnosis of Winchester syndrome should receive a complete skeletal survey, cardiac evaluation which includes an ultrasound of the heart (echocardiogram), and an eye examination. Referrals to an orthopedic surgeon, rheumatologist, physical therapist, clinical geneticist and/or genetic counselor are also necessary. After the initial diagnosis, individuals should receive annual check-ups by a rheumatologist and/or orthopedic surgeon for pain and joint assessment.
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Overview of WNT4 Deficiency
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WNT4 deficiency is a rare genetic disorder that affects females. It is characterized by the absence or underdevelopment of the uterus and sometimes absence or underdevelopment of the vagina. Affected females also experience abnormally high levels of androgens (hyperandrogenism), which are male sex hormones. Androgens promote and control the development of male sex characteristics and, consequently, affected females may have certain symptoms such as a male pattern of hair growth (hirsutism). Females with WNT4 deficiency develop normal secondary sexual characteristics during puberty (e.g., breast development and pubic hair), but do not have a menstrual cycle (primary amenorrhea). The failure to begin the menstrual cycle may be the initial clinical sign of WNT4 deficiency. Because of the nature of the disorder, WNT4 deficiency can cause significant psychological challenges and counseling is recommended. WNT4 deficiency is caused by mutations of the WNT4 gene.
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Overview of WNT4 Deficiency. WNT4 deficiency is a rare genetic disorder that affects females. It is characterized by the absence or underdevelopment of the uterus and sometimes absence or underdevelopment of the vagina. Affected females also experience abnormally high levels of androgens (hyperandrogenism), which are male sex hormones. Androgens promote and control the development of male sex characteristics and, consequently, affected females may have certain symptoms such as a male pattern of hair growth (hirsutism). Females with WNT4 deficiency develop normal secondary sexual characteristics during puberty (e.g., breast development and pubic hair), but do not have a menstrual cycle (primary amenorrhea). The failure to begin the menstrual cycle may be the initial clinical sign of WNT4 deficiency. Because of the nature of the disorder, WNT4 deficiency can cause significant psychological challenges and counseling is recommended. WNT4 deficiency is caused by mutations of the WNT4 gene.
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Symptoms of WNT4 Deficiency
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The case reports of individuals with WNT4 deficiency in the medical literature are limited, making it difficult to determine an accurate picture of the disorder. More cases must be indentified in order to achieve a better understanding of WNT4 deficiency and the potential spectrum of associated symptoms.WNT4 deficiency is characterized by mullerian aplasia, which is the failure of structures derived from the mullerian ducts to develop properly. The mullerian duct is a structure within a growing embryo that ultimately develops into the uterus, fallopian tubes, cervix and the upper portion of the vagina. Affected females have an absent or underdeveloped (rudimentary) uterus. In some cases, the vagina may be absent or underdeveloped as well. The external genitalia are unaffected. The ovaries are functional, although they may produce abnormal amounts of androgens.In most cases, the initial symptom of WNT4 deficiency is the failure to begin menstrual cycles (primary amenorrhea). Despite amenorrhea, affected females do experience normal secondary sexual development including breast development, the growth of hair under the arms and in the pubic area, and an increase in body fat around the hips and other areas. Because of the absence of the uterus, all affected females are unable to bear children (infertile). Some affected females may experience difficulty while attempting sexual intercourse due to the shortness of the vagina. Some women may also experience pain during intercourse.Females with WNT4 deficiency may also have abnormally high levels of androgens in the blood. Consequently, affected females may develop acne and a male pattern of hair growth (hirsutism) including hair on the face and/or chest.In some cases, affected individuals may have kidney (renal) abnormalities such as absence of one kidney (unilateral kidney agenesis). This condition may cause affected individuals to have an increased susceptibility to urinary tract infections and/or kidney stones (renal calculi).
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Symptoms of WNT4 Deficiency. The case reports of individuals with WNT4 deficiency in the medical literature are limited, making it difficult to determine an accurate picture of the disorder. More cases must be indentified in order to achieve a better understanding of WNT4 deficiency and the potential spectrum of associated symptoms.WNT4 deficiency is characterized by mullerian aplasia, which is the failure of structures derived from the mullerian ducts to develop properly. The mullerian duct is a structure within a growing embryo that ultimately develops into the uterus, fallopian tubes, cervix and the upper portion of the vagina. Affected females have an absent or underdeveloped (rudimentary) uterus. In some cases, the vagina may be absent or underdeveloped as well. The external genitalia are unaffected. The ovaries are functional, although they may produce abnormal amounts of androgens.In most cases, the initial symptom of WNT4 deficiency is the failure to begin menstrual cycles (primary amenorrhea). Despite amenorrhea, affected females do experience normal secondary sexual development including breast development, the growth of hair under the arms and in the pubic area, and an increase in body fat around the hips and other areas. Because of the absence of the uterus, all affected females are unable to bear children (infertile). Some affected females may experience difficulty while attempting sexual intercourse due to the shortness of the vagina. Some women may also experience pain during intercourse.Females with WNT4 deficiency may also have abnormally high levels of androgens in the blood. Consequently, affected females may develop acne and a male pattern of hair growth (hirsutism) including hair on the face and/or chest.In some cases, affected individuals may have kidney (renal) abnormalities such as absence of one kidney (unilateral kidney agenesis). This condition may cause affected individuals to have an increased susceptibility to urinary tract infections and/or kidney stones (renal calculi).
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Causes of WNT4 Deficiency
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WNT4 deficiency is caused by mutations in the WNT4 gene. This genetic mutation can occur randomly as a spontaneous event (i.e., new mutation) or it can be inherited as an autosomal dominant trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.Investigators have determined that the WNT4 gene is located on the short arm (p) of chromosome 1 (1p35). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 1p35” refers to band 35 on the short arm of chromosome 1. The numbered bands specify the location of the thousands of genes that are present on each chromosome.The WNT4 gene creates (encodes) a protein that is vital to suppressing male sex differentiation and promoting female sexual development. Mutations in the WNT4 gene can cause a complete loss of function of this protein, which is believed to be critical to the development of structures derived from the mullerian duct as well as the kidneys (nephrogenesis). The WNT4 protein product is also involved in controlling the production of androgens in the ovaries (ovarian steroidogenesis).The exact functions of the protein product of the WNT4 gene are not fully understood. More research is necessary to determine the exact, underlying mechanisms that ultimately cause the symptoms associated with WNT4 deficiency.
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Causes of WNT4 Deficiency. WNT4 deficiency is caused by mutations in the WNT4 gene. This genetic mutation can occur randomly as a spontaneous event (i.e., new mutation) or it can be inherited as an autosomal dominant trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.Investigators have determined that the WNT4 gene is located on the short arm (p) of chromosome 1 (1p35). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 1p35” refers to band 35 on the short arm of chromosome 1. The numbered bands specify the location of the thousands of genes that are present on each chromosome.The WNT4 gene creates (encodes) a protein that is vital to suppressing male sex differentiation and promoting female sexual development. Mutations in the WNT4 gene can cause a complete loss of function of this protein, which is believed to be critical to the development of structures derived from the mullerian duct as well as the kidneys (nephrogenesis). The WNT4 protein product is also involved in controlling the production of androgens in the ovaries (ovarian steroidogenesis).The exact functions of the protein product of the WNT4 gene are not fully understood. More research is necessary to determine the exact, underlying mechanisms that ultimately cause the symptoms associated with WNT4 deficiency.
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Affects of WNT4 Deficiency
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WNT4 deficiency is an extremely rare disorder that affects females. The exact incidence of the disorder is unknown and it has only been identified in several women worldwide. Researchers believe that cases of WNT4 deficiency may often go undiagnosed or misdiagnosed, making it difficult to determine the disorder’s true frequency in the general population. WNT4 deficiency is present at birth (congenital), but can go unidentified until adolescence.
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Affects of WNT4 Deficiency. WNT4 deficiency is an extremely rare disorder that affects females. The exact incidence of the disorder is unknown and it has only been identified in several women worldwide. Researchers believe that cases of WNT4 deficiency may often go undiagnosed or misdiagnosed, making it difficult to determine the disorder’s true frequency in the general population. WNT4 deficiency is present at birth (congenital), but can go unidentified until adolescence.
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Related disorders of WNT4 Deficiency
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Symptoms of the following disorders can be similar to those of WNT4 deficiency. Comparisons may be useful for a differential diagnosis.Mayer-Rokitansky-Kuster-HauserWNT4 deficiency is extremely similar to another rare disorder known as Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome. Many women who have WNT4 deficiency may have originally received a diagnosis of MRKH syndrome. Although the two disorders have similar signs and symptoms, most women with MRKH syndrome who have been tested do not have mutations of the WNT4 gene. MRKH syndrome is characterized by the failure of the uterus and the vagina to develop properly in women who have normal ovarian function and normal external genitalia. Women with this disorder develop secondary sexual characteristics during puberty (e.g., breast development and pubic hair), but do not have a menstrual cycle (primary amenorrhea). As with WNT4 deficiency, failure to begin the menstrual cycle is the initial clinical sign of MRKH syndrome. The range and severity of MRKH syndrome can vary greatly and the disorder is generally broken down into type I, which occurs as an isolated finding, and type II, which occurs with abnormalities of additional organ systems including the kidneys and the skeleton. The exact cause of MRKH syndrome is unknown. (For more information on this disorder, choose “Mayer-Rokitansky-Kuster-Hauser” as your search term in the Rare Disease Database.)Complete Androgen Insensitivity SyndromeComplete androgen insensitivity syndrome is a rare disorder in which individuals who are genetically male (46, XY), but do not respond to male sex hormones known as androgens. The disorder is characterized by the failure of a developing fetus to respond to the presence of androgens in the fetal bloodstream. Consequently, infants appear female at birth, but are genetically male and lack a uterus, fallopian tubes and ovaries. A vagina may be absent or present, although is usually abnormally short or small. The initial clinical sign of complete androgen insensitivity syndrome may be the failure to start menstruation. Breast development, however, may occur normally. Pubic and underarm hair growth is sparse or absent. Complete androgen insensitivity syndrome is caused by mutations of the androgen receptor gene and is inherited as an X-linked recessive trait.
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Related disorders of WNT4 Deficiency. Symptoms of the following disorders can be similar to those of WNT4 deficiency. Comparisons may be useful for a differential diagnosis.Mayer-Rokitansky-Kuster-HauserWNT4 deficiency is extremely similar to another rare disorder known as Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome. Many women who have WNT4 deficiency may have originally received a diagnosis of MRKH syndrome. Although the two disorders have similar signs and symptoms, most women with MRKH syndrome who have been tested do not have mutations of the WNT4 gene. MRKH syndrome is characterized by the failure of the uterus and the vagina to develop properly in women who have normal ovarian function and normal external genitalia. Women with this disorder develop secondary sexual characteristics during puberty (e.g., breast development and pubic hair), but do not have a menstrual cycle (primary amenorrhea). As with WNT4 deficiency, failure to begin the menstrual cycle is the initial clinical sign of MRKH syndrome. The range and severity of MRKH syndrome can vary greatly and the disorder is generally broken down into type I, which occurs as an isolated finding, and type II, which occurs with abnormalities of additional organ systems including the kidneys and the skeleton. The exact cause of MRKH syndrome is unknown. (For more information on this disorder, choose “Mayer-Rokitansky-Kuster-Hauser” as your search term in the Rare Disease Database.)Complete Androgen Insensitivity SyndromeComplete androgen insensitivity syndrome is a rare disorder in which individuals who are genetically male (46, XY), but do not respond to male sex hormones known as androgens. The disorder is characterized by the failure of a developing fetus to respond to the presence of androgens in the fetal bloodstream. Consequently, infants appear female at birth, but are genetically male and lack a uterus, fallopian tubes and ovaries. A vagina may be absent or present, although is usually abnormally short or small. The initial clinical sign of complete androgen insensitivity syndrome may be the failure to start menstruation. Breast development, however, may occur normally. Pubic and underarm hair growth is sparse or absent. Complete androgen insensitivity syndrome is caused by mutations of the androgen receptor gene and is inherited as an X-linked recessive trait.
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Diagnosis of WNT4 Deficiency
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In some cases, females with WTN4 deficiency come to the attention of physicians due to the failure of menstrual cycles to begin during puberty (primary amenorrhea). A diagnosis of WNT4 deficiency may be suspected based upon a thorough clinical evaluation, a detailed patient history and the identification of characteristic symptoms such as an absent or underdevelopment uterus and/or vagina occurring in association with normal external genitalia. Molecular genetic analysis can reveal characteristic mutations of the WNT4 gene and confirm a diagnosis of WNT4 deficiency.Specialized imaging techniques including ultrasonography and magnetic resonance imaging (MRI) may be used to aid in a diagnosis of WNT4 deficiency. An ultrasound records echoes of high-frequency sound waves to produce a detailed image of deep structures within the body. An ultrasound can depict the uterus and vagina. It can also be used to evaluate the kidneys. An ultrasound is a simple, noninvasive procedure that lacks radiation. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. It is also noninvasive and is generally more sensitive than an ultrasound. In addition to evaluating the uterus and vagina, an MRI can simultaneously be used to evaluate the kidney and skeleton.Karyotyping may be performed to rule out other conditions. Karyotyping is used to examine the chromosomes in a sample of cells. Females with WNT4 deficiency have a normal 46, XX karyotype.
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Diagnosis of WNT4 Deficiency. In some cases, females with WTN4 deficiency come to the attention of physicians due to the failure of menstrual cycles to begin during puberty (primary amenorrhea). A diagnosis of WNT4 deficiency may be suspected based upon a thorough clinical evaluation, a detailed patient history and the identification of characteristic symptoms such as an absent or underdevelopment uterus and/or vagina occurring in association with normal external genitalia. Molecular genetic analysis can reveal characteristic mutations of the WNT4 gene and confirm a diagnosis of WNT4 deficiency.Specialized imaging techniques including ultrasonography and magnetic resonance imaging (MRI) may be used to aid in a diagnosis of WNT4 deficiency. An ultrasound records echoes of high-frequency sound waves to produce a detailed image of deep structures within the body. An ultrasound can depict the uterus and vagina. It can also be used to evaluate the kidneys. An ultrasound is a simple, noninvasive procedure that lacks radiation. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. It is also noninvasive and is generally more sensitive than an ultrasound. In addition to evaluating the uterus and vagina, an MRI can simultaneously be used to evaluate the kidney and skeleton.Karyotyping may be performed to rule out other conditions. Karyotyping is used to examine the chromosomes in a sample of cells. Females with WNT4 deficiency have a normal 46, XX karyotype.
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Therapies of WNT4 Deficiency
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TreatmentThe treatment of WNT4 deficiency is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Depending upon the affected individual's age at diagnosis, pediatricians or internists, gynecologists, kidney specialists (nephrologists), endocrinologists, orthopedic surgeons, plastic surgeons, physical therapists, psychiatrists and other health care professionals may need to work together to ensure a comprehensive approach to treatment.Women with WNT4 deficiency are encouraged to seek counseling after a diagnosis and before treatment because the diagnosis can cause anxiety and extreme psychological distress. Psychological support and counseling both professionally and through support groups is recommended for affected females and their families.Treatment will usually include appropriate management of the physical findings associated with WNT4 deficiency and psychological support for the emotional issues that often accompany the diagnosis.In women with mullerian aplasia, nonsurgical techniques, including the use of vaginal dilators, may increase the depth of the vagina to a normal length. Such treatment can ease the pain and difficulty that may be associated with sexual intercourse. Nonsurgical techniques are considered the first-line approach. Vaginal dilators are specially designed plastic tubes that are used to help enlarge or create a vagina. The most common method is known as Franck's dilator method. With this method, a physician (and then woman herself) applies a vaginal dilator, which progressively stretches and widens the vagina. This daily procedure may be continued for up to six weeks to several months.In some cases, plastic surgery may be necessary to create an artificial vagina (vaginoplasty). There are a variety of different surgical techniques that may be used and there is no consensus as to which technique is best. Females who undergo surgery to create an artificial vagina will most likely need to use vaginal dilators after the surgery to enhance the chance of success.Because females with WNT4 deficiency do not have a functional uterus, they cannot bear children (infertile). Since affected women have functional ovaries alternative reproductive methods for having children such as in vitro fertilization may be possible. However, because WNT4 deficiency is an inherited as an autosomal dominant trait, the risk of passing on the disorder to children is 50 percent. Any decision to conceive should be undertaken after careful consultation with their physicians, genetic counselors and appropriate medical personnel.Females with WNT4 deficiency who exhibit absence of one kidney (unilateral renal agenesis) may have an increased susceptibility to urinary tract infections and/or kidney stones (renal calculi). Physicians should carefully monitor affected females for infection and prescribe antibiotics as necessary.Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
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Therapies of WNT4 Deficiency. TreatmentThe treatment of WNT4 deficiency is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Depending upon the affected individual's age at diagnosis, pediatricians or internists, gynecologists, kidney specialists (nephrologists), endocrinologists, orthopedic surgeons, plastic surgeons, physical therapists, psychiatrists and other health care professionals may need to work together to ensure a comprehensive approach to treatment.Women with WNT4 deficiency are encouraged to seek counseling after a diagnosis and before treatment because the diagnosis can cause anxiety and extreme psychological distress. Psychological support and counseling both professionally and through support groups is recommended for affected females and their families.Treatment will usually include appropriate management of the physical findings associated with WNT4 deficiency and psychological support for the emotional issues that often accompany the diagnosis.In women with mullerian aplasia, nonsurgical techniques, including the use of vaginal dilators, may increase the depth of the vagina to a normal length. Such treatment can ease the pain and difficulty that may be associated with sexual intercourse. Nonsurgical techniques are considered the first-line approach. Vaginal dilators are specially designed plastic tubes that are used to help enlarge or create a vagina. The most common method is known as Franck's dilator method. With this method, a physician (and then woman herself) applies a vaginal dilator, which progressively stretches and widens the vagina. This daily procedure may be continued for up to six weeks to several months.In some cases, plastic surgery may be necessary to create an artificial vagina (vaginoplasty). There are a variety of different surgical techniques that may be used and there is no consensus as to which technique is best. Females who undergo surgery to create an artificial vagina will most likely need to use vaginal dilators after the surgery to enhance the chance of success.Because females with WNT4 deficiency do not have a functional uterus, they cannot bear children (infertile). Since affected women have functional ovaries alternative reproductive methods for having children such as in vitro fertilization may be possible. However, because WNT4 deficiency is an inherited as an autosomal dominant trait, the risk of passing on the disorder to children is 50 percent. Any decision to conceive should be undertaken after careful consultation with their physicians, genetic counselors and appropriate medical personnel.Females with WNT4 deficiency who exhibit absence of one kidney (unilateral renal agenesis) may have an increased susceptibility to urinary tract infections and/or kidney stones (renal calculi). Physicians should carefully monitor affected females for infection and prescribe antibiotics as necessary.Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
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Overview of Wolf-Hirschhorn Syndrome
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SummaryWolf-Hirschhorn syndrome (WHS) is an extremely rare chromosomal disorder caused by a missing piece (partial deletion or monosomy) of the short arm of chromosome 4. Major symptoms may include extremely wide-set eyes (ocular hypertelorism) with a broad or beaked nose, a small head (microcephaly), low-set malformed ears, growth deficiency, heart (cardiac) defects, intellectual disability, and seizures. The symptoms of this syndrome vary from person to person based the size and location of the missing piece of chromosome 4.
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Overview of Wolf-Hirschhorn Syndrome. SummaryWolf-Hirschhorn syndrome (WHS) is an extremely rare chromosomal disorder caused by a missing piece (partial deletion or monosomy) of the short arm of chromosome 4. Major symptoms may include extremely wide-set eyes (ocular hypertelorism) with a broad or beaked nose, a small head (microcephaly), low-set malformed ears, growth deficiency, heart (cardiac) defects, intellectual disability, and seizures. The symptoms of this syndrome vary from person to person based the size and location of the missing piece of chromosome 4.
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Symptoms of Wolf-Hirschhorn Syndrome
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The features of WHS can vary widely between different affected individuals. The most distinctive feature of WHS is the typical facial appearance. Individuals with WHS usually have widening and prominence of the area located at the top of the nose between the eyebrows (the glabella). This is associated with prominent, wide-spaced eyes, arched eyebrows, and a smallness of the lower part of the face, including a short upper lip and smallness of the mouth and jaw. This leads to the bridge of the nose being the focal point of the face.Findings present in nearly all individuals with WHS include: marked growth problems (both low weight and low height) starting prior to birth and resistant to intervention, intellectual deficits (which are variable, but are often quite marked), low muscle tone (hypotonia), and seizures.Other common findings include small head (microcephaly); eye differences (turning in or out of the eyes, droopy eyelids, eye malformations); ear differences (small, simple, tags and/or pits); cleft lip and/or palate; abnormalities of the penis, testicles, or vagina; abnormalities of the kidneys; problems with bones; problems with teeth.Birth defects of the heart are common in individuals with WHS, but are usually simple, such as a hole between the two top chambers of the heart (atrial septal defect or ASD), and able to be corrected with surgery.
Many individuals have an increased number of infections. Some have a true immune deficiency, most commonly a decreased ability to make antibodies.Feeding problems are extremely common and may be quite severe. The majority of affected individuals require tube feeding at some point in their lives, and many need this lifelong. Some individuals have serious problems with their gut, including malrotation (a birth defect of the gut which increases the risk that it may twist and cut off blood supply), very poor movement of the gut (dysmotility), or poor ability of the gut to absorb nutrients.The intellectual and developmental problems are variable but are quite significant in most people with WHS. Individuals struggle with all areas including: communication, gross motor skills, fine motor skills, and quantitative reasoning. Bowel and bladder control is typically delayed into late childhood and is sometimes not achieved. Most individuals require facilitation of communication with speaking devices or sign language.Originally, Pitt-Rogers-Danks syndrome (PRDS) was described as a separate disorder from WHS. However, individuals with PRDS were eventually found to also have deletions of the short arm of the fourth chromosome in the same region associated with WHS, so this condition is now felt to be a description of the milder end of WHS.
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Symptoms of Wolf-Hirschhorn Syndrome. The features of WHS can vary widely between different affected individuals. The most distinctive feature of WHS is the typical facial appearance. Individuals with WHS usually have widening and prominence of the area located at the top of the nose between the eyebrows (the glabella). This is associated with prominent, wide-spaced eyes, arched eyebrows, and a smallness of the lower part of the face, including a short upper lip and smallness of the mouth and jaw. This leads to the bridge of the nose being the focal point of the face.Findings present in nearly all individuals with WHS include: marked growth problems (both low weight and low height) starting prior to birth and resistant to intervention, intellectual deficits (which are variable, but are often quite marked), low muscle tone (hypotonia), and seizures.Other common findings include small head (microcephaly); eye differences (turning in or out of the eyes, droopy eyelids, eye malformations); ear differences (small, simple, tags and/or pits); cleft lip and/or palate; abnormalities of the penis, testicles, or vagina; abnormalities of the kidneys; problems with bones; problems with teeth.Birth defects of the heart are common in individuals with WHS, but are usually simple, such as a hole between the two top chambers of the heart (atrial septal defect or ASD), and able to be corrected with surgery.
Many individuals have an increased number of infections. Some have a true immune deficiency, most commonly a decreased ability to make antibodies.Feeding problems are extremely common and may be quite severe. The majority of affected individuals require tube feeding at some point in their lives, and many need this lifelong. Some individuals have serious problems with their gut, including malrotation (a birth defect of the gut which increases the risk that it may twist and cut off blood supply), very poor movement of the gut (dysmotility), or poor ability of the gut to absorb nutrients.The intellectual and developmental problems are variable but are quite significant in most people with WHS. Individuals struggle with all areas including: communication, gross motor skills, fine motor skills, and quantitative reasoning. Bowel and bladder control is typically delayed into late childhood and is sometimes not achieved. Most individuals require facilitation of communication with speaking devices or sign language.Originally, Pitt-Rogers-Danks syndrome (PRDS) was described as a separate disorder from WHS. However, individuals with PRDS were eventually found to also have deletions of the short arm of the fourth chromosome in the same region associated with WHS, so this condition is now felt to be a description of the milder end of WHS.
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Causes of Wolf-Hirschhorn Syndrome
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Wolf-Hirschhorn syndrome is an extremely rare chromosomal disorder in which the WHSCR (Wolf Hirschhorn syndrome critical region) on the short arm of chromosome 4 is missing (deleted). In most instances, additional material around the WHSCR is deleted as well.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 the 23rd pair made up of the X and Y chromosomes, with XX associated with female sex, and XY associated with male sex. Each chromosome has a short arm designated “p” and a long arm designated “q.” Chromosomes are further sub-divided into numbered bands. For example, “chromosome 4p16.3” (pronounced “four p one-six point three”) refers to band 16.3 on the short arm of chromosome 4. The numbered bands are used to specify the location of the genes found on each chromosome.Deletion of part of the short arm of chromosome 4 (4p) causes this disorder. It is believed that a portion of band 16.3 on chromosome 4p (4p16.3) is the “critical region” for the disorder, meaning that deletion of this area leads to full expression of Wolf-Hirschhorn syndrome.In most people, the deletion causing WHS happened extremely early in that individual’s development (possibly in the egg or sperm prior to fertilization) and is not inherited from that person’s parents (this is referred to as spontaneous or de novo). Much less commonly, the disorder is inherited from a parent who has a balanced translocation.A translocation is an abnormal chromosome made when pieces of two or more chromosomes break off and trade places. If all of the parts of both chromosomes that participated in the swap are present, this is said to be “balanced.” Because a person with a balanced translocation has all the necessary genetic material for normal development, individuals with balanced translocations do not usually have health problems related to their abnormal chromosome. Unfortunately, a balanced translocation can be transmitted to a child in an unbalanced fashion, leading to missing or extra genetic material in a child and causing a chromosome disorder like WHS. Chromosome (cytogenetic) testing can determine if a parent has a balanced translocation.
