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Causes of Hypokalemia
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Hypokalemia always occurs as a result of excessive loss of potassium through the urine, sweat or stool. It is always a symptom of another disorder, rather than a disease that occurs by itself. The excessive excretion of potassium in the urine (kaliuresis) may result from the use of diuretic drugs (which increases urination), a deficiency of magnesium in the blood, excessive mineralocorticoids such as aldosterone in the blood which affect the electrolyte and fluid balance in the body (usually caused by endocrine diseases), kidney disorders, or from the use of high doses of penicillin. Gastrointestinal losses of potassium usually are due to prolonged diarrhea or vomiting, chronic laxative abuse, inadequate dietary intake of potassium, intestinal obstruction or infections such as fistulas in the intestines which continually drain intestinal fluids. Additionally, excessive perspiration due to hot weather or exercise can cause hypokalemia.
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Causes of Hypokalemia. Hypokalemia always occurs as a result of excessive loss of potassium through the urine, sweat or stool. It is always a symptom of another disorder, rather than a disease that occurs by itself. The excessive excretion of potassium in the urine (kaliuresis) may result from the use of diuretic drugs (which increases urination), a deficiency of magnesium in the blood, excessive mineralocorticoids such as aldosterone in the blood which affect the electrolyte and fluid balance in the body (usually caused by endocrine diseases), kidney disorders, or from the use of high doses of penicillin. Gastrointestinal losses of potassium usually are due to prolonged diarrhea or vomiting, chronic laxative abuse, inadequate dietary intake of potassium, intestinal obstruction or infections such as fistulas in the intestines which continually drain intestinal fluids. Additionally, excessive perspiration due to hot weather or exercise can cause hypokalemia.
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Affects of Hypokalemia
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Hypokalemia may affect both males and females. However, it occurs more commonly in females.
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Affects of Hypokalemia. Hypokalemia may affect both males and females. However, it occurs more commonly in females.
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Related disorders of Hypokalemia
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Symptoms of the following disorders include Hypokalemia. Comparisons may be useful for a differential diagnosis:Bartter's Syndrome is a metabolic disorder involving the kidneys. Major symptoms include slowed growth, weakness, excessive thirst and excessive urination. Bartter's Syndrome is characterized by the excessive loss of potassium through the kidneys. (For more information on this disorder, choose “Bartter” as your search term in the Rare Disease Database.)Periodic Paralysis, Hypokalemic Type, is a disorder characterized by episodes of paralysis with loss of deep tendon reflexes and failure of muscles to respond to electrical stimulation. The cause is unknown. The paralysis may be limited to certain muscle groups or it may affect all four limbs. The attacks usually last between 24 and 48 hours. Potassium levels are usually abnormally low (hypokalemia).Metabolic Alkalosis is a disorder characterized by an increase in blood bicarbonate. Symptoms include irritability, neuromuscular hyperexcitability, low blood potassium (hypokalemia), muscular weakness, impaired gastrointestinal motility and excessive urination.(To find other disorders that include Hypokalemia as a symptom, choose “Hypokalemia” as your search term in the Rare Disease Database.)
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Related disorders of Hypokalemia. Symptoms of the following disorders include Hypokalemia. Comparisons may be useful for a differential diagnosis:Bartter's Syndrome is a metabolic disorder involving the kidneys. Major symptoms include slowed growth, weakness, excessive thirst and excessive urination. Bartter's Syndrome is characterized by the excessive loss of potassium through the kidneys. (For more information on this disorder, choose “Bartter” as your search term in the Rare Disease Database.)Periodic Paralysis, Hypokalemic Type, is a disorder characterized by episodes of paralysis with loss of deep tendon reflexes and failure of muscles to respond to electrical stimulation. The cause is unknown. The paralysis may be limited to certain muscle groups or it may affect all four limbs. The attacks usually last between 24 and 48 hours. Potassium levels are usually abnormally low (hypokalemia).Metabolic Alkalosis is a disorder characterized by an increase in blood bicarbonate. Symptoms include irritability, neuromuscular hyperexcitability, low blood potassium (hypokalemia), muscular weakness, impaired gastrointestinal motility and excessive urination.(To find other disorders that include Hypokalemia as a symptom, choose “Hypokalemia” as your search term in the Rare Disease Database.)
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Diagnosis of Hypokalemia
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Diagnosis of Hypokalemia.
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Therapies of Hypokalemia
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The underlying cause of Hypokalemia must first be treated. When the hypokalemia is severe, potassium chloride may be administered orally or intravenously. Treatment must be carefully monitored by a physician. Any associated acid-base disorders or hormonal disturbances must be evaluated before treatment is planned. The administration of potassium and potassium- sparing diuretics is usually discouraged in patients with kidney disease, diabetes mellitus, or dysfunctions of the autonomic nervous system. The imbalance of external and internal potassium levels in these individuals may predispose them to life-threatening degrees of Hyperkalemia (too much potassium). Hypokalemia in individuals with high blood pressure taking diuretics may be improved by replacing lost potassium in the diet through certain fruits or potassium drugs. Hypokalemia may also be minimized by dietary restriction of salt since high rates of sodium excretion promote urinary potassium losses. People who participate in vigorous sports or exercise in warm weather should be sure to replace potassium that is lost through excessive sweating. This can be accomplished through dietary planning.
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Therapies of Hypokalemia. The underlying cause of Hypokalemia must first be treated. When the hypokalemia is severe, potassium chloride may be administered orally or intravenously. Treatment must be carefully monitored by a physician. Any associated acid-base disorders or hormonal disturbances must be evaluated before treatment is planned. The administration of potassium and potassium- sparing diuretics is usually discouraged in patients with kidney disease, diabetes mellitus, or dysfunctions of the autonomic nervous system. The imbalance of external and internal potassium levels in these individuals may predispose them to life-threatening degrees of Hyperkalemia (too much potassium). Hypokalemia in individuals with high blood pressure taking diuretics may be improved by replacing lost potassium in the diet through certain fruits or potassium drugs. Hypokalemia may also be minimized by dietary restriction of salt since high rates of sodium excretion promote urinary potassium losses. People who participate in vigorous sports or exercise in warm weather should be sure to replace potassium that is lost through excessive sweating. This can be accomplished through dietary planning.
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Overview of Hypomelanosis of Ito
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Hypomelanosis of Ito is a rare condition characterized by distinctive skin changes, in which areas of the body lack skin color (hypopigmentation). These skin changes may present as patches, streaks or spiral-shaped (whorled) areas. In many affected individuals, additional symptoms affecting areas outside of the skin also occur. There are a wide variety of symptoms potentially associated with hypomelanosis of Ito. Neurological findings such as seizures and developmental delays and musculoskeletal symptoms such as abnormal curvature of the spine (scoliosis) are commonly associated with this condition. Because of the neurological and skin symptoms, hypomelanosis of Ito may be referred to as a “neurocutaneous” syndrome. However, in many patients the condition arises from genetic irregularities that are present in some cells of the body, but not in others (mosaicism). Some researchers believe that hypomelanosis of Ito does not represent a distinct disorder but rather a symptom common to a group of disorders involving genetic mosaicism.
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Overview of Hypomelanosis of Ito. Hypomelanosis of Ito is a rare condition characterized by distinctive skin changes, in which areas of the body lack skin color (hypopigmentation). These skin changes may present as patches, streaks or spiral-shaped (whorled) areas. In many affected individuals, additional symptoms affecting areas outside of the skin also occur. There are a wide variety of symptoms potentially associated with hypomelanosis of Ito. Neurological findings such as seizures and developmental delays and musculoskeletal symptoms such as abnormal curvature of the spine (scoliosis) are commonly associated with this condition. Because of the neurological and skin symptoms, hypomelanosis of Ito may be referred to as a “neurocutaneous” syndrome. However, in many patients the condition arises from genetic irregularities that are present in some cells of the body, but not in others (mosaicism). Some researchers believe that hypomelanosis of Ito does not represent a distinct disorder but rather a symptom common to a group of disorders involving genetic mosaicism.
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Symptoms of Hypomelanosis of Ito
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The most distinctive finding associated with hypomelanosis of Ito is characteristic skin changes. Most affected individuals develop areas that lack skin color (hypopigmentation). Any area of the body may be involved although the scalp, palms and soles are rarely affected. Skin changes may occur as patches, streaks or spiral-shaped (whorled) areas of discoloration and may affect one side of the body (unilateral) or both sides (bilateral). Affected areas of skin are usually normal otherwise. The skin lesions usually appear during the first year of life and remain unchanged through childhood, but may fade or darken in adulthood. Skin lesions are not associated with inflammation or a premalignant (verrucous) condition.In some cases of hypomelanosis of Ito, additional non-cutaneous features may occur. It is important to note that the specific symptoms that occur vary greatly from person to person and affected children will not have all the symptoms discussed below. Because children with the characteristic skin changes of hypomelanosis of Ito and no associated abnormalities may go unreported, determining the actually frequency of associated findings is difficult. The number of affected individuals with additional symptoms has been estimated to be anywhere from 30-90 percent.Neurological findings may occur in some cases including seizures that occur during infancy and are often resistant to therapy, some degree of cognitive impairment, and delays in attaining milestones that require the coordination of muscular and mental activity (psychomotor impairment). In some cases, one side of the brain may be larger than the other (hemimegalencephaly).Less often, some individuals have crossed eyes (strabismus), eyes that a spaced apart wider than normal (hypertelorism), cleft palate, cleft lip, and dental anomalies such as missing teeth (anodontia). Loss of hair usually in a patchy pattern (alopecia) may also occur. Some infants may have microcephaly, a condition that indicates that the head circumference is smaller than would be expected for age and sex; others may have macrocephaly, which indicates that head circumference is larger than would normally be expected.A variety of skeletal abnormalities have occurred in individuals with hypomelanosis of Ito including abnormal side-to-side curvature of the spine (scoliosis), disproportionate length of the legs (limb length discrepancy), and abnormal fixation or “locking” of the pinky in a bent position (clinodactyly). Diminished muscle tone (hypotonia) may also occur.Additional symptoms that may affect individuals with hypomelanosis of Ito include additional eye abnormalities, deafness, overgrowth of one side of the body (hemihypertrophy), heart (cardiac) abnormalities, kidney (renal) malformations, and abnormalities of the genitourinary tract, which contains the reproductive organs and urinary system.
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Symptoms of Hypomelanosis of Ito. The most distinctive finding associated with hypomelanosis of Ito is characteristic skin changes. Most affected individuals develop areas that lack skin color (hypopigmentation). Any area of the body may be involved although the scalp, palms and soles are rarely affected. Skin changes may occur as patches, streaks or spiral-shaped (whorled) areas of discoloration and may affect one side of the body (unilateral) or both sides (bilateral). Affected areas of skin are usually normal otherwise. The skin lesions usually appear during the first year of life and remain unchanged through childhood, but may fade or darken in adulthood. Skin lesions are not associated with inflammation or a premalignant (verrucous) condition.In some cases of hypomelanosis of Ito, additional non-cutaneous features may occur. It is important to note that the specific symptoms that occur vary greatly from person to person and affected children will not have all the symptoms discussed below. Because children with the characteristic skin changes of hypomelanosis of Ito and no associated abnormalities may go unreported, determining the actually frequency of associated findings is difficult. The number of affected individuals with additional symptoms has been estimated to be anywhere from 30-90 percent.Neurological findings may occur in some cases including seizures that occur during infancy and are often resistant to therapy, some degree of cognitive impairment, and delays in attaining milestones that require the coordination of muscular and mental activity (psychomotor impairment). In some cases, one side of the brain may be larger than the other (hemimegalencephaly).Less often, some individuals have crossed eyes (strabismus), eyes that a spaced apart wider than normal (hypertelorism), cleft palate, cleft lip, and dental anomalies such as missing teeth (anodontia). Loss of hair usually in a patchy pattern (alopecia) may also occur. Some infants may have microcephaly, a condition that indicates that the head circumference is smaller than would be expected for age and sex; others may have macrocephaly, which indicates that head circumference is larger than would normally be expected.A variety of skeletal abnormalities have occurred in individuals with hypomelanosis of Ito including abnormal side-to-side curvature of the spine (scoliosis), disproportionate length of the legs (limb length discrepancy), and abnormal fixation or “locking” of the pinky in a bent position (clinodactyly). Diminished muscle tone (hypotonia) may also occur.Additional symptoms that may affect individuals with hypomelanosis of Ito include additional eye abnormalities, deafness, overgrowth of one side of the body (hemihypertrophy), heart (cardiac) abnormalities, kidney (renal) malformations, and abnormalities of the genitourinary tract, which contains the reproductive organs and urinary system.
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Causes of Hypomelanosis of Ito
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The exact cause of hypomelanosis of Ito is unknown. Many cases are associated with genetic mosaicism and sporadic gene mutations. Genetic mosaicism is the term for individuals who have two distinct cell lines in the body that developed because of a gene mutation that occurred during embryonic development. The two cell lines have differences involving the chromosomes (chromosomal mosaicism).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. The numbered bands specify the location of the thousands of genes that are present on each chromosome.In many individuals with hypomelanosis of Ito, certain cells have the normal 46 chromosomes (one cell line) while others cells do not have the normal 46 chromosomes (second cell line). This second cell line may contain various abnormalities affecting the chromosomes such as a mutation in a specific gene, or the presence of an extra material on a chromosome (trisomy), loss of a portion of chromosome (monosomy), or a chromosomal translocation. Translocations occur when portions of certain chromosomes break off and are rearranged, resulting in shifting of genetic material and an altered set of chromosomes in the immediate daughter cells and their subsequent progeny cells. Specific chromosomal abnormalities have been identified in certain cases of hypomelanosis of Ito including ones affecting chromosome 9q33, chromosome 15q11-q13, chromosome Xp11 and Xp21.2. Chromosomal abnormalities have been identified in approximately 60 percent of cases of hypomelanosis of Ito and have included up to 64 distinct cytogenetic (chromosomal) abnormalities.The chromosomal abnormalities affecting hypomelanosis of Ito occur after fertilization, often for unknown reasons (spontaneously). The disorder is not inherited. The specific gene(s) involved in the development of hypomelanosis of Ito have not been identified.
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Causes of Hypomelanosis of Ito. The exact cause of hypomelanosis of Ito is unknown. Many cases are associated with genetic mosaicism and sporadic gene mutations. Genetic mosaicism is the term for individuals who have two distinct cell lines in the body that developed because of a gene mutation that occurred during embryonic development. The two cell lines have differences involving the chromosomes (chromosomal mosaicism).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. The numbered bands specify the location of the thousands of genes that are present on each chromosome.In many individuals with hypomelanosis of Ito, certain cells have the normal 46 chromosomes (one cell line) while others cells do not have the normal 46 chromosomes (second cell line). This second cell line may contain various abnormalities affecting the chromosomes such as a mutation in a specific gene, or the presence of an extra material on a chromosome (trisomy), loss of a portion of chromosome (monosomy), or a chromosomal translocation. Translocations occur when portions of certain chromosomes break off and are rearranged, resulting in shifting of genetic material and an altered set of chromosomes in the immediate daughter cells and their subsequent progeny cells. Specific chromosomal abnormalities have been identified in certain cases of hypomelanosis of Ito including ones affecting chromosome 9q33, chromosome 15q11-q13, chromosome Xp11 and Xp21.2. Chromosomal abnormalities have been identified in approximately 60 percent of cases of hypomelanosis of Ito and have included up to 64 distinct cytogenetic (chromosomal) abnormalities.The chromosomal abnormalities affecting hypomelanosis of Ito occur after fertilization, often for unknown reasons (spontaneously). The disorder is not inherited. The specific gene(s) involved in the development of hypomelanosis of Ito have not been identified.
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Affects of Hypomelanosis of Ito
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In earlier reports, hypomelanosis of Ito affected women more often than men by a ratio of 2.5:1. More recent, larger studies suggest that the difference may not be as large. The incidence of hypomelanosis of Ito is estimated to be 1 in 8,000-10,000 people in the general population. The symptoms usually become apparent during the first or second year of life. Hypomelanosis of Ito was first described in the medical literature in 1952.
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Affects of Hypomelanosis of Ito. In earlier reports, hypomelanosis of Ito affected women more often than men by a ratio of 2.5:1. More recent, larger studies suggest that the difference may not be as large. The incidence of hypomelanosis of Ito is estimated to be 1 in 8,000-10,000 people in the general population. The symptoms usually become apparent during the first or second year of life. Hypomelanosis of Ito was first described in the medical literature in 1952.
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Related disorders of Hypomelanosis of Ito
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Symptoms of the following disorders can be similar to those of hypomelanosis of Ito. Comparisons may be useful for a differential diagnosis.Incontinentia pigmenti (IP) is a rare genetic dermatological disorder affecting the skin, hair, teeth, and central nervous system. It is inherited as an X-linked dominant trait. IP is characterized by four stages, some of which may overlap. The first stage may be present at birth or appear in early infancy and consists of redness or inflammation of the skin. This irritation includes the scalp as well as the extremities and can last from a few weeks to several months. In the second stage, blisters develop into a raised, wart-like appearance with lesions that look like pustules. The extremities are involved almost exclusively in this stage, which may last for several months but rarely as long as a year. In the third phase, the skin darkens in a swirled pattern sometimes described as a “marble cake” appearance. The fourth stage is called the “atrophic” stage. Pale, hairless patches appear among adolescent and adult patients. The skin changes may fade later in life. (For more information on this disorder, choose “incontinentia pigmenti” as your search term in the Rare Disease Database.)Tuberous sclerosis is a rare genetic multisystem disorder that is typically apparent shortly after birth. The disorder can cause a wide range of potential signs and symptoms and is associated with the formation of benign (non-cancerous) tumors in various organ systems of the body. The skin, brain, eyes, heart, kidneys and lungs are frequently affected. These tumors are often referred to as hamartomas. Hamartoma is a general term for a tumor or tumor-like growth that is made up of cells normally found in the area of the body where the hamartoma forms. Hamartomas are not malignant; they do not metastasize and spread to other areas of the body. However, these abnormal growths can grow larger and can damage the affected organ system. The number, size, and specific location of these abnormal growths in individuals with tuberous sclerosis can vary widely and consequently the severity of the disorder can vary widely as well. Tuberous sclerosis results from alterations (mutations) in a gene or genes that may occur spontaneously (sporadically) for unknown reasons or be inherited as an autosomal dominant trait. Most cases represent new (sporadic or de novo) gene mutations, with no family history of the disease. Mutations of at least two different genes are known to cause tuberous sclerosis, the TSC1 gene or the TSC2 gene. (For more information on this disorder, choose “tuberous sclerosis” as your search term in the Rare Disease Database.)Vitiligo is a dermatological condition characterized by the appearance of white patches of skin on different parts of the body as a result of the destruction of the cells that make pigment (melanocytes). Hypopigmented lesions are not present at birth in vitiligo but develop later in life. This may vary from one or two white spots on the skin to large areas of depigmentation. Vitiligo is not contagious. It seems to occur more often among people who have certain autoimmune diseases. For some people, although not for everyone, the depigmentation is progressive
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Related disorders of Hypomelanosis of Ito. Symptoms of the following disorders can be similar to those of hypomelanosis of Ito. Comparisons may be useful for a differential diagnosis.Incontinentia pigmenti (IP) is a rare genetic dermatological disorder affecting the skin, hair, teeth, and central nervous system. It is inherited as an X-linked dominant trait. IP is characterized by four stages, some of which may overlap. The first stage may be present at birth or appear in early infancy and consists of redness or inflammation of the skin. This irritation includes the scalp as well as the extremities and can last from a few weeks to several months. In the second stage, blisters develop into a raised, wart-like appearance with lesions that look like pustules. The extremities are involved almost exclusively in this stage, which may last for several months but rarely as long as a year. In the third phase, the skin darkens in a swirled pattern sometimes described as a “marble cake” appearance. The fourth stage is called the “atrophic” stage. Pale, hairless patches appear among adolescent and adult patients. The skin changes may fade later in life. (For more information on this disorder, choose “incontinentia pigmenti” as your search term in the Rare Disease Database.)Tuberous sclerosis is a rare genetic multisystem disorder that is typically apparent shortly after birth. The disorder can cause a wide range of potential signs and symptoms and is associated with the formation of benign (non-cancerous) tumors in various organ systems of the body. The skin, brain, eyes, heart, kidneys and lungs are frequently affected. These tumors are often referred to as hamartomas. Hamartoma is a general term for a tumor or tumor-like growth that is made up of cells normally found in the area of the body where the hamartoma forms. Hamartomas are not malignant; they do not metastasize and spread to other areas of the body. However, these abnormal growths can grow larger and can damage the affected organ system. The number, size, and specific location of these abnormal growths in individuals with tuberous sclerosis can vary widely and consequently the severity of the disorder can vary widely as well. Tuberous sclerosis results from alterations (mutations) in a gene or genes that may occur spontaneously (sporadically) for unknown reasons or be inherited as an autosomal dominant trait. Most cases represent new (sporadic or de novo) gene mutations, with no family history of the disease. Mutations of at least two different genes are known to cause tuberous sclerosis, the TSC1 gene or the TSC2 gene. (For more information on this disorder, choose “tuberous sclerosis” as your search term in the Rare Disease Database.)Vitiligo is a dermatological condition characterized by the appearance of white patches of skin on different parts of the body as a result of the destruction of the cells that make pigment (melanocytes). Hypopigmented lesions are not present at birth in vitiligo but develop later in life. This may vary from one or two white spots on the skin to large areas of depigmentation. Vitiligo is not contagious. It seems to occur more often among people who have certain autoimmune diseases. For some people, although not for everyone, the depigmentation is progressive
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Diagnosis of Hypomelanosis of Ito
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A diagnosis of hypomelanosis of Ito is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic findings and a variety of specialized tests such as the finding of chromosomal mosaicism in fibroblasts (the major cell type of the lower layer of the skin) or keratinocytes (the major cell of the outer layer of the skin [epidermis]) obtained from an area of affected (hypopigmented) skin. Computed tomography (CT) scans or magnetic resonance imaging (MRI) may be able to detect structural abnormalities of the brain if neurological abnormalities are present.
During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs, tissues and structures.
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Diagnosis of Hypomelanosis of Ito. A diagnosis of hypomelanosis of Ito is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic findings and a variety of specialized tests such as the finding of chromosomal mosaicism in fibroblasts (the major cell type of the lower layer of the skin) or keratinocytes (the major cell of the outer layer of the skin [epidermis]) obtained from an area of affected (hypopigmented) skin. Computed tomography (CT) scans or magnetic resonance imaging (MRI) may be able to detect structural abnormalities of the brain if neurological abnormalities are present.
During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs, tissues and structures.
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Therapies of Hypomelanosis of Ito
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TreatmentThe treatment of hypomelanosis of Ito is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, dermatologists, neurologists, specialists who diagnose and treat skeletal disorders (orthopedists), dental specialists, specialists who diagnose and treat eye disorders (ophthalmologists), surgeons and other healthcare providers may need to systematically and comprehensively plan an affect child's treatment.The characteristic skin abnormality (hypopigmentation) of hypomelanosis of Ito tends to darken or fade without treatment. Some individuals may use cosmetics to hide or darken these areas. Antiseizure medications (anticonvulsants) may be used to treat infants and children with seizures, but are ineffective in some cases. Surgical techniques to treat seizures may be necessary for some affected individuals.Additional treatment is symptomatic and supportive and consultation with proper specialists may be necessary. For example, consultation with an orthopedist may be necessary to treat scoliosis.Services that may be beneficial to some children with hypomelanosis of Ito include special remedial education and other medical, social, and/or vocational services. Genetic counseling may be of benefit for affected individuals and their families.
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Therapies of Hypomelanosis of Ito. TreatmentThe treatment of hypomelanosis of Ito is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, dermatologists, neurologists, specialists who diagnose and treat skeletal disorders (orthopedists), dental specialists, specialists who diagnose and treat eye disorders (ophthalmologists), surgeons and other healthcare providers may need to systematically and comprehensively plan an affect child's treatment.The characteristic skin abnormality (hypopigmentation) of hypomelanosis of Ito tends to darken or fade without treatment. Some individuals may use cosmetics to hide or darken these areas. Antiseizure medications (anticonvulsants) may be used to treat infants and children with seizures, but are ineffective in some cases. Surgical techniques to treat seizures may be necessary for some affected individuals.Additional treatment is symptomatic and supportive and consultation with proper specialists may be necessary. For example, consultation with an orthopedist may be necessary to treat scoliosis.Services that may be beneficial to some children with hypomelanosis of Ito include special remedial education and other medical, social, and/or vocational services. Genetic counseling may be of benefit for affected individuals and their families.
