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nord_742_6
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Therapies of Machado-Joseph Disease
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TreatmentTreatment is symptomatic and supportive. The drugs L- dopa and baclofen may relieve muscle rigidity and spasticity. Individuals with at least one family member who has been diagnosed with this disease should consider genetic counseling.
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Therapies of Machado-Joseph Disease. TreatmentTreatment is symptomatic and supportive. The drugs L- dopa and baclofen may relieve muscle rigidity and spasticity. Individuals with at least one family member who has been diagnosed with this disease should consider genetic counseling.
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Machado-Joseph Disease
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nord_743_0
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Overview of Macroglossia
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Macroglossia is the abnormal enlargement of the tongue. In rare cases, macroglossia occurs as an isolated finding that is present at birth (congenital). In many cases, macroglossia may occur secondary to a primary disorder that may be either congenital (e.g., Down syndrome or Beckwith-Wiedemann syndrome) or acquired (e.g., as a result of trauma or malignancy). Symptoms and physical findings associated with macroglossia may include noisy, high-pitched breathing (stridor), snoring, and/or feeding difficulties. In some cases, the tongue may protrude from the mouth. When inherited, macroglossia is transmitted as an autosomal dominant genetic trait.
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Overview of Macroglossia. Macroglossia is the abnormal enlargement of the tongue. In rare cases, macroglossia occurs as an isolated finding that is present at birth (congenital). In many cases, macroglossia may occur secondary to a primary disorder that may be either congenital (e.g., Down syndrome or Beckwith-Wiedemann syndrome) or acquired (e.g., as a result of trauma or malignancy). Symptoms and physical findings associated with macroglossia may include noisy, high-pitched breathing (stridor), snoring, and/or feeding difficulties. In some cases, the tongue may protrude from the mouth. When inherited, macroglossia is transmitted as an autosomal dominant genetic trait.
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Macroglossia
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nord_743_1
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Symptoms of Macroglossia
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Macroglossia is a disorder characterized by a tongue that is large in proportion to other structures in the mouth. In the congenital type of the disorder, protrusion of the tongue from the mouth may interfere with feeding of the infant. Later, talking may be affected. The large size of the tongue may also cause abnormal development of the jaw and teeth, resulting in misaligned or protruding teeth. Ulceration and dying tissue on the tip of the tongue may be other symptoms of the disorder.
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Symptoms of Macroglossia. Macroglossia is a disorder characterized by a tongue that is large in proportion to other structures in the mouth. In the congenital type of the disorder, protrusion of the tongue from the mouth may interfere with feeding of the infant. Later, talking may be affected. The large size of the tongue may also cause abnormal development of the jaw and teeth, resulting in misaligned or protruding teeth. Ulceration and dying tissue on the tip of the tongue may be other symptoms of the disorder.
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Macroglossia
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nord_743_2
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Causes of Macroglossia
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Macroglossia may be found in individuals affected by certain inherited or congenital disorders including Beckwith-Wiedemann syndrome, acromegaly, primary amyloidosis, congenital hypothyroidism, Down syndrome, Apert syndrome, and many others. Macroglossia may also be a sign of certain acquired disorders, including malignancies, metabolic/endocrine disorders, and inflammatory or infectious diseases.In rare cases, macroglossia is an inherited disorder not associated with any other cause, either congenital or acquired. In such instances, the disorder is genetically transmitted as an autosomal dominant trait. 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% for each pregnancy regardless of the sex of the resulting child.
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Causes of Macroglossia. Macroglossia may be found in individuals affected by certain inherited or congenital disorders including Beckwith-Wiedemann syndrome, acromegaly, primary amyloidosis, congenital hypothyroidism, Down syndrome, Apert syndrome, and many others. Macroglossia may also be a sign of certain acquired disorders, including malignancies, metabolic/endocrine disorders, and inflammatory or infectious diseases.In rare cases, macroglossia is an inherited disorder not associated with any other cause, either congenital or acquired. In such instances, the disorder is genetically transmitted as an autosomal dominant trait. 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% for each pregnancy regardless of the sex of the resulting child.
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Macroglossia
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nord_743_3
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Affects of Macroglossia
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Isolated autosomal dominant macroglossia is very rare, with about 50 cases reported in the medical literature. The prevalence in other instances depends on the underlying disorder for which the macroglossia is secondary. For example, macroglossia occurs in most cases of Beckwith-Wiedemann syndrome, and the prevalence of that syndrome is estimated at 1 in 17,000 births.
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Affects of Macroglossia. Isolated autosomal dominant macroglossia is very rare, with about 50 cases reported in the medical literature. The prevalence in other instances depends on the underlying disorder for which the macroglossia is secondary. For example, macroglossia occurs in most cases of Beckwith-Wiedemann syndrome, and the prevalence of that syndrome is estimated at 1 in 17,000 births.
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Macroglossia
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nord_743_4
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Related disorders of Macroglossia
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Macroglossia may be an early sign of Acromegaly.In people who have lost their teeth (edentulous), in the absence of dentures, enlargement of the tongue may occur.In Moeller's Glossitis, the tongue is slick, glossy, or glazed. The lesions can be very distressing and persistent.Median Rhomboid Glossitis is a developmental lesion of the tongue. This lesion consists of a smooth, reddish, nodular area on the back portion of the middle third of the tongue.Hairy Tongue is characterized by yellowish, brownish, blackish or bluish discoloration of the tongue. Excessive growth of the threadlike elevations (filiform papillae) in front of the taste buds also occurs.Geographic Tongue is an inflammation of the tongue that may go into remission and recur again. This form of inflammation is characterized by smooth areas on the tongue which may feel slightly sore and sometimes itchy.Severe Acute Glossitis can be caused by local infection, burns, or injury to the tongue. This type of Glossitis may develop rapidly, producing marked tenderness or pain with swelling. In the most severe cases the swelling may be sufficient to cause the tongue to block air passages.For more information on the above disorders, choose tongue, acromegaly, hairy tongue, and geographic tongue as your search terms in the Rare Disease Database.
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Related disorders of Macroglossia. Macroglossia may be an early sign of Acromegaly.In people who have lost their teeth (edentulous), in the absence of dentures, enlargement of the tongue may occur.In Moeller's Glossitis, the tongue is slick, glossy, or glazed. The lesions can be very distressing and persistent.Median Rhomboid Glossitis is a developmental lesion of the tongue. This lesion consists of a smooth, reddish, nodular area on the back portion of the middle third of the tongue.Hairy Tongue is characterized by yellowish, brownish, blackish or bluish discoloration of the tongue. Excessive growth of the threadlike elevations (filiform papillae) in front of the taste buds also occurs.Geographic Tongue is an inflammation of the tongue that may go into remission and recur again. This form of inflammation is characterized by smooth areas on the tongue which may feel slightly sore and sometimes itchy.Severe Acute Glossitis can be caused by local infection, burns, or injury to the tongue. This type of Glossitis may develop rapidly, producing marked tenderness or pain with swelling. In the most severe cases the swelling may be sufficient to cause the tongue to block air passages.For more information on the above disorders, choose tongue, acromegaly, hairy tongue, and geographic tongue as your search terms in the Rare Disease Database.
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Macroglossia
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nord_743_5
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Diagnosis of Macroglossia
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Infants born with isolated autosomal dominant macroglossia present with the obvious sign at birth. A family history and physical exam can confirm the diagnosis.
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Diagnosis of Macroglossia. Infants born with isolated autosomal dominant macroglossia present with the obvious sign at birth. A family history and physical exam can confirm the diagnosis.
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Macroglossia
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nord_743_6
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Therapies of Macroglossia
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TreatmentThe tongue may be reduced in size by surgery with remodeling of the mouth and orthodontic procedures.
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Therapies of Macroglossia. TreatmentThe tongue may be reduced in size by surgery with remodeling of the mouth and orthodontic procedures.
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Macroglossia
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nord_744_0
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Overview of Madelung’s Disease
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SummaryMadelung’s disease is a rare disorder of fat metabolism (lipid storage) that results in an unusual accumulation of subcutaneous fat (adipose tissue) deposits around the neck, shoulders, trunk, hips, upper arms and thighs. The fat masses can progress quickly over months or slowly over years. Face and legs are usually spared in this benign condition, and biochemical parameters can also remain within normal limits. Madelung’s disease can be mistaken for obesity due to the symmetrical deposition of fat. Although painless, the fatty tumors can compromise function of other structures in the affected area causing patients to experience symptoms such as difficulty swallowing, speaking and breathing.Adult males between ages 30-70 with a history of excessive drinking (chronic alcoholism) are most often affected, although women and those who do not drink alcohol can also get Madelung's disease. This condition is more common in Mediterranean and European populations, and less frequent in Asian populations. The underlying causes of this condition aren’t fully understood which can lead to limitations in treatment options. Scientists have suggested that a dysregulation in the fat breakdown (lipolytic) pathway could be the culprit behind the excessive growth and division of fat cells (adipocytes). Familial cases with an autosomal dominant inheritance pattern have also been noted. For now, surgical removal of the fatty tumors through resection (lipectomy) or liposuction remains the primary treatment. Unfortunately, the effectiveness of current treatment options is limited as the disease has a high tendency to reoccur.IntroductionMadelung’s disease was first described by Benjamin Brodie in 1846, and then later as ‘fat neck’ (Fetthals) by Otto Madelung in 1888.
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Overview of Madelung’s Disease. SummaryMadelung’s disease is a rare disorder of fat metabolism (lipid storage) that results in an unusual accumulation of subcutaneous fat (adipose tissue) deposits around the neck, shoulders, trunk, hips, upper arms and thighs. The fat masses can progress quickly over months or slowly over years. Face and legs are usually spared in this benign condition, and biochemical parameters can also remain within normal limits. Madelung’s disease can be mistaken for obesity due to the symmetrical deposition of fat. Although painless, the fatty tumors can compromise function of other structures in the affected area causing patients to experience symptoms such as difficulty swallowing, speaking and breathing.Adult males between ages 30-70 with a history of excessive drinking (chronic alcoholism) are most often affected, although women and those who do not drink alcohol can also get Madelung's disease. This condition is more common in Mediterranean and European populations, and less frequent in Asian populations. The underlying causes of this condition aren’t fully understood which can lead to limitations in treatment options. Scientists have suggested that a dysregulation in the fat breakdown (lipolytic) pathway could be the culprit behind the excessive growth and division of fat cells (adipocytes). Familial cases with an autosomal dominant inheritance pattern have also been noted. For now, surgical removal of the fatty tumors through resection (lipectomy) or liposuction remains the primary treatment. Unfortunately, the effectiveness of current treatment options is limited as the disease has a high tendency to reoccur.IntroductionMadelung’s disease was first described by Benjamin Brodie in 1846, and then later as ‘fat neck’ (Fetthals) by Otto Madelung in 1888.
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Madelung’s Disease
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nord_744_1
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Symptoms of Madelung’s Disease
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Madelung’s disease is characterized by the presence of fatty tumors (lipomas) located symmetrically around the neck, shoulders, trunk, hips, upper arms and thighs. While these abnormal fatty tumors may grow over the course of months to years, the disease usually demonstrates a rapid progression at first and then slows down as the size of the fatty mass stabilizes. The rest of the body may be lean in contrast to the affected parts. In 1984, Enzi classified two variants of Madelung’s disease – type 1 and 2 – based on where the excess fat accumulated. The more frequent type 1 variant is common in males and manifests as fatty tumors primarily around the neck (known as ‘Madelung’s collar’) and upper shoulders with relative sparing of the trunk and arms. As a result, type 1 variant patients have a ‘pseudo-athletic’ appearance. In contrast, the type 2 variant is observed in both males and females equally and resembles ‘generalized obesity’ as the fatty deposition occurs in the trunk, upper portion of arms, abdomen, hips and upper thighs. In 1991, a type 3 (gynecoid type) variant was added to the classification characterized by fat accumulation primarily in the pelvic region.Peripheral neuropathy, or impaired function of the nerves in the arms and legs, often accompanies Madelung’s disease, especially as the affected person grows older. However, these neurological deficits may be difficult to distinguish from the long-term effects of alcoholism when overuse of alcohol is a factor. Nevertheless, the peripheral neuropathy may lead to decreased power in the muscles of the upper (proximal) portion of the arms and legs (myopathy). Symptoms can also arise from the fatty masses compressing important structures in the neck such as the airway (trachea), voice box (larynx), esophagus, and carotid blood vessels. Depending on the severity of the disease, the fatty tumors may cause patients to experience difficulty breathing (dyspnea), swallowing (dysphagia) and speaking (dysphonia). The patient can present with limited mobility of the neck and may even develop sleep apnea as the disease progresses. It is important to note that the physical changes in a patient’s body resulting from the excessive fatty deposition can take a toll on the patient’s mental health and lead them to suffer from depressive disorders. Social loss (ex. difficulty performing or maintaining a job) due to impaired mobility and other issues has been reported in patients.There are metabolic abnormalities and other conditions usually associated with Madelung’s disease. These include diabetes mellitus, hypertension, hypothyroidism, liver disease and gout. A vast majority of the patients (~90%) diagnosed with Madelung’s disease have secondary (alcohol-induced) liver cirrhosis. Although rare, some cases have demonstrated malignant transformation and association of the disease with airway and digestive tract malignancies.
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Symptoms of Madelung’s Disease. Madelung’s disease is characterized by the presence of fatty tumors (lipomas) located symmetrically around the neck, shoulders, trunk, hips, upper arms and thighs. While these abnormal fatty tumors may grow over the course of months to years, the disease usually demonstrates a rapid progression at first and then slows down as the size of the fatty mass stabilizes. The rest of the body may be lean in contrast to the affected parts. In 1984, Enzi classified two variants of Madelung’s disease – type 1 and 2 – based on where the excess fat accumulated. The more frequent type 1 variant is common in males and manifests as fatty tumors primarily around the neck (known as ‘Madelung’s collar’) and upper shoulders with relative sparing of the trunk and arms. As a result, type 1 variant patients have a ‘pseudo-athletic’ appearance. In contrast, the type 2 variant is observed in both males and females equally and resembles ‘generalized obesity’ as the fatty deposition occurs in the trunk, upper portion of arms, abdomen, hips and upper thighs. In 1991, a type 3 (gynecoid type) variant was added to the classification characterized by fat accumulation primarily in the pelvic region.Peripheral neuropathy, or impaired function of the nerves in the arms and legs, often accompanies Madelung’s disease, especially as the affected person grows older. However, these neurological deficits may be difficult to distinguish from the long-term effects of alcoholism when overuse of alcohol is a factor. Nevertheless, the peripheral neuropathy may lead to decreased power in the muscles of the upper (proximal) portion of the arms and legs (myopathy). Symptoms can also arise from the fatty masses compressing important structures in the neck such as the airway (trachea), voice box (larynx), esophagus, and carotid blood vessels. Depending on the severity of the disease, the fatty tumors may cause patients to experience difficulty breathing (dyspnea), swallowing (dysphagia) and speaking (dysphonia). The patient can present with limited mobility of the neck and may even develop sleep apnea as the disease progresses. It is important to note that the physical changes in a patient’s body resulting from the excessive fatty deposition can take a toll on the patient’s mental health and lead them to suffer from depressive disorders. Social loss (ex. difficulty performing or maintaining a job) due to impaired mobility and other issues has been reported in patients.There are metabolic abnormalities and other conditions usually associated with Madelung’s disease. These include diabetes mellitus, hypertension, hypothyroidism, liver disease and gout. A vast majority of the patients (~90%) diagnosed with Madelung’s disease have secondary (alcohol-induced) liver cirrhosis. Although rare, some cases have demonstrated malignant transformation and association of the disease with airway and digestive tract malignancies.
| 744 |
Madelung’s Disease
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nord_744_2
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Causes of Madelung’s Disease
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The exact cause of Madelung’s disease is not fully understood. The body’s inability to properly metabolize fat indicates that it may be an endocrine disorder. One theory is that a defect in the adrenergic (epinephrine or norepinephrine)-stimulated fat breakdown (lipolysis) process results in improper deposition of fat. Alcohol can also negatively impact the enzymatic processes in mitochondria (energy-supplying part of the cell) and can alter adrenergic lipolysis in the body. Radial red fibers in the muscles of Madelung’s patients have often been found, indicating a sign of impaired mitochondrial respiratory chain function. Some researchers have noted that the distribution and type of fat cells in the fatty tumors is similar to the brown fat found in infants. Linking this to the aforementioned theory, one study suggested that the fatty tumors formed in Madelung’s disease result from impaired mitochondrial regulation in the brown fat, causing increased division of fat cells (adipocyte hyperplasia). While current research suggests adrenergic pathways and mitochondrial dysfunction to be implicated in Madelung’s disease, a clear picture of the pathogenesis is yet to be determined.Most occurrences of Madelung’s disease tend to be sporadic, with no family history of the disease. However, some scientists believe a predisposition to the disorder may be inherited from parents (in this case, maternal inheritance) and there have been some reports of cases that appear to be familial. The mode of transmission has been suspected to be autosomal dominant in nature with a variable penetrance in mitochondrial DNA. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.Madelung’s disease research on multigenerational blood-related family members showed that each affected member carried an ultrarare MTTT c.8344A>G mutation in their mitochondrial DNA. Similarly, in another study, siblings with Madelung’s disease demonstrated mutations in the gene encoding for the enzyme that breaks down fat (lipase), thereby depressing the fat breakdown pathway. Disease-causing mutations have also been reported in the MFN2 gene encoding mitofusin 2 (a key protein in many mitochondrial processes) and the LIPE gene encoding the hormone sensitive lipase (protein involved in breaking down stored fats). While these are promising breakthroughs, science currently lags behind in understanding the full molecular pathway responsible for Madelung’s disease.
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Causes of Madelung’s Disease. The exact cause of Madelung’s disease is not fully understood. The body’s inability to properly metabolize fat indicates that it may be an endocrine disorder. One theory is that a defect in the adrenergic (epinephrine or norepinephrine)-stimulated fat breakdown (lipolysis) process results in improper deposition of fat. Alcohol can also negatively impact the enzymatic processes in mitochondria (energy-supplying part of the cell) and can alter adrenergic lipolysis in the body. Radial red fibers in the muscles of Madelung’s patients have often been found, indicating a sign of impaired mitochondrial respiratory chain function. Some researchers have noted that the distribution and type of fat cells in the fatty tumors is similar to the brown fat found in infants. Linking this to the aforementioned theory, one study suggested that the fatty tumors formed in Madelung’s disease result from impaired mitochondrial regulation in the brown fat, causing increased division of fat cells (adipocyte hyperplasia). While current research suggests adrenergic pathways and mitochondrial dysfunction to be implicated in Madelung’s disease, a clear picture of the pathogenesis is yet to be determined.Most occurrences of Madelung’s disease tend to be sporadic, with no family history of the disease. However, some scientists believe a predisposition to the disorder may be inherited from parents (in this case, maternal inheritance) and there have been some reports of cases that appear to be familial. The mode of transmission has been suspected to be autosomal dominant in nature with a variable penetrance in mitochondrial DNA. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.Madelung’s disease research on multigenerational blood-related family members showed that each affected member carried an ultrarare MTTT c.8344A>G mutation in their mitochondrial DNA. Similarly, in another study, siblings with Madelung’s disease demonstrated mutations in the gene encoding for the enzyme that breaks down fat (lipase), thereby depressing the fat breakdown pathway. Disease-causing mutations have also been reported in the MFN2 gene encoding mitofusin 2 (a key protein in many mitochondrial processes) and the LIPE gene encoding the hormone sensitive lipase (protein involved in breaking down stored fats). While these are promising breakthroughs, science currently lags behind in understanding the full molecular pathway responsible for Madelung’s disease.
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Madelung’s Disease
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nord_744_3
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Affects of Madelung’s Disease
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Madelung’s disease most frequently affects males between 30-70 years of age, with a male to female ratio ranging from 15-30:1. The condition is most common in those who consume excessive amounts of alcohol (especially red wine), for a long period of time. However, this disease is also found in women and persons who do not consume alcohol. For reasons that are unclear, the disorder appears to be more prevalent in Mediterranean and European population as compared to North American and Asian population.
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Affects of Madelung’s Disease. Madelung’s disease most frequently affects males between 30-70 years of age, with a male to female ratio ranging from 15-30:1. The condition is most common in those who consume excessive amounts of alcohol (especially red wine), for a long period of time. However, this disease is also found in women and persons who do not consume alcohol. For reasons that are unclear, the disorder appears to be more prevalent in Mediterranean and European population as compared to North American and Asian population.
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Madelung’s Disease
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nord_744_4
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Related disorders of Madelung’s Disease
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The differential diagnosis for Madelung’s disease includes lipomas, liposarcoma, lymphatic tumor, sialadenitis, neurofibromatosis, drug-induced lipomatosis (steroidal and antiretroviral drugs), and angiolipoma and hibernoma. Some of these diseases are briefly described below:Lipomas
Lipomas are single, painless lumps that most often appear in older women. Varying in size from a dime to a quarter, they are composed of fatty tissue, and are slow growing, soft and movable.Liposarcoma
Liposarcoma is a rare tumor derived from fat tissue that occurs in the “soft tissues” of the body (soft tissue sarcoma). It is classified as a cancer (malignancy) because of its potential to recur locally and spread to other areas of the body. It can arise in various locations throughout the body, although it is most frequently found in the extremities, particularly in the thighs. Some individuals with liposarcoma may not have symptoms in the early stages, but as the tumor grows and advances to later stages, it can potentially compress other tissues and cause pain. It is more common in middle-aged males from 50-65 years of age compared to females and is very rare in children. (For more information on this disorder, choose “Liposarcoma” as your search term in the Rare Disease Database)Lymphatic Tumor
A lymphatic tumor is also called a lymphoma. It is a cancer involving cells of the lymphatic system. Hodgkin’s disease is the most common lymphoma in the general population. Among children, however, several other types of lymphoma classified together as non-Hodgkin’s lymphoma are more likely to occur. Unlike Hodgkin’s disease, non-Hodgkin’s lymphoma can run in families. Boys are affected more often than girls. Fortunately, this kind of lymphoma is highly treatable and the cure rate is excellent, particularly if the illness is detected early. There are three major types of non-Hodgkin’s lymphoma, classified on the basis of the type of lymphatic cell (lymphocyte) involved and the organs affected at the time of diagnosis. (For more information on this disorder, choose “Hodgkin’s Disease” as your search term in the Rare Disease Database)Sialadenitis
Madelung’s disease is sometimes misdiagnosed as sialadenitis, an inflammation of the salivary glands, the glands that secrete saliva into the mouth. The inflammation may involve any of the glands that make up the salivary gland system (parotid, submandibular and sublingual glands). There are both acute and chronic forms. Sialadenitis is often associated with pain, tenderness, redness, and gradual, localized swelling of the affected area. (For more information on this disorder, choose “Sialadenitis” as your search term in the Rare Disease Database)Hibernoma
Hibernoma is a rare benign tumour that arises from the remaining parts of fetal brown adipose tissue. It is a slow growing tumor that can look like a malignancy clinically and on MRI. It occurs generally in the thigh but can also occur in the neck. There is a slight female predominance and patients are generally 40-50 years old. If large enough, hibernomas can compress vital structures in the body. Current treatment includes a complete excision of the tumor. As hibernomas have extensive vascularity, care should be taken during surgery to avoid post-operative bleeding.
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Related disorders of Madelung’s Disease. The differential diagnosis for Madelung’s disease includes lipomas, liposarcoma, lymphatic tumor, sialadenitis, neurofibromatosis, drug-induced lipomatosis (steroidal and antiretroviral drugs), and angiolipoma and hibernoma. Some of these diseases are briefly described below:Lipomas
Lipomas are single, painless lumps that most often appear in older women. Varying in size from a dime to a quarter, they are composed of fatty tissue, and are slow growing, soft and movable.Liposarcoma
Liposarcoma is a rare tumor derived from fat tissue that occurs in the “soft tissues” of the body (soft tissue sarcoma). It is classified as a cancer (malignancy) because of its potential to recur locally and spread to other areas of the body. It can arise in various locations throughout the body, although it is most frequently found in the extremities, particularly in the thighs. Some individuals with liposarcoma may not have symptoms in the early stages, but as the tumor grows and advances to later stages, it can potentially compress other tissues and cause pain. It is more common in middle-aged males from 50-65 years of age compared to females and is very rare in children. (For more information on this disorder, choose “Liposarcoma” as your search term in the Rare Disease Database)Lymphatic Tumor
A lymphatic tumor is also called a lymphoma. It is a cancer involving cells of the lymphatic system. Hodgkin’s disease is the most common lymphoma in the general population. Among children, however, several other types of lymphoma classified together as non-Hodgkin’s lymphoma are more likely to occur. Unlike Hodgkin’s disease, non-Hodgkin’s lymphoma can run in families. Boys are affected more often than girls. Fortunately, this kind of lymphoma is highly treatable and the cure rate is excellent, particularly if the illness is detected early. There are three major types of non-Hodgkin’s lymphoma, classified on the basis of the type of lymphatic cell (lymphocyte) involved and the organs affected at the time of diagnosis. (For more information on this disorder, choose “Hodgkin’s Disease” as your search term in the Rare Disease Database)Sialadenitis
Madelung’s disease is sometimes misdiagnosed as sialadenitis, an inflammation of the salivary glands, the glands that secrete saliva into the mouth. The inflammation may involve any of the glands that make up the salivary gland system (parotid, submandibular and sublingual glands). There are both acute and chronic forms. Sialadenitis is often associated with pain, tenderness, redness, and gradual, localized swelling of the affected area. (For more information on this disorder, choose “Sialadenitis” as your search term in the Rare Disease Database)Hibernoma
Hibernoma is a rare benign tumour that arises from the remaining parts of fetal brown adipose tissue. It is a slow growing tumor that can look like a malignancy clinically and on MRI. It occurs generally in the thigh but can also occur in the neck. There is a slight female predominance and patients are generally 40-50 years old. If large enough, hibernomas can compress vital structures in the body. Current treatment includes a complete excision of the tumor. As hibernomas have extensive vascularity, care should be taken during surgery to avoid post-operative bleeding.
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Madelung’s Disease
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nord_744_5
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Diagnosis of Madelung’s Disease
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The diagnosis of Madelung’s disease is based on a good clinical history, careful assessment of the appearance of the patient, and imaging tests such as ultrasound, computerized tomography (CT)-scan or magnetic resonance imaging (MRI). Imaging tests can allow physicians to recognize the extent of fat deposition in the affected areas, appreciate compression of deeper structures, and assess the presence of blood vessels in the fatty tumors. Furthermore, imaging tests can help rule out other diagnoses and provide insight for pre-operative surgical planning. In most cases, patients come in with a complaint of their appearance due to the cosmetic deformity associated with Madelung’s disease. The diagnosis can be challenging in cases where the patient is obese from other factors (sedentary lifestyle, poor diet, etc.).Clinical Testing and Work-UpClinical work-up involves physical examination and imaging of the affected area using ultrasound/sonography, CT-scan or MRI. A procedure known as fine needle aspiration (FNA) may be performed, involving insertion of a needle into the swelling and obtaining a small sample of the tissue to be analyzed by pathology for fatty (lipomatous) lesion. FNA procedure may also help distinguish between benign and malignant forms of disease. Nerve conduction and muscle function studies (electromyography) might be done to assess the degree of accompanying peripheral neuropathy for some patients.
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Diagnosis of Madelung’s Disease. The diagnosis of Madelung’s disease is based on a good clinical history, careful assessment of the appearance of the patient, and imaging tests such as ultrasound, computerized tomography (CT)-scan or magnetic resonance imaging (MRI). Imaging tests can allow physicians to recognize the extent of fat deposition in the affected areas, appreciate compression of deeper structures, and assess the presence of blood vessels in the fatty tumors. Furthermore, imaging tests can help rule out other diagnoses and provide insight for pre-operative surgical planning. In most cases, patients come in with a complaint of their appearance due to the cosmetic deformity associated with Madelung’s disease. The diagnosis can be challenging in cases where the patient is obese from other factors (sedentary lifestyle, poor diet, etc.).Clinical Testing and Work-UpClinical work-up involves physical examination and imaging of the affected area using ultrasound/sonography, CT-scan or MRI. A procedure known as fine needle aspiration (FNA) may be performed, involving insertion of a needle into the swelling and obtaining a small sample of the tissue to be analyzed by pathology for fatty (lipomatous) lesion. FNA procedure may also help distinguish between benign and malignant forms of disease. Nerve conduction and muscle function studies (electromyography) might be done to assess the degree of accompanying peripheral neuropathy for some patients.
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Madelung’s Disease
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nord_744_6
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Therapies of Madelung’s Disease
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TreatmentTreatment usually consists of surgical removal of the fatty deposits from the affected areas. Treatment options include surgical resection of fatty tumor(s), liposuction, or injection lipolysis. Surgical interventions may be complicated by high number of blood vessels supplying the fatty tumor, as well as fat invasion into nearby tissues and deeper structures. Ultrasound-assisted liposuction has been used successfully to remove single fatty tumors.The fat deposits never undergo spontaneous degeneration and can reoccur even after surgical removal. Therefore, frequent follow-ups are required after treatment. Fibrosis and adhesions can form after lipolysis injection and may interfere with subsequent surgical or liposuction treatment if the disease were to reoccur in the same area. Unfortunately, drug therapy has not been highly effective in the treatment of Madelung’s disease thus far. The effectiveness of salbutamol in helping fat breakdown through beta-adrenergic receptor stimulation is being tested as a potential therapeutic agent, but results have been inconsistent.
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Therapies of Madelung’s Disease. TreatmentTreatment usually consists of surgical removal of the fatty deposits from the affected areas. Treatment options include surgical resection of fatty tumor(s), liposuction, or injection lipolysis. Surgical interventions may be complicated by high number of blood vessels supplying the fatty tumor, as well as fat invasion into nearby tissues and deeper structures. Ultrasound-assisted liposuction has been used successfully to remove single fatty tumors.The fat deposits never undergo spontaneous degeneration and can reoccur even after surgical removal. Therefore, frequent follow-ups are required after treatment. Fibrosis and adhesions can form after lipolysis injection and may interfere with subsequent surgical or liposuction treatment if the disease were to reoccur in the same area. Unfortunately, drug therapy has not been highly effective in the treatment of Madelung’s disease thus far. The effectiveness of salbutamol in helping fat breakdown through beta-adrenergic receptor stimulation is being tested as a potential therapeutic agent, but results have been inconsistent.
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Madelung’s Disease
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Overview of Maffucci Syndrome
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Maffucci syndrome is an extremely rare disorder characterized by benign cartilage overgrowths (enchondromas), skeletal deformities and cutaneous lesions composed of abnormal blood vessels. Enchondromas arise in bones, most frequently in the hands and feet, and less often in the legs and long bones of the arm.
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Overview of Maffucci Syndrome. Maffucci syndrome is an extremely rare disorder characterized by benign cartilage overgrowths (enchondromas), skeletal deformities and cutaneous lesions composed of abnormal blood vessels. Enchondromas arise in bones, most frequently in the hands and feet, and less often in the legs and long bones of the arm.
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Maffucci Syndrome
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Symptoms of Maffucci Syndrome
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Maffucci syndrome is not recognizable at birth. Lesions usually develop early in childhood, most often between 1-5 years of age. The severity of the disorder is variable. Some patients have a very benign course, whereas others develop serious complications.The first sign of Maffucci syndrome is usually finding an enchondroma in a long bone. Enchondromas distort and weaken the affected bones, thus initial presentation with a pathologic fracture is common. These cartilaginous tumors cause bulging of the bones, bowing of the arms and legs, and often disproportionate (asymmetric) growth (different lengths of the arms or legs). The patient may exhibit short stature in adulthood. Enchondromas affect only one side of the body in approximately 40 percent of patients.Vascular lesions on the skin also usually appear in early childhood (around 4-5 years of age) and often are progressive. These lesions do not necessarily occur near the bones that have enchondromas. Cutaneous vascular lesions begin as compressible, round, bluish spots. In time, they become firm, knotty, warty, and often form calcium stones (phleboliths). The hand is the most common location; however vascular lesions can also occur in internal structures, such as the membranes that cover the brain and spinal cord (meninges), the tongue and the oral mucosa.The vascular lesions used to be called “cavernous hemangiomas”. Microscopic studies have shown that they are comprised of abnormally formed veins; the modern term is “venous malformation.” A benign vascular tumor, designated as “spindle cell hemangioma,” often arises in these malformed veins.Patients with Maffucci syndrome are at risk to developing a malignant tumor, particularly a tumor of cartilage known as “chondrosarcoma.” The more enchondromas, the higher the risk of malignancy. The frequency of tumors has been estimated to be between 15-40 %, however, some researchers think chondrosarcoma in Maffucci syndrome is over-reported. Less frequently, other malignant non-skeletal connective tissue neoplasms occur in patients with Maffucci syndrome.