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Causes of Wolf-Hirschhorn Syndrome. Wolf-Hirschhorn syndrome is an extremely rare chromosomal disorder in which the WHSCR (Wolf Hirschhorn syndrome critical region) on the short arm of chromosome 4 is missing (deleted). In most instances, additional material around the WHSCR is deleted as well.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 the 23rd pair made up of the X and Y chromosomes, with XX associated with female sex, and XY associated with male sex. Each chromosome has a short arm designated “p” and a long arm designated “q.” Chromosomes are further sub-divided into numbered bands. For example, “chromosome 4p16.3” (pronounced “four p one-six point three”) refers to band 16.3 on the short arm of chromosome 4. The numbered bands are used to specify the location of the genes found on each chromosome.Deletion of part of the short arm of chromosome 4 (4p) causes this disorder. It is believed that a portion of band 16.3 on chromosome 4p (4p16.3) is the “critical region” for the disorder, meaning that deletion of this area leads to full expression of Wolf-Hirschhorn syndrome.In most people, the deletion causing WHS happened extremely early in that individual’s development (possibly in the egg or sperm prior to fertilization) and is not inherited from that person’s parents (this is referred to as spontaneous or de novo). Much less commonly, the disorder is inherited from a parent who has a balanced translocation.A translocation is an abnormal chromosome made when pieces of two or more chromosomes break off and trade places. If all of the parts of both chromosomes that participated in the swap are present, this is said to be “balanced.” Because a person with a balanced translocation has all the necessary genetic material for normal development, individuals with balanced translocations do not usually have health problems related to their abnormal chromosome. Unfortunately, a balanced translocation can be transmitted to a child in an unbalanced fashion, leading to missing or extra genetic material in a child and causing a chromosome disorder like WHS. Chromosome (cytogenetic) testing can determine if a parent has a balanced translocation.
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Affects of Wolf-Hirschhorn Syndrome
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WHS is an extremely rare disorder. Studies undertaken about 25 years ago suggested that the disorder occurred in approximately 1 in about 50,000 live births with a female to male ratio of 2:1. More recent studies suggest that the frequency of the disorder is underestimated because of misdiagnosis.
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Affects of Wolf-Hirschhorn Syndrome. WHS is an extremely rare disorder. Studies undertaken about 25 years ago suggested that the disorder occurred in approximately 1 in about 50,000 live births with a female to male ratio of 2:1. More recent studies suggest that the frequency of the disorder is underestimated because of misdiagnosis.
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Related disorders of Wolf-Hirschhorn Syndrome
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Syndromes involving deletions of other chromosomes may be similar to Wolf- Hirschhorn syndrome. Comparisons may be useful for a differential diagnosis.
Chromosomal disorders that involve extra chromosomes (trisomy) have some similarities (particularly growth failure and marked developmental impacts) to Wolf-Hirschhorn syndrome. (For more information on these disorders, choose “Trisomy,” “Trisomy 13,” and “Trisomy 18” as your search terms in the Rare Disease Database.)Cri-du-chat syndrome is a congenital chromosomal disorder that involves a partial deletion of chromosome 5. It can also have overlapping features with WHS, particularly including poor growth, small head, feeding problems and intellectual impacts. Persons with this disorder have breathing and airway problems and a high, shrill cry. They have distinctive facial features that are not the same as those seen in WHS.Down syndrome is a congenital chromosomal disorder involving three copies of chromosome 21. Distinctive facial features (different from those seen in WHS), low muscle tone, small stature, and intellectual disability are major symptoms. Serious birth defects such as heart defects and abnormalities of the GI tract are also common.Angelman syndrome (AS), is characterized by severe developmental delay, intellectual disability, severe speech impairment, posture and movement problems, microcephaly and seizures. Abnormalities in the q11.2-q13 region of chromosome 15 are associated with AS.Williams syndrome (WS) is characterized by mild intellectual disability, unique personality characteristics, distinctive facial features, and cardiovascular disease. Kidney problems and digestive issues may occur due to calcium build up in different parts of the body. WS is caused by the deletion of the WSCR (Williams syndrome critical region) in the 11.23 region of the long arm of chromosome 7.Smith-Lemli-Opitz syndrome (SLOS) is characterized by growth delay, small head, intellectual disability, distinctive facial features, heart defects and under-developed penis and testicles in males.
For more information about these conditions, search for them in the Rare Disease Database.
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Related disorders of Wolf-Hirschhorn Syndrome. Syndromes involving deletions of other chromosomes may be similar to Wolf- Hirschhorn syndrome. Comparisons may be useful for a differential diagnosis.
Chromosomal disorders that involve extra chromosomes (trisomy) have some similarities (particularly growth failure and marked developmental impacts) to Wolf-Hirschhorn syndrome. (For more information on these disorders, choose “Trisomy,” “Trisomy 13,” and “Trisomy 18” as your search terms in the Rare Disease Database.)Cri-du-chat syndrome is a congenital chromosomal disorder that involves a partial deletion of chromosome 5. It can also have overlapping features with WHS, particularly including poor growth, small head, feeding problems and intellectual impacts. Persons with this disorder have breathing and airway problems and a high, shrill cry. They have distinctive facial features that are not the same as those seen in WHS.Down syndrome is a congenital chromosomal disorder involving three copies of chromosome 21. Distinctive facial features (different from those seen in WHS), low muscle tone, small stature, and intellectual disability are major symptoms. Serious birth defects such as heart defects and abnormalities of the GI tract are also common.Angelman syndrome (AS), is characterized by severe developmental delay, intellectual disability, severe speech impairment, posture and movement problems, microcephaly and seizures. Abnormalities in the q11.2-q13 region of chromosome 15 are associated with AS.Williams syndrome (WS) is characterized by mild intellectual disability, unique personality characteristics, distinctive facial features, and cardiovascular disease. Kidney problems and digestive issues may occur due to calcium build up in different parts of the body. WS is caused by the deletion of the WSCR (Williams syndrome critical region) in the 11.23 region of the long arm of chromosome 7.Smith-Lemli-Opitz syndrome (SLOS) is characterized by growth delay, small head, intellectual disability, distinctive facial features, heart defects and under-developed penis and testicles in males.
For more information about these conditions, search for them in the Rare Disease Database.
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Diagnosis of Wolf-Hirschhorn Syndrome
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A diagnosis of WHS may be suggested by the characteristic facial appearance, growth failure, developmental delays, and seizures. The diagnosis is confirmed by detection of a deletion of the Wolf-Hirschhorn syndrome critical region (WHSCR) by cytogenetic (chromosome) analysis. Conventional cytogenetic analysis (karyotype) detects less than half of the deletions that cause WHS. Fluorescence in situ hybridization (FISH) using a WHSCR probe has much better detection rate than standard karyotype and will detect most patients. However, the diagnostic test of choice is chromosomal microarray, which detects essentially all deletions of the WHSCR and defines the size of the deletion. Chromosomal microarray can also find other chromosome rearrangements, such as extra pieces of other chromosomes that are seen in many patients with WHS.
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Diagnosis of Wolf-Hirschhorn Syndrome. A diagnosis of WHS may be suggested by the characteristic facial appearance, growth failure, developmental delays, and seizures. The diagnosis is confirmed by detection of a deletion of the Wolf-Hirschhorn syndrome critical region (WHSCR) by cytogenetic (chromosome) analysis. Conventional cytogenetic analysis (karyotype) detects less than half of the deletions that cause WHS. Fluorescence in situ hybridization (FISH) using a WHSCR probe has much better detection rate than standard karyotype and will detect most patients. However, the diagnostic test of choice is chromosomal microarray, which detects essentially all deletions of the WHSCR and defines the size of the deletion. Chromosomal microarray can also find other chromosome rearrangements, such as extra pieces of other chromosomes that are seen in many patients with WHS.
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Wolf-Hirschhorn Syndrome
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Therapies of Wolf-Hirschhorn Syndrome
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Treatment
Because WHS is so variable, treatment and intervention must be tailored to the affected individual’s needs. Patients with a known or suspected diagnosis of WHS should have a comprehensive evaluation by an experienced genetics professional. Most patients will need to be followed by multiple subspecialists. Patients should have a neurology evaluation with evaluation for seizures, detailed cardiology (heart) evaluation, eye exam, hearing exam, kidney evaluation, feeding evaluation, and developmental evaluation as soon as possible after diagnosis. Kidney function must be monitored on an ongoing basis. All patients benefit from comprehensive developmental and rehabilitation support including: feeding therapy, assistive communication, speech, physical therapy, occupational therapy, and school support. Genetic counseling is recommended for families of children with Wolf-Hirschhorn syndrome.
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Therapies of Wolf-Hirschhorn Syndrome. Treatment
Because WHS is so variable, treatment and intervention must be tailored to the affected individual’s needs. Patients with a known or suspected diagnosis of WHS should have a comprehensive evaluation by an experienced genetics professional. Most patients will need to be followed by multiple subspecialists. Patients should have a neurology evaluation with evaluation for seizures, detailed cardiology (heart) evaluation, eye exam, hearing exam, kidney evaluation, feeding evaluation, and developmental evaluation as soon as possible after diagnosis. Kidney function must be monitored on an ongoing basis. All patients benefit from comprehensive developmental and rehabilitation support including: feeding therapy, assistive communication, speech, physical therapy, occupational therapy, and school support. Genetic counseling is recommended for families of children with Wolf-Hirschhorn syndrome.
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Overview of Wolfram Syndrome
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SummaryWolfram syndrome is an inherited condition that is typically associated with childhood-onset insulin-dependent diabetes mellitus and progressive optic atrophy. In addition, many people with Wolfram syndrome also develop diabetes insipidus and sensorineural hearing loss. Another name for the syndrome is DIDMOAD, which refers to diabetes insipidus, diabetes mellitus, optic atrophy, and deafness. Most cases of Wolfram syndrome are caused by changes (mutations) in the WFS-1 gene. Less severe mutations in the WFS-1 gene cause WFS1-related disorders, in which the affected person has only some of the features of Wolfram syndrome, such as sensorineural hearing loss without diabetes or other features.
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Overview of Wolfram Syndrome. SummaryWolfram syndrome is an inherited condition that is typically associated with childhood-onset insulin-dependent diabetes mellitus and progressive optic atrophy. In addition, many people with Wolfram syndrome also develop diabetes insipidus and sensorineural hearing loss. Another name for the syndrome is DIDMOAD, which refers to diabetes insipidus, diabetes mellitus, optic atrophy, and deafness. Most cases of Wolfram syndrome are caused by changes (mutations) in the WFS-1 gene. Less severe mutations in the WFS-1 gene cause WFS1-related disorders, in which the affected person has only some of the features of Wolfram syndrome, such as sensorineural hearing loss without diabetes or other features.
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Symptoms of Wolfram Syndrome
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The symptoms and rate of progression of Wolfram syndrome can be quite variable. The primary symptoms of Wolfram syndrome (diabetes mellitus, optic atrophy, diabetes insipidus and hearing loss) can emerge at different ages and change at different rates. If some of these symptoms never appear at all, the patient’s condition would be called a WFS1-related disorder. Most people affected by Wolfram syndrome develop insulin-dependent diabetes mellitus before the age of 16 (87%). The starches and sugars (carbohydrates) in the foods we eat are normally processed by the digestive system into glucose that circulates in the blood as one energy source for body functions. A hormone produced by the pancreas (insulin) allows muscle and fat cells to take up glucose. In diabetes mellitus, the pancreas does not make enough insulin so the cells cannot take up glucose normally and the blood sugar gets too high. In diabetes mellitus caused by the Wolfram gene, the patient needs daily injections of insulin to control the blood sugar. Symptoms of diabetes may include frequent urination, excessive thirst, increased appetite, weight loss, and blurred vision. In addition, it is thought that almost all of those affected by Wolfram syndrome have primary optic atrophy (OA) and subsequent vision impairment of varying severity before the age of 16 (80%). The optic nerve conducts visual information to the brain for processing. Loss of the nerve fibers and/or their insulation (myelin) results in color blindness and reduced vision typically beginning in childhood and progressing with age, though some progress quickly and others slowly. Some people who have Wolfram syndrome also develop diabetes insipidus (42%). This is not related to diabetes or insulin. The only thing it has in common with diabetes is the symptoms of excessive thirst and urination. This condition results in excretion of large quantities of very watery-appearing urine and excessive thirst due to the brain not making enough of a hormone (vasopressin) that causes the kidneys to hold onto water. Patients tend to drink enormous quantities of fluid and urinate very often. Other symptoms may be dehydration, weakness, dryness of the mouth, and sometimes constipation, which may develop rapidly if the loss of fluid is not continuously replaced. Diabetes insipidus can be treated with vasopressin hormone replacement called dDAVP. Hearing loss is the fourth major symptom of Wolfram syndrome and occurs in approximately 48% of patients. This symptom may occur at any age and may be partial or complete. The hearing loss is due to a loss of sound perception transmitted by nerves (sensorineural). Symptoms may include loss of sound intensity or pitch, or loss of the ability to hear high tones. Some of the following additional symptoms may develop: Urinary tract abnormalities (33%) – this is most often a problem with the bladder not emptying properly, so that the person needs to empty often. This symptom may be confused or complicated by diabetes insipidus, so both need to be checked if a person with Wolfram syndrome is having frequent urination. Neurological symptoms such as poor smell, poor balance, an awkward, unbalanced way of walking (ataxia) and central sleep apnea can occur. In addition, imaging of the brain reveals that people with Wolfram syndrome have smaller brainstem and cerebellum volumes and smaller optic nerves than those without Wolfram syndrome. These differences may increase over time. Psychiatric and behavioral problems such as depression, anxiety and fatigue can occur in patients with Wolfram syndrome (26%). These symptoms may be related to the changes in the nervous system from Wolfram syndrome itself or to the psychological and quality of life burden caused by the effects of the disease. Disordered sleep may be a problem and can be due to sleep apnea or to frequent waking to urinate. Other problems that may occur: Lowered production of testosterone (hypogonadism) in males (6%) Gastrointestinal disorders (5%) – including constipation, trouble swallowing, choking, diarrhea. Bilateral clouding of the lens of the eyes (cataracts) (1%) Abnormal temperature regulation (e.g. overheating).
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Symptoms of Wolfram Syndrome. The symptoms and rate of progression of Wolfram syndrome can be quite variable. The primary symptoms of Wolfram syndrome (diabetes mellitus, optic atrophy, diabetes insipidus and hearing loss) can emerge at different ages and change at different rates. If some of these symptoms never appear at all, the patient’s condition would be called a WFS1-related disorder. Most people affected by Wolfram syndrome develop insulin-dependent diabetes mellitus before the age of 16 (87%). The starches and sugars (carbohydrates) in the foods we eat are normally processed by the digestive system into glucose that circulates in the blood as one energy source for body functions. A hormone produced by the pancreas (insulin) allows muscle and fat cells to take up glucose. In diabetes mellitus, the pancreas does not make enough insulin so the cells cannot take up glucose normally and the blood sugar gets too high. In diabetes mellitus caused by the Wolfram gene, the patient needs daily injections of insulin to control the blood sugar. Symptoms of diabetes may include frequent urination, excessive thirst, increased appetite, weight loss, and blurred vision. In addition, it is thought that almost all of those affected by Wolfram syndrome have primary optic atrophy (OA) and subsequent vision impairment of varying severity before the age of 16 (80%). The optic nerve conducts visual information to the brain for processing. Loss of the nerve fibers and/or their insulation (myelin) results in color blindness and reduced vision typically beginning in childhood and progressing with age, though some progress quickly and others slowly. Some people who have Wolfram syndrome also develop diabetes insipidus (42%). This is not related to diabetes or insulin. The only thing it has in common with diabetes is the symptoms of excessive thirst and urination. This condition results in excretion of large quantities of very watery-appearing urine and excessive thirst due to the brain not making enough of a hormone (vasopressin) that causes the kidneys to hold onto water. Patients tend to drink enormous quantities of fluid and urinate very often. Other symptoms may be dehydration, weakness, dryness of the mouth, and sometimes constipation, which may develop rapidly if the loss of fluid is not continuously replaced. Diabetes insipidus can be treated with vasopressin hormone replacement called dDAVP. Hearing loss is the fourth major symptom of Wolfram syndrome and occurs in approximately 48% of patients. This symptom may occur at any age and may be partial or complete. The hearing loss is due to a loss of sound perception transmitted by nerves (sensorineural). Symptoms may include loss of sound intensity or pitch, or loss of the ability to hear high tones. Some of the following additional symptoms may develop: Urinary tract abnormalities (33%) – this is most often a problem with the bladder not emptying properly, so that the person needs to empty often. This symptom may be confused or complicated by diabetes insipidus, so both need to be checked if a person with Wolfram syndrome is having frequent urination. Neurological symptoms such as poor smell, poor balance, an awkward, unbalanced way of walking (ataxia) and central sleep apnea can occur. In addition, imaging of the brain reveals that people with Wolfram syndrome have smaller brainstem and cerebellum volumes and smaller optic nerves than those without Wolfram syndrome. These differences may increase over time. Psychiatric and behavioral problems such as depression, anxiety and fatigue can occur in patients with Wolfram syndrome (26%). These symptoms may be related to the changes in the nervous system from Wolfram syndrome itself or to the psychological and quality of life burden caused by the effects of the disease. Disordered sleep may be a problem and can be due to sleep apnea or to frequent waking to urinate. Other problems that may occur: Lowered production of testosterone (hypogonadism) in males (6%) Gastrointestinal disorders (5%) – including constipation, trouble swallowing, choking, diarrhea. Bilateral clouding of the lens of the eyes (cataracts) (1%) Abnormal temperature regulation (e.g. overheating).
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Wolfram Syndrome
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Causes of Wolfram Syndrome
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Wolfram syndrome is caused by mutations in the WFS1 (most common) or WFS2 (CISD2) gene that are inherited in an autosomal recessive pattern in most affected individuals, although dominant forms exist. Recessive genetic disorders occur when an individual inherits two copies of an altered gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same altered gene, which increases the risk to have children with a recessive genetic disorder. Dominant genetic disorders occur when only a single copy of an altered gene is necessary to cause a disease. The altered gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the altered gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females. In some individuals, the disorder is due to a spontaneous (de novo) gene mutation that occurs in the egg or sperm cell. In such situations, the disorder is not inherited from the parents.
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Causes of Wolfram Syndrome. Wolfram syndrome is caused by mutations in the WFS1 (most common) or WFS2 (CISD2) gene that are inherited in an autosomal recessive pattern in most affected individuals, although dominant forms exist. Recessive genetic disorders occur when an individual inherits two copies of an altered gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same altered gene, which increases the risk to have children with a recessive genetic disorder. Dominant genetic disorders occur when only a single copy of an altered gene is necessary to cause a disease. The altered gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the altered gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females. In some individuals, the disorder is due to a spontaneous (de novo) gene mutation that occurs in the egg or sperm cell. In such situations, the disorder is not inherited from the parents.
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Wolfram Syndrome
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Affects of Wolfram Syndrome
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Since diabetes mellitus and optic atrophy usually begin before the age of 16, Wolfram syndrome is typically diagnosed in childhood to adolescence. However, onset of key symptoms or the genetic confirmation can come much later in some patients. Wolfram syndrome affects males and females in equal numbers and is equally prevalent worldwide.
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Affects of Wolfram Syndrome. Since diabetes mellitus and optic atrophy usually begin before the age of 16, Wolfram syndrome is typically diagnosed in childhood to adolescence. However, onset of key symptoms or the genetic confirmation can come much later in some patients. Wolfram syndrome affects males and females in equal numbers and is equally prevalent worldwide.
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Wolfram Syndrome
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Related disorders of Wolfram Syndrome
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The following disorders have symptoms like some of the symptoms of Wolfram syndrome: Leber hereditary optic atrophy (LHOA) is a rare inherited disorder of the eye that is characterized by the relatively slow, painless, progressive loss of vision. The optic atrophy in LHOA and the optic atrophy in Wolfram syndrome may look the same and have the same symptoms. LHOA can start in one eye or both, but both eyes are usually affected within six months. In most people, vision loss is permanent. LHOA is a genetic disorder that occurs as the result of a mutation in the mitochondrial DNA that is inherited from the mother or arises as a new sporadic mitochondrial DNA mutation. (For more information on this disorder, choose “Leber hereditary optic neuropathy” as your search term in the Rare Disease Database.) Thiamine-responsive megaloblastic anemia syndrome (TRMA) is an autosomal recessive disorder with features that include megaloblastic anemia, sensorineural hearing loss and diabetes mellitus. Megaloblastic anemia is a blood disorder characterized by anemia, with red blood cells that are larger than normal, usually resulting from a deficiency of folic acid or of vitamin B-12. The hearing loss and diabetes mellitus in this disorder can look the same as the hearing loss and diabetes mellitus in Wolfram. Other disorders that may be confused with Wolfram syndrome include Alstrom syndrome; Friedreich ataxia; Kearns-Sayre syndrome; Lawrence-Moon syndrome; Refsum disease; autosomal dominant optic atrophy; X-linked Charcot-Marie-Tooth disease type 5; deafness, dystonia, optic neuropathy syndrome; mitochondrial DNA disorders, and Bardet-Biedl syndrome. (For more information on these disorders, choose the appropriate name as your search term in the Rare Disease Database.)
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Related disorders of Wolfram Syndrome. The following disorders have symptoms like some of the symptoms of Wolfram syndrome: Leber hereditary optic atrophy (LHOA) is a rare inherited disorder of the eye that is characterized by the relatively slow, painless, progressive loss of vision. The optic atrophy in LHOA and the optic atrophy in Wolfram syndrome may look the same and have the same symptoms. LHOA can start in one eye or both, but both eyes are usually affected within six months. In most people, vision loss is permanent. LHOA is a genetic disorder that occurs as the result of a mutation in the mitochondrial DNA that is inherited from the mother or arises as a new sporadic mitochondrial DNA mutation. (For more information on this disorder, choose “Leber hereditary optic neuropathy” as your search term in the Rare Disease Database.) Thiamine-responsive megaloblastic anemia syndrome (TRMA) is an autosomal recessive disorder with features that include megaloblastic anemia, sensorineural hearing loss and diabetes mellitus. Megaloblastic anemia is a blood disorder characterized by anemia, with red blood cells that are larger than normal, usually resulting from a deficiency of folic acid or of vitamin B-12. The hearing loss and diabetes mellitus in this disorder can look the same as the hearing loss and diabetes mellitus in Wolfram. Other disorders that may be confused with Wolfram syndrome include Alstrom syndrome; Friedreich ataxia; Kearns-Sayre syndrome; Lawrence-Moon syndrome; Refsum disease; autosomal dominant optic atrophy; X-linked Charcot-Marie-Tooth disease type 5; deafness, dystonia, optic neuropathy syndrome; mitochondrial DNA disorders, and Bardet-Biedl syndrome. (For more information on these disorders, choose the appropriate name as your search term in the Rare Disease Database.)
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Wolfram Syndrome
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Diagnosis of Wolfram Syndrome
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Wolfram syndrome is difficult to diagnose. In many instances, people with this disorder and their doctors may be unaware that the various symptoms and complaints are related and indicate a specific disorder. Initially, the focus may be on one symptom, typically diabetes mellitus, and its treatment. Later, the presence of other symptoms may become apparent. Wolfram syndrome should be considered in anyone with diabetes mellitus and optic atrophy; anyone with low frequency sensorineural hearing loss; anyone with either diabetes mellitus or optic atrophy in addition to hearing loss or diabetes insipidus or bladder dysfunction or loss of sense of smell or a family member with Wolfram syndrome. Molecular genetic testing for mutations in the WFS1 and WFS2 genes is available to confirm the diagnosis.
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Diagnosis of Wolfram Syndrome. Wolfram syndrome is difficult to diagnose. In many instances, people with this disorder and their doctors may be unaware that the various symptoms and complaints are related and indicate a specific disorder. Initially, the focus may be on one symptom, typically diabetes mellitus, and its treatment. Later, the presence of other symptoms may become apparent. Wolfram syndrome should be considered in anyone with diabetes mellitus and optic atrophy; anyone with low frequency sensorineural hearing loss; anyone with either diabetes mellitus or optic atrophy in addition to hearing loss or diabetes insipidus or bladder dysfunction or loss of sense of smell or a family member with Wolfram syndrome. Molecular genetic testing for mutations in the WFS1 and WFS2 genes is available to confirm the diagnosis.
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Wolfram Syndrome
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Therapies of Wolfram Syndrome
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Treatment
Treatment of Wolfram syndrome is symptomatic and supportive. It requires a multidisciplinary effort to manage the various aspects of this condition. When diabetes mellitus is present, the patient will need insulin treatment. Diabetes insipidus can be difficult to diagnose and may need to be treated with intranasal or oral dDAVP. Treatment of diabetes insipidus in Wolfram may be very complicated as the person may also have diabetes mellitus and bladder dysfunction. Patients with hearing loss may benefit from hearing aids or cochlear implants as well as accommodations for hearing loss. All patients should be followed closely by an eye doctor (ophthalmologist) and may need glasses or other accommodations for low vision such as large print reading materials, high contrast visuals at school or work, allowances for colorblindness, etc. Occupational therapy may be helpful in some cases. Regular evaluation of the bladder is important to detect poor bladder emptying. Psychological evaluation and care are important for many, particularly with school performance issues. Treatment of constipation, diarrhea, and trouble swallowing may be needed. Sleep should be monitored, and sleep apnea considered. Patients may have trouble tolerating high or low temperatures and may need accommodations for air conditioning or heating. Genetic counseling is recommended for Wolfram syndrome patients and their families.
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Therapies of Wolfram Syndrome. Treatment
Treatment of Wolfram syndrome is symptomatic and supportive. It requires a multidisciplinary effort to manage the various aspects of this condition. When diabetes mellitus is present, the patient will need insulin treatment. Diabetes insipidus can be difficult to diagnose and may need to be treated with intranasal or oral dDAVP. Treatment of diabetes insipidus in Wolfram may be very complicated as the person may also have diabetes mellitus and bladder dysfunction. Patients with hearing loss may benefit from hearing aids or cochlear implants as well as accommodations for hearing loss. All patients should be followed closely by an eye doctor (ophthalmologist) and may need glasses or other accommodations for low vision such as large print reading materials, high contrast visuals at school or work, allowances for colorblindness, etc. Occupational therapy may be helpful in some cases. Regular evaluation of the bladder is important to detect poor bladder emptying. Psychological evaluation and care are important for many, particularly with school performance issues. Treatment of constipation, diarrhea, and trouble swallowing may be needed. Sleep should be monitored, and sleep apnea considered. Patients may have trouble tolerating high or low temperatures and may need accommodations for air conditioning or heating. Genetic counseling is recommended for Wolfram syndrome patients and their families.