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Overview of Hypoparathyroidism
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Hypoparathyroidism is a rare condition in which the parathyroid glands fail to produce sufficient amounts of parathyroid hormone or the parathyroid hormone produced lacks biologic activity. The parathyroid glands are part of the endocrine system, the network of glands that secrete hormones into the bloodstream where they travel to various areas of the body. These hormones regulate the chemical processes (metabolism) that influence the function of various organs and activities within the body. Hormones are involved in numerous vital processes including regulating heart rate, body temperature and blood pressure as well as cell differentiation and growth and also in modulation of several metabolic processes. Parathyroid hormone (along with vitamin D and the hormone calcitonin, which is produced by the thyroid gland) plays a role in regulating the levels of calcium and phosphorus in the blood and in determining bone growth and bone cell activity. Due to a deficiency of parathyroid hormone, individuals may exhibit abnormally low levels of calcium in the blood (hypocalcemia) and high levels of phosphorus (hyperphosphatemia). Hypocalcemia can cause a variety of symptoms including weakness, muscle cramps, excessive nervousness, headaches, and/or uncontrollable twitching and cramping spasms of certain muscles such as those of the hands, feet, arms, legs, and/or face (tetany). Numbness and tingling around the mouth and in the fingers and toes can also occur. The most common cause of hypoparathyroidism is damage to or removal of the parathyroid glands due to surgery for another condition. Hypoparathyroidism can also be caused by an autoimmune process or can occur for unknown reasons (idiopathic) or in association with a number of different underlying disorders. In rare cases, hypoparathyroidism may occur as a genetic disorder. Such cases can include familial hypoparathyroidism, which may be inherited as an autosomal recessive, autosomal dominant or X-linked recessive trait. NORD has a separate report on familial isolated hypoparathyroidism.
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Overview of Hypoparathyroidism. Hypoparathyroidism is a rare condition in which the parathyroid glands fail to produce sufficient amounts of parathyroid hormone or the parathyroid hormone produced lacks biologic activity. The parathyroid glands are part of the endocrine system, the network of glands that secrete hormones into the bloodstream where they travel to various areas of the body. These hormones regulate the chemical processes (metabolism) that influence the function of various organs and activities within the body. Hormones are involved in numerous vital processes including regulating heart rate, body temperature and blood pressure as well as cell differentiation and growth and also in modulation of several metabolic processes. Parathyroid hormone (along with vitamin D and the hormone calcitonin, which is produced by the thyroid gland) plays a role in regulating the levels of calcium and phosphorus in the blood and in determining bone growth and bone cell activity. Due to a deficiency of parathyroid hormone, individuals may exhibit abnormally low levels of calcium in the blood (hypocalcemia) and high levels of phosphorus (hyperphosphatemia). Hypocalcemia can cause a variety of symptoms including weakness, muscle cramps, excessive nervousness, headaches, and/or uncontrollable twitching and cramping spasms of certain muscles such as those of the hands, feet, arms, legs, and/or face (tetany). Numbness and tingling around the mouth and in the fingers and toes can also occur. The most common cause of hypoparathyroidism is damage to or removal of the parathyroid glands due to surgery for another condition. Hypoparathyroidism can also be caused by an autoimmune process or can occur for unknown reasons (idiopathic) or in association with a number of different underlying disorders. In rare cases, hypoparathyroidism may occur as a genetic disorder. Such cases can include familial hypoparathyroidism, which may be inherited as an autosomal recessive, autosomal dominant or X-linked recessive trait. NORD has a separate report on familial isolated hypoparathyroidism.
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Symptoms of Hypoparathyroidism
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The symptoms of hypoparathyroidism occur due to low levels of calcium in the blood. The severity of the condition can range from mild symptoms such as a tingling or numbness in the fingers, toes or around the lips (paresthesias) to severe muscle cramps and muscle spasms. The muscle symptoms are often called tetany, a condition characterized by uncontrollable twitching and cramping spasms of certain muscles such as those of the hands, feet, legs, and arms. In rare cases, seizures or fits can occur, or the level of consciousness can be depressed.Additional symptoms that may be associated with hypoparathyroidism include fatigue, generalized weakness, muscle aches, anxiety or nervousness, and headaches. Affected individuals may also have dry, coarse skin, brittle nails, and patchy hair loss such as the thinning of the eyebrows. Some individuals with hypoparathyroidism, especially those with chronic hypoparathyroidism since childhood, may have abnormalities affecting the teeth including the underdevelopment of the hard outer layer of the teeth (enamel hypoplasia), malformation of the roots and an increased risk of cavities (dental caries).Hoarseness or voice changes, wheezing and difficulty breathing (dyspnea) can also be associated with chronic hypoparathyroidism. Sudden, muscular spasms affecting the larynx (laryngospasm) and the bronchial tubes (bronchospasm) may also occur. Laryngospasm causes closure of the upper end of the trachea and prevents air from reaching the lungs. Bronchospasm can restrict the flow of air into and out of the lungs. These are serious issues and are rare.Depression, irritability, confusion, disorientation, mood swings and loss of memory have also been reported in individuals with hypoparathyroidism. In children, chronic hypoparathyroidism can result in stunted growth and slow mental development if it is not treated.Less often, more serious complications can occur in individuals with hypoparathyroidism especially when hypoparathyroidism goes untreated or persists. Such symptoms include clouding of the lens of the eyes (cataracts), seizures or convulsions, fainting, abnormal heartbeats (cardiac arrhythmias) and, potentially, signs of congestive heart failure. Some individuals may develop calcium deposits (calcifications) in the brain or the kidneys. If enough calcifications occur in the kidneys, kidney function can become impaired. Individuals with hypoparathyroidism may be prone to developing kidney stones. Increased pressure of cerebrospinal fluid in the skull (intracranial hypertension) can also occur and may cause severe headaches and vision changes.
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Symptoms of Hypoparathyroidism. The symptoms of hypoparathyroidism occur due to low levels of calcium in the blood. The severity of the condition can range from mild symptoms such as a tingling or numbness in the fingers, toes or around the lips (paresthesias) to severe muscle cramps and muscle spasms. The muscle symptoms are often called tetany, a condition characterized by uncontrollable twitching and cramping spasms of certain muscles such as those of the hands, feet, legs, and arms. In rare cases, seizures or fits can occur, or the level of consciousness can be depressed.Additional symptoms that may be associated with hypoparathyroidism include fatigue, generalized weakness, muscle aches, anxiety or nervousness, and headaches. Affected individuals may also have dry, coarse skin, brittle nails, and patchy hair loss such as the thinning of the eyebrows. Some individuals with hypoparathyroidism, especially those with chronic hypoparathyroidism since childhood, may have abnormalities affecting the teeth including the underdevelopment of the hard outer layer of the teeth (enamel hypoplasia), malformation of the roots and an increased risk of cavities (dental caries).Hoarseness or voice changes, wheezing and difficulty breathing (dyspnea) can also be associated with chronic hypoparathyroidism. Sudden, muscular spasms affecting the larynx (laryngospasm) and the bronchial tubes (bronchospasm) may also occur. Laryngospasm causes closure of the upper end of the trachea and prevents air from reaching the lungs. Bronchospasm can restrict the flow of air into and out of the lungs. These are serious issues and are rare.Depression, irritability, confusion, disorientation, mood swings and loss of memory have also been reported in individuals with hypoparathyroidism. In children, chronic hypoparathyroidism can result in stunted growth and slow mental development if it is not treated.Less often, more serious complications can occur in individuals with hypoparathyroidism especially when hypoparathyroidism goes untreated or persists. Such symptoms include clouding of the lens of the eyes (cataracts), seizures or convulsions, fainting, abnormal heartbeats (cardiac arrhythmias) and, potentially, signs of congestive heart failure. Some individuals may develop calcium deposits (calcifications) in the brain or the kidneys. If enough calcifications occur in the kidneys, kidney function can become impaired. Individuals with hypoparathyroidism may be prone to developing kidney stones. Increased pressure of cerebrospinal fluid in the skull (intracranial hypertension) can also occur and may cause severe headaches and vision changes.
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Causes of Hypoparathyroidism
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Hypoparathyroidism may result from removal of or damage to the parathyroid glands or their blood supply, the absence of or failure to function properly of the parathyroid glands at birth (congenital hypoparathyroidism) or due to or in association with a number of different underlying disorders.Hypoparathyroidism most often occurs because of the surgical removal of some or all of the parathyroid glands. Surgical damage or removal of parathyroid tissue usually occurs following treatment for another condition, especially hyperparathyroidism (in which there is too much production of parathyroid hormone). Hyperparathyroidism may be treated by the surgical removal of parathyroid tissue. In some cases, such surgery may result in too much parathyroid tissue being removed and, consequently, cause hypoparathyroidism.Surgery to treat cancer of the thyroid (nearby the parathyroid glands) or goiter (enlargement) of the thyroid gland may also cause hypoparathyroidism, usually through damage to the blood supply for the parathyroid glands or inadvertent removal of the glands during surgery. In such cases, hypoparathyroidism may be temporary (transient in 75% of cases) depending upon the extent of the damage. Transient post-surgical hypoparathyroidism can become permanent (25% of cases). Post-surgical hypoparathyroidism may occur shortly after surgery or appear months to years later. When hypoparathyroidism occurs due to external factors such as surgery, these cases are sometimes referred to as acquired hypoparathyroidism.Although very rare, cancer from another tissue can spread to the parathyroid glands and alter their function. In extremely rare cases, hypoparathyroidism is caused by extensive radiation therapy to the neck region as may be done as part of a cancer treatment regimen.In rare cases, hypoparathyroidism occurs as an autoimmune disorder. Autoimmune disorders are caused when the body’s natural defenses (antibodies, lymphocytes, etc.) against invading organisms suddenly begin to attack perfectly healthy tissue for unknown reasons. These cases may be called autoimmune hypoparathyroidism and develop when the body’s own immune system mistakenly attacks parathyroid tissue and leads to the loss of the secretion of parathyroid hormone. Autoimmune hypoparathyroidism can occur as part of a larger autoimmune syndrome (complex of diseases occurring together in the same person) that damages many organs of the body or as isolated damage to the parathyroid glands. This may be called the autoimmune polyendocrine syndrome type 1 or APS1. Congenital hypoparathyroidism refers to infants who are born without parathyroid tissue, the ability to make parathyroid hormone, or with parathyroid glands that do not function properly. Congenital hypoparathyroidism that occurs during the first few months of life may be temporary (transient) or permanent. In some patients, the cause of hypoparathyroidism is unknown (idiopathic). In some of these cases, hypoparathyroidism may resolve (spontaneously), but most do not resolve and usually need treatment.Congenital hypoparathyroidism may also occur in infants whose mothers have hyperparathyroidism. As opposed to “hypo”-parathyroidism, “hyper”-parathyroidism results in excessive calcium levels in the bloodstream. In a pregnant woman, the excess calcium may cross the placenta reaching the developing fetus and suppress fetal parathyroid hormone production by the growing infant’s parathyroid glands. In a newborn infant, this may result in abnormally low levels of blood calcium after birth. However, this is only a temporary condition and is not associated with permanent changes in the infant’s parathyroid glands. They will recover later in the newborn period and do their job of making parathyroid hormone. It will just take some time. Transient hypoparathyroidism can also occur in preterm infants of women who have diabetes mellitus. This may resolve but should be carefully watched until it does.Congenital hypoparathyroidism can also refer to cases that occur as an isolated genetic disorder. (For more information these disorders, choose “familial isolated hypoparathyroidism” as your search term in the NORD Rare Disease Database.)One of the more common causes (after post-surgery) of hypoparathyroidism is an activating mutation of the extracellular calcium-sensing receptor (CASR) gene. This has been called autosomal dominant hypocalcemia type 1. The CASR gene encodes for a protein that is found in the chief cells of the parathyroid gland. Activating mutations of this gene ultimately lead to suppression of parathyroid hormone secretion and hypoparathyroidism. In many affected individuals, this condition is mild and often detected incidentally. Treatment may not be needed unless symptoms develop. This mutation may be inherited as an autosomal dominant trait, but sporadic cases occur as well. In most cases in addition to the low blood calcium levels, there are high urinary calcium levels. This is because the same gene — the CASR — is also important in controlling calcium excretion by the kidneys. Recently, another gene encoding for the production of a G protein (G-alpha 11) that works with the CASR in the parathyroid gland to control the synthesis of parathyroid hormone was also shown to be involved in calcium-sensing by the parathyroid cell. Mutations in that gene also cause autosomal dominant hypoparathyroidism and this is the form called type 2. Another common cause of hypoparathyroidism is abnormally low levels of magnesium (hypomagnesemia) in the blood. This is often called functional hypoparathyroidism because it resolves when magnesium is restored. Magnesium is a mineral that is very important in the function of the parathyroid glands. When magnesium levels are low, it often leads to low levels of calcium in the blood as well. Without proper levels of magnesium, the parathyroid glands fail to function normally. One common cause of low levels of magnesium in the body is chronic alcoholism. Other causes of hypomagnesemia include malnutrition, malabsorption, diabetes, chronic diarrhea, certain kidney disorders, and the use of certain medications.Less often, hypoparathyroidism can be caused by abnormally high levels of magnesium (hypermagnesemia) in the blood. Magnesium can activate the CASR protein on the parathyroid chief cells (hormone-secreting cells) and inhibit the secretion of parathyroid hormone. Hypermagnesemia can be occur when magnesium accumulates because of impaired kidney function or when magnesium is given as a therapy as in tocolytic therapy (which is given to women to suppress preterm labor).Hypoparathyroidism can also develop as part of a larger syndrome such as chromosome 22q11.2 deletion syndrome (sometimes called DiGeorge syndrome), Barakat syndrome (hypoparathyroidism – sensorineural deafness – renal disease also called the HDR syndrome), Kenney-Caffey disease, Sanjad-Sakati syndrome (hypoparathyroidism – intellectual disability – dysmorphism), autoimmune polyendocrine syndrome type 1 (APS1) or lymphedema-hypoparathyroidism syndrome. It can also occur as part of certain mitochondrial disorders such as Kearns-Sayre syndrome or MELAS syndrome. In some patients, hypoparathyroidism may occur in association with Wilson disease (due to copper accumulating in the parathyroid glands) or hemochromatosis (due to iron accumulating in the parathyroid glands). (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Causes of Hypoparathyroidism. Hypoparathyroidism may result from removal of or damage to the parathyroid glands or their blood supply, the absence of or failure to function properly of the parathyroid glands at birth (congenital hypoparathyroidism) or due to or in association with a number of different underlying disorders.Hypoparathyroidism most often occurs because of the surgical removal of some or all of the parathyroid glands. Surgical damage or removal of parathyroid tissue usually occurs following treatment for another condition, especially hyperparathyroidism (in which there is too much production of parathyroid hormone). Hyperparathyroidism may be treated by the surgical removal of parathyroid tissue. In some cases, such surgery may result in too much parathyroid tissue being removed and, consequently, cause hypoparathyroidism.Surgery to treat cancer of the thyroid (nearby the parathyroid glands) or goiter (enlargement) of the thyroid gland may also cause hypoparathyroidism, usually through damage to the blood supply for the parathyroid glands or inadvertent removal of the glands during surgery. In such cases, hypoparathyroidism may be temporary (transient in 75% of cases) depending upon the extent of the damage. Transient post-surgical hypoparathyroidism can become permanent (25% of cases). Post-surgical hypoparathyroidism may occur shortly after surgery or appear months to years later. When hypoparathyroidism occurs due to external factors such as surgery, these cases are sometimes referred to as acquired hypoparathyroidism.Although very rare, cancer from another tissue can spread to the parathyroid glands and alter their function. In extremely rare cases, hypoparathyroidism is caused by extensive radiation therapy to the neck region as may be done as part of a cancer treatment regimen.In rare cases, hypoparathyroidism occurs as an autoimmune disorder. Autoimmune disorders are caused when the body’s natural defenses (antibodies, lymphocytes, etc.) against invading organisms suddenly begin to attack perfectly healthy tissue for unknown reasons. These cases may be called autoimmune hypoparathyroidism and develop when the body’s own immune system mistakenly attacks parathyroid tissue and leads to the loss of the secretion of parathyroid hormone. Autoimmune hypoparathyroidism can occur as part of a larger autoimmune syndrome (complex of diseases occurring together in the same person) that damages many organs of the body or as isolated damage to the parathyroid glands. This may be called the autoimmune polyendocrine syndrome type 1 or APS1. Congenital hypoparathyroidism refers to infants who are born without parathyroid tissue, the ability to make parathyroid hormone, or with parathyroid glands that do not function properly. Congenital hypoparathyroidism that occurs during the first few months of life may be temporary (transient) or permanent. In some patients, the cause of hypoparathyroidism is unknown (idiopathic). In some of these cases, hypoparathyroidism may resolve (spontaneously), but most do not resolve and usually need treatment.Congenital hypoparathyroidism may also occur in infants whose mothers have hyperparathyroidism. As opposed to “hypo”-parathyroidism, “hyper”-parathyroidism results in excessive calcium levels in the bloodstream. In a pregnant woman, the excess calcium may cross the placenta reaching the developing fetus and suppress fetal parathyroid hormone production by the growing infant’s parathyroid glands. In a newborn infant, this may result in abnormally low levels of blood calcium after birth. However, this is only a temporary condition and is not associated with permanent changes in the infant’s parathyroid glands. They will recover later in the newborn period and do their job of making parathyroid hormone. It will just take some time. Transient hypoparathyroidism can also occur in preterm infants of women who have diabetes mellitus. This may resolve but should be carefully watched until it does.Congenital hypoparathyroidism can also refer to cases that occur as an isolated genetic disorder. (For more information these disorders, choose “familial isolated hypoparathyroidism” as your search term in the NORD Rare Disease Database.)One of the more common causes (after post-surgery) of hypoparathyroidism is an activating mutation of the extracellular calcium-sensing receptor (CASR) gene. This has been called autosomal dominant hypocalcemia type 1. The CASR gene encodes for a protein that is found in the chief cells of the parathyroid gland. Activating mutations of this gene ultimately lead to suppression of parathyroid hormone secretion and hypoparathyroidism. In many affected individuals, this condition is mild and often detected incidentally. Treatment may not be needed unless symptoms develop. This mutation may be inherited as an autosomal dominant trait, but sporadic cases occur as well. In most cases in addition to the low blood calcium levels, there are high urinary calcium levels. This is because the same gene — the CASR — is also important in controlling calcium excretion by the kidneys. Recently, another gene encoding for the production of a G protein (G-alpha 11) that works with the CASR in the parathyroid gland to control the synthesis of parathyroid hormone was also shown to be involved in calcium-sensing by the parathyroid cell. Mutations in that gene also cause autosomal dominant hypoparathyroidism and this is the form called type 2. Another common cause of hypoparathyroidism is abnormally low levels of magnesium (hypomagnesemia) in the blood. This is often called functional hypoparathyroidism because it resolves when magnesium is restored. Magnesium is a mineral that is very important in the function of the parathyroid glands. When magnesium levels are low, it often leads to low levels of calcium in the blood as well. Without proper levels of magnesium, the parathyroid glands fail to function normally. One common cause of low levels of magnesium in the body is chronic alcoholism. Other causes of hypomagnesemia include malnutrition, malabsorption, diabetes, chronic diarrhea, certain kidney disorders, and the use of certain medications.Less often, hypoparathyroidism can be caused by abnormally high levels of magnesium (hypermagnesemia) in the blood. Magnesium can activate the CASR protein on the parathyroid chief cells (hormone-secreting cells) and inhibit the secretion of parathyroid hormone. Hypermagnesemia can be occur when magnesium accumulates because of impaired kidney function or when magnesium is given as a therapy as in tocolytic therapy (which is given to women to suppress preterm labor).Hypoparathyroidism can also develop as part of a larger syndrome such as chromosome 22q11.2 deletion syndrome (sometimes called DiGeorge syndrome), Barakat syndrome (hypoparathyroidism – sensorineural deafness – renal disease also called the HDR syndrome), Kenney-Caffey disease, Sanjad-Sakati syndrome (hypoparathyroidism – intellectual disability – dysmorphism), autoimmune polyendocrine syndrome type 1 (APS1) or lymphedema-hypoparathyroidism syndrome. It can also occur as part of certain mitochondrial disorders such as Kearns-Sayre syndrome or MELAS syndrome. In some patients, hypoparathyroidism may occur in association with Wilson disease (due to copper accumulating in the parathyroid glands) or hemochromatosis (due to iron accumulating in the parathyroid glands). (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Affects of Hypoparathyroidism
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Hypoparathyroidism affects males and females in equal numbers. The incidence and prevalence of hypoparathyroidism in the general population are unknown. There are approximately 70,000 people with hypoparathyroidism in the United States. Hypoparathyroidism can affect individuals of any age.
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Affects of Hypoparathyroidism. Hypoparathyroidism affects males and females in equal numbers. The incidence and prevalence of hypoparathyroidism in the general population are unknown. There are approximately 70,000 people with hypoparathyroidism in the United States. Hypoparathyroidism can affect individuals of any age.
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Related disorders of Hypoparathyroidism
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Symptoms of the following disorders can be similar to those of hypoparathyroidism. Comparisons may be useful for a differential diagnosis.Pseudohypoparathyroidism is a rare disorder characterized by the resistance of the body to parathyroid hormone. Unlike hypoparathyroidism, in which there are abnormally low levels of functional parathyroid hormone, individuals with pseudohypoparathyroidism produce enough parathyroid hormone, but are unable to use it properly. There are three main subtypes – pseudohypoparathyroidism 1a and 1b and pseudohypoparathyroidism II. All forms of pseudohypoparathyroidism are extremely rare. Common symptoms include abnormalities of the bone and teeth, behavioral problems, cognitive deficits and short stature. Additional symptoms that may develop include cataracts, seizures, and osteoporosis. Affected individuals may have a round face with full cheeks and be prone to obesity. Albright’s hereditary osteodystrophy, a unique constellation of developmental and skeletal defects, occurs mostly in type 1a, which is due to a mutation of a specific gene encoding for a G-protein. Pseudohypoparathyroidism is inherited as an autosomal dominant trait. (For more information on this disorder, choose “pseudohypoparathyroidism” as your search term in the Rare Disease Database.)
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Related disorders of Hypoparathyroidism. Symptoms of the following disorders can be similar to those of hypoparathyroidism. Comparisons may be useful for a differential diagnosis.Pseudohypoparathyroidism is a rare disorder characterized by the resistance of the body to parathyroid hormone. Unlike hypoparathyroidism, in which there are abnormally low levels of functional parathyroid hormone, individuals with pseudohypoparathyroidism produce enough parathyroid hormone, but are unable to use it properly. There are three main subtypes – pseudohypoparathyroidism 1a and 1b and pseudohypoparathyroidism II. All forms of pseudohypoparathyroidism are extremely rare. Common symptoms include abnormalities of the bone and teeth, behavioral problems, cognitive deficits and short stature. Additional symptoms that may develop include cataracts, seizures, and osteoporosis. Affected individuals may have a round face with full cheeks and be prone to obesity. Albright’s hereditary osteodystrophy, a unique constellation of developmental and skeletal defects, occurs mostly in type 1a, which is due to a mutation of a specific gene encoding for a G-protein. Pseudohypoparathyroidism is inherited as an autosomal dominant trait. (For more information on this disorder, choose “pseudohypoparathyroidism” as your search term in the Rare Disease Database.)