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Symptoms of Maffucci Syndrome. Maffucci syndrome is not recognizable at birth. Lesions usually develop early in childhood, most often between 1-5 years of age. The severity of the disorder is variable. Some patients have a very benign course, whereas others develop serious complications.The first sign of Maffucci syndrome is usually finding an enchondroma in a long bone. Enchondromas distort and weaken the affected bones, thus initial presentation with a pathologic fracture is common. These cartilaginous tumors cause bulging of the bones, bowing of the arms and legs, and often disproportionate (asymmetric) growth (different lengths of the arms or legs). The patient may exhibit short stature in adulthood. Enchondromas affect only one side of the body in approximately 40 percent of patients.Vascular lesions on the skin also usually appear in early childhood (around 4-5 years of age) and often are progressive. These lesions do not necessarily occur near the bones that have enchondromas. Cutaneous vascular lesions begin as compressible, round, bluish spots. In time, they become firm, knotty, warty, and often form calcium stones (phleboliths). The hand is the most common location; however vascular lesions can also occur in internal structures, such as the membranes that cover the brain and spinal cord (meninges), the tongue and the oral mucosa.The vascular lesions used to be called “cavernous hemangiomas”. Microscopic studies have shown that they are comprised of abnormally formed veins; the modern term is “venous malformation.” A benign vascular tumor, designated as “spindle cell hemangioma,” often arises in these malformed veins.Patients with Maffucci syndrome are at risk to developing a malignant tumor, particularly a tumor of cartilage known as “chondrosarcoma.” The more enchondromas, the higher the risk of malignancy. The frequency of tumors has been estimated to be between 15-40 %, however, some researchers think chondrosarcoma in Maffucci syndrome is over-reported. Less frequently, other malignant non-skeletal connective tissue neoplasms occur in patients with Maffucci syndrome.
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Maffucci Syndrome
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Causes of Maffucci Syndrome
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In 2011, the cause of Maffucci syndrome was discovered to be a change (variant or mutation) in a gene known as IDH1 (rarely IDH2). The same gene variants are found in the related disorder Ollier disease. Since the variant occurs after fertilization (called a somatic mutation), Maffucci syndrome is not thought to be hereditary, that is, it cannot be passed along in a family. The cases occur randomly and there are no known families with multiple affected family members.
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Causes of Maffucci Syndrome. In 2011, the cause of Maffucci syndrome was discovered to be a change (variant or mutation) in a gene known as IDH1 (rarely IDH2). The same gene variants are found in the related disorder Ollier disease. Since the variant occurs after fertilization (called a somatic mutation), Maffucci syndrome is not thought to be hereditary, that is, it cannot be passed along in a family. The cases occur randomly and there are no known families with multiple affected family members.
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Maffucci Syndrome
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Affects of Maffucci Syndrome
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Maffucci syndrome occurs in all ethnic groups and equally affects males and females.
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Affects of Maffucci Syndrome. Maffucci syndrome occurs in all ethnic groups and equally affects males and females.
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Maffucci Syndrome
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Related disorders of Maffucci Syndrome
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The following disorders can look similar to Maffucci syndrome; however, they usually can be differentiated by clinical examination.Ollier Disease
This is a rare skeletal disorder characterized by abnormal bony development and enchondromas, in the absence of cutaneous vascular lesions that characterize Maffucci syndrome. While Ollier disease is present at birth, it may not become apparent until early childhood when skeletal deformities or abnormal growth of a limb occurs. Ollier disease primarily affects the long bones and cartilage of the joints of the arms and legs, specifically where the shaft and head of the long bone meet (metaphysis). Different limb lengths can occur. The pelvis is also often involved and more rarely, ribs, breastbone (sternum) and cranium are affected. The disease involves growth of enchondromas from cartilage in the long bones so that the outer layer (cortical bone) becomes thin and fragile. After puberty, these cartilaginous growths stabilize as cartilage is replaced by bone. Enchondromas may undergo malignant degeneration but far less frequently than in Maffucci syndrome. In many patients, somatic mutations are found in the IDH1 or IDH2 gene. The disorder is not inherited. (For more information on this disorder, choose “Ollier” as your search term in the Rare Disease Database).Blue Rubber Bleb Nevus Syndrome
The blue vascular lesions of Maffucci syndrome can be mistaken for this rare vascular disorder that is characterized by multiple, soft, elevated, blue, blue-black or purplish-red swellings (venous malformations). The lesions arise in the skin and internal organs, particularly the gastrointestinal tract. They typically appear on the hands and soles of the feet, but can also arise anywhere on the body, including the face and trunk, and in the liver, lungs, spleen, gallbladder, kidney and skeletal muscles. These internal lesions can cause serious complications. Bleeding from the gastrointestinal tract usually results in chronic anemia that may require blood transfusion. The cause is known to be a somatic mutation in the gene TIE 2 (TEK) (For more information on this disorder, choose “Blue Rubber Bleb Nevus” as your search term in the Rare Disease Database).Proteus Syndrome
This extremely rare overgrowth disorder may be confused with Maffucci syndrome. It is characterized by cerebriform connective tissue nevi (“moccasin feet”), epidermal nevi, lipomas and disproportionate, relentless, and asymmetrical skeletal overgrowth. Patients with Proteus syndrome may not have symptoms at birth, except for the nevi. They also can have capillary malformations and venous malformations. The enlarged veins put them at risk for pulmonary thromboembolism that can be fatal. The cause is a somatic activating mutation in the gene AKT1 occurring in cells during the early embryonic period. It is not hereditary. (For more information on this disorder, choose “Proteus” as your search term in the Rare Disease Database).A subset of patients initially diagnosed with Proteus syndrome have another overgrowth disorder called CLOVES caused by somatic mutations in the gene PIK3CA. (For more information on this disorder, choose “CLOVES” as your search term in the Rare Disease Database). PIK3CA-related overgrowth syndromes are called by the acronym PROS. More information about this group of disorders is available here.
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Related disorders of Maffucci Syndrome. The following disorders can look similar to Maffucci syndrome; however, they usually can be differentiated by clinical examination.Ollier Disease
This is a rare skeletal disorder characterized by abnormal bony development and enchondromas, in the absence of cutaneous vascular lesions that characterize Maffucci syndrome. While Ollier disease is present at birth, it may not become apparent until early childhood when skeletal deformities or abnormal growth of a limb occurs. Ollier disease primarily affects the long bones and cartilage of the joints of the arms and legs, specifically where the shaft and head of the long bone meet (metaphysis). Different limb lengths can occur. The pelvis is also often involved and more rarely, ribs, breastbone (sternum) and cranium are affected. The disease involves growth of enchondromas from cartilage in the long bones so that the outer layer (cortical bone) becomes thin and fragile. After puberty, these cartilaginous growths stabilize as cartilage is replaced by bone. Enchondromas may undergo malignant degeneration but far less frequently than in Maffucci syndrome. In many patients, somatic mutations are found in the IDH1 or IDH2 gene. The disorder is not inherited. (For more information on this disorder, choose “Ollier” as your search term in the Rare Disease Database).Blue Rubber Bleb Nevus Syndrome
The blue vascular lesions of Maffucci syndrome can be mistaken for this rare vascular disorder that is characterized by multiple, soft, elevated, blue, blue-black or purplish-red swellings (venous malformations). The lesions arise in the skin and internal organs, particularly the gastrointestinal tract. They typically appear on the hands and soles of the feet, but can also arise anywhere on the body, including the face and trunk, and in the liver, lungs, spleen, gallbladder, kidney and skeletal muscles. These internal lesions can cause serious complications. Bleeding from the gastrointestinal tract usually results in chronic anemia that may require blood transfusion. The cause is known to be a somatic mutation in the gene TIE 2 (TEK) (For more information on this disorder, choose “Blue Rubber Bleb Nevus” as your search term in the Rare Disease Database).Proteus Syndrome
This extremely rare overgrowth disorder may be confused with Maffucci syndrome. It is characterized by cerebriform connective tissue nevi (“moccasin feet”), epidermal nevi, lipomas and disproportionate, relentless, and asymmetrical skeletal overgrowth. Patients with Proteus syndrome may not have symptoms at birth, except for the nevi. They also can have capillary malformations and venous malformations. The enlarged veins put them at risk for pulmonary thromboembolism that can be fatal. The cause is a somatic activating mutation in the gene AKT1 occurring in cells during the early embryonic period. It is not hereditary. (For more information on this disorder, choose “Proteus” as your search term in the Rare Disease Database).A subset of patients initially diagnosed with Proteus syndrome have another overgrowth disorder called CLOVES caused by somatic mutations in the gene PIK3CA. (For more information on this disorder, choose “CLOVES” as your search term in the Rare Disease Database). PIK3CA-related overgrowth syndromes are called by the acronym PROS. More information about this group of disorders is available here.
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Maffucci Syndrome
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Diagnosis of Maffucci Syndrome
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The diagnosis of Maffucci syndrome is made by a detailed history, thorough physical examination and radiologic assessment. Surgical removal and microscopic study of the skeletal lesions confirm the presence of enchondroma and distinguish the tumor from chondrosarcoma.
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Diagnosis of Maffucci Syndrome. The diagnosis of Maffucci syndrome is made by a detailed history, thorough physical examination and radiologic assessment. Surgical removal and microscopic study of the skeletal lesions confirm the presence of enchondroma and distinguish the tumor from chondrosarcoma.
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Maffucci Syndrome
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Therapies of Maffucci Syndrome
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Treatment
Management of Maffucci syndrome is focused on the specific signs and symptoms in the patient. No intervention is needed for asymptomatic patients. Treatment requires coordinated efforts of a team of specialists (multidisciplinary care). The warty (verrucous) vascular lesions can be injected with a drug that shrinks and hardens the area (sclerosing agent); however, often surgery is also needed. Enchondromas can be surgically removed (resected) if necessary. A specialist in hand surgery is needed to correct the skeletal abnormalities of the hand if there is loss of function or recurrent fracture. An orthopedic surgeon addresses leg length discrepancy, abnormal curvature of the spine (scoliosis) or other skeletal abnormalities.A patient with Maffucci syndrome should be regularly monitored because of the risk of malignant transformation of an enchondroma or development of a tumor elsewhere in the body. If a malignancy does not occur, patients with Maffucci syndrome have an otherwise normal life expectancy. Conservative management is recommended for patients with Ollier disease. Operations may be necessary for complications, such as pathologic fracture, growth disturbance or malignant change.
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Therapies of Maffucci Syndrome. Treatment
Management of Maffucci syndrome is focused on the specific signs and symptoms in the patient. No intervention is needed for asymptomatic patients. Treatment requires coordinated efforts of a team of specialists (multidisciplinary care). The warty (verrucous) vascular lesions can be injected with a drug that shrinks and hardens the area (sclerosing agent); however, often surgery is also needed. Enchondromas can be surgically removed (resected) if necessary. A specialist in hand surgery is needed to correct the skeletal abnormalities of the hand if there is loss of function or recurrent fracture. An orthopedic surgeon addresses leg length discrepancy, abnormal curvature of the spine (scoliosis) or other skeletal abnormalities.A patient with Maffucci syndrome should be regularly monitored because of the risk of malignant transformation of an enchondroma or development of a tumor elsewhere in the body. If a malignancy does not occur, patients with Maffucci syndrome have an otherwise normal life expectancy. Conservative management is recommended for patients with Ollier disease. Operations may be necessary for complications, such as pathologic fracture, growth disturbance or malignant change.
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Maffucci Syndrome
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nord_746_0
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Overview of Mal de Debarquement
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Mal de debarquement (MDD) is a rare and poorly understood disorder of the vestibular system that results in a phantom perception of self- motion typically described as rocking, bobbing or swaying. The symptoms tend to be exacerbated when a patient is not moving, for example, when sleeping or standing still. Studies have shown that a brief period of these symptoms is common in healthy individuals after prolonged episodes of passive motion, normally lasting seconds to three days. However, in MDD, significant balance impairment can persist for months to years. Symptoms may diminish in time or may reappear spontaneously or after another exposure. The most common triggers are water-based activities such as ocean cruising. Less common triggers include airplane travel, extended landing travel and sleeping on water beds. Other common complaints of patients with MDD include a sensation of uneven ground below their feet while walking, or feeling as if they are still on a boat. It is rare for MDD patients to have true rotational vertigo or motion sickness.
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Overview of Mal de Debarquement. Mal de debarquement (MDD) is a rare and poorly understood disorder of the vestibular system that results in a phantom perception of self- motion typically described as rocking, bobbing or swaying. The symptoms tend to be exacerbated when a patient is not moving, for example, when sleeping or standing still. Studies have shown that a brief period of these symptoms is common in healthy individuals after prolonged episodes of passive motion, normally lasting seconds to three days. However, in MDD, significant balance impairment can persist for months to years. Symptoms may diminish in time or may reappear spontaneously or after another exposure. The most common triggers are water-based activities such as ocean cruising. Less common triggers include airplane travel, extended landing travel and sleeping on water beds. Other common complaints of patients with MDD include a sensation of uneven ground below their feet while walking, or feeling as if they are still on a boat. It is rare for MDD patients to have true rotational vertigo or motion sickness.
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Mal de Debarquement
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Symptoms of Mal de Debarquement
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The primary symptom is the persistence of a sense of motion and rocking. Some patients may experience fatigue, mood changes and confusion. Imbalance is a common complaint. Symptoms often increase when exposed to fast movements, flickering lights and grocery store aisles. There may be transient improvement in symptoms with re-exposure to passive motion, for example, riding in cars or trains. After completion of the trip, however, the symptoms tend to recur.Studies have shown that the length of time one is exposed to a motion experience does not determine the severity or duration of the syndrome, but most typical cases are triggered by day trips lasting several days.
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Symptoms of Mal de Debarquement. The primary symptom is the persistence of a sense of motion and rocking. Some patients may experience fatigue, mood changes and confusion. Imbalance is a common complaint. Symptoms often increase when exposed to fast movements, flickering lights and grocery store aisles. There may be transient improvement in symptoms with re-exposure to passive motion, for example, riding in cars or trains. After completion of the trip, however, the symptoms tend to recur.Studies have shown that the length of time one is exposed to a motion experience does not determine the severity or duration of the syndrome, but most typical cases are triggered by day trips lasting several days.
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Mal de Debarquement
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Causes of Mal de Debarquement
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The true cause behind MDD is still unknown. MDD likely results from the body’s balance system inadequately processing and adapting to multiple sensory inputs (visual, vestibular, proprioceptive and cognitive) from the environment once the stimulus (trigger) has ended. It is as yet undetermined as to the cause of the balance system’s inability to appropriately compensate and adapt. How or why this happens remains a mystery.
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Causes of Mal de Debarquement. The true cause behind MDD is still unknown. MDD likely results from the body’s balance system inadequately processing and adapting to multiple sensory inputs (visual, vestibular, proprioceptive and cognitive) from the environment once the stimulus (trigger) has ended. It is as yet undetermined as to the cause of the balance system’s inability to appropriately compensate and adapt. How or why this happens remains a mystery.
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Mal de Debarquement
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Affects of Mal de Debarquement
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The majority of people affected are adult females, although there have been reports of males having the diagnosis. Patients with migraine may have any increased susceptibility through unknown mechanisms.
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Affects of Mal de Debarquement. The majority of people affected are adult females, although there have been reports of males having the diagnosis. Patients with migraine may have any increased susceptibility through unknown mechanisms.
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Mal de Debarquement
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Related disorders of Mal de Debarquement
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Benign paroxysmal positional vertigo (BPPV) is a common cause of dizziness, especially among the elderly. It comes about as a result of a movement of the head. Under normal conditions, calcium particles are attached to a specific location within the inner ear. As a result of injury or degeneration, these calcium particles clump together causing a sudden and brief episode of dizziness. (For more information on this disorder, choose “BPPV” as your search term in the Rare Disease Database.)Meniere’s disease is a disorder characterized by periodic episodes of vertigo or dizziness; fluctuating, progressive hearing loss; tinnitus; and a sensation of fullness or pressure in the ear.
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Related disorders of Mal de Debarquement. Benign paroxysmal positional vertigo (BPPV) is a common cause of dizziness, especially among the elderly. It comes about as a result of a movement of the head. Under normal conditions, calcium particles are attached to a specific location within the inner ear. As a result of injury or degeneration, these calcium particles clump together causing a sudden and brief episode of dizziness. (For more information on this disorder, choose “BPPV” as your search term in the Rare Disease Database.)Meniere’s disease is a disorder characterized by periodic episodes of vertigo or dizziness; fluctuating, progressive hearing loss; tinnitus; and a sensation of fullness or pressure in the ear.
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Mal de Debarquement
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Diagnosis of Mal de Debarquement
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The diagnosis of MDD still remains mostly clinical. As such, the history is very important. Persistent “dizziness” after an ocean cruise, a sailing trip, a prolonged airplane flight or a cross-country road trip is highly suggestive of MDD. Vestibular function tests in patients with MDD have been normal or nonspecific in their abnormality. These tests are important in excluding other etiologies for the patient’s symptoms.
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Diagnosis of Mal de Debarquement. The diagnosis of MDD still remains mostly clinical. As such, the history is very important. Persistent “dizziness” after an ocean cruise, a sailing trip, a prolonged airplane flight or a cross-country road trip is highly suggestive of MDD. Vestibular function tests in patients with MDD have been normal or nonspecific in their abnormality. These tests are important in excluding other etiologies for the patient’s symptoms.
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Mal de Debarquement
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nord_746_6
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Therapies of Mal de Debarquement
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TreatmentMDD is very difficult to treat, with little effectiveness of most treatments. Clonazepam at low doses once or twice a day has shown improvement in patients. Higher doses were not proven to be effective. Vestibular rehabilitation has shown effectiveness in a small number of patients.
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Therapies of Mal de Debarquement. TreatmentMDD is very difficult to treat, with little effectiveness of most treatments. Clonazepam at low doses once or twice a day has shown improvement in patients. Higher doses were not proven to be effective. Vestibular rehabilitation has shown effectiveness in a small number of patients.
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Mal de Debarquement
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nord_747_0
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Overview of Malan Syndrome
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Summary
Malan syndrome is a rare genetic disorder that belongs to a larger group of disorders known as overgrowth syndromes. In general, overgrowth syndromes are characterized by a faster rate of growth before or after birth and can occur in any part of the body including bone, skin, muscles and organs. Malan syndrome is caused by genetic changes (pathogenic variants) in the NFIX gene. The age of onset is typically in infancy. Characteristics of this disorder include mild to moderate overgrowth in height at an early age, large head size (macrocephaly), weak muscles (hypotonia), intellectual disability, speech delay, motor delay, vision problems, brain abnormalities seen on MRI, breastbone abnormalities, curvature of the spine (scoliosis), seizures, autistic-like traits and mental health concerns such as anxiety. Less commonly, individuals with Malan syndrome can have differences in the shape or structure of their heart (congenital heart defect) and might have an abnormally wide aorta (aortic dilatation).Introduction
Malan syndrome was first described in 2010 by Dr. Valerie Malan. Prior to 2010, individuals with these symptoms and characteristics were diagnosed with “Sotos-like syndrome” because many of the medical problems associated with Malan syndrome are similar to a different genetic disorder, known as Sotos syndrome.
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Overview of Malan Syndrome. Summary
Malan syndrome is a rare genetic disorder that belongs to a larger group of disorders known as overgrowth syndromes. In general, overgrowth syndromes are characterized by a faster rate of growth before or after birth and can occur in any part of the body including bone, skin, muscles and organs. Malan syndrome is caused by genetic changes (pathogenic variants) in the NFIX gene. The age of onset is typically in infancy. Characteristics of this disorder include mild to moderate overgrowth in height at an early age, large head size (macrocephaly), weak muscles (hypotonia), intellectual disability, speech delay, motor delay, vision problems, brain abnormalities seen on MRI, breastbone abnormalities, curvature of the spine (scoliosis), seizures, autistic-like traits and mental health concerns such as anxiety. Less commonly, individuals with Malan syndrome can have differences in the shape or structure of their heart (congenital heart defect) and might have an abnormally wide aorta (aortic dilatation).Introduction
Malan syndrome was first described in 2010 by Dr. Valerie Malan. Prior to 2010, individuals with these symptoms and characteristics were diagnosed with “Sotos-like syndrome” because many of the medical problems associated with Malan syndrome are similar to a different genetic disorder, known as Sotos syndrome.
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Malan Syndrome
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Symptoms of Malan Syndrome
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Symptoms of Malan syndrome generally appear in infancy. Most symptoms are related to a child’s size or developmental milestones. Malan syndrome is reported to have variable expressivity. Variable expressivity means that there is a range of symptoms that can occur in people affected with the same genetic condition.
Most affected individuals have a larger head size (macrocephaly, 75%), intellectual disability, motor delay, speech delay, autism or autistic-like behaviors (such as difficulty with social situations, understanding emotions, repetitive behaviors or dislike of certain sounds or textures), mental health concerns such as anxiety, weak muscles (hypotonia), seizures, differences noted on brain MRI imaging (such as underdevelopment of corpus callosum [part of the brain that connects the left and the right side], wide ventricles, brain atrophy [smaller size of the brain], and Chiari malformation [brain tissue extends into the spinal canal], misaligned eyes (strabismus), involuntary shaking of eyes (nystagmus), vision issues (difficulty seeing near or far away), smaller size in the optic nerve causing vision loss (optic nerve hypoplasia or atrophy), above average height for age (tall stature), slender or thin body shape, advanced bone age, spine curvature, bones in the chest growing inward making a dip in the chest (pectus excavatum) or bones in the chest grow outward causing a bulge in the chest (pectus carinatum). Less common medical problems include hearing problems or reduced tolerance of sound (hyperacusis), increased risk for bone fractures, difference in shape or structure of the heart (congenital heart defect), including a larger aorta, which is the part of the heart that carries blood to the rest of your body (aortic dilatation). Malan syndrome is an exceptionally rare condition, and other medical problems might be found to be associated with this condition in the future. Individuals with Malan syndrome can look similar to one another, and geneticists or other healthcare providers may use specific terms to describe what they see on the physical exam. Things they might note may include a long, narrow, triangular-shaped face, broad forehead, down-slanting eyes, prominent chin, small mouth, misaligned and twisted teeth because of lack of space in the mouth (dental crowding), roof of the mouth that is deeper than expected (high arched palate), anteverted nose (tip of the nose is upturned), short nose, long fingers and toes, increased range of movement of joints (hypermobility) and blue tint to the whites of the eyes (blue sclera).
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Symptoms of Malan Syndrome. Symptoms of Malan syndrome generally appear in infancy. Most symptoms are related to a child’s size or developmental milestones. Malan syndrome is reported to have variable expressivity. Variable expressivity means that there is a range of symptoms that can occur in people affected with the same genetic condition.
Most affected individuals have a larger head size (macrocephaly, 75%), intellectual disability, motor delay, speech delay, autism or autistic-like behaviors (such as difficulty with social situations, understanding emotions, repetitive behaviors or dislike of certain sounds or textures), mental health concerns such as anxiety, weak muscles (hypotonia), seizures, differences noted on brain MRI imaging (such as underdevelopment of corpus callosum [part of the brain that connects the left and the right side], wide ventricles, brain atrophy [smaller size of the brain], and Chiari malformation [brain tissue extends into the spinal canal], misaligned eyes (strabismus), involuntary shaking of eyes (nystagmus), vision issues (difficulty seeing near or far away), smaller size in the optic nerve causing vision loss (optic nerve hypoplasia or atrophy), above average height for age (tall stature), slender or thin body shape, advanced bone age, spine curvature, bones in the chest growing inward making a dip in the chest (pectus excavatum) or bones in the chest grow outward causing a bulge in the chest (pectus carinatum). Less common medical problems include hearing problems or reduced tolerance of sound (hyperacusis), increased risk for bone fractures, difference in shape or structure of the heart (congenital heart defect), including a larger aorta, which is the part of the heart that carries blood to the rest of your body (aortic dilatation). Malan syndrome is an exceptionally rare condition, and other medical problems might be found to be associated with this condition in the future. Individuals with Malan syndrome can look similar to one another, and geneticists or other healthcare providers may use specific terms to describe what they see on the physical exam. Things they might note may include a long, narrow, triangular-shaped face, broad forehead, down-slanting eyes, prominent chin, small mouth, misaligned and twisted teeth because of lack of space in the mouth (dental crowding), roof of the mouth that is deeper than expected (high arched palate), anteverted nose (tip of the nose is upturned), short nose, long fingers and toes, increased range of movement of joints (hypermobility) and blue tint to the whites of the eyes (blue sclera).
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Malan Syndrome
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Causes of Malan Syndrome
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Malan syndrome is caused by genetic changes (pathogenic variants) in the nuclear factor I X (NFIX) gene. Genes are the body’s instruction manual for creating proteins that play critical roles in how the body grows and develops properly. When a pathogenic variant in a gene occurs, it causes the protein to stop working. Depending on the function of the protein, it can affect many parts of the body. The NFIX gene encodes for a transcription factor and is important for brain, muscle, and bone development and differentiation. Transcription factors turn specific genes ‘on’ and ‘off’ in the body. Pathogenic variants in the NFIX gene cause this transcription factor to be partially unavailable for the body to use (haploinsufficiency), and as a result, other genes in the body do not know when to properly turn ‘on’ or ‘off.’ The transcription factor is needed for normal development, and when not working properly leads to the signs and symptoms of Malan syndrome. Malan syndrome can also be caused by microdeletions in the region of chromosome 19 where the NFIX gene is located (19p13.2).Malan syndrome is an autosomal dominant disorder. This means that a genetic change (pathogenic variant) in only one of the two copies of the NFIX gene is necessary to cause the disease. The risk of passing the genetic change from an affected person to a child is 50% for each pregnancy. The risk is the same for males and females. So far, most individuals reported to be diagnosed with Malan syndrome did not inherit the pathogenic variant from either parent. In these patients, the variant occurred for the first time in them (referred to as de novo). There are a few reports of siblings who both have a diagnosis of Malan syndrome due to the same pathogenic variant, but their parents do not have the same pathogenic variant as the children. This is referred to as germline mosaicism, meaning the genetic change was only present in either the parents’ egg or sperm.
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Causes of Malan Syndrome. Malan syndrome is caused by genetic changes (pathogenic variants) in the nuclear factor I X (NFIX) gene. Genes are the body’s instruction manual for creating proteins that play critical roles in how the body grows and develops properly. When a pathogenic variant in a gene occurs, it causes the protein to stop working. Depending on the function of the protein, it can affect many parts of the body. The NFIX gene encodes for a transcription factor and is important for brain, muscle, and bone development and differentiation. Transcription factors turn specific genes ‘on’ and ‘off’ in the body. Pathogenic variants in the NFIX gene cause this transcription factor to be partially unavailable for the body to use (haploinsufficiency), and as a result, other genes in the body do not know when to properly turn ‘on’ or ‘off.’ The transcription factor is needed for normal development, and when not working properly leads to the signs and symptoms of Malan syndrome. Malan syndrome can also be caused by microdeletions in the region of chromosome 19 where the NFIX gene is located (19p13.2).Malan syndrome is an autosomal dominant disorder. This means that a genetic change (pathogenic variant) in only one of the two copies of the NFIX gene is necessary to cause the disease. The risk of passing the genetic change from an affected person to a child is 50% for each pregnancy. The risk is the same for males and females. So far, most individuals reported to be diagnosed with Malan syndrome did not inherit the pathogenic variant from either parent. In these patients, the variant occurred for the first time in them (referred to as de novo). There are a few reports of siblings who both have a diagnosis of Malan syndrome due to the same pathogenic variant, but their parents do not have the same pathogenic variant as the children. This is referred to as germline mosaicism, meaning the genetic change was only present in either the parents’ egg or sperm.
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Malan Syndrome
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Affects of Malan Syndrome
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There are approximately 300 individuals worldwide who have a diagnosis of Malan syndrome, making this an exceptionally rare diagnosis. Malan syndrome affects males and females equally and does not occur more frequently in any specific ethnic group. As of 2023, the oldest person living with Malan syndrome is 60 years old.
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Affects of Malan Syndrome. There are approximately 300 individuals worldwide who have a diagnosis of Malan syndrome, making this an exceptionally rare diagnosis. Malan syndrome affects males and females equally and does not occur more frequently in any specific ethnic group. As of 2023, the oldest person living with Malan syndrome is 60 years old.
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Related disorders of Malan Syndrome
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Symptoms of the following genetic disorders can be similar to those of Malan syndrome. Sotos syndrome
Sotos syndrome is a rare genetic disorder characterized by rapid growth before and after birth. Individuals with Sotos syndrome typically have a height 2 to 3 years ahead of their peers during childhood and adult height is above average. Medical problems can include developmental delays, low muscle tone (hypotonia), speech difficulties and intellectual disability. In most patients, Sotos syndrome is caused by a single genetic change (pathogenic variant) in the NSD1 gene and is inherited in an autosomal dominant pattern. (For more information on this disorder, choose “Sotos Syndrome” as your search term in the Rare Disease Database.)Marshall-Smith syndrome
Marshall-Smith Syndrome (MSS) is a rare genetic disorder characterized by accelerated bone formation and problems with growth and nutrition.This syndrome is associated with low muscle tone (hypotonia), difficulty gaining weight, intellectual disability, developmental delays, frequent infections (weaker immune system), difference in the structure and shape of the brain and breathing difficulties. This genetic disorder is also caused by a change in the NFIX gene. The genetic changes that cause MSS are at a specific location within the NFIX gene. MSS is inherited in an autosomal dominant pattern. (For more information on this disorder, choose “Marshall-Smith Syndrome” as your search term in the Rare Disease Database.)Snyder-Robinson syndrome
Snyder-Robinson syndrome (SRS) is a rare genetic syndrome associated with intellectual disability and tall stature and typically only affects males. Characteristics of this syndrome include above average height (tall stature), thin body shape (low muscle mass), vision issues, intellectual disability, seizures, bones in the chest grow inward making a dip in the chest (pectus excavatum) and weaker bones leading to fractures (osteoporosis). The genetic change (pathogenic variant) that causes SRS is in the SMS gene on the X chromosome. (For more information on this disorder, choose “Snyder-Robinson Syndrome” as your search term in the Rare Disease Database.) Lujan-Fryns syndrome
Lujan-Fryns syndrome is a rare genetic syndrome that typically affects males and is characterized by above average height (tall stature) and intellectual disability. Features of this syndrome include a large head size (macrocephaly), extra or crowded teeth, differences in the shape or structure of the heart, bones in the chest growing inward making a dip in the chest (pectus excavatum), flexible joints, seizures, low muscle tone (hypotonia, and various behavioral problems. The genetic change (pathogenic variant) that causes Lujan-Fyrns syndrome is in the MED12 gene on the X chromosome.Marfan syndrome
Marfan syndrome is a genetic disorder that varies significantly in symptoms and severity. The condition can affect multiple systems in the body, including the heart, blood vessels, skeleton, eyes, lungs and skin. Common physical findings in individuals with Marfan syndrome include a thin body shape with long limbs, slender fingers and facial features such as a long, narrow skull, deep-set eyes and a small jaw. Cardiovascular problems are common, such as a leaky valve in the heart (mitral valve prolapse) and enlarged aorta, the part of the heart that delivers oxygen to the body. Curvature in the spine (scoliosis) and trouble seeing far away items (nearsightedness) and dislocation of the lenses in the eyes (lens displacement, ectopia lentis) are also common. Marfan syndrome is caused by genetic changes (pathogenic variants) in the FBN1 gene and is inherited in an autosomal dominant manner. (For more information on this disorder, choose “Marfan Syndrome” as your search term in the Rare Disease Database.) Weaver syndrome
Weaver syndrome (WS) is a rare genetic disorder primarily characterized by above average height (tall stature) and faster bone growth. Children with WS may show symptoms that include normal or high weight, a large head (macrocephaly) and uncoordinated movements. Muscle rigidity in the arms and legs, along with looser core muscles, can lead to poor coordination. Individuals with WS can have a range of intellectual abilities, from normal intelligence to severe intellectual disability. The condition is often caused by genetic changes (pathogenic variants) in the EZH2 gene and is inherited in an autosomal dominant pattern. (For more information on this disorder, choose “Weaver Syndrome” as your search term in the Rare Disease Database.)