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Wolfram Syndrome
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Overview of Wolman Disease
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SummaryWolman disease is a type of lysosomal acid lipase (LAL) deficiency; a rare genetic disorder characterized by complete absence of an enzyme known as lysosomal acid lipase (LIPA or LAL). This enzyme is required to breakdown (metabolize) certain fats (lipids) in the body. Without the LIPA enzyme, certain fats may abnormally accumulate in the tissues and organs of the body causing a variety of symptoms. Wolman disease may cause bloating or swelling of the stomach (abdominal distention), vomiting, and significant enlargement of the liver or spleen (hepatosplenomegaly). Life-threatening complications often develop during early childhood. Wolman disease is caused by mutations in the lysosomal acid lipase (LIPA) gene and is inherited as an autosomal recessive trait.IntroductionWolman disease is the most severe expression of LAL deficiency; a milder form of LAL deficiency is known as cholesteryl ester storage disease (CESD). (see the Related Disorders section of this report).LIPA gene mutations that cause CESD result in some enzyme activity, whereas LIPA gene mutations that cause Wolman disease produce an enzyme with no residual activity or no enzyme at all. Genetic and biochemical evidence indicates that CESD and Wolman disease are distinguished by residual lysosomal acid lipase activity.
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Overview of Wolman Disease. SummaryWolman disease is a type of lysosomal acid lipase (LAL) deficiency; a rare genetic disorder characterized by complete absence of an enzyme known as lysosomal acid lipase (LIPA or LAL). This enzyme is required to breakdown (metabolize) certain fats (lipids) in the body. Without the LIPA enzyme, certain fats may abnormally accumulate in the tissues and organs of the body causing a variety of symptoms. Wolman disease may cause bloating or swelling of the stomach (abdominal distention), vomiting, and significant enlargement of the liver or spleen (hepatosplenomegaly). Life-threatening complications often develop during early childhood. Wolman disease is caused by mutations in the lysosomal acid lipase (LIPA) gene and is inherited as an autosomal recessive trait.IntroductionWolman disease is the most severe expression of LAL deficiency; a milder form of LAL deficiency is known as cholesteryl ester storage disease (CESD). (see the Related Disorders section of this report).LIPA gene mutations that cause CESD result in some enzyme activity, whereas LIPA gene mutations that cause Wolman disease produce an enzyme with no residual activity or no enzyme at all. Genetic and biochemical evidence indicates that CESD and Wolman disease are distinguished by residual lysosomal acid lipase activity.
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Wolman Disease
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Symptoms of Wolman Disease
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The symptoms of Wolman disease usually become apparent shortly after birth, usually during the first few weeks of life. Affected infants may develop bloating or swelling of the stomach (abdominal distention) and may have significant enlargement of the liver and spleen (hepatosplenomegaly). Scarring (fibrosis) of the liver may also occur. In some cases, fluid may accumulate in the abdominal cavity (ascites).Infants with Wolman disease have serious digestive abnormalities including malabsorption, a condition in which the intestines fail to absorb nutrients and calories form food. Malabsorption associated with Wolman disease causes persistent and often forceful vomiting, frequent diarrhea, foul-smelling, fatty stools (steatorrhea) and malnutrition. Because of these digestive complications, affected infants usually fail to grow and gain weight at the expected rate for their age and sex (failure to thrive).Enlargement of the liver and spleen and protrusion of the abdomen can cause umbilical hernia, a condition in which the contents of the stomach may push through an abnormal opening or tear in the abdominal wall near the bellybutton. Additional symptoms may also occur in Wolman disease including yellowing of the skin, mucous membranes and whites of the eyes (jaundice), a persistent low-grade fever, and poor muscle tone (hypotonia). Infants may exhibit delays in the development of motor skills.A distinct finding associated with Wolman disease is the hardening of adrenal gland tissue due to the accumulation of calcium (calcification). The adrenal glands are located on top of the kidneys and produce two hormones called epinephrine and norepinephrine. Other hormones produced by the adrenal glands help to regulate the fluid and electrolyte balance in the body. Calcification of the adrenal glands is not detectable by physical examination, but can be seen with x-ray study. Calcification may prevent the adrenal glands from producing enough essential hormones and can affect metabolism, blood pressure, the immune system and other vital processes of the body.Infants with Wolman disease may experience the loss of previously acquired skills required the coordination of muscle and motor skills (psychomotor regression). The symptoms of Wolman disease often get progressively worse eventually leading to life-threatening complications during infancy including extremely low levels of circulating red blood cells (severe anemia), liver (hepatic) dysfunction or failure, and physical wasting away and severe weakness often associated with chronic disease and marked by weight loss and loss of muscle mass (cachexia or inanition).
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Symptoms of Wolman Disease. The symptoms of Wolman disease usually become apparent shortly after birth, usually during the first few weeks of life. Affected infants may develop bloating or swelling of the stomach (abdominal distention) and may have significant enlargement of the liver and spleen (hepatosplenomegaly). Scarring (fibrosis) of the liver may also occur. In some cases, fluid may accumulate in the abdominal cavity (ascites).Infants with Wolman disease have serious digestive abnormalities including malabsorption, a condition in which the intestines fail to absorb nutrients and calories form food. Malabsorption associated with Wolman disease causes persistent and often forceful vomiting, frequent diarrhea, foul-smelling, fatty stools (steatorrhea) and malnutrition. Because of these digestive complications, affected infants usually fail to grow and gain weight at the expected rate for their age and sex (failure to thrive).Enlargement of the liver and spleen and protrusion of the abdomen can cause umbilical hernia, a condition in which the contents of the stomach may push through an abnormal opening or tear in the abdominal wall near the bellybutton. Additional symptoms may also occur in Wolman disease including yellowing of the skin, mucous membranes and whites of the eyes (jaundice), a persistent low-grade fever, and poor muscle tone (hypotonia). Infants may exhibit delays in the development of motor skills.A distinct finding associated with Wolman disease is the hardening of adrenal gland tissue due to the accumulation of calcium (calcification). The adrenal glands are located on top of the kidneys and produce two hormones called epinephrine and norepinephrine. Other hormones produced by the adrenal glands help to regulate the fluid and electrolyte balance in the body. Calcification of the adrenal glands is not detectable by physical examination, but can be seen with x-ray study. Calcification may prevent the adrenal glands from producing enough essential hormones and can affect metabolism, blood pressure, the immune system and other vital processes of the body.Infants with Wolman disease may experience the loss of previously acquired skills required the coordination of muscle and motor skills (psychomotor regression). The symptoms of Wolman disease often get progressively worse eventually leading to life-threatening complications during infancy including extremely low levels of circulating red blood cells (severe anemia), liver (hepatic) dysfunction or failure, and physical wasting away and severe weakness often associated with chronic disease and marked by weight loss and loss of muscle mass (cachexia or inanition).
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Causes of Wolman Disease
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Wolman disease is caused by mutations in the lysosomal acid lipase (LIPA) gene. The LIPA gene contains instructions for producing the enzyme lysosomal acid lipase. This enzyme is essential for breaking down (metabolizing) certain fats in the body, especially cholesterol (specifically cholesteryl esters) and to a lesser degree triglycerides. Without proper levels of this enzyme, these fats abnormally accumulate in and damage various tissues and organs of the body. Mutations in the LIPA gene that cause Wolman disease result in the lack of production of the LIPA enzyme or production of a defective, inactive form of the LIPA enzyme.Wolman disease is inherited as an autosomal recessive trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and 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. 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 Wolman Disease. Wolman disease is caused by mutations in the lysosomal acid lipase (LIPA) gene. The LIPA gene contains instructions for producing the enzyme lysosomal acid lipase. This enzyme is essential for breaking down (metabolizing) certain fats in the body, especially cholesterol (specifically cholesteryl esters) and to a lesser degree triglycerides. Without proper levels of this enzyme, these fats abnormally accumulate in and damage various tissues and organs of the body. Mutations in the LIPA gene that cause Wolman disease result in the lack of production of the LIPA enzyme or production of a defective, inactive form of the LIPA enzyme.Wolman disease is inherited as an autosomal recessive trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and 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. 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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Affects of Wolman Disease
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Wolman disease is an extremely rare disorder that affects males and females in equal numbers. More than 50 cases have been reported in the medical literature. However, cases may go undiagnosed or misdiagnosed making it difficult to determine the disorder’s true frequency in the general population. Wolman disease is named after one of the physicians who first identified the disorder in the medical literature in 1956.
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Affects of Wolman Disease. Wolman disease is an extremely rare disorder that affects males and females in equal numbers. More than 50 cases have been reported in the medical literature. However, cases may go undiagnosed or misdiagnosed making it difficult to determine the disorder’s true frequency in the general population. Wolman disease is named after one of the physicians who first identified the disorder in the medical literature in 1956.
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Related disorders of Wolman Disease
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Symptoms of the following disorders can be similar to those of Wolman disease. Comparisons may be useful for a differential diagnosis.Cholesteryl ester storage disease (CESD) is a type of lysosomal acid lipase (LAL) deficiency; a rare genetic disorder characterized by a deficiency of the lysosomal acid lipase (LIPA or LAL) enzyme. This enzyme is essential for hydrolysis of triglycerides and cholesteryl esters in lysosomes. Deficiency of the LIPA enzyme causes accumulation of certain fatty substances (mucolipids) and certain complex carbohydrates (mucopolysaccharides) within the cells of many tissues of the body, potentially causing a variety of symptoms. In the liver, the consequences are abnormally enlarged liver (hepatomegaly) due to hepatic steatosis (fatty liver) and fibrosis that can lead to micronodular cirrhosis. Some individuals may not be diagnosed with CESD until adulthood. CESD is caused by mutations in the lysosomal acid lipase (LIPA) gene and is inherited as an autosomal recessive trait. (For more information on this disorder, choose “cholesteryl ester storage disease” as your search term in the Rare Disease Database.)Niemann-Pick disease (NPD) is a group of rare inherited disorders of fat metabolism. At least five types of Niemann-Pick disease have been identified (NPD types A, B, C, D, and E). Symptoms of types A and B occur as a result of a deficiency of the enzyme acid sphingomyelinase (ASM), which is needed to break down sphingomyelin, a fatty substance found mostly in the brain and nervous system. This deficiency results in abnormal accumulation of excessive amounts of sphingomyelin in many organs of the body such as the liver, spleen, and brain. Symptoms of type C occur because of impaired trafficking of large molecules within cells, which results in the accumulation of excessive amounts of cholesterol and other lipids (glycosphingolipids) tissues throughout the body. The metabolic defect in type C can lead to a secondary reduction in ASM activity in some cells. Symptoms common to all types of NPD include yellow discoloration of the skin, eyes, and/or mucous membranes (jaundice), progressive loss of motor skills, feeding difficulties, learning disabilities, and an abnormally enlarged liver and/or spleen (hepatosplenomegaly). The different types of NPD are inherited as autosomal recessive traits. (For more information on this disorder, choose “Niemann Pick” as your search term in the Rare Disease Database.)Chanarin Dorfman syndrome is a rare genetic disorder of fat (lipid) metabolism. It is characterized by scaly skin (ichthyosis), degeneration of the muscles (myopathy), and abnormal white blood cells with small spaces (vacuoles) filled with fat (lipids). Additional symptoms may occur including hearing loss, vision abnormalities, an enlarged liver (hepatomegaly) and a condition in which fat accumulates in the liver (liver steatosis or “fatty” liver). Cognitive decline may occur in some cases. Chanarin Dorfman syndrome is inherited as an autosomal recessive trait. (For more information on this disorder, choose “Chanarin Dorfman” as your search term in the Rare Disease Database.)There are several types of metabolic disorders in which secondary accumulation of certain fats (triglycerides) in the body. These disorders include galactosemia, fructose intolerance, and specific disorders of amino acid metabolism. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Related disorders of Wolman Disease. Symptoms of the following disorders can be similar to those of Wolman disease. Comparisons may be useful for a differential diagnosis.Cholesteryl ester storage disease (CESD) is a type of lysosomal acid lipase (LAL) deficiency; a rare genetic disorder characterized by a deficiency of the lysosomal acid lipase (LIPA or LAL) enzyme. This enzyme is essential for hydrolysis of triglycerides and cholesteryl esters in lysosomes. Deficiency of the LIPA enzyme causes accumulation of certain fatty substances (mucolipids) and certain complex carbohydrates (mucopolysaccharides) within the cells of many tissues of the body, potentially causing a variety of symptoms. In the liver, the consequences are abnormally enlarged liver (hepatomegaly) due to hepatic steatosis (fatty liver) and fibrosis that can lead to micronodular cirrhosis. Some individuals may not be diagnosed with CESD until adulthood. CESD is caused by mutations in the lysosomal acid lipase (LIPA) gene and is inherited as an autosomal recessive trait. (For more information on this disorder, choose “cholesteryl ester storage disease” as your search term in the Rare Disease Database.)Niemann-Pick disease (NPD) is a group of rare inherited disorders of fat metabolism. At least five types of Niemann-Pick disease have been identified (NPD types A, B, C, D, and E). Symptoms of types A and B occur as a result of a deficiency of the enzyme acid sphingomyelinase (ASM), which is needed to break down sphingomyelin, a fatty substance found mostly in the brain and nervous system. This deficiency results in abnormal accumulation of excessive amounts of sphingomyelin in many organs of the body such as the liver, spleen, and brain. Symptoms of type C occur because of impaired trafficking of large molecules within cells, which results in the accumulation of excessive amounts of cholesterol and other lipids (glycosphingolipids) tissues throughout the body. The metabolic defect in type C can lead to a secondary reduction in ASM activity in some cells. Symptoms common to all types of NPD include yellow discoloration of the skin, eyes, and/or mucous membranes (jaundice), progressive loss of motor skills, feeding difficulties, learning disabilities, and an abnormally enlarged liver and/or spleen (hepatosplenomegaly). The different types of NPD are inherited as autosomal recessive traits. (For more information on this disorder, choose “Niemann Pick” as your search term in the Rare Disease Database.)Chanarin Dorfman syndrome is a rare genetic disorder of fat (lipid) metabolism. It is characterized by scaly skin (ichthyosis), degeneration of the muscles (myopathy), and abnormal white blood cells with small spaces (vacuoles) filled with fat (lipids). Additional symptoms may occur including hearing loss, vision abnormalities, an enlarged liver (hepatomegaly) and a condition in which fat accumulates in the liver (liver steatosis or “fatty” liver). Cognitive decline may occur in some cases. Chanarin Dorfman syndrome is inherited as an autosomal recessive trait. (For more information on this disorder, choose “Chanarin Dorfman” as your search term in the Rare Disease Database.)There are several types of metabolic disorders in which secondary accumulation of certain fats (triglycerides) in the body. These disorders include galactosemia, fructose intolerance, and specific disorders of amino acid metabolism. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Diagnosis of Wolman Disease
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A diagnosis of Wolman disease may be suspected in newborn infants based upon identification of characteristic symptoms such as abnormally enlarged liver and gastrointestinal problems. A diagnosis may be confirmed by a thorough clinical evaluation, a detail patient history (including family history) and specialized tests that reveal absence or deficient activity of the enzyme lysosomal lipase acid (LIPA) in certain cells and tissues of the body. Molecular genetic testing for mutations in the LIPA gene is also available.
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Diagnosis of Wolman Disease. A diagnosis of Wolman disease may be suspected in newborn infants based upon identification of characteristic symptoms such as abnormally enlarged liver and gastrointestinal problems. A diagnosis may be confirmed by a thorough clinical evaluation, a detail patient history (including family history) and specialized tests that reveal absence or deficient activity of the enzyme lysosomal lipase acid (LIPA) in certain cells and tissues of the body. Molecular genetic testing for mutations in the LIPA gene is also available.
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Therapies of Wolman Disease
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TreatmentIn December 2015, the U.S. Food and Drug Administration (FDA) approved Kanuma (sebelipase alfa) as the first treatment for people with lysosomal acid lipase (LAL) deficiency.Other treatment is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Proper nutrition can be maintained intravenously. If the adrenal glands are not functioning properly, medications may be used to supplement the hormones normally produced by these glands.A team approach for individuals with Wolman disease may be necessary and may include special social support and other medical services. Genetic counseling is recommended for affected individuals and their families.
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Therapies of Wolman Disease. TreatmentIn December 2015, the U.S. Food and Drug Administration (FDA) approved Kanuma (sebelipase alfa) as the first treatment for people with lysosomal acid lipase (LAL) deficiency.Other treatment is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Proper nutrition can be maintained intravenously. If the adrenal glands are not functioning properly, medications may be used to supplement the hormones normally produced by these glands.A team approach for individuals with Wolman disease may be necessary and may include special social support and other medical services. Genetic counseling is recommended for affected individuals and their families.
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Overview of Wyburn-Mason Syndrome
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SummaryWyburn-Mason syndrome is a rare nonhereditary disorder that is present at birth (congenital). Affected infants have arteriovenous malformations (AVMs), which are developmental abnormalities affecting the blood vessels, specifically the arteries, veins and capillaries. Arteries typically carry oxygen-rich blood from the heart to body cells, while veins transport oxygen-deficient blood to the heart and lungs for the exchange of oxygen and carbon dioxide. The network of very tiny blood vessels (capillaries) that normally connects arteries and veins may be absent and the arteries and veins may be directly linked together forming a malformation. Without the capillaries, there can be damage to the walls of the arteries and veins, causing abnormal and high blood flow and leakage, and lack of blood flow further downstream. Larger AVMs may consist of a tangled mass of abnormal or malformed blood vessels (the nidus). AVMs associated with Wyburn-Mason syndrome are usually found in the eyes (retina) and brain. The exact cause of Wyburn-Mason syndrome is unknown, although it is hypothesized that during early development, the precursor cells to blood vessels have abnormal movement (migration) causing abnormal development later.IntroductionThe disorder is named for the investigator (Dr. R. Wyburn-Mason) who extensively described the disease entity in 1943. It is also referred to as Bonnet-Dechaume-Blanc syndrome after 3 investigators who identified AVMs in the face, retina and brain in 1937.Wyburn-Mason syndrome is sometimes grouped with the phakomatoses or neurocutaneous syndromes. This broad group of disorders is characterized by masses or tumors that may grow in the brain, spinal cord and other organs. In children, skin lesions are also prominent. Unlike other so-called phakomatoses, Wyburn-Mason syndrome rarely has skin abnormalities.
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Overview of Wyburn-Mason Syndrome. SummaryWyburn-Mason syndrome is a rare nonhereditary disorder that is present at birth (congenital). Affected infants have arteriovenous malformations (AVMs), which are developmental abnormalities affecting the blood vessels, specifically the arteries, veins and capillaries. Arteries typically carry oxygen-rich blood from the heart to body cells, while veins transport oxygen-deficient blood to the heart and lungs for the exchange of oxygen and carbon dioxide. The network of very tiny blood vessels (capillaries) that normally connects arteries and veins may be absent and the arteries and veins may be directly linked together forming a malformation. Without the capillaries, there can be damage to the walls of the arteries and veins, causing abnormal and high blood flow and leakage, and lack of blood flow further downstream. Larger AVMs may consist of a tangled mass of abnormal or malformed blood vessels (the nidus). AVMs associated with Wyburn-Mason syndrome are usually found in the eyes (retina) and brain. The exact cause of Wyburn-Mason syndrome is unknown, although it is hypothesized that during early development, the precursor cells to blood vessels have abnormal movement (migration) causing abnormal development later.IntroductionThe disorder is named for the investigator (Dr. R. Wyburn-Mason) who extensively described the disease entity in 1943. It is also referred to as Bonnet-Dechaume-Blanc syndrome after 3 investigators who identified AVMs in the face, retina and brain in 1937.Wyburn-Mason syndrome is sometimes grouped with the phakomatoses or neurocutaneous syndromes. This broad group of disorders is characterized by masses or tumors that may grow in the brain, spinal cord and other organs. In children, skin lesions are also prominent. Unlike other so-called phakomatoses, Wyburn-Mason syndrome rarely has skin abnormalities.
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Symptoms of Wyburn-Mason Syndrome
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The symptoms associated with Wyburn-Mason syndrome vary greatly among affected individuals based upon the specific number and location(s) of associated arteriovenous malformations. Affected infants may have abnormalities affecting the eyes, central nervous system and, in rare cases, the skin.In Wyburn-Mason syndrome, AVMs may range from absence of the capillaries to the presence of large masses of widened, twisted, tangled blood vessels known as a racemose hemangioma. Absence of capillaries results in the abnormal, direct connection of the arteries to the veins. This abnormal connection can result in excessive blood flow and subsequently inadequate blood flow (ischemia) further downstream.AVMs in Wyburn-Mason syndrome often affect the thin layer of nerve cells that lines the back of the eyes (retina). In some cases, an AVM may extend into the eye socket (orbit) or brain. The specific symptoms associated with an ocular AVM vary depending upon the exact location and extent the abnormality. Small AVMs affecting tiny blood vessels may not cause any symptoms (asymptomatic) and may be difficult to detect. Large AVMs such as a racemose hemangioma may cause significant loss of vision, usually from lack of blood flow to the retina (retinal ischemia).Additional eye abnormalities may occur in some individuals with Wyburn-Mason syndrome including pressure on the eyeball so that the eyes bulge forward (proptosis), drooping of the upper eyelid (blepharoptosis), difficulty moving the eyes (ocular motility disorders), abnormally widened (dilated) blood vessels of the thin membrane that covers the outer surface of the eye (conjunctiva), and nerve paralysis (palsies).AVMs of the central nervous system may not cause any symptoms (asymptomatic) or can cause severe symptoms. Although AVMs are present at birth, in many cases they may not cause symptoms until the second or third decade of life or even later. Neurological symptoms associated with Wyburn-Mason syndrome include severe headaches, vomiting, seizures, paralysis (palsy) of various cranial nerves and neck stiffness (nuchal rigidity). Spontaneous bleeding (hemorrhaging) of these lesions can lead to the sudden onset of symptoms. If the bleeding is severe, it can cause partial or full paralysis of one side of the body (hemiparesis or hemiplegia) or even death.In rare cases, the skin may be involved in Wyburn-Mason syndrome including the formation of small bumps or clusters of blood vessels (angiomas) on the face. If the jaw bones are involved, dental procedures can lead to excessive bleeding. Other areas of the body may also develop AVMs including the lungs or the kidneys or other bones and muscles.
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Symptoms of Wyburn-Mason Syndrome. The symptoms associated with Wyburn-Mason syndrome vary greatly among affected individuals based upon the specific number and location(s) of associated arteriovenous malformations. Affected infants may have abnormalities affecting the eyes, central nervous system and, in rare cases, the skin.In Wyburn-Mason syndrome, AVMs may range from absence of the capillaries to the presence of large masses of widened, twisted, tangled blood vessels known as a racemose hemangioma. Absence of capillaries results in the abnormal, direct connection of the arteries to the veins. This abnormal connection can result in excessive blood flow and subsequently inadequate blood flow (ischemia) further downstream.AVMs in Wyburn-Mason syndrome often affect the thin layer of nerve cells that lines the back of the eyes (retina). In some cases, an AVM may extend into the eye socket (orbit) or brain. The specific symptoms associated with an ocular AVM vary depending upon the exact location and extent the abnormality. Small AVMs affecting tiny blood vessels may not cause any symptoms (asymptomatic) and may be difficult to detect. Large AVMs such as a racemose hemangioma may cause significant loss of vision, usually from lack of blood flow to the retina (retinal ischemia).Additional eye abnormalities may occur in some individuals with Wyburn-Mason syndrome including pressure on the eyeball so that the eyes bulge forward (proptosis), drooping of the upper eyelid (blepharoptosis), difficulty moving the eyes (ocular motility disorders), abnormally widened (dilated) blood vessels of the thin membrane that covers the outer surface of the eye (conjunctiva), and nerve paralysis (palsies).AVMs of the central nervous system may not cause any symptoms (asymptomatic) or can cause severe symptoms. Although AVMs are present at birth, in many cases they may not cause symptoms until the second or third decade of life or even later. Neurological symptoms associated with Wyburn-Mason syndrome include severe headaches, vomiting, seizures, paralysis (palsy) of various cranial nerves and neck stiffness (nuchal rigidity). Spontaneous bleeding (hemorrhaging) of these lesions can lead to the sudden onset of symptoms. If the bleeding is severe, it can cause partial or full paralysis of one side of the body (hemiparesis or hemiplegia) or even death.In rare cases, the skin may be involved in Wyburn-Mason syndrome including the formation of small bumps or clusters of blood vessels (angiomas) on the face. If the jaw bones are involved, dental procedures can lead to excessive bleeding. Other areas of the body may also develop AVMs including the lungs or the kidneys or other bones and muscles.
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Causes of Wyburn-Mason Syndrome
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The exact cause of Wyburn-Mason syndrome is unknown. It is considered a developmental abnormality characterized by AVMs. No specific genetic abnormality or hereditary tendencies have been identified. The specific, underlying mechanism(s) that cause AVMs in Wyburn-Mason syndrome are not known. However, they are thought to result from abnormalities of blood vessel development during embryonic or fetal growth.
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Causes of Wyburn-Mason Syndrome. The exact cause of Wyburn-Mason syndrome is unknown. It is considered a developmental abnormality characterized by AVMs. No specific genetic abnormality or hereditary tendencies have been identified. The specific, underlying mechanism(s) that cause AVMs in Wyburn-Mason syndrome are not known. However, they are thought to result from abnormalities of blood vessel development during embryonic or fetal growth.
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Affects of Wyburn-Mason Syndrome
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Wyburn-Mason syndrome is an extremely rare disorder that appears to affect males and females in equal numbers. The incidence or prevalence rates of Wyburn-Mason syndrome in the general population are unknown, with less than 100 cases reported.