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Diagnosis of Hypoparathyroidism
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A diagnosis of hypoparathyroidism is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Blood tests can reveal abnormal levels of calcium, phosphorus, magnesium, creatinine and intact parathyroid hormone. Urine tests can reveal if the body is excreting too much calcium.In addition, the Food and Drug Administration (FDA) has approved the use of the synthetic parathyroid hormone, teriparatide as a diagnostic agent to distinguish hypoparathyroidism from pseudohypoparathyroidism.Additional tests may be performed to detect complications that may be associated with hypoparathyroidism. For example, an electrocardiogram, a test that records electrical activity of the heart, can reveal arrhythmias that are sometimes associated with low calcium levels and hypoparathyroidism. An ophthalmologic exam should also be done to check for cataracts.Molecular genetic testing is available through commercial and academic research laboratories to detect specific gene mutations that cause genetic forms of hypoparathyroidism.
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Diagnosis of Hypoparathyroidism. A diagnosis of hypoparathyroidism is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Blood tests can reveal abnormal levels of calcium, phosphorus, magnesium, creatinine and intact parathyroid hormone. Urine tests can reveal if the body is excreting too much calcium.In addition, the Food and Drug Administration (FDA) has approved the use of the synthetic parathyroid hormone, teriparatide as a diagnostic agent to distinguish hypoparathyroidism from pseudohypoparathyroidism.Additional tests may be performed to detect complications that may be associated with hypoparathyroidism. For example, an electrocardiogram, a test that records electrical activity of the heart, can reveal arrhythmias that are sometimes associated with low calcium levels and hypoparathyroidism. An ophthalmologic exam should also be done to check for cataracts.Molecular genetic testing is available through commercial and academic research laboratories to detect specific gene mutations that cause genetic forms of hypoparathyroidism.
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Therapies of Hypoparathyroidism
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TreatmentThe treatment of hypoparathyroidism is directed toward the specific symptoms that are apparent in each individual and the lab tests. Treatment is aimed at raising calcium levels high enough to provide symptom relief without causing abnormally high levels of calcium in the blood (hypercalcemia) or in the urine (hypercalciuria). The specific therapies used may vary depending upon the disease severity, the specific symptoms present, an individual’s age and overall health, personal preference and additional factors. Individuals are recommended to see a physician who specializes in diagnosing and treating disorders affecting the endocrine system (endocrinologist) for optimal treatment of hypoparathyroidism and family screening and specialized testing.The primary therapies for individuals with hypoparathyroidism are calcium supplements and activated vitamin D, except in individuals whose condition is caused by hypo- or hypermagnesemia. In these cases, hypoparathyroidism is treated by normalizing magnesium levels (e.g., taking magnesium supplements to treat hypomagnesemia).These are several different types of calcium supplements available. Some brands may work better for certain people. High doses of calcium can cause gastrointestinal side effects such as constipation and should only be taken at the instruction of a physician.The main supplemental form of vitamin D used for individuals with hypoparathyroidism is calcitriol. Another form of vitamin D that may be used is ergocalciferol or cholecalciferol. Outside the USA, doctors use alpha calcidol. Ergocalciferol and cholecalciferol have a longer duration of action than calcitriol or alpha calcidol because the former two forms of vitamin D are stored in the body for long times. Long-term therapy with vitamin D and its analogues and metabolites (like calcitriol) carries a risk of serious side effects including calcium deposits accumulating in the kidneys (nephrocalcinosis), the development of kidney stones and, ultimately, improper function of the kidneys if blood tests are not carefully monitored.Some individuals, especially those with severe symptoms due to low blood calcium levels, may require immediate relief through intravenous calcium therapy, even if their calcium levels are only mildly reduced. Intravenous therapy means that a substance (e.g., calcium) is delivered into the bloodstream through an injection or infusion directly into a vein.In 2015, the US Food and Drug Administration approved the use of recombinant human parathyroid hormone (1-84) [rhPTH(1-84)] as a treatment for adult patients with chronic hypoparathyroidism who are uncontrolled with conventional therapy (calcium and activated vitamin D). Their approval was based on open-label studies conducted at Columbia University which have now reported out on 6 years of treatment; studies from Denmark using rhPTH(1-84) as an add-on to conventional therapy; and a phase 3 randomized controlled multinational clinical trial of 24 weeks duration. Ongoing studies continue to look at long-term safety of that medication. Some individuals with severe hypoparathyroidism that do have a high urinary calcium level may be treated with thiazide diuretics. These drugs enhance calcium absorption in the kidneys and can help control or prevent hypercalciuria in individuals taking vitamin D and calcium.Some individuals with hypoparathyroidism may be encouraged to make dietary changes to help treat their condition. Affected individuals may be encouraged to eat foods high in calcium such as dairy products, breakfast cereals, fortified orange juice and green, leafy vegetables. Affected individuals may also be encouraged to avoid foods high in phosphorus such as carbonated soft drinks, eggs and meat to keep the blood phosphorus levels as low as possible.
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Therapies of Hypoparathyroidism. TreatmentThe treatment of hypoparathyroidism is directed toward the specific symptoms that are apparent in each individual and the lab tests. Treatment is aimed at raising calcium levels high enough to provide symptom relief without causing abnormally high levels of calcium in the blood (hypercalcemia) or in the urine (hypercalciuria). The specific therapies used may vary depending upon the disease severity, the specific symptoms present, an individual’s age and overall health, personal preference and additional factors. Individuals are recommended to see a physician who specializes in diagnosing and treating disorders affecting the endocrine system (endocrinologist) for optimal treatment of hypoparathyroidism and family screening and specialized testing.The primary therapies for individuals with hypoparathyroidism are calcium supplements and activated vitamin D, except in individuals whose condition is caused by hypo- or hypermagnesemia. In these cases, hypoparathyroidism is treated by normalizing magnesium levels (e.g., taking magnesium supplements to treat hypomagnesemia).These are several different types of calcium supplements available. Some brands may work better for certain people. High doses of calcium can cause gastrointestinal side effects such as constipation and should only be taken at the instruction of a physician.The main supplemental form of vitamin D used for individuals with hypoparathyroidism is calcitriol. Another form of vitamin D that may be used is ergocalciferol or cholecalciferol. Outside the USA, doctors use alpha calcidol. Ergocalciferol and cholecalciferol have a longer duration of action than calcitriol or alpha calcidol because the former two forms of vitamin D are stored in the body for long times. Long-term therapy with vitamin D and its analogues and metabolites (like calcitriol) carries a risk of serious side effects including calcium deposits accumulating in the kidneys (nephrocalcinosis), the development of kidney stones and, ultimately, improper function of the kidneys if blood tests are not carefully monitored.Some individuals, especially those with severe symptoms due to low blood calcium levels, may require immediate relief through intravenous calcium therapy, even if their calcium levels are only mildly reduced. Intravenous therapy means that a substance (e.g., calcium) is delivered into the bloodstream through an injection or infusion directly into a vein.In 2015, the US Food and Drug Administration approved the use of recombinant human parathyroid hormone (1-84) [rhPTH(1-84)] as a treatment for adult patients with chronic hypoparathyroidism who are uncontrolled with conventional therapy (calcium and activated vitamin D). Their approval was based on open-label studies conducted at Columbia University which have now reported out on 6 years of treatment; studies from Denmark using rhPTH(1-84) as an add-on to conventional therapy; and a phase 3 randomized controlled multinational clinical trial of 24 weeks duration. Ongoing studies continue to look at long-term safety of that medication. Some individuals with severe hypoparathyroidism that do have a high urinary calcium level may be treated with thiazide diuretics. These drugs enhance calcium absorption in the kidneys and can help control or prevent hypercalciuria in individuals taking vitamin D and calcium.Some individuals with hypoparathyroidism may be encouraged to make dietary changes to help treat their condition. Affected individuals may be encouraged to eat foods high in calcium such as dairy products, breakfast cereals, fortified orange juice and green, leafy vegetables. Affected individuals may also be encouraged to avoid foods high in phosphorus such as carbonated soft drinks, eggs and meat to keep the blood phosphorus levels as low as possible.
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Overview of Hypophosphatasia
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SummaryHypophosphatasia (HPP) is a rare genetic disorder characterized by impaired mineralization (“calcification”) of bones and teeth. Problems occur because mineralization is the process by which bones and teeth take up calcium and phosphorus required for proper hardness and strength.Defective mineralization results in bones that are soft and prone to fracture and deformity. Defective mineralization of teeth can lead to tooth loss. The specific symptoms of HPP are broad-ranging in severity, and can vary greatly from one person to another, sometimes even among affected members of the same family. There are six major clinical forms of HPP that range from an extremely severe “perinatal” (at birth) form that can cause stillbirth to a more common (“odonto”) form associated with only early loss of baby (deciduous) teeth, but no bone abnormalities. HPP is caused by changes (mutations) in the ALPL gene that produces an enzyme called tissue nonspecific alkaline phosphatase (TNSALP). Such mutations lead to low activity of this enzyme that should be breaking down a chemical called inorganic pyrophosphate that blocks mineralization. Depending on the specific form, HPP can be inherited in an autosomal recessive (among brothers and sisters) or autosomal dominant (multiple generations) manner.
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Overview of Hypophosphatasia. SummaryHypophosphatasia (HPP) is a rare genetic disorder characterized by impaired mineralization (“calcification”) of bones and teeth. Problems occur because mineralization is the process by which bones and teeth take up calcium and phosphorus required for proper hardness and strength.Defective mineralization results in bones that are soft and prone to fracture and deformity. Defective mineralization of teeth can lead to tooth loss. The specific symptoms of HPP are broad-ranging in severity, and can vary greatly from one person to another, sometimes even among affected members of the same family. There are six major clinical forms of HPP that range from an extremely severe “perinatal” (at birth) form that can cause stillbirth to a more common (“odonto”) form associated with only early loss of baby (deciduous) teeth, but no bone abnormalities. HPP is caused by changes (mutations) in the ALPL gene that produces an enzyme called tissue nonspecific alkaline phosphatase (TNSALP). Such mutations lead to low activity of this enzyme that should be breaking down a chemical called inorganic pyrophosphate that blocks mineralization. Depending on the specific form, HPP can be inherited in an autosomal recessive (among brothers and sisters) or autosomal dominant (multiple generations) manner.
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Symptoms of Hypophosphatasia
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HPP has remarkably wide-ranging severity. The six major clinical forms are separated based primarily upon the age when symptoms occur and the diagnosis is made. By decreasing severity, these forms are called perinatal, infantile, childhood (severe or mild), adult, and odontohypophosphatasia.Generally, HPP severity correlates with how much alkaline phosphatase activity remains in the body, with less enzyme activity causing more severe disease. Because HPP has broad-ranging severity, it is important to note that affected individuals rarely have all of the symptoms discussed below, and that every affected individual is essentially unique. Some children have severe complications early in life; others have mild disease that may improve during young adult life. Parents should talk to their child’s physician and medical team about the specific symptoms and what the future might hold.Perinatal HPP has very low alkaline phosphatase markedly blocking skeletal mineralization, including in the womb. Short, bowed arms and legs, underdeveloped ribs, and chest deformity are typical. Some pregnancies end in stillbirth. Some affected newborns survive for several days, but if untreated die from respiratory failure due to deformities and weakness of the chest.Prenatal benign HPP at birth is much less severe than perinatal HPP and features bowed limbs. Skeletal deformity can be identified by ultrasound studies during the pregnancy. In this form, the skeletal malformations improve gradually after birth, eventually with the signs and symptoms ranging from infantile HPP to odontohypophosphatasia.Infantile HPP may have no noticeable abnormalities at birth, but complications become apparent within the first six months of life. The initial problem may be the baby’s failure to gain weight and grow as expected, referred to as “failure to thrive.” Sometimes the skull bones fuse, called craniosynostosis, which can lead to a deformed head (brachycephaly). Craniosynostosis may also increase the pressure of the fluid (cerebrospinal fluid) that surrounds the brain, a condition known as “intracranial hypertension.” This can cause headaches and bulging of the eyes (proptosis), and be detected at the back of the eye by swelling of the optic disk (papilledema). Affected infants have softened, weakened and deformed bones consistent with rickets. Rickets is a general term for the complications due to defective skeletal mineralization during growth with softening of bone and characteristic bowing deformities. Widened bones at the wrists and ankles may occur. Affected infants often have chest and rib deformities and fractures, predisposing them to pneumonia. Varying degrees of pulmonary insufficiency and breathing difficulties may develop, sometimes progressing to life-threatening respiratory failure. Episodes of fever and painful and tender bones may occur. Diminished muscle tone (hypotonia) is characteristic, so that the baby appears “floppy”, sometimes caused by elevated levels of calcium in the blood (hypercalcemia) that may also cause vomiting, constipation, weakness, poor feeding, and kidney (renal) damage. Vitamin B6-dependent seizures may occur. Sometimes skeletal mineralization improves spontaneously during early childhood, but if untreated short stature and skeletal deformities may persist lifelong.Childhood HPP is highly variable, and severe and mild forms should be considered. Affected children sometimes develop craniosynostosis with intracranial hypertension. Skeletal malformations may become apparent at 2 to 3 years of age. Bone and joint pain may occur. Typically, one or more baby teeth fall out earlier than the fifth birthday. Some patients are weak with delayed walking, and then with a distinct, waddling gait. Sometimes spontaneous improvements occur in young adult life, but complications can recur during middle-age or late adult life.Adult HPP too has wide-ranging signs and symptoms. Affected men and women have “adult rickets” called “osteomalacia”, a softening of the bones in adults. Bone pain is common. Affected adults may experience loss of teeth. Some have a history of rickets during childhood, or baby teeth lost early.Fractures can occur, especially “stress fractures” in the feet early on, or subsequently “pseudofractures” in the thigh. Repeated fracturing can cause chronic pain and weakness. Spine fractures are less common. Joint inflammation and pain near or around certain joints due to the accumulation of calcium phosphate crystals (calcific periarthritis), or a condition called chondrocalcinosis within cartilage sometimes damages joints. Some affected individuals have sudden, severe arthritis called pseudogout. Odontohypophosphatasia features early loss of “baby” teeth in infancy or early childhood, or unexpected loss of teeth sometime in adulthood. Here, the dental problems are an isolated finding without the characteristic bone problems of other forms of HPP.Individuals with an extremely rare form of HPP called pseudohypophosphatasia have normal rather than low blood levels of alkaline phosphatase in the routine clinical laboratory.
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Symptoms of Hypophosphatasia. HPP has remarkably wide-ranging severity. The six major clinical forms are separated based primarily upon the age when symptoms occur and the diagnosis is made. By decreasing severity, these forms are called perinatal, infantile, childhood (severe or mild), adult, and odontohypophosphatasia.Generally, HPP severity correlates with how much alkaline phosphatase activity remains in the body, with less enzyme activity causing more severe disease. Because HPP has broad-ranging severity, it is important to note that affected individuals rarely have all of the symptoms discussed below, and that every affected individual is essentially unique. Some children have severe complications early in life; others have mild disease that may improve during young adult life. Parents should talk to their child’s physician and medical team about the specific symptoms and what the future might hold.Perinatal HPP has very low alkaline phosphatase markedly blocking skeletal mineralization, including in the womb. Short, bowed arms and legs, underdeveloped ribs, and chest deformity are typical. Some pregnancies end in stillbirth. Some affected newborns survive for several days, but if untreated die from respiratory failure due to deformities and weakness of the chest.Prenatal benign HPP at birth is much less severe than perinatal HPP and features bowed limbs. Skeletal deformity can be identified by ultrasound studies during the pregnancy. In this form, the skeletal malformations improve gradually after birth, eventually with the signs and symptoms ranging from infantile HPP to odontohypophosphatasia.Infantile HPP may have no noticeable abnormalities at birth, but complications become apparent within the first six months of life. The initial problem may be the baby’s failure to gain weight and grow as expected, referred to as “failure to thrive.” Sometimes the skull bones fuse, called craniosynostosis, which can lead to a deformed head (brachycephaly). Craniosynostosis may also increase the pressure of the fluid (cerebrospinal fluid) that surrounds the brain, a condition known as “intracranial hypertension.” This can cause headaches and bulging of the eyes (proptosis), and be detected at the back of the eye by swelling of the optic disk (papilledema). Affected infants have softened, weakened and deformed bones consistent with rickets. Rickets is a general term for the complications due to defective skeletal mineralization during growth with softening of bone and characteristic bowing deformities. Widened bones at the wrists and ankles may occur. Affected infants often have chest and rib deformities and fractures, predisposing them to pneumonia. Varying degrees of pulmonary insufficiency and breathing difficulties may develop, sometimes progressing to life-threatening respiratory failure. Episodes of fever and painful and tender bones may occur. Diminished muscle tone (hypotonia) is characteristic, so that the baby appears “floppy”, sometimes caused by elevated levels of calcium in the blood (hypercalcemia) that may also cause vomiting, constipation, weakness, poor feeding, and kidney (renal) damage. Vitamin B6-dependent seizures may occur. Sometimes skeletal mineralization improves spontaneously during early childhood, but if untreated short stature and skeletal deformities may persist lifelong.Childhood HPP is highly variable, and severe and mild forms should be considered. Affected children sometimes develop craniosynostosis with intracranial hypertension. Skeletal malformations may become apparent at 2 to 3 years of age. Bone and joint pain may occur. Typically, one or more baby teeth fall out earlier than the fifth birthday. Some patients are weak with delayed walking, and then with a distinct, waddling gait. Sometimes spontaneous improvements occur in young adult life, but complications can recur during middle-age or late adult life.Adult HPP too has wide-ranging signs and symptoms. Affected men and women have “adult rickets” called “osteomalacia”, a softening of the bones in adults. Bone pain is common. Affected adults may experience loss of teeth. Some have a history of rickets during childhood, or baby teeth lost early.Fractures can occur, especially “stress fractures” in the feet early on, or subsequently “pseudofractures” in the thigh. Repeated fracturing can cause chronic pain and weakness. Spine fractures are less common. Joint inflammation and pain near or around certain joints due to the accumulation of calcium phosphate crystals (calcific periarthritis), or a condition called chondrocalcinosis within cartilage sometimes damages joints. Some affected individuals have sudden, severe arthritis called pseudogout. Odontohypophosphatasia features early loss of “baby” teeth in infancy or early childhood, or unexpected loss of teeth sometime in adulthood. Here, the dental problems are an isolated finding without the characteristic bone problems of other forms of HPP.Individuals with an extremely rare form of HPP called pseudohypophosphatasia have normal rather than low blood levels of alkaline phosphatase in the routine clinical laboratory.
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Causes of Hypophosphatasia
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HPP is caused by mutations in the ALPL gene. This is the only gene that causes HPP. Genes provide instructions for making proteins that have an important function in the body. When a mutation occurs, the protein may be faulty, inefficient, or absent, as in HPP. Depending upon the protein’s function, one or more organ systems of the body can be compromised.The ALPL gene creates (encodes) a type of protein called an enzyme named TNSALP. Enzymes are specialized proteins that break down specific chemicals in the body. TNSALP is essential for the proper development and health of bones and teeth, and is abundant in the skeleton, liver, and kidneys. Mutations in the ALPL gene lower the activity of TNSALP, in turn leading to accumulation of phosphoethanolamine (PEA), pyridoxal 5’-phosphate (PLP), and inorganic pyrophosphate (PPi). Inorganic pyrophosphate is an inhibitor of mineralization that controls mineral entry into the skeleton. Elevated PPi levels can block calcium and phosphorus from entering bone, and thereby cause elevated levels of calcium in the blood and urine. Generally, the reduction of TNSALP enzyme activity correlates with HPP severity (less enzyme activity causes more severe disease).HPP can be inherited in an autosomal recessive (affecting siblings) or autosomal dominant (affecting multiple generations) manner. The perinatal and infantile forms of HPP are autosomal recessive. The childhood form can be either autosomal recessive or autosomal dominant. The adult form and odontohypophosphatasia typically are autosomal dominant disorders, but rarely autosomal recessive.Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a changed (mutated) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.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 Hypophosphatasia. HPP is caused by mutations in the ALPL gene. This is the only gene that causes HPP. Genes provide instructions for making proteins that have an important function in the body. When a mutation occurs, the protein may be faulty, inefficient, or absent, as in HPP. Depending upon the protein’s function, one or more organ systems of the body can be compromised.The ALPL gene creates (encodes) a type of protein called an enzyme named TNSALP. Enzymes are specialized proteins that break down specific chemicals in the body. TNSALP is essential for the proper development and health of bones and teeth, and is abundant in the skeleton, liver, and kidneys. Mutations in the ALPL gene lower the activity of TNSALP, in turn leading to accumulation of phosphoethanolamine (PEA), pyridoxal 5’-phosphate (PLP), and inorganic pyrophosphate (PPi). Inorganic pyrophosphate is an inhibitor of mineralization that controls mineral entry into the skeleton. Elevated PPi levels can block calcium and phosphorus from entering bone, and thereby cause elevated levels of calcium in the blood and urine. Generally, the reduction of TNSALP enzyme activity correlates with HPP severity (less enzyme activity causes more severe disease).HPP can be inherited in an autosomal recessive (affecting siblings) or autosomal dominant (affecting multiple generations) manner. The perinatal and infantile forms of HPP are autosomal recessive. The childhood form can be either autosomal recessive or autosomal dominant. The adult form and odontohypophosphatasia typically are autosomal dominant disorders, but rarely autosomal recessive.Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a changed (mutated) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.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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Affects of Hypophosphatasia
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HPP affects males and females in equal numbers. In Canada, severe HPP is estimated to occur in approximately 1 in 100,000 live births. The overall incidence and prevalence of the various forms of HPP is poorly understood or unknown. Milder cases can go undiagnosed or misdiagnosed. HPP occurs with greatest frequency in the Mennonite population in Canada, is relatively prevalent in Japan, and seems to be rare in individuals with Black ancestry.
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Affects of Hypophosphatasia. HPP affects males and females in equal numbers. In Canada, severe HPP is estimated to occur in approximately 1 in 100,000 live births. The overall incidence and prevalence of the various forms of HPP is poorly understood or unknown. Milder cases can go undiagnosed or misdiagnosed. HPP occurs with greatest frequency in the Mennonite population in Canada, is relatively prevalent in Japan, and seems to be rare in individuals with Black ancestry.