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Related disorders of Malan Syndrome. Symptoms of the following genetic disorders can be similar to those of Malan syndrome. Sotos syndrome
Sotos syndrome is a rare genetic disorder characterized by rapid growth before and after birth. Individuals with Sotos syndrome typically have a height 2 to 3 years ahead of their peers during childhood and adult height is above average. Medical problems can include developmental delays, low muscle tone (hypotonia), speech difficulties and intellectual disability. In most patients, Sotos syndrome is caused by a single genetic change (pathogenic variant) in the NSD1 gene and is inherited in an autosomal dominant pattern. (For more information on this disorder, choose “Sotos Syndrome” as your search term in the Rare Disease Database.)Marshall-Smith syndrome
Marshall-Smith Syndrome (MSS) is a rare genetic disorder characterized by accelerated bone formation and problems with growth and nutrition.This syndrome is associated with low muscle tone (hypotonia), difficulty gaining weight, intellectual disability, developmental delays, frequent infections (weaker immune system), difference in the structure and shape of the brain and breathing difficulties. This genetic disorder is also caused by a change in the NFIX gene. The genetic changes that cause MSS are at a specific location within the NFIX gene. MSS is inherited in an autosomal dominant pattern. (For more information on this disorder, choose “Marshall-Smith Syndrome” as your search term in the Rare Disease Database.)Snyder-Robinson syndrome
Snyder-Robinson syndrome (SRS) is a rare genetic syndrome associated with intellectual disability and tall stature and typically only affects males. Characteristics of this syndrome include above average height (tall stature), thin body shape (low muscle mass), vision issues, intellectual disability, seizures, bones in the chest grow inward making a dip in the chest (pectus excavatum) and weaker bones leading to fractures (osteoporosis). The genetic change (pathogenic variant) that causes SRS is in the SMS gene on the X chromosome. (For more information on this disorder, choose “Snyder-Robinson Syndrome” as your search term in the Rare Disease Database.) Lujan-Fryns syndrome
Lujan-Fryns syndrome is a rare genetic syndrome that typically affects males and is characterized by above average height (tall stature) and intellectual disability. Features of this syndrome include a large head size (macrocephaly), extra or crowded teeth, differences in the shape or structure of the heart, bones in the chest growing inward making a dip in the chest (pectus excavatum), flexible joints, seizures, low muscle tone (hypotonia, and various behavioral problems. The genetic change (pathogenic variant) that causes Lujan-Fyrns syndrome is in the MED12 gene on the X chromosome.Marfan syndrome
Marfan syndrome is a genetic disorder that varies significantly in symptoms and severity. The condition can affect multiple systems in the body, including the heart, blood vessels, skeleton, eyes, lungs and skin. Common physical findings in individuals with Marfan syndrome include a thin body shape with long limbs, slender fingers and facial features such as a long, narrow skull, deep-set eyes and a small jaw. Cardiovascular problems are common, such as a leaky valve in the heart (mitral valve prolapse) and enlarged aorta, the part of the heart that delivers oxygen to the body. Curvature in the spine (scoliosis) and trouble seeing far away items (nearsightedness) and dislocation of the lenses in the eyes (lens displacement, ectopia lentis) are also common. Marfan syndrome is caused by genetic changes (pathogenic variants) in the FBN1 gene and is inherited in an autosomal dominant manner. (For more information on this disorder, choose “Marfan Syndrome” as your search term in the Rare Disease Database.) Weaver syndrome
Weaver syndrome (WS) is a rare genetic disorder primarily characterized by above average height (tall stature) and faster bone growth. Children with WS may show symptoms that include normal or high weight, a large head (macrocephaly) and uncoordinated movements. Muscle rigidity in the arms and legs, along with looser core muscles, can lead to poor coordination. Individuals with WS can have a range of intellectual abilities, from normal intelligence to severe intellectual disability. The condition is often caused by genetic changes (pathogenic variants) in the EZH2 gene and is inherited in an autosomal dominant pattern. (For more information on this disorder, choose “Weaver Syndrome” as your search term in the Rare Disease Database.)
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Diagnosis of Malan Syndrome
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A thorough evaluation by a clinical geneticist is necessary to accurately diagnose Malan syndrome. Genetic testing is the primary method of diagnosis. Exome or NFIX sanger sequencing can be used to read the letters of the genetic code to look for pathogenic changes in the NFIX gene. Another genetic test that may be ordered is a chromosome microarray, which is a test that looks for extra or missing pieces of the genetic code. Individuals who have a partial or completely missing copy of the NFIX gene are also affected with Malan syndrome. Clinical Testing and Work-Up
Physical exam and imaging can evaluate for medical problems associated with Malan syndrome. An electroencephalogram (EEG) is used to assess brain activity for the risk of seizures. A brain MRI can be used to look for differences in the size and structure of the brain. An echocardiogram, or a scan of the heart, can identify structural or functional differences in the heart. If any are identified, long-term follow-up with a cardiologist may be needed. Routine screening is recommended for aortic dilatation. Scoliosis can be monitored by a pediatrician and a referral to orthopedics (bone doctor) can be provided, if needed.
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Diagnosis of Malan Syndrome. A thorough evaluation by a clinical geneticist is necessary to accurately diagnose Malan syndrome. Genetic testing is the primary method of diagnosis. Exome or NFIX sanger sequencing can be used to read the letters of the genetic code to look for pathogenic changes in the NFIX gene. Another genetic test that may be ordered is a chromosome microarray, which is a test that looks for extra or missing pieces of the genetic code. Individuals who have a partial or completely missing copy of the NFIX gene are also affected with Malan syndrome. Clinical Testing and Work-Up
Physical exam and imaging can evaluate for medical problems associated with Malan syndrome. An electroencephalogram (EEG) is used to assess brain activity for the risk of seizures. A brain MRI can be used to look for differences in the size and structure of the brain. An echocardiogram, or a scan of the heart, can identify structural or functional differences in the heart. If any are identified, long-term follow-up with a cardiologist may be needed. Routine screening is recommended for aortic dilatation. Scoliosis can be monitored by a pediatrician and a referral to orthopedics (bone doctor) can be provided, if needed.
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Therapies of Malan Syndrome
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There currently is no cure for Malan syndrome and treatment is focused on the management of the medical problems that are present. Treatment and management is often coordinated by a neurologist. Seizures can be treated with antiepileptic drugs.For vision issues, an optometrist, low vision specialist, ophthalmologist and/or neuro-ophthalmologist can monitor and provide glasses or other therapies as needed. Routine eye evaluations may be recommended to monitor for vision loss or other eye problems such as small optic nerves or cataracts. For individuals with developmental delays or a diagnosis of autism, interventional therapies including speech, occupational, physical and behavior therapies may be recommended. Mental health concerns such as anxiety may be treated with medication.Academic support for individuals with intellectual disability may include but is not limited to a 504 plan, teacher’s aide or an individualized educational plan (IEP). Genetic counseling is recommended for families with an affected child.
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Therapies of Malan Syndrome. There currently is no cure for Malan syndrome and treatment is focused on the management of the medical problems that are present. Treatment and management is often coordinated by a neurologist. Seizures can be treated with antiepileptic drugs.For vision issues, an optometrist, low vision specialist, ophthalmologist and/or neuro-ophthalmologist can monitor and provide glasses or other therapies as needed. Routine eye evaluations may be recommended to monitor for vision loss or other eye problems such as small optic nerves or cataracts. For individuals with developmental delays or a diagnosis of autism, interventional therapies including speech, occupational, physical and behavior therapies may be recommended. Mental health concerns such as anxiety may be treated with medication.Academic support for individuals with intellectual disability may include but is not limited to a 504 plan, teacher’s aide or an individualized educational plan (IEP). Genetic counseling is recommended for families with an affected child.
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Malan Syndrome
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Overview of Malaria
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Malaria is a communicable parasitic disorder spread through the bite of the Anopheles mosquito. Major symptoms may vary depending on which species of parasite causes the infection and the stage of development of the parasite. Chills and fever commonly occur, although not every case follows the same pattern. Although the disorder was once thought to be under control throughout the world, malaria is a widespread infection especially in the tropics where certain types of mosquitos are becoming resistant to pesticides. The annual number of cases reported in the United States has increased in recent years.
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Overview of Malaria. Malaria is a communicable parasitic disorder spread through the bite of the Anopheles mosquito. Major symptoms may vary depending on which species of parasite causes the infection and the stage of development of the parasite. Chills and fever commonly occur, although not every case follows the same pattern. Although the disorder was once thought to be under control throughout the world, malaria is a widespread infection especially in the tropics where certain types of mosquitos are becoming resistant to pesticides. The annual number of cases reported in the United States has increased in recent years.
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Symptoms of Malaria
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Symptoms of malaria vary depending on which of the four parasite species is the cause. Severity of symptoms may differ as the parasite goes through three different stages of development in humans. It is possible to contract more than one kind of malaria at a time. Symptoms may begin a week after exposure to the mosquito or may show up months later, even with preventive treatment.An incubation period ranging of up to forty days is usually followed by a feeling of listlessness, loss of appetite, headaches, muscle aches, low fever, and other flu-like symptoms. Then onset of rigidity or spasms usually lasting twenty to thirty minutes may occur. Following this, teeth rattling chills and fever (possibly reaching 107 degrees F.) may last from three to eight hours. Profuse sweating and a feeling of exhaustion mark the end of the feverish stage. Cold sores may appear on the lips or nose, skin may be pale, slightly bluish, or dry and flushed in appearance. An increased heart rate may be associated with heavy breathing. The spleen may become enlarged. Bloody diarrhea rarely may occur. If the brain is involved, headaches or depression may develop. Anemia, marked weight loss, mild yellowish discoloration of the skin (jaundice), swelling of the ankles, digestive difficulties, and muscle weakness can occur.Until drugs are administered, symptoms such as diarrhea, vomiting or nausea may recur. Between episodes of these symptoms, patients may feel well except for tiredness. Without treatment, symptoms often redevelop months or even years later. Although subsequent attacks may be milder due to built-up immunity, the infection can last from one to twenty years. With treatment, patients usually recover and live a normal life span. Cerebral malaria is a form of malaria that occurs when the immune system produces a certain protein called “tumor necrosis factor” (TNF) or “cachectin.” This complication develops in less than one percent of cases. In third world countries, malaria frequently presents life threatening complications.
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Symptoms of Malaria. Symptoms of malaria vary depending on which of the four parasite species is the cause. Severity of symptoms may differ as the parasite goes through three different stages of development in humans. It is possible to contract more than one kind of malaria at a time. Symptoms may begin a week after exposure to the mosquito or may show up months later, even with preventive treatment.An incubation period ranging of up to forty days is usually followed by a feeling of listlessness, loss of appetite, headaches, muscle aches, low fever, and other flu-like symptoms. Then onset of rigidity or spasms usually lasting twenty to thirty minutes may occur. Following this, teeth rattling chills and fever (possibly reaching 107 degrees F.) may last from three to eight hours. Profuse sweating and a feeling of exhaustion mark the end of the feverish stage. Cold sores may appear on the lips or nose, skin may be pale, slightly bluish, or dry and flushed in appearance. An increased heart rate may be associated with heavy breathing. The spleen may become enlarged. Bloody diarrhea rarely may occur. If the brain is involved, headaches or depression may develop. Anemia, marked weight loss, mild yellowish discoloration of the skin (jaundice), swelling of the ankles, digestive difficulties, and muscle weakness can occur.Until drugs are administered, symptoms such as diarrhea, vomiting or nausea may recur. Between episodes of these symptoms, patients may feel well except for tiredness. Without treatment, symptoms often redevelop months or even years later. Although subsequent attacks may be milder due to built-up immunity, the infection can last from one to twenty years. With treatment, patients usually recover and live a normal life span. Cerebral malaria is a form of malaria that occurs when the immune system produces a certain protein called “tumor necrosis factor” (TNF) or “cachectin.” This complication develops in less than one percent of cases. In third world countries, malaria frequently presents life threatening complications.
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Causes of Malaria
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Malaria is most commonly transmitted through the bite of the female Anopheles mosquito which is infected by a malaria parasite (Plasmodium). Plasmodium Falciparum, Plasmodium Ovale, Plasmodium Malariae and Plasmodium Vivax are the four species of the parasite which can affect humans. Additionally, transfusion of blood from an infected donor, or sharing contaminated needles may transmit the infection from one person to another. In very rare cases, the disorder has been transmitted from an infected mother to a fetus.
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Causes of Malaria. Malaria is most commonly transmitted through the bite of the female Anopheles mosquito which is infected by a malaria parasite (Plasmodium). Plasmodium Falciparum, Plasmodium Ovale, Plasmodium Malariae and Plasmodium Vivax are the four species of the parasite which can affect humans. Additionally, transfusion of blood from an infected donor, or sharing contaminated needles may transmit the infection from one person to another. In very rare cases, the disorder has been transmitted from an infected mother to a fetus.
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Malaria
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Affects of Malaria
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According to the Centers for Disease Control and Prevention (CDC) in Atlanta, malaria is uncommon in the United States where approximately 1,200 cases are diagnosed each year, usually having been contracted abroad. In the United States, malaria results in two to five deaths, on the average, each year. Most cases in the U.S. occur among travelers, immigrants, and refugees.
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Affects of Malaria. According to the Centers for Disease Control and Prevention (CDC) in Atlanta, malaria is uncommon in the United States where approximately 1,200 cases are diagnosed each year, usually having been contracted abroad. In the United States, malaria results in two to five deaths, on the average, each year. Most cases in the U.S. occur among travelers, immigrants, and refugees.
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Malaria
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Related disorders of Malaria
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Symptoms of the following disorders can be similar to those of malaria. Comparisons may be useful for a differential diagnosis:Babesiosis is a rare infectious disease caused by single-celled microorganisms (protozoa) belonging to the Babesia family. It is believed that the Babesia protozoa are usually carried and transmitted by ticks (vectors). Babesiosis occurs primarily in animals; however, in rare cases, babesiosis infection may occur in humans. Certain Babesia species are known to cause babesiosis infection in humans (e.g., Babesia microti), and the deer tick is a known vector. Human babesiosis infection may cause fever, chills, headache, nausea, vomiting, and/or muscle aches (myalgia). Symptoms may be mild in otherwise healthy people; in addition, some infected individuals may exhibit no symptoms (asymptomatic). However, a severe form of babesiosis, which may be life-threatening if untreated, may occur in individuals who have had their spleens removed (splenectomized) or who have an impaired immune system. A different form of babesiosis has been reported in Europe that is associated with a more severe expression of symptoms. (For more information on this disorder, choose “Babesiosis” as your search term in the Rare Disease Database.)Toxoplasmosis is an infectious disorder that is caused by a parasite (Toxoplasma Gondii). This infection is found worldwide and may be either acquired or transmitted to a fetus from an infected mother. When the disorder is acquired, cases may either resemble mononucleosis or involve lesions of the lungs, liver, heart, skin, muscle, brain, and spinal cord membranes. Lesions are often accompanied by inflammation and in some cases, hepatitis. Acute cases are often characterized by rash, high fever, chills, and prostration. The prognosis for the acquired forms of toxoplasmosis (of moderate severity) is usually good with treatment and complications are uncommon. However, without treatment this disorder may persist for many months. It is rarely fatal in adults. (For more information on this disorder, choose “Toxoplasmosis” as your search term in the Rare Disease Database.)
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Related disorders of Malaria. Symptoms of the following disorders can be similar to those of malaria. Comparisons may be useful for a differential diagnosis:Babesiosis is a rare infectious disease caused by single-celled microorganisms (protozoa) belonging to the Babesia family. It is believed that the Babesia protozoa are usually carried and transmitted by ticks (vectors). Babesiosis occurs primarily in animals; however, in rare cases, babesiosis infection may occur in humans. Certain Babesia species are known to cause babesiosis infection in humans (e.g., Babesia microti), and the deer tick is a known vector. Human babesiosis infection may cause fever, chills, headache, nausea, vomiting, and/or muscle aches (myalgia). Symptoms may be mild in otherwise healthy people; in addition, some infected individuals may exhibit no symptoms (asymptomatic). However, a severe form of babesiosis, which may be life-threatening if untreated, may occur in individuals who have had their spleens removed (splenectomized) or who have an impaired immune system. A different form of babesiosis has been reported in Europe that is associated with a more severe expression of symptoms. (For more information on this disorder, choose “Babesiosis” as your search term in the Rare Disease Database.)Toxoplasmosis is an infectious disorder that is caused by a parasite (Toxoplasma Gondii). This infection is found worldwide and may be either acquired or transmitted to a fetus from an infected mother. When the disorder is acquired, cases may either resemble mononucleosis or involve lesions of the lungs, liver, heart, skin, muscle, brain, and spinal cord membranes. Lesions are often accompanied by inflammation and in some cases, hepatitis. Acute cases are often characterized by rash, high fever, chills, and prostration. The prognosis for the acquired forms of toxoplasmosis (of moderate severity) is usually good with treatment and complications are uncommon. However, without treatment this disorder may persist for many months. It is rarely fatal in adults. (For more information on this disorder, choose “Toxoplasmosis” as your search term in the Rare Disease Database.)
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Malaria
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Diagnosis of Malaria
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Diagnosis of Malaria.
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Malaria
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Therapies of Malaria
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TreatmentThe Centers for Disease Control and Prevention (CDC) in Atlanta provide extensive information on standard therapies for malaria. Treatment should begin as soon as possible, but not until the diagnosis has been confirmed by laboratory investigations. Once the diagnosis has been confirmed, treatment with an antimalarial drug should begin right away. Antimalarial drugs that combat the parasite forms in the blood include Aralen (chloroquine), Fansidar (sulfadoxine-pyrimethamine), Lariam (mefloquine), Malarone (atovaquone-proguanil), and Doxy-100 (doxycycline). In 2020, the U.S. Food and Drug Administration (FDA) approved artesunate for injection as the only drug to treat severe malaria in adult and pediatric patients. Prior to this approval, there had been no FDA-approved drug for treatment of severe malaria in the U.S. since the marketing of quinine was discontinued by the manufacturer in 2019. Another drug, Primaquine (primaquine phosphate), is active against the dormant parasite liver forms and prevents relapses. However, Primaquine should not be taken by pregnant women or by people who are deficient in glucose-6 phosphate dehydrogenase (G6PD). Patients who have severe P. falciparum malaria or who cannot take oral medications should be given the treatment by continuous intravenous infusion. Several antimalarial drugs are available that can be administered in this way. Determining how to treat a patient with malaria depends on the species of the infecting parasite, the area where infection took place, the clinical status of the patient, and whether the patient is pregnant, has drug allergies, or is taking other medications. Prevention is the most effective means of controlling malaria. In areas where malaria is known to be present, this is done through taking steps to avoid exposure to mosquitoes, especially at night, and wearing insect repellent and clothing that covers the arms and legs when outside. Rural areas carry a higher risk for malaria than do cities. Travelers should remain in well-screened areas, especially at night when mosquitos usually feed. Clothes should cover most of the body and mosquito netting should be used around the bed. An insect repellent containing DEET should be used on any exposed area of the skin. For travel information related to malaria and the degree of risk in an intended travel destination, call the CDC toll-free number (877) FYI-TRIP or (877) 394-8747 or visit CDC’s Travelers’ Health Web site, which has country-specific information, including where malaria is found, which antimalarial drugs to take, steps to protect children, and how to avoid mosquito bites. Also, the CDC recommends that travelers going to a country with malaria risk should purchase antimalarial drug before leaving the United States. In recent years, the number of cases of malaria in the United States caused by the P. falciparum parasite has increased. This is believed to be due to travel to areas where malaria is endemic.
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Therapies of Malaria. TreatmentThe Centers for Disease Control and Prevention (CDC) in Atlanta provide extensive information on standard therapies for malaria. Treatment should begin as soon as possible, but not until the diagnosis has been confirmed by laboratory investigations. Once the diagnosis has been confirmed, treatment with an antimalarial drug should begin right away. Antimalarial drugs that combat the parasite forms in the blood include Aralen (chloroquine), Fansidar (sulfadoxine-pyrimethamine), Lariam (mefloquine), Malarone (atovaquone-proguanil), and Doxy-100 (doxycycline). In 2020, the U.S. Food and Drug Administration (FDA) approved artesunate for injection as the only drug to treat severe malaria in adult and pediatric patients. Prior to this approval, there had been no FDA-approved drug for treatment of severe malaria in the U.S. since the marketing of quinine was discontinued by the manufacturer in 2019. Another drug, Primaquine (primaquine phosphate), is active against the dormant parasite liver forms and prevents relapses. However, Primaquine should not be taken by pregnant women or by people who are deficient in glucose-6 phosphate dehydrogenase (G6PD). Patients who have severe P. falciparum malaria or who cannot take oral medications should be given the treatment by continuous intravenous infusion. Several antimalarial drugs are available that can be administered in this way. Determining how to treat a patient with malaria depends on the species of the infecting parasite, the area where infection took place, the clinical status of the patient, and whether the patient is pregnant, has drug allergies, or is taking other medications. Prevention is the most effective means of controlling malaria. In areas where malaria is known to be present, this is done through taking steps to avoid exposure to mosquitoes, especially at night, and wearing insect repellent and clothing that covers the arms and legs when outside. Rural areas carry a higher risk for malaria than do cities. Travelers should remain in well-screened areas, especially at night when mosquitos usually feed. Clothes should cover most of the body and mosquito netting should be used around the bed. An insect repellent containing DEET should be used on any exposed area of the skin. For travel information related to malaria and the degree of risk in an intended travel destination, call the CDC toll-free number (877) FYI-TRIP or (877) 394-8747 or visit CDC’s Travelers’ Health Web site, which has country-specific information, including where malaria is found, which antimalarial drugs to take, steps to protect children, and how to avoid mosquito bites. Also, the CDC recommends that travelers going to a country with malaria risk should purchase antimalarial drug before leaving the United States. In recent years, the number of cases of malaria in the United States caused by the P. falciparum parasite has increased. This is believed to be due to travel to areas where malaria is endemic.
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Overview of Malignant Hyperthermia
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Malignant hyperthermia (MH) is a dominantly inherited disorder of skeletal muscle that predisposes susceptible individuals to a life threatening adverse reaction (fulminant MH event) upon exposure to potent volatile anesthetics (halothane, isoflurane, sevoflurane, desflurane, etc.) and the skeletal muscle relaxant succinylcholine.The anesthetic drugs trigger an uncontrolled calcium (Ca2+) release from the sarcoplasmic reticulum (SR) through the ryanodine receptor (RYR1) causing a rapid and sustained rise in myoplasmic Ca2+. The high intracellular Ca2+ activates Ca2+ pumps at the SR and the sarcolemma to reuptake calcium into SR or to transport it into the extracellular space respectively. The energetic cost to regain cellular Ca2+ control causes a need for ATP, which in turn produces heat. Muscle membrane integrity is compromised leading to hyperkalemia and rhabdomyolysis.1 If not treated promptly, by withdrawing the anesthetic and administering dantrolene, mortality can be greater than 70%.2 In some individuals, fulminant MH events can be induced by stress, exercise and high environmental temperatures in the absence of anesthetics.3 Pediatric patients may be at greater risk.4
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Overview of Malignant Hyperthermia. Malignant hyperthermia (MH) is a dominantly inherited disorder of skeletal muscle that predisposes susceptible individuals to a life threatening adverse reaction (fulminant MH event) upon exposure to potent volatile anesthetics (halothane, isoflurane, sevoflurane, desflurane, etc.) and the skeletal muscle relaxant succinylcholine.The anesthetic drugs trigger an uncontrolled calcium (Ca2+) release from the sarcoplasmic reticulum (SR) through the ryanodine receptor (RYR1) causing a rapid and sustained rise in myoplasmic Ca2+. The high intracellular Ca2+ activates Ca2+ pumps at the SR and the sarcolemma to reuptake calcium into SR or to transport it into the extracellular space respectively. The energetic cost to regain cellular Ca2+ control causes a need for ATP, which in turn produces heat. Muscle membrane integrity is compromised leading to hyperkalemia and rhabdomyolysis.1 If not treated promptly, by withdrawing the anesthetic and administering dantrolene, mortality can be greater than 70%.2 In some individuals, fulminant MH events can be induced by stress, exercise and high environmental temperatures in the absence of anesthetics.3 Pediatric patients may be at greater risk.4
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Symptoms of Malignant Hyperthermia
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A fulminant MH episode is characterized by hypermetabolism that produces heat (hypethermia), increased oxygen uptake, and carbon dioxide production, along with hyperkalemia, and acidosis with hyperlacactemia. Skeletal muscle rigidity may either be localized to the masseter muscle or generalized. Muscle damage is reflected by increases in serum creatine kinase, potassium, calcium, and phosphate. Rhabdomyolysis with myoglobinuria and myoglobinemia often occurs. The time of onset after induction of general anesthesia may vary from minutes to hours, and patients may have had previously uneventful exposure to anesthetics.
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Symptoms of Malignant Hyperthermia. A fulminant MH episode is characterized by hypermetabolism that produces heat (hypethermia), increased oxygen uptake, and carbon dioxide production, along with hyperkalemia, and acidosis with hyperlacactemia. Skeletal muscle rigidity may either be localized to the masseter muscle or generalized. Muscle damage is reflected by increases in serum creatine kinase, potassium, calcium, and phosphate. Rhabdomyolysis with myoglobinuria and myoglobinemia often occurs. The time of onset after induction of general anesthesia may vary from minutes to hours, and patients may have had previously uneventful exposure to anesthetics.
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Causes of Malignant Hyperthermia
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The MH phenotype is inherited as an autosomal-dominant trait with incomplete penetrance and variable expression. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females. Molecular genetic studies in humans have established the type 1 ryanodine receptor (RYR1) calcium release channel gene on chromosome 19 (19q13.1) as the primary locus for MH. A number of studies in different populations reported that mutations in the RYR1 gene account for approximately 50% of MH cases, while 1% of MH cases have been linked to the CACNA1S gene located on chromosome 1 (1q32) (encoding the a1 subunit of the voltage-gated dihydropyridine receptor (DHPR)). Currently, more than 400 different variants have been identified in the RYR1 gene (Leiden Open Variation Database).5 Only 31 of these have been functionally characterized and meet all the requirements for inclusion in the European MH Group (EMHG) panel of mutations causative for MH.
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Causes of Malignant Hyperthermia. The MH phenotype is inherited as an autosomal-dominant trait with incomplete penetrance and variable expression. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females. Molecular genetic studies in humans have established the type 1 ryanodine receptor (RYR1) calcium release channel gene on chromosome 19 (19q13.1) as the primary locus for MH. A number of studies in different populations reported that mutations in the RYR1 gene account for approximately 50% of MH cases, while 1% of MH cases have been linked to the CACNA1S gene located on chromosome 1 (1q32) (encoding the a1 subunit of the voltage-gated dihydropyridine receptor (DHPR)). Currently, more than 400 different variants have been identified in the RYR1 gene (Leiden Open Variation Database).5 Only 31 of these have been functionally characterized and meet all the requirements for inclusion in the European MH Group (EMHG) panel of mutations causative for MH.
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Affects of Malignant Hyperthermia
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The incidence of MH during general anesthesia is estimated at 1/4,200 (suspicion of MH) to 1/250,000 (fulminant MH). Published reports probably underestimate the true incidence because of the difficulty in defining mild MH events. In the past decade, two independent studies have estimated the incidence of RYR1 variants in the general population as 1 in 2,000 to 1 in 3,000 persons. More recent exome studies suggest that the frequency of RYR1 variants may be higher than that.6 Demographic data on age and sex distribution of patients referred for testing indicates that 68% are males and 32% are females. Acute MH is distributed worldwide and affects all ethnic groups, with a mean age of 21-23 years.
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Affects of Malignant Hyperthermia. The incidence of MH during general anesthesia is estimated at 1/4,200 (suspicion of MH) to 1/250,000 (fulminant MH). Published reports probably underestimate the true incidence because of the difficulty in defining mild MH events. In the past decade, two independent studies have estimated the incidence of RYR1 variants in the general population as 1 in 2,000 to 1 in 3,000 persons. More recent exome studies suggest that the frequency of RYR1 variants may be higher than that.6 Demographic data on age and sex distribution of patients referred for testing indicates that 68% are males and 32% are females. Acute MH is distributed worldwide and affects all ethnic groups, with a mean age of 21-23 years.
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Related disorders of Malignant Hyperthermia
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MH has been associated with other myopathies such as central core disease (CCD), multiminicore disease (MMD), and nemaline rod myopathy, as well as exertional rhabdomyolysis (ER) and exertional heat illness (EHI). MYOPATHIES ASSOCIATED WITH MUTATIONS IN THE RYR1 GENE: An increasing number of congenital myopathies have been associated with highly penetrant dominant and recessive mutations in the RYR1 gene.7-9 Congenital myopathies are a clinically and genetically heterogeneous group of inherited muscle disorders characterized by childhood onset, muscle weakness, and histopathological features that include: central cores, nemaline bodies and central nuclei. Recent studies suggest that in >50% of patients with congenital myopathies had RYR1 mutations.9 These myopathies include nemaline myopathy, congenital fiber type disproportion and core myopathy that comprise central core disease and multi-minicore disease.7-9 While congenital myopathies are recessive disorders, most patients with central core disease carry dominant mutations in the RYR1 gene. EXERTIONAL HEAT-ILLNESS, RHABDOMYOLYSIS, & MH: A subset of MH susceptible individuals will develop MH-associated symptoms in conjunction with exercise and/or environmental heat exposure. There are numerous reports of known MH susceptible patients who have developed lethal or near lethal hypermetabolic crises in association with exercise and/or heat exposure. It has long been known that MH susceptible swine will develop hypermetabolic crises when exposed to volatile anesthetics, exercise or heat. Furthermore, MH susceptible patients are now being identified not through exposure to volatile anesthetics, but through unexplained heat intolerance or exercise-induced rhabdomyolysis. A European study of 12 subjects with unexplained exertional rhabdomyolysis identified 10 as MH susceptible through muscle contracture testing.10 Three of these 10 MH susceptible subjects were found to have RYR1 gene mutations. Although once doubted, it is now readily accepted that some people will manifest awake MH-like episodes, and that exertional rhabdomyolysis may be a frequent presenting symptom.11-12 The association between exertional heat illness and MH is further supported by RYR1 mouse ‘knock-in’ gene studies.13
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Related disorders of Malignant Hyperthermia. MH has been associated with other myopathies such as central core disease (CCD), multiminicore disease (MMD), and nemaline rod myopathy, as well as exertional rhabdomyolysis (ER) and exertional heat illness (EHI). MYOPATHIES ASSOCIATED WITH MUTATIONS IN THE RYR1 GENE: An increasing number of congenital myopathies have been associated with highly penetrant dominant and recessive mutations in the RYR1 gene.7-9 Congenital myopathies are a clinically and genetically heterogeneous group of inherited muscle disorders characterized by childhood onset, muscle weakness, and histopathological features that include: central cores, nemaline bodies and central nuclei. Recent studies suggest that in >50% of patients with congenital myopathies had RYR1 mutations.9 These myopathies include nemaline myopathy, congenital fiber type disproportion and core myopathy that comprise central core disease and multi-minicore disease.7-9 While congenital myopathies are recessive disorders, most patients with central core disease carry dominant mutations in the RYR1 gene. EXERTIONAL HEAT-ILLNESS, RHABDOMYOLYSIS, & MH: A subset of MH susceptible individuals will develop MH-associated symptoms in conjunction with exercise and/or environmental heat exposure. There are numerous reports of known MH susceptible patients who have developed lethal or near lethal hypermetabolic crises in association with exercise and/or heat exposure. It has long been known that MH susceptible swine will develop hypermetabolic crises when exposed to volatile anesthetics, exercise or heat. Furthermore, MH susceptible patients are now being identified not through exposure to volatile anesthetics, but through unexplained heat intolerance or exercise-induced rhabdomyolysis. A European study of 12 subjects with unexplained exertional rhabdomyolysis identified 10 as MH susceptible through muscle contracture testing.10 Three of these 10 MH susceptible subjects were found to have RYR1 gene mutations. Although once doubted, it is now readily accepted that some people will manifest awake MH-like episodes, and that exertional rhabdomyolysis may be a frequent presenting symptom.11-12 The association between exertional heat illness and MH is further supported by RYR1 mouse ‘knock-in’ gene studies.13
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Diagnosis of Malignant Hyperthermia
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Many individuals with MH are otherwise unaffected. Thus, identifying these individuals before they are given general anesthesia is difficult. Family history of the disorder is important, as is the history of any adverse metabolic responses to anesthesia. Definitive diagnosis of MH susceptibility is made by in vitro contracture test performed on biopsied leg muscle. These tests are based on the differential contractile response of normal and MH muscle to halothane and caffeine. In North America, the test is the caffeine halothane contracture test (CHCT), and in Europe the test is the in vitro contracture test (IVCT). Both tests are invasive, requiring a muscle biopsy, and can only be performed in specialized MH diagnostic centers.Currently, three CLIA (Clinical Laboratory Improvement Amendments) laboratories offer diagnostic RYR1 genetic testing: Prevention Genetics (Marshfield, WI; http://www.preventiongenetics.org), the Center for Medical Genetics (Pittsburgh, PA; http://path.upmc.edu/divisions/mdx/diagnostics.html), and Medical Neurogenetics (Atlanta, GA; http://www.medicalneurogenetics.com). If one of the mutations causative for MH is identified, the patient can be safely labeled as MH susceptible; however, if no mutation in the RYR1 is identified, the MH diagnosis cannot be ruled out.2
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Diagnosis of Malignant Hyperthermia. Many individuals with MH are otherwise unaffected. Thus, identifying these individuals before they are given general anesthesia is difficult. Family history of the disorder is important, as is the history of any adverse metabolic responses to anesthesia. Definitive diagnosis of MH susceptibility is made by in vitro contracture test performed on biopsied leg muscle. These tests are based on the differential contractile response of normal and MH muscle to halothane and caffeine. In North America, the test is the caffeine halothane contracture test (CHCT), and in Europe the test is the in vitro contracture test (IVCT). Both tests are invasive, requiring a muscle biopsy, and can only be performed in specialized MH diagnostic centers.Currently, three CLIA (Clinical Laboratory Improvement Amendments) laboratories offer diagnostic RYR1 genetic testing: Prevention Genetics (Marshfield, WI; http://www.preventiongenetics.org), the Center for Medical Genetics (Pittsburgh, PA; http://path.upmc.edu/divisions/mdx/diagnostics.html), and Medical Neurogenetics (Atlanta, GA; http://www.medicalneurogenetics.com). If one of the mutations causative for MH is identified, the patient can be safely labeled as MH susceptible; however, if no mutation in the RYR1 is identified, the MH diagnosis cannot be ruled out.2
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Therapies of Malignant Hyperthermia
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TreatmentSuccessful treatment of an MH episode involves the rapid cessation of the anesthetic triggering agent, cooling, and administration of Dantrolene intravenously. Dantrolene inhibits the calcium release channel in skeletal muscle without affecting neuromuscular transmission and is effective for both prophylaxis and treatment of fulminant MH. The recommended initial dose is 2.4 mg/kg intravenously, with further increments as needed for an acute episode. Further details about MH treatment are more information about MH for patients and physicians are available at the following URL: www.MHAUS.org
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Therapies of Malignant Hyperthermia. TreatmentSuccessful treatment of an MH episode involves the rapid cessation of the anesthetic triggering agent, cooling, and administration of Dantrolene intravenously. Dantrolene inhibits the calcium release channel in skeletal muscle without affecting neuromuscular transmission and is effective for both prophylaxis and treatment of fulminant MH. The recommended initial dose is 2.4 mg/kg intravenously, with further increments as needed for an acute episode. Further details about MH treatment are more information about MH for patients and physicians are available at the following URL: www.MHAUS.org
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Overview of Mallory Weiss Syndrome
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Mallory-Weiss syndrome refers to a tear or laceration of the mucous membrane, most commonly at the point where the esophagus and the stomach meet (gastroesophageal junction). Such a tear may result in severe bleeding from the gastrointestinal tract. The immediate cause of the lesion is usually a protracted period of vomiting.