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Affects of Wyburn-Mason Syndrome. Wyburn-Mason syndrome is an extremely rare disorder that appears to affect males and females in equal numbers. The incidence or prevalence rates of Wyburn-Mason syndrome in the general population are unknown, with less than 100 cases reported.
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Related disorders of Wyburn-Mason Syndrome
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Comparisons with the following conditions may be useful for a differential diagnosis.Sturge-Weber syndrome is a rare inherited disorder characterized by the presence of a port wine colored birthmark (angioma) on the facial area and intracranial abnormalities that are present at birth (congenital). Affected infants may also have an enlarged head (macrocephaly). Generalized seizures and additional neurological symptoms usually occur between one and two years of age. Vascular lesions (telangiectasias and angiomas) in the brain usually involve the occipital or parieto-occipital regions. Glaucoma may be present in the eye located on the same side of the face where the port wine stain occurs. This eye may also be enlarged (buphthalmos). The iris color may be different between the two eyes (heterochromia). (For more information on this disorder, choose “Sturge Weber” as your search term in the Rare Disease Database.)Von Hippel-Lindau disease is an autosomal dominant condition characterized by multiple localized tissue malformations called hemangioblastomas and angiomas. These growths may be found in the retina, brain, kidneys, adrenal glands, and other organs. Symptoms may include headaches, dizziness and difficulty coordinating muscle movement (ataxia). Chronic high blood pressure (hypertension) can also occur. The disorder may begin during young adulthood or may develop during early childhood. Tumors (pheochromocytomas) of the adrenal glands may be present as well, causing chronic high blood pressure, pounding heartbeat, headache, cold hands and feet, and excessive sweating. This condition is found equally in males and females and can affect any ethnic group. (For more information on this disorder, choose “von Hippel Lindau” as your search term in the Rare Disease Database.)
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Related disorders of Wyburn-Mason Syndrome. Comparisons with the following conditions may be useful for a differential diagnosis.Sturge-Weber syndrome is a rare inherited disorder characterized by the presence of a port wine colored birthmark (angioma) on the facial area and intracranial abnormalities that are present at birth (congenital). Affected infants may also have an enlarged head (macrocephaly). Generalized seizures and additional neurological symptoms usually occur between one and two years of age. Vascular lesions (telangiectasias and angiomas) in the brain usually involve the occipital or parieto-occipital regions. Glaucoma may be present in the eye located on the same side of the face where the port wine stain occurs. This eye may also be enlarged (buphthalmos). The iris color may be different between the two eyes (heterochromia). (For more information on this disorder, choose “Sturge Weber” as your search term in the Rare Disease Database.)Von Hippel-Lindau disease is an autosomal dominant condition characterized by multiple localized tissue malformations called hemangioblastomas and angiomas. These growths may be found in the retina, brain, kidneys, adrenal glands, and other organs. Symptoms may include headaches, dizziness and difficulty coordinating muscle movement (ataxia). Chronic high blood pressure (hypertension) can also occur. The disorder may begin during young adulthood or may develop during early childhood. Tumors (pheochromocytomas) of the adrenal glands may be present as well, causing chronic high blood pressure, pounding heartbeat, headache, cold hands and feet, and excessive sweating. This condition is found equally in males and females and can affect any ethnic group. (For more information on this disorder, choose “von Hippel Lindau” as your search term in the Rare Disease Database.)
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Diagnosis of Wyburn-Mason Syndrome
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A diagnosis of Wyburn-Mason syndrome may be made based upon a thorough clinical evaluation, a detailed patient history, and identification of characteristic findings, especially ocular findings. Imaging studies such as a computed tomography (CT) scan or magnetic resonance imaging (MRI) may be performed to detect potentially dangerous central nervous system (CNS) malformations. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field to produce cross-sectional images of particular organs such as the brain. Dye (contrast) can be injected into blood vessels and X-ray images taken (cerebral angiogram) to see AVMs in the brain, or photos can be taken of the back of the eye (fluorescein angiogram) to detect the AVM in the eye. The combination of AVM in the brain and eye make the diagnosis of Wyburn Mason syndrome.
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Diagnosis of Wyburn-Mason Syndrome. A diagnosis of Wyburn-Mason syndrome may be made based upon a thorough clinical evaluation, a detailed patient history, and identification of characteristic findings, especially ocular findings. Imaging studies such as a computed tomography (CT) scan or magnetic resonance imaging (MRI) may be performed to detect potentially dangerous central nervous system (CNS) malformations. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field to produce cross-sectional images of particular organs such as the brain. Dye (contrast) can be injected into blood vessels and X-ray images taken (cerebral angiogram) to see AVMs in the brain, or photos can be taken of the back of the eye (fluorescein angiogram) to detect the AVM in the eye. The combination of AVM in the brain and eye make the diagnosis of Wyburn Mason syndrome.
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Therapies of Wyburn-Mason Syndrome
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Treatment
No specific treatment for Wyburn-Mason syndrome exists. Treatment is directed toward the specific symptoms that are apparent in each individual. Some AVMs may not require treatment, especially retinal lesions which usually remain stable. If lesions in the eyes cause bleeding (hemorrhaging) in the retina or the clear, jelly-like substance that fills the middle of the eye (vitreous), laser treatment or the use of extreme cold to destroy abnormal tissue (cryosurgery) may be performed in an attempt to control the bleeding. Surgical removal of the vitreous (vitrectomy) has been performed in some cases if bleeding is persistent, although surgery is controversial.
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Therapies of Wyburn-Mason Syndrome. Treatment
No specific treatment for Wyburn-Mason syndrome exists. Treatment is directed toward the specific symptoms that are apparent in each individual. Some AVMs may not require treatment, especially retinal lesions which usually remain stable. If lesions in the eyes cause bleeding (hemorrhaging) in the retina or the clear, jelly-like substance that fills the middle of the eye (vitreous), laser treatment or the use of extreme cold to destroy abnormal tissue (cryosurgery) may be performed in an attempt to control the bleeding. Surgical removal of the vitreous (vitrectomy) has been performed in some cases if bleeding is persistent, although surgery is controversial.
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Overview of X linked Lymphoproliferative Syndrome
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X-linked lymphoproliferative (XLP) syndrome is an extremely rare inherited (primary) immunodeficiency disorder characterized by a defective immune system that is powerfully responsive to infection with the Epstein-Barr virus (EBV). This virus is common among the general population and is relatively well-known because it is the cause of infectious mononucleosis (IM), usually with no long-lasting effects. However, in individuals with XLP, exposure to EBV may result in severe, life-threatening fulminant hepatitis; abnormally low levels of antibodies in the blood and body secretions (hypogammaglobulinemia), resulting in increased susceptibility to various infections; malignancies of certain types of lymphoid tissue (B-cell lymphomas); and/or other abnormalities. The range of symptoms and findings associated with XLP may vary considerably from case to case. In addition, the range of effects may change in an affected individual over time. In most cases, individuals with XLP experience an onset of symptoms anytime from ages about 6 months to 10 years of age.
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Overview of X linked Lymphoproliferative Syndrome. X-linked lymphoproliferative (XLP) syndrome is an extremely rare inherited (primary) immunodeficiency disorder characterized by a defective immune system that is powerfully responsive to infection with the Epstein-Barr virus (EBV). This virus is common among the general population and is relatively well-known because it is the cause of infectious mononucleosis (IM), usually with no long-lasting effects. However, in individuals with XLP, exposure to EBV may result in severe, life-threatening fulminant hepatitis; abnormally low levels of antibodies in the blood and body secretions (hypogammaglobulinemia), resulting in increased susceptibility to various infections; malignancies of certain types of lymphoid tissue (B-cell lymphomas); and/or other abnormalities. The range of symptoms and findings associated with XLP may vary considerably from case to case. In addition, the range of effects may change in an affected individual over time. In most cases, individuals with XLP experience an onset of symptoms anytime from ages about 6 months to 10 years of age.
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Symptoms of X linked Lymphoproliferative Syndrome
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X-linked lymphoproliferative syndrome (XLP), an extremely rare inherited disorder, is characterized by a range of symptoms and findings that occur due to a defective immune system response to infection with the Epstein-Barr virus (EBV). This virus is common among the general population and usually infects “silently,” causing no apparent symptoms (asymptomatic). In some other cases, particularly during adolescence, EBV infection may cause infectious mononucleosis (IM), usually with no long-lasting effects (benign, self-limited IM). However, males with XLP who are exposed to Epstein-Barr virus may develop severe, life-threatening hepatic (liver) form infectious mononucleosis and hepatitis, abnormally low levels of antibodies or immunoglobulins (hypogammaglobulinemia) in the blood and body secretions, malignancies of certain types of lymphoid tissue (B-cell lymphomas), or other abnormalities. Approximately half of individuals with X-linked lymphoproliferative syndrome experience severe, life-threatening mononucleosis characterized by fever, inflammation and soreness of the throat (pharyngitis), swollen lymph glands, enlargement of the spleen (splenomegaly), enlargement of the liver (hepatomegaly), and/or abnormal functioning of the liver, resulting in yellowing of the skin, mucous membranes, and whites of the eyes (jaundice or icterus). In some cases, individuals who experience life-threatening mononucleosis infection may subsequently have an abnormal increase (i.e., proliferation) of certain white blood cells (lymphocytes and histiocytes) in particular organs, severe liver damage and/or failure, damage to the blood-cell generating bone marrow (hematopoietic marrow cells) that may result in aplastic anemia, and/or other symptoms that may result in life-threatening complications in affected children or adults. Aplastic anemia is characterized by a marked deficiency of all types of blood cells (pancytopenia) including low levels of red blood cells, certain white blood cells, and platelets, specialized red blood cells that function to assist appropriate blood clotting. In individuals with XLP, a decrease in platelets (thrombocytopenia) results in increased susceptibility to bruising and excessive bleeding (hemorrhaging). Because X-linked lymphoproliferative syndrome is inherited as an X-linked recessive genetic trait, the disorder is usually fully expressed in males only.X-linked lymphoproliferative syndrome is considered a rare primary immunodeficiency disorder; one of a group of disorders characterized by irregularities in the cell development and/or cell maturation process of the immune system. The immune system is divided into several components, the combined actions of which are responsible for defending against different infectious agents (i.e., invading microscopic life-forms). The T-cell system (cell-mediated immune response) is responsible for fighting yeast and fungi, several viruses, and some bacteria. The B-cell system (humoral immune response) fights infection caused by other viruses and bacteria by secreting immune factors called antibodies or immunoglobulins into the blood and body secretions (e.g., saliva). Antibodies can kill microorganisms or “coat” them so they are more easily destroyed by certain white blood cells. White blood cells (leukocytes) are part of the body's immune system, playing an essential role in protecting against infection as well as fighting infection once it occurs. In addition, antibodies are produced following vaccination, providing protection from infectious diseases like polio, measles, and tetanus. The immune deficiency in XLP affects both T-cell and B-cell immune responses and therefore is classified as a “combined immunodeficiency.”According to the medical literature, either directly after EBV exposure or following infectious mononucleosis, approximately one third of males with XLP may begin to exhibit abnormally low levels of antibodies (immunoglobulins) in the blood and body secretions (acquired hypogammaglobulinemia). As with bone marrow suppression, low levels of protective antibodies in the blood and body secretions may result in an increased susceptibility to various “opportunistic” infections.In addition, approximately one fourth of males with XLP may develop malignancies of certain types of lymphoid tissue (B-cell lymphomas) subsequent to EBV exposure or development of infectious mononucleosis. Such lymphomas are characterized by malignant transformation of abnormally proliferating B cells. Burkitt's Lymphoma involving the area where the small intestine joins the large intestine (ileocecal area) is the most commonly reported B-cell lymphoma among affected males. Symptoms and findings associated with Burkitt's Lymphoma involving the intestines may include abdominal swelling (distention) and discomfort, impaired absorption of nutrients by the gastrointestinal (GI) tract (malabsorption), nausea, vomiting, changes in bowel habits, weakness, and/or weight loss.
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Symptoms of X linked Lymphoproliferative Syndrome. X-linked lymphoproliferative syndrome (XLP), an extremely rare inherited disorder, is characterized by a range of symptoms and findings that occur due to a defective immune system response to infection with the Epstein-Barr virus (EBV). This virus is common among the general population and usually infects “silently,” causing no apparent symptoms (asymptomatic). In some other cases, particularly during adolescence, EBV infection may cause infectious mononucleosis (IM), usually with no long-lasting effects (benign, self-limited IM). However, males with XLP who are exposed to Epstein-Barr virus may develop severe, life-threatening hepatic (liver) form infectious mononucleosis and hepatitis, abnormally low levels of antibodies or immunoglobulins (hypogammaglobulinemia) in the blood and body secretions, malignancies of certain types of lymphoid tissue (B-cell lymphomas), or other abnormalities. Approximately half of individuals with X-linked lymphoproliferative syndrome experience severe, life-threatening mononucleosis characterized by fever, inflammation and soreness of the throat (pharyngitis), swollen lymph glands, enlargement of the spleen (splenomegaly), enlargement of the liver (hepatomegaly), and/or abnormal functioning of the liver, resulting in yellowing of the skin, mucous membranes, and whites of the eyes (jaundice or icterus). In some cases, individuals who experience life-threatening mononucleosis infection may subsequently have an abnormal increase (i.e., proliferation) of certain white blood cells (lymphocytes and histiocytes) in particular organs, severe liver damage and/or failure, damage to the blood-cell generating bone marrow (hematopoietic marrow cells) that may result in aplastic anemia, and/or other symptoms that may result in life-threatening complications in affected children or adults. Aplastic anemia is characterized by a marked deficiency of all types of blood cells (pancytopenia) including low levels of red blood cells, certain white blood cells, and platelets, specialized red blood cells that function to assist appropriate blood clotting. In individuals with XLP, a decrease in platelets (thrombocytopenia) results in increased susceptibility to bruising and excessive bleeding (hemorrhaging). Because X-linked lymphoproliferative syndrome is inherited as an X-linked recessive genetic trait, the disorder is usually fully expressed in males only.X-linked lymphoproliferative syndrome is considered a rare primary immunodeficiency disorder; one of a group of disorders characterized by irregularities in the cell development and/or cell maturation process of the immune system. The immune system is divided into several components, the combined actions of which are responsible for defending against different infectious agents (i.e., invading microscopic life-forms). The T-cell system (cell-mediated immune response) is responsible for fighting yeast and fungi, several viruses, and some bacteria. The B-cell system (humoral immune response) fights infection caused by other viruses and bacteria by secreting immune factors called antibodies or immunoglobulins into the blood and body secretions (e.g., saliva). Antibodies can kill microorganisms or “coat” them so they are more easily destroyed by certain white blood cells. White blood cells (leukocytes) are part of the body's immune system, playing an essential role in protecting against infection as well as fighting infection once it occurs. In addition, antibodies are produced following vaccination, providing protection from infectious diseases like polio, measles, and tetanus. The immune deficiency in XLP affects both T-cell and B-cell immune responses and therefore is classified as a “combined immunodeficiency.”According to the medical literature, either directly after EBV exposure or following infectious mononucleosis, approximately one third of males with XLP may begin to exhibit abnormally low levels of antibodies (immunoglobulins) in the blood and body secretions (acquired hypogammaglobulinemia). As with bone marrow suppression, low levels of protective antibodies in the blood and body secretions may result in an increased susceptibility to various “opportunistic” infections.In addition, approximately one fourth of males with XLP may develop malignancies of certain types of lymphoid tissue (B-cell lymphomas) subsequent to EBV exposure or development of infectious mononucleosis. Such lymphomas are characterized by malignant transformation of abnormally proliferating B cells. Burkitt's Lymphoma involving the area where the small intestine joins the large intestine (ileocecal area) is the most commonly reported B-cell lymphoma among affected males. Symptoms and findings associated with Burkitt's Lymphoma involving the intestines may include abdominal swelling (distention) and discomfort, impaired absorption of nutrients by the gastrointestinal (GI) tract (malabsorption), nausea, vomiting, changes in bowel habits, weakness, and/or weight loss.
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X linked Lymphoproliferative Syndrome
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Causes of X linked Lymphoproliferative Syndrome
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X-linked lymphoproliferative syndrome (XLP) is inherited as an X-linked recessive genetic trait. The gene map location of the altered (mutated) has been tracked to a site at Xq25. The genetic trait is transmitted in an X-linked recessive mode as a result of which it is nearly always fatal to the male fetus or to male babies. Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome Xq25” refers to band 25 on the long arm of the X chromosome. The numbered bands specify the location of the thousands of genes that are present on each chromosome.Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. All individuals carry 4-5 abnormal genes. Parents who are close relatives (consan-guineous) 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. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females have two X chromosomes but one of the X chromosomes is “turned off” and all of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder because it is usually the X chromosome with the abnormal gene that is “turned off”. A male has one X chromosome and if he inherits an X chromosome that contains a disease gene, he will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers. 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. The gene responsible for XLP is called “SH2D1A.” Certain abnormal changes (mutations) in or deletions of material from the gene may result in X-linked lymphoproliferative syndrome in affected individuals. Researchers have determined that the gene encodes a unique protein called “SAP” that regulates another protein known as “SLAM.” SLAM, which stands for “signaling lymphocyte activation molecule,” controls communication between B cells and T cells. It is suspected that, in individuals with XLP, uncontrolled functioning of the SLAM protein causes improper communication between these immune cells, resulting in an abnormal immune response following EBV infection. There have been a few reports in the medical literature in which females have symptoms and physical findings that appear very similar to those seen in males with XLP. In such cases, the underlying genetic and immunological causes are not known and are under investigation. Therefore, the implications of such findings are not yet understood.
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Causes of X linked Lymphoproliferative Syndrome. X-linked lymphoproliferative syndrome (XLP) is inherited as an X-linked recessive genetic trait. The gene map location of the altered (mutated) has been tracked to a site at Xq25. The genetic trait is transmitted in an X-linked recessive mode as a result of which it is nearly always fatal to the male fetus or to male babies. Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome Xq25” refers to band 25 on the long arm of the X chromosome. The numbered bands specify the location of the thousands of genes that are present on each chromosome.Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. All individuals carry 4-5 abnormal genes. Parents who are close relatives (consan-guineous) 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. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females have two X chromosomes but one of the X chromosomes is “turned off” and all of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder because it is usually the X chromosome with the abnormal gene that is “turned off”. A male has one X chromosome and if he inherits an X chromosome that contains a disease gene, he will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers. 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. The gene responsible for XLP is called “SH2D1A.” Certain abnormal changes (mutations) in or deletions of material from the gene may result in X-linked lymphoproliferative syndrome in affected individuals. Researchers have determined that the gene encodes a unique protein called “SAP” that regulates another protein known as “SLAM.” SLAM, which stands for “signaling lymphocyte activation molecule,” controls communication between B cells and T cells. It is suspected that, in individuals with XLP, uncontrolled functioning of the SLAM protein causes improper communication between these immune cells, resulting in an abnormal immune response following EBV infection. There have been a few reports in the medical literature in which females have symptoms and physical findings that appear very similar to those seen in males with XLP. In such cases, the underlying genetic and immunological causes are not known and are under investigation. Therefore, the implications of such findings are not yet understood.
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X linked Lymphoproliferative Syndrome
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Affects of X linked Lymphoproliferative Syndrome
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X-linked lymphoproliferative syndrome is an extremely rare disorder that is usually fully expressed in males only. About 400± cases affecting males in more than 80 multigenerational families (kindreds) from several different countries have been reported in the medical literature. Researchers estimate that approximately one to two in every one million males are affected by XLP.
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Affects of X linked Lymphoproliferative Syndrome. X-linked lymphoproliferative syndrome is an extremely rare disorder that is usually fully expressed in males only. About 400± cases affecting males in more than 80 multigenerational families (kindreds) from several different countries have been reported in the medical literature. Researchers estimate that approximately one to two in every one million males are affected by XLP.
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Related disorders of X linked Lymphoproliferative Syndrome
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Symptoms of the following disorders may be similar to those of X-linked lymphoproliferative syndrome. Comparisons may be useful for a differential diagnosis: There are additional congenital disorders that may be characterized by impairment of the T-lymphocyte and/or B-lymphocyte systems, resulting in abnormally low levels of antibodies or immunoglobulins (hypogamma-globulinemia) in the blood and body secretions, increased susceptibility to certain infections such as severe infection with Epstein-Barr virus, liver dysfunction, aplastic anemia, and/or other symptoms and findings similar to those occurring in association with X-linked lymphoproliferative syndrome. Such disorders usually have other physical features that may differentiate them from XLP. (For more information on these disorders, choose the disease name in question as your search term in the Rare Disease Database.)
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Related disorders of X linked Lymphoproliferative Syndrome. Symptoms of the following disorders may be similar to those of X-linked lymphoproliferative syndrome. Comparisons may be useful for a differential diagnosis: There are additional congenital disorders that may be characterized by impairment of the T-lymphocyte and/or B-lymphocyte systems, resulting in abnormally low levels of antibodies or immunoglobulins (hypogamma-globulinemia) in the blood and body secretions, increased susceptibility to certain infections such as severe infection with Epstein-Barr virus, liver dysfunction, aplastic anemia, and/or other symptoms and findings similar to those occurring in association with X-linked lymphoproliferative syndrome. Such disorders usually have other physical features that may differentiate them from XLP. (For more information on these disorders, choose the disease name in question as your search term in the Rare Disease Database.)
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X linked Lymphoproliferative Syndrome
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Diagnosis of X linked Lymphoproliferative Syndrome
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Because gene mutations that cause X-linked lymphoproliferative syndrome (XLP) have been identified, precise genetic testing may now be possible. However, such testing may only be available through research laboratories with a special interest in this disease.Therefore, in many cases, XLP is diagnosed when affected males become symptomatic, which is typically anytime from approximately six months to 10 years of age. Diagnosis of X-linked lymphoproliferative syndrome may be based upon a thorough clinical evaluation, identification of characteristic physical findings, a detailed patient and family history, and a pattern of immune system defects detected by specialized laboratory testing on blood from affected individuals. Diagnosis is most easily established when a clear family history is present.In individuals with severe infectious mononucleosis or fulminant hepatitis, specialized imaging tests may reveal abnormal enlargement of the liver and spleen (hepatosplenomegaly) and/or other findings. After EBV exposure or following infectious mononucleosis, specialized laboratory tests may reveal abnormally high concentrations of certain lymphocytes in the blood (lymphocytosis), deficient or absent antibody response to EBV antigens (e.g., EBV nuclear antigen), and, in some cases, abnormally low levels of all classes of immunoglobulins (acquired hypogammaglobulinemia) in the blood and body secretions. In some affected individuals, laboratory testing may also reveal abnormal liver function and/or a marked deficiency of all types of blood cells (pancytopenia), suggesting aplastic anemia. In some cases, specialized laboratory and imaging tests may also reveal additional findings associated with XLP.According to the medical literature, in families with males affected by X-linked lymphoproliferative syndrome, other male family members who have not yet been exposed to EBV (EBV seronegative) should be considered at risk for XLP. Because exposure to EBV may result in life-threatening complications in those with the disorder, it is essential that a diagnosis of XLP be confirmed or excluded in such family members before EBV exposure occurs.In addition, if males are diagnosed with Burkitt's Lymphoma involving the area where the small intestine joins the large intestine (i.e., the ileocecal area), they and their male family members should receive testing for XLP. If XLP is confirmed, carrier testing may also be considered for female family members.
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Diagnosis of X linked Lymphoproliferative Syndrome. Because gene mutations that cause X-linked lymphoproliferative syndrome (XLP) have been identified, precise genetic testing may now be possible. However, such testing may only be available through research laboratories with a special interest in this disease.Therefore, in many cases, XLP is diagnosed when affected males become symptomatic, which is typically anytime from approximately six months to 10 years of age. Diagnosis of X-linked lymphoproliferative syndrome may be based upon a thorough clinical evaluation, identification of characteristic physical findings, a detailed patient and family history, and a pattern of immune system defects detected by specialized laboratory testing on blood from affected individuals. Diagnosis is most easily established when a clear family history is present.In individuals with severe infectious mononucleosis or fulminant hepatitis, specialized imaging tests may reveal abnormal enlargement of the liver and spleen (hepatosplenomegaly) and/or other findings. After EBV exposure or following infectious mononucleosis, specialized laboratory tests may reveal abnormally high concentrations of certain lymphocytes in the blood (lymphocytosis), deficient or absent antibody response to EBV antigens (e.g., EBV nuclear antigen), and, in some cases, abnormally low levels of all classes of immunoglobulins (acquired hypogammaglobulinemia) in the blood and body secretions. In some affected individuals, laboratory testing may also reveal abnormal liver function and/or a marked deficiency of all types of blood cells (pancytopenia), suggesting aplastic anemia. In some cases, specialized laboratory and imaging tests may also reveal additional findings associated with XLP.According to the medical literature, in families with males affected by X-linked lymphoproliferative syndrome, other male family members who have not yet been exposed to EBV (EBV seronegative) should be considered at risk for XLP. Because exposure to EBV may result in life-threatening complications in those with the disorder, it is essential that a diagnosis of XLP be confirmed or excluded in such family members before EBV exposure occurs.In addition, if males are diagnosed with Burkitt's Lymphoma involving the area where the small intestine joins the large intestine (i.e., the ileocecal area), they and their male family members should receive testing for XLP. If XLP is confirmed, carrier testing may also be considered for female family members.
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X linked Lymphoproliferative Syndrome
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Therapies of X linked Lymphoproliferative Syndrome
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TreatmentThe treatment of X-linked lymphoproliferative syndrome may require the coordinated efforts of a team of specialists who need to plan, systematically and comprehensively, an affected individual's treatment. Such specialists may include pediatricians and/or internists, specialists in the functioning of the immune system (immunologists), physicians specializing in the diagnosis and treatment of blood disorders (hematologists) or cancers (oncologists), and/or other health care specialists.Because of the life-threatening implications of this disorder, it is important to identify those males with XLP as soon as possible. If affected individuals are identified before EBV exposure, infusion with immunoglobulins (intravenous gammaglobulin) with EBV antibodies may be recommended to help prevent life-threatening infectious mononucleosis and the onset of other symptoms and findings potentially associated with XLP.In affected individuals who are diagnosed with XLP subsequent to EBV exposure, treatment may include therapies to help prevent opportunistic infections associated with XLP such as the administration of antibiotic medications (prophylactic antibiotic therapy) and/or intravenous gammaglobulin therapy.Affected individuals who develop B-cell lymphoma such as Burkitt's lymphoma may be treated with surgery, radiation, and/or chemotherapy.Genetic counseling will be of benefit for affected males and their family members. Other treatment is symptomatic and supportive.