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Related disorders of Hypophosphatasia
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Other disorders can resemble HPP. Osteogenesis imperfecta (OI), also called “brittle bone disease”, is a group of rare disorders that together are more common than HPP. OI features bones that fracture easily from osteoporosis rather than rickets. OI may be mild or severe. As for HPP, the signs and symptoms and physical findings of OI vary greatly from affected person to person, even among individuals in the same family. Four main types of OI have been identified. OI type I is the most common and the mildest form. OI type II is the most severe. Most forms of OI are inherited as an autosomal dominant trait (For more information on this disorder, choose “osteogenesis imperfecta” as your search term in the Rare Disease Database.)Vitamin-D deficiency rickets, a disorder that often becomes apparent during infancy or early childhood, results from poor nutrition, a lack of exposure to sunshine, or malabsorption syndromes in which the intestines do not adequately absorb nutrients including vitamin D added to some foods. Vitamin D is needed for calcium and phosphorus uptake from the gut to then be deposited into the skeleton. Thus, adequate vitamin D is essential for proper bone development and growth. Vitamin D deficiency rickets features bone softening, slow growth, and muscle weakness. This disorder is more common than HPP in the United States and much more common in certain underprivileged areas worldwide (For more information on this disorder, choose “vitamin D deficiency rickets” as your search term in the Rare Disease Database.)Hypophosphatemia spelling looks like hypophosphatasia, but refers to low blood phosphate levels. X-linked hypophosphatemia (XLH) is the most common inherited form of rickets/osteomalacia, and characterized by inability of the kidneys to activate vitamin-D and to keep phosphate out of the urine and in the blood stream. Also, phosphate in food may not be absorbed well from the intestines. Low blood phosphate (hypophosphatemia) leads to rickets or osteomalacia. In early childhood, bowing deformities of the legs reflect softened bones. Growth is impaired, frequently resulting in short stature. In adults, there is osteomalacia. XLH is caused by mutations in the PHEX gene located on the X-chromosome (incidence approx. 1/25,000 births). However, rarer autosomal dominant and recessive forms of hypophosphatemia occur as well (For more information on this disorder, choose “familial hypophosphatemia” as your search term in the Rare Disease Database.)A wide variety of metabolic bone disorders and skeletal dysplasias have some symptoms similar to HPP (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Related disorders of Hypophosphatasia. Other disorders can resemble HPP. Osteogenesis imperfecta (OI), also called “brittle bone disease”, is a group of rare disorders that together are more common than HPP. OI features bones that fracture easily from osteoporosis rather than rickets. OI may be mild or severe. As for HPP, the signs and symptoms and physical findings of OI vary greatly from affected person to person, even among individuals in the same family. Four main types of OI have been identified. OI type I is the most common and the mildest form. OI type II is the most severe. Most forms of OI are inherited as an autosomal dominant trait (For more information on this disorder, choose “osteogenesis imperfecta” as your search term in the Rare Disease Database.)Vitamin-D deficiency rickets, a disorder that often becomes apparent during infancy or early childhood, results from poor nutrition, a lack of exposure to sunshine, or malabsorption syndromes in which the intestines do not adequately absorb nutrients including vitamin D added to some foods. Vitamin D is needed for calcium and phosphorus uptake from the gut to then be deposited into the skeleton. Thus, adequate vitamin D is essential for proper bone development and growth. Vitamin D deficiency rickets features bone softening, slow growth, and muscle weakness. This disorder is more common than HPP in the United States and much more common in certain underprivileged areas worldwide (For more information on this disorder, choose “vitamin D deficiency rickets” as your search term in the Rare Disease Database.)Hypophosphatemia spelling looks like hypophosphatasia, but refers to low blood phosphate levels. X-linked hypophosphatemia (XLH) is the most common inherited form of rickets/osteomalacia, and characterized by inability of the kidneys to activate vitamin-D and to keep phosphate out of the urine and in the blood stream. Also, phosphate in food may not be absorbed well from the intestines. Low blood phosphate (hypophosphatemia) leads to rickets or osteomalacia. In early childhood, bowing deformities of the legs reflect softened bones. Growth is impaired, frequently resulting in short stature. In adults, there is osteomalacia. XLH is caused by mutations in the PHEX gene located on the X-chromosome (incidence approx. 1/25,000 births). However, rarer autosomal dominant and recessive forms of hypophosphatemia occur as well (For more information on this disorder, choose “familial hypophosphatemia” as your search term in the Rare Disease Database.)A wide variety of metabolic bone disorders and skeletal dysplasias have some symptoms similar to HPP (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Diagnosis of Hypophosphatasia
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HPP is diagnosed by identifying its symptoms and complications beginning with a detailed patient history. HPP signs are revealed by a thorough clinical examination, and supported by routine x-rays and various laboratory tests including biochemical studies. HPP is often easy for physicians to identify for those familiar or experienced with this disorder. Understandably, however, most physicians have little or no knowledge of HPP. Consequently, affected individuals and families may face a frustrating delay in diagnosis. Now, genetic mutation analysis of the ALPL gene is available from commercial laboratories to support a diagnosis of HPP.Clinical Testing and Workup
HPP is sometimes first suspected from routine testing of blood that includes assay of alkaline phosphatase (ALP). Otherwise, signs and symptoms typically lead to routine testing and the low level of ALP stands out and is recognized. Individuals with HPP have reduced serum ALP activity for their age, except for extremely rare normal ALP levels in pseudohypophosphatasia. Identification of deficient ALP activity is consistent with HPP, but not diagnostic since a variety of other conditions can be the cause. Additionally, some individuals who are genetic “carriers” of HPP, but who do not develop any symptoms may also have low blood ALP levels.Importantly, serum ALP activity varies by age. Healthy children normally have higher ALP levels than healthy adults. If the laboratory doing the testing only gives the normal range for adults, a diagnosis of HPP in a child can be missed because his/her ALP activity will mistakenly considered “normal”.In the U.S. and elsewhere, a diagnosis of HPP can be supported, but not made, by measuring the blood level of the form of vitamin B6 called pyridoxal 5ʹ-phosphate (PLP). This test is performed by several commercial laboratories. Individuals with HPP have elevated levels because PLP is normally broken down by TNSALP. PLP is elevated even in mild HPP. However, some genetic carriers of HPP can have an elevated PLP. Blood and urine can be tested for increased amounts of phosphoethanolamine (PEA), another chemical normally broken down by TNSALP, yet some individuals with HPP have normal PEA levels and PEA elevations can occur in other metabolic bone diseases. Screening for elevated PLP is preferred over screening for elevated PEA because it is more sensitive, more precise and less expensive.In severe HPP, specifically the perinatal and infantile forms, x-ray studies involving the bones can reveal diagnostic changes of HPP. However, these changes may not be recognized as HPP except by radiologists familiar with HPP.Molecular genetic testing can support a diagnosis of HPP because it can detect mutations in the ALPL gene known to cause HPP, but it is only available as a diagnostic service at certain laboratories. The test can be expensive and often not necessary to diagnose HPP.
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Diagnosis of Hypophosphatasia. HPP is diagnosed by identifying its symptoms and complications beginning with a detailed patient history. HPP signs are revealed by a thorough clinical examination, and supported by routine x-rays and various laboratory tests including biochemical studies. HPP is often easy for physicians to identify for those familiar or experienced with this disorder. Understandably, however, most physicians have little or no knowledge of HPP. Consequently, affected individuals and families may face a frustrating delay in diagnosis. Now, genetic mutation analysis of the ALPL gene is available from commercial laboratories to support a diagnosis of HPP.Clinical Testing and Workup
HPP is sometimes first suspected from routine testing of blood that includes assay of alkaline phosphatase (ALP). Otherwise, signs and symptoms typically lead to routine testing and the low level of ALP stands out and is recognized. Individuals with HPP have reduced serum ALP activity for their age, except for extremely rare normal ALP levels in pseudohypophosphatasia. Identification of deficient ALP activity is consistent with HPP, but not diagnostic since a variety of other conditions can be the cause. Additionally, some individuals who are genetic “carriers” of HPP, but who do not develop any symptoms may also have low blood ALP levels.Importantly, serum ALP activity varies by age. Healthy children normally have higher ALP levels than healthy adults. If the laboratory doing the testing only gives the normal range for adults, a diagnosis of HPP in a child can be missed because his/her ALP activity will mistakenly considered “normal”.In the U.S. and elsewhere, a diagnosis of HPP can be supported, but not made, by measuring the blood level of the form of vitamin B6 called pyridoxal 5ʹ-phosphate (PLP). This test is performed by several commercial laboratories. Individuals with HPP have elevated levels because PLP is normally broken down by TNSALP. PLP is elevated even in mild HPP. However, some genetic carriers of HPP can have an elevated PLP. Blood and urine can be tested for increased amounts of phosphoethanolamine (PEA), another chemical normally broken down by TNSALP, yet some individuals with HPP have normal PEA levels and PEA elevations can occur in other metabolic bone diseases. Screening for elevated PLP is preferred over screening for elevated PEA because it is more sensitive, more precise and less expensive.In severe HPP, specifically the perinatal and infantile forms, x-ray studies involving the bones can reveal diagnostic changes of HPP. However, these changes may not be recognized as HPP except by radiologists familiar with HPP.Molecular genetic testing can support a diagnosis of HPP because it can detect mutations in the ALPL gene known to cause HPP, but it is only available as a diagnostic service at certain laboratories. The test can be expensive and often not necessary to diagnose HPP.
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Therapies of Hypophosphatasia
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In 2015, the U.S. Food and Drug Administration (FDA) approved asfotase alfa (Strensiq) as the first medical treatment for perinatal, infantile and juvenile-onset HPP. In the US, patients of any age with pediatric-onset HPP are eligible for this bone-targeted TNSALP replacement therapy given by subcutaneous injection.Supportive treatments for HPP are directed toward specific symptoms and complications. Treatment may require a team of specialists. Pediatricians, orthopedic surgeons, pedodontists, pain management specialists and other healthcare professionals may be needed for comprehensive treatment.Non-steroidal anti-inflammatory drugs (NSAIDs) may help bone and joint pain. NSAIDs require caution and monitoring for side effects (e.g. they can hurt the stomach and kidneys), especially in excess and if used too long. If craniosynostosis causes intracranial pressure, shunting or skull surgery may be necessary.Vitamin B6 can help to control specific seizures in severely affected babies. Those with elevated levels of calcium in the blood (hypercalcemia) may need dietary calcium restriction, hydration, certain diuretics, and perhaps injections of calcitonin.Regular dental care beginning early on is recommended. Physical and occupational therapy may be helpful.Adults with recurring long bone fractures may need orthopedic “rodding” where a metal rod is inserted within the center cavity of a long bone to increase stability and strength. Special medical devices (foot orthotics) may help foot (metatarsal) fractures.Patients should avoid bisphosphonates, a class of drugs used to treat other bone disorders such as osteoporosis. Bisphosphonates may worsen HPP or cause problems in individuals with undiagnosed HPP. Examples of bisphosphonate drugs are alendronate, ibandronate, pamidronate, risedronate and zolendronate.Genetic counseling may be helpful for affected individuals and their families. For children with HPP, psychosocial support for the entire family may be beneficial.
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Therapies of Hypophosphatasia. In 2015, the U.S. Food and Drug Administration (FDA) approved asfotase alfa (Strensiq) as the first medical treatment for perinatal, infantile and juvenile-onset HPP. In the US, patients of any age with pediatric-onset HPP are eligible for this bone-targeted TNSALP replacement therapy given by subcutaneous injection.Supportive treatments for HPP are directed toward specific symptoms and complications. Treatment may require a team of specialists. Pediatricians, orthopedic surgeons, pedodontists, pain management specialists and other healthcare professionals may be needed for comprehensive treatment.Non-steroidal anti-inflammatory drugs (NSAIDs) may help bone and joint pain. NSAIDs require caution and monitoring for side effects (e.g. they can hurt the stomach and kidneys), especially in excess and if used too long. If craniosynostosis causes intracranial pressure, shunting or skull surgery may be necessary.Vitamin B6 can help to control specific seizures in severely affected babies. Those with elevated levels of calcium in the blood (hypercalcemia) may need dietary calcium restriction, hydration, certain diuretics, and perhaps injections of calcitonin.Regular dental care beginning early on is recommended. Physical and occupational therapy may be helpful.Adults with recurring long bone fractures may need orthopedic “rodding” where a metal rod is inserted within the center cavity of a long bone to increase stability and strength. Special medical devices (foot orthotics) may help foot (metatarsal) fractures.Patients should avoid bisphosphonates, a class of drugs used to treat other bone disorders such as osteoporosis. Bisphosphonates may worsen HPP or cause problems in individuals with undiagnosed HPP. Examples of bisphosphonate drugs are alendronate, ibandronate, pamidronate, risedronate and zolendronate.Genetic counseling may be helpful for affected individuals and their families. For children with HPP, psychosocial support for the entire family may be beneficial.
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Overview of Hypoplastic Left Heart Syndrome
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Hypoplastic left heart syndrome is a term used to describe a group of closely related rare heart defects that are present at birth (congenital). The normal heart has four chambers. The two upper chambers, known as atria, are separated from each other by a fibrous partition known as the atrial septum. The two lower chambers are known as ventricles and are separated from each other by the ventricular septum. Valves connect the atria (left and right) to their respective ventricles. The valves allow for blood to be pumped through the chambers. Blood travels from the right ventricle through the pulmonary artery to the lungs where it receives oxygen. The blood returns to the heart through pulmonary veins and enters the left ventricle. The left ventricle sends the now oxygen-filled blood into the main artery of the body (aorta). The aorta sends the blood throughout the body.Hypoplastic left heart syndrome is characterized by the underdevelopment (hypoplasia) of the chambers on the left side of the heart (i.e., left atrium and ventricle). In addition, the mitral valve, which connects these chambers to each other, is usually abnormally narrow (stenosis) or closed (atresia) and the aortic valve, which connects the heart to the major vessels that lead from the lungs (ascending aorta), may also be narrow or closed. Infants with hypoplastic left heart syndrome also have an abnormally narrow ascending aorta.
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Overview of Hypoplastic Left Heart Syndrome. Hypoplastic left heart syndrome is a term used to describe a group of closely related rare heart defects that are present at birth (congenital). The normal heart has four chambers. The two upper chambers, known as atria, are separated from each other by a fibrous partition known as the atrial septum. The two lower chambers are known as ventricles and are separated from each other by the ventricular septum. Valves connect the atria (left and right) to their respective ventricles. The valves allow for blood to be pumped through the chambers. Blood travels from the right ventricle through the pulmonary artery to the lungs where it receives oxygen. The blood returns to the heart through pulmonary veins and enters the left ventricle. The left ventricle sends the now oxygen-filled blood into the main artery of the body (aorta). The aorta sends the blood throughout the body.Hypoplastic left heart syndrome is characterized by the underdevelopment (hypoplasia) of the chambers on the left side of the heart (i.e., left atrium and ventricle). In addition, the mitral valve, which connects these chambers to each other, is usually abnormally narrow (stenosis) or closed (atresia) and the aortic valve, which connects the heart to the major vessels that lead from the lungs (ascending aorta), may also be narrow or closed. Infants with hypoplastic left heart syndrome also have an abnormally narrow ascending aorta.
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Symptoms of Hypoplastic Left Heart Syndrome
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The symptoms of hypoplastic left heart syndrome are directly related to the underdevelopment of the left side of the heart and associated structures. In all cases, infants have impaired blood flow from the lungs, through the heart, and on to other parts of the body (systemic circulation). Symptoms may include difficulty breathing (dyspnea), a high-pitched noise while inhaling (rales), and grayish-blue discoloration of the skin (cyanosis) during the first 48 hours of life, which occurs because of low levels of circulating oxygen in the blood. Impaired blood flow characteristic of hypoplastic left heart syndrome results in fluid buildup in the heart, lung and various body tissues (congestive heart failure).Infants with hypoplastic left heart syndrome may accumulate excessive acids in their blood and other body tissues (metabolic acidosis). Symptoms may include poor feeding habits, frequent vomiting, lethargy, and/or shock. When shock occurs, the symptoms may include abnormally high pulse (tachycardia) and respiration rate, respiratory distress, abnormally enlarged liver (hepatomegaly), cool moist skin, abnormally low blood pressure, and/or paleness. In most cases, if left untreated, life-threatening complications usually occur.The progression and severity of hypoplastic left heart syndrome depend upon a structure called the ductus arteriosus, which is present in all newborns. The ductus arteriosus is a passageway that allows blood to travel from the right ventricle to the aorta and then throughout the body, bypassing the left side of the heart and the lungs. However, the ductus arteriosus closes shortly after birth forcing blood to travel through the malformed left ventricle resulting in impaired blood flow throughout the body.
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Symptoms of Hypoplastic Left Heart Syndrome. The symptoms of hypoplastic left heart syndrome are directly related to the underdevelopment of the left side of the heart and associated structures. In all cases, infants have impaired blood flow from the lungs, through the heart, and on to other parts of the body (systemic circulation). Symptoms may include difficulty breathing (dyspnea), a high-pitched noise while inhaling (rales), and grayish-blue discoloration of the skin (cyanosis) during the first 48 hours of life, which occurs because of low levels of circulating oxygen in the blood. Impaired blood flow characteristic of hypoplastic left heart syndrome results in fluid buildup in the heart, lung and various body tissues (congestive heart failure).Infants with hypoplastic left heart syndrome may accumulate excessive acids in their blood and other body tissues (metabolic acidosis). Symptoms may include poor feeding habits, frequent vomiting, lethargy, and/or shock. When shock occurs, the symptoms may include abnormally high pulse (tachycardia) and respiration rate, respiratory distress, abnormally enlarged liver (hepatomegaly), cool moist skin, abnormally low blood pressure, and/or paleness. In most cases, if left untreated, life-threatening complications usually occur.The progression and severity of hypoplastic left heart syndrome depend upon a structure called the ductus arteriosus, which is present in all newborns. The ductus arteriosus is a passageway that allows blood to travel from the right ventricle to the aorta and then throughout the body, bypassing the left side of the heart and the lungs. However, the ductus arteriosus closes shortly after birth forcing blood to travel through the malformed left ventricle resulting in impaired blood flow throughout the body.
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Causes of Hypoplastic Left Heart Syndrome
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The exact cause of most cases of hypoplastic left heart syndrome is not known. It occurs for no apparent reason (sporadically) in the majority of cases. Research suggests that the interaction of many genes and other environmental factors (multifactorial inheritance) may be responsible for hypoplastic left heart syndrome. In some cases, autosomal dominant and recessive inheritance has been suggested.In most cases, the malformations associated with hypoplastic left heart syndrome occur as a result of a developmental failure during early fetal (embryonic) growth. The reason that this occurs is not fully understood. Conditions that limit blood flow from the right to left atrium during fetal development may result in underdevelopment of the left heart. Such conditions may include premature closure of the foramen ovale and fetal heart muscle disease (cardiomyopathy).
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Causes of Hypoplastic Left Heart Syndrome. The exact cause of most cases of hypoplastic left heart syndrome is not known. It occurs for no apparent reason (sporadically) in the majority of cases. Research suggests that the interaction of many genes and other environmental factors (multifactorial inheritance) may be responsible for hypoplastic left heart syndrome. In some cases, autosomal dominant and recessive inheritance has been suggested.In most cases, the malformations associated with hypoplastic left heart syndrome occur as a result of a developmental failure during early fetal (embryonic) growth. The reason that this occurs is not fully understood. Conditions that limit blood flow from the right to left atrium during fetal development may result in underdevelopment of the left heart. Such conditions may include premature closure of the foramen ovale and fetal heart muscle disease (cardiomyopathy).
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Affects of Hypoplastic Left Heart Syndrome
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Hypoplastic left heart syndrome is a rare disorder that affects males (67 percent) more often than females. The estimated prevalence of the disorder is 1 in 100,000 live births. Hypoplastic left heart syndrome accounts for 7-9 percent of all congenital heart defects. The symptoms of this disorder are present at birth (congenital).
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Affects of Hypoplastic Left Heart Syndrome. Hypoplastic left heart syndrome is a rare disorder that affects males (67 percent) more often than females. The estimated prevalence of the disorder is 1 in 100,000 live births. Hypoplastic left heart syndrome accounts for 7-9 percent of all congenital heart defects. The symptoms of this disorder are present at birth (congenital).
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Related disorders of Hypoplastic Left Heart Syndrome
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Symptoms of the following disorders can be similar to those of Hypoplastic Left Heart Syndrome. Comparisons may be useful for a differential diagnosis:Atrioventricular Septal Defect is a rare heart defect that is present at birth (congenital) and is characterized by the improper development of the septa and valves (atrial and ventricular septa and atrioventricular valves). Infants with the complete form of Atrioventricular Septal Defect usually develop congestive heart failure. Excessive fluid also accumulates in other areas of the body, especially the lungs. Pulmonary congestion may lead to difficulty breathing (dyspnea). Other symptoms may include a bluish discoloration of the skin and mucous membranes (cyanosis), poor feeding, abnormally rapid breathing (tachypnea), excessive sweating, and/or an abnormally rapid heartbeat (tachycardia). (For more information on this disorder, choose “Atrioventricular Septal Defect” as your search term in the Rare Disease Database.)Atrial Septal Defects are common congenital heart defects characterized by the presence of a small opening between the two atria of the heart. This defect leads to an increase in the workload on the right heart, and excessive blood flow to the lungs. The symptoms, which may become apparent during infancy, childhood, or adulthood, can vary greatly and depend on the severity of the defect. The symptoms tend to be mild at first and may include difficulty breathing (dyspnea), increased susceptibility to respiratory infections, and/or an abnormal bluish discoloration of the skin and mucous membranes (cyanosis). Some people with Atrial Septal Defects may be at increased risk for the formation of blood clots that can travel to the major arteries (embolism), possibly blocking blood circulation. (For more information on this disorder, choose “Atrial Septal Defects” as your search term in the Rare Disease Database.)Ventricular Septal Defects (Cor Triloculare Biventricularis) are a group of common congenital heart defects characterized by the absence of one atrium. Infants with this defect have 2 ventricles and 1 large atrium. Symptoms of these defects may include an abnormally rapid rate of breathing (tachypnea), wheezing, a rapid heartbeat (tachycardia), and/or an abnormally enlarged liver (hepatomegaly). Ventricular Septal Defects can also cause the excessive accumulation of fluid around the heart leading to congestive heart failure. (For more information on this disorder, choose “Ventricular Septal Defects” as your search term in the Rare Disease Database.)Cor Triatriatum is an extremely rare congenital heart defect characterized by the presence of an extra chamber above the left atrium of the heart. The pulmonary veins, returning blood from the lungs, drain into this extra “third atrium.” The symptoms of Cor Triatriatum vary greatly and depend on the size of the opening between the chambers. Symptoms may include abnormally rapid breathing (tachypnea), wheezing, coughing, and/or abnormal accumulation of fluid in the lungs (pulmonary congestion). (For more information on this disorder, choose “Cor Triatriatum” as your search term in the Rare Disease Database.)Cor Triloculare Biatriatum is an extremely rare congenital heart defect characterized by the absence of one ventricle. Infants with this defect have two atria and one large ventricle. The symptoms are similar to those of Hypoplastic Left Heart Syndrome and may include breathing difficulties (dyspnea), excessive accumulation of fluid in the lungs and around the heart (pulmonary edema), and/or a bluish discoloration of the skin and mucous membranes (cyanosis). Other symptoms may include poor feeding habits, abnormally rapid breathing (tachypnea), and/or an abnormally rapid heartbeat (tachycardia).Mitral Valve Stenosis is a rare heart defect that may be present at birth (congenital) or acquired. In the congenital form, the symptoms vary greatly and may include coughing, difficulty breathing, heart palpitations, and/or frequent respiratory infections. In acquired Mitral Valve Stenosis, the symptoms may also include weakness, abdominal discomfort, chest pain angina), and/or periodic loss of consciousness.
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Related disorders of Hypoplastic Left Heart Syndrome. Symptoms of the following disorders can be similar to those of Hypoplastic Left Heart Syndrome. Comparisons may be useful for a differential diagnosis:Atrioventricular Septal Defect is a rare heart defect that is present at birth (congenital) and is characterized by the improper development of the septa and valves (atrial and ventricular septa and atrioventricular valves). Infants with the complete form of Atrioventricular Septal Defect usually develop congestive heart failure. Excessive fluid also accumulates in other areas of the body, especially the lungs. Pulmonary congestion may lead to difficulty breathing (dyspnea). Other symptoms may include a bluish discoloration of the skin and mucous membranes (cyanosis), poor feeding, abnormally rapid breathing (tachypnea), excessive sweating, and/or an abnormally rapid heartbeat (tachycardia). (For more information on this disorder, choose “Atrioventricular Septal Defect” as your search term in the Rare Disease Database.)Atrial Septal Defects are common congenital heart defects characterized by the presence of a small opening between the two atria of the heart. This defect leads to an increase in the workload on the right heart, and excessive blood flow to the lungs. The symptoms, which may become apparent during infancy, childhood, or adulthood, can vary greatly and depend on the severity of the defect. The symptoms tend to be mild at first and may include difficulty breathing (dyspnea), increased susceptibility to respiratory infections, and/or an abnormal bluish discoloration of the skin and mucous membranes (cyanosis). Some people with Atrial Septal Defects may be at increased risk for the formation of blood clots that can travel to the major arteries (embolism), possibly blocking blood circulation. (For more information on this disorder, choose “Atrial Septal Defects” as your search term in the Rare Disease Database.)Ventricular Septal Defects (Cor Triloculare Biventricularis) are a group of common congenital heart defects characterized by the absence of one atrium. Infants with this defect have 2 ventricles and 1 large atrium. Symptoms of these defects may include an abnormally rapid rate of breathing (tachypnea), wheezing, a rapid heartbeat (tachycardia), and/or an abnormally enlarged liver (hepatomegaly). Ventricular Septal Defects can also cause the excessive accumulation of fluid around the heart leading to congestive heart failure. (For more information on this disorder, choose “Ventricular Septal Defects” as your search term in the Rare Disease Database.)Cor Triatriatum is an extremely rare congenital heart defect characterized by the presence of an extra chamber above the left atrium of the heart. The pulmonary veins, returning blood from the lungs, drain into this extra “third atrium.” The symptoms of Cor Triatriatum vary greatly and depend on the size of the opening between the chambers. Symptoms may include abnormally rapid breathing (tachypnea), wheezing, coughing, and/or abnormal accumulation of fluid in the lungs (pulmonary congestion). (For more information on this disorder, choose “Cor Triatriatum” as your search term in the Rare Disease Database.)Cor Triloculare Biatriatum is an extremely rare congenital heart defect characterized by the absence of one ventricle. Infants with this defect have two atria and one large ventricle. The symptoms are similar to those of Hypoplastic Left Heart Syndrome and may include breathing difficulties (dyspnea), excessive accumulation of fluid in the lungs and around the heart (pulmonary edema), and/or a bluish discoloration of the skin and mucous membranes (cyanosis). Other symptoms may include poor feeding habits, abnormally rapid breathing (tachypnea), and/or an abnormally rapid heartbeat (tachycardia).Mitral Valve Stenosis is a rare heart defect that may be present at birth (congenital) or acquired. In the congenital form, the symptoms vary greatly and may include coughing, difficulty breathing, heart palpitations, and/or frequent respiratory infections. In acquired Mitral Valve Stenosis, the symptoms may also include weakness, abdominal discomfort, chest pain angina), and/or periodic loss of consciousness.