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Overview of Mallory Weiss Syndrome. Mallory-Weiss syndrome refers to a tear or laceration of the mucous membrane, most commonly at the point where the esophagus and the stomach meet (gastroesophageal junction). Such a tear may result in severe bleeding from the gastrointestinal tract. The immediate cause of the lesion is usually a protracted period of vomiting.
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Symptoms of Mallory Weiss Syndrome
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Mallory-Weiss syndrome is most commonly characterized by abdominal pain, a history of severe vomiting, vomiting of blood (hematemesis), and the strong involuntary effort to vomit (retching). The blood is often clotted and has the appearance of “coffee grounds”. The stools may be as dark as tar (melenic). In cases in which there is substantial loss of blood, there may be shock and collapse. Individuals with Mallory-Weiss syndrome may also experience severe, painless internal gastrointestinal bleeding (hemorrhaging) due to the tears in the mucous membranes. In most cases (80-90%) however, such bleeding ceases spontaneously. In very rare cases, the bleeding may become life-threatening.
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Symptoms of Mallory Weiss Syndrome. Mallory-Weiss syndrome is most commonly characterized by abdominal pain, a history of severe vomiting, vomiting of blood (hematemesis), and the strong involuntary effort to vomit (retching). The blood is often clotted and has the appearance of “coffee grounds”. The stools may be as dark as tar (melenic). In cases in which there is substantial loss of blood, there may be shock and collapse. Individuals with Mallory-Weiss syndrome may also experience severe, painless internal gastrointestinal bleeding (hemorrhaging) due to the tears in the mucous membranes. In most cases (80-90%) however, such bleeding ceases spontaneously. In very rare cases, the bleeding may become life-threatening.
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Causes of Mallory Weiss Syndrome
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In most instances, the immediate cause of Mallory-Weiss syndrome is severe vomiting. This can be associated with chronic alcoholism, but MWS may also result from a severe trauma to the chest or abdomen, chronic hiccups, intense snoring, lifting and straining, inflammation of the lining of the stomach (gastritis) or esophagus (esophagitis), hiatus hernia, convulsions or CPR (cardiopulmonary resuscitation). Cancer patients undergoing chemotherapy may develop this disorder as a complication of chemotherapy.
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Causes of Mallory Weiss Syndrome. In most instances, the immediate cause of Mallory-Weiss syndrome is severe vomiting. This can be associated with chronic alcoholism, but MWS may also result from a severe trauma to the chest or abdomen, chronic hiccups, intense snoring, lifting and straining, inflammation of the lining of the stomach (gastritis) or esophagus (esophagitis), hiatus hernia, convulsions or CPR (cardiopulmonary resuscitation). Cancer patients undergoing chemotherapy may develop this disorder as a complication of chemotherapy.
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Affects of Mallory Weiss Syndrome
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Mallory-Weiss syndrome accounts for 1 to 15% of all gastrointestinal bleeding episodes. However, it occurs more frequently in individuals with alcoholism. MWS appears to affect more males then females. The ages of those affected varies considerably, with a peak at ages 40 through 60. However, some cases have been reported in children.
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Affects of Mallory Weiss Syndrome. Mallory-Weiss syndrome accounts for 1 to 15% of all gastrointestinal bleeding episodes. However, it occurs more frequently in individuals with alcoholism. MWS appears to affect more males then females. The ages of those affected varies considerably, with a peak at ages 40 through 60. However, some cases have been reported in children.
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Related disorders of Mallory Weiss Syndrome
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Symptoms of the following disorders can be similar to those of Mallory-Weiss Syndrome. Comparisons may be useful for a differential diagnosis:Zollinger-Ellison Syndrome is a rare disorder characterized by small tumors (usually in the pancreas) which secrete a hormone that produces excess amounts of stomach acids that cause ulcers. These tumors can also appear in the lower stomach wall, spleen or lymph nodes close to the stomach. Large amounts of gastric acid can be found in lower stomach areas where many ulcers form. Ulcers can appear suddenly even in areas where they are rarely found, may persist following treatment, and can be accompanied by diarrhea. Prompt medical treatment of these ulcers is necessary to prevent complications such as bleeding and perforation. (For more information on this disorder, choose “Zollinger” as your search term in the Rare Disease Database.)Chronic Erosive Gastritis is a common inflammation of the stomach characterized by multiple lesions in the mucous lining, causing ulcer-like symptoms. These symptoms may include a burning and heavy feeling in the pit of the stomach, mild nausea, vomiting, loss of appetite and weakness. In severe cases there can be bleeding of the stomach which may result in anemia. Some people with this disorder, especially chronic aspirin users, may show no apparent symptoms until the disease has advanced. An accurate diagnosis can be made by a physician's visual inspection of the stomach using a gastroscope. (For more information on this disorder, choose “Gastritis, Chronic Erosive” as your search term in the Rare Disease Database.)Boerhaave's Syndrome is a very serious disorder that is characterized by a rupture of the esophagus. It usually occurs from severe vomiting after excessive eating. Those with this disorder may have severe stomach and chest pain, shortness of breath (dyspnea), rapid heartbeat (tachycardia), a blue discoloration of the skin (cyanosis) and eventually circulatory failure due to the loss of blood (shock) through the esophagus. Surgery is usually required to repair this type of rupture. It is important that this disorder be diagnosed promptly so that medical treatment may be administered as soon as possible.Esophagus Perforation is a rupture of the esophagus. When the rupture occurs in the throat area there may be swelling of the neck and continuous pain that extends from the chest to the back. If it occurs in the chest, there may be vomiting, upper abdominal pain, shortness of breath (dyspnea), and severe chest pain. This disorder can be caused by chemical burns in the throat, complications due to an inflammation of the esophagus (esophagitis), peptic ulcer, or an abnormal growth (neoplasm). Diagnostic medical procedures such as endoscopy or gastroscopy can also cause perforation of the esophagus.Peptic Ulcer is a very common disorder characterized by lesions of the mucous membranes of the esophagus, stomach or duodenum. These lesions are caused by an over-secretion of acid or pepsin and are characterized by pain, heartburn, nausea and vomiting.Esophageal Varices are dilated, enlarged, and tortuous veins, arteries or lymphatic vessels at the lower end of the esophagus as a result of portal hypertension; they are superficial and liable to ulceration and massive bleeding.The following disorder may be associated with Mallory-Weiss Syndrome. It is not necessary for a differential diagnosis:Chronic hiccups are sudden, involuntary repeated spasms of the diaphragm. They can last for hours or days, or they recur very often with only a few hours relief between spasms. The persistence of hiccups may indicate a serious illness. Some of the illnesses that include persistent hiccups as a symptom are: pleurisy of the diaphragm, pneumonia, uremia, alcoholism, disorders of the stomach or esophagus, and bowel diseases. Hiccups may also be associated with pancreatitis, pregnancy, bladder irritation, liver cancer, hepatitis, surgery, tumors, lesions and gastroesophageal tears. (For more information on this disorder, choose “Hiccups” as your search term in the Rare Disease Database.)
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Related disorders of Mallory Weiss Syndrome. Symptoms of the following disorders can be similar to those of Mallory-Weiss Syndrome. Comparisons may be useful for a differential diagnosis:Zollinger-Ellison Syndrome is a rare disorder characterized by small tumors (usually in the pancreas) which secrete a hormone that produces excess amounts of stomach acids that cause ulcers. These tumors can also appear in the lower stomach wall, spleen or lymph nodes close to the stomach. Large amounts of gastric acid can be found in lower stomach areas where many ulcers form. Ulcers can appear suddenly even in areas where they are rarely found, may persist following treatment, and can be accompanied by diarrhea. Prompt medical treatment of these ulcers is necessary to prevent complications such as bleeding and perforation. (For more information on this disorder, choose “Zollinger” as your search term in the Rare Disease Database.)Chronic Erosive Gastritis is a common inflammation of the stomach characterized by multiple lesions in the mucous lining, causing ulcer-like symptoms. These symptoms may include a burning and heavy feeling in the pit of the stomach, mild nausea, vomiting, loss of appetite and weakness. In severe cases there can be bleeding of the stomach which may result in anemia. Some people with this disorder, especially chronic aspirin users, may show no apparent symptoms until the disease has advanced. An accurate diagnosis can be made by a physician's visual inspection of the stomach using a gastroscope. (For more information on this disorder, choose “Gastritis, Chronic Erosive” as your search term in the Rare Disease Database.)Boerhaave's Syndrome is a very serious disorder that is characterized by a rupture of the esophagus. It usually occurs from severe vomiting after excessive eating. Those with this disorder may have severe stomach and chest pain, shortness of breath (dyspnea), rapid heartbeat (tachycardia), a blue discoloration of the skin (cyanosis) and eventually circulatory failure due to the loss of blood (shock) through the esophagus. Surgery is usually required to repair this type of rupture. It is important that this disorder be diagnosed promptly so that medical treatment may be administered as soon as possible.Esophagus Perforation is a rupture of the esophagus. When the rupture occurs in the throat area there may be swelling of the neck and continuous pain that extends from the chest to the back. If it occurs in the chest, there may be vomiting, upper abdominal pain, shortness of breath (dyspnea), and severe chest pain. This disorder can be caused by chemical burns in the throat, complications due to an inflammation of the esophagus (esophagitis), peptic ulcer, or an abnormal growth (neoplasm). Diagnostic medical procedures such as endoscopy or gastroscopy can also cause perforation of the esophagus.Peptic Ulcer is a very common disorder characterized by lesions of the mucous membranes of the esophagus, stomach or duodenum. These lesions are caused by an over-secretion of acid or pepsin and are characterized by pain, heartburn, nausea and vomiting.Esophageal Varices are dilated, enlarged, and tortuous veins, arteries or lymphatic vessels at the lower end of the esophagus as a result of portal hypertension; they are superficial and liable to ulceration and massive bleeding.The following disorder may be associated with Mallory-Weiss Syndrome. It is not necessary for a differential diagnosis:Chronic hiccups are sudden, involuntary repeated spasms of the diaphragm. They can last for hours or days, or they recur very often with only a few hours relief between spasms. The persistence of hiccups may indicate a serious illness. Some of the illnesses that include persistent hiccups as a symptom are: pleurisy of the diaphragm, pneumonia, uremia, alcoholism, disorders of the stomach or esophagus, and bowel diseases. Hiccups may also be associated with pancreatitis, pregnancy, bladder irritation, liver cancer, hepatitis, surgery, tumors, lesions and gastroesophageal tears. (For more information on this disorder, choose “Hiccups” as your search term in the Rare Disease Database.)
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Diagnosis of Mallory Weiss Syndrome
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The diagnosis of Mallory-Weiss syndrome is usually determined by endoscopic examination of the esophagus membrane.
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Diagnosis of Mallory Weiss Syndrome. The diagnosis of Mallory-Weiss syndrome is usually determined by endoscopic examination of the esophagus membrane.
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Therapies of Mallory Weiss Syndrome
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TreatmentIn many cases, bleeding caused by Mallory-Weiss syndrome will stop without treatment. In cases where the bleeding persists, treatment may include sealing the lesion by applying heat or chemicals (cauterization) or high frequency electrical current (electrocoagulation). Blood transfusions and/or the use of the vasopressive drug, pitressin, may be required. (Among other actions, the hormone pitressin acts upon the muscles of the capillaries to affect blood pressure.. Direct pressure may also be used by inserting a catheter which is surrounded by a balloon. The balloon is then inflated (balloon tamponade) to stop the bleeding. Surgery is usually not necessary unless the bleeding cannot be controlled by conservative measures. Other treatment is symptomatic and supportive.Embolization may be necessary as a treatment for massive uncontrolled bleeding of the esophagus. This procedure consists of inserting a substance, such as gelfoam, bucrylate, or alcohol (ethanol) and stainless steel coils into the affected area.
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Therapies of Mallory Weiss Syndrome. TreatmentIn many cases, bleeding caused by Mallory-Weiss syndrome will stop without treatment. In cases where the bleeding persists, treatment may include sealing the lesion by applying heat or chemicals (cauterization) or high frequency electrical current (electrocoagulation). Blood transfusions and/or the use of the vasopressive drug, pitressin, may be required. (Among other actions, the hormone pitressin acts upon the muscles of the capillaries to affect blood pressure.. Direct pressure may also be used by inserting a catheter which is surrounded by a balloon. The balloon is then inflated (balloon tamponade) to stop the bleeding. Surgery is usually not necessary unless the bleeding cannot be controlled by conservative measures. Other treatment is symptomatic and supportive.Embolization may be necessary as a treatment for massive uncontrolled bleeding of the esophagus. This procedure consists of inserting a substance, such as gelfoam, bucrylate, or alcohol (ethanol) and stainless steel coils into the affected area.
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Overview of Mandibuloacral Dysplasia
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Mandibuloacral dysplasia (MAD) is an extremely rare genetic disorder characterized by underdevelopment (hypoplasia) of the lower jaw (mandible) and the collarbone (clavicle), bone loss at the ends of the fingers and toes (acro-osteolysis), skin degeneration (cutaneous atrophy), and partial lipodystrophy, a condition marked by selective loss of body fat (adipose tissue) from various areas of the body. Cutaneous atrophy and lipodystrophy may contribute to affected children having a prematurely-aged appearance (progeroid features). Lipodystrophy may be associated with clinical features of metabolic syndrome including insulin resistance, impaired glucose tolerance, and diabetes mellitus. Additional symptoms can occur as well. Two types of mandibuloacral dysplasia have been identified, type A and type B. Both types are inherited as autosomal recessive conditions. Mandibuloacral dysplasia type A (MADA) is caused by mutations of the lamin A/C (LMNA) gene; mandibuloacral dysplasia type B (MADB) is caused by mutations of the zinc metalloproteinase (ZMPSTE24) gene.Mandibuloacral dysplasia may be classified as a form of lipodystrophy or progeria because of its overlapping symptoms. Mandibuloacral dysplasia type A may also be classified as a laminopathy, a general term for the group of disorders associated with a mutation of the LMNA gene. The ZMPSTE24 mutation that causes mandibuloacral dysplasia type B can also cause restrictive dermopathy syndrome.
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Overview of Mandibuloacral Dysplasia. Mandibuloacral dysplasia (MAD) is an extremely rare genetic disorder characterized by underdevelopment (hypoplasia) of the lower jaw (mandible) and the collarbone (clavicle), bone loss at the ends of the fingers and toes (acro-osteolysis), skin degeneration (cutaneous atrophy), and partial lipodystrophy, a condition marked by selective loss of body fat (adipose tissue) from various areas of the body. Cutaneous atrophy and lipodystrophy may contribute to affected children having a prematurely-aged appearance (progeroid features). Lipodystrophy may be associated with clinical features of metabolic syndrome including insulin resistance, impaired glucose tolerance, and diabetes mellitus. Additional symptoms can occur as well. Two types of mandibuloacral dysplasia have been identified, type A and type B. Both types are inherited as autosomal recessive conditions. Mandibuloacral dysplasia type A (MADA) is caused by mutations of the lamin A/C (LMNA) gene; mandibuloacral dysplasia type B (MADB) is caused by mutations of the zinc metalloproteinase (ZMPSTE24) gene.Mandibuloacral dysplasia may be classified as a form of lipodystrophy or progeria because of its overlapping symptoms. Mandibuloacral dysplasia type A may also be classified as a laminopathy, a general term for the group of disorders associated with a mutation of the LMNA gene. The ZMPSTE24 mutation that causes mandibuloacral dysplasia type B can also cause restrictive dermopathy syndrome.
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Symptoms of Mandibuloacral Dysplasia
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The signs and symptoms of mandibuloacral dysplasia can vary from one person to another. The age of onset of certain symptoms can vary as well. Children with mandibuloacral dysplasia type A often develop normally for the first 4 to 5 years of life. Children with mandibuloacral dysplasia type B can develop noticeable symptoms of the disorder by the age of 2. Mandibuloacral dysplasia type B has only been described in a handful of children. Common symptoms associated with both forms of the disorder have been characterized, but, because of the low number of identified cases, it is difficult to get an accurate picture of associated symptoms and prognosis. Affected individuals often develop skeletal abnormalities including underdevelopment of the jaw bone giving the appearance of a receding chin. The collarbone may be underdeveloped or malformed (dysplastic) giving the appearance of sloping shoulders. Delayed closure of the fibrous joints of the skull (cranial sutures) in affected infants is common. Bone loss may occur at the ends of the finger and toes, giving them a rounded (bulbous) or stubby appearance. Affected individuals may have “progeroid” features that give them a prematurely aged appearance. Such features include a distinctive facial appearance, a mottled skin color (pigmentation), thin, sparse hair with patchy areas of hair loss (alopecia), loss of eyebrows, malformation of the fingernails and toenails, and degeneration of the skin, especially the skin of the hands and feet. The distinctive facial features associated with this disorder may include prominent eyes, pointed (pinched) nose, small mouth, and a receding chin (due to mandibular hypoplasia). Affected individuals may also have a high-pitched voice. Some individuals may experience delayed sexual maturation. The progeroid appearance may be more pronounced in individuals with mandibuloacral dysplasia type B.Individuals with mandibuloacral dysplasia may develop lipodystrophy, a condition characterized by the loss of body (subcutaneous) fat. Two different patterns of partial lipodystrophy have been identified. In one form, fat loss occurs primarily on the arms and legs and sometimes the trunk. Fat may be normal or slightly excess in the neck, the back of the head (occiput) and upper back causing a hump, and trunk areas. In the other form, fat loss occurs in a more widespread (generalized) form affecting the face, trunk and arms and legs. Many individuals with mandibuloacral dysplasia type A have developed lipodystrophy around puberty, but earlier development has been reported. Individuals with mandibuloacral dysplasia type B have developed the generalized form of lipodystrophy, but onset may not be until later during childhood. Lipodystrophy may be associated with the clinical features of metabolic syndrome. Metabolic complications have generally been mild in individuals with mandibuloacral dysplasia. Insulin resistance may occur and can be associated with a condition called acanthosis nigricans, a skin condition characterized by abnormally increased coloration (hyperpigmentation) and “velvety” thickening (hyperkeratosis) of the skin, particularly of skin fold regions, such as of the neck and groin and under the arms (axillae). Acanthosis nigricans has not been reported in individuals with mandibuloacral dysplasia type B. Other complications of insulin resistance may occur including glucose intolerance, hypertriglyceridemia, and diabetes. Additional symptoms have been reported including dental abnormalities such as premature loss of teeth and overcrowding, stiff and/or rigid joints, and growth retardation ultimately resulting in adult height that is below normal (short stature). Some individuals with mandibuloacral dysplasia type B have developed muscle disease (myopathy). Later in life, they are at risk of developing calcified skin nodules, cardiovascular disease such as high blood pressure or hardening of the arteries (atherosclerosis), and a kidney disease known as focal segmental glomerulosclerosis (FSGS). This kidney disorder occurs when clusters of capillaries known as renal glomeruli, which normally filter the blood that passes through the kidneys, are replaced by scar tissue. This condition can cause foamy urine due to the presence of excess protein, swelling due to abnormal fluid accumulation (edema), high blood pressure, and weight gain. FSGS can potentially progress to cause severe complications such as nephrotic syndrome and, ultimately, kidney failure.
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Symptoms of Mandibuloacral Dysplasia. The signs and symptoms of mandibuloacral dysplasia can vary from one person to another. The age of onset of certain symptoms can vary as well. Children with mandibuloacral dysplasia type A often develop normally for the first 4 to 5 years of life. Children with mandibuloacral dysplasia type B can develop noticeable symptoms of the disorder by the age of 2. Mandibuloacral dysplasia type B has only been described in a handful of children. Common symptoms associated with both forms of the disorder have been characterized, but, because of the low number of identified cases, it is difficult to get an accurate picture of associated symptoms and prognosis. Affected individuals often develop skeletal abnormalities including underdevelopment of the jaw bone giving the appearance of a receding chin. The collarbone may be underdeveloped or malformed (dysplastic) giving the appearance of sloping shoulders. Delayed closure of the fibrous joints of the skull (cranial sutures) in affected infants is common. Bone loss may occur at the ends of the finger and toes, giving them a rounded (bulbous) or stubby appearance. Affected individuals may have “progeroid” features that give them a prematurely aged appearance. Such features include a distinctive facial appearance, a mottled skin color (pigmentation), thin, sparse hair with patchy areas of hair loss (alopecia), loss of eyebrows, malformation of the fingernails and toenails, and degeneration of the skin, especially the skin of the hands and feet. The distinctive facial features associated with this disorder may include prominent eyes, pointed (pinched) nose, small mouth, and a receding chin (due to mandibular hypoplasia). Affected individuals may also have a high-pitched voice. Some individuals may experience delayed sexual maturation. The progeroid appearance may be more pronounced in individuals with mandibuloacral dysplasia type B.Individuals with mandibuloacral dysplasia may develop lipodystrophy, a condition characterized by the loss of body (subcutaneous) fat. Two different patterns of partial lipodystrophy have been identified. In one form, fat loss occurs primarily on the arms and legs and sometimes the trunk. Fat may be normal or slightly excess in the neck, the back of the head (occiput) and upper back causing a hump, and trunk areas. In the other form, fat loss occurs in a more widespread (generalized) form affecting the face, trunk and arms and legs. Many individuals with mandibuloacral dysplasia type A have developed lipodystrophy around puberty, but earlier development has been reported. Individuals with mandibuloacral dysplasia type B have developed the generalized form of lipodystrophy, but onset may not be until later during childhood. Lipodystrophy may be associated with the clinical features of metabolic syndrome. Metabolic complications have generally been mild in individuals with mandibuloacral dysplasia. Insulin resistance may occur and can be associated with a condition called acanthosis nigricans, a skin condition characterized by abnormally increased coloration (hyperpigmentation) and “velvety” thickening (hyperkeratosis) of the skin, particularly of skin fold regions, such as of the neck and groin and under the arms (axillae). Acanthosis nigricans has not been reported in individuals with mandibuloacral dysplasia type B. Other complications of insulin resistance may occur including glucose intolerance, hypertriglyceridemia, and diabetes. Additional symptoms have been reported including dental abnormalities such as premature loss of teeth and overcrowding, stiff and/or rigid joints, and growth retardation ultimately resulting in adult height that is below normal (short stature). Some individuals with mandibuloacral dysplasia type B have developed muscle disease (myopathy). Later in life, they are at risk of developing calcified skin nodules, cardiovascular disease such as high blood pressure or hardening of the arteries (atherosclerosis), and a kidney disease known as focal segmental glomerulosclerosis (FSGS). This kidney disorder occurs when clusters of capillaries known as renal glomeruli, which normally filter the blood that passes through the kidneys, are replaced by scar tissue. This condition can cause foamy urine due to the presence of excess protein, swelling due to abnormal fluid accumulation (edema), high blood pressure, and weight gain. FSGS can potentially progress to cause severe complications such as nephrotic syndrome and, ultimately, kidney failure.
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Causes of Mandibuloacral Dysplasia
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Mandibuloacral dysplasia type A is caused by mutations of the LMNA gene; type B is caused by mutations of the ZMPSTE24 gene. Some individuals with mandibuloacral dysplasia do not have mutations of either gene suggesting that additional, as-yet-unidentified genes may also cause the disorder. The identified mutations that cause mandibuloacral dysplasia are inherited as autosomal recessive traits. 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 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. The LMNA gene is located on the long arm (q) of chromosome 1 (1q21-q22). It contains instructions for creating (encoding) the proteins lamin A and lamin C. These proteins are active in the nuclear lamina, a structure found within many types of cells. The exact functions of lamins A and C and their exact roles in causing the symptoms of mandibuloacral dysplasia are not fully understood. However, researchers believe that the lamin A protein serves as the scaffolding that holds the nucleus of a cell together. Defective lamin A most likely causes the nucleus to become unstable and ultimately leads to the premature aging symptoms seen in mandibuloacral dysplasia. Researchers also suspect that mutations in the LMNA gene ultimately result in the impairment of fat cells (adipocytes) differentiation causing lipodystrophy and of bone cells (osteoclasts) differentiation causing altered bone turnover.Mutations of the LMNA gene have also been shown to cause a variety of other disorders (allelic disorders) including a form of familial partial lipodystrophy (Dunnigan variety), a couple forms of Emery-Dreifuss muscular dystrophy, a form of limb-girdle muscular dystrophy, a form of hereditary spastic paraplegia, a form of Charcot-Marie-Tooth disease, a form of dilated cardiomyopathy, Malouf syndrome, and some cases of Hutchinson-Gilford progeria syndrome. Individuals whose symptoms overlap among these disorders have been reported in the medical literature. Some individuals with mutations of the LMNA gene are at a greater risk than the general population of developing cardiovascular disease; it is not known whether individuals with mandibuloacral dysplasia type A are affected by this risk. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)The ZMPSTE24 gene is located on the short arm (p) of chromosome 1 (1p34.2). It contains instructions for creating (encoding) an enzyme whose exact roles in the body is not fully understood, but that is involved in the maturation of lamin A. Researcher believe that this enzyme is required for prelamin A to be processed into mature lamin A. Mutations of the ZMPSTE24 gene ultimately result in an accumulation of prelamin A in various tissues of the body. Mutations of the ZMPSTE24 gene have also been shown to cause restrictive dermopathy syndrome, a rare, severe disorder characterized by intrauterine growth retardation, malformed collarbones, joint contractures, a fixed facial expression and tight, rigid skin that is easily eroded. In restrictive dermopathy syndrome, there are almost no detectable levels of the enzyme encoded by the ZMPSTE24 gene and the disorder is often fatal during the newborn period. Consequently, some researchers believe that mutations of this gene result in a spectrum of disease, with restrictive dermopathy syndrome representing the severe end of the syndrome and mandibuloacral dysplasia type B representing a less severe form. Researchers believe that the amount of residual enzyme activity among individuals with a ZMPSTE24 gene mutation correlates directly with the severity of the disorder.
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Causes of Mandibuloacral Dysplasia. Mandibuloacral dysplasia type A is caused by mutations of the LMNA gene; type B is caused by mutations of the ZMPSTE24 gene. Some individuals with mandibuloacral dysplasia do not have mutations of either gene suggesting that additional, as-yet-unidentified genes may also cause the disorder. The identified mutations that cause mandibuloacral dysplasia are inherited as autosomal recessive traits. 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 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. The LMNA gene is located on the long arm (q) of chromosome 1 (1q21-q22). It contains instructions for creating (encoding) the proteins lamin A and lamin C. These proteins are active in the nuclear lamina, a structure found within many types of cells. The exact functions of lamins A and C and their exact roles in causing the symptoms of mandibuloacral dysplasia are not fully understood. However, researchers believe that the lamin A protein serves as the scaffolding that holds the nucleus of a cell together. Defective lamin A most likely causes the nucleus to become unstable and ultimately leads to the premature aging symptoms seen in mandibuloacral dysplasia. Researchers also suspect that mutations in the LMNA gene ultimately result in the impairment of fat cells (adipocytes) differentiation causing lipodystrophy and of bone cells (osteoclasts) differentiation causing altered bone turnover.Mutations of the LMNA gene have also been shown to cause a variety of other disorders (allelic disorders) including a form of familial partial lipodystrophy (Dunnigan variety), a couple forms of Emery-Dreifuss muscular dystrophy, a form of limb-girdle muscular dystrophy, a form of hereditary spastic paraplegia, a form of Charcot-Marie-Tooth disease, a form of dilated cardiomyopathy, Malouf syndrome, and some cases of Hutchinson-Gilford progeria syndrome. Individuals whose symptoms overlap among these disorders have been reported in the medical literature. Some individuals with mutations of the LMNA gene are at a greater risk than the general population of developing cardiovascular disease; it is not known whether individuals with mandibuloacral dysplasia type A are affected by this risk. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)The ZMPSTE24 gene is located on the short arm (p) of chromosome 1 (1p34.2). It contains instructions for creating (encoding) an enzyme whose exact roles in the body is not fully understood, but that is involved in the maturation of lamin A. Researcher believe that this enzyme is required for prelamin A to be processed into mature lamin A. Mutations of the ZMPSTE24 gene ultimately result in an accumulation of prelamin A in various tissues of the body. Mutations of the ZMPSTE24 gene have also been shown to cause restrictive dermopathy syndrome, a rare, severe disorder characterized by intrauterine growth retardation, malformed collarbones, joint contractures, a fixed facial expression and tight, rigid skin that is easily eroded. In restrictive dermopathy syndrome, there are almost no detectable levels of the enzyme encoded by the ZMPSTE24 gene and the disorder is often fatal during the newborn period. Consequently, some researchers believe that mutations of this gene result in a spectrum of disease, with restrictive dermopathy syndrome representing the severe end of the syndrome and mandibuloacral dysplasia type B representing a less severe form. Researchers believe that the amount of residual enzyme activity among individuals with a ZMPSTE24 gene mutation correlates directly with the severity of the disorder.
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Affects of Mandibuloacral Dysplasia
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Approximately 40 cases of mandibuloacral dysplasia have been reported in the medical literature. Fewer than 10 cases of mandibuloacral dysplasia type B have been reported in the medical literature. Many cases of the disorder most likely go misdiagnosed or undiagnosed, making it difficult to determine the true frequency of mandibuloacral dysplasia in the general population.
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Affects of Mandibuloacral Dysplasia. Approximately 40 cases of mandibuloacral dysplasia have been reported in the medical literature. Fewer than 10 cases of mandibuloacral dysplasia type B have been reported in the medical literature. Many cases of the disorder most likely go misdiagnosed or undiagnosed, making it difficult to determine the true frequency of mandibuloacral dysplasia in the general population.