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Therapies of X linked Lymphoproliferative Syndrome. TreatmentThe treatment of X-linked lymphoproliferative syndrome may require the coordinated efforts of a team of specialists who need to plan, systematically and comprehensively, an affected individual's treatment. Such specialists may include pediatricians and/or internists, specialists in the functioning of the immune system (immunologists), physicians specializing in the diagnosis and treatment of blood disorders (hematologists) or cancers (oncologists), and/or other health care specialists.Because of the life-threatening implications of this disorder, it is important to identify those males with XLP as soon as possible. If affected individuals are identified before EBV exposure, infusion with immunoglobulins (intravenous gammaglobulin) with EBV antibodies may be recommended to help prevent life-threatening infectious mononucleosis and the onset of other symptoms and findings potentially associated with XLP.In affected individuals who are diagnosed with XLP subsequent to EBV exposure, treatment may include therapies to help prevent opportunistic infections associated with XLP such as the administration of antibiotic medications (prophylactic antibiotic therapy) and/or intravenous gammaglobulin therapy.Affected individuals who develop B-cell lymphoma such as Burkitt's lymphoma may be treated with surgery, radiation, and/or chemotherapy.Genetic counseling will be of benefit for affected males and their family members. Other treatment is symptomatic and supportive.
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X linked Lymphoproliferative Syndrome
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Overview of X-Linked Adrenoleukodystrophy
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Summary
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Overview of X-Linked Adrenoleukodystrophy. Summary
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X-Linked Adrenoleukodystrophy
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Symptoms of X-Linked Adrenoleukodystrophy
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The signs and symptoms of can vary widely, even among members of the same family. Some individuals have serious complications in infancy or childhood while others develop symptoms as adults. Some individuals do not develop symptoms (asymptomatic) until adulthood. The progression of the disorder can also vary. There are different forms of ALD.Childhood Cerebral ALD
35% of affected males develop neurological symptoms between three and ten years of age. It almost never occurs before approximately two and a half to three years of age. Affected males will develop normally and then start to show a loss (regression) of previously acquired skills. Before the loss of skills, affected males may exhibit behavioral problems including attention deficit and hyperactivity disorder (ADHD) and learning disabilities. Affected individuals usually develop cognitive deficits which means that they may have impairment of their mental processes and have difficulty acquiring information and knowledge. This means affected children may show a decline in performance at school. They may “space out” in school or at various times, have difficulty understanding speech, difficulty reading or understanding written words, difficulty with spatial references, and show a deterioration in handwriting skills.Later on, they will develop additional symptoms including diminished clarity of vision (diminished visual acuity), hearing loss, gait difficulty, and eventually weakness and stiffness of limbs, convulsions or seizures. Eventually, affected children loose most neurological function and become totally disabled with blindness, deafness and inability to move voluntarily. The disorder will further progress to result in a vegetative state and death typically within 2-3 years from onset of neurological symptoms.Addison’s Disease
Affected males may also have adrenal insufficiency. The adrenal glands are located on top of the kidneys and produce two hormones called cortisol and aldosterone. Other hormones produced by the adrenal glands help to regulate the fluid and electrolyte balance in the body. When the adrenal glands fail to produce these hormones the term primary adrenal insufficiency is used. Symptoms can include fatigue, unintended weight loss, nausea, vomiting, gastrointestinal issues, weakness, morning headaches, low blood pressure (hypotension), and low blood sugar levels (hypoglycemia). These symptoms are reminiscent of Addison’s disease. Many affected males may develop tanning of skin including areas not exposed to sunlight (hyperpigmented skin).Adrenomyeloneuropathy (AMN)
Adrenomyeloneuropathy is a specific form of ALD characterized by onset in the late 20s to middle ages in affected men. It eventually affects almost all males who do not present in childhood. Initial symptoms are usually progressive stiffness and weakness in the legs (spastic paraparesis). Affected men may develop problems walking or walk in an unusual manner (abnormal gait). Numbness and pain from polyneuropathy are also common symptoms. Polyneuropathy is a general term for degeneration of the peripheral nerves, which are the nerves outside of the brain and spinal cord (i.e. central nervous system).Affected men may also exhibit erectile dysfunction and problems with bowel and bladder control due to sphincter dysfunction. Sphincters are muscles which control the narrowing or widening certain passageways in the body. The urinary sphincters are two muscles that control the passage of urine from the bladder through the tiny tube that carries urine out of the body (urethra). Poor control of the urinary sphincter leads to urinary dysfunction. In addition, many men also develop premature balding and thinning of hair.Adult Cerebral ALD
At least 20 percent of all affected men develop cognitive decline similar to that seen in boys with childhood cerebral forms. These patients develop progressive neurological symptoms similar to childhood cerebral ALD and typically result in severe neurological impairment, and eventually vegetative state or death.Addison’s-only ALD
In a small percentage of people, adrenocortical insufficiency reminiscent of Addison’s disease may be the only symptom. Sometimes, these individuals are said to have Addison’s-only ALD; they account for about 10% of people with ALD. Most of these individuals eventually develop additional symptoms during middle-age, although adrenal insufficiency may develop years or often decades before neurological problems.Women with ALD
Women who are carriers (see Causes section below) for ALD often develop adrenomyeloenuropathy in adulthood although the symptoms are often less severe compared to males.Approximately 20% of female ALD carriers under 40 develop symptoms. By the age of 60 that percentage reaches about 90%. Adrenal insufficiency and involvement of the brain are rare in women, but can occur.
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Symptoms of X-Linked Adrenoleukodystrophy. The signs and symptoms of can vary widely, even among members of the same family. Some individuals have serious complications in infancy or childhood while others develop symptoms as adults. Some individuals do not develop symptoms (asymptomatic) until adulthood. The progression of the disorder can also vary. There are different forms of ALD.Childhood Cerebral ALD
35% of affected males develop neurological symptoms between three and ten years of age. It almost never occurs before approximately two and a half to three years of age. Affected males will develop normally and then start to show a loss (regression) of previously acquired skills. Before the loss of skills, affected males may exhibit behavioral problems including attention deficit and hyperactivity disorder (ADHD) and learning disabilities. Affected individuals usually develop cognitive deficits which means that they may have impairment of their mental processes and have difficulty acquiring information and knowledge. This means affected children may show a decline in performance at school. They may “space out” in school or at various times, have difficulty understanding speech, difficulty reading or understanding written words, difficulty with spatial references, and show a deterioration in handwriting skills.Later on, they will develop additional symptoms including diminished clarity of vision (diminished visual acuity), hearing loss, gait difficulty, and eventually weakness and stiffness of limbs, convulsions or seizures. Eventually, affected children loose most neurological function and become totally disabled with blindness, deafness and inability to move voluntarily. The disorder will further progress to result in a vegetative state and death typically within 2-3 years from onset of neurological symptoms.Addison’s Disease
Affected males may also have adrenal insufficiency. The adrenal glands are located on top of the kidneys and produce two hormones called cortisol and aldosterone. Other hormones produced by the adrenal glands help to regulate the fluid and electrolyte balance in the body. When the adrenal glands fail to produce these hormones the term primary adrenal insufficiency is used. Symptoms can include fatigue, unintended weight loss, nausea, vomiting, gastrointestinal issues, weakness, morning headaches, low blood pressure (hypotension), and low blood sugar levels (hypoglycemia). These symptoms are reminiscent of Addison’s disease. Many affected males may develop tanning of skin including areas not exposed to sunlight (hyperpigmented skin).Adrenomyeloneuropathy (AMN)
Adrenomyeloneuropathy is a specific form of ALD characterized by onset in the late 20s to middle ages in affected men. It eventually affects almost all males who do not present in childhood. Initial symptoms are usually progressive stiffness and weakness in the legs (spastic paraparesis). Affected men may develop problems walking or walk in an unusual manner (abnormal gait). Numbness and pain from polyneuropathy are also common symptoms. Polyneuropathy is a general term for degeneration of the peripheral nerves, which are the nerves outside of the brain and spinal cord (i.e. central nervous system).Affected men may also exhibit erectile dysfunction and problems with bowel and bladder control due to sphincter dysfunction. Sphincters are muscles which control the narrowing or widening certain passageways in the body. The urinary sphincters are two muscles that control the passage of urine from the bladder through the tiny tube that carries urine out of the body (urethra). Poor control of the urinary sphincter leads to urinary dysfunction. In addition, many men also develop premature balding and thinning of hair.Adult Cerebral ALD
At least 20 percent of all affected men develop cognitive decline similar to that seen in boys with childhood cerebral forms. These patients develop progressive neurological symptoms similar to childhood cerebral ALD and typically result in severe neurological impairment, and eventually vegetative state or death.Addison’s-only ALD
In a small percentage of people, adrenocortical insufficiency reminiscent of Addison’s disease may be the only symptom. Sometimes, these individuals are said to have Addison’s-only ALD; they account for about 10% of people with ALD. Most of these individuals eventually develop additional symptoms during middle-age, although adrenal insufficiency may develop years or often decades before neurological problems.Women with ALD
Women who are carriers (see Causes section below) for ALD often develop adrenomyeloenuropathy in adulthood although the symptoms are often less severe compared to males.Approximately 20% of female ALD carriers under 40 develop symptoms. By the age of 60 that percentage reaches about 90%. Adrenal insufficiency and involvement of the brain are rare in women, but can occur.
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Causes of X-Linked Adrenoleukodystrophy
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ALD is caused by a variation (mutation) in the ABCD1 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.The ABCD1 gene contains instructions for creating a protein called X-linked adrenoleukodystrophy protein or ALDP. This is a transporter protein; it helps to transport fat molecules called very long-chain fatty acids into structures called peroxisomes. Peroxisomes are small membrane-bound structures or sacs within the gel-like fluid (cytoplasm) of cells that play a vital role in numerous biochemical processes in the body. Very long-chain fatty acids are then broken down (metabolized). Because these is a deficiency of ALDP, the transport and, ultimately, the breakdown of very long-chain fatty acids are disrupted and, consequently, these fatty molecules build up in the tissues of the body. Two specific areas affected are the myelin of nerve cells and the adrenal cortex. Originally, it was believed that these fatty molecules were directly toxic to brain tissue. However, some research suggests that the abnormal accumulation of very long-chain fatty acids in the brain sets off an inflammatory response by the immune system that damages the myelin leading to the neurological symptoms associated with x-linked adrenoleukodystrophy.In the adrenal cortex, abnormal accumulation of very long-chain fatty acids is associated with dying of the hormone producing cells while the exact mechanism are not yet known. It is also possible that damage to adrenal cortex results from an abnormal immune system response to fatty accumulation.X-linked genetic disorders are caused by an abnormal gene on the X chromosome. Females have two X chromosomes but one of the X chromosomes is “turned off” and all of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder because it is usually the X chromosome with the abnormal gene that is “turned off.” A male has one X-chromosome and if he inherits an X chromosome that contains a disease gene, he will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers if the other X chromosome from their mother is normal. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease, and a 25% chance to have an unaffected son.In some females, known as heterozygotes, who inherit a single copy of the disease gene for ALD, disease traits on the X chromosome may not always be masked by the normal gene on the other X chromosome. As a result, these females may exhibit symptoms associated with ALD.
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Causes of X-Linked Adrenoleukodystrophy. ALD is caused by a variation (mutation) in the ABCD1 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.The ABCD1 gene contains instructions for creating a protein called X-linked adrenoleukodystrophy protein or ALDP. This is a transporter protein; it helps to transport fat molecules called very long-chain fatty acids into structures called peroxisomes. Peroxisomes are small membrane-bound structures or sacs within the gel-like fluid (cytoplasm) of cells that play a vital role in numerous biochemical processes in the body. Very long-chain fatty acids are then broken down (metabolized). Because these is a deficiency of ALDP, the transport and, ultimately, the breakdown of very long-chain fatty acids are disrupted and, consequently, these fatty molecules build up in the tissues of the body. Two specific areas affected are the myelin of nerve cells and the adrenal cortex. Originally, it was believed that these fatty molecules were directly toxic to brain tissue. However, some research suggests that the abnormal accumulation of very long-chain fatty acids in the brain sets off an inflammatory response by the immune system that damages the myelin leading to the neurological symptoms associated with x-linked adrenoleukodystrophy.In the adrenal cortex, abnormal accumulation of very long-chain fatty acids is associated with dying of the hormone producing cells while the exact mechanism are not yet known. It is also possible that damage to adrenal cortex results from an abnormal immune system response to fatty accumulation.X-linked genetic disorders are caused by an abnormal gene on the X chromosome. Females have two X chromosomes but one of the X chromosomes is “turned off” and all of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder because it is usually the X chromosome with the abnormal gene that is “turned off.” A male has one X-chromosome and if he inherits an X chromosome that contains a disease gene, he will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers if the other X chromosome from their mother is normal. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease, and a 25% chance to have an unaffected son.In some females, known as heterozygotes, who inherit a single copy of the disease gene for ALD, disease traits on the X chromosome may not always be masked by the normal gene on the other X chromosome. As a result, these females may exhibit symptoms associated with ALD.
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Affects of X-Linked Adrenoleukodystrophy
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The prevalence of ALD is estimated to be between 1 in 10,000 and 1 in 17,000 individuals in the general population. Prevalence refers to the number of people in the general population who have a disorder at any given time. Rare disorders like ALD often go undiagnosed or misdiagnosed making it difficult to determine the true frequency of the disorder in the general population. The condition occurs throughout the world in all ethnic groups.
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Affects of X-Linked Adrenoleukodystrophy. The prevalence of ALD is estimated to be between 1 in 10,000 and 1 in 17,000 individuals in the general population. Prevalence refers to the number of people in the general population who have a disorder at any given time. Rare disorders like ALD often go undiagnosed or misdiagnosed making it difficult to determine the true frequency of the disorder in the general population. The condition occurs throughout the world in all ethnic groups.
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Related disorders of X-Linked Adrenoleukodystrophy
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Symptoms of the following disorders can be similar to those of ALD. Comparisons may be useful for a differential diagnosis. Specific differential diagnoses depend upon the specific form of ALD. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)Childhood cerebral ALD needs to be differentiated from others form of leukodystrophy such as Krabbe disease or arylsulfatase A deficiency, Lyme disease, multiple sclerosis, attention deficit hyperactivity disorder, and various brain tumors. Adrenomyeloneuropathy needs to be differentiated from multiple sclerosis, hereditary spastic paraplegia, amyotrophic lateral sclerosis, and spinal cord tumors.
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Related disorders of X-Linked Adrenoleukodystrophy. Symptoms of the following disorders can be similar to those of ALD. Comparisons may be useful for a differential diagnosis. Specific differential diagnoses depend upon the specific form of ALD. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)Childhood cerebral ALD needs to be differentiated from others form of leukodystrophy such as Krabbe disease or arylsulfatase A deficiency, Lyme disease, multiple sclerosis, attention deficit hyperactivity disorder, and various brain tumors. Adrenomyeloneuropathy needs to be differentiated from multiple sclerosis, hereditary spastic paraplegia, amyotrophic lateral sclerosis, and spinal cord tumors.
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Diagnosis of X-Linked Adrenoleukodystrophy
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A diagnosis of ALD is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests.Some infants may be diagnosed through newborn screening. Newborn screening is a special type of screening test that newborns receive to see if they have certain diseases. This screening is primarily done through the examination of dried blood spots. Because the newborn screen is a screening test, a positive result does not mean that an infant definitely has a disease. Often, a repeat test must be done to confirm the diagnosis. If a newborn screen is positive, then a genetic test may be ordered to identify the specific gene change (mutation) that causes ALD.In 2016, ALD was added to the Recommended Uniform Newborn Screening Panel (RUSP) in the United States. However, each state determines what specific disorders are included in its newborn screening program within that state. As of October 2019, only a dozen of states test for ALD through newborn screening, although more states are planning on adding the disorder to testing programs.Clinical Testing and Workup
The initial diagnostic test is usually a blood test to measure the levels of very long-chain fatty acids in the blood plasma. If these levels are notably high or if the ratio of these fatty molecules in the blood is off, physicians will order genetic testing to confirm a diagnosis. Some women who are carriers for ALD can have normal levels of very long-chain fatty acids in the blood. Women who are suspected of having the disorder may require genetic testing to definitely rule out the diagnosis.Molecular genetic testing can confirm a diagnosis. Molecular genetic testing can detect mutations in the ABCD1 gene known to cause ALD, but is available only as a diagnostic service at specialized laboratories.Physicians will also test the function of the adrenal glands through a test called ACTH stimulation test. ACTH stands for adrenocorticotropic hormone and is produced by the pituitary gland. An increase in the concentration of ACTH leads to an increase in the production of adrenal hormones. Specifically, there should be a rise in cortisol in the blood plasma.A specialized imaging technique called magnetic resonance imaging (MRI) may be recommended to assess how ALD has affected the brain. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues including the brain. This allows physicians to see whether the brain has been damaged, including the loss of myelin in the cerebral white matter.
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Diagnosis of X-Linked Adrenoleukodystrophy. A diagnosis of ALD is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests.Some infants may be diagnosed through newborn screening. Newborn screening is a special type of screening test that newborns receive to see if they have certain diseases. This screening is primarily done through the examination of dried blood spots. Because the newborn screen is a screening test, a positive result does not mean that an infant definitely has a disease. Often, a repeat test must be done to confirm the diagnosis. If a newborn screen is positive, then a genetic test may be ordered to identify the specific gene change (mutation) that causes ALD.In 2016, ALD was added to the Recommended Uniform Newborn Screening Panel (RUSP) in the United States. However, each state determines what specific disorders are included in its newborn screening program within that state. As of October 2019, only a dozen of states test for ALD through newborn screening, although more states are planning on adding the disorder to testing programs.Clinical Testing and Workup
The initial diagnostic test is usually a blood test to measure the levels of very long-chain fatty acids in the blood plasma. If these levels are notably high or if the ratio of these fatty molecules in the blood is off, physicians will order genetic testing to confirm a diagnosis. Some women who are carriers for ALD can have normal levels of very long-chain fatty acids in the blood. Women who are suspected of having the disorder may require genetic testing to definitely rule out the diagnosis.Molecular genetic testing can confirm a diagnosis. Molecular genetic testing can detect mutations in the ABCD1 gene known to cause ALD, but is available only as a diagnostic service at specialized laboratories.Physicians will also test the function of the adrenal glands through a test called ACTH stimulation test. ACTH stands for adrenocorticotropic hormone and is produced by the pituitary gland. An increase in the concentration of ACTH leads to an increase in the production of adrenal hormones. Specifically, there should be a rise in cortisol in the blood plasma.A specialized imaging technique called magnetic resonance imaging (MRI) may be recommended to assess how ALD has affected the brain. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues including the brain. This allows physicians to see whether the brain has been damaged, including the loss of myelin in the cerebral white matter.
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Therapies of X-Linked Adrenoleukodystrophy
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Treatment may require the coordinated efforts of a team of specialists. Pediatricians, general internists, physicians who specialize in diagnosing and treating disorders of the brain and nervous system (pediatric neurologists), adult neurologists, physicians who specialize in diagnosing and treating disorders of the urinary system (urologists), physicians who specialize in diagnosing and treating disorders of the endocrine system (endocrinologists), psychiatrists, physical therapists, and other healthcare professionals may need to systematically and comprehensively plan treatment. Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well. Boys without symptoms (asymptomatic) should be closely monitored for signs of cerebral disease. This group tends to be boys identified through newborn screening or were diagnosed early because of a previous affected family member. Treatment such as hematopoietic stem cell transplantation should only be considered in boys with abnormal MRI changes who do not yet have neurological symptoms. For individuals with adrenal insufficiency, corticosteroid replacement therapy is essential. Management of spinal cord disease, urinary complications, polyneuropathy tend to follow routine or standard guidelines. Following an initial diagnosis in infants or children, a neurodevelopmental assessment may be performed, and affected boys need to undergo repeated MRI studies on a routine basis for disease surveillance. It is important to identify the brain MRI changes as early as possible, since individuals with early MRI changes prior to neurological symptoms have the best outcome when undergoing therapy. Periodic reassessments and adjustment of services should be provided with all children and adults. Additional medical, social, and/or vocational services including specialized learning programs may be necessary. In 2022, elivaldogene autotemcel (Skysona) was approved by the U.S Food and Drug Administration (FDA) as the first cell-based gene therapy indicated to slow the progression of neurologic dysfunction in boys 4-17 years of age with early, active cerebral adrenoleukodystrophy. In gene therapy, the defective gene present in a patient is replaced with a normal gene to enable the produce of the active enzyme and prevent the development and progression of the disease in question. Given the permanent transfer of the normal gene, which is able to produce working protein at all sites of disease, this form of therapy is theoretically most likely to lead to a “cure.” Initial studies are ongoing to determine the long-term safety and effectiveness of gene therapy for boys with cerebral ALD. Allogeneic hematopoietic stem cell transplantation (HSCT) for the treatment of certain individuals, particularly young boys or adolescents with evidence of central nervous system involvement who are early in the course of the disease and have no neurological symptoms is currently standard of care to stop progression of neurological symptoms in childhood. Hematopoietic stem cells are special cells found in bone marrow that grow or mature into different types of cells. In allogenic stem cell transplantation, affected individuals receive hematopoietic stem cells from a healthy person, referred to as the donor. A series of studies conducted over the last two decades have shown that HSCT stops the progression of neurological disease in ALD, although it does not improve adrenal insufficiency. HSCT is a major medical procedure that carries significant risk. Since Allogeneic HSCT is only effective in early stages of the disease, it is important that newborn screening be expanded to all states and that all boys diagnosed with ALD undergo repeated brain MRI studies and follow up routinely with a neurologist.
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Therapies of X-Linked Adrenoleukodystrophy. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, general internists, physicians who specialize in diagnosing and treating disorders of the brain and nervous system (pediatric neurologists), adult neurologists, physicians who specialize in diagnosing and treating disorders of the urinary system (urologists), physicians who specialize in diagnosing and treating disorders of the endocrine system (endocrinologists), psychiatrists, physical therapists, and other healthcare professionals may need to systematically and comprehensively plan treatment. Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well. Boys without symptoms (asymptomatic) should be closely monitored for signs of cerebral disease. This group tends to be boys identified through newborn screening or were diagnosed early because of a previous affected family member. Treatment such as hematopoietic stem cell transplantation should only be considered in boys with abnormal MRI changes who do not yet have neurological symptoms. For individuals with adrenal insufficiency, corticosteroid replacement therapy is essential. Management of spinal cord disease, urinary complications, polyneuropathy tend to follow routine or standard guidelines. Following an initial diagnosis in infants or children, a neurodevelopmental assessment may be performed, and affected boys need to undergo repeated MRI studies on a routine basis for disease surveillance. It is important to identify the brain MRI changes as early as possible, since individuals with early MRI changes prior to neurological symptoms have the best outcome when undergoing therapy. Periodic reassessments and adjustment of services should be provided with all children and adults. Additional medical, social, and/or vocational services including specialized learning programs may be necessary. In 2022, elivaldogene autotemcel (Skysona) was approved by the U.S Food and Drug Administration (FDA) as the first cell-based gene therapy indicated to slow the progression of neurologic dysfunction in boys 4-17 years of age with early, active cerebral adrenoleukodystrophy. In gene therapy, the defective gene present in a patient is replaced with a normal gene to enable the produce of the active enzyme and prevent the development and progression of the disease in question. Given the permanent transfer of the normal gene, which is able to produce working protein at all sites of disease, this form of therapy is theoretically most likely to lead to a “cure.” Initial studies are ongoing to determine the long-term safety and effectiveness of gene therapy for boys with cerebral ALD. Allogeneic hematopoietic stem cell transplantation (HSCT) for the treatment of certain individuals, particularly young boys or adolescents with evidence of central nervous system involvement who are early in the course of the disease and have no neurological symptoms is currently standard of care to stop progression of neurological symptoms in childhood. Hematopoietic stem cells are special cells found in bone marrow that grow or mature into different types of cells. In allogenic stem cell transplantation, affected individuals receive hematopoietic stem cells from a healthy person, referred to as the donor. A series of studies conducted over the last two decades have shown that HSCT stops the progression of neurological disease in ALD, although it does not improve adrenal insufficiency. HSCT is a major medical procedure that carries significant risk. Since Allogeneic HSCT is only effective in early stages of the disease, it is important that newborn screening be expanded to all states and that all boys diagnosed with ALD undergo repeated brain MRI studies and follow up routinely with a neurologist.
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Overview of X-Linked Myopathy with Excessive Autophagy
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X-linked myopathy with excessive autophagy (XMEA) is a very rare genetic condition. Autophagy is the process of breaking down damaged or unnecessary cell parts such as proteins and organelles. The most common feature of XMEA is muscle disease (myopathy) and slowly worsening muscle weakness, especially in the legs. This disorder is caused by a harmful change (mutation) in the VMA21 gene located on the X chromosome. The inheritance pattern of XMEA is X-linked, meaning that typically only males are affected and females are unaffected carriers. Signs and symptoms usually start between 5-10 years of age, but some patients do not become symptomatic until later in life. There are currently no specific treatments for XMEA. Management focuses on symptoms and may include physical therapy and exercise. XMEA was first reported in medical literature in 1988 and the VMA21 gene was discovered to be the cause of XMEA in 2013.
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Overview of X-Linked Myopathy with Excessive Autophagy. X-linked myopathy with excessive autophagy (XMEA) is a very rare genetic condition. Autophagy is the process of breaking down damaged or unnecessary cell parts such as proteins and organelles. The most common feature of XMEA is muscle disease (myopathy) and slowly worsening muscle weakness, especially in the legs. This disorder is caused by a harmful change (mutation) in the VMA21 gene located on the X chromosome. The inheritance pattern of XMEA is X-linked, meaning that typically only males are affected and females are unaffected carriers. Signs and symptoms usually start between 5-10 years of age, but some patients do not become symptomatic until later in life. There are currently no specific treatments for XMEA. Management focuses on symptoms and may include physical therapy and exercise. XMEA was first reported in medical literature in 1988 and the VMA21 gene was discovered to be the cause of XMEA in 2013.