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Diagnosis of Hypoplastic Left Heart Syndrome
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The diagnosis of hypoplastic left heart syndrome is made based upon a thorough clinical evaluation, identification of characteristic findings and a variety of specialized tests. Such tests used to confirm hypoplastic left heart syndrome in newborns include x-ray examination and a special ultrasound test to study the structure and function of the heart (echocardiography).
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Diagnosis of Hypoplastic Left Heart Syndrome. The diagnosis of hypoplastic left heart syndrome is made based upon a thorough clinical evaluation, identification of characteristic findings and a variety of specialized tests. Such tests used to confirm hypoplastic left heart syndrome in newborns include x-ray examination and a special ultrasound test to study the structure and function of the heart (echocardiography).
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Therapies of Hypoplastic Left Heart Syndrome
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TreatmentTreatment of hypoplastic left heart syndrome is directed toward the maintenance of adequate oxygen levels in the blood. The intravenous administration of prostaglandin E-1 (PGE-1) may help to keep the ductus arteriosus open allowing blood flow to bypass the malformed left side of the heart.Eventually, infants with hypoplastic left heart syndrome require surgical intervention. In most cases, affected infants undergo a process that involves three separate surgical procedures (i.e., Norwood, hemi-Fontan, and Fontan procedures). The goal of this three-stage process is to separate systemic and pulmonary circulation. In some cases, affected infants have been treated by heart (cardiac) transplantation. A neonatal cardiologist is best qualified to give parents an opinion as to the type of treatment which best suits their child.Other medications to prevent and control congestive heart failure may also be administered including digoxin and various diuretics. Antibodies, such as amoxicillin, may be used to treat infection of the valves of the heart (endocarditis) that may occur after heart surgery. Genetic counseling may be of benefit for families with a child who has hypoplastic left heart syndrome. Other treatment is symptomatic and supportive.
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Therapies of Hypoplastic Left Heart Syndrome. TreatmentTreatment of hypoplastic left heart syndrome is directed toward the maintenance of adequate oxygen levels in the blood. The intravenous administration of prostaglandin E-1 (PGE-1) may help to keep the ductus arteriosus open allowing blood flow to bypass the malformed left side of the heart.Eventually, infants with hypoplastic left heart syndrome require surgical intervention. In most cases, affected infants undergo a process that involves three separate surgical procedures (i.e., Norwood, hemi-Fontan, and Fontan procedures). The goal of this three-stage process is to separate systemic and pulmonary circulation. In some cases, affected infants have been treated by heart (cardiac) transplantation. A neonatal cardiologist is best qualified to give parents an opinion as to the type of treatment which best suits their child.Other medications to prevent and control congestive heart failure may also be administered including digoxin and various diuretics. Antibodies, such as amoxicillin, may be used to treat infection of the valves of the heart (endocarditis) that may occur after heart surgery. Genetic counseling may be of benefit for families with a child who has hypoplastic left heart syndrome. Other treatment is symptomatic and supportive.
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Overview of Hypothalamic Hamartoma
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Hypothalamic hamartomas (HH) are rare, tumor-like malformations that occur during fetal development and are present at birth. They are non-progressive lesions and do not expand, spread or metastasize to other locations. They grow in proportion to normal brain growth, and consequently their relative size to the rest of the brain is the same for the lifetime of the patient. There is tremendous diversity in the type and severity of symptoms from patient to patient. However, symptoms are apparent during childhood in the overwhelming majority of patients. Two clinical phenotypes of HH are recognized: 1) central precocious puberty and 2) epilepsy and related neurobehavioral symptoms.For those with central precocious puberty only, symptoms may occur as early as 1-3 years of age. These patients present with precocious (abnormally early) development of the physical changes associated with puberty. Neurological problems, such as epilepsy, are usually absent. Magnetic resonance (MR) imaging on patients with central precocious puberty typically shows attachment of the HH lesion in an anterior location in the hypothalamus, in the region of the tuber cinereum or pituitary stalk.For those with epilepsy, gelastic (laughing) seizures are usually the first symptom, often during infancy. Associated symptoms can include developmental delay, cognitive deterioration, and psychiatric symptoms such as rage behaviors. MR imaging on patients with epilepsy typically shows attachment of the HH in a posterior location in the hypothalamus, in the region of the mammillary bodies. Approximately 40% of HH patients with epilepsy also have precocious puberty. These patients tend to have large lesions, which are broadly attached both anteriorly and posteriorly in the hypothalamus.Anti-epilepsy medications usually do not control the gelastic seizures associated with HH, and seizures often worsen with additional seizures types that begin around 4-7 years of age. Cognitive deficits and psychiatric symptoms may also present at this time.For some patients, HH can be a progressively disabling condition. For others, symptoms may be stable and represent little or no disability.Patients with precocious puberty can usually be treated successfully with medications, specifically with a class of drugs known as gonadotropin-releasing hormone agonists. Medications, specifically anti-epilepsy drugs (AEDs) are less successful for controlling the seizures associated with HH, and therefore surgical treatment is often required. There has been rapid progress over the past 15 years on developing various surgical approaches for treating HH. The selection of the most appropriate surgical technique is individualized to the clinical symptoms and HH anatomy of each patient.
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Overview of Hypothalamic Hamartoma. Hypothalamic hamartomas (HH) are rare, tumor-like malformations that occur during fetal development and are present at birth. They are non-progressive lesions and do not expand, spread or metastasize to other locations. They grow in proportion to normal brain growth, and consequently their relative size to the rest of the brain is the same for the lifetime of the patient. There is tremendous diversity in the type and severity of symptoms from patient to patient. However, symptoms are apparent during childhood in the overwhelming majority of patients. Two clinical phenotypes of HH are recognized: 1) central precocious puberty and 2) epilepsy and related neurobehavioral symptoms.For those with central precocious puberty only, symptoms may occur as early as 1-3 years of age. These patients present with precocious (abnormally early) development of the physical changes associated with puberty. Neurological problems, such as epilepsy, are usually absent. Magnetic resonance (MR) imaging on patients with central precocious puberty typically shows attachment of the HH lesion in an anterior location in the hypothalamus, in the region of the tuber cinereum or pituitary stalk.For those with epilepsy, gelastic (laughing) seizures are usually the first symptom, often during infancy. Associated symptoms can include developmental delay, cognitive deterioration, and psychiatric symptoms such as rage behaviors. MR imaging on patients with epilepsy typically shows attachment of the HH in a posterior location in the hypothalamus, in the region of the mammillary bodies. Approximately 40% of HH patients with epilepsy also have precocious puberty. These patients tend to have large lesions, which are broadly attached both anteriorly and posteriorly in the hypothalamus.Anti-epilepsy medications usually do not control the gelastic seizures associated with HH, and seizures often worsen with additional seizures types that begin around 4-7 years of age. Cognitive deficits and psychiatric symptoms may also present at this time.For some patients, HH can be a progressively disabling condition. For others, symptoms may be stable and represent little or no disability.Patients with precocious puberty can usually be treated successfully with medications, specifically with a class of drugs known as gonadotropin-releasing hormone agonists. Medications, specifically anti-epilepsy drugs (AEDs) are less successful for controlling the seizures associated with HH, and therefore surgical treatment is often required. There has been rapid progress over the past 15 years on developing various surgical approaches for treating HH. The selection of the most appropriate surgical technique is individualized to the clinical symptoms and HH anatomy of each patient.
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Symptoms of Hypothalamic Hamartoma
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Central precocious puberty (CPP) is one of the hallmark clinical syndromes associated with HH. Puberty is abnormally early if it occurs prior to the age of 8 years in girls or 9 years in boys. “Central” indicates that the disease process responsible for triggering puberty at an abnormally early age involves the brain, with premature pulsatile release of gonadotropin-releasing hormone (GnRH) which in turn signals the ovaries or testes to begin production of sex hormones (estrogen and progesterone in females and testosterone in males).Central precocious puberty has many causes, and requires evaluation by a pediatric endocrinologist to identify and treat the underlying etiology. Hypothalamic hamartoma is one of the most important causes and is notable in that puberty associated with HH can occur at particularly early ages, even prior to 12 months of age in some patients. The health consequences of abnormally early puberty include short stature and problems with age-appropriate psychosocial adjustment.For girls, physical signs associated with CPP include breast development and the appearance of mature-appearing pubic and axillary hair. For untreated girls, menses (first menstrual bleeding) will follow. For boys, physical signs begin with testicular growth, followed by enlargement of the penis and maturation of the scrotum, with the development of pubic and axillary hair. Associated features include deepening of the voice and acne.For patients with epilepsy and neurological symptoms, there is a great deal of variability with respect to the age of onset, severity and changes over time. This clinical diversity must be borne in mind when considering the diagnosis of HH, and are equally important when considering treatment options, including the timing of surgical intervention.Gelastic seizures are the most characteristic symptom associated with HH. Superficially resembling laughter, they have a peculiar appearance that usually differs from true laughter, and most family members can readily distinguish between the two. Not uncommonly, patients may have seizures that more closely resemble crying rather than laughter (known dacrystic seizures). Gelastic seizures can be quite subtle, and may be mistaken for other conditions, particularly during infancy, including colic and gastroesophageal reflux disease (GERD).They are brief, sometimes just a few seconds, and usually less than 30 seconds in duration. They can be very frequent, however, with multiple seizures per day, and even multiple seizures per hour in more severely affected patients. Gelastic seizures may or may not be associated with altered consciousness (altered awareness of the event). However, making this determination in infants and young children can be challenging.Gelastic seizures associated with HH usually begin at an early age, and are usually the first seizure type. The correct diagnosis can be delayed by the unusual nature of this seizure. However, in retrospect, parents can identify the onset of these peculiar laughing spells at a very early age. In a series of patients with HH and epilepsy, the mean age of onset for gelastic seizures is 10.8 months, and 75% of all patients had onset before one year of age. Gelastic seizures become less frequent after 10 years of age, and may disappear entirely as other seizure types develop. Uncommonly, patients with HH may not develop gelastic seizures until adolescence or early adulthood.Other seizure types that are more disabling to the patient develop in approximately 75% of children with HH and gelastic seizures, most commonly between 4-7 years of age. Virtually all possible types of seizures have been reported, and individual patients may have multiple active seizure types, including focal (localization-related) and generalized seizures.Cognitive deficits are evident in the majority of patients with HH and epilepsy. Difficulties with processing speed and short-term memory are most common. Here again, there is significant diversity from patient to patient. Recent studies with neuropsychological testing in HH patients undergoing evaluation for surgical treatment show approximately 50% have intellectual disability (full-scale intelligence quotient [IQ] less than 70). Factors contributing to a greater degree of cognitive impairment include 1) higher number of anti-epilepsy medications taken at the time of testing, 2) larger HH lesion size, 3) younger age of seizure onset, and 4) higher seizure frequency. Conversely, patients with HH and central precocious puberty without epilepsy typically do not have developmental or cognitive deficits.Behavioral and psychiatric symptoms are also common in the group of patients with HH and epilepsy. Episodes of behavioral aggression associated with poor frustration tolerance, often described as rage attacks, are particularly problematic and are a hallmark symptom of HH. Rage attacks are usually reactive to external (often minor) stimuli, and consist of explosive anger. These behaviors can be the most disabling feature of the disease for some patients. There is a greater likelihood of rage behaviors with 1) male gender, 2) the presence of intellectual disability, 3) younger age at the time of first seizure, and 4) multiple seizure types (rather than only gelastic seizures).Psychiatric symptoms are reported in over 80% of children and adults with HH and epilepsy. A wide range of symptom types, symptom severity and psychiatric diagnoses can be involved. In children with HH, these include oppositional-defiant disorder (83%), attention-deficit/hyperactivity disorder (75%), conduct disorder (33%) and mood disorder (17%), which are far more common in affected patients compared to their unaffected siblings.Roughly half of children with HH and epilepsy experience deterioration (worsening) of their symptoms over time, with a decline in cognitive functioning and worsening of behavioral symptoms. Worsening seizures, cognitive decline, and behavioral deterioration often occur simultaneously, and probably share a biological link. HH appears to be a clinical model for epileptic encephalopathy, although the basic mechanisms responsible for the deterioration experienced by these patients are poorly understood.
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Symptoms of Hypothalamic Hamartoma. Central precocious puberty (CPP) is one of the hallmark clinical syndromes associated with HH. Puberty is abnormally early if it occurs prior to the age of 8 years in girls or 9 years in boys. “Central” indicates that the disease process responsible for triggering puberty at an abnormally early age involves the brain, with premature pulsatile release of gonadotropin-releasing hormone (GnRH) which in turn signals the ovaries or testes to begin production of sex hormones (estrogen and progesterone in females and testosterone in males).Central precocious puberty has many causes, and requires evaluation by a pediatric endocrinologist to identify and treat the underlying etiology. Hypothalamic hamartoma is one of the most important causes and is notable in that puberty associated with HH can occur at particularly early ages, even prior to 12 months of age in some patients. The health consequences of abnormally early puberty include short stature and problems with age-appropriate psychosocial adjustment.For girls, physical signs associated with CPP include breast development and the appearance of mature-appearing pubic and axillary hair. For untreated girls, menses (first menstrual bleeding) will follow. For boys, physical signs begin with testicular growth, followed by enlargement of the penis and maturation of the scrotum, with the development of pubic and axillary hair. Associated features include deepening of the voice and acne.For patients with epilepsy and neurological symptoms, there is a great deal of variability with respect to the age of onset, severity and changes over time. This clinical diversity must be borne in mind when considering the diagnosis of HH, and are equally important when considering treatment options, including the timing of surgical intervention.Gelastic seizures are the most characteristic symptom associated with HH. Superficially resembling laughter, they have a peculiar appearance that usually differs from true laughter, and most family members can readily distinguish between the two. Not uncommonly, patients may have seizures that more closely resemble crying rather than laughter (known dacrystic seizures). Gelastic seizures can be quite subtle, and may be mistaken for other conditions, particularly during infancy, including colic and gastroesophageal reflux disease (GERD).They are brief, sometimes just a few seconds, and usually less than 30 seconds in duration. They can be very frequent, however, with multiple seizures per day, and even multiple seizures per hour in more severely affected patients. Gelastic seizures may or may not be associated with altered consciousness (altered awareness of the event). However, making this determination in infants and young children can be challenging.Gelastic seizures associated with HH usually begin at an early age, and are usually the first seizure type. The correct diagnosis can be delayed by the unusual nature of this seizure. However, in retrospect, parents can identify the onset of these peculiar laughing spells at a very early age. In a series of patients with HH and epilepsy, the mean age of onset for gelastic seizures is 10.8 months, and 75% of all patients had onset before one year of age. Gelastic seizures become less frequent after 10 years of age, and may disappear entirely as other seizure types develop. Uncommonly, patients with HH may not develop gelastic seizures until adolescence or early adulthood.Other seizure types that are more disabling to the patient develop in approximately 75% of children with HH and gelastic seizures, most commonly between 4-7 years of age. Virtually all possible types of seizures have been reported, and individual patients may have multiple active seizure types, including focal (localization-related) and generalized seizures.Cognitive deficits are evident in the majority of patients with HH and epilepsy. Difficulties with processing speed and short-term memory are most common. Here again, there is significant diversity from patient to patient. Recent studies with neuropsychological testing in HH patients undergoing evaluation for surgical treatment show approximately 50% have intellectual disability (full-scale intelligence quotient [IQ] less than 70). Factors contributing to a greater degree of cognitive impairment include 1) higher number of anti-epilepsy medications taken at the time of testing, 2) larger HH lesion size, 3) younger age of seizure onset, and 4) higher seizure frequency. Conversely, patients with HH and central precocious puberty without epilepsy typically do not have developmental or cognitive deficits.Behavioral and psychiatric symptoms are also common in the group of patients with HH and epilepsy. Episodes of behavioral aggression associated with poor frustration tolerance, often described as rage attacks, are particularly problematic and are a hallmark symptom of HH. Rage attacks are usually reactive to external (often minor) stimuli, and consist of explosive anger. These behaviors can be the most disabling feature of the disease for some patients. There is a greater likelihood of rage behaviors with 1) male gender, 2) the presence of intellectual disability, 3) younger age at the time of first seizure, and 4) multiple seizure types (rather than only gelastic seizures).Psychiatric symptoms are reported in over 80% of children and adults with HH and epilepsy. A wide range of symptom types, symptom severity and psychiatric diagnoses can be involved. In children with HH, these include oppositional-defiant disorder (83%), attention-deficit/hyperactivity disorder (75%), conduct disorder (33%) and mood disorder (17%), which are far more common in affected patients compared to their unaffected siblings.Roughly half of children with HH and epilepsy experience deterioration (worsening) of their symptoms over time, with a decline in cognitive functioning and worsening of behavioral symptoms. Worsening seizures, cognitive decline, and behavioral deterioration often occur simultaneously, and probably share a biological link. HH appears to be a clinical model for epileptic encephalopathy, although the basic mechanisms responsible for the deterioration experienced by these patients are poorly understood.
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Hypothalamic Hamartoma
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Causes of Hypothalamic Hamartoma
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The underlying cause for hypothalamic hamartomas remains unknown. Over 95% of cases are sporadic (that is, there is no prior family history and the identified patient remains the only affected individual in the family). A defect in factors that regulate fetal development of the hypothalamus is most likely.However, HH can also occur in patients with identified genetic disorders. Of these, Pallister-Hall syndrome accounts for the majority. This is a rare dysmorphology syndrome that can include HH, deformities of the hands and feet (postaxial polydactyly and syndactyly), abnormalities of the larynx (bifid epiglottis), imperforate anus, and others. Pallister-Hall syndrome is known to be associated with a genetic mutation in the GLI3 gene, which acts as a transcription factor (a regulator protein for turning on and off gene expression) in the sonic hedgehog intracellular signaling pathway. This is a genomic (or genome-wide) mutation, which is to say, a mutation present in every cell in the body. (For further information, choose “Pallister-Hall” as your search term in the Rare Disease Database.)Knowing that Pallister-Hall syndrome is due to a mutation in GLI3, researchers have examined the possibility that a somatic (tumor-only) mutation of GLI3 is responsible for sporadic HH cases. Using tissue removed at surgery, it has been discovered that up to 25% of patients have a somatic mutation of GLI3 in HH tissue. More recently, advanced genotyping has shown that several other genes within the sonic hedgehog pathway can also have somatic mutations that result in HH. With current (2017) genotyping technology, somatic mutations can be identified in approximately 40% of HH lesions. It is also likely that other, as yet unidentified mutations in other genes can be responsible. At this time, mutation analysis (genotyping) of HH lesions is not recommended for routine clinical care of patients with HH.
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Causes of Hypothalamic Hamartoma. The underlying cause for hypothalamic hamartomas remains unknown. Over 95% of cases are sporadic (that is, there is no prior family history and the identified patient remains the only affected individual in the family). A defect in factors that regulate fetal development of the hypothalamus is most likely.However, HH can also occur in patients with identified genetic disorders. Of these, Pallister-Hall syndrome accounts for the majority. This is a rare dysmorphology syndrome that can include HH, deformities of the hands and feet (postaxial polydactyly and syndactyly), abnormalities of the larynx (bifid epiglottis), imperforate anus, and others. Pallister-Hall syndrome is known to be associated with a genetic mutation in the GLI3 gene, which acts as a transcription factor (a regulator protein for turning on and off gene expression) in the sonic hedgehog intracellular signaling pathway. This is a genomic (or genome-wide) mutation, which is to say, a mutation present in every cell in the body. (For further information, choose “Pallister-Hall” as your search term in the Rare Disease Database.)Knowing that Pallister-Hall syndrome is due to a mutation in GLI3, researchers have examined the possibility that a somatic (tumor-only) mutation of GLI3 is responsible for sporadic HH cases. Using tissue removed at surgery, it has been discovered that up to 25% of patients have a somatic mutation of GLI3 in HH tissue. More recently, advanced genotyping has shown that several other genes within the sonic hedgehog pathway can also have somatic mutations that result in HH. With current (2017) genotyping technology, somatic mutations can be identified in approximately 40% of HH lesions. It is also likely that other, as yet unidentified mutations in other genes can be responsible. At this time, mutation analysis (genotyping) of HH lesions is not recommended for routine clinical care of patients with HH.
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Hypothalamic Hamartoma
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nord_619_3
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Affects of Hypothalamic Hamartoma
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Hypothalamic hamartomas are relatively rare. Population-based research has shown that HH with epilepsy occurs in 1 of 200,000 children and adolescents. The prevalence of HH with only precocious puberty is unknown. At least for HH with epilepsy, males appear to have a slightly higher risk than females (approximately 1.3 to 1 ratio). HH occurs worldwide, without any obvious geographical concentration of cases. It is currently felt that all ethnic groups are at equal risk. There are no identified maternal risk factors or fetal exposures that increase the risk of HH.
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Affects of Hypothalamic Hamartoma. Hypothalamic hamartomas are relatively rare. Population-based research has shown that HH with epilepsy occurs in 1 of 200,000 children and adolescents. The prevalence of HH with only precocious puberty is unknown. At least for HH with epilepsy, males appear to have a slightly higher risk than females (approximately 1.3 to 1 ratio). HH occurs worldwide, without any obvious geographical concentration of cases. It is currently felt that all ethnic groups are at equal risk. There are no identified maternal risk factors or fetal exposures that increase the risk of HH.
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Hypothalamic Hamartoma
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nord_619_4
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Related disorders of Hypothalamic Hamartoma
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As malformations of the ventral (inferior) hypothalamus, hypothalamic hamartomas are rather distinct from other conditions. It is important to note that tumors that occur in the same region (such as craniopharyngiomas, astrocytomas, optic nerve gliomas, etc) usually do not cause gelastic seizures. These tumors can, however, be associated with endocrine dysfunction, which includes precocious puberty under rare circumstances.
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Related disorders of Hypothalamic Hamartoma. As malformations of the ventral (inferior) hypothalamus, hypothalamic hamartomas are rather distinct from other conditions. It is important to note that tumors that occur in the same region (such as craniopharyngiomas, astrocytomas, optic nerve gliomas, etc) usually do not cause gelastic seizures. These tumors can, however, be associated with endocrine dysfunction, which includes precocious puberty under rare circumstances.