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Related disorders of Mandibuloacral Dysplasia
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Symptoms of the following disorders can be similar to those of mandibuloacral dysplasia. Comparisons may be useful for a differential diagnosis.Progeria, or Hutchinson-Gilford progeria syndrome (HGPS), is a rare, fatal, genetic condition of childhood with striking features resembling premature aging. Children with progeria usually have a normal appearance in early infancy. At approximately nine to 24 months of age, affected children begin to experience profound growth delays, resulting in short stature and low weight. They also develop a distinctive facial appearance characterized by a disproportionately small face in comparison to the head; an underdeveloped jaw (micrognathia); malformation and crowding of the teeth; abnormally prominent eyes; a small nose; prominent eyes and a subtle blueness around the mouth. In addition, by the second year of life, the scalp hair, eyebrows, and eyelashes are lost (alopecia), and the scalp hair may be replaced by small, downy, white or blond hairs. Additional characteristic features include generalized atherosclerosis, cardiovascular disease and stroke, hip dislocations, unusually prominent veins of the scalp, loss of the layer of fat beneath the skin (subcutaneous adipose tissue), defects of the nails, joint stiffness, skeletal defects, and/or other abnormalities. According to reports in the medical literature, individuals with HGPS develop premature, widespread thickening and loss of elasticity of artery walls (arteriosclerosis), which result in life-threatening complications during childhood, adolescence, or early adulthood. Children with progeria die of heart disease (atherosclerosis) at an average age of 13 years, with a range of about eight to 21 years. As with any person suffering from heart disease, the common events as heart disease advances for children with progeria can include high blood pressure, strokes, angina (chest pain due to poor blood flow to the heart itself), enlarged heart, and heart failure, all conditions associated with aging. Progeria is caused by a mutation of the LMNA gene. (For more information on this disorder, choose “progeria” as your search term in the Rare Disease Database.)Familial partial lipodystrophy (FPL) is a rare genetic disorder characterized by selective, progressive loss of body fat (adipose tissue) in various areas of the body. Individuals with FPL often have reduced subcutaneous fat in the arms and legs and the chest and trunk of the body. Conversely, affected individuals may also have excess subcutaneous fat deposits in other areas of the body, especially the neck, face and intra-abdominal regions. In most cases, adipose tissue loss begins during puberty. FPL can be associated with a variety of metabolic abnormalities. The extent of adipose tissue loss usually determines the severity of the associated metabolic complications. These complications can include glucose intolerance, hypertriglyceridemia and diabetes. Additional findings can occur in some cases. Five different subtypes of FPL have been identified. Each subtype is caused by mutations in a different gene. Three forms of FPL are inherited as autosomal dominant traits. One form is inherited as an autosomal recessive trait. The mode of inheritance of one form is not fully understood. FPL, Dunnigan variety is caused by mutations to the same gene that causes mandibuloacral dysplasia type A (allelic disorders). (For more information on this disorder, choose “familial partial lipodystrophy” as your search term in the Rare Disease Database.)
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Related disorders of Mandibuloacral Dysplasia. Symptoms of the following disorders can be similar to those of mandibuloacral dysplasia. Comparisons may be useful for a differential diagnosis.Progeria, or Hutchinson-Gilford progeria syndrome (HGPS), is a rare, fatal, genetic condition of childhood with striking features resembling premature aging. Children with progeria usually have a normal appearance in early infancy. At approximately nine to 24 months of age, affected children begin to experience profound growth delays, resulting in short stature and low weight. They also develop a distinctive facial appearance characterized by a disproportionately small face in comparison to the head; an underdeveloped jaw (micrognathia); malformation and crowding of the teeth; abnormally prominent eyes; a small nose; prominent eyes and a subtle blueness around the mouth. In addition, by the second year of life, the scalp hair, eyebrows, and eyelashes are lost (alopecia), and the scalp hair may be replaced by small, downy, white or blond hairs. Additional characteristic features include generalized atherosclerosis, cardiovascular disease and stroke, hip dislocations, unusually prominent veins of the scalp, loss of the layer of fat beneath the skin (subcutaneous adipose tissue), defects of the nails, joint stiffness, skeletal defects, and/or other abnormalities. According to reports in the medical literature, individuals with HGPS develop premature, widespread thickening and loss of elasticity of artery walls (arteriosclerosis), which result in life-threatening complications during childhood, adolescence, or early adulthood. Children with progeria die of heart disease (atherosclerosis) at an average age of 13 years, with a range of about eight to 21 years. As with any person suffering from heart disease, the common events as heart disease advances for children with progeria can include high blood pressure, strokes, angina (chest pain due to poor blood flow to the heart itself), enlarged heart, and heart failure, all conditions associated with aging. Progeria is caused by a mutation of the LMNA gene. (For more information on this disorder, choose “progeria” as your search term in the Rare Disease Database.)Familial partial lipodystrophy (FPL) is a rare genetic disorder characterized by selective, progressive loss of body fat (adipose tissue) in various areas of the body. Individuals with FPL often have reduced subcutaneous fat in the arms and legs and the chest and trunk of the body. Conversely, affected individuals may also have excess subcutaneous fat deposits in other areas of the body, especially the neck, face and intra-abdominal regions. In most cases, adipose tissue loss begins during puberty. FPL can be associated with a variety of metabolic abnormalities. The extent of adipose tissue loss usually determines the severity of the associated metabolic complications. These complications can include glucose intolerance, hypertriglyceridemia and diabetes. Additional findings can occur in some cases. Five different subtypes of FPL have been identified. Each subtype is caused by mutations in a different gene. Three forms of FPL are inherited as autosomal dominant traits. One form is inherited as an autosomal recessive trait. The mode of inheritance of one form is not fully understood. FPL, Dunnigan variety is caused by mutations to the same gene that causes mandibuloacral dysplasia type A (allelic disorders). (For more information on this disorder, choose “familial partial lipodystrophy” as your search term in the Rare Disease Database.)
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Diagnosis of Mandibuloacral Dysplasia
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A diagnosis of mandibuloacral dysplasia is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests.Molecular genetic testing can confirm a diagnosis of mandibuloacral dysplasia in some cases. Molecular genetic testing can detect mutations in the specific genes that cause the disorder, but the test is only available on a clinical basis.
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Diagnosis of Mandibuloacral Dysplasia. A diagnosis of mandibuloacral dysplasia is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests.Molecular genetic testing can confirm a diagnosis of mandibuloacral dysplasia in some cases. Molecular genetic testing can detect mutations in the specific genes that cause the disorder, but the test is only available on a clinical basis.
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Therapies of Mandibuloacral Dysplasia
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TreatmentThe treatment of mandibuloacral dysplasia is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, orthopedists, endocrinologists, dermatologists, nutritionists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment.Individuals with mandibuloacral dysplasia and their families are encouraged to seek counseling after a diagnosis because the diagnosis can cause anxiety, stress, and extreme psychological distress. Psychological support and counseling both professionally and through support groups is recommended for affected individuals and their families. Genetic counseling may be of benefit for affected individuals and their families as well.Additional therapies to treat individuals with mandibuloacral dysplasia are symptomatic and supportive and follow regular, standard guidelines. Diabetes is treated with standard therapies. After the onset of diabetes, hyperglycemic drugs such as metformin may be recommended to treat hyperglycemia. Insulin or insulin analogues can also be used to treat affected individuals. There have been no clinical trials to establish the optimal use of drug therapy to treat the metabolic complications in individuals with mandibuloacral dysplasia.Regular exercise and maintaining a healthy weight are also encouraged as a way to decrease the chances of developing diabetes. Individuals with extreme hypertriglyceridemia may be treated with fibric acid derivatives, statins, or n-3 polyunsaturated fatty acids.
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Therapies of Mandibuloacral Dysplasia. TreatmentThe treatment of mandibuloacral dysplasia is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, orthopedists, endocrinologists, dermatologists, nutritionists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment.Individuals with mandibuloacral dysplasia and their families are encouraged to seek counseling after a diagnosis because the diagnosis can cause anxiety, stress, and extreme psychological distress. Psychological support and counseling both professionally and through support groups is recommended for affected individuals and their families. Genetic counseling may be of benefit for affected individuals and their families as well.Additional therapies to treat individuals with mandibuloacral dysplasia are symptomatic and supportive and follow regular, standard guidelines. Diabetes is treated with standard therapies. After the onset of diabetes, hyperglycemic drugs such as metformin may be recommended to treat hyperglycemia. Insulin or insulin analogues can also be used to treat affected individuals. There have been no clinical trials to establish the optimal use of drug therapy to treat the metabolic complications in individuals with mandibuloacral dysplasia.Regular exercise and maintaining a healthy weight are also encouraged as a way to decrease the chances of developing diabetes. Individuals with extreme hypertriglyceridemia may be treated with fibric acid derivatives, statins, or n-3 polyunsaturated fatty acids.
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Overview of Mantle Cell Lymphoma
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SummaryMantle cell lymphoma (MCL) is a type of non-Hodgkin’s lymphoma, which is a form of cancer that affects the lymphatic system. Lymphomas are cancers that involve white blood cells, and can be divided depending on the type of cell involved, either B-lymphocytes or T-lymphocytes. MCL is a B-cell lymphoma that develops from malignant B-lymphocytes within a region of the lymph node known as the mantle zone. It affects mostly men who are usually 60 to 70 years old. Approximately one out of 200,000 individuals per year are diagnosed with MCL. The symptoms individuals experience depends on the extent of the disease and the region of the body that is affected. Many affected individuals have widespread disease at diagnosis, with involved regions often including multiple lymph nodes, the spleen, and, potentially, the bone marrow, the liver, and/or regions of the digestive (gastrointestinal) tract. Examples of symptoms include swollen painless lymph nodes, headache, weakness, decreased appetite, and indigestion. Other non-specific symptoms may include fever, weight loss, sweating at night (“night sweats”), fatigue, reduced energy, easy bruising or bleeding. Several treatment options are available. The management selected will be based on a number of patient and disease characteristics. The first-line treatment typically includes chemotherapy combined with immunotherapy, which is a combination of medications that destroy the cancer cells. This approach is meant to cause complete or partial disappearance of the cancer (remission). Following that, patients may be eligible for a stem cell transplant, and/or an extended course of immunotherapy that is meant to prolong cancer remission.IntroductionMantle cell lymphoma belongs to a group of diseases known as non-Hodgkin's lymphomas, which are related malignancies (cancers) that affect the lymphatic system. Functioning as part of the immune system, the lymphatic system helps to protect the body against infection and disease. It consists of a network of tubular channels (lymph vessels) that drain a thin watery fluid known as lymph from different areas of the body into the bloodstream. Lymph accumulates in the tiny spaces between tissue cells and contains proteins, fats, and certain white blood cells known as lymphocytes.As lymph moves through the lymphatic system, it is filtered by a network of small structures known as lymph nodes that help to remove microorganisms (e.g., viruses, bacteria, etc.) and other foreign bodies. Groups of lymph nodes are located throughout the body, including in the neck, under the arms (axillae), at the elbows, and in the chest, abdomen, and groin. Lymphocytes are stored within lymph nodes and may also be found in other lymphatic tissues. In addition to the lymph nodes, the lymphatic system includes the spleen. Lymphatic tissues also include the thymus, a relatively small organ behind the breastbone that is thought to play an important role in the immune system until puberty, as well as the bone marrow, which is the spongy tissue inside the cavities of bones that manufactures blood cells. Lymphatic tissue or circulating lymphocytes may also be located in other regions of the body, such as the skin, small intestine, liver, and other organs. There are two main types of lymphocytes: B-lymphocytes, which may produce specific antibodies to “neutralize” certain invading microorganisms, and T-lymphocytes, which may directly destroy microorganisms or assist in the activities of other lymphocytes.Mantle cell lymphoma and other cancers of the lymphatic system (lymphomas) result from errors in the production of a lymphocyte or transformation of a lymphocyte into a malignant cell. Abnormal, uncontrolled growth and multiplication (proliferation) of malignant lymphocytes may lead to enlargement of a specific lymph node region or regions; involvement of other lymphatic tissues, such as the spleen and bone marrow; and spread to other bodily tissues and organs, potentially resulting in life-threatening complications. The specific symptoms and physical findings may vary from case to case, depending upon the extent and region(s) of involvement and other factors.Mantle cell lymphoma is a B-cell lymphoma that develops from malignant B-lymphocytes within a region of the lymph node known as the mantle zone. As previously mentioned, the signs and symptoms of MCL are dependent on the extent of the region of the body that is affected. Although the exact underlying cause is unknown, researchers have identified several genetic changes (or mutations) in the B-cells, which contribute to the multiplication of the cancer cells. For MCL, a mutation referred to as t(11;14) and denotes the exchange of genetic information between chromosome 11 and 14, leads to the overproduction of a protein called cyclin D1 in the lymphoma cells as will be further explained in the “Causes” section of this report below. These changes are found in more than 90 percent of patients with MCL and are important for diagnosis.Several disease characteristics are considered when attempting to determine if the cancer will be indolent or aggressive. Indolent lymphomas tend to grow slowly and result in few associated symptoms, whereas more aggressive lymphomas, typically grow rapidly, requiring prompt treatment. There is some debate concerning whether MCL should be categorized as a slow-growing (indolent) or rapidly-growing (aggressive) lymphoma. Although experts have classified MCL as an aggressive lymphoma, it has been shown to have certain characteristics of indolent lymphoma.
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Overview of Mantle Cell Lymphoma. SummaryMantle cell lymphoma (MCL) is a type of non-Hodgkin’s lymphoma, which is a form of cancer that affects the lymphatic system. Lymphomas are cancers that involve white blood cells, and can be divided depending on the type of cell involved, either B-lymphocytes or T-lymphocytes. MCL is a B-cell lymphoma that develops from malignant B-lymphocytes within a region of the lymph node known as the mantle zone. It affects mostly men who are usually 60 to 70 years old. Approximately one out of 200,000 individuals per year are diagnosed with MCL. The symptoms individuals experience depends on the extent of the disease and the region of the body that is affected. Many affected individuals have widespread disease at diagnosis, with involved regions often including multiple lymph nodes, the spleen, and, potentially, the bone marrow, the liver, and/or regions of the digestive (gastrointestinal) tract. Examples of symptoms include swollen painless lymph nodes, headache, weakness, decreased appetite, and indigestion. Other non-specific symptoms may include fever, weight loss, sweating at night (“night sweats”), fatigue, reduced energy, easy bruising or bleeding. Several treatment options are available. The management selected will be based on a number of patient and disease characteristics. The first-line treatment typically includes chemotherapy combined with immunotherapy, which is a combination of medications that destroy the cancer cells. This approach is meant to cause complete or partial disappearance of the cancer (remission). Following that, patients may be eligible for a stem cell transplant, and/or an extended course of immunotherapy that is meant to prolong cancer remission.IntroductionMantle cell lymphoma belongs to a group of diseases known as non-Hodgkin's lymphomas, which are related malignancies (cancers) that affect the lymphatic system. Functioning as part of the immune system, the lymphatic system helps to protect the body against infection and disease. It consists of a network of tubular channels (lymph vessels) that drain a thin watery fluid known as lymph from different areas of the body into the bloodstream. Lymph accumulates in the tiny spaces between tissue cells and contains proteins, fats, and certain white blood cells known as lymphocytes.As lymph moves through the lymphatic system, it is filtered by a network of small structures known as lymph nodes that help to remove microorganisms (e.g., viruses, bacteria, etc.) and other foreign bodies. Groups of lymph nodes are located throughout the body, including in the neck, under the arms (axillae), at the elbows, and in the chest, abdomen, and groin. Lymphocytes are stored within lymph nodes and may also be found in other lymphatic tissues. In addition to the lymph nodes, the lymphatic system includes the spleen. Lymphatic tissues also include the thymus, a relatively small organ behind the breastbone that is thought to play an important role in the immune system until puberty, as well as the bone marrow, which is the spongy tissue inside the cavities of bones that manufactures blood cells. Lymphatic tissue or circulating lymphocytes may also be located in other regions of the body, such as the skin, small intestine, liver, and other organs. There are two main types of lymphocytes: B-lymphocytes, which may produce specific antibodies to “neutralize” certain invading microorganisms, and T-lymphocytes, which may directly destroy microorganisms or assist in the activities of other lymphocytes.Mantle cell lymphoma and other cancers of the lymphatic system (lymphomas) result from errors in the production of a lymphocyte or transformation of a lymphocyte into a malignant cell. Abnormal, uncontrolled growth and multiplication (proliferation) of malignant lymphocytes may lead to enlargement of a specific lymph node region or regions; involvement of other lymphatic tissues, such as the spleen and bone marrow; and spread to other bodily tissues and organs, potentially resulting in life-threatening complications. The specific symptoms and physical findings may vary from case to case, depending upon the extent and region(s) of involvement and other factors.Mantle cell lymphoma is a B-cell lymphoma that develops from malignant B-lymphocytes within a region of the lymph node known as the mantle zone. As previously mentioned, the signs and symptoms of MCL are dependent on the extent of the region of the body that is affected. Although the exact underlying cause is unknown, researchers have identified several genetic changes (or mutations) in the B-cells, which contribute to the multiplication of the cancer cells. For MCL, a mutation referred to as t(11;14) and denotes the exchange of genetic information between chromosome 11 and 14, leads to the overproduction of a protein called cyclin D1 in the lymphoma cells as will be further explained in the “Causes” section of this report below. These changes are found in more than 90 percent of patients with MCL and are important for diagnosis.Several disease characteristics are considered when attempting to determine if the cancer will be indolent or aggressive. Indolent lymphomas tend to grow slowly and result in few associated symptoms, whereas more aggressive lymphomas, typically grow rapidly, requiring prompt treatment. There is some debate concerning whether MCL should be categorized as a slow-growing (indolent) or rapidly-growing (aggressive) lymphoma. Although experts have classified MCL as an aggressive lymphoma, it has been shown to have certain characteristics of indolent lymphoma.
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Symptoms of Mantle Cell Lymphoma
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Many individuals with mantle cell lymphoma may not have symptoms (asymptomatic) during early stages of the disease. However, affected individuals may eventually seek medical attention due to persistent, usually painless, swelling of certain lymph nodes, particularly nodes within the neck and throat region (e.g., Waldeyer’s ring). Waldeyer’s ring consists of the protective ring of lymphoid tissues near the base of the tongue (lingual tonsils); on either side of the throat (palantine tonsils); and near the back opening of the nasal cavity (pharyngeal tonsils or adenoids). Individuals with non-Hodgkin’s lymphomas (NHLs), including MCL, may also have enlargement of other lymph nodes, such as nodes at the elbows or shoulders; under the arms (axillae); in the chest, abdominal, and/or pelvic regions; and/or in other areas. Lymph node enlargement may be confined to a single region or be present in various areas of the body.Some affected individuals may develop additional symptoms and signs that are “non-specific” in nature, meaning that they may be associated with any number of underlying disorders, including other forms of lymphoma (other non-Hodgkin’s lymphomas and Hodgkin’s disease). For example, some individuals may have lack of appetite (anorexia), nausea, vomiting, and indigestion. Additional symptoms may include a sense of “fullness” (satiety), abdominal swelling (distension) or bloating, and abdominal pain or discomfort. Such findings may be due to enlargement of abdominal lymph nodes and/or of the spleen (splenomegaly) or liver (hepatomegaly) or involvement of the gastrointestinal tract.Some individuals with MCL may also develop certain generalized (systemic) symptoms known as “B symptoms.” Such symptoms include persistent or repeated fever, unexplained weight loss (i.e., loss of at least 10 percent of normal body weight in the 6 months prior to diagnosis), and/or sweating, particularly at night (known as “night sweats”). It is suggested that up to one third of individuals with MCL may have “B symptoms” by the time they present to their doctor. However, such findings more commonly occur in individuals with Hodgkin’s disease as compared to those with different forms of NHL. (For further information on Hodgkin’s disease, please see the “Related Disorders” section below.)Depending upon the extent and region(s) of involvement, some individuals with MCL may develop other or additional symptoms and findings due to infiltration by proliferating lymphoma cells within and impaired functioning or failure of certain organs and tissues. If MCL has spread to involve the bone marrow, for example, malignant lymphocytes may essentially crowd the bone marrow, resulting in decreased manufacture of certain blood cells. (The bone marrow is the soft, spongy tissue located within the cavities of bones that produces blood cells. More specifically, immature cells known as stem cells within the bone marrow develop into the three cellular components of the blood: i.e., red blood cells, which contain the oxygen-carrying pigment hemoglobin; white blood cells, which help to fight infection; and platelets, which play an essential role in blood clotting [coagulation].) Some individuals with bone marrow involvement may develop anemia or abnormally low levels of the oxygen-transporting component of red blood cells. Associated symptoms may include fatigue, listlessness and lack of energy (lethargy), paleness of the skin (pallor), headaches, and/or other symptoms. Affected individuals may also become susceptible to certain infections, easy bruising and excessive bleeding, and/or other findings.In some individuals with MCL, there may be involvement of the digestive (gastrointestinal [GI]) tract. In some of these cases, GI involvement may be associated with the development of multiple polyps within the intestines (lymphomatous polyposis). Intestinal polyps are growths of tissue that project, often on a stalk, from the intestinal wall. In addition, in some rare cases, MCL may also spread to involve the brain and spinal cord (central nervous system [CNS]), potentially resulting in certain neurologic signs. Although such symptoms may be variable, they may include lethargy, headaches, weakness, confusion, personality changes, sudden episodes of uncontrolled electrical activity in the brain (seizures), and/or other findings.Depending on MCL subtype, sites and extent of involvement, disease management, and other factors, disease progression may eventually lead to life-threatening complications. (For further information on subtypes, disease staging, treatment options, etc., please see the “Classification,” “Staging,” and “Standard Therapies” section of this report below.)
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Symptoms of Mantle Cell Lymphoma. Many individuals with mantle cell lymphoma may not have symptoms (asymptomatic) during early stages of the disease. However, affected individuals may eventually seek medical attention due to persistent, usually painless, swelling of certain lymph nodes, particularly nodes within the neck and throat region (e.g., Waldeyer’s ring). Waldeyer’s ring consists of the protective ring of lymphoid tissues near the base of the tongue (lingual tonsils); on either side of the throat (palantine tonsils); and near the back opening of the nasal cavity (pharyngeal tonsils or adenoids). Individuals with non-Hodgkin’s lymphomas (NHLs), including MCL, may also have enlargement of other lymph nodes, such as nodes at the elbows or shoulders; under the arms (axillae); in the chest, abdominal, and/or pelvic regions; and/or in other areas. Lymph node enlargement may be confined to a single region or be present in various areas of the body.Some affected individuals may develop additional symptoms and signs that are “non-specific” in nature, meaning that they may be associated with any number of underlying disorders, including other forms of lymphoma (other non-Hodgkin’s lymphomas and Hodgkin’s disease). For example, some individuals may have lack of appetite (anorexia), nausea, vomiting, and indigestion. Additional symptoms may include a sense of “fullness” (satiety), abdominal swelling (distension) or bloating, and abdominal pain or discomfort. Such findings may be due to enlargement of abdominal lymph nodes and/or of the spleen (splenomegaly) or liver (hepatomegaly) or involvement of the gastrointestinal tract.Some individuals with MCL may also develop certain generalized (systemic) symptoms known as “B symptoms.” Such symptoms include persistent or repeated fever, unexplained weight loss (i.e., loss of at least 10 percent of normal body weight in the 6 months prior to diagnosis), and/or sweating, particularly at night (known as “night sweats”). It is suggested that up to one third of individuals with MCL may have “B symptoms” by the time they present to their doctor. However, such findings more commonly occur in individuals with Hodgkin’s disease as compared to those with different forms of NHL. (For further information on Hodgkin’s disease, please see the “Related Disorders” section below.)Depending upon the extent and region(s) of involvement, some individuals with MCL may develop other or additional symptoms and findings due to infiltration by proliferating lymphoma cells within and impaired functioning or failure of certain organs and tissues. If MCL has spread to involve the bone marrow, for example, malignant lymphocytes may essentially crowd the bone marrow, resulting in decreased manufacture of certain blood cells. (The bone marrow is the soft, spongy tissue located within the cavities of bones that produces blood cells. More specifically, immature cells known as stem cells within the bone marrow develop into the three cellular components of the blood: i.e., red blood cells, which contain the oxygen-carrying pigment hemoglobin; white blood cells, which help to fight infection; and platelets, which play an essential role in blood clotting [coagulation].) Some individuals with bone marrow involvement may develop anemia or abnormally low levels of the oxygen-transporting component of red blood cells. Associated symptoms may include fatigue, listlessness and lack of energy (lethargy), paleness of the skin (pallor), headaches, and/or other symptoms. Affected individuals may also become susceptible to certain infections, easy bruising and excessive bleeding, and/or other findings.In some individuals with MCL, there may be involvement of the digestive (gastrointestinal [GI]) tract. In some of these cases, GI involvement may be associated with the development of multiple polyps within the intestines (lymphomatous polyposis). Intestinal polyps are growths of tissue that project, often on a stalk, from the intestinal wall. In addition, in some rare cases, MCL may also spread to involve the brain and spinal cord (central nervous system [CNS]), potentially resulting in certain neurologic signs. Although such symptoms may be variable, they may include lethargy, headaches, weakness, confusion, personality changes, sudden episodes of uncontrolled electrical activity in the brain (seizures), and/or other findings.Depending on MCL subtype, sites and extent of involvement, disease management, and other factors, disease progression may eventually lead to life-threatening complications. (For further information on subtypes, disease staging, treatment options, etc., please see the “Classification,” “Staging,” and “Standard Therapies” section of this report below.)
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Causes of Mantle Cell Lymphoma
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The exact underlying cause of mantle cell lymphoma is unknown. As with numerous types of cancer, there are many possible factors that may contribute to its development. These factors include genetic and immunologic abnormalities, environmental factors (e.g., exposure to ultraviolet rays, certain chemicals, ionizing radiation [carcinogens]; certain viral infections; etc.), diet, stress and others. Current investigations are researching the possibility of an association between family history, inflammation, infection and the development of MCL. In individuals with cancer, including MCL, malignancies may develop due to abnormal changes in the structure and orientation of certain cells (e.g., lymphocytes). As mentioned above, the specific factors that cause such changes are unknown. However, current research suggests that abnormalities of DNA (deoxyribonucleic acid), which is the carrier of the body’s genetic code, are the underlying basis of cellular malignant transformation. Depending upon the form of cancer present and several other factors, these abnormal genetic changes may occur spontaneously for unknown reasons (sporadically), such as due to exposure to certain environmental factors, or, more rarely, may be inherited. Specifically, for MCL, several genetic abnormalities have been identified. Evidence suggests that many individuals with MCL have a specific, acquired genetic change in which there was an exchange of chromosomal material (translocation) between certain regions of the long arms of chromosomes 11 and 14 (11q13 and 14q32). Chromosomes, which are present in the nucleus of human cells, carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q.” Chromosomes are further subdivided into bands that are numbered. For example, “chromosome 11q13” refers to band 13 on the long arm of chromosome 11.This specific chromosomal translocation–t(11;14)(q13;q32)–has been shown to lead to impaired functioning (i.e., dysregulation) of a gene (CCND1) that regulates production of a protein known as cyclin D1. According to researchers, the CCND1 gene, located at chromosome 11q13, may function as an oncogene. In other words, when functioning normally, the gene is thought to have some role in controlling cellular growth and multiplication; however, if it is altered in some way (e.g., by exposure to certain environmental factors), it may cause the cell to be converted to a malignant state (malignant transformation). Evidence suggests that dysregulation of the CCND1 gene leads to increased production of the cyclin D1 protein. Cyclin D1 protein belongs to a family of proteins involved in regulating cell cycle progression and therefore, cell proliferation. Therefore, overexpression of cyclin D1 likely contributes to malignant transformation of cells and excessive growth of malignant B-lymphocytes. However, increased expression of cyclin D1 is not sufficient to cause MCL on its own. Investigators also indicate that abnormalities in the expression of other genes (e.g., the p53 gene, which normally functions as a tumor suppressor gene) may play some role in leading to MCL.The cancerous cells often express another gene, which is known as SOX11. SOX11 is not typically found in B-cells; however, it may be found in the malignant B-cells of MCL. In cells that have undergone malignant transformation, there is typically reversion to a less specialized, more primitive form (i.e., loss of “differentiation” or anaplasia), meaning that the cells do not perform their “intended,” specialized functions within the tissue in question. SOX11 is believed to block the differentiation of B cells so that they remain in their more primitive form. Malignant cells pass their abnormal changes on to all their “daughter” cells and typically grow and divide at an unusually rapid, uncontrolled rate that cannot be contained by the body’s natural immune defenses. Eventually, such proliferation of abnormal cells may result in formation of a mass known as a tumor (neoplasm).In individuals with MCL, lymphocytic malignant transformation and uncontrolled cellular growth may lead to abnormal expansion of a region of the lymph node known as the mantle zone; eventual destruction of the region with loss of the mantle zone boundaries; and potentially widespread growth of malignant lymphocytes throughout the node (i.e., diffuse lymphoma). Disease progression may be characterized by involvement of additional lymph node regions and/or other lymphatic tissues and spread of the malignancy to other bodily tissues and organs. The rate of malignant cell growth, resulting symptoms and findings, and overall disease course may vary, depending upon various factors.
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Causes of Mantle Cell Lymphoma. The exact underlying cause of mantle cell lymphoma is unknown. As with numerous types of cancer, there are many possible factors that may contribute to its development. These factors include genetic and immunologic abnormalities, environmental factors (e.g., exposure to ultraviolet rays, certain chemicals, ionizing radiation [carcinogens]; certain viral infections; etc.), diet, stress and others. Current investigations are researching the possibility of an association between family history, inflammation, infection and the development of MCL. In individuals with cancer, including MCL, malignancies may develop due to abnormal changes in the structure and orientation of certain cells (e.g., lymphocytes). As mentioned above, the specific factors that cause such changes are unknown. However, current research suggests that abnormalities of DNA (deoxyribonucleic acid), which is the carrier of the body’s genetic code, are the underlying basis of cellular malignant transformation. Depending upon the form of cancer present and several other factors, these abnormal genetic changes may occur spontaneously for unknown reasons (sporadically), such as due to exposure to certain environmental factors, or, more rarely, may be inherited. Specifically, for MCL, several genetic abnormalities have been identified. Evidence suggests that many individuals with MCL have a specific, acquired genetic change in which there was an exchange of chromosomal material (translocation) between certain regions of the long arms of chromosomes 11 and 14 (11q13 and 14q32). Chromosomes, which are present in the nucleus of human cells, carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q.” Chromosomes are further subdivided into bands that are numbered. For example, “chromosome 11q13” refers to band 13 on the long arm of chromosome 11.This specific chromosomal translocation–t(11;14)(q13;q32)–has been shown to lead to impaired functioning (i.e., dysregulation) of a gene (CCND1) that regulates production of a protein known as cyclin D1. According to researchers, the CCND1 gene, located at chromosome 11q13, may function as an oncogene. In other words, when functioning normally, the gene is thought to have some role in controlling cellular growth and multiplication; however, if it is altered in some way (e.g., by exposure to certain environmental factors), it may cause the cell to be converted to a malignant state (malignant transformation). Evidence suggests that dysregulation of the CCND1 gene leads to increased production of the cyclin D1 protein. Cyclin D1 protein belongs to a family of proteins involved in regulating cell cycle progression and therefore, cell proliferation. Therefore, overexpression of cyclin D1 likely contributes to malignant transformation of cells and excessive growth of malignant B-lymphocytes. However, increased expression of cyclin D1 is not sufficient to cause MCL on its own. Investigators also indicate that abnormalities in the expression of other genes (e.g., the p53 gene, which normally functions as a tumor suppressor gene) may play some role in leading to MCL.The cancerous cells often express another gene, which is known as SOX11. SOX11 is not typically found in B-cells; however, it may be found in the malignant B-cells of MCL. In cells that have undergone malignant transformation, there is typically reversion to a less specialized, more primitive form (i.e., loss of “differentiation” or anaplasia), meaning that the cells do not perform their “intended,” specialized functions within the tissue in question. SOX11 is believed to block the differentiation of B cells so that they remain in their more primitive form. Malignant cells pass their abnormal changes on to all their “daughter” cells and typically grow and divide at an unusually rapid, uncontrolled rate that cannot be contained by the body’s natural immune defenses. Eventually, such proliferation of abnormal cells may result in formation of a mass known as a tumor (neoplasm).In individuals with MCL, lymphocytic malignant transformation and uncontrolled cellular growth may lead to abnormal expansion of a region of the lymph node known as the mantle zone; eventual destruction of the region with loss of the mantle zone boundaries; and potentially widespread growth of malignant lymphocytes throughout the node (i.e., diffuse lymphoma). Disease progression may be characterized by involvement of additional lymph node regions and/or other lymphatic tissues and spread of the malignancy to other bodily tissues and organs. The rate of malignant cell growth, resulting symptoms and findings, and overall disease course may vary, depending upon various factors.