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Symptoms of X-Linked Myopathy with Excessive Autophagy
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Symptoms of XMEA often appear in the first 10 years of life. First signs include an unusual walking pattern (gait) and problems running or climbing stairs. The muscles most affected include the shoulders, hips, thighs and occasionally ankles. The slowly progressive weakness tends to start with muscles that are closer to the center of the body (proximal muscles) such as the upper legs. During the second decade of life the upper limbs and shoulders may be affected. In some patients, muscles far away from the center of the body (distal muscles) such as the hands and feet may become involved. Patients may also experience joints that are tightened or flexed in fixed positions (joint contractures). Symptoms tend to stay consistent, but it is possible that they may worsen with age. Older patients often need help walking and may experience muscle wasting (atrophy). It is common for patients in their 50s and 60s to use a wheelchair. The heart, brain, spinal cord and lungs are not usually affected by XMEA. This condition does not typically lead to a shortened life span.XMEA is most often diagnosed in children under 10 years of age. Additional research has identified patients with a mild form of the condition who do not develop symptoms until late adulthood. There are also children who experience onset of symptoms shortly after birth.
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Symptoms of X-Linked Myopathy with Excessive Autophagy. Symptoms of XMEA often appear in the first 10 years of life. First signs include an unusual walking pattern (gait) and problems running or climbing stairs. The muscles most affected include the shoulders, hips, thighs and occasionally ankles. The slowly progressive weakness tends to start with muscles that are closer to the center of the body (proximal muscles) such as the upper legs. During the second decade of life the upper limbs and shoulders may be affected. In some patients, muscles far away from the center of the body (distal muscles) such as the hands and feet may become involved. Patients may also experience joints that are tightened or flexed in fixed positions (joint contractures). Symptoms tend to stay consistent, but it is possible that they may worsen with age. Older patients often need help walking and may experience muscle wasting (atrophy). It is common for patients in their 50s and 60s to use a wheelchair. The heart, brain, spinal cord and lungs are not usually affected by XMEA. This condition does not typically lead to a shortened life span.XMEA is most often diagnosed in children under 10 years of age. Additional research has identified patients with a mild form of the condition who do not develop symptoms until late adulthood. There are also children who experience onset of symptoms shortly after birth.
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Causes of X-Linked Myopathy with Excessive Autophagy
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XMEA is caused by a harmful change (mutation) in the VMA21 gene. The VMA21 gene is responsible for creating a protein that aids in an important cellular process known as autophagy. Autophagy comes from the Greek words auto (self) and phagein (to eat). It is a normal and important process in which cells get rid of toxins and waste and recycle damaged cell parts. A non-working VMA21 gene leads to an incorrect and increased process of autophagy. This process occurs in the lysosomes which are specialized compartments inside our cells. They aid in autophagy, help the cell dispose of waste and break down particles. The mutation in the VMA21 gene causes increased acidity in the lysosomes, and they are no longer able to fully break down cell waste. This leads to build-up of lysosomes and other cell parts responsible for autophagy. This is what causes the symptoms commonly seen in XMEA.Because the VMA21 gene is located on the X chromosome, the inheritance pattern of this condition is called X-linked and affects mostly males. Females that have a non-working gene on one of their X chromosomes are carriers for that condition. Carrier females usually do not have symptoms because they have two X chromosomes (one from each parent) and only one has the non-working gene. Males have one X chromosome that is inherited from their mother and one Y chromosome inherited from their father. If a male inherits an X chromosome that contains a non-working gene he will develop the condition.Female carriers of an X-linked condition have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.If a male with an X-linked disorder is able to reproduce, he will pass the non-working gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.
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Causes of X-Linked Myopathy with Excessive Autophagy. XMEA is caused by a harmful change (mutation) in the VMA21 gene. The VMA21 gene is responsible for creating a protein that aids in an important cellular process known as autophagy. Autophagy comes from the Greek words auto (self) and phagein (to eat). It is a normal and important process in which cells get rid of toxins and waste and recycle damaged cell parts. A non-working VMA21 gene leads to an incorrect and increased process of autophagy. This process occurs in the lysosomes which are specialized compartments inside our cells. They aid in autophagy, help the cell dispose of waste and break down particles. The mutation in the VMA21 gene causes increased acidity in the lysosomes, and they are no longer able to fully break down cell waste. This leads to build-up of lysosomes and other cell parts responsible for autophagy. This is what causes the symptoms commonly seen in XMEA.Because the VMA21 gene is located on the X chromosome, the inheritance pattern of this condition is called X-linked and affects mostly males. Females that have a non-working gene on one of their X chromosomes are carriers for that condition. Carrier females usually do not have symptoms because they have two X chromosomes (one from each parent) and only one has the non-working gene. Males have one X chromosome that is inherited from their mother and one Y chromosome inherited from their father. If a male inherits an X chromosome that contains a non-working gene he will develop the condition.Female carriers of an X-linked condition have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.If a male with an X-linked disorder is able to reproduce, he will pass the non-working gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.
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X-Linked Myopathy with Excessive Autophagy
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Affects of X-Linked Myopathy with Excessive Autophagy
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XMEA is very rare. Less than 1 in 1,000,000 people are affected with this condition. Because this disorder is often unrecognized, it may not be diagnosed in all affected individuals. This can make it difficult to determine the true number of people who have XMEA.
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Affects of X-Linked Myopathy with Excessive Autophagy. XMEA is very rare. Less than 1 in 1,000,000 people are affected with this condition. Because this disorder is often unrecognized, it may not be diagnosed in all affected individuals. This can make it difficult to determine the true number of people who have XMEA.
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Related disorders of X-Linked Myopathy with Excessive Autophagy
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There are several other muscle diseases that occur due to irregular autophagy. Conditions in this category have similar findings on a muscle biopsy and are caused by a problem with autophagy and/or lysosomal function. Lysosomes are specialized compartments inside cells that aid in autophagy, help the cell dispose of waste, and break down particles. Diseases related to abnormal autophagy (autophagic vacuolar myopathies) tend to primarily affect heart and skeletal muscles.Pompe disease (glycogen storage disease type II) falls into this category. It may also be classified as a lysosomal storage disorder. Pompe disease affects multiple body systems including the heart, brain and muscles. It is a progressive condition in which symptoms worsen over time. It is caused by mutations in the GAA gene and has a recessive mode of inheritance. Pompe disease is one of the first muscle diseases with an effective treatment (enzyme replacement therapy) that dramatically improves symptoms. For more information on this disorder, choose “Pompe disease” as your search term in the Rare Disease Database.Danon disease (also known as glycogen storage disease type IIB) is characterized by intellectual disability, muscle disease and weakening of the heart. It is also a lysosomal storage disorder. Like XMEA, Danon disease has an X-linked mode of inheritance. It is caused by mutations in the LAMP2 gene. For more information on this disorder, choose “Danon disease” as your search term in the Rare Disease Database.Other conditions that have similar symptoms to XMEA include Emery-Dreifuss muscular dystrophy and Limb-girdle muscular dystrophy. Both are rare muscle disorders. Emery-Dreifuss muscular dystrophy is characterized by muscle weakness and breakdown, joint contractures, and weakness of the heart. Emery-Dreifuss is also inherited in an X-linked fashion. Limb-girdle muscular dystrophy is characterized by muscle weakness around the hips, shoulders, and girdle starting in childhood or young adulthood. There are many different subtypes of Limb-girdle muscular dystrophy and most are inherited in an autosomal recessive pattern. For more information on this disorder, choose “Emery Dreifuss” or “Limb-girdle muscular dystrophy” as your search term in the Rare Disease Database.
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Related disorders of X-Linked Myopathy with Excessive Autophagy. There are several other muscle diseases that occur due to irregular autophagy. Conditions in this category have similar findings on a muscle biopsy and are caused by a problem with autophagy and/or lysosomal function. Lysosomes are specialized compartments inside cells that aid in autophagy, help the cell dispose of waste, and break down particles. Diseases related to abnormal autophagy (autophagic vacuolar myopathies) tend to primarily affect heart and skeletal muscles.Pompe disease (glycogen storage disease type II) falls into this category. It may also be classified as a lysosomal storage disorder. Pompe disease affects multiple body systems including the heart, brain and muscles. It is a progressive condition in which symptoms worsen over time. It is caused by mutations in the GAA gene and has a recessive mode of inheritance. Pompe disease is one of the first muscle diseases with an effective treatment (enzyme replacement therapy) that dramatically improves symptoms. For more information on this disorder, choose “Pompe disease” as your search term in the Rare Disease Database.Danon disease (also known as glycogen storage disease type IIB) is characterized by intellectual disability, muscle disease and weakening of the heart. It is also a lysosomal storage disorder. Like XMEA, Danon disease has an X-linked mode of inheritance. It is caused by mutations in the LAMP2 gene. For more information on this disorder, choose “Danon disease” as your search term in the Rare Disease Database.Other conditions that have similar symptoms to XMEA include Emery-Dreifuss muscular dystrophy and Limb-girdle muscular dystrophy. Both are rare muscle disorders. Emery-Dreifuss muscular dystrophy is characterized by muscle weakness and breakdown, joint contractures, and weakness of the heart. Emery-Dreifuss is also inherited in an X-linked fashion. Limb-girdle muscular dystrophy is characterized by muscle weakness around the hips, shoulders, and girdle starting in childhood or young adulthood. There are many different subtypes of Limb-girdle muscular dystrophy and most are inherited in an autosomal recessive pattern. For more information on this disorder, choose “Emery Dreifuss” or “Limb-girdle muscular dystrophy” as your search term in the Rare Disease Database.
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Diagnosis of X-Linked Myopathy with Excessive Autophagy
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Muscle biopsy can diagnose XMEA and findings are consistent across all patients with XMEA. A diagnosis can also be made by genetic testing if a mutation is found in the VMA21 gene that results in a reduced amount of protein product.Many individuals with XMEA show high CPK (creatine phosphokinase) levels. However there have been people who have XMEA with normal CPK levels. CPK is an enzyme found in muscle and various tissues in the body. Elevated CPK indicates muscle damage. Neurological findings can sometimes be used in making a diagnosis. Nerve conduction studies are typically normal, but EMG (electromyography) findings are often abnormal. EMG is a procedure to assess the health of muscle and nerves. Findings from special staining of muscle biopsy tissue can distinguish XMEA from Danon disease.
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Diagnosis of X-Linked Myopathy with Excessive Autophagy. Muscle biopsy can diagnose XMEA and findings are consistent across all patients with XMEA. A diagnosis can also be made by genetic testing if a mutation is found in the VMA21 gene that results in a reduced amount of protein product.Many individuals with XMEA show high CPK (creatine phosphokinase) levels. However there have been people who have XMEA with normal CPK levels. CPK is an enzyme found in muscle and various tissues in the body. Elevated CPK indicates muscle damage. Neurological findings can sometimes be used in making a diagnosis. Nerve conduction studies are typically normal, but EMG (electromyography) findings are often abnormal. EMG is a procedure to assess the health of muscle and nerves. Findings from special staining of muscle biopsy tissue can distinguish XMEA from Danon disease.
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X-Linked Myopathy with Excessive Autophagy
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nord_1310_6
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Therapies of X-Linked Myopathy with Excessive Autophagy
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Currently there are no therapies specific to XMEA. Management of the condition is based on specific symptoms. Physical therapy can be helpful to improve mobility and reduce joint contractures. It is also important to exercise and keep a healthy diet.Genetic counseling is recommended for affected individuals and their families
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Therapies of X-Linked Myopathy with Excessive Autophagy. Currently there are no therapies specific to XMEA. Management of the condition is based on specific symptoms. Physical therapy can be helpful to improve mobility and reduce joint contractures. It is also important to exercise and keep a healthy diet.Genetic counseling is recommended for affected individuals and their families
| 1,310 |
X-Linked Myopathy with Excessive Autophagy
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nord_1311_0
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Overview of X-Linked Myotubular Myopathy
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SummaryX-linked myotubular myopathy (XLMTM) is a rare genetic neuromuscular disorder that is characterized by muscle weakness that is most typically severe but can range from mild to profound. Symptoms are often present at birth, though may develop later in infancy or early childhood. Rarely, symptoms may not present until adolescence or adulthood. Common symptoms include mild to profound muscle weakness, diminished muscle tone (hypotonia or “floppiness”), feeding difficulties, and potentially severe breathing complications (respiratory distress). Feeding difficulties and respiratory distress develop because of weakness of the muscles that are involved in swallowing and breathing. The overall severity of the disorder can range from mildly affected individuals to individuals who develop severe, life-threatening complications during infancy and early childhood. Most affected individuals have a severe form of the disorder and respiratory failure is an almost uniform occurrence. XLMTM is caused by mutations to the myotubularin (MTM1) gene. The disorder is inherited as an X-linked condition. The disorder predominantly affects males, but female carriers, while typically asymptomatic, can develop a range of symptoms. In rare specific cases, females can develop a severe form similar to that seen in males.IntroductionXLMTM belongs to a larger group of disorders known as the centronuclear myopathies. In addition to XLMTM, there are forms of centronuclear myopathy that are inherited as autosomal dominant or autosomal recessive conditions. Generally, the autosomal forms are less severe than XLMTM; however, in rare cases, individuals with an autosomal form can develop severe complications that are similar to those seen in XLMTM. Centronuclear myopathies derive their name from the abnormal location of the nucleus in the center of the muscle fiber (muscle cell) rather than its normal position on the edge. Additional pathologic features include disorganized perinuclear organelles and abnormalities in oxidative staining patterns. Centronuclear myopathies can be further classified into the larger, broader category of congenital myopathies, a group of genetic muscle disorders that are present at birth.In the medical literature, centronuclear myopathy is generally used for the autosomal forms of the disorder and myotubular myopathy is generally used for the X-linked form. Distinguishing between the X-linked (myotubular) form and the autosomal forms is essential as the symptoms are usually more severe in the X-linked form. NORD has a separate report on centronuclear myopathy that describes the autosomal forms in greater detail. This report specifically deals with X-linked centronuclear (myotubular) myopathy.
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Overview of X-Linked Myotubular Myopathy. SummaryX-linked myotubular myopathy (XLMTM) is a rare genetic neuromuscular disorder that is characterized by muscle weakness that is most typically severe but can range from mild to profound. Symptoms are often present at birth, though may develop later in infancy or early childhood. Rarely, symptoms may not present until adolescence or adulthood. Common symptoms include mild to profound muscle weakness, diminished muscle tone (hypotonia or “floppiness”), feeding difficulties, and potentially severe breathing complications (respiratory distress). Feeding difficulties and respiratory distress develop because of weakness of the muscles that are involved in swallowing and breathing. The overall severity of the disorder can range from mildly affected individuals to individuals who develop severe, life-threatening complications during infancy and early childhood. Most affected individuals have a severe form of the disorder and respiratory failure is an almost uniform occurrence. XLMTM is caused by mutations to the myotubularin (MTM1) gene. The disorder is inherited as an X-linked condition. The disorder predominantly affects males, but female carriers, while typically asymptomatic, can develop a range of symptoms. In rare specific cases, females can develop a severe form similar to that seen in males.IntroductionXLMTM belongs to a larger group of disorders known as the centronuclear myopathies. In addition to XLMTM, there are forms of centronuclear myopathy that are inherited as autosomal dominant or autosomal recessive conditions. Generally, the autosomal forms are less severe than XLMTM; however, in rare cases, individuals with an autosomal form can develop severe complications that are similar to those seen in XLMTM. Centronuclear myopathies derive their name from the abnormal location of the nucleus in the center of the muscle fiber (muscle cell) rather than its normal position on the edge. Additional pathologic features include disorganized perinuclear organelles and abnormalities in oxidative staining patterns. Centronuclear myopathies can be further classified into the larger, broader category of congenital myopathies, a group of genetic muscle disorders that are present at birth.In the medical literature, centronuclear myopathy is generally used for the autosomal forms of the disorder and myotubular myopathy is generally used for the X-linked form. Distinguishing between the X-linked (myotubular) form and the autosomal forms is essential as the symptoms are usually more severe in the X-linked form. NORD has a separate report on centronuclear myopathy that describes the autosomal forms in greater detail. This report specifically deals with X-linked centronuclear (myotubular) myopathy.
| 1,311 |
X-Linked Myotubular Myopathy
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nord_1311_1
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Symptoms of X-Linked Myotubular Myopathy
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The specific symptoms and severity of XLMTM can vary greatly from one person to another, though the majority of individuals with MTM have a severe presentation. While the disorder may be fatal during infancy or childhood, some affected individuals will only develop mild to moderate symptoms. Because of the variable nature of XLMTM, parents should talk to their child’s physician and medical team about their specific case, associated symptoms and overall prognosis.One classification subdivides XLMTM into a severe (classic) form, a moderate form and a mild form. Most affected individuals have the severe (classic) form of XLMTM. Moderate and mild forms of XLMTM are far less common. In the severe form, affected male infants exhibit extreme muscle weakness and hypotonia (floppiness) at or shortly after birth. Weakness of the muscles used to breathe and swallow can cause respiratory distress and feeding difficulties during infancy often noticeable within the first few days or weeks of life. Respiratory distress can be present at birth and can cause affected infants to require constant, prolonged ventilation during infancy. Affected infants may be unable to suck, swallow or breathe on their own. In the U.S., the initial hospital stay for surviving infants is approximately 90 days.Some children with XLMTM will die during the first few months or years of life. Other individuals will survive this initial period but require 24 hour ventilator, feeding, and wheelchair support. However, other individuals will become independent of a ventilator or only require periodic assisted ventilation such as during sleep. A proportion of affected individuals will survive into the teenage years and beyond. Of note, long-term ventilation during infancy carries risks including recurrent infection, inadequate shallow breathing (hypoventilation), and lack of oxygen in the blood (hypoxia).Muscle weakness and poor muscle development can also cause delays in the attainment of motor milestones. Most affected individuals are unable to walk (non-ambulatory). Muscle weakness associated with XLMTM is not believed to be progressive, but this has not been definitely confirmed. Individuals with XLMTM often grow tired more easily than their peers.Affected infants often have distinctive facial features including a high forehead, underdevelopment of the middle of the face (midface hypoplasia), weakness of facial muscles, and a disproportionately long and narrow head (dolichocephaly) with a long face. Some infants have a narrow, high-arched roof of the mouth (palate) and later on develop severe misalignment of the teeth (malocclusion). Partial or complete paralysis of one or more of the muscles that control the movements of the eye (ophthalmoparesis) is also common. Drooping of the upper eyelids (ptosis) and nearsightedness (myopia) may also occur.In some individuals, growth parameters may be abnormal. In general, head circumference is larger than would be expected based on age and gender (macrocephaly). Affected infants may be in the 90th percentile for length at birth. Weakness of the facial muscles is often very obvious.Additional symptoms may occur including abnormally long fingers and toes, absence of reflexes (areflexia), and shortening or hardening of tissue that causes deformity and restricts movements of affected areas, especially the joints (contractures). Failure of the testes to descend into the scrotum (cryptorchidism) may also occur. As affected individuals grow older, more symptoms can occur including fractures of the long bones, malformation of the hip (hip dysplasia) and abnormal side-to-side curvature of the spine (scoliosis). Scoliosis can worsen respiratory problems and cause individuals who no longer require assisted ventilation to go back onto ventilator support. In some cases, advanced bone age and premature production of sex hormones called androgens (premature adrenarche) has also been reported.Many long-term survivors with severe XLMTM require a wheelchair and need assistance for normal daily activities. A variety of additional low incidence complications have been reported in long-term survivors. Such complications include narrowing of the outlet that connects the stomach to the small intestine (pyloric stenosis), gallstones, kidney stones, mild anemia due to the formation of abnormal red blood cells (spherocytosis), bleeding abnormalities, and liver dysfunction. Some individuals develop peliosis hepatitis, a liver condition characterized by randomly located, multiple blood-filled cavities throughout the liver. This condition can cause life-threatening bleeding (hemorrhaging) episodes.Cognitive development and intelligence are usually unaffected, except in extremely rare cases or in individuals who suffer a significant hypoxic episode, in which the brain is deprived of oxygen.Mild and Moderate Myotubular Myopathy
Some individuals may have milder forms of the disorder. The moderate form of XLMTM is generally characterized by similar signs and symptoms to the severe form. However, individuals will have longer periods of time where the need for ventilator support is decreased. In addition, affected individuals will attain motor milestones faster than individuals with the severe form.Individuals with the mild form of XLMTM only experience slight delays in attaining motor milestones and most achieve the ability to walk. These individuals may only require ventilator support in the newborn period. Some individuals with the mild form do not have the characteristic facial features that are seen in the severe form of XLMTM, and often also have eye movement paralysis.Individuals with mild or moderate XLMTM are at risk for breathing problems including especially nocturnal hypoventilation and sleep apnea. In addition, respiratory decompensation can develop when dealing with an unrelated illness. This may require a return to or an increase in ventilator support.At least three multigenerational families have been described in the medical literature with male family members who developed mild cases of XLMTM, sometimes not developing symptoms until adulthood.
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Symptoms of X-Linked Myotubular Myopathy. The specific symptoms and severity of XLMTM can vary greatly from one person to another, though the majority of individuals with MTM have a severe presentation. While the disorder may be fatal during infancy or childhood, some affected individuals will only develop mild to moderate symptoms. Because of the variable nature of XLMTM, parents should talk to their child’s physician and medical team about their specific case, associated symptoms and overall prognosis.One classification subdivides XLMTM into a severe (classic) form, a moderate form and a mild form. Most affected individuals have the severe (classic) form of XLMTM. Moderate and mild forms of XLMTM are far less common. In the severe form, affected male infants exhibit extreme muscle weakness and hypotonia (floppiness) at or shortly after birth. Weakness of the muscles used to breathe and swallow can cause respiratory distress and feeding difficulties during infancy often noticeable within the first few days or weeks of life. Respiratory distress can be present at birth and can cause affected infants to require constant, prolonged ventilation during infancy. Affected infants may be unable to suck, swallow or breathe on their own. In the U.S., the initial hospital stay for surviving infants is approximately 90 days.Some children with XLMTM will die during the first few months or years of life. Other individuals will survive this initial period but require 24 hour ventilator, feeding, and wheelchair support. However, other individuals will become independent of a ventilator or only require periodic assisted ventilation such as during sleep. A proportion of affected individuals will survive into the teenage years and beyond. Of note, long-term ventilation during infancy carries risks including recurrent infection, inadequate shallow breathing (hypoventilation), and lack of oxygen in the blood (hypoxia).Muscle weakness and poor muscle development can also cause delays in the attainment of motor milestones. Most affected individuals are unable to walk (non-ambulatory). Muscle weakness associated with XLMTM is not believed to be progressive, but this has not been definitely confirmed. Individuals with XLMTM often grow tired more easily than their peers.Affected infants often have distinctive facial features including a high forehead, underdevelopment of the middle of the face (midface hypoplasia), weakness of facial muscles, and a disproportionately long and narrow head (dolichocephaly) with a long face. Some infants have a narrow, high-arched roof of the mouth (palate) and later on develop severe misalignment of the teeth (malocclusion). Partial or complete paralysis of one or more of the muscles that control the movements of the eye (ophthalmoparesis) is also common. Drooping of the upper eyelids (ptosis) and nearsightedness (myopia) may also occur.In some individuals, growth parameters may be abnormal. In general, head circumference is larger than would be expected based on age and gender (macrocephaly). Affected infants may be in the 90th percentile for length at birth. Weakness of the facial muscles is often very obvious.Additional symptoms may occur including abnormally long fingers and toes, absence of reflexes (areflexia), and shortening or hardening of tissue that causes deformity and restricts movements of affected areas, especially the joints (contractures). Failure of the testes to descend into the scrotum (cryptorchidism) may also occur. As affected individuals grow older, more symptoms can occur including fractures of the long bones, malformation of the hip (hip dysplasia) and abnormal side-to-side curvature of the spine (scoliosis). Scoliosis can worsen respiratory problems and cause individuals who no longer require assisted ventilation to go back onto ventilator support. In some cases, advanced bone age and premature production of sex hormones called androgens (premature adrenarche) has also been reported.Many long-term survivors with severe XLMTM require a wheelchair and need assistance for normal daily activities. A variety of additional low incidence complications have been reported in long-term survivors. Such complications include narrowing of the outlet that connects the stomach to the small intestine (pyloric stenosis), gallstones, kidney stones, mild anemia due to the formation of abnormal red blood cells (spherocytosis), bleeding abnormalities, and liver dysfunction. Some individuals develop peliosis hepatitis, a liver condition characterized by randomly located, multiple blood-filled cavities throughout the liver. This condition can cause life-threatening bleeding (hemorrhaging) episodes.Cognitive development and intelligence are usually unaffected, except in extremely rare cases or in individuals who suffer a significant hypoxic episode, in which the brain is deprived of oxygen.Mild and Moderate Myotubular Myopathy
Some individuals may have milder forms of the disorder. The moderate form of XLMTM is generally characterized by similar signs and symptoms to the severe form. However, individuals will have longer periods of time where the need for ventilator support is decreased. In addition, affected individuals will attain motor milestones faster than individuals with the severe form.Individuals with the mild form of XLMTM only experience slight delays in attaining motor milestones and most achieve the ability to walk. These individuals may only require ventilator support in the newborn period. Some individuals with the mild form do not have the characteristic facial features that are seen in the severe form of XLMTM, and often also have eye movement paralysis.Individuals with mild or moderate XLMTM are at risk for breathing problems including especially nocturnal hypoventilation and sleep apnea. In addition, respiratory decompensation can develop when dealing with an unrelated illness. This may require a return to or an increase in ventilator support.At least three multigenerational families have been described in the medical literature with male family members who developed mild cases of XLMTM, sometimes not developing symptoms until adulthood.
| 1,311 |
X-Linked Myotubular Myopathy
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nord_1311_2
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Causes of X-Linked Myotubular Myopathy
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XLMTM is caused by a mutation in the myotubularin (MTM1) gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.XLMTM is inherited as an X-linked genetic disorder. X-linked genetic disorders are conditions caused by a gene change on the X chromosome. Females have two X chromosomes but one of the X chromosomes is “turned off” and all of the genes on that chromosome are inactivated. This is a normal process known as random X-chromosome inactivation. Females who have a disease gene change present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder because the X chromosome with the abnormal gene change is “turned off” in approximately 50% of the cells of the body. A male has one X-chromosome and if he inherits an X chromosome that contains a disease gene change, he will develop the disease. Males with X-linked disorders pass the disease gene change to all of their daughters, who will be carriers if the other X chromosome from their mother is normal. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease, and a 25% chance to have an unaffected son. In a minority of cases, a mutation in the MTM1 gene that causes the disorder occurs randomly for no apparent reason (de novo mutation). In these cases, the mother is not a carrier and the risk of recurrence of the mutation in a subsequent pregnancy is extremely low.As a result of random X-chromosome inactivation, most females with a MTM1 mutation do not develop symptoms, although some females will exhibit mild symptoms such as mild weakness of certain muscles. In extremely rare cases, females can develop a severe form of XLMTM similar to the one seen in males. This may be due to a skewing of the inactivation of the X-chromosome without the gene change; therefore the majority of the instructions for the myotubularin protein come from the X-chromosome with the gene change.In a few children recently reported in the medical literature, male children with XLMTM developed the disorder not because of a mutation, but because of a duplication involving the MTM1 gene. A duplication is a structural chromosomal abnormality in which a portion of the X chromosome appears three times in the cells of the body instead of twice. Researchers believe that some cases in which individuals have XLMTM but do not have a mutation of the MTM1 gene are caused by a duplication of the X chromosome involving the MTM1 gene. There is also now evidence for changes/mutations at the MTM1 gene locus that occur outside of the protein making region but that impact the processing of the MTM1 RNA. Investigators have determined that the MTM1 gene is located on the long arm (q) of the X chromosome X (Xq28). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome Xq28” refers to band 28 on the long arm of the X chromosome. The numbered bands specify the location of the thousands of genes that are present on each chromosome.The MTM1 gene creates (encodes) a protein known as myotubularin. This protein is believed to be critical for the proper development, maintenance, and function of muscle tissue. The exact, specific functions of this protein are not fully understood, though recent work has suggested in plays a role in maintaining aspects of muscle structure including the part of the muscle fiber responsible for excitation-contraction coupling, which is a normal process involved in skeletal muscle contraction. A mutation in the MTM1 gene leads to low levels of functional myotubularin.