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Hypothalamic Hamartoma
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nord_619_5
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Diagnosis of Hypothalamic Hamartoma
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Brain imaging with magnetic resonance (MR) techniques is the single most important diagnostic test. MR imaging is sufficient to establish (or exclude) the diagnosis of HH. However, there are important considerations to imaging for HH. Imaging must be technically adequate to permit detailed visualization of the hypothalamus. Movement artifact resulting from restlessness of the patient within the scanner can obscure small HH lesions. Accordingly, for children or other patients with limited cooperation, a sedated study is recommended. Additionally, the choice of specific MR imaging sequences is also important. A coronal T2 fast spin echo (FSE) sequence is recommended, with thin slices and no gap or space between slices. Lastly, the radiologist should be informed that HH is one of the clinical conditions under consideration, so as to include careful inspection of that region of the brain. Most patients (over 90%) have normal brain findings on MR imaging aside from the HH. A small number of patients may have additional abnormalities, such as malformations of cortical development.Computed tomography (CT) imaging is not adequate for detecting small HH lesions, and has the added disadvantage of radiation exposure.Physical signs of precocious puberty require evaluation by an endocrinologist. The hypothalamus and pituitary together produce a number of different hormones, including the reproductive hormones responsible for puberty. Consequently, evaluation of patients with HH should include testing for other factors such as thyroid, adrenal, and growth-related hormones.Electroencephalography (EEG) testing is routinely performed in patients with epileptic seizures or suspected epileptic seizures, and can be useful in evaluating patients with HH and epilepsy. However, for HH patients the EEG results may be normal, particularly at younger ages when gelastic seizures are the only seizure type. This includes video-EEG monitoring that captures gelastic seizures. That is, the EEG may show no change even during the actual gelastic seizure event. This is due to the fact that gelastic seizures arise in the HH, and as a structure located deep at the base of the brain, it is distant from EEG electrodes on the scalp. This can lead to incorrect diagnoses.EEG studies can show abnormal results, particularly in older patients who have developed other types of seizures. A wide variety of findings is possible, and can suggest either focal or generalized disturbances. Consultation with a neurologist experienced with evaluating patients with HH and epilepsy is recommended whenever possible. This expertise is usually available at regional epilepsy referral centers.Neuropsychological testing can be an important tool for patient management, particularly those with HH and epilepsy. These patients are “at-risk” for developmental and cognitive deficits. For some patients, these difficulties may be progressive, with deterioration or worsening in their level of function. Neuropsychological testing can help define the pattern of functioning (i.e., strengths and weaknesses) in the various skills of higher brain functioning (such as memory, language, problem-solving, etc). This can help with adaptive therapies and provides a baseline for those patients who may be declining. Additionally, neuropsychological testing is very important for those undergoing surgical intervention in order to clarify changes (for either the better or worse) that may accompany surgical treatment.
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Diagnosis of Hypothalamic Hamartoma. Brain imaging with magnetic resonance (MR) techniques is the single most important diagnostic test. MR imaging is sufficient to establish (or exclude) the diagnosis of HH. However, there are important considerations to imaging for HH. Imaging must be technically adequate to permit detailed visualization of the hypothalamus. Movement artifact resulting from restlessness of the patient within the scanner can obscure small HH lesions. Accordingly, for children or other patients with limited cooperation, a sedated study is recommended. Additionally, the choice of specific MR imaging sequences is also important. A coronal T2 fast spin echo (FSE) sequence is recommended, with thin slices and no gap or space between slices. Lastly, the radiologist should be informed that HH is one of the clinical conditions under consideration, so as to include careful inspection of that region of the brain. Most patients (over 90%) have normal brain findings on MR imaging aside from the HH. A small number of patients may have additional abnormalities, such as malformations of cortical development.Computed tomography (CT) imaging is not adequate for detecting small HH lesions, and has the added disadvantage of radiation exposure.Physical signs of precocious puberty require evaluation by an endocrinologist. The hypothalamus and pituitary together produce a number of different hormones, including the reproductive hormones responsible for puberty. Consequently, evaluation of patients with HH should include testing for other factors such as thyroid, adrenal, and growth-related hormones.Electroencephalography (EEG) testing is routinely performed in patients with epileptic seizures or suspected epileptic seizures, and can be useful in evaluating patients with HH and epilepsy. However, for HH patients the EEG results may be normal, particularly at younger ages when gelastic seizures are the only seizure type. This includes video-EEG monitoring that captures gelastic seizures. That is, the EEG may show no change even during the actual gelastic seizure event. This is due to the fact that gelastic seizures arise in the HH, and as a structure located deep at the base of the brain, it is distant from EEG electrodes on the scalp. This can lead to incorrect diagnoses.EEG studies can show abnormal results, particularly in older patients who have developed other types of seizures. A wide variety of findings is possible, and can suggest either focal or generalized disturbances. Consultation with a neurologist experienced with evaluating patients with HH and epilepsy is recommended whenever possible. This expertise is usually available at regional epilepsy referral centers.Neuropsychological testing can be an important tool for patient management, particularly those with HH and epilepsy. These patients are “at-risk” for developmental and cognitive deficits. For some patients, these difficulties may be progressive, with deterioration or worsening in their level of function. Neuropsychological testing can help define the pattern of functioning (i.e., strengths and weaknesses) in the various skills of higher brain functioning (such as memory, language, problem-solving, etc). This can help with adaptive therapies and provides a baseline for those patients who may be declining. Additionally, neuropsychological testing is very important for those undergoing surgical intervention in order to clarify changes (for either the better or worse) that may accompany surgical treatment.
| 619 |
Hypothalamic Hamartoma
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nord_619_6
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Therapies of Hypothalamic Hamartoma
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Treatment
Central precocious puberty (CPP) can usually be treated successfully with medication. Surgery is not required for most patients with CPP. Effective treatment consists of administration of gonadotropin-releasing hormone (GnRH) agonists, such as leuprolide acetate [Lupron], which have the effect of feedback inhibition of the pulsatile (pulse-like) release of GnRH that is required to trigger puberty. Leuprolide acetate is customarily administered as a once-monthly intramuscular injection for the duration of time that puberty needs to be suppressed. Once discontinued, puberty occurs normally. Long-term follow-up studies for HH patients with a history of successfully treated CPP show that normal adult height and normal reproductive function are expected.Treatment options that avoid once-monthly injections have also been developed. Consultation with a pediatric endocrinologist experienced in the treatment of CPP is important to review the treatment options and for discussion of possible side effects.Gelastic seizures usually do not respond to anti-epilepsy drugs (AEDs). Exceptions to this appear to be rare. Additionally, while the other seizure types that occur later in childhood may be helped with AED therapy, it is unlikely that these seizures will be completely controlled with AEDs (“treatment-resistant”). Consequently, surgical treatment is usually required, as discussed below.The timing of surgical intervention (including gamma knife radiosurgery) is a major decision point facing the patient, family and doctor. Surgical intervention carries the risk of complications and should not be performed until the degree of clinical severity calls for it. For example, relatively brief and infrequent gelastic seizures are usually not significantly disabling. If the child is making good developmental progress, a decision to withhold surgical intervention may be appropriate. However, under these circumstances, the clinical course needs to be observed carefully for any adverse changes in symptoms, such as worsening of seizures, slowing of developmental progress, or emergence of psychiatric symptoms.However, our current understanding of epilepsy associated with HH also argues against excessive delay in surgical treatment, since it appears that some patients undergo a process known as secondary epileptogenesis, in which uncontrolled seizures from the original location can provoke a process by which seizures begin to arise from a second, distant location elsewhere in the brain. When this occurs (a process that is likely to occur over a period of years rather than months) then surgery removing the HH lesion may be less successful for completely controlling seizures. Outcome studies of surgery for HH associated with epilepsy have shown that success in controlling seizures is inversely related to the patent’s age. That is, older patients are less likely to gain complete seizure control. A recent research study on HH patients undergoing surgery has also shown that a higher likelihood of cognitive improvement after surgery correlates with younger age at the time of surgery. Gelastic seizures begin in the HH lesion and removing (or otherwise damaging or ablating) the HH can cure seizures. Until recently, HH with epilepsy was considered not treatable, since surgery on the hypothalamus was too dangerous. However, since 2000, several different treatment approaches have been developed that are recognized as effective and safe. These treatment decisions (selecting one of several surgical options including radiosurgery) are highly individualized to the unique circumstances of each patient. This includes an assessment of their clinical course and symptoms, but also the exact anatomy of their HH lesion. Consequently, consultation at a referral center that specializes in the treatment of HH is highly recommended.A brief discussion of each of these treatment modalities follows. The relative merits of any of these therapies for an individual patient require consultation with a specialist in the field of HH treatment.Gamma Knife Radiosurgery. Gamma Knife Radiosurgery (GKR) is a relatively non-invasive radiosurgical technique in which a stereotactic frame is temporarily attached to the patient’s head along with a helmet-like device with multiple radiation entry ports. These ports are aligned (targeted) so that multiple beams of radiation are delivered to converge upon the selected target, injuring this tissue, but delivering doses well below the threshold for tissue injury to the rest of the brain. The safety profile for GKR is excellent relative to surgical resection. A small number of patients have transient temperature irregularities following treatment or experience a temporary increase in seizure frequency several weeks after treatment. The biggest disadvantage to GKR is that the therapeutic effect is delayed, typically 6-18 months, but sometimes up to 2-3 years following treatment. This therapy is most appropriate for patients who are clinically stable with respect to their seizures and other symptoms, and can tolerate waiting for effectiveness. Currently published data suggests that 40% of patients treated with GKR will be completely free of seizures upon long-term follow-up.Stereotactic Thermoablation (with or without intraoperative MR thermography). Thermoablation involves image-guided stereotactic placement of thin probes into the HH and then heating the lesion to approximately 60°C, injuring the tissue and eradicating its ability to generate seizures. When effective, this therapy works immediately. Multiple passes of the probe into the brain may be required to treat the entire lesion, depending upon its size.There are two technologies that can be utilized for HH thermoablation treatment. Radiofrequency thermoablation can be successful for complete seizure control in up to 71% of patients (32% of these patients required more than one treatment). The safety profile appears favorable in comparison to open surgery, and outcome with pre- and post-operative neuropsychological testing also shows improvement for most patients.A newer technology utilizes laser-mediated heating of the stereotactic probe within the HH lesion, and also includes the use of real-time MR thermography (visualizing the heat signature of the treatment in near-real time) to build in safeguards so that the heating is limited at pre-determined safety targets as it spreads to healthy tissue. This approach also appears to be highly effective (67-90% seizure-free outcomes in the reports published to date) and the safety profile has been favorable. However, only a small number of research reports have been published thus far, with relatively small numbers of patients and brief follow-up. Additional studies are anticipated.Transcallosal Interforniceal Resection. Popularized by Dr. Jeffrey Rosenfeld in Melbourne, Australia, this was the first innovative technique for HH surgery, with an open surgical approach (through a craniotomy) to the HH from above (between the two hemispheres of the brain) rather than below (traversing under the temporal or frontal lobes). Although a longer distance, this approach turns out to be safer and more effective. The HH lesion (and its connection) is directly visualized by the surgeon. This technique is often used in younger patients with large lesions including bilateral connections to the hypothalamus, where surgical visualization is particularly critical. Open resection procedures are favored in circumstances where the child is deteriorating, and the delay in treatment effectiveness inherent with gamma knife radiosurgery is not acceptable. Surgical outcome results from two large series have been published with very similar results (complete seizure control in 52% and 54% of patients, respectively). The potential for surgical complications are important to consider: 8% of patients have residual decrease in short term memory function, for example.Transventricular Endoscopic Resection. This approach involves placing a small burr hole in the skull and then passing an operating endoscope into the ventricular system, entering the third ventricle (the fluid-filled space between the right and left halves of the hypothalamus). This approach is ideal for those who require prompt intervention and who have relatively small HH lesions with unilateral attachment to the wall of the hypothalamus. The effectiveness is comparable to the transcallosal resection (49% seizure-free after one year), but the procedure is more easily tolerated with a shorter length of stay in the hospital. Short-term memory is still at-risk however, with 8% of patients experiencing a decline in short-term memory function following endoscopic surgery. Recent experience is such that stereotactic thermoablation is now the preferred technique for most patients that would have been candidates for endoscopic resection in the past.Pterional (Orbitozygomatic) Resection. While surgical approaches from below (under the frontal or temporal lobe) are to be discouraged as a treatment approach for most patients with HH and epilepsy, there are still a substantial number of patients (perhaps 10% of the entire group) where a pterional or orbitozygomatic approach is the most appropriate choice. This approach is chosen for those patients in whom the HH is attached below the hypothalamus and traversing below the brain is therefore the most direct way of getting to the lesion and visualizing its attachment. (Most HH cases with precocious puberty only have this anatomy.)Combined or Staged Resection for Large (or “Giant”) HH Lesions. Patients with HH and epilepsy associated with giant HH lesions may require two approaches from both above and below to optimize resection and/or disconnection. These HH lesions have complicated planes of attachment within the third ventricle but also below the hypothalamus. It is difficult for the surgeon “to see around corners”, and therefore two procedures may be required.Repeat Surgery in HH Patients with Continued Seizures. Surgical teams that are experienced with HH surgery are conservative with HH resection and treatment. That is, if the precise limits of the HH are unclear, it is preferred to err on the side of removing or destroying less HH and avoiding injury or destruction of normal adjacent brain, rather than undertaking an aggressive approach in which the entire HH is removed along with normal hypothalamus. Therefore, some patients may have residual HH tissue and continued seizures. These patients are candidates for a second surgical treatment, often with a different approach or technique, depending upon the anatomy of the remaining tissue.
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Therapies of Hypothalamic Hamartoma. Treatment
Central precocious puberty (CPP) can usually be treated successfully with medication. Surgery is not required for most patients with CPP. Effective treatment consists of administration of gonadotropin-releasing hormone (GnRH) agonists, such as leuprolide acetate [Lupron], which have the effect of feedback inhibition of the pulsatile (pulse-like) release of GnRH that is required to trigger puberty. Leuprolide acetate is customarily administered as a once-monthly intramuscular injection for the duration of time that puberty needs to be suppressed. Once discontinued, puberty occurs normally. Long-term follow-up studies for HH patients with a history of successfully treated CPP show that normal adult height and normal reproductive function are expected.Treatment options that avoid once-monthly injections have also been developed. Consultation with a pediatric endocrinologist experienced in the treatment of CPP is important to review the treatment options and for discussion of possible side effects.Gelastic seizures usually do not respond to anti-epilepsy drugs (AEDs). Exceptions to this appear to be rare. Additionally, while the other seizure types that occur later in childhood may be helped with AED therapy, it is unlikely that these seizures will be completely controlled with AEDs (“treatment-resistant”). Consequently, surgical treatment is usually required, as discussed below.The timing of surgical intervention (including gamma knife radiosurgery) is a major decision point facing the patient, family and doctor. Surgical intervention carries the risk of complications and should not be performed until the degree of clinical severity calls for it. For example, relatively brief and infrequent gelastic seizures are usually not significantly disabling. If the child is making good developmental progress, a decision to withhold surgical intervention may be appropriate. However, under these circumstances, the clinical course needs to be observed carefully for any adverse changes in symptoms, such as worsening of seizures, slowing of developmental progress, or emergence of psychiatric symptoms.However, our current understanding of epilepsy associated with HH also argues against excessive delay in surgical treatment, since it appears that some patients undergo a process known as secondary epileptogenesis, in which uncontrolled seizures from the original location can provoke a process by which seizures begin to arise from a second, distant location elsewhere in the brain. When this occurs (a process that is likely to occur over a period of years rather than months) then surgery removing the HH lesion may be less successful for completely controlling seizures. Outcome studies of surgery for HH associated with epilepsy have shown that success in controlling seizures is inversely related to the patent’s age. That is, older patients are less likely to gain complete seizure control. A recent research study on HH patients undergoing surgery has also shown that a higher likelihood of cognitive improvement after surgery correlates with younger age at the time of surgery. Gelastic seizures begin in the HH lesion and removing (or otherwise damaging or ablating) the HH can cure seizures. Until recently, HH with epilepsy was considered not treatable, since surgery on the hypothalamus was too dangerous. However, since 2000, several different treatment approaches have been developed that are recognized as effective and safe. These treatment decisions (selecting one of several surgical options including radiosurgery) are highly individualized to the unique circumstances of each patient. This includes an assessment of their clinical course and symptoms, but also the exact anatomy of their HH lesion. Consequently, consultation at a referral center that specializes in the treatment of HH is highly recommended.A brief discussion of each of these treatment modalities follows. The relative merits of any of these therapies for an individual patient require consultation with a specialist in the field of HH treatment.Gamma Knife Radiosurgery. Gamma Knife Radiosurgery (GKR) is a relatively non-invasive radiosurgical technique in which a stereotactic frame is temporarily attached to the patient’s head along with a helmet-like device with multiple radiation entry ports. These ports are aligned (targeted) so that multiple beams of radiation are delivered to converge upon the selected target, injuring this tissue, but delivering doses well below the threshold for tissue injury to the rest of the brain. The safety profile for GKR is excellent relative to surgical resection. A small number of patients have transient temperature irregularities following treatment or experience a temporary increase in seizure frequency several weeks after treatment. The biggest disadvantage to GKR is that the therapeutic effect is delayed, typically 6-18 months, but sometimes up to 2-3 years following treatment. This therapy is most appropriate for patients who are clinically stable with respect to their seizures and other symptoms, and can tolerate waiting for effectiveness. Currently published data suggests that 40% of patients treated with GKR will be completely free of seizures upon long-term follow-up.Stereotactic Thermoablation (with or without intraoperative MR thermography). Thermoablation involves image-guided stereotactic placement of thin probes into the HH and then heating the lesion to approximately 60°C, injuring the tissue and eradicating its ability to generate seizures. When effective, this therapy works immediately. Multiple passes of the probe into the brain may be required to treat the entire lesion, depending upon its size.There are two technologies that can be utilized for HH thermoablation treatment. Radiofrequency thermoablation can be successful for complete seizure control in up to 71% of patients (32% of these patients required more than one treatment). The safety profile appears favorable in comparison to open surgery, and outcome with pre- and post-operative neuropsychological testing also shows improvement for most patients.A newer technology utilizes laser-mediated heating of the stereotactic probe within the HH lesion, and also includes the use of real-time MR thermography (visualizing the heat signature of the treatment in near-real time) to build in safeguards so that the heating is limited at pre-determined safety targets as it spreads to healthy tissue. This approach also appears to be highly effective (67-90% seizure-free outcomes in the reports published to date) and the safety profile has been favorable. However, only a small number of research reports have been published thus far, with relatively small numbers of patients and brief follow-up. Additional studies are anticipated.Transcallosal Interforniceal Resection. Popularized by Dr. Jeffrey Rosenfeld in Melbourne, Australia, this was the first innovative technique for HH surgery, with an open surgical approach (through a craniotomy) to the HH from above (between the two hemispheres of the brain) rather than below (traversing under the temporal or frontal lobes). Although a longer distance, this approach turns out to be safer and more effective. The HH lesion (and its connection) is directly visualized by the surgeon. This technique is often used in younger patients with large lesions including bilateral connections to the hypothalamus, where surgical visualization is particularly critical. Open resection procedures are favored in circumstances where the child is deteriorating, and the delay in treatment effectiveness inherent with gamma knife radiosurgery is not acceptable. Surgical outcome results from two large series have been published with very similar results (complete seizure control in 52% and 54% of patients, respectively). The potential for surgical complications are important to consider: 8% of patients have residual decrease in short term memory function, for example.Transventricular Endoscopic Resection. This approach involves placing a small burr hole in the skull and then passing an operating endoscope into the ventricular system, entering the third ventricle (the fluid-filled space between the right and left halves of the hypothalamus). This approach is ideal for those who require prompt intervention and who have relatively small HH lesions with unilateral attachment to the wall of the hypothalamus. The effectiveness is comparable to the transcallosal resection (49% seizure-free after one year), but the procedure is more easily tolerated with a shorter length of stay in the hospital. Short-term memory is still at-risk however, with 8% of patients experiencing a decline in short-term memory function following endoscopic surgery. Recent experience is such that stereotactic thermoablation is now the preferred technique for most patients that would have been candidates for endoscopic resection in the past.Pterional (Orbitozygomatic) Resection. While surgical approaches from below (under the frontal or temporal lobe) are to be discouraged as a treatment approach for most patients with HH and epilepsy, there are still a substantial number of patients (perhaps 10% of the entire group) where a pterional or orbitozygomatic approach is the most appropriate choice. This approach is chosen for those patients in whom the HH is attached below the hypothalamus and traversing below the brain is therefore the most direct way of getting to the lesion and visualizing its attachment. (Most HH cases with precocious puberty only have this anatomy.)Combined or Staged Resection for Large (or “Giant”) HH Lesions. Patients with HH and epilepsy associated with giant HH lesions may require two approaches from both above and below to optimize resection and/or disconnection. These HH lesions have complicated planes of attachment within the third ventricle but also below the hypothalamus. It is difficult for the surgeon “to see around corners”, and therefore two procedures may be required.Repeat Surgery in HH Patients with Continued Seizures. Surgical teams that are experienced with HH surgery are conservative with HH resection and treatment. That is, if the precise limits of the HH are unclear, it is preferred to err on the side of removing or destroying less HH and avoiding injury or destruction of normal adjacent brain, rather than undertaking an aggressive approach in which the entire HH is removed along with normal hypothalamus. Therefore, some patients may have residual HH tissue and continued seizures. These patients are candidates for a second surgical treatment, often with a different approach or technique, depending upon the anatomy of the remaining tissue.
| 619 |
Hypothalamic Hamartoma
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nord_620_0
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Overview of Hypothalamic Obesity, Acquired
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Summary“Hypothalamic obesity” refers to excess weight gain that may follow from an injury to the hypothalamus, a brain region with many important functions. The hypothalamus affects energy intake, by regulating how much we eat, and energy expenditure, by regulating how much energy our bodies use. Damage to the hypothalamus disrupts the carefully coordinated balance between energy intake and expenditure, often leading to increased calorie intake and/or decreased calorie burning, and thereby to rapid weight gain. This weight gain can be difficult to reverse with currently available treatments. The term “hypothalamic obesity” in clinical practice, and for the purposes of this report, is often used to refer specifically to obesity caused by anatomical injury to the hypothalamus. In contrast to these acquired forms of hypothalamic obesity, there are many genetic disorders that affect the function of the hypothalamus and include a tendency to excess weight gain, for example, Prader-Willi syndrome. Also, some individuals born with malformations of the brain may also experience hypothalamic dysfunction and excess weight gain. These genetic or inborn conditions highlight the importance of the hypothalamus for metabolism. For purposes of this report, however, the focus is on acquired hypothalamic obesity. Frequently, acquired hypothalamic obesity is a complication of the surgical removal of a hypothalamic brain tumor, or a complication of the tumor itself. Tumors that arise from the pituitary gland or invade the hypothalamus such as craniopharyngiomas, germinomas, gliomas, hamartomas and pituitary adenomas.1 Other causes of acquired hypothalamic obesity include traumatic brain injury, infectious or inflammatory injury, radiation or hemorrhage (bleeding in the brain).The hypothalamus regulates the balance between eating calories and burning off calories; damage to this area affects different people in different ways. Some individuals are excessively hungry (hyperphagia) and/or are not easily satisfied by food. Others gain weight rapidly even when restricting calories due to a low resting metabolic rate which results in the individual burning fewer calories (energy) at rest, and individuals also tend to have lower levels of physical activity and exercise. The etiology, magnitude and severity of abnormalities in hypothalamic regulation of energy balance distinguish hypothalamic obesity from “common” forms of obesity.The hypothalamus influences other body functions besides energy balance, and as a result, individuals with hypothalamic obesity can also have other related health problems. One very frequently encountered health problem is hypopituitarism. The pituitary gland is often called the “master gland” because it governs the production of endocrine hormones throughout the body. The pituitary gland, in turn, receives signals from the hypothalamus. Individuals with damage to the hypothalamus and/or pituitary often require medications to treat endocrine hormone deficiencies. Without proper supplementation, some of these hormone deficiencies, such as growth hormone deficiency or hypothyroidism, can also contribute to the development of obesity. Other health issues include fluid and electrolyte balance problems, difficulties with heart rate and blood pressure regulation, sleep problems, day-night (circadian) problems and difficulties with body temperature regulation. Tumors in this area can also damage the optic nerves and chiasm, leading to visual impairment, including blindness. Hypothalamic injury, along with the condition that produced the injury, can have complex psychosocial effects as well, on both the affected individual and their family.Currently, there are no FDA approved treatments specifically for hypothalamic obesity, highlighting a substantial unmet need. There are strategies that may have some benefit, though responses are not uniform in all affected individuals. Indeed, there is substantial variation between individuals with hypothalamic obesity, thus the most appropriate management approach will be personalized and delivered by an experienced, multi-disciplinary team. Nutrition, physical activity, behavior, medication and in some cases, surgery, can all play a role. Identifying and treating related disorders is critical. It is also vital to ensure there are mental and behavioral health supports in place to help individuals with hypothalamic obesity thrive while also managing their medical conditions.HistorySome of the earliest insights about the many roles of the hypothalamus in health and disease come from historical descriptions of individuals with hypothalamic brain tumors.2 Individuals with hypothalamic tumors often came to medical attention for the combination of obesity and hormone deficiencies. Notably, both Dr. Joseph Babinski (in 1900)3 and Dr. Alfred Froehlich (in 1901)4 described individuals with tumors in the hypothalamic/pituitary region who developed obesity and did not experience typical pubertal development. Critically, Dr. Paul Ehrlich (in 1904) argued that it was damage to the hypothalamus, and not the pituitary, that lead to the symptoms of the tumor. Subsequent studies by Dr. Harvey Cushing and others in experimental animal models showed that hypothalamic injury was the true cause of the weight gain and hormone problems.2Historically, acquired hypothalamic obesity has been referred to as Froehlich syndrome or adiposogenital dystrophy, but these terms are no longer in widespread clinical use.