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Affects of Mantle Cell Lymphoma
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Mantle cell lymphoma is an uncommon form of non-Hodgkin’s lymphoma (NHL), accounting for 5% to 7% of all cases of NHL. Approximately one out of 200,000 individuals is diagnosed each year with MCL. The disease primarily affects older adults, with males representing approximately three-quarters of those with MCL. Many affected individuals are diagnosed at approximately 60 to 70 years old. Reports suggest that most individuals with MCL have advanced (i.e., stage III or stage IV) disease at diagnosis.
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Affects of Mantle Cell Lymphoma. Mantle cell lymphoma is an uncommon form of non-Hodgkin’s lymphoma (NHL), accounting for 5% to 7% of all cases of NHL. Approximately one out of 200,000 individuals is diagnosed each year with MCL. The disease primarily affects older adults, with males representing approximately three-quarters of those with MCL. Many affected individuals are diagnosed at approximately 60 to 70 years old. Reports suggest that most individuals with MCL have advanced (i.e., stage III or stage IV) disease at diagnosis.
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Related disorders of Mantle Cell Lymphoma
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Symptoms of the following conditions may be similar to those of mantle cell lymphoma (MCL). Comparisons may be useful for a differential diagnosis:Hodgkin’s disease and non-Hodgkin’s lymphoma (NHL) are the two major types of cancer affecting the lymphatic system (lymphoma). In contrast to NHL, Hodgkin’s disease is typically characterized by the presence of a specific type of cancer cell known as a Reed-Sternberg cell that has more than one nucleus. The disease is categorized into several subtypes according to certain features of affected lymphatic tissue as seen under a microscope (microscopic examination), such as relative number of Reed-Sternberg cells, proportion of other types of white blood cells, certain tissue changes, etc. (For further information, choose “Hodgkin” as your search term in the Rare Disease Database.)As mentioned earlier, non-Hodgkin’s lymphoma (NHL) refers to a group of malignancies that also arise within the lymphatic system and may spread to involve other tissues and organs. Although MCL is a form of NHL, there are other forms of NHL that present in a similar way. In contrast to Hodgkin’s disease, NHLs tend to progress in a less predictable manner. In addition, they cannot be distinguished by one specific type of cancer cell (i.e., Reed-Sternberg cells). Rather, the NHLs may be broadly classified into lymphomas that arise from abnormal B-lymphocytes (B-cell lymphomas) or abnormal T-lymphocytes (T-cell lymphomas) and may also be categorized based upon how quickly they may tend to grow and spread as well as additional, specific features of the cancerous cells. Individuals with NHL may develop painless swelling of a particular lymph node region or various lymph node regions of the body. For example, enlarged lymph nodes may be present in the neck and throat region; under the arms; in the abdominal, chest, and/or pelvic regions; and/or in other areas. Associated non-specific symptoms may include lack of appetite (anorexia), weight loss, nausea, indigestion, and abdominal pain or discomfort. Some individuals may also develop unexplained fever, chills, night sweats, lack of energy, persistent fatigue, itching, and/or other abnormalities. In some cases, additional symptoms and signs may also develop, depending upon the site(s) of involvement, disease stage, and other factors. The specific treatments recommended may include radiation therapy, certain combinations of chemotherapeutic and immunotherapy drugs, and/or other measures, based upon the specific form, grade, and subtype of NHL, disease stage, etc. Numerous additional disorders may be characterized by painless swelling of certain lymph nodes, loss of appetite, abdominal discomfort, unexplained weight loss, fever, and/or other non-specific symptoms and findings similar to those potentially associated with MCL including infection and autoimmune conditions. Thorough diagnostic evaluation is necessary to help differentiate MCL from such disorders, including the removal (biopsy) and microscopic examination of lymphatic tissue that is suspected of being cancerous.
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Related disorders of Mantle Cell Lymphoma. Symptoms of the following conditions may be similar to those of mantle cell lymphoma (MCL). Comparisons may be useful for a differential diagnosis:Hodgkin’s disease and non-Hodgkin’s lymphoma (NHL) are the two major types of cancer affecting the lymphatic system (lymphoma). In contrast to NHL, Hodgkin’s disease is typically characterized by the presence of a specific type of cancer cell known as a Reed-Sternberg cell that has more than one nucleus. The disease is categorized into several subtypes according to certain features of affected lymphatic tissue as seen under a microscope (microscopic examination), such as relative number of Reed-Sternberg cells, proportion of other types of white blood cells, certain tissue changes, etc. (For further information, choose “Hodgkin” as your search term in the Rare Disease Database.)As mentioned earlier, non-Hodgkin’s lymphoma (NHL) refers to a group of malignancies that also arise within the lymphatic system and may spread to involve other tissues and organs. Although MCL is a form of NHL, there are other forms of NHL that present in a similar way. In contrast to Hodgkin’s disease, NHLs tend to progress in a less predictable manner. In addition, they cannot be distinguished by one specific type of cancer cell (i.e., Reed-Sternberg cells). Rather, the NHLs may be broadly classified into lymphomas that arise from abnormal B-lymphocytes (B-cell lymphomas) or abnormal T-lymphocytes (T-cell lymphomas) and may also be categorized based upon how quickly they may tend to grow and spread as well as additional, specific features of the cancerous cells. Individuals with NHL may develop painless swelling of a particular lymph node region or various lymph node regions of the body. For example, enlarged lymph nodes may be present in the neck and throat region; under the arms; in the abdominal, chest, and/or pelvic regions; and/or in other areas. Associated non-specific symptoms may include lack of appetite (anorexia), weight loss, nausea, indigestion, and abdominal pain or discomfort. Some individuals may also develop unexplained fever, chills, night sweats, lack of energy, persistent fatigue, itching, and/or other abnormalities. In some cases, additional symptoms and signs may also develop, depending upon the site(s) of involvement, disease stage, and other factors. The specific treatments recommended may include radiation therapy, certain combinations of chemotherapeutic and immunotherapy drugs, and/or other measures, based upon the specific form, grade, and subtype of NHL, disease stage, etc. Numerous additional disorders may be characterized by painless swelling of certain lymph nodes, loss of appetite, abdominal discomfort, unexplained weight loss, fever, and/or other non-specific symptoms and findings similar to those potentially associated with MCL including infection and autoimmune conditions. Thorough diagnostic evaluation is necessary to help differentiate MCL from such disorders, including the removal (biopsy) and microscopic examination of lymphatic tissue that is suspected of being cancerous.
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Diagnosis of Mantle Cell Lymphoma
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Mantle cell lymphoma is diagnosed based upon a detailed patient history, thorough clinical evaluation and a variety of specialized tests, including a biopsy of an affected lymph node or the bone marrow. Such testing is necessary to confirm the specific type (and subtype) of NHL present, to assess the nature and extent of the disease, and to determine the most appropriate treatments.During a complete physical examination, physicians may feel (i.e., palpate) the lymph nodes in certain regions to detect any swelling, including in the neck, tonsil, and adenoidal region, under the arms, and in the groin. They may also examine other regions to help determine whether there is enlargement of certain internal organs, particularly the spleen and liver, and to detect swelling and abnormal fluid accumulation that may be associated with disease of the lymphatic system.For those with suspected lymphoma as suggested by thorough patient history and clinical examination, various diagnostic tests may be recommended. In order to confirm the diagnosis, a biopsy of an affected lymph node or of the bone marrow must be done. Such evaluation is necessary to help differentiate MCL from other malignancies, including different forms of NHL and Hodgkin's disease, as well as other diseases that may affect the lymph nodes. (For further information, please see the “Related Disorders” section of this report above.)Biopsies typically involve the removal and microscopic (i.e., histologic) examination of small samples of tissue cells from a lymph node–or, in some instances, removal of an entire, enlarged lymph node–that is suspected of being cancerous. Depending upon the specific type of biopsy performed, the procedure may be conducted under local or whole body (general) anesthesia. In addition, in some cases, such as when involvement appears to be restricted to the abdominal or pelvic region, laparoscopy or laparotomy may be necessary to obtain biopsy samples. Laparoscopy involves examination of the abdominal cavity with an illuminated viewing tube (laparoscope) inserted through incisions in the abdominal wall. Laparotomy is a surgical procedure in which the abdomen is opened, organs are carefully examined to detect signs of disease, and samples of tissue are removed for microscopic examination. (Biopsy samples are examined by physicians who specialize in analyzing cells and tissues to help obtain accurate diagnosis [pathologists].)For individuals with MCL, microscopic evaluation of biopsy samples may reveal abnormalities of the normal structure (architecture) of the lymph nodes, such as expansion of the region of the lymph node known as the mantle zone. More specifically, there may be abnormal infiltration and expansion of the mantle zone around germinal centers* of the lymph node, eventual loss of mantle zone boundaries, and potentially widespread growth of malignant lymphocytes throughout the node. (*Lymph nodes are comprised of a fibrous outer capsule and an inner mass of lymphatic tissue. The outer region or cortex includes groups of lymphocytes known as follicles; regions known as germinal centers are at the center of the follicles. Germinal cells are primarily B-lymphocytes.)Microscopic analysis also enables pathologists to determine additional histologic features that may be important in the malignancy's classification, such as size of malignant lymphocytes, appearance of the nucleus within a lymphoma cell, distribution or pattern of the abnormal cells, etc. (For further information, please see “Classification/Grading” below). In addition, specialized studies are conducted to help determine the malignancy's specific cell type of origin. For example, MCL cells–and the normal cells from which the malignancy develops– have specific antigens located on their cell surface that can be identified using specialized tests, such as immunohistochemistry. Examples of some of the antigens that should be identified to diagnose MCL include CD5, CD19, CD20, and CD22. Thus, testing to identify such markers assists in differentiating normal cells from malignant cells, and helping to distinguish MCL from other B-cell lymphomas to aid in disease management decisions.Additional specialized tests may also be conducted on biopsy samples to assist in a diagnosis of MCL. These may include studies to detect the presence of the chromosome 11;14 translocation in malignant lymphocytes and the cyclin D1 protein. Immunohistochemistry may also be used to identify the expression of gene SOX11, which may be helpful in rare cases that do not express cyclin D1. (For further information, please see the “Causes” section of this report above.)In a specific subtype of MCL (“leukemic non-nodal subtype”), a procedure known as a bone marrow biopsy may also be recommended to help determine whether the malignancy involves the bone marrow. (For further information on subtypes, please see “Classification” below). During this procedure, a sample of bone marrow is obtained, usually from the hip bone (iliac crest). Skin and tissue over the bone is first numbed with local anesthetic, and a needle is inserted into the bone through which a bone marrow sample is withdrawn. The sample is then examined under a microscope by a pathologist. Because a bone marrow biopsy may be painful, a mild, calming (sedative) medication may be offered before the procedure is conducted.Clinical Testing
Although the lymph node biopsy is the crucial test in diagnosing MCL, there are several other tests that must be done in order to evaluate the extent and the effects of the illness. Several of these tests may occur prior to the biopsy.Blood tests will be done to evaluate the number and appearance of white blood cells, red blood cells, and platelets, liver enzyme studies, renal function tests, tests to measure levels of the enzyme lactate dehydrogenase (LDH), calcium, uric acid and/or other studies. Various specialized imaging procedures may also be recommended, such as standard x-ray imaging; computed tomography (CT) scanning; magnetic resonance imaging (MRI); positron emission tomography scans (PET); and/or other studies. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of internal structures. For those with suspected or diagnosed NHL including MCL, CT scans may be taken of the neck, chest, abdominal, and/or pelvic regions to help detect enlargement of certain lymph nodes or spread of the malignancy to certain organs. This helps to assess the extent (stage) of the disease. MRI uses a magnetic field and radio waves to create detailed cross-sectional images of certain organs and tissues. This may be particularly valuable in helping to detect involvement of the brain and spinal cord (central nervous system [CNS]).PET scans may also be used stage the disease and as a follow-up after treatment to assess response to therapy (mostly used in clinical trials). During this procedure, a small dose of radioactive chemical is injected. The body is then scanned from various angles and an image is produced, showing where the radioactive chemical has collected within the body. This helps to identify areas of active disease. As mentioned earlier, NHL, including MCL, may sometimes spread to the brain and spinal cord. In such cases, analysis of cerebrospinal fluid (CSF) may reveal certain abnormalities of chemical content as well as the presence of cancerous cells. CSF is a watery fluid that flows through and protects the cavities (ventricles) of the brain; the space (i.e., subarachnoid space) between the brain and spinal cord and their protective membranes (meninges); and the cavity within the spinal column that contains the spinal cord (spinal canal). CSF is obtained for analysis by a procedure known as a lumbar puncture. During the procedure, skin and overlying tissue at the base of the spine is numbed with local anesthetic; a needle is then inserted between certain bones in the lower back and a sample of CSF is removed.As the gastrointestinal tract may develop polyps (lymphomatous polyposis), individuals with early stages of MCL or those with specific symptoms should undergo an endoscopy. An endoscopy is a procedure where a physician will put a camera in the esophagus to look for polyps, while the patient is given medication that keeps him/her comfortable.In some cases, physicians may recommend other testing procedures to help assess the extent of disease and to follow treatment. In addition, tests may be required to help evaluate the health and functioning of certain organs that may potentially be adversely affected due to certain treatments (e.g., particular anticancer [chemotherapeutic] drugs]). For example, such tests may include certain procedures to evaluate functioning of the heart and lungs.Classification
As discussed above, non-Hodgkin's lymphomas (NHLs) may be broadly classified into B-cell and T-cell lymphomas based upon the cell type of origin. In addition, the NHLs may be categorized according to how quickly the malignancy is growing; the growth pattern and appearance of malignant cells; genetic findings; and/or a combination of such factors. Several systems of identification have been proposed based upon certain or all of these elements. These include the Rappaport classification (no longer used), the National Cancer Institute's (NCI's) International Working Formulation (IWF), which consolidated terms from past systems of classification; the Revised European-American Lymphoma (REAL) Classification, and the World Health Organization (WHO) classification. The WHO classification originated as a modification to the REAL classification in 2001, and has undergone several updates, most recently in 2018. These classification systems have been developed in order to describe and define diseases, to help with diagnoses and plan management. Mantle cell lymphoma has been called by various terms according to different classifications, including diffuse small-cleaved cell lymphoma, centrocytic lymphoma, and lymphocytic lymphoma of intermediate differentiation. However, in 1992, an international consensus conference of experts proposed the name mantle cell lymphoma to help distinguish it more appropriately from other NHLs.The WHO classification system divides NHL according to the cell which the cancer started from and how the malignant cells look under the microscope. This classification system provides information about the genetic components of the disease and the organs which are commonly involved. Non-Hodgkin’s lymphomas have been divided into two categories. These categories depend on whether the NHL starts from a precursor cell or from a more mature version of the cell. Well over 50 subtypes of NHL have been identified with this classification system. In the WHO classification, mantle cell lymphoma has been classified into the mature cell group. MCL is described as a mature B-cell neoplasm. Microscopic evaluation of biopsy samples usually reveals small to medium sized lymphocytes with irregular nuclei. MCL has been divided into two subtypes as they have been found to have different clinical presentations, different histological findings when evaluated under the microscope, and various molecular pathways involved. The first subtype, known as “Classical MCL” has limited mutations in a gene called IGHV and expresses the gene SOX11. It develops outside the germinal center of lymph nodes. In addition to lymph node involvement, other extranodal sites are often involved. If this subtype acquires additional genetic abnormalities in cell cycle regulation, it could lead to a more aggressive form known as blastoid or pleomorphic MCL. The second subtype, known as “leukemic non-nodal MCL” develops in the germinal center of lymph nodes. This subtype has mutations in the IGHV gene and does not express SOX11. There is no or minimal enlargement of lymph nodes (lymphadenopathy). It involves peripheral blood, bone marrow and possibly leads to enlargement of the spleen (splenomegaly). It is known to be a more indolent subtype, meaning it may grow relatively slowly. However, if secondary genetic abnormalities do occur, (i.e., TP53 mutation), it could lead to a more aggressive disease. Accordingly, experts disagree whether mantle cell lymphoma as a whole is more appropriately classified as indolent or aggressive. Although the National Cancer Institute (NCI) has categorized MCL as an aggressive lymphoma, the malignancy is known to have certain features associated with indolent lymphomas in some cases.Staging
When an individual is diagnosed with a NHL such as MCL, assessment is also required to determine the extent or “stage” of the disease. Staging is important to help characterize the potential disease course and determine appropriate treatment approaches. A variety of diagnostic tests described above may be used in staging NHL (e.g., blood tests, CT scanning, PET scanning, bone marrow biopsy). In addition, in some cases, additional biopsies may be obtained to assist in lymphoma staging.The specific stage of NHL may be based upon the number of lymph node regions involved; whether such lymph nodes are located above, below, or on both sides of the diaphragm*; and/or whether the malignancy has infiltrated other lymphatic tissues, such as the spleen or bone marrow, or spread to involve other organs outside the lymphatic system, such as the liver. (*The diaphragm is the dome-shaped muscle that separates the chest from the abdomen and plays an essential role in breathing.)Although various staging systems have been described, a system commonly used for adult NHLs (i.e., the Ann Arbor staging system or Lugano staging system) includes the following stages:Stage I indicates early, localized disease in which the malignancy is limited to a single lymph node region or in a single organ or region outside the lymph node (extra-lymphatic organ or site).Stage II refers to locally advanced disease in which the malignancy involves more than one lymph node region on one side of the diaphragm or is found within one extra-lymphatic organ or site and its regional lymph node region (with or without involvement of other lymph nodes on the same side of the diaphragm).Stage III indicates advanced disease in which the lymphoma involves lymph node regions on both sides of (i.e., above and below) the diaphragm and may involve the spleen. There may also be localized involvement of an extra-lymphatic organ or site.Stage IV indicates widespread (disseminated) disease in which the malignancy is diffusely spread throughout one or more extra-lymphatic organs or sites with or without associated lymph node involvement.Each stage of NHL may be further divided into categories A, B, E, S and X based upon whether or not affected individuals have symptoms. More specifically:A indicates that no generalized (systemic) symptoms are present upon diagnosis.B indicates that an affected individual has experienced drenching night sweats, unexplained fever (above 38 degrees Celsius), and/or unexplained weight loss (i.e., loss of at least 10 percent of total body weight in the six months prior to diagnosis). Thus, individuals with such features may be said to have “B symptoms.”E indicates that the malignancy affects a single organ outside the lymphatic system or has spread from a lymph node to an organ.S indicates the lymphoma has spread to the spleen.X indicates there are large masses of lymphoma, known as bulky disease. To classify the mass as bulky, it needs to meet specific criteria, such as being larger than 10 cm across.Various additional elements may be considered as physicians determine the stage of NHL, potential disease course, and appropriate treatment options. Such factors may include patient age and general health, tumor size, levels of the enzyme lactate dehydrogenase, extranodal site involvement, and other factors.As discussed above, many individuals with MCL may not appear to have symptoms during the early stages of the disease. As a result, the disease is most often diagnosed in later, advanced stages (i.e., Stage III or Stage IV). Accordingly, at diagnosis, the malignancy may have spread beyond lymph nodes and may often affect the spleen, the bone marrow, and organs outside the lymphatic system, such as the liver or regions of the digestive (gastrointestinal [GI]) tract.
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Diagnosis of Mantle Cell Lymphoma. Mantle cell lymphoma is diagnosed based upon a detailed patient history, thorough clinical evaluation and a variety of specialized tests, including a biopsy of an affected lymph node or the bone marrow. Such testing is necessary to confirm the specific type (and subtype) of NHL present, to assess the nature and extent of the disease, and to determine the most appropriate treatments.During a complete physical examination, physicians may feel (i.e., palpate) the lymph nodes in certain regions to detect any swelling, including in the neck, tonsil, and adenoidal region, under the arms, and in the groin. They may also examine other regions to help determine whether there is enlargement of certain internal organs, particularly the spleen and liver, and to detect swelling and abnormal fluid accumulation that may be associated with disease of the lymphatic system.For those with suspected lymphoma as suggested by thorough patient history and clinical examination, various diagnostic tests may be recommended. In order to confirm the diagnosis, a biopsy of an affected lymph node or of the bone marrow must be done. Such evaluation is necessary to help differentiate MCL from other malignancies, including different forms of NHL and Hodgkin's disease, as well as other diseases that may affect the lymph nodes. (For further information, please see the “Related Disorders” section of this report above.)Biopsies typically involve the removal and microscopic (i.e., histologic) examination of small samples of tissue cells from a lymph node–or, in some instances, removal of an entire, enlarged lymph node–that is suspected of being cancerous. Depending upon the specific type of biopsy performed, the procedure may be conducted under local or whole body (general) anesthesia. In addition, in some cases, such as when involvement appears to be restricted to the abdominal or pelvic region, laparoscopy or laparotomy may be necessary to obtain biopsy samples. Laparoscopy involves examination of the abdominal cavity with an illuminated viewing tube (laparoscope) inserted through incisions in the abdominal wall. Laparotomy is a surgical procedure in which the abdomen is opened, organs are carefully examined to detect signs of disease, and samples of tissue are removed for microscopic examination. (Biopsy samples are examined by physicians who specialize in analyzing cells and tissues to help obtain accurate diagnosis [pathologists].)For individuals with MCL, microscopic evaluation of biopsy samples may reveal abnormalities of the normal structure (architecture) of the lymph nodes, such as expansion of the region of the lymph node known as the mantle zone. More specifically, there may be abnormal infiltration and expansion of the mantle zone around germinal centers* of the lymph node, eventual loss of mantle zone boundaries, and potentially widespread growth of malignant lymphocytes throughout the node. (*Lymph nodes are comprised of a fibrous outer capsule and an inner mass of lymphatic tissue. The outer region or cortex includes groups of lymphocytes known as follicles; regions known as germinal centers are at the center of the follicles. Germinal cells are primarily B-lymphocytes.)Microscopic analysis also enables pathologists to determine additional histologic features that may be important in the malignancy's classification, such as size of malignant lymphocytes, appearance of the nucleus within a lymphoma cell, distribution or pattern of the abnormal cells, etc. (For further information, please see “Classification/Grading” below). In addition, specialized studies are conducted to help determine the malignancy's specific cell type of origin. For example, MCL cells–and the normal cells from which the malignancy develops– have specific antigens located on their cell surface that can be identified using specialized tests, such as immunohistochemistry. Examples of some of the antigens that should be identified to diagnose MCL include CD5, CD19, CD20, and CD22. Thus, testing to identify such markers assists in differentiating normal cells from malignant cells, and helping to distinguish MCL from other B-cell lymphomas to aid in disease management decisions.Additional specialized tests may also be conducted on biopsy samples to assist in a diagnosis of MCL. These may include studies to detect the presence of the chromosome 11;14 translocation in malignant lymphocytes and the cyclin D1 protein. Immunohistochemistry may also be used to identify the expression of gene SOX11, which may be helpful in rare cases that do not express cyclin D1. (For further information, please see the “Causes” section of this report above.)In a specific subtype of MCL (“leukemic non-nodal subtype”), a procedure known as a bone marrow biopsy may also be recommended to help determine whether the malignancy involves the bone marrow. (For further information on subtypes, please see “Classification” below). During this procedure, a sample of bone marrow is obtained, usually from the hip bone (iliac crest). Skin and tissue over the bone is first numbed with local anesthetic, and a needle is inserted into the bone through which a bone marrow sample is withdrawn. The sample is then examined under a microscope by a pathologist. Because a bone marrow biopsy may be painful, a mild, calming (sedative) medication may be offered before the procedure is conducted.Clinical Testing
Although the lymph node biopsy is the crucial test in diagnosing MCL, there are several other tests that must be done in order to evaluate the extent and the effects of the illness. Several of these tests may occur prior to the biopsy.Blood tests will be done to evaluate the number and appearance of white blood cells, red blood cells, and platelets, liver enzyme studies, renal function tests, tests to measure levels of the enzyme lactate dehydrogenase (LDH), calcium, uric acid and/or other studies. Various specialized imaging procedures may also be recommended, such as standard x-ray imaging; computed tomography (CT) scanning; magnetic resonance imaging (MRI); positron emission tomography scans (PET); and/or other studies. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of internal structures. For those with suspected or diagnosed NHL including MCL, CT scans may be taken of the neck, chest, abdominal, and/or pelvic regions to help detect enlargement of certain lymph nodes or spread of the malignancy to certain organs. This helps to assess the extent (stage) of the disease. MRI uses a magnetic field and radio waves to create detailed cross-sectional images of certain organs and tissues. This may be particularly valuable in helping to detect involvement of the brain and spinal cord (central nervous system [CNS]).PET scans may also be used stage the disease and as a follow-up after treatment to assess response to therapy (mostly used in clinical trials). During this procedure, a small dose of radioactive chemical is injected. The body is then scanned from various angles and an image is produced, showing where the radioactive chemical has collected within the body. This helps to identify areas of active disease. As mentioned earlier, NHL, including MCL, may sometimes spread to the brain and spinal cord. In such cases, analysis of cerebrospinal fluid (CSF) may reveal certain abnormalities of chemical content as well as the presence of cancerous cells. CSF is a watery fluid that flows through and protects the cavities (ventricles) of the brain; the space (i.e., subarachnoid space) between the brain and spinal cord and their protective membranes (meninges); and the cavity within the spinal column that contains the spinal cord (spinal canal). CSF is obtained for analysis by a procedure known as a lumbar puncture. During the procedure, skin and overlying tissue at the base of the spine is numbed with local anesthetic; a needle is then inserted between certain bones in the lower back and a sample of CSF is removed.As the gastrointestinal tract may develop polyps (lymphomatous polyposis), individuals with early stages of MCL or those with specific symptoms should undergo an endoscopy. An endoscopy is a procedure where a physician will put a camera in the esophagus to look for polyps, while the patient is given medication that keeps him/her comfortable.In some cases, physicians may recommend other testing procedures to help assess the extent of disease and to follow treatment. In addition, tests may be required to help evaluate the health and functioning of certain organs that may potentially be adversely affected due to certain treatments (e.g., particular anticancer [chemotherapeutic] drugs]). For example, such tests may include certain procedures to evaluate functioning of the heart and lungs.Classification
As discussed above, non-Hodgkin's lymphomas (NHLs) may be broadly classified into B-cell and T-cell lymphomas based upon the cell type of origin. In addition, the NHLs may be categorized according to how quickly the malignancy is growing; the growth pattern and appearance of malignant cells; genetic findings; and/or a combination of such factors. Several systems of identification have been proposed based upon certain or all of these elements. These include the Rappaport classification (no longer used), the National Cancer Institute's (NCI's) International Working Formulation (IWF), which consolidated terms from past systems of classification; the Revised European-American Lymphoma (REAL) Classification, and the World Health Organization (WHO) classification. The WHO classification originated as a modification to the REAL classification in 2001, and has undergone several updates, most recently in 2018. These classification systems have been developed in order to describe and define diseases, to help with diagnoses and plan management. Mantle cell lymphoma has been called by various terms according to different classifications, including diffuse small-cleaved cell lymphoma, centrocytic lymphoma, and lymphocytic lymphoma of intermediate differentiation. However, in 1992, an international consensus conference of experts proposed the name mantle cell lymphoma to help distinguish it more appropriately from other NHLs.The WHO classification system divides NHL according to the cell which the cancer started from and how the malignant cells look under the microscope. This classification system provides information about the genetic components of the disease and the organs which are commonly involved. Non-Hodgkin’s lymphomas have been divided into two categories. These categories depend on whether the NHL starts from a precursor cell or from a more mature version of the cell. Well over 50 subtypes of NHL have been identified with this classification system. In the WHO classification, mantle cell lymphoma has been classified into the mature cell group. MCL is described as a mature B-cell neoplasm. Microscopic evaluation of biopsy samples usually reveals small to medium sized lymphocytes with irregular nuclei. MCL has been divided into two subtypes as they have been found to have different clinical presentations, different histological findings when evaluated under the microscope, and various molecular pathways involved. The first subtype, known as “Classical MCL” has limited mutations in a gene called IGHV and expresses the gene SOX11. It develops outside the germinal center of lymph nodes. In addition to lymph node involvement, other extranodal sites are often involved. If this subtype acquires additional genetic abnormalities in cell cycle regulation, it could lead to a more aggressive form known as blastoid or pleomorphic MCL. The second subtype, known as “leukemic non-nodal MCL” develops in the germinal center of lymph nodes. This subtype has mutations in the IGHV gene and does not express SOX11. There is no or minimal enlargement of lymph nodes (lymphadenopathy). It involves peripheral blood, bone marrow and possibly leads to enlargement of the spleen (splenomegaly). It is known to be a more indolent subtype, meaning it may grow relatively slowly. However, if secondary genetic abnormalities do occur, (i.e., TP53 mutation), it could lead to a more aggressive disease. Accordingly, experts disagree whether mantle cell lymphoma as a whole is more appropriately classified as indolent or aggressive. Although the National Cancer Institute (NCI) has categorized MCL as an aggressive lymphoma, the malignancy is known to have certain features associated with indolent lymphomas in some cases.Staging
When an individual is diagnosed with a NHL such as MCL, assessment is also required to determine the extent or “stage” of the disease. Staging is important to help characterize the potential disease course and determine appropriate treatment approaches. A variety of diagnostic tests described above may be used in staging NHL (e.g., blood tests, CT scanning, PET scanning, bone marrow biopsy). In addition, in some cases, additional biopsies may be obtained to assist in lymphoma staging.The specific stage of NHL may be based upon the number of lymph node regions involved; whether such lymph nodes are located above, below, or on both sides of the diaphragm*; and/or whether the malignancy has infiltrated other lymphatic tissues, such as the spleen or bone marrow, or spread to involve other organs outside the lymphatic system, such as the liver. (*The diaphragm is the dome-shaped muscle that separates the chest from the abdomen and plays an essential role in breathing.)Although various staging systems have been described, a system commonly used for adult NHLs (i.e., the Ann Arbor staging system or Lugano staging system) includes the following stages:Stage I indicates early, localized disease in which the malignancy is limited to a single lymph node region or in a single organ or region outside the lymph node (extra-lymphatic organ or site).Stage II refers to locally advanced disease in which the malignancy involves more than one lymph node region on one side of the diaphragm or is found within one extra-lymphatic organ or site and its regional lymph node region (with or without involvement of other lymph nodes on the same side of the diaphragm).Stage III indicates advanced disease in which the lymphoma involves lymph node regions on both sides of (i.e., above and below) the diaphragm and may involve the spleen. There may also be localized involvement of an extra-lymphatic organ or site.Stage IV indicates widespread (disseminated) disease in which the malignancy is diffusely spread throughout one or more extra-lymphatic organs or sites with or without associated lymph node involvement.Each stage of NHL may be further divided into categories A, B, E, S and X based upon whether or not affected individuals have symptoms. More specifically:A indicates that no generalized (systemic) symptoms are present upon diagnosis.B indicates that an affected individual has experienced drenching night sweats, unexplained fever (above 38 degrees Celsius), and/or unexplained weight loss (i.e., loss of at least 10 percent of total body weight in the six months prior to diagnosis). Thus, individuals with such features may be said to have “B symptoms.”E indicates that the malignancy affects a single organ outside the lymphatic system or has spread from a lymph node to an organ.S indicates the lymphoma has spread to the spleen.X indicates there are large masses of lymphoma, known as bulky disease. To classify the mass as bulky, it needs to meet specific criteria, such as being larger than 10 cm across.Various additional elements may be considered as physicians determine the stage of NHL, potential disease course, and appropriate treatment options. Such factors may include patient age and general health, tumor size, levels of the enzyme lactate dehydrogenase, extranodal site involvement, and other factors.As discussed above, many individuals with MCL may not appear to have symptoms during the early stages of the disease. As a result, the disease is most often diagnosed in later, advanced stages (i.e., Stage III or Stage IV). Accordingly, at diagnosis, the malignancy may have spread beyond lymph nodes and may often affect the spleen, the bone marrow, and organs outside the lymphatic system, such as the liver or regions of the digestive (gastrointestinal [GI]) tract.