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Causes of X-Linked Myotubular Myopathy. XLMTM is caused by a mutation in the myotubularin (MTM1) gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.XLMTM is inherited as an X-linked genetic disorder. X-linked genetic disorders are conditions caused by a gene change on the X chromosome. Females have two X chromosomes but one of the X chromosomes is “turned off” and all of the genes on that chromosome are inactivated. This is a normal process known as random X-chromosome inactivation. Females who have a disease gene change present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder because the X chromosome with the abnormal gene change is “turned off” in approximately 50% of the cells of the body. A male has one X-chromosome and if he inherits an X chromosome that contains a disease gene change, he will develop the disease. Males with X-linked disorders pass the disease gene change to all of their daughters, who will be carriers if the other X chromosome from their mother is normal. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease, and a 25% chance to have an unaffected son. In a minority of cases, a mutation in the MTM1 gene that causes the disorder occurs randomly for no apparent reason (de novo mutation). In these cases, the mother is not a carrier and the risk of recurrence of the mutation in a subsequent pregnancy is extremely low.As a result of random X-chromosome inactivation, most females with a MTM1 mutation do not develop symptoms, although some females will exhibit mild symptoms such as mild weakness of certain muscles. In extremely rare cases, females can develop a severe form of XLMTM similar to the one seen in males. This may be due to a skewing of the inactivation of the X-chromosome without the gene change; therefore the majority of the instructions for the myotubularin protein come from the X-chromosome with the gene change.In a few children recently reported in the medical literature, male children with XLMTM developed the disorder not because of a mutation, but because of a duplication involving the MTM1 gene. A duplication is a structural chromosomal abnormality in which a portion of the X chromosome appears three times in the cells of the body instead of twice. Researchers believe that some cases in which individuals have XLMTM but do not have a mutation of the MTM1 gene are caused by a duplication of the X chromosome involving the MTM1 gene. There is also now evidence for changes/mutations at the MTM1 gene locus that occur outside of the protein making region but that impact the processing of the MTM1 RNA. Investigators have determined that the MTM1 gene is located on the long arm (q) of the X chromosome X (Xq28). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome Xq28” refers to band 28 on the long arm of the X chromosome. The numbered bands specify the location of the thousands of genes that are present on each chromosome.The MTM1 gene creates (encodes) a protein known as myotubularin. This protein is believed to be critical for the proper development, maintenance, and function of muscle tissue. The exact, specific functions of this protein are not fully understood, though recent work has suggested in plays a role in maintaining aspects of muscle structure including the part of the muscle fiber responsible for excitation-contraction coupling, which is a normal process involved in skeletal muscle contraction. A mutation in the MTM1 gene leads to low levels of functional myotubularin.
| 1,311 |
X-Linked Myotubular Myopathy
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nord_1311_3
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Affects of X-Linked Myotubular Myopathy
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XLMTM primarily affects males. Some carrier females may develop mild symptoms associated with the disorder. The exact incidence of the disorder is unknown, but one estimate places it at 1 in every 50,000 male births in the general population. It is the most common form of centronuclear myopathy.
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Affects of X-Linked Myotubular Myopathy. XLMTM primarily affects males. Some carrier females may develop mild symptoms associated with the disorder. The exact incidence of the disorder is unknown, but one estimate places it at 1 in every 50,000 male births in the general population. It is the most common form of centronuclear myopathy.
| 1,311 |
X-Linked Myotubular Myopathy
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nord_1311_4
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Related disorders of X-Linked Myotubular Myopathy
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Symptoms of the following disorders can be similar to those of XLMTM. Comparisons may be useful for a differential diagnosis.XLMTM belongs to a group of disorders known as centronuclear myopathy (CNM). Other types of CNM include an autosomal dominant form and three autosomal recessive forms, known by the mutated gene associated with each form. Currently, one primary autosomal dominant form has been identified and is known as DNM2-related CNM. Three autosomal recessive forms have been identified and are known as RYR1-related CNM, BIN1-CNM, and SPEG related CNM (found only in a small number of families. Of note, a small number of individuals with BIN1 mutations have been discovered to have autosomal dominant CNM. Some individuals with CNM do not have mutations in any of these genes, suggesting that additional genes may cause autosomal forms of CNM. The autosomal forms are generally less severe than X-linked myotubular myopathy and usually do not display abnormal growth parameters. However, the severity of the autosomal forms can vary dramatically from one person to another. In some cases, individuals with an autosomal form can develop severe complications and a presentation that is very similar to severe XLMTM. (For more information on these disorders, choose “centronuclear myopathy” as your search term in the Rare Disease Database.)Congenital myopathy is a group of muscle disorders (myopathies) where symptoms are typically present at birth (congenital). These conditions are typically distinguished from other early-onset muscle disorders (such as the congenital muscular dystrophies and congenital myotonic dystrophy) by features on muscle biopsy, creatine phosphokinase (CPK) levels in the blood, and genetic testing results. These disorders are characterized by muscle weakness, low muscle tone (hypotonia), diminished reflexes, and delays in reaching motor milestones (e.g., walking). In some disorders, muscle weakness is progressive. The severity of these disorders can range from mild to those associated with severe, life-threatening complications. This group of disorders includes nemaline myopathy, central core disease, congenital fiber type disproportion, minimulticore myopathy, and the centronuclear myopathies. Congenital myopathies are usually apparent in the newborn (neonatal) period, but may present much later in life, even in adulthood. In most cases, inheritance of these disorders is either autosomal recessive or autosomal dominant or X-linked. Of note, congenital myotonic dystrophy can clinically resemble severe CNM and may contain a CNM-like pattern on muscle biopsy. Therefore, this disease is an important condition to consider in the differential diagnosis of MTM. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)Congenital myasthenic syndromes are a group of rare genetic disorders characterized by abnormalities affecting the neuromuscular junction, which is the point where the nerve and muscle cells meet. The underlying defect in these disorders can involve the nerve cell, the muscle cells, or the space in between. These disorders are characterized by muscle weakness and fatigue of the skeletal muscle. Onset is usually at birth or during infancy or early childhood. The severity of these disorders is highly variable, ranging from mild symptoms to severe, disabling symptoms. Symptoms that can be associated with these disorders include respiratory insufficiency or distress, feeding difficulties, paralysis of eye movements, drooping of the upper eyelids (ptosis), and multiple joint contractures. Affected infants and children may exhibit delays in attaining motor milestones. They may fatigue rapidly from normal activities such as climbing stairs or running. Additional symptoms are usually present as well. Because of the overlapping signs and symptoms between CNMs and congenital myasthenic syndromes, and because of the fact that many congenital myasthenic syndrome patients respond favorably to specific therapies, it is always important to consider these conditions in the differential diagnosis of centronuclear myopathy. Congenital myasthenic syndromes can be inherited as autosomal recessive conditions or, less frequently, as autosomal dominant conditions.Myotonic dystrophy type 1 (DM1) is an autosomal dominant, multi-system disorder that affects both smooth and skeletal muscles and may affect the central nervous system, heart, eyes, and/or endocrine systems. There are three types of DM1 that are distinguished by the severity of disease and age of onset. Mild DM1 is characterized by cataracts and sustained muscle contractions (myotonia). Classic DM1 is characterized by muscle weakness and wasting (atrophy), cataracts, myotonia and abnormalities in the heart's conduction of electrical impulses. Congenital DM1 is characterized by muscle weakness (hypotonia), difficulty breathing, intellectual disability and early death. (For more information choose “myotonic dystrophy” as your search term in the Rare Disease Database.)
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Related disorders of X-Linked Myotubular Myopathy. Symptoms of the following disorders can be similar to those of XLMTM. Comparisons may be useful for a differential diagnosis.XLMTM belongs to a group of disorders known as centronuclear myopathy (CNM). Other types of CNM include an autosomal dominant form and three autosomal recessive forms, known by the mutated gene associated with each form. Currently, one primary autosomal dominant form has been identified and is known as DNM2-related CNM. Three autosomal recessive forms have been identified and are known as RYR1-related CNM, BIN1-CNM, and SPEG related CNM (found only in a small number of families. Of note, a small number of individuals with BIN1 mutations have been discovered to have autosomal dominant CNM. Some individuals with CNM do not have mutations in any of these genes, suggesting that additional genes may cause autosomal forms of CNM. The autosomal forms are generally less severe than X-linked myotubular myopathy and usually do not display abnormal growth parameters. However, the severity of the autosomal forms can vary dramatically from one person to another. In some cases, individuals with an autosomal form can develop severe complications and a presentation that is very similar to severe XLMTM. (For more information on these disorders, choose “centronuclear myopathy” as your search term in the Rare Disease Database.)Congenital myopathy is a group of muscle disorders (myopathies) where symptoms are typically present at birth (congenital). These conditions are typically distinguished from other early-onset muscle disorders (such as the congenital muscular dystrophies and congenital myotonic dystrophy) by features on muscle biopsy, creatine phosphokinase (CPK) levels in the blood, and genetic testing results. These disorders are characterized by muscle weakness, low muscle tone (hypotonia), diminished reflexes, and delays in reaching motor milestones (e.g., walking). In some disorders, muscle weakness is progressive. The severity of these disorders can range from mild to those associated with severe, life-threatening complications. This group of disorders includes nemaline myopathy, central core disease, congenital fiber type disproportion, minimulticore myopathy, and the centronuclear myopathies. Congenital myopathies are usually apparent in the newborn (neonatal) period, but may present much later in life, even in adulthood. In most cases, inheritance of these disorders is either autosomal recessive or autosomal dominant or X-linked. Of note, congenital myotonic dystrophy can clinically resemble severe CNM and may contain a CNM-like pattern on muscle biopsy. Therefore, this disease is an important condition to consider in the differential diagnosis of MTM. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)Congenital myasthenic syndromes are a group of rare genetic disorders characterized by abnormalities affecting the neuromuscular junction, which is the point where the nerve and muscle cells meet. The underlying defect in these disorders can involve the nerve cell, the muscle cells, or the space in between. These disorders are characterized by muscle weakness and fatigue of the skeletal muscle. Onset is usually at birth or during infancy or early childhood. The severity of these disorders is highly variable, ranging from mild symptoms to severe, disabling symptoms. Symptoms that can be associated with these disorders include respiratory insufficiency or distress, feeding difficulties, paralysis of eye movements, drooping of the upper eyelids (ptosis), and multiple joint contractures. Affected infants and children may exhibit delays in attaining motor milestones. They may fatigue rapidly from normal activities such as climbing stairs or running. Additional symptoms are usually present as well. Because of the overlapping signs and symptoms between CNMs and congenital myasthenic syndromes, and because of the fact that many congenital myasthenic syndrome patients respond favorably to specific therapies, it is always important to consider these conditions in the differential diagnosis of centronuclear myopathy. Congenital myasthenic syndromes can be inherited as autosomal recessive conditions or, less frequently, as autosomal dominant conditions.Myotonic dystrophy type 1 (DM1) is an autosomal dominant, multi-system disorder that affects both smooth and skeletal muscles and may affect the central nervous system, heart, eyes, and/or endocrine systems. There are three types of DM1 that are distinguished by the severity of disease and age of onset. Mild DM1 is characterized by cataracts and sustained muscle contractions (myotonia). Classic DM1 is characterized by muscle weakness and wasting (atrophy), cataracts, myotonia and abnormalities in the heart's conduction of electrical impulses. Congenital DM1 is characterized by muscle weakness (hypotonia), difficulty breathing, intellectual disability and early death. (For more information choose “myotonic dystrophy” as your search term in the Rare Disease Database.)
| 1,311 |
X-Linked Myotubular Myopathy
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nord_1311_5
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Diagnosis of X-Linked Myotubular Myopathy
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XLMTM should be suspected in newborns with hypotonia and muscle weakness and older male children with weakness in the arms and legs and diminished muscle bulk. A diagnosis is based upon identification of additional characteristic symptoms (e.g. cryptorchidism, long fingers and toes, macrocephaly), a detailed family history, a thorough clinical evaluation, and a variety of specialized tests.Clinical Testing and WorkupA muscle biopsy may be performed to aid in obtaining a diagnosis. A biopsy involves surgical removal of a small sample of affected muscle tissue and examining the sample under a microscope. This allows physicians to note the characteristic, microscopic changes to muscle tissue, specifically the presence of the nucleus in the center of the muscle fiber (muscle cell) rather than toward the edge.A diagnosis of XLMTM is confirmed through molecular genetic testing, which can detect mutations in the MTM1 gene causative of the disorder. Molecular genetic testing can detect a mutation in approximately 60%-98% of affected individuals and is available on a clinical basis.
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Diagnosis of X-Linked Myotubular Myopathy. XLMTM should be suspected in newborns with hypotonia and muscle weakness and older male children with weakness in the arms and legs and diminished muscle bulk. A diagnosis is based upon identification of additional characteristic symptoms (e.g. cryptorchidism, long fingers and toes, macrocephaly), a detailed family history, a thorough clinical evaluation, and a variety of specialized tests.Clinical Testing and WorkupA muscle biopsy may be performed to aid in obtaining a diagnosis. A biopsy involves surgical removal of a small sample of affected muscle tissue and examining the sample under a microscope. This allows physicians to note the characteristic, microscopic changes to muscle tissue, specifically the presence of the nucleus in the center of the muscle fiber (muscle cell) rather than toward the edge.A diagnosis of XLMTM is confirmed through molecular genetic testing, which can detect mutations in the MTM1 gene causative of the disorder. Molecular genetic testing can detect a mutation in approximately 60%-98% of affected individuals and is available on a clinical basis.
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Therapies of X-Linked Myotubular Myopathy
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TreatmentThe treatment of XLMTM is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists with expertise in treating neuromuscular disorders. Pediatricians, pulmonologists, neurologists, orthopedists, eye specialists, dental specialists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Genetic counseling will be of benefit for affected individuals and their families.The treatment of affected individuals usually requires intensive medical intervention. Some affected individuals will require prolonged, constant ventilation support. There are different methods for ventilation including noninvasive and invasive techniques. The decision about the duration of respiratory support is best made by the family in careful consultation with the patient’s physicians and other members of the healthcare team based upon the specifics of their case.In some individuals feeding difficulties will require the insertion of a feeding tube (gastrostomy). This procedure involves inserted a tube directly into the stomach through a small surgical opening in the abdominal wall.Physical and occupational therapy is recommended to improve muscle strength and prevent contractures. Special measures may be necessary to allow ventilator-dependent individuals to communicate. Additional therapies are symptomatic and supportive. For example, scoliosis may require surgical intervention.
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Therapies of X-Linked Myotubular Myopathy. TreatmentThe treatment of XLMTM is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists with expertise in treating neuromuscular disorders. Pediatricians, pulmonologists, neurologists, orthopedists, eye specialists, dental specialists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Genetic counseling will be of benefit for affected individuals and their families.The treatment of affected individuals usually requires intensive medical intervention. Some affected individuals will require prolonged, constant ventilation support. There are different methods for ventilation including noninvasive and invasive techniques. The decision about the duration of respiratory support is best made by the family in careful consultation with the patient’s physicians and other members of the healthcare team based upon the specifics of their case.In some individuals feeding difficulties will require the insertion of a feeding tube (gastrostomy). This procedure involves inserted a tube directly into the stomach through a small surgical opening in the abdominal wall.Physical and occupational therapy is recommended to improve muscle strength and prevent contractures. Special measures may be necessary to allow ventilator-dependent individuals to communicate. Additional therapies are symptomatic and supportive. For example, scoliosis may require surgical intervention.
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Overview of X-linked Opitz G/BBB Syndrome
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X-linked Opitz G/BBB syndrome is a rare genetic disorder characterized by facial differences, respiratory and genitourinary abnormalities and other midline abnormalities as well as developmental delay and intellectual disabilities. There is a wide variability in severity of this condition, even among members of the same family. X-linked Opitz G/BBB syndrome is an X-linked genetic condition associated with changes (pathogenic variants or mutations) in the MID1 gene.
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Overview of X-linked Opitz G/BBB Syndrome. X-linked Opitz G/BBB syndrome is a rare genetic disorder characterized by facial differences, respiratory and genitourinary abnormalities and other midline abnormalities as well as developmental delay and intellectual disabilities. There is a wide variability in severity of this condition, even among members of the same family. X-linked Opitz G/BBB syndrome is an X-linked genetic condition associated with changes (pathogenic variants or mutations) in the MID1 gene.
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X-linked Opitz G/BBB Syndrome
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Symptoms of X-linked Opitz G/BBB Syndrome
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X-linked Opitz G/BBB syndrome is a rare genetic disorder mainly characterized by facial differences, respiratory and genitourinary abnormalities as well as developmental delay or intellectual disabilities.Facial features may include widely spaced eyes (hypertelorism), a prominent forehead, widow’s peak, broad nasal bridge, nostrils that are tipped forward and cleft lip/palate.Respiratory abnormalities can include laryngo-esophageal clefts or the less severe laryngomalacia (soft larynx) that result in difficult swallowing and breathing. Genitourinary problems can include abnormal placement of the urethra in the penis (hypospadias), undescended testes and sometimes kidney abnormalities. Anal abnormalities may also be present and include absent or mis-positioned anal opening. Congenital heart defects such as ventral septal defects and atrial septal defects might be present as well as brain abnormalities such as agenesis or hypoplasia of the brain region that connects the two hemispheres (corpus callosum) and hypoplasia of the cerebellum also in the context of more complex defects such as Dandy-Walker malformation.There is a wide variation in the presentation of the clinical signs and in the severity of this condition, even among members of the same family.Approximately 50% of affected males have developmental delay or intellectual disability that can range from mild to severe. Carrier females usually have hypertelorism only.
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Symptoms of X-linked Opitz G/BBB Syndrome. X-linked Opitz G/BBB syndrome is a rare genetic disorder mainly characterized by facial differences, respiratory and genitourinary abnormalities as well as developmental delay or intellectual disabilities.Facial features may include widely spaced eyes (hypertelorism), a prominent forehead, widow’s peak, broad nasal bridge, nostrils that are tipped forward and cleft lip/palate.Respiratory abnormalities can include laryngo-esophageal clefts or the less severe laryngomalacia (soft larynx) that result in difficult swallowing and breathing. Genitourinary problems can include abnormal placement of the urethra in the penis (hypospadias), undescended testes and sometimes kidney abnormalities. Anal abnormalities may also be present and include absent or mis-positioned anal opening. Congenital heart defects such as ventral septal defects and atrial septal defects might be present as well as brain abnormalities such as agenesis or hypoplasia of the brain region that connects the two hemispheres (corpus callosum) and hypoplasia of the cerebellum also in the context of more complex defects such as Dandy-Walker malformation.There is a wide variation in the presentation of the clinical signs and in the severity of this condition, even among members of the same family.Approximately 50% of affected males have developmental delay or intellectual disability that can range from mild to severe. Carrier females usually have hypertelorism only.
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X-linked Opitz G/BBB Syndrome
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Causes of X-linked Opitz G/BBB Syndrome
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The MID1 gene is the only gene known to be associated with X-linked Opitz G/BBB syndrome.X-linked Opitz G/BBB syndrome is inherited as an X-linked genetic condition. X-linked genetic disorders are conditions caused by a mutated gene on the X chromosome and mostly affect males. Females who have a mutated gene on one of their X chromosomes are carriers for that disorder. Carrier females usually do not have symptoms because females have two X chromosomes and only one carries the mutated gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a mutated gene, he will develop the disease. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son. If a male with an X-linked disorder can reproduce, he will pass the mutated gene to all his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male children.
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Causes of X-linked Opitz G/BBB Syndrome. The MID1 gene is the only gene known to be associated with X-linked Opitz G/BBB syndrome.X-linked Opitz G/BBB syndrome is inherited as an X-linked genetic condition. X-linked genetic disorders are conditions caused by a mutated gene on the X chromosome and mostly affect males. Females who have a mutated gene on one of their X chromosomes are carriers for that disorder. Carrier females usually do not have symptoms because females have two X chromosomes and only one carries the mutated gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a mutated gene, he will develop the disease. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son. If a male with an X-linked disorder can reproduce, he will pass the mutated gene to all his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male children.
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X-linked Opitz G/BBB Syndrome
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Affects of X-linked Opitz G/BBB Syndrome
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The prevalence of X-linked Opitz G/BBB syndrome is estimated to be 1/50,000-1/100,000 males.
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Affects of X-linked Opitz G/BBB Syndrome. The prevalence of X-linked Opitz G/BBB syndrome is estimated to be 1/50,000-1/100,000 males.
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Related disorders of X-linked Opitz G/BBB Syndrome
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Chromosome 22q11.2 deletion syndrome is now known to include the autosomal dominant form of Opitz G/BBB syndrome. In addition to the different inheritance pattern, this condition can be distinguished from X-linked Opitz G/BBB syndrome by chromosome analysis that often shows a submicroscopic deletion of chromosome 22. (For more information on this disorder, choose “chromosome 22q11.2 deletion” as your search term in the Rare Disease Database.) Variants in the SPECC1L gene located on chromosome 22 have been reported in some patients with autosomal dominant Opitz syndrome, suggesting that this is a cause of this form of this disease (Kruszka P, et al. 2015). However, publications that reviewed the spectrum of characteristics associated with SPECC1L variants indicated that some clinical features specific to Opitz syndrome are not seen in patients with variants in the SPECC1L gene (Bho, EJ, et al. 2015; Zhang, T., et al 2020). Further, a study confirmed that patients with a diagnosis of Opitz syndrome are not likely to have SPECC1L pathogenic missense variants (Migliore C, et al. 2022).FG syndrome type 1 (FGS1) is an X-linked genetic disorder that is characterized by poor muscle tone (hypotonia), intellectual disability, constipation and or anal anomalies and complete or partial absence of the part of the brain that connects the two hemispheres of the brain (corpus callosum). Other features of the disorder are small and simple ears, tall and prominent forehead, wide and flat thumbs and great toes and down slanting eyes. FGS1 is an X-linked genetic disorder caused by a variant in the MED12 gene. The spectrum of disorders caused by variants in this gene is still being defined. (For more information on this disorder, choose “FG” as your search term in the Rare Disease Database.)Craniofrontonasal dysplasia is a very rare inherited disorder characterized by differences of the head and face (craniofacial area), hands and feet and certain skeletal bones. Major symptoms of this disorder may include widely spaced eyes (ocular hypertelorism), a groove (cleft) on the tip of the nose, an unusually wide mouth, malformations of the fingers and toes and/or underdevelopment of portions of the face (midface hypoplasia), such as the forehead, nose and chin. In addition, the head may have an unusual shape due to premature closure of the fibrous joints (sutures) between certain bones in the skull (coronal synostosis). Craniofrontonasal dysplasia follows X-linked inheritance in most families, but females are more severely affected than males. An autosomal dominant form of the disorder has also been discussed in the medical literature. (For more information on this disorder, choose “craniofrontonasal” as your search term in the Rare Disease Database.)Mowat-Wilson syndrome (MWS) is a rare genetic disorder that may be apparent at birth or in the first year of life. MWS is characterized by intellectual disability, distinctive facial features and seizures. Other congenital anomalies occur in some individuals and can include a gastrointestinal disease known as Hirschsprung disease in which a narrowing of a portion of the colon is present, heart (cardiac) defects, kidney (renal) abnormalities, male genital abnormalities and short stature. Some affected individuals may not be recognized until childhood or adulthood, especially when Hirschsprung disease is not present. Mowat-Wilson syndrome is caused by a variant in the ZFHX1B gene that is usually not inherited. (For more information on this disorder, choose “Mowat-Wilson” as your search term in the Rare Disease Database.)