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Overview of Hypothalamic Obesity, Acquired. Summary“Hypothalamic obesity” refers to excess weight gain that may follow from an injury to the hypothalamus, a brain region with many important functions. The hypothalamus affects energy intake, by regulating how much we eat, and energy expenditure, by regulating how much energy our bodies use. Damage to the hypothalamus disrupts the carefully coordinated balance between energy intake and expenditure, often leading to increased calorie intake and/or decreased calorie burning, and thereby to rapid weight gain. This weight gain can be difficult to reverse with currently available treatments. The term “hypothalamic obesity” in clinical practice, and for the purposes of this report, is often used to refer specifically to obesity caused by anatomical injury to the hypothalamus. In contrast to these acquired forms of hypothalamic obesity, there are many genetic disorders that affect the function of the hypothalamus and include a tendency to excess weight gain, for example, Prader-Willi syndrome. Also, some individuals born with malformations of the brain may also experience hypothalamic dysfunction and excess weight gain. These genetic or inborn conditions highlight the importance of the hypothalamus for metabolism. For purposes of this report, however, the focus is on acquired hypothalamic obesity. Frequently, acquired hypothalamic obesity is a complication of the surgical removal of a hypothalamic brain tumor, or a complication of the tumor itself. Tumors that arise from the pituitary gland or invade the hypothalamus such as craniopharyngiomas, germinomas, gliomas, hamartomas and pituitary adenomas.1 Other causes of acquired hypothalamic obesity include traumatic brain injury, infectious or inflammatory injury, radiation or hemorrhage (bleeding in the brain).The hypothalamus regulates the balance between eating calories and burning off calories; damage to this area affects different people in different ways. Some individuals are excessively hungry (hyperphagia) and/or are not easily satisfied by food. Others gain weight rapidly even when restricting calories due to a low resting metabolic rate which results in the individual burning fewer calories (energy) at rest, and individuals also tend to have lower levels of physical activity and exercise. The etiology, magnitude and severity of abnormalities in hypothalamic regulation of energy balance distinguish hypothalamic obesity from “common” forms of obesity.The hypothalamus influences other body functions besides energy balance, and as a result, individuals with hypothalamic obesity can also have other related health problems. One very frequently encountered health problem is hypopituitarism. The pituitary gland is often called the “master gland” because it governs the production of endocrine hormones throughout the body. The pituitary gland, in turn, receives signals from the hypothalamus. Individuals with damage to the hypothalamus and/or pituitary often require medications to treat endocrine hormone deficiencies. Without proper supplementation, some of these hormone deficiencies, such as growth hormone deficiency or hypothyroidism, can also contribute to the development of obesity. Other health issues include fluid and electrolyte balance problems, difficulties with heart rate and blood pressure regulation, sleep problems, day-night (circadian) problems and difficulties with body temperature regulation. Tumors in this area can also damage the optic nerves and chiasm, leading to visual impairment, including blindness. Hypothalamic injury, along with the condition that produced the injury, can have complex psychosocial effects as well, on both the affected individual and their family.Currently, there are no FDA approved treatments specifically for hypothalamic obesity, highlighting a substantial unmet need. There are strategies that may have some benefit, though responses are not uniform in all affected individuals. Indeed, there is substantial variation between individuals with hypothalamic obesity, thus the most appropriate management approach will be personalized and delivered by an experienced, multi-disciplinary team. Nutrition, physical activity, behavior, medication and in some cases, surgery, can all play a role. Identifying and treating related disorders is critical. It is also vital to ensure there are mental and behavioral health supports in place to help individuals with hypothalamic obesity thrive while also managing their medical conditions.HistorySome of the earliest insights about the many roles of the hypothalamus in health and disease come from historical descriptions of individuals with hypothalamic brain tumors.2 Individuals with hypothalamic tumors often came to medical attention for the combination of obesity and hormone deficiencies. Notably, both Dr. Joseph Babinski (in 1900)3 and Dr. Alfred Froehlich (in 1901)4 described individuals with tumors in the hypothalamic/pituitary region who developed obesity and did not experience typical pubertal development. Critically, Dr. Paul Ehrlich (in 1904) argued that it was damage to the hypothalamus, and not the pituitary, that lead to the symptoms of the tumor. Subsequent studies by Dr. Harvey Cushing and others in experimental animal models showed that hypothalamic injury was the true cause of the weight gain and hormone problems.2Historically, acquired hypothalamic obesity has been referred to as Froehlich syndrome or adiposogenital dystrophy, but these terms are no longer in widespread clinical use.
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Symptoms of Hypothalamic Obesity, Acquired
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The key clinical feature of acquired hypothalamic obesity is excess weight gain following injury to the hypothalamus. The patient’s clinical presentation depends on the cause of the injury. For individuals with hypothalamic obesity related to brain tumors, a minority are obese at the time they are diagnosed with the brain tumor, suggesting that the brain tumor has already caused damage leading to weight gain that is unfortunately likely to be persistent.5 More often, weight gain occurs after the tumor is removed surgically, suggesting a side effect of traditional surgical approaches is hypothalamic obesity and excess weight gain.6 Newer, less invasive surgical techniques, including endoscopic endonasal techniques (approaching the tumor through the nose) may be less likely to cause hypothalamic damage that leads to obesity.7,8 For individuals with hypothalamic damage from other causes, for example, traumatic brain injury or inflammation, the weight gain tends to begin at the time of the injury or very shortly after the acute problem has been treated.The most common concern expressed by individuals with hypothalamic obesity is how resistant the weight gain is to conventional approaches to weight management, such as healthy nutrition, caloric restriction, and exercise. Another frequent observation is that individuals with hypothalamic obesity use less energy, both at rest9,10 and/or with physical activity and exercise.11 Because their bodies use less energy, individuals find that they can continue to gain weight even when caloric intake is restricted. Some, but not all, individuals also experience a severe disorder of appetite regulation, called hyperphagia, or excess appetite, and rarely feel satisfied after meals.12 These abnormal eating behaviors are often distressing to individuals and families, and further contribute to weight gain. The hypothalamus also regulates other body functions that, when disrupted, cause symptoms. For example, individuals can have difficulty initiating and sustaining sleep. They can have excess daytime sleepiness, related to sleep impairment and also to problems maintaining circadian (day-night) alignment. Some individuals experience difficulties maintaining body temperature within typical range. Some also have challenges with regulating heart rate and blood pressure in response to the body’s needs. Individuals with hypothalamic hamartomas can have a particular kind of seizure called gelastic seizures. Tumors located in this area can also lead to damage of the optic nerves and chiasm, leading to visual impairment, including blindness. While hypothalamic and pituitary damage often leads to delayed puberty and hypogonadism, sometimes hypothalamic injury causes early puberty development, which first manifests as breast development in girls and testicular enlargement in boys. Often, individuals are affected by pituitary hormone deficiencies, most notably diabetes insipidus, or vasopressin deficiency, which affects fluid balance. (See “Related Disorders” and “Clinical Testing and Work-up” sections below for additional details regarding hypopituitarism.)
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Symptoms of Hypothalamic Obesity, Acquired. The key clinical feature of acquired hypothalamic obesity is excess weight gain following injury to the hypothalamus. The patient’s clinical presentation depends on the cause of the injury. For individuals with hypothalamic obesity related to brain tumors, a minority are obese at the time they are diagnosed with the brain tumor, suggesting that the brain tumor has already caused damage leading to weight gain that is unfortunately likely to be persistent.5 More often, weight gain occurs after the tumor is removed surgically, suggesting a side effect of traditional surgical approaches is hypothalamic obesity and excess weight gain.6 Newer, less invasive surgical techniques, including endoscopic endonasal techniques (approaching the tumor through the nose) may be less likely to cause hypothalamic damage that leads to obesity.7,8 For individuals with hypothalamic damage from other causes, for example, traumatic brain injury or inflammation, the weight gain tends to begin at the time of the injury or very shortly after the acute problem has been treated.The most common concern expressed by individuals with hypothalamic obesity is how resistant the weight gain is to conventional approaches to weight management, such as healthy nutrition, caloric restriction, and exercise. Another frequent observation is that individuals with hypothalamic obesity use less energy, both at rest9,10 and/or with physical activity and exercise.11 Because their bodies use less energy, individuals find that they can continue to gain weight even when caloric intake is restricted. Some, but not all, individuals also experience a severe disorder of appetite regulation, called hyperphagia, or excess appetite, and rarely feel satisfied after meals.12 These abnormal eating behaviors are often distressing to individuals and families, and further contribute to weight gain. The hypothalamus also regulates other body functions that, when disrupted, cause symptoms. For example, individuals can have difficulty initiating and sustaining sleep. They can have excess daytime sleepiness, related to sleep impairment and also to problems maintaining circadian (day-night) alignment. Some individuals experience difficulties maintaining body temperature within typical range. Some also have challenges with regulating heart rate and blood pressure in response to the body’s needs. Individuals with hypothalamic hamartomas can have a particular kind of seizure called gelastic seizures. Tumors located in this area can also lead to damage of the optic nerves and chiasm, leading to visual impairment, including blindness. While hypothalamic and pituitary damage often leads to delayed puberty and hypogonadism, sometimes hypothalamic injury causes early puberty development, which first manifests as breast development in girls and testicular enlargement in boys. Often, individuals are affected by pituitary hormone deficiencies, most notably diabetes insipidus, or vasopressin deficiency, which affects fluid balance. (See “Related Disorders” and “Clinical Testing and Work-up” sections below for additional details regarding hypopituitarism.)
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Causes of Hypothalamic Obesity, Acquired
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The single most important cause of acquired hypothalamic obesity is injury to the parts of the hypothalamus that regulate energy balance. Magnetic resonance imaging (MRI) studies have found that damage in particular areas in the hypothalamus towards that back of the brain, including the mamillary bodies, predicts obesity after surgical resection of a brain tumor.13 Other risk factors for the development of future obesity include obesity at the time of treatment, and in individuals with brain tumors, papilledema, or swelling in the back of the eye indicating high pressure around the brain, at time of initial diagnosis.5 Finally, children whose mothers had higher body mass index (BMI) at diagnosis were also at increased risk for future obesity, indicating that complex genetic and environmental factors can continue to contribute to weight gain even in hypothalamic forms of obesity.14Multiple factors likely combine to cause excess weight gain after hypothalamic injury, and individuals vary in the extent to which they experience these different phenomena.15 These factors include: decreased energy use (both at rest, and with activity), increased appetite and decreased sense of being full after meals, chronically high circulating levels of the energy-storing hormone insulin, potential resistance to the appetite-regulating hormone leptin, disordered sleep and circadian phase regulation, pituitary hormone deficiencies and psychosocial factors that influence healthful behaviors.16,17 The potential roles for disordered signaling by enteroendocrine hormones and/or neuropeptides that regulate energy balance (e.g., ghrelin, oxytocin) are the focus of investigation. Much remains to be learned from ongoing research.
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Causes of Hypothalamic Obesity, Acquired. The single most important cause of acquired hypothalamic obesity is injury to the parts of the hypothalamus that regulate energy balance. Magnetic resonance imaging (MRI) studies have found that damage in particular areas in the hypothalamus towards that back of the brain, including the mamillary bodies, predicts obesity after surgical resection of a brain tumor.13 Other risk factors for the development of future obesity include obesity at the time of treatment, and in individuals with brain tumors, papilledema, or swelling in the back of the eye indicating high pressure around the brain, at time of initial diagnosis.5 Finally, children whose mothers had higher body mass index (BMI) at diagnosis were also at increased risk for future obesity, indicating that complex genetic and environmental factors can continue to contribute to weight gain even in hypothalamic forms of obesity.14Multiple factors likely combine to cause excess weight gain after hypothalamic injury, and individuals vary in the extent to which they experience these different phenomena.15 These factors include: decreased energy use (both at rest, and with activity), increased appetite and decreased sense of being full after meals, chronically high circulating levels of the energy-storing hormone insulin, potential resistance to the appetite-regulating hormone leptin, disordered sleep and circadian phase regulation, pituitary hormone deficiencies and psychosocial factors that influence healthful behaviors.16,17 The potential roles for disordered signaling by enteroendocrine hormones and/or neuropeptides that regulate energy balance (e.g., ghrelin, oxytocin) are the focus of investigation. Much remains to be learned from ongoing research.
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Affects of Hypothalamic Obesity, Acquired
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The epidemiology of acquired forms hypothalamic obesity directly reflects the epidemiology of the underlying causes of hypothalamic injury and rates of associated obesity. Multiple hypothalamic/pituitary brain tumors can lead to hypothalamic obesity. In one registry study, individuals with craniopharyngioma accounted for the majority (62%) of the cohort. By some estimates, there are 0.5-2.5 new cases of craniopharyngioma per 1 million individuals per year.18,19 The adamantinomatous sub-type of craniopharyngioma presents typically at one of two times in life, childhood (ages 5-15y) or middle adulthood (45-60y), while the papillary sub-type occurs almost entirely in adults.20 The epidemiology of the other types of tumors and injuries that lead to hypothalamic obesity demonstrates that this condition can affect individuals at any age.
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Affects of Hypothalamic Obesity, Acquired. The epidemiology of acquired forms hypothalamic obesity directly reflects the epidemiology of the underlying causes of hypothalamic injury and rates of associated obesity. Multiple hypothalamic/pituitary brain tumors can lead to hypothalamic obesity. In one registry study, individuals with craniopharyngioma accounted for the majority (62%) of the cohort. By some estimates, there are 0.5-2.5 new cases of craniopharyngioma per 1 million individuals per year.18,19 The adamantinomatous sub-type of craniopharyngioma presents typically at one of two times in life, childhood (ages 5-15y) or middle adulthood (45-60y), while the papillary sub-type occurs almost entirely in adults.20 The epidemiology of the other types of tumors and injuries that lead to hypothalamic obesity demonstrates that this condition can affect individuals at any age.
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Related disorders of Hypothalamic Obesity, Acquired
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In addition to damage to the hypothalamus, individuals with acquired hypothalamic obesity often have damage to the pituitary gland. This damage causes pituitary multiple hormone deficiencies and is called hypopituitarism. The hormone deficiencies can include some or all of the following: thyroid hormone, cortisol, growth hormone, vasopressin (resulting in diabetes insipidus, the inability to concentrate urine), and sex steroids (estrogen for females and testosterone for males). Hypopituitarism is also a feature of other congenital and acquired conditions.Individuals with acquired hypothalamic obesity can share clinical features with individuals who have genetic disorders and/or brain malformations that impact hypothalamic function. The previous diagnosis of a brain tumor or other injury to the hypothalamus is the main differentiating feature of acquired hypothalamic obesity. For example, craniopharyngioma and hypothalamic hamartoma are two types of hypothalamic/pituitary brain tumor that can be complicated by hypothalamic obesity. Genetic disorders that can impact hypothalamic function and are associated with obesity include (but are not limited to) Prader-Willi syndrome, Albright hereditary osteodystrophy, Bardet-Biedl syndrome, Alstrom syndrome, Cohen syndrome, 16p11.2 microdeletion syndrome, Rapid Onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD), Smith-Magenis syndrome and a range of monogenic (single-gene) disorders that impact the leptin-melanocortin signaling pathway (e.g., mutations in gene encoding the melanocortin 4 receptor). A full discussion of these and related conditions is beyond the scope of this report. For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.
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Related disorders of Hypothalamic Obesity, Acquired. In addition to damage to the hypothalamus, individuals with acquired hypothalamic obesity often have damage to the pituitary gland. This damage causes pituitary multiple hormone deficiencies and is called hypopituitarism. The hormone deficiencies can include some or all of the following: thyroid hormone, cortisol, growth hormone, vasopressin (resulting in diabetes insipidus, the inability to concentrate urine), and sex steroids (estrogen for females and testosterone for males). Hypopituitarism is also a feature of other congenital and acquired conditions.Individuals with acquired hypothalamic obesity can share clinical features with individuals who have genetic disorders and/or brain malformations that impact hypothalamic function. The previous diagnosis of a brain tumor or other injury to the hypothalamus is the main differentiating feature of acquired hypothalamic obesity. For example, craniopharyngioma and hypothalamic hamartoma are two types of hypothalamic/pituitary brain tumor that can be complicated by hypothalamic obesity. Genetic disorders that can impact hypothalamic function and are associated with obesity include (but are not limited to) Prader-Willi syndrome, Albright hereditary osteodystrophy, Bardet-Biedl syndrome, Alstrom syndrome, Cohen syndrome, 16p11.2 microdeletion syndrome, Rapid Onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD), Smith-Magenis syndrome and a range of monogenic (single-gene) disorders that impact the leptin-melanocortin signaling pathway (e.g., mutations in gene encoding the melanocortin 4 receptor). A full discussion of these and related conditions is beyond the scope of this report. For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.
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Diagnosis of Hypothalamic Obesity, Acquired
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The diagnosis of hypothalamic obesity is suspected when excess weight gain occurs in the context of a hypothalamic injury, as suggested by brain imaging studies. The diagnosis is additionally supported when the timing of the injury coincides with the onset of brisk and recalcitrant weight gain. The presence of one or more hypothalamic/pituitary hormone deficits is also evidence of clinically relevant injury.21 These signals (evidence of hypothalamic injury by brain imaging, timing of weight gain related to the injury and frequently the presence of other hormone deficits) help distinguish acquired hypothalamic obesity from prevalent “common” obesity that occurs from a complex interaction of genetic and environmental risk factors.Clinical Testing & Work-UpClinical testing in the setting of hypothalamic obesity includes evaluation for disorders related to potential associated hypothalamic/pituitary hormone deficiencies: diabetes insipidus (vasopressin deficiency), adrenal insufficiency (cortisol deficiency), hypothyroidism (thyroid hormone deficiency), growth hormone deficiency, and hypogonadism (deficiency of sex steroids or estrogen in females and testosterone in males). Also, it is important that individuals be evaluated for the myriad potential downstream health effects of obesity, including fatty liver disease, type 2 diabetes mellitus, abnormal lipid profile, sleep-disordered breathing, pseudotumor cerebri syndrome, orthopedic problems and psychosocial/mental health disorders.22 These complications of obesity may occur at excess rates in individuals with hypothalamic obesity as compared to individuals with “common” obesity with similar body mass index (BMI).
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Diagnosis of Hypothalamic Obesity, Acquired. The diagnosis of hypothalamic obesity is suspected when excess weight gain occurs in the context of a hypothalamic injury, as suggested by brain imaging studies. The diagnosis is additionally supported when the timing of the injury coincides with the onset of brisk and recalcitrant weight gain. The presence of one or more hypothalamic/pituitary hormone deficits is also evidence of clinically relevant injury.21 These signals (evidence of hypothalamic injury by brain imaging, timing of weight gain related to the injury and frequently the presence of other hormone deficits) help distinguish acquired hypothalamic obesity from prevalent “common” obesity that occurs from a complex interaction of genetic and environmental risk factors.Clinical Testing & Work-UpClinical testing in the setting of hypothalamic obesity includes evaluation for disorders related to potential associated hypothalamic/pituitary hormone deficiencies: diabetes insipidus (vasopressin deficiency), adrenal insufficiency (cortisol deficiency), hypothyroidism (thyroid hormone deficiency), growth hormone deficiency, and hypogonadism (deficiency of sex steroids or estrogen in females and testosterone in males). Also, it is important that individuals be evaluated for the myriad potential downstream health effects of obesity, including fatty liver disease, type 2 diabetes mellitus, abnormal lipid profile, sleep-disordered breathing, pseudotumor cerebri syndrome, orthopedic problems and psychosocial/mental health disorders.22 These complications of obesity may occur at excess rates in individuals with hypothalamic obesity as compared to individuals with “common” obesity with similar body mass index (BMI).
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Therapies of Hypothalamic Obesity, Acquired
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At the time of this writing, there are no FDA approved therapies specifically for hypothalamic obesity. Currently, treatment includes evaluation and treatment of the underlying condition and other health problems, as well as trying a variety of strategies to manage obesity, which unfortunately is often not responsive to treatment. Hypothalamic obesity is most appropriately addressed by an experienced, well-coordinated, multi-disciplinary team that designs and implements an individualized treatment approach. This approach should take into consideration other medical problems that the patient has, as well as patient/family circumstances and preferences. Ongoing care for the cause of the injury can help minimize the risk or extent of further hypothalamic injury. For survivors of brain tumors, care includes regular imaging surveillance to ensure early detection of any tumor recurrence. Management of hypothalamic obesity is complex, and includes optimization of pituitary hormone replacement, nutrition (often, lower- or controlled carbohydrate approaches and/or portion control are trialed), physical activity and exercise, mental and behavioral health interventions and sometimes weight loss medications and/or or metabolic/bariatric surgery.17 Overall, aside from surgery, the benefits, if any, of these interventions are modest, and may not be experienced by all patients. Medications with some evidence for potential benefit in at least a sub-set of patients include stimulants, Metformin, and glucagon-like peptide 1 receptor (GLP1R) agonists23; the GLP1R agonist class of medications is growing, and includes agents already approved for “common” forms of both adolescent and adult obesity.23,24 Other medications already approved for use in “common” obesity are also often trialed in hypothalamic obesity, with variable degrees of success. For some patients, metabolic/bariatric surgery is an alternative to consider that may be helpful. For all individuals, it is critical to support both the patient and family at diagnosis and over time, since hypothalamic obesity can have significant impact on function and quality of life.
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Therapies of Hypothalamic Obesity, Acquired. At the time of this writing, there are no FDA approved therapies specifically for hypothalamic obesity. Currently, treatment includes evaluation and treatment of the underlying condition and other health problems, as well as trying a variety of strategies to manage obesity, which unfortunately is often not responsive to treatment. Hypothalamic obesity is most appropriately addressed by an experienced, well-coordinated, multi-disciplinary team that designs and implements an individualized treatment approach. This approach should take into consideration other medical problems that the patient has, as well as patient/family circumstances and preferences. Ongoing care for the cause of the injury can help minimize the risk or extent of further hypothalamic injury. For survivors of brain tumors, care includes regular imaging surveillance to ensure early detection of any tumor recurrence. Management of hypothalamic obesity is complex, and includes optimization of pituitary hormone replacement, nutrition (often, lower- or controlled carbohydrate approaches and/or portion control are trialed), physical activity and exercise, mental and behavioral health interventions and sometimes weight loss medications and/or or metabolic/bariatric surgery.17 Overall, aside from surgery, the benefits, if any, of these interventions are modest, and may not be experienced by all patients. Medications with some evidence for potential benefit in at least a sub-set of patients include stimulants, Metformin, and glucagon-like peptide 1 receptor (GLP1R) agonists23; the GLP1R agonist class of medications is growing, and includes agents already approved for “common” forms of both adolescent and adult obesity.23,24 Other medications already approved for use in “common” obesity are also often trialed in hypothalamic obesity, with variable degrees of success. For some patients, metabolic/bariatric surgery is an alternative to consider that may be helpful. For all individuals, it is critical to support both the patient and family at diagnosis and over time, since hypothalamic obesity can have significant impact on function and quality of life.