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Mantle Cell Lymphoma
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Therapies of Mantle Cell Lymphoma
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Treatment The diagnosis and therapeutic management of MCL may require the coordinated efforts of a team of medical professionals, such as physicians who specialize in the diagnosis and treatment of cancer (medical oncologists), disorders of the blood and blood-forming tissues (hematologists), or the use of radiation to treat cancers (radiation oncologists); oncology nurses; surgeons; dietitians; and/or other professionals.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease stage (see “Stages” above); tumor size; subtype of MCL (i.e., classical vs leukemic non-nodal); the presence or absence of certain symptoms; individual’s age and general health; and/or other elements. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.Certain factors can be measured to determine if the MCL is more indolent or more aggressive. When individuals are diagnosed with a more indolent form, with no apparent symptoms, physicians may recommend a short period of waiting before implementing treatment. In such cases, thorough, frequent checkups are required to ensure that appropriate therapies are begun when the disease course accelerates. This approach to disease management is often called “watchful waiting.”Individuals who are diagnosed with a more aggressive form will often need to start treatment near the time of diagnosis. The physicians may recommend combination therapy with multiple anticancer drugs that have different modes of action in destroying tumor cells and/or preventing them from multiplying. The most common types of anticancer agents used in MCL for initial therapy are chemotherapy and immunotherapy. Chemotherapy refers to anticancer medications that have a direct toxic effect on cancer cell replication. Immunotherapy refers to anticancer medications that use the body’s own immune system to fight cancer cells. An example of immunotherapy is the monoclonal antibody rituximab. Rituximab binds to a specific target on tumor cells that express CD20 causing the immune system to attack and lyse (break apart) the tumor cells.Although most anticancer medications are provided via a vein (intravenously [IV]), some may be administered by mouth (orally). Chemotherapy and/or immunotherapy is typically provided at regular intervals or “cycles” on an outpatient basis, such as at a physician’s office, at the hospital, and/or at home. However, it may sometimes be necessary to receive such therapy on an inpatient basis. The number of treatment cycles may depend upon several factors, including the specific drug regimen(s), response to treatment, patient’s overall health, etc.Most of the management options start with an induction phase, meaning the goal of that treatment is to put the lymphoma into remission. This may include chemotherapy and immunotherapy. Remission refers to the partial or complete disappearance of symptoms and physical signs of cancer. Following the induction, another treatment is given with the goal of keeping the cancer in remission. This treatment is often referred to as “consolidation.” In MCL, an extended course of treatment referred to as “maintenance” is used to prolong cancer remission as well. At the time of diagnosis, if the illness is in stage 1 or 2, without bulky disease, patients may first be treated with chemotherapy and immunotherapy induction followed by consolidation radiation therapy to the affected site. During radiotherapy, radiation (via x-rays or other sources of radioactivity) is passed through selected regions of the body to destroy cancer cells and shrink tumors. Radiotherapy is provided in carefully determined dosages to help minimize damage to normal body cells. The total amount of radiation is typically provided on an outpatient basis over several weeks. For those with bulky disease or adverse prognostic factors, they will be treated similarly to patients in the later stages. If MCL is determined to be more advanced in stage (stage 3 or 4), physicians must consider patient characteristics and preferences as well as clinical and disease factors when determining which treatment to provide. For younger patients (usually less than 65 years old) old and fit patients, it is recommended for them to receive an intensive treatment course with induction therapy followed by autologous stem cell transplant (ASCT) and immunotherapy maintenance. ASCT is a procedure that involves collecting healthy blood stem cells from the patient, and following chemotherapy, the stem cells are put back into the patient after high-dose chemotherapy is used. There are various combinations of medications that can be used for induction therapy but typically incorporate the monoclonal antibody rituximab and a combination chemotherapy regimen that includes cytarabine as a drug. Examples include R-hyperCVAD, which represents a combination of the following medications – rituximab with cyclophosphamide, vincristine, doxorubicin [Adriamycin], dexamethasone alternating with high-dose methotrexate and cytarabine), or R-DHAP, which represents rituximab with dexamethasone, cytarabine and cisplatin. After induction, ASCT consolidation is administered to those in remission. This is followed with rituximab as a maintenance therapy for several years with the goal of prolonging remission. Elderly patients will also receive immunochemotherapeutic medications to induce remission. There are several combinations of medications that can be given. Examples of possible combinations are R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone), BR (bendamustine and rituximab) and rituximab, bendamustine and cytarabine (R-BAC). The induction would be followed with rituximab as the maintenance medication. In frail patients, a less toxic medication regimen may be prescribed, usually with the goal of palliation. An example of a medication used in this circumstance is rituximab alone. If a patient were to experience a relapse in their illness following initial therapy, there are several treatment options available. Similarly to determining the initial therapy, the relapse therapy will be dependent on patient characteristic and preferences, as well as disease factors. In the relapsed setting, chemotherapy, immunotherapy, immunomodulatory agents, targeted therapies and cellular therapies are available.Immunomodulatory agents refer to drugs that alter the functioning of the immune system and include Revlamid (lenalidomide). Targeted therapies are agents that target a specific protein and stop signals in cancer cells responsible for growth and survival. Examples of targeted agents approved by the Food and Drug Administration (FDA) in relapsed MCL include Bruton tyrosine kinase inhibitors (BTKi), Imbruvica (ibrutinib) Calquence (acalabrutinib), and Brukinsa (zanubrutinib). Most recently, in 2020, the FDA also approved a cellular therapy Tecartus (Brexucabtagene) for treatment of adults with MCL who have received at least one prior therapy. This treatment utilizes the patient’s own T-cells and reprograms them to better detect and destroy cancer cells. Because certain therapies directed against destroying cancer cells may also damage healthy cells, many of these therapies may be associated with various side effects. Therefore, patients should ask their physicians about the specific effects that may be associated with certain treatments. In addition, physicians and other members of the health care team may be able to take certain steps during and following treatment and may advise patients to take particular precautions during therapy that may help to alleviate or prevent certain side effects. Other standard therapies for individuals with MCL include symptomatic and supportive measures as required.
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Therapies of Mantle Cell Lymphoma. Treatment The diagnosis and therapeutic management of MCL may require the coordinated efforts of a team of medical professionals, such as physicians who specialize in the diagnosis and treatment of cancer (medical oncologists), disorders of the blood and blood-forming tissues (hematologists), or the use of radiation to treat cancers (radiation oncologists); oncology nurses; surgeons; dietitians; and/or other professionals.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease stage (see “Stages” above); tumor size; subtype of MCL (i.e., classical vs leukemic non-nodal); the presence or absence of certain symptoms; individual’s age and general health; and/or other elements. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.Certain factors can be measured to determine if the MCL is more indolent or more aggressive. When individuals are diagnosed with a more indolent form, with no apparent symptoms, physicians may recommend a short period of waiting before implementing treatment. In such cases, thorough, frequent checkups are required to ensure that appropriate therapies are begun when the disease course accelerates. This approach to disease management is often called “watchful waiting.”Individuals who are diagnosed with a more aggressive form will often need to start treatment near the time of diagnosis. The physicians may recommend combination therapy with multiple anticancer drugs that have different modes of action in destroying tumor cells and/or preventing them from multiplying. The most common types of anticancer agents used in MCL for initial therapy are chemotherapy and immunotherapy. Chemotherapy refers to anticancer medications that have a direct toxic effect on cancer cell replication. Immunotherapy refers to anticancer medications that use the body’s own immune system to fight cancer cells. An example of immunotherapy is the monoclonal antibody rituximab. Rituximab binds to a specific target on tumor cells that express CD20 causing the immune system to attack and lyse (break apart) the tumor cells.Although most anticancer medications are provided via a vein (intravenously [IV]), some may be administered by mouth (orally). Chemotherapy and/or immunotherapy is typically provided at regular intervals or “cycles” on an outpatient basis, such as at a physician’s office, at the hospital, and/or at home. However, it may sometimes be necessary to receive such therapy on an inpatient basis. The number of treatment cycles may depend upon several factors, including the specific drug regimen(s), response to treatment, patient’s overall health, etc.Most of the management options start with an induction phase, meaning the goal of that treatment is to put the lymphoma into remission. This may include chemotherapy and immunotherapy. Remission refers to the partial or complete disappearance of symptoms and physical signs of cancer. Following the induction, another treatment is given with the goal of keeping the cancer in remission. This treatment is often referred to as “consolidation.” In MCL, an extended course of treatment referred to as “maintenance” is used to prolong cancer remission as well. At the time of diagnosis, if the illness is in stage 1 or 2, without bulky disease, patients may first be treated with chemotherapy and immunotherapy induction followed by consolidation radiation therapy to the affected site. During radiotherapy, radiation (via x-rays or other sources of radioactivity) is passed through selected regions of the body to destroy cancer cells and shrink tumors. Radiotherapy is provided in carefully determined dosages to help minimize damage to normal body cells. The total amount of radiation is typically provided on an outpatient basis over several weeks. For those with bulky disease or adverse prognostic factors, they will be treated similarly to patients in the later stages. If MCL is determined to be more advanced in stage (stage 3 or 4), physicians must consider patient characteristics and preferences as well as clinical and disease factors when determining which treatment to provide. For younger patients (usually less than 65 years old) old and fit patients, it is recommended for them to receive an intensive treatment course with induction therapy followed by autologous stem cell transplant (ASCT) and immunotherapy maintenance. ASCT is a procedure that involves collecting healthy blood stem cells from the patient, and following chemotherapy, the stem cells are put back into the patient after high-dose chemotherapy is used. There are various combinations of medications that can be used for induction therapy but typically incorporate the monoclonal antibody rituximab and a combination chemotherapy regimen that includes cytarabine as a drug. Examples include R-hyperCVAD, which represents a combination of the following medications – rituximab with cyclophosphamide, vincristine, doxorubicin [Adriamycin], dexamethasone alternating with high-dose methotrexate and cytarabine), or R-DHAP, which represents rituximab with dexamethasone, cytarabine and cisplatin. After induction, ASCT consolidation is administered to those in remission. This is followed with rituximab as a maintenance therapy for several years with the goal of prolonging remission. Elderly patients will also receive immunochemotherapeutic medications to induce remission. There are several combinations of medications that can be given. Examples of possible combinations are R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone), BR (bendamustine and rituximab) and rituximab, bendamustine and cytarabine (R-BAC). The induction would be followed with rituximab as the maintenance medication. In frail patients, a less toxic medication regimen may be prescribed, usually with the goal of palliation. An example of a medication used in this circumstance is rituximab alone. If a patient were to experience a relapse in their illness following initial therapy, there are several treatment options available. Similarly to determining the initial therapy, the relapse therapy will be dependent on patient characteristic and preferences, as well as disease factors. In the relapsed setting, chemotherapy, immunotherapy, immunomodulatory agents, targeted therapies and cellular therapies are available.Immunomodulatory agents refer to drugs that alter the functioning of the immune system and include Revlamid (lenalidomide). Targeted therapies are agents that target a specific protein and stop signals in cancer cells responsible for growth and survival. Examples of targeted agents approved by the Food and Drug Administration (FDA) in relapsed MCL include Bruton tyrosine kinase inhibitors (BTKi), Imbruvica (ibrutinib) Calquence (acalabrutinib), and Brukinsa (zanubrutinib). Most recently, in 2020, the FDA also approved a cellular therapy Tecartus (Brexucabtagene) for treatment of adults with MCL who have received at least one prior therapy. This treatment utilizes the patient’s own T-cells and reprograms them to better detect and destroy cancer cells. Because certain therapies directed against destroying cancer cells may also damage healthy cells, many of these therapies may be associated with various side effects. Therefore, patients should ask their physicians about the specific effects that may be associated with certain treatments. In addition, physicians and other members of the health care team may be able to take certain steps during and following treatment and may advise patients to take particular precautions during therapy that may help to alleviate or prevent certain side effects. Other standard therapies for individuals with MCL include symptomatic and supportive measures as required.
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Mantle Cell Lymphoma
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nord_753_0
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Overview of MAPK8IP3-Related Neurodevelopmental Disorder
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SummaryMAPK8IP3-related neurodevelopmental disorder is a rare genetic condition caused by harmful changes (pathogenic variants) in the MAPK8IP3 gene, leading to neurodevelopmental disease. There is a spectrum of severity ranging from mild developmental delays to intellectual disability and physical impairments. Treatment of affected individuals is typically symptom-driven and supportive, focusing on speech, physical and social development.
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Overview of MAPK8IP3-Related Neurodevelopmental Disorder. SummaryMAPK8IP3-related neurodevelopmental disorder is a rare genetic condition caused by harmful changes (pathogenic variants) in the MAPK8IP3 gene, leading to neurodevelopmental disease. There is a spectrum of severity ranging from mild developmental delays to intellectual disability and physical impairments. Treatment of affected individuals is typically symptom-driven and supportive, focusing on speech, physical and social development.
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MAPK8IP3-Related Neurodevelopmental Disorder
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nord_753_1
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Symptoms of MAPK8IP3-Related Neurodevelopmental Disorder
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Individuals with MAPK8IP3-related disorder have a spectrum of neurodevelopmental disabilities. All affected individuals experience some level of global developmental delay including problems with muscle tone (both hypertonia and hypotonia have been reported) and walking, impaired intellectual development, and poor or absent speech. Some individuals have brain abnormalities visible on a MRI. EEG abnormalities including slow waves with spikes have also been reported. Other reported features include:
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Symptoms of MAPK8IP3-Related Neurodevelopmental Disorder. Individuals with MAPK8IP3-related disorder have a spectrum of neurodevelopmental disabilities. All affected individuals experience some level of global developmental delay including problems with muscle tone (both hypertonia and hypotonia have been reported) and walking, impaired intellectual development, and poor or absent speech. Some individuals have brain abnormalities visible on a MRI. EEG abnormalities including slow waves with spikes have also been reported. Other reported features include:
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MAPK8IP3-Related Neurodevelopmental Disorder
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nord_753_2
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Causes of MAPK8IP3-Related Neurodevelopmental Disorder
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MAPK8IP3-related neurodevelopmental disorder is caused by harmful changes (pathogenic variants) in the MAPK8IP3 gene. To date, almost all cases have been due de novo gene changes that were not inherited. There have been rare patients with two types of egg or sperm cells (gonadal mosaicism) with and without the genetic variant in MAPK8IP3 in one parent. Both missense and truncating variants in the MAPK8IP3 gene have been reported. Specific symptoms have not yet been associated with particular gene variants. (No clear phenotype-genotype correlation).Defective transport of cargo along the axons of neurons underlies a variety of rare genetic neurodevelopmental disorders. MAPK8IP3 (mitogen-activated protein kinase 8 interacting protein 3) is highly expressed in brain cells and encodes for the JIP3 protein (JNK-interacting protein 3) which functions as a scaffold/adapter protein that links cargos to the dynein and kinesin motors. JIP3 is important for multiple cellular processes in the developing brain, including axon guidance and the development of the brain (thalamus, hippocampus and cortical plate).
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Causes of MAPK8IP3-Related Neurodevelopmental Disorder. MAPK8IP3-related neurodevelopmental disorder is caused by harmful changes (pathogenic variants) in the MAPK8IP3 gene. To date, almost all cases have been due de novo gene changes that were not inherited. There have been rare patients with two types of egg or sperm cells (gonadal mosaicism) with and without the genetic variant in MAPK8IP3 in one parent. Both missense and truncating variants in the MAPK8IP3 gene have been reported. Specific symptoms have not yet been associated with particular gene variants. (No clear phenotype-genotype correlation).Defective transport of cargo along the axons of neurons underlies a variety of rare genetic neurodevelopmental disorders. MAPK8IP3 (mitogen-activated protein kinase 8 interacting protein 3) is highly expressed in brain cells and encodes for the JIP3 protein (JNK-interacting protein 3) which functions as a scaffold/adapter protein that links cargos to the dynein and kinesin motors. JIP3 is important for multiple cellular processes in the developing brain, including axon guidance and the development of the brain (thalamus, hippocampus and cortical plate).
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MAPK8IP3-Related Neurodevelopmental Disorder
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nord_753_3
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Affects of MAPK8IP3-Related Neurodevelopmental Disorder
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The number of individuals with MAPK8IP3-related disorder is unknown, due to the newly described nature of this condition and variable access to genetic testing. To date, there are 18 affected individuals in the published literature.
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Affects of MAPK8IP3-Related Neurodevelopmental Disorder. The number of individuals with MAPK8IP3-related disorder is unknown, due to the newly described nature of this condition and variable access to genetic testing. To date, there are 18 affected individuals in the published literature.
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MAPK8IP3-Related Neurodevelopmental Disorder
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nord_753_4
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Related disorders of MAPK8IP3-Related Neurodevelopmental Disorder
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KIF1A-related disorder is another rare neurodegenerative disorder that affects motor proteins involved in the transport of vesicles and organelles. Pathogenic variants in the KIF1A gene cause neurological disorders and disabilities ranging from mild to life threatening. Symptoms include intellectual disability, developmental delay, seizures, hypotonia and hypertonia. The treatment for KIF1A-related disorder is directed at the specific symptoms that each patient develops. (For more information on this condition, search for KIF1A in the Rare Disease Database.)
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Related disorders of MAPK8IP3-Related Neurodevelopmental Disorder. KIF1A-related disorder is another rare neurodegenerative disorder that affects motor proteins involved in the transport of vesicles and organelles. Pathogenic variants in the KIF1A gene cause neurological disorders and disabilities ranging from mild to life threatening. Symptoms include intellectual disability, developmental delay, seizures, hypotonia and hypertonia. The treatment for KIF1A-related disorder is directed at the specific symptoms that each patient develops. (For more information on this condition, search for KIF1A in the Rare Disease Database.)
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MAPK8IP3-Related Neurodevelopmental Disorder
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nord_753_5
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Diagnosis of MAPK8IP3-Related Neurodevelopmental Disorder
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Diagnosis of MAPK8IP3-Related Neurodevelopmental Disorder.
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MAPK8IP3-Related Neurodevelopmental Disorder
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nord_753_6
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Therapies of MAPK8IP3-Related Neurodevelopmental Disorder
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Occupational, physical, speech and feeding therapies may be utilized to address specific developmental delays. Genetic counseling is recommended for affected individuals and their families.
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Therapies of MAPK8IP3-Related Neurodevelopmental Disorder. Occupational, physical, speech and feeding therapies may be utilized to address specific developmental delays. Genetic counseling is recommended for affected individuals and their families.
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MAPK8IP3-Related Neurodevelopmental Disorder
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nord_754_0
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Overview of Maple Syrup Urine Disease
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SummaryMaple syrup urine disease (MSUD) is a rare genetic disorder characterized by deficiency of an enzyme complex (branched-chain alpha-keto acid dehydrogenase) that is required to break down (metabolize) the three branched-chain amino acids (BCAAs) leucine, isoleucine and valine, in the body. The result of this metabolic failure is that all three BCAAs, along with a number of their toxic byproducts, (specifically their respective organic acids), all accumulate abnormally. In the classic, severe form of MSUD, plasma concentrations of the BCAAs begin to rise within a few hours of birth. If untreated, symptoms begin to emerge, often within the first 24-48 hours of life.The presentation starts with non-specific symptoms of increasing neurological dysfunction and include lethargy, irritability and poor feeding, soon followed by focal neurological signs such as abnormal movements, increasing spasticity, and shortly thereafter, by seizures and deepening coma. If untreated, progressive brain damage is inevitable and death occurs usually within weeks or months. The only specific finding that is unique to MSUD is the development of a characteristic odor, reminiscent of maple syrup that can most readily be detected in the urine and earwax and may be smelled within a day or two of birth. The toxicity is the result of damaging effects of leucine on the brain accompanied by severe ketoacidosis caused by accumulation of the three branched-chain ketoacids (BCKAs).The disorder can be successfully managed through a specialized diet in which the three BCAAs are rigorously controlled. However, even with treatment, patients of any age with MSUD remain at high risk for developing acute metabolic decompensation (metabolic crises) often triggered by infection, injury, failure to eat (fasting) or even by psychological stress. During these episodes there is a rapid, sudden rise in amino acid levels necessitating immediate medical intervention.There are three or possibly four types of MSUD: the classic type; intermediate type, intermittent type, and possibly a thiamine-responsive type. Each of the various subtypes of MSUD have different levels of residual enzyme activity which account for the variable severity and age of onset. All forms are inherited in an autosomal recessive pattern.IntroductionNewborn screening for MSUD is performed throughout the US and in many other countries so that most such infants are detected through these programs. Where such screening is not available, infants with MSUD usually present with advancing neurological signs. Early diagnosis and treatment stabilizes the infants and, if well and consistently performed, can largely mitigate against serious long-term complications.
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Overview of Maple Syrup Urine Disease. SummaryMaple syrup urine disease (MSUD) is a rare genetic disorder characterized by deficiency of an enzyme complex (branched-chain alpha-keto acid dehydrogenase) that is required to break down (metabolize) the three branched-chain amino acids (BCAAs) leucine, isoleucine and valine, in the body. The result of this metabolic failure is that all three BCAAs, along with a number of their toxic byproducts, (specifically their respective organic acids), all accumulate abnormally. In the classic, severe form of MSUD, plasma concentrations of the BCAAs begin to rise within a few hours of birth. If untreated, symptoms begin to emerge, often within the first 24-48 hours of life.The presentation starts with non-specific symptoms of increasing neurological dysfunction and include lethargy, irritability and poor feeding, soon followed by focal neurological signs such as abnormal movements, increasing spasticity, and shortly thereafter, by seizures and deepening coma. If untreated, progressive brain damage is inevitable and death occurs usually within weeks or months. The only specific finding that is unique to MSUD is the development of a characteristic odor, reminiscent of maple syrup that can most readily be detected in the urine and earwax and may be smelled within a day or two of birth. The toxicity is the result of damaging effects of leucine on the brain accompanied by severe ketoacidosis caused by accumulation of the three branched-chain ketoacids (BCKAs).The disorder can be successfully managed through a specialized diet in which the three BCAAs are rigorously controlled. However, even with treatment, patients of any age with MSUD remain at high risk for developing acute metabolic decompensation (metabolic crises) often triggered by infection, injury, failure to eat (fasting) or even by psychological stress. During these episodes there is a rapid, sudden rise in amino acid levels necessitating immediate medical intervention.There are three or possibly four types of MSUD: the classic type; intermediate type, intermittent type, and possibly a thiamine-responsive type. Each of the various subtypes of MSUD have different levels of residual enzyme activity which account for the variable severity and age of onset. All forms are inherited in an autosomal recessive pattern.IntroductionNewborn screening for MSUD is performed throughout the US and in many other countries so that most such infants are detected through these programs. Where such screening is not available, infants with MSUD usually present with advancing neurological signs. Early diagnosis and treatment stabilizes the infants and, if well and consistently performed, can largely mitigate against serious long-term complications.
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Maple Syrup Urine Disease
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nord_754_1
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Symptoms of Maple Syrup Urine Disease
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The symptoms and severity of MSUD varies greatly from patient to patient and largely depends upon the amount of residual enzyme activity.Classic maple syrup urine disease is the most common and most severe form of MSUD characterized by little to no enzyme activity. Most infants with classic MSUD show subtle emerging non-specific symptoms within 2-3 days; these include poor feeding at bottle or breast and increasing lethargy and irritability. As the decline continues, the infant further disengages and then starts to show increasing focal neurologic signs including abnormal movements together with increasing hypertonia and spasticity progressing to seizures and coma. There may be temporary episodes of extreme hypotonia. In the end, central neurologic function fails with respiratory failure and death. By the time that the early symptoms have emerged, a distinctive odor of maple syrup may be detected in cerumen, sweat, and urine. This is derived from one of the BCKA organic acids derived from its respective BCAA that accumulate as the disorder spirals out of control. The odor cannot usually be detected during periods of metabolic stability.Once the disorder has been treated and stabilized, there remains a life-long threat of sudden or gradual recurrent metabolic decompensation that results in a return of all the symptoms typical of untreated cases. Dietary intake of the BCAAs must be strictly controlled and monitored. But even without any change in dietary intake, metabolic crises can occur caused by an imbalance between the inherent residual activity of the enzyme and increased BCAAs release of protein from the tissues due to increased breakdown (catabolism). An increasing catabolic rate can occur insidiously or may develop rapidly during any metabolic stress, including infection, even if very mild, psychological or physical stress, trauma or fasting. These episodes are characterized by emergence of the symptoms that are typical in an untreated case and are due to elevated BCAAs, especially leucine and the three associated BCKAs. Every episode can turn into a metabolic crisis and must be treated as vigorously as any episode in a newborn. Individuals with classic MSUD may show a degree of intellectual limitation and may develop a variety of behavioral issues including attention deficient hyperactivity disorder (ADHD), impulsivity, anxiety and/or depression and seizures.Additional complications with classic MSUD include generalized loss of bone mass (osteoporosis) that may predispose to fractures, and inflammation of the pancreas (pancreatitis). Some individuals may develop increased pressure in the skull (intracranial hypertension), which causes painful headaches that are sometimes associated with nausea and vomiting.Intermediate MSUD is characterized by greater levels of residual enzyme activity than is seen with classic MSUD. The onset and symptoms of intermediate MSUD may be neonatal, but the majority of children are diagnosed between the ages of five months and seven years. Symptoms, when they occur, are similar to those of the classical form and may include lethargy, feeding problems, poor growth, ataxia, and acute metabolic crises that result in seizures, coma, brain damage, and, in rare cases, life-threatening neurological complications. It should be noted that Intermediate MSUD patients are susceptible to the same degree of neurologic complications and extreme acidosis as those with classic MSUD. The characteristic odor of maple syrup in the earwax, sweat and urine, is present. Some affected children may remain asymptomatic until later in life. Disease management principles are the same for both.Intermittent MSUD is usually characterized by normal growth and intellectual development and affected individuals often can tolerate normal levels of protein in their diet. Symptoms are provoked by the same stressors as in classical MSUD. Thiamine-response MSUD responds to treatment with thiamine (vitamin B1). Thiamine plays a role in the BCAA enzyme complex. The symptoms and clinical course of thiamine-responsive MSUD resembles intermediate MSUD and rarely presents in the newborn period. Affected infants respond to large doses of thiamine, which boosts residual enzyme activity. No individuals with thiamine-responsive MSUD have been treated solely with thiamine – most follow a combination of thiamine with a partially-restricted protein diet.While the majority of patients fall into the categories above, several families with multiple affected members have been identified who do not fit the criteria for any of the above subtypes. These unique patients are deemed unclassified MSUD.It should be emphasized that in the presence of such apparently non-specific neurologic findings, the diagnosis of MSUD cannot be excluded by the absence of the maple syrup smell.
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Symptoms of Maple Syrup Urine Disease. The symptoms and severity of MSUD varies greatly from patient to patient and largely depends upon the amount of residual enzyme activity.Classic maple syrup urine disease is the most common and most severe form of MSUD characterized by little to no enzyme activity. Most infants with classic MSUD show subtle emerging non-specific symptoms within 2-3 days; these include poor feeding at bottle or breast and increasing lethargy and irritability. As the decline continues, the infant further disengages and then starts to show increasing focal neurologic signs including abnormal movements together with increasing hypertonia and spasticity progressing to seizures and coma. There may be temporary episodes of extreme hypotonia. In the end, central neurologic function fails with respiratory failure and death. By the time that the early symptoms have emerged, a distinctive odor of maple syrup may be detected in cerumen, sweat, and urine. This is derived from one of the BCKA organic acids derived from its respective BCAA that accumulate as the disorder spirals out of control. The odor cannot usually be detected during periods of metabolic stability.Once the disorder has been treated and stabilized, there remains a life-long threat of sudden or gradual recurrent metabolic decompensation that results in a return of all the symptoms typical of untreated cases. Dietary intake of the BCAAs must be strictly controlled and monitored. But even without any change in dietary intake, metabolic crises can occur caused by an imbalance between the inherent residual activity of the enzyme and increased BCAAs release of protein from the tissues due to increased breakdown (catabolism). An increasing catabolic rate can occur insidiously or may develop rapidly during any metabolic stress, including infection, even if very mild, psychological or physical stress, trauma or fasting. These episodes are characterized by emergence of the symptoms that are typical in an untreated case and are due to elevated BCAAs, especially leucine and the three associated BCKAs. Every episode can turn into a metabolic crisis and must be treated as vigorously as any episode in a newborn. Individuals with classic MSUD may show a degree of intellectual limitation and may develop a variety of behavioral issues including attention deficient hyperactivity disorder (ADHD), impulsivity, anxiety and/or depression and seizures.Additional complications with classic MSUD include generalized loss of bone mass (osteoporosis) that may predispose to fractures, and inflammation of the pancreas (pancreatitis). Some individuals may develop increased pressure in the skull (intracranial hypertension), which causes painful headaches that are sometimes associated with nausea and vomiting.Intermediate MSUD is characterized by greater levels of residual enzyme activity than is seen with classic MSUD. The onset and symptoms of intermediate MSUD may be neonatal, but the majority of children are diagnosed between the ages of five months and seven years. Symptoms, when they occur, are similar to those of the classical form and may include lethargy, feeding problems, poor growth, ataxia, and acute metabolic crises that result in seizures, coma, brain damage, and, in rare cases, life-threatening neurological complications. It should be noted that Intermediate MSUD patients are susceptible to the same degree of neurologic complications and extreme acidosis as those with classic MSUD. The characteristic odor of maple syrup in the earwax, sweat and urine, is present. Some affected children may remain asymptomatic until later in life. Disease management principles are the same for both.Intermittent MSUD is usually characterized by normal growth and intellectual development and affected individuals often can tolerate normal levels of protein in their diet. Symptoms are provoked by the same stressors as in classical MSUD. Thiamine-response MSUD responds to treatment with thiamine (vitamin B1). Thiamine plays a role in the BCAA enzyme complex. The symptoms and clinical course of thiamine-responsive MSUD resembles intermediate MSUD and rarely presents in the newborn period. Affected infants respond to large doses of thiamine, which boosts residual enzyme activity. No individuals with thiamine-responsive MSUD have been treated solely with thiamine – most follow a combination of thiamine with a partially-restricted protein diet.While the majority of patients fall into the categories above, several families with multiple affected members have been identified who do not fit the criteria for any of the above subtypes. These unique patients are deemed unclassified MSUD.It should be emphasized that in the presence of such apparently non-specific neurologic findings, the diagnosis of MSUD cannot be excluded by the absence of the maple syrup smell.
| 754 |
Maple Syrup Urine Disease
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nord_754_2
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Causes of Maple Syrup Urine Disease
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MSUD is caused by changes (mutations) in one of three different genes: BCKDHA, BCKDHB and DBT. Mutations in these genes result in absent or decreased activity of human branched-chain alpha-ketoacid dehydrogenase complex (BCKAD) enzymes. These enzymes are responsible for breaking down the branched chain amino acids leucine, isoleucine, and valine that are in all proteins. Accumulation of these amino acids and their toxic byproducts (ketoacids) results in the serious health problems associated with MSUD. The toxicity of these amino acids is restricted to leucine; indeed, extra valine and isoleucine are often given during treatment. Accumulation of their respective ketoacids results in the metabolic acidosis.MSUD follows autosomal recessive inheritance. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
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Causes of Maple Syrup Urine Disease. MSUD is caused by changes (mutations) in one of three different genes: BCKDHA, BCKDHB and DBT. Mutations in these genes result in absent or decreased activity of human branched-chain alpha-ketoacid dehydrogenase complex (BCKAD) enzymes. These enzymes are responsible for breaking down the branched chain amino acids leucine, isoleucine, and valine that are in all proteins. Accumulation of these amino acids and their toxic byproducts (ketoacids) results in the serious health problems associated with MSUD. The toxicity of these amino acids is restricted to leucine; indeed, extra valine and isoleucine are often given during treatment. Accumulation of their respective ketoacids results in the metabolic acidosis.MSUD follows autosomal recessive inheritance. 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.
| 754 |
Maple Syrup Urine Disease
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nord_754_3
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Affects of Maple Syrup Urine Disease
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The estimated incidence in a general population is 1 in 185,000 live births. 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. Due to this “founder effect”, the disorder occurs with greater frequency among individuals in the Mennonite populations in the United States, where the incidence is estimated to be as high as in 1 in 380. MSUD occurs in the Ashkenazi Jewish population with an incidence estimated at 1:26,000 live births.
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Affects of Maple Syrup Urine Disease. The estimated incidence in a general population is 1 in 185,000 live births. 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. Due to this “founder effect”, the disorder occurs with greater frequency among individuals in the Mennonite populations in the United States, where the incidence is estimated to be as high as in 1 in 380. MSUD occurs in the Ashkenazi Jewish population with an incidence estimated at 1:26,000 live births.