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Related disorders of X-linked Opitz G/BBB Syndrome. Chromosome 22q11.2 deletion syndrome is now known to include the autosomal dominant form of Opitz G/BBB syndrome. In addition to the different inheritance pattern, this condition can be distinguished from X-linked Opitz G/BBB syndrome by chromosome analysis that often shows a submicroscopic deletion of chromosome 22. (For more information on this disorder, choose “chromosome 22q11.2 deletion” as your search term in the Rare Disease Database.) Variants in the SPECC1L gene located on chromosome 22 have been reported in some patients with autosomal dominant Opitz syndrome, suggesting that this is a cause of this form of this disease (Kruszka P, et al. 2015). However, publications that reviewed the spectrum of characteristics associated with SPECC1L variants indicated that some clinical features specific to Opitz syndrome are not seen in patients with variants in the SPECC1L gene (Bho, EJ, et al. 2015; Zhang, T., et al 2020). Further, a study confirmed that patients with a diagnosis of Opitz syndrome are not likely to have SPECC1L pathogenic missense variants (Migliore C, et al. 2022).FG syndrome type 1 (FGS1) is an X-linked genetic disorder that is characterized by poor muscle tone (hypotonia), intellectual disability, constipation and or anal anomalies and complete or partial absence of the part of the brain that connects the two hemispheres of the brain (corpus callosum). Other features of the disorder are small and simple ears, tall and prominent forehead, wide and flat thumbs and great toes and down slanting eyes. FGS1 is an X-linked genetic disorder caused by a variant in the MED12 gene. The spectrum of disorders caused by variants in this gene is still being defined. (For more information on this disorder, choose “FG” as your search term in the Rare Disease Database.)Craniofrontonasal dysplasia is a very rare inherited disorder characterized by differences of the head and face (craniofacial area), hands and feet and certain skeletal bones. Major symptoms of this disorder may include widely spaced eyes (ocular hypertelorism), a groove (cleft) on the tip of the nose, an unusually wide mouth, malformations of the fingers and toes and/or underdevelopment of portions of the face (midface hypoplasia), such as the forehead, nose and chin. In addition, the head may have an unusual shape due to premature closure of the fibrous joints (sutures) between certain bones in the skull (coronal synostosis). Craniofrontonasal dysplasia follows X-linked inheritance in most families, but females are more severely affected than males. An autosomal dominant form of the disorder has also been discussed in the medical literature. (For more information on this disorder, choose “craniofrontonasal” as your search term in the Rare Disease Database.)Mowat-Wilson syndrome (MWS) is a rare genetic disorder that may be apparent at birth or in the first year of life. MWS is characterized by intellectual disability, distinctive facial features and seizures. Other congenital anomalies occur in some individuals and can include a gastrointestinal disease known as Hirschsprung disease in which a narrowing of a portion of the colon is present, heart (cardiac) defects, kidney (renal) abnormalities, male genital abnormalities and short stature. Some affected individuals may not be recognized until childhood or adulthood, especially when Hirschsprung disease is not present. Mowat-Wilson syndrome is caused by a variant in the ZFHX1B gene that is usually not inherited. (For more information on this disorder, choose “Mowat-Wilson” as your search term in the Rare Disease Database.)
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X-linked Opitz G/BBB Syndrome
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Diagnosis of X-linked Opitz G/BBB Syndrome
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The diagnosis of Opitz G/BBB syndrome is usually suspected based on clinical findings. It is not possible to distinguish this condition from chromosome 22q11.2 deletion syndrome (autosomal dominant Opitz G/BBB syndrome) based on physical features alone. Diagnosis of X-linked Opitz syndrome can be confirmed by molecular genetic testing for variants in the MID1 gene and 15%-45% of affected males have been found to have a MID1 gene variant.
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Diagnosis of X-linked Opitz G/BBB Syndrome. The diagnosis of Opitz G/BBB syndrome is usually suspected based on clinical findings. It is not possible to distinguish this condition from chromosome 22q11.2 deletion syndrome (autosomal dominant Opitz G/BBB syndrome) based on physical features alone. Diagnosis of X-linked Opitz syndrome can be confirmed by molecular genetic testing for variants in the MID1 gene and 15%-45% of affected males have been found to have a MID1 gene variant.
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X-linked Opitz G/BBB Syndrome
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Therapies of X-linked Opitz G/BBB Syndrome
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Treatment
X-linked Opitz G/BBB syndrome is treated by a team of specialists including surgeons, speech therapists, neuropsychologists and early intervention specialists. Regular assessment of hearing is recommended for affected children with cleft lip and palate.Genetic counseling is recommended for affected individuals and their family members.
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Therapies of X-linked Opitz G/BBB Syndrome. Treatment
X-linked Opitz G/BBB syndrome is treated by a team of specialists including surgeons, speech therapists, neuropsychologists and early intervention specialists. Regular assessment of hearing is recommended for affected children with cleft lip and palate.Genetic counseling is recommended for affected individuals and their family members.
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X-linked Opitz G/BBB Syndrome
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Overview of X-Linked Protoporphyria
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SummaryX-linked protoporphyria is an extremely rare genetic disorder characterized by an abnormal sensitivity to the sun (photosensitivity) that can cause severe pain, burning, and itching of sun-exposed skin. Symptoms may occur immediately or shortly after exposure to the sun, including direct exposure or indirect exposure such as sunlight that passes through window glass or that is reflected off water or sand. Redness and swelling of affected areas can also occur. Blistering and severe scarring occur infrequently. Chronic episodes of photosensitivity may lead to changes in the skin of sun-exposed areas. Some individuals eventually develop potentially severe liver disease. X-linked protoporphyria is caused by mutations of the ALAS2 gene and is inherited in an X-linked dominant pattern. Males often develop a severe form of the disorder while females may not develop any symptoms (asymptomatic) or can develop a form as severe as that seen in males.IntroductionX-linked protoporphyria belongs to a group of disorders known as the porphyrias. This group of at least eight disorders is characterized by abnormally high levels of porphyrins and porphyrin precursors due to deficiency of certain enzymes essential to the creation (synthesis) of heme, a part of hemoglobin and other hemoproteins. There are eight enzymes in the pathway for making heme and at least eight different forms of porphyria. The symptoms associated with the various forms of porphyria differ. It is important to note that people who have one type of porphyria do not develop any of the other types. Porphyrias are generally classified into two groups: the “hepatic” and “erythropoietic” types. Porphyrins and porphyrin precursors and related substances originate in excess amounts chiefly from the liver in the hepatic types and mostly from the bone marrow in the erythropoietic types. Porphyrias with skin manifestations are sometimes referred to as “cutaneous porphyrias.” The term “acute porphyria” is used to describe porphyrias that can be associated with sudden attacks of pain and other neurological symptoms.X-linked protoporphyria is an erythropoietic form of porphyria and is extremely similar clinically to erythropoietic protoporphyria (EPP). X-linked protoporphyria was first described in the medical literature in 2008.
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Overview of X-Linked Protoporphyria. SummaryX-linked protoporphyria is an extremely rare genetic disorder characterized by an abnormal sensitivity to the sun (photosensitivity) that can cause severe pain, burning, and itching of sun-exposed skin. Symptoms may occur immediately or shortly after exposure to the sun, including direct exposure or indirect exposure such as sunlight that passes through window glass or that is reflected off water or sand. Redness and swelling of affected areas can also occur. Blistering and severe scarring occur infrequently. Chronic episodes of photosensitivity may lead to changes in the skin of sun-exposed areas. Some individuals eventually develop potentially severe liver disease. X-linked protoporphyria is caused by mutations of the ALAS2 gene and is inherited in an X-linked dominant pattern. Males often develop a severe form of the disorder while females may not develop any symptoms (asymptomatic) or can develop a form as severe as that seen in males.IntroductionX-linked protoporphyria belongs to a group of disorders known as the porphyrias. This group of at least eight disorders is characterized by abnormally high levels of porphyrins and porphyrin precursors due to deficiency of certain enzymes essential to the creation (synthesis) of heme, a part of hemoglobin and other hemoproteins. There are eight enzymes in the pathway for making heme and at least eight different forms of porphyria. The symptoms associated with the various forms of porphyria differ. It is important to note that people who have one type of porphyria do not develop any of the other types. Porphyrias are generally classified into two groups: the “hepatic” and “erythropoietic” types. Porphyrins and porphyrin precursors and related substances originate in excess amounts chiefly from the liver in the hepatic types and mostly from the bone marrow in the erythropoietic types. Porphyrias with skin manifestations are sometimes referred to as “cutaneous porphyrias.” The term “acute porphyria” is used to describe porphyrias that can be associated with sudden attacks of pain and other neurological symptoms.X-linked protoporphyria is an erythropoietic form of porphyria and is extremely similar clinically to erythropoietic protoporphyria (EPP). X-linked protoporphyria was first described in the medical literature in 2008.
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X-Linked Protoporphyria
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Symptoms of X-Linked Protoporphyria
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Hypersensitivity of the skin to sunlight is the characteristic finding of X-linked protoporphyria. Affected individuals develop pain, itching, and burning of the skin after exposure to sunlight. Sometimes these symptoms are accompanied by swelling and redness (erythema) of the affected areas. Large blisters and severe scarring, which are common to other forms of cutaneous porphyria, usually do not occur in individuals with X-linked protoporphyria. Symptoms may be noticed as quickly as a few minutes after exposure to the sun. Although most symptoms usually subside within 24-48 hours, pain and a red or purple discoloration of the skin may persist for several days after the initial incident. Pain is disproportionately severe in relation to the visible skin lesions. Pain associated with X-linked protoporphyria can be excruciating and is often resistant to pain medications, even narcotics.Repeated episodes of photosensitivity may eventually cause changes in the skin of affected individuals. Such changes include thickening and hardening of the skin, development of a rough or leathery texture, small facial pock-like pits, and grooving around the lips.Some individuals with X-linked protoporphyria develop liver disease, which can range from mild liver abnormalities to liver failure. Information on liver disease is limited, but the risk of liver disease is believed to be higher in X-linked protoporphyria than in EPP. Affected individuals may experience back pain and severe abdominal pain especially in the upper right area of the abdomen. In some affected individuals, the flow of bile through the gallbladder and bile ducts may be interrupted (cholestasis) leading to gallstones. These stones can cause obstruction and inflammation of the gallbladder (cholecystitis). Scarring of the liver (cirrhosis) may also develop and some individuals may eventually develop end stage liver failure.Additional symptoms have been reported in individuals with X-linked protoporphyria including mild anemia (low levels of circulating red blood cells) and iron deficiency.
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Symptoms of X-Linked Protoporphyria. Hypersensitivity of the skin to sunlight is the characteristic finding of X-linked protoporphyria. Affected individuals develop pain, itching, and burning of the skin after exposure to sunlight. Sometimes these symptoms are accompanied by swelling and redness (erythema) of the affected areas. Large blisters and severe scarring, which are common to other forms of cutaneous porphyria, usually do not occur in individuals with X-linked protoporphyria. Symptoms may be noticed as quickly as a few minutes after exposure to the sun. Although most symptoms usually subside within 24-48 hours, pain and a red or purple discoloration of the skin may persist for several days after the initial incident. Pain is disproportionately severe in relation to the visible skin lesions. Pain associated with X-linked protoporphyria can be excruciating and is often resistant to pain medications, even narcotics.Repeated episodes of photosensitivity may eventually cause changes in the skin of affected individuals. Such changes include thickening and hardening of the skin, development of a rough or leathery texture, small facial pock-like pits, and grooving around the lips.Some individuals with X-linked protoporphyria develop liver disease, which can range from mild liver abnormalities to liver failure. Information on liver disease is limited, but the risk of liver disease is believed to be higher in X-linked protoporphyria than in EPP. Affected individuals may experience back pain and severe abdominal pain especially in the upper right area of the abdomen. In some affected individuals, the flow of bile through the gallbladder and bile ducts may be interrupted (cholestasis) leading to gallstones. These stones can cause obstruction and inflammation of the gallbladder (cholecystitis). Scarring of the liver (cirrhosis) may also develop and some individuals may eventually develop end stage liver failure.Additional symptoms have been reported in individuals with X-linked protoporphyria including mild anemia (low levels of circulating red blood cells) and iron deficiency.
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Causes of X-Linked Protoporphyria
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X-linked protoporphyria is caused by gain-of-function mutations to the ALAS2 gene located on the X chromosome and is inherited as an X-linked dominant disorder. In contrast to most X-linked disorders, which are recessive, X-linked dominant disorders are evident in a female with one normal X chromosome and one affected X chromosome.The ALAS2 gene encodes a protein known as erythroid specific 5-aminolevulinate synthase 2. Mutations of the ALAS2 gene lead to the overproduction of this enzyme, which, in turn, results in elevated levels of a chemical called protoporphyrin. Protoporphyrin abnormally accumulates in certain tissues of the body, especially the blood, liver, and skin. The symptoms of X-linked protoporphyria develop because of this abnormal accumulation of protoporphyrin. For example, when protoporphyrin molecules absorb energy from sunlight, they enter an excited state (photoactivation) and this abnormal activation results in the characteristic damage to the skin. Accumulation of protoporphyrin in the liver causes toxic damage to the liver and may contribute to the formation of gallstones. Protoporphyrin is formed within red blood cells in the bone marrow and then enters the blood plasma, which carries it to the skin where it can be photoactivated by sunlight and cause damage. The liver removes protoporphyrin from the blood plasma and secretes it into the bile.
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Causes of X-Linked Protoporphyria. X-linked protoporphyria is caused by gain-of-function mutations to the ALAS2 gene located on the X chromosome and is inherited as an X-linked dominant disorder. In contrast to most X-linked disorders, which are recessive, X-linked dominant disorders are evident in a female with one normal X chromosome and one affected X chromosome.The ALAS2 gene encodes a protein known as erythroid specific 5-aminolevulinate synthase 2. Mutations of the ALAS2 gene lead to the overproduction of this enzyme, which, in turn, results in elevated levels of a chemical called protoporphyrin. Protoporphyrin abnormally accumulates in certain tissues of the body, especially the blood, liver, and skin. The symptoms of X-linked protoporphyria develop because of this abnormal accumulation of protoporphyrin. For example, when protoporphyrin molecules absorb energy from sunlight, they enter an excited state (photoactivation) and this abnormal activation results in the characteristic damage to the skin. Accumulation of protoporphyrin in the liver causes toxic damage to the liver and may contribute to the formation of gallstones. Protoporphyrin is formed within red blood cells in the bone marrow and then enters the blood plasma, which carries it to the skin where it can be photoactivated by sunlight and cause damage. The liver removes protoporphyrin from the blood plasma and secretes it into the bile.
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X-Linked Protoporphyria
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Affects of X-Linked Protoporphyria
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X-linked protoporphyria affects males and females. However, males usually develop a severe form of the disorder while females with an ALAS2 mutation may range from having no symptoms (asymptomatic) to developing a severe form of the disorder. The exact incidence or prevalence of X-linked protoporphyria is unknown. The disorder has only been reported in the medical literature in a handful of families in Europe, South Africa and Japan.
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Affects of X-Linked Protoporphyria. X-linked protoporphyria affects males and females. However, males usually develop a severe form of the disorder while females with an ALAS2 mutation may range from having no symptoms (asymptomatic) to developing a severe form of the disorder. The exact incidence or prevalence of X-linked protoporphyria is unknown. The disorder has only been reported in the medical literature in a handful of families in Europe, South Africa and Japan.
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X-Linked Protoporphyria
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Related disorders of X-Linked Protoporphyria
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Symptoms of the following disorders can be similar to those of X-linked protoporphyria. Comparisons may be useful for a differential diagnosis.Erythropoietic protoporphyria (EPP) is a rare inherited metabolic disorder characterized by a deficiency of the enzyme ferrochelatase (FECH). Due to abnormally low activity of this enzyme, excessive amounts of protoporphyrin accumulate in the bone marrow, blood plasma, and red blood cells. The major symptom of this disorder is hypersensitivity of the skin to sunlight and some types of artificial light, such as fluorescent lights (photosensitivity). After exposure to light, the skin may become itchy or painful, and red or swollen. The hands, arms, and face are the most commonly affected areas. Some people with erythropoietic protoporphyria may also have complications related to liver and gallbladder function. (For more information on this disorder, choose “erythropoietic protoporphyria” as your search term in the Rare Disease Database.)There are other conditions that may cause signs and symptoms that are similar to those seen in X-linked protoporphyria. Such conditions include other cutaneous porphyrias such as variegate porphyria, drug-induced photosensitivity, various forms of lupus, and solar urticaria. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Related disorders of X-Linked Protoporphyria. Symptoms of the following disorders can be similar to those of X-linked protoporphyria. Comparisons may be useful for a differential diagnosis.Erythropoietic protoporphyria (EPP) is a rare inherited metabolic disorder characterized by a deficiency of the enzyme ferrochelatase (FECH). Due to abnormally low activity of this enzyme, excessive amounts of protoporphyrin accumulate in the bone marrow, blood plasma, and red blood cells. The major symptom of this disorder is hypersensitivity of the skin to sunlight and some types of artificial light, such as fluorescent lights (photosensitivity). After exposure to light, the skin may become itchy or painful, and red or swollen. The hands, arms, and face are the most commonly affected areas. Some people with erythropoietic protoporphyria may also have complications related to liver and gallbladder function. (For more information on this disorder, choose “erythropoietic protoporphyria” as your search term in the Rare Disease Database.)There are other conditions that may cause signs and symptoms that are similar to those seen in X-linked protoporphyria. Such conditions include other cutaneous porphyrias such as variegate porphyria, drug-induced photosensitivity, various forms of lupus, and solar urticaria. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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X-Linked Protoporphyria
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nord_1313_5
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Diagnosis of X-Linked Protoporphyria
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A diagnosis of X-linked protoporphyria is based upon identification of characteristic symptoms (e.g., non-blistering photosensitivity), a detailed patient history, a thorough clinical evaluation, and a variety of specialized tests.Clinical Testing and Workup
A diagnosis of X-linked protoporphyria may be made through blood tests that can detect markedly increased levels of metal-free and zinc-bound protoporphyrins within red blood cells (erythrocytes). A higher ratio of zinc-bound protoporphyrin to metal-free protoporphyrin can differentiate X-linked protoporphyria from EPP.Molecular genetic testing can confirm a diagnosis of X-linked protoporphyria by detecting mutations in the ALAS2 gene (the only gene known to cause this disorder).Additional tests may be performed such as blood tests to evaluate anemia and iron stores in the body and vitamin D levels, or an abdominal sonogram to detect and evaluate liver disease potentially associated with X-linked protoporphyria.
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Diagnosis of X-Linked Protoporphyria. A diagnosis of X-linked protoporphyria is based upon identification of characteristic symptoms (e.g., non-blistering photosensitivity), a detailed patient history, a thorough clinical evaluation, and a variety of specialized tests.Clinical Testing and Workup
A diagnosis of X-linked protoporphyria may be made through blood tests that can detect markedly increased levels of metal-free and zinc-bound protoporphyrins within red blood cells (erythrocytes). A higher ratio of zinc-bound protoporphyrin to metal-free protoporphyrin can differentiate X-linked protoporphyria from EPP.Molecular genetic testing can confirm a diagnosis of X-linked protoporphyria by detecting mutations in the ALAS2 gene (the only gene known to cause this disorder).Additional tests may be performed such as blood tests to evaluate anemia and iron stores in the body and vitamin D levels, or an abdominal sonogram to detect and evaluate liver disease potentially associated with X-linked protoporphyria.
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X-Linked Protoporphyria
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nord_1313_6
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Therapies of X-Linked Protoporphyria
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The treatment of X-linked protoporphyria is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, hematologists, dermatologists, hepatologists, and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment.Genetic counseling is recommended affected individuals and their families.There is no specific, FDA-approved therapy for individuals with X-linked protoporphyria. Because the disorder is so rare, most treatment information is based on EPP, which is clinically similar to X-linked protoporphyria.Avoidance of sunlight will benefit affected individuals and can include the use of clothing styles with long sleeves and pant legs, made with double layers of fabric or of light-exclusive fabrics, wide brimmed hats, gloves, and sunglasses. Topical sunscreens are generally ineffective, unless they contain light-reflective ingredients. Certain tanning products with ingredients that increase pigmentation may be helpful. Affected individuals may also benefit from window tinting and the use of light-filtering vinyl or films to cover the windows of their homes and cars.Avoidance of sunlight can potentially cause vitamin D deficiency and some individuals may require supplemental vitamin D.A high potency form of oral beta-carotene (Lumitene) may be given to improve an affected individual’s tolerance of sunlight. This drug causes skin discoloration and may improve tolerance to sunlight. For more information on this treatment, contact the organizations listed at the end of this report (i.e. American Porphyria Foundation and the EPPREF). Another drug sometimes used to improve tolerance to sunlight is cysteine.In some patients, the drug cholestyramine may be given. Cholestyramine absorbs porphyrin. The drug may interrupt the recirculation of protoporphyrin secreted into the bile back into the liver and promote its excretion through the feces. Other drugs that absorb porphyrins such as activated charcoal have also been used to treat affected individuals. These drugs may lead to improvement of liver disease.Individuals with any form of protoporphyria should avoid substances associated with cholestasis including alcohol and certain drugs such as estrogens. Immunizations for hepatitis A and B are recommended as well.Afamelanotide, an alpha-melanocyte-stimulating hormone analogue, increases the production of melanin in the skin. Afamelanotide has been available for adults with EPP in the European Union since 2014. It was approved for adults with EPP by the US Food and Drug Administration (FDA) in October 2019. The long-term safety and effectiveness of this drug and its role in treating individuals with X-linked protoporphyria remain under investigation.
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Therapies of X-Linked Protoporphyria. The treatment of X-linked protoporphyria is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, hematologists, dermatologists, hepatologists, and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment.Genetic counseling is recommended affected individuals and their families.There is no specific, FDA-approved therapy for individuals with X-linked protoporphyria. Because the disorder is so rare, most treatment information is based on EPP, which is clinically similar to X-linked protoporphyria.Avoidance of sunlight will benefit affected individuals and can include the use of clothing styles with long sleeves and pant legs, made with double layers of fabric or of light-exclusive fabrics, wide brimmed hats, gloves, and sunglasses. Topical sunscreens are generally ineffective, unless they contain light-reflective ingredients. Certain tanning products with ingredients that increase pigmentation may be helpful. Affected individuals may also benefit from window tinting and the use of light-filtering vinyl or films to cover the windows of their homes and cars.Avoidance of sunlight can potentially cause vitamin D deficiency and some individuals may require supplemental vitamin D.A high potency form of oral beta-carotene (Lumitene) may be given to improve an affected individual’s tolerance of sunlight. This drug causes skin discoloration and may improve tolerance to sunlight. For more information on this treatment, contact the organizations listed at the end of this report (i.e. American Porphyria Foundation and the EPPREF). Another drug sometimes used to improve tolerance to sunlight is cysteine.In some patients, the drug cholestyramine may be given. Cholestyramine absorbs porphyrin. The drug may interrupt the recirculation of protoporphyrin secreted into the bile back into the liver and promote its excretion through the feces. Other drugs that absorb porphyrins such as activated charcoal have also been used to treat affected individuals. These drugs may lead to improvement of liver disease.Individuals with any form of protoporphyria should avoid substances associated with cholestasis including alcohol and certain drugs such as estrogens. Immunizations for hepatitis A and B are recommended as well.Afamelanotide, an alpha-melanocyte-stimulating hormone analogue, increases the production of melanin in the skin. Afamelanotide has been available for adults with EPP in the European Union since 2014. It was approved for adults with EPP by the US Food and Drug Administration (FDA) in October 2019. The long-term safety and effectiveness of this drug and its role in treating individuals with X-linked protoporphyria remain under investigation.
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X-Linked Protoporphyria
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nord_1314_0
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Overview of X-linked Retinoschisis
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X-linked retinoschisis (XLRS) is a genetic condition affecting boys and men. It is typically diagnosed in childhood, in some cases as early as three months of age. The main symptom is reduced vision that cannot be improved with glasses. While some people with XLRS may experience progressive vision loss throughout their life, other people may have relatively stable vision throughout their lifetime. XLRS is caused by mutations in a gene on the X chromosome called RS1 which encodes a protein called retinoschisin. This protein is important for the development and maintenance of the retina (the tissue lining the back of the eye). Without normal retinoschisin protein, the layers of the retina split (“schisis”), inter-cell communication is disrupted and vision is lost.
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Overview of X-linked Retinoschisis. X-linked retinoschisis (XLRS) is a genetic condition affecting boys and men. It is typically diagnosed in childhood, in some cases as early as three months of age. The main symptom is reduced vision that cannot be improved with glasses. While some people with XLRS may experience progressive vision loss throughout their life, other people may have relatively stable vision throughout their lifetime. XLRS is caused by mutations in a gene on the X chromosome called RS1 which encodes a protein called retinoschisin. This protein is important for the development and maintenance of the retina (the tissue lining the back of the eye). Without normal retinoschisin protein, the layers of the retina split (“schisis”), inter-cell communication is disrupted and vision is lost.
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X-linked Retinoschisis
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nord_1314_1
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Symptoms of X-linked Retinoschisis
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The main symptom of XLRS is reduced visual acuity. While variable, vision is typically in the 20/60 to 20/120 range. Some people with XLRS experience retinal detachment or bleeding within the eye. Classically, the natural history of XLRS has been described as progressive in childhood, plateauing, then progressive in later adulthood. However, in uncomplicated cases, visual prognosis is usually good and there can be little progression in a person’s lifetime. Most patients with XLRS never reach the point of legal blindness.
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Symptoms of X-linked Retinoschisis. The main symptom of XLRS is reduced visual acuity. While variable, vision is typically in the 20/60 to 20/120 range. Some people with XLRS experience retinal detachment or bleeding within the eye. Classically, the natural history of XLRS has been described as progressive in childhood, plateauing, then progressive in later adulthood. However, in uncomplicated cases, visual prognosis is usually good and there can be little progression in a person’s lifetime. Most patients with XLRS never reach the point of legal blindness.
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X-linked Retinoschisis
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