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Maple Syrup Urine Disease
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nord_754_4
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Related disorders of Maple Syrup Urine Disease
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Symptoms of the following disorders can be similar to those of MSUD. Comparisons may be useful for a differential diagnosis.The urea cycle disorders are a group of rare disorders affecting the urea cycle, a series of biochemical processes in which nitrogen is converted into urea and removed from the body through the urine. The symptoms of all urea cycle disorders vary in severity and result from the excessive accumulation of ammonia in the blood and body tissues (hyperammonemia). Common symptoms include lack of appetite, vomiting, drowsiness, seizures, and/or coma. The liver may be abnormally enlarged (hepatomegaly), life-threatening complications may result. The urea cycle disorders include ornithine transcarbamylase (OTC) deficiency: carbamyl phosphate synthetase (CPS) deficiency; argininosuccinate synthetase deficiency (citrullinemia); argininosuccinate lyase (ASL) deficiency; arginase deficiency (argininemia); and N-acetylglutamate synthetase (NAGS) deficiency. (For more information on these disorders, choose the specific disorder name as your search terms in the Rare Disease Database.)Propionic acidemia is a rare autosomal recessively inherited metabolic disorder caused by a deficiency of the enzyme propionyl CoA carboxylase, one of the enzymes necessary for breaking down certain amino acids. Symptoms most commonly become apparent during the first weeks of life and may include hypotonia, poor feeding, vomiting, dehydration, and seizures accompanied by worsening metabolic acidosis and often with hyperammonemia. Without appropriate treatment, coma and life-threatening complications are usual. In milder cases, the condition may only present later during infancy and may then be associated with less severe symptoms and findings. (For more information on this disorder, choose “propionic acidemia” as your search term in the Rare Disease Database.)Methylmalonic acidemia (MMA) is a rare inborn error of metabolism in which people have trouble metabolizing certain proteins and fats in food. The symptoms usually arise during early infancy, but may even remain occult until adulthood. The presentation is similar to that of propionic acidemia. Over the course of the disease, patients can develop intellectual disability, chronic kidney disease, pancreatitis and feeding problems. Mutations in several different genes can cause MMA and thus different treatments are required for each type. The mainstay of treatment is a carefully balanced dietary restriction of certain amino acids; namely, methionine, threonine, isoleucine and valine. Some require specific forms of cobalamin (vitamin B 12). All MMAs are autosomal recessive genetic disorders and can caused by mutations in five different genes: MMAA, MMAB, MMADHC, MCEE and MUT. (For more information on this disorder, choose “methylmalonic acidemia” as your search term in the Rare Disease Database.)Glycine encephalopathy is an inborn error of metabolism characterized by the accumulation of large amounts of the amino acid glycine in blood and, particularly, in the cerebrospinal fluid (CSF). The metabolic block occurs in the conversion of glycine into smaller molecules. There are four forms of this disorder: a relatively common neonatal form, an infantile form, a mild-episodic form, and a late-onset form. Common presenting symptoms of the disease include hypotonia, seizures, unexplained coma, and developmental delay in neonates and infants. Metabolic acidosis is not a feature. For more information on this disorder, choose “glycine encephalopathy” as your search term in the Rare Disease Database.)
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Related disorders of Maple Syrup Urine Disease. Symptoms of the following disorders can be similar to those of MSUD. Comparisons may be useful for a differential diagnosis.The urea cycle disorders are a group of rare disorders affecting the urea cycle, a series of biochemical processes in which nitrogen is converted into urea and removed from the body through the urine. The symptoms of all urea cycle disorders vary in severity and result from the excessive accumulation of ammonia in the blood and body tissues (hyperammonemia). Common symptoms include lack of appetite, vomiting, drowsiness, seizures, and/or coma. The liver may be abnormally enlarged (hepatomegaly), life-threatening complications may result. The urea cycle disorders include ornithine transcarbamylase (OTC) deficiency: carbamyl phosphate synthetase (CPS) deficiency; argininosuccinate synthetase deficiency (citrullinemia); argininosuccinate lyase (ASL) deficiency; arginase deficiency (argininemia); and N-acetylglutamate synthetase (NAGS) deficiency. (For more information on these disorders, choose the specific disorder name as your search terms in the Rare Disease Database.)Propionic acidemia is a rare autosomal recessively inherited metabolic disorder caused by a deficiency of the enzyme propionyl CoA carboxylase, one of the enzymes necessary for breaking down certain amino acids. Symptoms most commonly become apparent during the first weeks of life and may include hypotonia, poor feeding, vomiting, dehydration, and seizures accompanied by worsening metabolic acidosis and often with hyperammonemia. Without appropriate treatment, coma and life-threatening complications are usual. In milder cases, the condition may only present later during infancy and may then be associated with less severe symptoms and findings. (For more information on this disorder, choose “propionic acidemia” as your search term in the Rare Disease Database.)Methylmalonic acidemia (MMA) is a rare inborn error of metabolism in which people have trouble metabolizing certain proteins and fats in food. The symptoms usually arise during early infancy, but may even remain occult until adulthood. The presentation is similar to that of propionic acidemia. Over the course of the disease, patients can develop intellectual disability, chronic kidney disease, pancreatitis and feeding problems. Mutations in several different genes can cause MMA and thus different treatments are required for each type. The mainstay of treatment is a carefully balanced dietary restriction of certain amino acids; namely, methionine, threonine, isoleucine and valine. Some require specific forms of cobalamin (vitamin B 12). All MMAs are autosomal recessive genetic disorders and can caused by mutations in five different genes: MMAA, MMAB, MMADHC, MCEE and MUT. (For more information on this disorder, choose “methylmalonic acidemia” as your search term in the Rare Disease Database.)Glycine encephalopathy is an inborn error of metabolism characterized by the accumulation of large amounts of the amino acid glycine in blood and, particularly, in the cerebrospinal fluid (CSF). The metabolic block occurs in the conversion of glycine into smaller molecules. There are four forms of this disorder: a relatively common neonatal form, an infantile form, a mild-episodic form, and a late-onset form. Common presenting symptoms of the disease include hypotonia, seizures, unexplained coma, and developmental delay in neonates and infants. Metabolic acidosis is not a feature. For more information on this disorder, choose “glycine encephalopathy” as your search term in the Rare Disease Database.)
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Maple Syrup Urine Disease
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nord_754_5
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Diagnosis of Maple Syrup Urine Disease
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Many infants with MSUD are identified through newborn screening programs. Tandem mass spectrometry, an advanced newborn screening test that screens for more than 40 different disorders through one blood sample, has aided in the diagnosis of MSUD. As with all inborn errors, Infants with mild or intermittent forms of the disorder may have totally normal blood metabolites after birth and thus can be missed by newborn screening.For patients who present later, the diagnosis usually comes at a time of metabolic decompensation when plasma amino acids and urine organic acids are normally tested at which time they are wildly abnormal. The presence of the maple syrup odor is so characteristic that this, together with appropriate symptoms, can be diagnostic enough to initiate therapy until the patient is transferred to an ICU. Initial confirmation is done by examination of plasma BCAAs and urine organic acids. The activity of the BCAA complex activity can be performed in white blood cells or cultured skin fibroblasts.Prenatal detection cannot, at present, be done on maternal blood (looking for the fetal DNA). It is done either through chorionic villus biopsy or by amniocentesis. These analyses must be performed in a laboratory that is experienced in the relevant techniques. Molecular genetic testing for mutations in the BCKDHA, BCKDHB and DBT genes is also available to confirm the diagnosis and is necessary for purposes of carrier testing for at-risk relatives and prenatal diagnosis for at-risk pregnancies.
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Diagnosis of Maple Syrup Urine Disease. Many infants with MSUD are identified through newborn screening programs. Tandem mass spectrometry, an advanced newborn screening test that screens for more than 40 different disorders through one blood sample, has aided in the diagnosis of MSUD. As with all inborn errors, Infants with mild or intermittent forms of the disorder may have totally normal blood metabolites after birth and thus can be missed by newborn screening.For patients who present later, the diagnosis usually comes at a time of metabolic decompensation when plasma amino acids and urine organic acids are normally tested at which time they are wildly abnormal. The presence of the maple syrup odor is so characteristic that this, together with appropriate symptoms, can be diagnostic enough to initiate therapy until the patient is transferred to an ICU. Initial confirmation is done by examination of plasma BCAAs and urine organic acids. The activity of the BCAA complex activity can be performed in white blood cells or cultured skin fibroblasts.Prenatal detection cannot, at present, be done on maternal blood (looking for the fetal DNA). It is done either through chorionic villus biopsy or by amniocentesis. These analyses must be performed in a laboratory that is experienced in the relevant techniques. Molecular genetic testing for mutations in the BCKDHA, BCKDHB and DBT genes is also available to confirm the diagnosis and is necessary for purposes of carrier testing for at-risk relatives and prenatal diagnosis for at-risk pregnancies.
| 754 |
Maple Syrup Urine Disease
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nord_754_6
|
Therapies of Maple Syrup Urine Disease
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TreatmentThe treatment of classic, intermediate, intermittent, and thiamine-responsive MSUD has three chief components: 1. Lifelong therapy to maintain an acceptable diet; 2. Life-long maintenance of normal metabolic conditions including the levels of the BCAAs in the body; 3. immediate medical intervention for metabolic crises.Individuals with MSUD must remain on a protein-restricted diet that limits the amount of branched-chain amino acids they can eat. Protein-restriction must start as soon as possible after birth to promote proper growth and development. Artificially-made (synthetic) formulas are available that provide all the nutrients necessary for proper growth and development, but lack leucine, isoleucine and valine. Diet management is a constant balancing act between giving enough food, protein and BCAAs to provide for normal growth and development on the one hand and trying to ensure that the patient’s condition and biochemistry remain in a therapeutic range on the other. It is particularly important to limit the amount of leucine in the diet. The three amino acids are essential nutrients. They are added to the diet separately in small amounts depending upon their plasma levels. The amount of leucine, isoleucine and valine that can be tolerated by a child depends upon residual enzyme activity. Affected children must be regularly monitored to ensure that their diet is adequate and that amino acid levels remain within acceptable normal ranges.Some physicians recommend a trial of thiamine therapy to determine whether an affected individual is thiamine-responsive. However, no individual with MSUD has been treated solely with thiamine.Even if affected individuals follow the specialized diet strictly, the risk of metabolic crisis always remains. Episodes of metabolic crisis require immediate medical intervention to lower the levels of branched-chain amino acids, especially leucine, in the blood. Various techniques have been used to reduce plasma leucine levels including dialysis or a process in which blood is removed from the body and passed through a filter before being returned to the body (hemofiltration).The aim of aggressive therapy for metabolic crises is to try and reduce, and then reverse, the increased protein catabolism that is the root cause of such episodes. This means that ANY method to increase calories, to reduce protein catabolism (for energy needs) may be helpful. This includes a high glucose intake with intravenous glucose, if necessary, supplemented by a “glucose-insulin drip” since insulin is known to enhance endogenous protein synthesis. Intravenous fat is another important source of calories. In addition, it is essential to provide all the other amino acids in amounts sufficient to permit new protein synthesis. This is done by the judicious use of intra GI drips or more usually, parenteral nutrition IV using solutions that lack leucine. Many hospitals may use total parenteral nutrition solutions that lack branched-chain amino acid. In addition, insulin may be used to stimulate a metabolic process known as anabolism. During anabolism, amino acids and other compounds are synthesized to form new muscle and other proteins as well as a huge variety of other compounds.Other treatment is symptomatic and supportive.Genetic counseling is recommended for affected individuals and their families.
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Therapies of Maple Syrup Urine Disease. TreatmentThe treatment of classic, intermediate, intermittent, and thiamine-responsive MSUD has three chief components: 1. Lifelong therapy to maintain an acceptable diet; 2. Life-long maintenance of normal metabolic conditions including the levels of the BCAAs in the body; 3. immediate medical intervention for metabolic crises.Individuals with MSUD must remain on a protein-restricted diet that limits the amount of branched-chain amino acids they can eat. Protein-restriction must start as soon as possible after birth to promote proper growth and development. Artificially-made (synthetic) formulas are available that provide all the nutrients necessary for proper growth and development, but lack leucine, isoleucine and valine. Diet management is a constant balancing act between giving enough food, protein and BCAAs to provide for normal growth and development on the one hand and trying to ensure that the patient’s condition and biochemistry remain in a therapeutic range on the other. It is particularly important to limit the amount of leucine in the diet. The three amino acids are essential nutrients. They are added to the diet separately in small amounts depending upon their plasma levels. The amount of leucine, isoleucine and valine that can be tolerated by a child depends upon residual enzyme activity. Affected children must be regularly monitored to ensure that their diet is adequate and that amino acid levels remain within acceptable normal ranges.Some physicians recommend a trial of thiamine therapy to determine whether an affected individual is thiamine-responsive. However, no individual with MSUD has been treated solely with thiamine.Even if affected individuals follow the specialized diet strictly, the risk of metabolic crisis always remains. Episodes of metabolic crisis require immediate medical intervention to lower the levels of branched-chain amino acids, especially leucine, in the blood. Various techniques have been used to reduce plasma leucine levels including dialysis or a process in which blood is removed from the body and passed through a filter before being returned to the body (hemofiltration).The aim of aggressive therapy for metabolic crises is to try and reduce, and then reverse, the increased protein catabolism that is the root cause of such episodes. This means that ANY method to increase calories, to reduce protein catabolism (for energy needs) may be helpful. This includes a high glucose intake with intravenous glucose, if necessary, supplemented by a “glucose-insulin drip” since insulin is known to enhance endogenous protein synthesis. Intravenous fat is another important source of calories. In addition, it is essential to provide all the other amino acids in amounts sufficient to permit new protein synthesis. This is done by the judicious use of intra GI drips or more usually, parenteral nutrition IV using solutions that lack leucine. Many hospitals may use total parenteral nutrition solutions that lack branched-chain amino acid. In addition, insulin may be used to stimulate a metabolic process known as anabolism. During anabolism, amino acids and other compounds are synthesized to form new muscle and other proteins as well as a huge variety of other compounds.Other treatment is symptomatic and supportive.Genetic counseling is recommended for affected individuals and their families.
| 754 |
Maple Syrup Urine Disease
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nord_755_0
|
Overview of Marcus Gunn Phenomenon
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Marcus Gunn phenomenon is a rare genetic disorder that is usually present at birth. It is characterized by the movement of one upper eyelid in a rapid rising motion each time the jaw moves. Other eye abnormalities and vision difficulties may also occur. The exact cause of this phenomenon is not known.
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Overview of Marcus Gunn Phenomenon. Marcus Gunn phenomenon is a rare genetic disorder that is usually present at birth. It is characterized by the movement of one upper eyelid in a rapid rising motion each time the jaw moves. Other eye abnormalities and vision difficulties may also occur. The exact cause of this phenomenon is not known.
| 755 |
Marcus Gunn Phenomenon
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nord_755_1
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Symptoms of Marcus Gunn Phenomenon
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In most patients with Marcus Gunn phenomenon, the upper eyelid of one eye (unilateral) droops (blepharoptosis). The major symptom of this disorder is the rapid and involuntary upward movement of the affected eyelid after almost any movement of the lower jaw. As a result, that eye appears to open even wider. This first becomes apparent soon after birth, especially during feeding and sucking. These activities cause the eyelid to move up and down. A few cases have been seen in adults. Individuals with Marcus Gunn phenomenon may experience visual impairment, such as crossing of the eyes (strabismus), slight impairment of vision in one eye as compared to the other (a difference in the refractive powers of the eyes [anisometropia], and other problems (e.g., superior rectus muscle palsy or double elevator palsy).In some cases, symptoms may be produced by movement of the lips, whistling, smiling, clenching the teeth, chewing, puffing out the cheeks, or swallowing.
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Symptoms of Marcus Gunn Phenomenon. In most patients with Marcus Gunn phenomenon, the upper eyelid of one eye (unilateral) droops (blepharoptosis). The major symptom of this disorder is the rapid and involuntary upward movement of the affected eyelid after almost any movement of the lower jaw. As a result, that eye appears to open even wider. This first becomes apparent soon after birth, especially during feeding and sucking. These activities cause the eyelid to move up and down. A few cases have been seen in adults. Individuals with Marcus Gunn phenomenon may experience visual impairment, such as crossing of the eyes (strabismus), slight impairment of vision in one eye as compared to the other (a difference in the refractive powers of the eyes [anisometropia], and other problems (e.g., superior rectus muscle palsy or double elevator palsy).In some cases, symptoms may be produced by movement of the lips, whistling, smiling, clenching the teeth, chewing, puffing out the cheeks, or swallowing.
| 755 |
Marcus Gunn Phenomenon
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nord_755_2
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Causes of Marcus Gunn Phenomenon
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The exact cause of Marcus Gunn phenomenon is not known. For reasons that are unclear, there is a bad connection between the nerves that stimulate, and the muscles that move, the eyelids and the jaw. Some clinical researchers believe that about half of the cases of Marcus Gunn phenomenon are genetically determined. The site and nature of the gene(s) at fault in this disorder are not known, but familial studies indicate that it is transmitted as an autosomal dominant trait. 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 11p13 refers to band 13 on the short arm of chromosome 11. 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 which 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% for each pregnancy regardless of the sex of the resulting child.
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Causes of Marcus Gunn Phenomenon. The exact cause of Marcus Gunn phenomenon is not known. For reasons that are unclear, there is a bad connection between the nerves that stimulate, and the muscles that move, the eyelids and the jaw. Some clinical researchers believe that about half of the cases of Marcus Gunn phenomenon are genetically determined. The site and nature of the gene(s) at fault in this disorder are not known, but familial studies indicate that it is transmitted as an autosomal dominant trait. 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 11p13 refers to band 13 on the short arm of chromosome 11. 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 which 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% for each pregnancy regardless of the sex of the resulting child.
| 755 |
Marcus Gunn Phenomenon
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nord_755_3
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Affects of Marcus Gunn Phenomenon
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Marcus Gunn phenomenon is a rare genetic disorder present at birth. It affects males and females in equal numbers. Approximately 300 cases have been reported in the medical literature.
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Affects of Marcus Gunn Phenomenon. Marcus Gunn phenomenon is a rare genetic disorder present at birth. It affects males and females in equal numbers. Approximately 300 cases have been reported in the medical literature.
| 755 |
Marcus Gunn Phenomenon
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nord_755_4
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Related disorders of Marcus Gunn Phenomenon
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Marcus Gunn Phenomenon may occur in conjunction with certain other eye disorders such as Duane Syndrome, or possibly Retinitis Pigmentosa. (For more information on these disorders, choose “Duane,” or “Retinitis Pigmentosa” as your search term in the Rare Disease Database.)Certain types of injury to the facial nerve may produce symptoms similar to Marcus Gunn Phenomenon.Marin-Amat Syndrome is similar to Marcus Gunn Phenomenon except that the eye closes, rather than opens wider, when the jaw moves to open the mouth. This disorder is also referred to as “Inverse Marcus Gunn Phenomenon”.Oral-Facial-Digital Syndrome is a rare genetic disorder. In patients with Type III of this syndrome, upon movement of the lower jaw, the eyelid involuntarily and rapidly raises, causing the eye to open wider (jaw-winking). More than the normal number of teeth are usually present. Other major symptoms may include disturbances involving the nervous and muscle (neuromuscular) systems, congenital (present at birth) malformations such as cleft palate, other facial deformities, malformation of the hands and feet, shortened limbs and various degrees of mental retardation. (For more information on this disorder, choose “Oral-Facial-Digital” as your search term in the Rare Disease Database.)Faciopalpebral Synkinesis is a rare disorder characterized by the upper eyelid of one eye raising when the individual smiles.
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Related disorders of Marcus Gunn Phenomenon. Marcus Gunn Phenomenon may occur in conjunction with certain other eye disorders such as Duane Syndrome, or possibly Retinitis Pigmentosa. (For more information on these disorders, choose “Duane,” or “Retinitis Pigmentosa” as your search term in the Rare Disease Database.)Certain types of injury to the facial nerve may produce symptoms similar to Marcus Gunn Phenomenon.Marin-Amat Syndrome is similar to Marcus Gunn Phenomenon except that the eye closes, rather than opens wider, when the jaw moves to open the mouth. This disorder is also referred to as “Inverse Marcus Gunn Phenomenon”.Oral-Facial-Digital Syndrome is a rare genetic disorder. In patients with Type III of this syndrome, upon movement of the lower jaw, the eyelid involuntarily and rapidly raises, causing the eye to open wider (jaw-winking). More than the normal number of teeth are usually present. Other major symptoms may include disturbances involving the nervous and muscle (neuromuscular) systems, congenital (present at birth) malformations such as cleft palate, other facial deformities, malformation of the hands and feet, shortened limbs and various degrees of mental retardation. (For more information on this disorder, choose “Oral-Facial-Digital” as your search term in the Rare Disease Database.)Faciopalpebral Synkinesis is a rare disorder characterized by the upper eyelid of one eye raising when the individual smiles.
| 755 |
Marcus Gunn Phenomenon
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nord_755_5
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Diagnosis of Marcus Gunn Phenomenon
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The diagnosis is obvious and is often made by one or both of the parents who become aware of the major symptom during feeding.
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Diagnosis of Marcus Gunn Phenomenon. The diagnosis is obvious and is often made by one or both of the parents who become aware of the major symptom during feeding.
| 755 |
Marcus Gunn Phenomenon
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nord_755_6
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Therapies of Marcus Gunn Phenomenon
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TreatmentTreatment of Marcus Gunn phenomenon is usually not needed because the condition tends to grow less noticeable with age. Genetic counseling may be of benefit for patients and their families. Other related eye problems such as strabismus, amblyopia, etc., may be corrected with eyeglasses, surgery and/or drugs.Surgical correction of the droopiness of the eyelid or of the jaw winking is recommended only if the patient (or parents) agree on which of the symptoms is the more cosmetically objectionable. Surgical procedures are available for several different intensities of the droop of the eyelids.
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Therapies of Marcus Gunn Phenomenon. TreatmentTreatment of Marcus Gunn phenomenon is usually not needed because the condition tends to grow less noticeable with age. Genetic counseling may be of benefit for patients and their families. Other related eye problems such as strabismus, amblyopia, etc., may be corrected with eyeglasses, surgery and/or drugs.Surgical correction of the droopiness of the eyelid or of the jaw winking is recommended only if the patient (or parents) agree on which of the symptoms is the more cosmetically objectionable. Surgical procedures are available for several different intensities of the droop of the eyelids.
| 755 |
Marcus Gunn Phenomenon
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nord_756_0
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Overview of Marden Walker Syndrome
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Marden-Walker syndrome is a rare connective tissue disorder that is inherited as an autosomal recessive trait. Patients with this disorder typically have a distinct facial expression, a cleft or high-arched palate, small or receding jaw (micrognathia), bone joints in a fixed position, growth delay and limited control of muscle movement. Marden-Walker syndrome affects males more often than females.
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Overview of Marden Walker Syndrome. Marden-Walker syndrome is a rare connective tissue disorder that is inherited as an autosomal recessive trait. Patients with this disorder typically have a distinct facial expression, a cleft or high-arched palate, small or receding jaw (micrognathia), bone joints in a fixed position, growth delay and limited control of muscle movement. Marden-Walker syndrome affects males more often than females.
| 756 |
Marden Walker Syndrome
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nord_756_1
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Symptoms of Marden Walker Syndrome
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Patients with Marden-Walker syndrome have distinct facial features including an abnormality of the jaw, droopy eyelids, a flat bridge of the nose, low-set ears, and a fixed facial position.Other characteristics of this disorder are curvature of the spine causing a hunchback, bent joints that will not move (joint contractures), a cleft or high-arched palate, growth delay, and slow muscle movement.Other symptoms of Marden-Walker syndrome may include a small head circumference, heart abnormalities, an irregular sexual and urinary system, a decrease in bone mass, a breastbone that pushes out or sinks in, a small projecting piece of tissue on the front of the outer ear (preauricular tag), abnormally small eyes, a short neck, a small mouth and/or a low hairline.A condition in which extra tissue causes obstruction of the small intestine (duodenal bands); narrowing of the ring that separates the stomach from the first part of the small intestine causing a blockage in the flow of partly digested food (pyloric stenosis); and/or loss of appetite, failure of the body to absorb nutrients adequately, stomach pain and weight loss caused by a condition in which there are not enough pancreatic hormones or enzymes (pancreatic insufficiency) have all been associated with Marden-Walker syndrome.
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Symptoms of Marden Walker Syndrome. Patients with Marden-Walker syndrome have distinct facial features including an abnormality of the jaw, droopy eyelids, a flat bridge of the nose, low-set ears, and a fixed facial position.Other characteristics of this disorder are curvature of the spine causing a hunchback, bent joints that will not move (joint contractures), a cleft or high-arched palate, growth delay, and slow muscle movement.Other symptoms of Marden-Walker syndrome may include a small head circumference, heart abnormalities, an irregular sexual and urinary system, a decrease in bone mass, a breastbone that pushes out or sinks in, a small projecting piece of tissue on the front of the outer ear (preauricular tag), abnormally small eyes, a short neck, a small mouth and/or a low hairline.A condition in which extra tissue causes obstruction of the small intestine (duodenal bands); narrowing of the ring that separates the stomach from the first part of the small intestine causing a blockage in the flow of partly digested food (pyloric stenosis); and/or loss of appetite, failure of the body to absorb nutrients adequately, stomach pain and weight loss caused by a condition in which there are not enough pancreatic hormones or enzymes (pancreatic insufficiency) have all been associated with Marden-Walker syndrome.
| 756 |
Marden Walker Syndrome
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nord_756_2
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Causes of Marden Walker Syndrome
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Marden-Walker syndrome is inherited as an autosomal recessive trait. The exact genetic malfunction is not yet established but some clinicians believe a single gene defect may be responsible.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 11p13” refers to band 13 on the short arm of chromosome 11. 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. 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. All individuals carry a few abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
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Causes of Marden Walker Syndrome. Marden-Walker syndrome is inherited as an autosomal recessive trait. The exact genetic malfunction is not yet established but some clinicians believe a single gene defect may be responsible.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 11p13” refers to band 13 on the short arm of chromosome 11. 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. 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. All individuals carry a few abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
| 756 |
Marden Walker Syndrome
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nord_756_3
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Affects of Marden Walker Syndrome
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Marden-Walker Syndrome is a very rare disorder that affects males more often than females with a ratio of 11 to 3. There have been approximately twenty cases reported in the medical literature.
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Affects of Marden Walker Syndrome. Marden-Walker Syndrome is a very rare disorder that affects males more often than females with a ratio of 11 to 3. There have been approximately twenty cases reported in the medical literature.
| 756 |
Marden Walker Syndrome
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nord_756_4
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Related disorders of Marden Walker Syndrome
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Symptoms of the following disorders can be similar to those of Marden-Walker syndrome. Comparisons may be useful for a differential diagnosis:Van den Ende-Gupta syndrome (VDEGS) is a “Marden-Walker-like” disorder in which many of the skeletal symptoms of Marden-Walker syndrome are present. (For more information on this disorder, see the Online Mendelian Inheritance in Man or OMIM database, entry 600920.)Arthrogryposis multiplex congenita is a rare congenital disease characterized by reduced mobility of multiple joints at birth due to proliferation of fibrous tissue. Typically the range of motion of the joints of all limbs is limited. (For more information on this disorder choose “Arthrogryposis Multiplex Congenita” as your search term in the Rare Disease Database.)Cerebro-oculo-facio-skeletal syndrome is a genetic degenerative disorder of the brain and spinal chord that is present at birth. The disorder is characterized by an extremely small head, abnormally small eyes, clouding of the eye's lens (cataract), a horizontally narrow opening between the eyelids, abnormally large ears, a small jaw, fixed bending of the elbows and knees, and/or a hunched back. Cerebro-oculo-facio-skeletal syndrome is inherited as an autosomal recessive trait. (For more information on this disorder, choose “Cerebro-Oculo-Facio-Skeletal Syndrome” as your search term in the Rare Disease Database.)Schwartz-Jampel syndrome is a rare disorder inherited as an autosomal recessive trait. People with this disorder have muscles that do not relax after contracting (myotonia). The main characteristics of Schwartz-Jampel syndrome are abnormal bone formation and abnormalities of the face and eyes. Other abnormalities that may be found in some patients with this disorder are short stature, low birth weight, a short neck, a pigeon breast, curvature of the spine causing a hunchback and/or a condition in which the joints are bent and will not move (joint contractures).
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Related disorders of Marden Walker Syndrome. Symptoms of the following disorders can be similar to those of Marden-Walker syndrome. Comparisons may be useful for a differential diagnosis:Van den Ende-Gupta syndrome (VDEGS) is a “Marden-Walker-like” disorder in which many of the skeletal symptoms of Marden-Walker syndrome are present. (For more information on this disorder, see the Online Mendelian Inheritance in Man or OMIM database, entry 600920.)Arthrogryposis multiplex congenita is a rare congenital disease characterized by reduced mobility of multiple joints at birth due to proliferation of fibrous tissue. Typically the range of motion of the joints of all limbs is limited. (For more information on this disorder choose “Arthrogryposis Multiplex Congenita” as your search term in the Rare Disease Database.)Cerebro-oculo-facio-skeletal syndrome is a genetic degenerative disorder of the brain and spinal chord that is present at birth. The disorder is characterized by an extremely small head, abnormally small eyes, clouding of the eye's lens (cataract), a horizontally narrow opening between the eyelids, abnormally large ears, a small jaw, fixed bending of the elbows and knees, and/or a hunched back. Cerebro-oculo-facio-skeletal syndrome is inherited as an autosomal recessive trait. (For more information on this disorder, choose “Cerebro-Oculo-Facio-Skeletal Syndrome” as your search term in the Rare Disease Database.)Schwartz-Jampel syndrome is a rare disorder inherited as an autosomal recessive trait. People with this disorder have muscles that do not relax after contracting (myotonia). The main characteristics of Schwartz-Jampel syndrome are abnormal bone formation and abnormalities of the face and eyes. Other abnormalities that may be found in some patients with this disorder are short stature, low birth weight, a short neck, a pigeon breast, curvature of the spine causing a hunchback and/or a condition in which the joints are bent and will not move (joint contractures).
| 756 |
Marden Walker Syndrome
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nord_756_5
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Diagnosis of Marden Walker Syndrome
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Diagnosis of Marden Walker Syndrome.
| 756 |
Marden Walker Syndrome
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nord_756_6
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Therapies of Marden Walker Syndrome
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Genetic counseling may be of benefit for patients and their families. Other treatment is symptomatic and supportive.
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Therapies of Marden Walker Syndrome. Genetic counseling may be of benefit for patients and their families. Other treatment is symptomatic and supportive.
| 756 |
Marden Walker Syndrome
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nord_757_0
|
Overview of Marfan Syndrome
|
Marfan syndrome is a genetic disorder that affects connective tissue, which is the material between cells of the body that gives the tissues form and strength. Connective tissue is found all over the body and multiple organ systems may be affected in individuals with Marfan syndrome. The heart and blood vessels (cardiovascular), skeletal, and eye (ocular) systems are most often affected. Major symptoms include overgrowth of the long bones of the arms and legs, abnormal side-to-side curvature of the spine (scoliosis), indentation or protrusion of the chest wall (pectus deformity), dislocation of the lenses of the eyes (ectopia lentis), nearsightedness (myopia), widening (aneurysm) and tear (dissection) of the main artery that carries blood away from the heart (aorta), floppiness of the mitral valve (mitral valve prolapse) and backward flow of blood through the aortic and mitral valves (aortic and mitral regurgitation). The specific symptoms and the severity of Marfan syndrome vary greatly from person to person. Marfan syndrome is inherited as an autosomal dominant trait, meaning that only one abnormal copy of the Marfan gene inherited from one parent is sufficient to have the condition. Defects or deletions (pathogenic variants) of the fibrillin-1 (FBN1) gene have been shown to cause Marfan syndrome.
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Overview of Marfan Syndrome. Marfan syndrome is a genetic disorder that affects connective tissue, which is the material between cells of the body that gives the tissues form and strength. Connective tissue is found all over the body and multiple organ systems may be affected in individuals with Marfan syndrome. The heart and blood vessels (cardiovascular), skeletal, and eye (ocular) systems are most often affected. Major symptoms include overgrowth of the long bones of the arms and legs, abnormal side-to-side curvature of the spine (scoliosis), indentation or protrusion of the chest wall (pectus deformity), dislocation of the lenses of the eyes (ectopia lentis), nearsightedness (myopia), widening (aneurysm) and tear (dissection) of the main artery that carries blood away from the heart (aorta), floppiness of the mitral valve (mitral valve prolapse) and backward flow of blood through the aortic and mitral valves (aortic and mitral regurgitation). The specific symptoms and the severity of Marfan syndrome vary greatly from person to person. Marfan syndrome is inherited as an autosomal dominant trait, meaning that only one abnormal copy of the Marfan gene inherited from one parent is sufficient to have the condition. Defects or deletions (pathogenic variants) of the fibrillin-1 (FBN1) gene have been shown to cause Marfan syndrome.
| 757 |
Marfan Syndrome
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