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Overview of I Cell Disease
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I-cell disease (mucolipidosis II) is a rare inherited metabolic disorder characterized by coarse facial features, skeletal abnormalities and mental retardation. The symptoms of I-cell disease are similar to but more severe than those of Hurler syndrome. The symptoms associated with this disorder typically become obvious during infancy and may include multiple abnormalities of the skull and face and growth delays.This disorder belongs to a group of diseases known as lysosomal storage disorders. Lysosomes are particles bound in membranes within cells that break down certain fats and carbohydrates. Multiple enzyme deficiencies associated with I-cell disease lead to the accumulation of certain fatty substances (mucolipids) and certain complex carbohydrates (mucopolysaccharides) within the cells of many tissues of the body.I-cell disease is caused by a mutation in the GNPTA gene that leads to a deficiency in the enzyme UDP-N-acetylglucoseamine-1-phosphotransferase. I-cell disease is inherited as an autosomal recessive genetic trait.
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Overview of I Cell Disease. I-cell disease (mucolipidosis II) is a rare inherited metabolic disorder characterized by coarse facial features, skeletal abnormalities and mental retardation. The symptoms of I-cell disease are similar to but more severe than those of Hurler syndrome. The symptoms associated with this disorder typically become obvious during infancy and may include multiple abnormalities of the skull and face and growth delays.This disorder belongs to a group of diseases known as lysosomal storage disorders. Lysosomes are particles bound in membranes within cells that break down certain fats and carbohydrates. Multiple enzyme deficiencies associated with I-cell disease lead to the accumulation of certain fatty substances (mucolipids) and certain complex carbohydrates (mucopolysaccharides) within the cells of many tissues of the body.I-cell disease is caused by a mutation in the GNPTA gene that leads to a deficiency in the enzyme UDP-N-acetylglucoseamine-1-phosphotransferase. I-cell disease is inherited as an autosomal recessive genetic trait.
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Symptoms of I Cell Disease
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Some of the physical features associated with I-cell disease (ML II) may be apparent at birth (congenital), whereas other features may become apparent between the ages of 6 to 10 months. Craniofacial abnormalities may include coarse facial features, a depressed nasal bridge, a long and narrow head, an unusually high and narrow forehead, and/or skin folds on the inner corners of the eyes (epicanthal folds). The skin may appear to be unusually thick and tight in certain areas of the body (e.g., face, arms, and legs). The corneas of the eyes may appear cloudy.Infants with I-cell disease may also have skeletal malformations including abnormal curvature of the spine from side to side (scoliosis) and/or from front to back (kyphosis), an unusually short neck, dislocation of the hip at birth (congenital), swelling or enlargement of the top portion of the spine (lumbar gibbus), and/or limited mobility of the shoulders. Skeletal abnormalities may also include misaligned bones in the spinal column (vertebral breaking and wedging), wider than normal spaces between ribs, and/or unusual positioning of the fingers (metacarpal pointing). On occasion, infants with I-cell disease may have fingers that are fused together (split hand deformity or ectrodactyly). (For more information on this disorder, choose “split hand” as your search term in the Rare Disease Database.)Children with I-cell disease typically have severe delays in the development of gross and fine motor skills, hearing loss, lack of muscle tone (hypotonia), and varying degrees of mental retardation. Growth delays usually result in short stature (dwarfism). In some children with this disorder, a portion of the intestines may protrude through an abnormal opening in the abdominal wall in the area of the navel (umbilical hernia) and/or the groin (inguinal hernia). Abnormal enlargement of the liver (hepatomegaly), is often observed in association with a protruding abdomen in infants with I-cell disease.Other symptoms of I-cell disease may include frequent respiratory infections, constipation and/or diarrhea, overgrowth of gum tissue (gingival hyperplasia), and/or joint stiffness or joints that are “frozen” in place (contractures). Some children with I-cell disease may have abnormalities of the heart such as defects of the heart valves, enlargement of the heart (cardiomegaly), congestive heart failure and/or heart murmurs.Individuals with I-cell disease often die in childhood, although some patients survive into their teens.
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Symptoms of I Cell Disease. Some of the physical features associated with I-cell disease (ML II) may be apparent at birth (congenital), whereas other features may become apparent between the ages of 6 to 10 months. Craniofacial abnormalities may include coarse facial features, a depressed nasal bridge, a long and narrow head, an unusually high and narrow forehead, and/or skin folds on the inner corners of the eyes (epicanthal folds). The skin may appear to be unusually thick and tight in certain areas of the body (e.g., face, arms, and legs). The corneas of the eyes may appear cloudy.Infants with I-cell disease may also have skeletal malformations including abnormal curvature of the spine from side to side (scoliosis) and/or from front to back (kyphosis), an unusually short neck, dislocation of the hip at birth (congenital), swelling or enlargement of the top portion of the spine (lumbar gibbus), and/or limited mobility of the shoulders. Skeletal abnormalities may also include misaligned bones in the spinal column (vertebral breaking and wedging), wider than normal spaces between ribs, and/or unusual positioning of the fingers (metacarpal pointing). On occasion, infants with I-cell disease may have fingers that are fused together (split hand deformity or ectrodactyly). (For more information on this disorder, choose “split hand” as your search term in the Rare Disease Database.)Children with I-cell disease typically have severe delays in the development of gross and fine motor skills, hearing loss, lack of muscle tone (hypotonia), and varying degrees of mental retardation. Growth delays usually result in short stature (dwarfism). In some children with this disorder, a portion of the intestines may protrude through an abnormal opening in the abdominal wall in the area of the navel (umbilical hernia) and/or the groin (inguinal hernia). Abnormal enlargement of the liver (hepatomegaly), is often observed in association with a protruding abdomen in infants with I-cell disease.Other symptoms of I-cell disease may include frequent respiratory infections, constipation and/or diarrhea, overgrowth of gum tissue (gingival hyperplasia), and/or joint stiffness or joints that are “frozen” in place (contractures). Some children with I-cell disease may have abnormalities of the heart such as defects of the heart valves, enlargement of the heart (cardiomegaly), congestive heart failure and/or heart murmurs.Individuals with I-cell disease often die in childhood, although some patients survive into their teens.
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Causes of I Cell Disease
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I-cell disease (Mucolipidosis II) is caused by a mutation in the GNPTA gene that is located on the long arm of chromosome 4 (4q21-q23).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 4q21” refers to band 21 on the long arm of chromosome 4. The numbered bands specify the location of the thousands of genes that are present on each chromosome.The GNPTA gene mutation leads to a deficiency in the enzyme UDP-N-acetylglucoseamine-1-phosphotransferase that is involved in the synthesis of mannose-6-phosphate, resulting in decreased intracellular levels of lysosomal enzymes and increased levels in blood serum and body fluid. The symptoms of I-cell disease develop due to deficiencies of a variety of lysosomal enzymes in the cells of the body causing an abnormal accumulation of certain fatty substances (mucolipids) and certain complex carbohydrates (mucopolysaccharides) within the cells of many tissues of the body.I-cell disease is inherited as an autosomal recessive genetic trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.Recessive genetic disorders occur when an individual inherits 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.
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Causes of I Cell Disease. I-cell disease (Mucolipidosis II) is caused by a mutation in the GNPTA gene that is located on the long arm of chromosome 4 (4q21-q23).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 4q21” refers to band 21 on the long arm of chromosome 4. The numbered bands specify the location of the thousands of genes that are present on each chromosome.The GNPTA gene mutation leads to a deficiency in the enzyme UDP-N-acetylglucoseamine-1-phosphotransferase that is involved in the synthesis of mannose-6-phosphate, resulting in decreased intracellular levels of lysosomal enzymes and increased levels in blood serum and body fluid. The symptoms of I-cell disease develop due to deficiencies of a variety of lysosomal enzymes in the cells of the body causing an abnormal accumulation of certain fatty substances (mucolipids) and certain complex carbohydrates (mucopolysaccharides) within the cells of many tissues of the body.I-cell disease is inherited as an autosomal recessive genetic trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.Recessive genetic disorders occur when an individual inherits 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.
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I Cell Disease
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nord_621_3
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Affects of I Cell Disease
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I-Cell Disease is a rare disorder that affects males and females in equal numbers. Siblings of affected infants have a 1 in 4 chance of being affected by this disorder. Approximately 30 cases of I-Cell Disease have been reported in the medical literature. This disease appears to be more common in Japan than in other countries.
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Affects of I Cell Disease. I-Cell Disease is a rare disorder that affects males and females in equal numbers. Siblings of affected infants have a 1 in 4 chance of being affected by this disorder. Approximately 30 cases of I-Cell Disease have been reported in the medical literature. This disease appears to be more common in Japan than in other countries.
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I Cell Disease
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nord_621_4
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Related disorders of I Cell Disease
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Symptoms of the following disorders can be similar to those I-cell disease. Comparisons may be useful for a differential diagnosis:The mucopolysaccharidoses are a group of inherited lysosomal storage disorders characterized by the accumulation of certain complex carbohydrates (mucopolysaccharides) in many tissues and organs of the body (e.g., eyes, skeleton, arteries, joints, ears, skin, and/or teeth). In general, the symptoms of these disorders are progressive and vary greatly depending on the specific enzyme deficiencies. Symptoms of the mucopolysaccharidoses, which generally affect many systems of the body, may include abnormal enlargement of different organs (e.g., liver and spleen), multiple bone deformities (dysostosis multiplex) and/or unusual facial features. (For more information on these disorders, choose “mucopolysaccharidoses” as your search term in the Rare Disease Database.)Hurler syndrome (mucopolysaccharidosis type I [MPS I]) is a rare inherited metabolic disorder that appears in 3 forms of varying severity. Infants with Hurler syndrome (MPS 1-H) usually appear normal at birth, although hernias may be present. Onset of symptoms occurs between the ages of 6 months and 2 years and may include coarse facial features, a prominent forehead, an unusually large tongue (macroglossia), misaligned teeth, and/or clouding of the corneas of the eyes. Repeated upper respiratory infections, noisy breathing, and a persistent nasal discharge may also be present. Other symptoms may include growth delays, mental retardation, joint stiffness, deafness, and/or heart disease. Hurler syndrome is inherited as an autosomal recessive genetic trait. (For more information on this disorder, choose “Hurler” as your search term in the Rare Disease Database.)Sialidosis (mucolipidosis I, type I and II) is a very rare inherited metabolic disorder characterized by a deficiency of the enzyme alpha-neuraminidase. This disorder belongs to a group of diseases known as lysosomal storage diseases. The symptoms of sialidosis type I, which typically begin during the 2nd decade of life, may include sudden involuntary muscle contractions (myoclonus), other neurological symptoms, and/or the appearance of red spots (cherry-red macules) in the eyes. The symptoms associated with sialidosis yype II may begin during infancy or later. It is characterized by the same visual abnormalities as sialidosis type I as well as other findings such as mildly coarse facial features, skeletal changes, and/or mild mental retardation. Sialidosis is inherited as an autosomal recessive genetic trait. (For more information on this disorder, choose “sialidosis” as your search term in the Rare Disease Database.)Mucolipidosis III (pseudo-Hurler polydystrophy [ML III]) is a rare inherited metabolic disorder characterized by the accumulation of certain complex carbohydrates (mucopolysaccharides) and fatty substances (mucolipids) in various tissues of the body. The symptoms of this disorder are less severe than those of I-cell disease (ML II) and may include progressive joint stiffness, curvature of the spine (scoliosis), and/or skeletal deformities of the hands (e.g., claw-hands). Growth delays accompanied by deterioration of the hip joints typically develop in children with mucolipidosis III. Other symptoms may include clouding of the corneas of the eyes, mild to moderate coarseness of facial features, mild mental retardation, easy fatigability, and/or heart disease (e.g., congestive heart failure). Mucolipidosis III is inherited as an autosomal recessive trait. For more information on this disorder, choose “Pseudo-Hurler” as your search term in the Rare Disease Database.)Galactosialidosis is a rare inherited metabolic disorder characterized by deficiencies of the enzymes neuraminidase and beta-galactosidase. Symptoms may include severe swelling of many soft tissues of the body and abdominal swelling due to the development of fluid-filled sacs (ascites). Cherry red spots in the eyes, skeletal abnormalities, abnormal enlargement of many organs of the body (visceromegaly), and/or mental retardation may also occur. Growth delays, joint stiffness, and/or coarse facial features are also characteristic of this disorder. Galactosialidosis is inherited as an autosomal recessive genetic trait.Sly syndrome (mucopolysaccharidosis VII), is an extremely rare inherited metabolic disorder characterized by a deficiency of the lysosomal enzyme known as beta-glucuronidase. This deficiency leads to the abnormal accumulation of certain complex carbohydrates (mucopolysaccharides) in many tissues and organs of the body. The symptoms of Sly Syndrome are similar to those of Hurler syndrome (MPS I) and the other mucopolysaccharidoses. Symptoms may include mental retardation, short stature with an unusually short trunk, and/or abnormalities of the intestines, corneas of the eyes, and/or the skeletal system. Sly syndrome is inherited as an autosomal recessive genetic trait. (For more information on this disorder, choose “Sly” as your search term in the Rare Disease Database.)Hunter syndrome (mucopolysaccharidosis II), is a rare inborn error of metabolism characterized by deficiency of an enzyme known as iduronate sulfatase. Initial symptoms and findings associated with Hunter syndrome usually become apparent between two to four years of age. Such abnormalities may include progressive growth delays, resulting in short stature; joint stiffness, with associated restriction of movements; and coarsening of facial features, including thickening of the lips, tongue, and nostrils. Affected children may also have an abnormally large head (macrocephaly), a short neck and broad chest, delayed tooth eruption, progressive hearing loss, and enlargement of the liver and spleen (hepatosplenomegaly). Hunter syndrome is inherited as an X-linked recessive genetic trait. (For more information on this disorder, choose “Hunter” as your search term in the Rare Disease Database.)Maroteaux-Lamy syndrome (mucopolysaccharidosis VI) occurs in three types: a classic severe type, an intermediate type, and a mild type. The syndrome is characterized by a deficiency in the enzyme arylsulfatase B (also called N- acetylgalactosamine-4-sulfatase), which leads to an excess of dermatan sulfate in the urine. In general, growth retardation occurs from two to three years of age, with coarsening of facial features and abnormalities in the bones of hands and spine. Joint stiffness also occurs. The intellect is usually normal. Maroteaux-Lamy syndrome is inherited as an autosomal recessive genetic trait. (For more information on this disorder, choose “Maroteaux” as your search term in the Rare Disease Database.)
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Related disorders of I Cell Disease. Symptoms of the following disorders can be similar to those I-cell disease. Comparisons may be useful for a differential diagnosis:The mucopolysaccharidoses are a group of inherited lysosomal storage disorders characterized by the accumulation of certain complex carbohydrates (mucopolysaccharides) in many tissues and organs of the body (e.g., eyes, skeleton, arteries, joints, ears, skin, and/or teeth). In general, the symptoms of these disorders are progressive and vary greatly depending on the specific enzyme deficiencies. Symptoms of the mucopolysaccharidoses, which generally affect many systems of the body, may include abnormal enlargement of different organs (e.g., liver and spleen), multiple bone deformities (dysostosis multiplex) and/or unusual facial features. (For more information on these disorders, choose “mucopolysaccharidoses” as your search term in the Rare Disease Database.)Hurler syndrome (mucopolysaccharidosis type I [MPS I]) is a rare inherited metabolic disorder that appears in 3 forms of varying severity. Infants with Hurler syndrome (MPS 1-H) usually appear normal at birth, although hernias may be present. Onset of symptoms occurs between the ages of 6 months and 2 years and may include coarse facial features, a prominent forehead, an unusually large tongue (macroglossia), misaligned teeth, and/or clouding of the corneas of the eyes. Repeated upper respiratory infections, noisy breathing, and a persistent nasal discharge may also be present. Other symptoms may include growth delays, mental retardation, joint stiffness, deafness, and/or heart disease. Hurler syndrome is inherited as an autosomal recessive genetic trait. (For more information on this disorder, choose “Hurler” as your search term in the Rare Disease Database.)Sialidosis (mucolipidosis I, type I and II) is a very rare inherited metabolic disorder characterized by a deficiency of the enzyme alpha-neuraminidase. This disorder belongs to a group of diseases known as lysosomal storage diseases. The symptoms of sialidosis type I, which typically begin during the 2nd decade of life, may include sudden involuntary muscle contractions (myoclonus), other neurological symptoms, and/or the appearance of red spots (cherry-red macules) in the eyes. The symptoms associated with sialidosis yype II may begin during infancy or later. It is characterized by the same visual abnormalities as sialidosis type I as well as other findings such as mildly coarse facial features, skeletal changes, and/or mild mental retardation. Sialidosis is inherited as an autosomal recessive genetic trait. (For more information on this disorder, choose “sialidosis” as your search term in the Rare Disease Database.)Mucolipidosis III (pseudo-Hurler polydystrophy [ML III]) is a rare inherited metabolic disorder characterized by the accumulation of certain complex carbohydrates (mucopolysaccharides) and fatty substances (mucolipids) in various tissues of the body. The symptoms of this disorder are less severe than those of I-cell disease (ML II) and may include progressive joint stiffness, curvature of the spine (scoliosis), and/or skeletal deformities of the hands (e.g., claw-hands). Growth delays accompanied by deterioration of the hip joints typically develop in children with mucolipidosis III. Other symptoms may include clouding of the corneas of the eyes, mild to moderate coarseness of facial features, mild mental retardation, easy fatigability, and/or heart disease (e.g., congestive heart failure). Mucolipidosis III is inherited as an autosomal recessive trait. For more information on this disorder, choose “Pseudo-Hurler” as your search term in the Rare Disease Database.)Galactosialidosis is a rare inherited metabolic disorder characterized by deficiencies of the enzymes neuraminidase and beta-galactosidase. Symptoms may include severe swelling of many soft tissues of the body and abdominal swelling due to the development of fluid-filled sacs (ascites). Cherry red spots in the eyes, skeletal abnormalities, abnormal enlargement of many organs of the body (visceromegaly), and/or mental retardation may also occur. Growth delays, joint stiffness, and/or coarse facial features are also characteristic of this disorder. Galactosialidosis is inherited as an autosomal recessive genetic trait.Sly syndrome (mucopolysaccharidosis VII), is an extremely rare inherited metabolic disorder characterized by a deficiency of the lysosomal enzyme known as beta-glucuronidase. This deficiency leads to the abnormal accumulation of certain complex carbohydrates (mucopolysaccharides) in many tissues and organs of the body. The symptoms of Sly Syndrome are similar to those of Hurler syndrome (MPS I) and the other mucopolysaccharidoses. Symptoms may include mental retardation, short stature with an unusually short trunk, and/or abnormalities of the intestines, corneas of the eyes, and/or the skeletal system. Sly syndrome is inherited as an autosomal recessive genetic trait. (For more information on this disorder, choose “Sly” as your search term in the Rare Disease Database.)Hunter syndrome (mucopolysaccharidosis II), is a rare inborn error of metabolism characterized by deficiency of an enzyme known as iduronate sulfatase. Initial symptoms and findings associated with Hunter syndrome usually become apparent between two to four years of age. Such abnormalities may include progressive growth delays, resulting in short stature; joint stiffness, with associated restriction of movements; and coarsening of facial features, including thickening of the lips, tongue, and nostrils. Affected children may also have an abnormally large head (macrocephaly), a short neck and broad chest, delayed tooth eruption, progressive hearing loss, and enlargement of the liver and spleen (hepatosplenomegaly). Hunter syndrome is inherited as an X-linked recessive genetic trait. (For more information on this disorder, choose “Hunter” as your search term in the Rare Disease Database.)Maroteaux-Lamy syndrome (mucopolysaccharidosis VI) occurs in three types: a classic severe type, an intermediate type, and a mild type. The syndrome is characterized by a deficiency in the enzyme arylsulfatase B (also called N- acetylgalactosamine-4-sulfatase), which leads to an excess of dermatan sulfate in the urine. In general, growth retardation occurs from two to three years of age, with coarsening of facial features and abnormalities in the bones of hands and spine. Joint stiffness also occurs. The intellect is usually normal. Maroteaux-Lamy syndrome is inherited as an autosomal recessive genetic trait. (For more information on this disorder, choose “Maroteaux” as your search term in the Rare Disease Database.)
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I Cell Disease
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nord_621_5
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Diagnosis of I Cell Disease
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I-cell disease can be diagnosed before birth (prenatally) utilizing amniocentesis or chorionic villus sampling. Amniocentesis is a procedure in which a small portion of the fluid that surrounds the fetus (amniotic fluid) is removed and cells from the fluid are then tested in the laboratory. Chorionic villus sampling (CVS) is a prenatal diagnostic procedure in which a small sample of tissue is removed from the placenta. Abnormally low levels of UDP-N-acetylglucoseamine-1-phosphotransferase enzyme activity in amniotic fluid cells or chorionic villi suggest the diagnosis of I-cell disease.The diagnosis of I-cell disease may be confirmed in an infant by a thorough clinical evaluation, patient history, and specialized laboratory testing. UDP-N-acetylglucoseamine-1-phosphotransferase enzyme activity can be measured in white blood cells or in cultured fibroblasts. Lysosomal enzymes are typically elevated in the blood serum and decreased in cultured fibroblasts.
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Diagnosis of I Cell Disease. I-cell disease can be diagnosed before birth (prenatally) utilizing amniocentesis or chorionic villus sampling. Amniocentesis is a procedure in which a small portion of the fluid that surrounds the fetus (amniotic fluid) is removed and cells from the fluid are then tested in the laboratory. Chorionic villus sampling (CVS) is a prenatal diagnostic procedure in which a small sample of tissue is removed from the placenta. Abnormally low levels of UDP-N-acetylglucoseamine-1-phosphotransferase enzyme activity in amniotic fluid cells or chorionic villi suggest the diagnosis of I-cell disease.The diagnosis of I-cell disease may be confirmed in an infant by a thorough clinical evaluation, patient history, and specialized laboratory testing. UDP-N-acetylglucoseamine-1-phosphotransferase enzyme activity can be measured in white blood cells or in cultured fibroblasts. Lysosomal enzymes are typically elevated in the blood serum and decreased in cultured fibroblasts.
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I Cell Disease
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nord_621_6
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Therapies of I Cell Disease
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TreatmentThe treatment of I-cell disease is symptomatic and supportive. Antibiotics are often prescribed for respiratory infections and yearly flu shots are important. Physical therapy is encouraged to maintain joint function and mobility as long as possible. Total hip replacement has been most effective when performed after puberty. Other orthopedic complications may be managed as they arise. Hearing aids should be considered. Sleep studies can determine the degree of obstructive sleep apnea and the need for treatment. In some cases, heart problems may be treated surgically.Genetic counseling is advised for families who have a child with this disorder.
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Therapies of I Cell Disease. TreatmentThe treatment of I-cell disease is symptomatic and supportive. Antibiotics are often prescribed for respiratory infections and yearly flu shots are important. Physical therapy is encouraged to maintain joint function and mobility as long as possible. Total hip replacement has been most effective when performed after puberty. Other orthopedic complications may be managed as they arise. Hearing aids should be considered. Sleep studies can determine the degree of obstructive sleep apnea and the need for treatment. In some cases, heart problems may be treated surgically.Genetic counseling is advised for families who have a child with this disorder.
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I Cell Disease
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nord_622_0
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Overview of Ichthyosis
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Ichthyosis is a general term for a family of rare genetic skin diseases characterized by dry, thickened, scaling skin. The various forms are distinguished from one another by: 1) extent of the scaling and how widely and where the scaling is scattered over the body; 2) the presence or absence and intensity of reddening of the skin (erythroderma); 3) the mode of inheritance; and 4) the character of associated abnormalities.
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Overview of Ichthyosis. Ichthyosis is a general term for a family of rare genetic skin diseases characterized by dry, thickened, scaling skin. The various forms are distinguished from one another by: 1) extent of the scaling and how widely and where the scaling is scattered over the body; 2) the presence or absence and intensity of reddening of the skin (erythroderma); 3) the mode of inheritance; and 4) the character of associated abnormalities.
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Ichthyosis
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Symptoms of Ichthyosis
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Ichthyosis is characterized by scaly and dry skin usually over large areas of the body. The skin may also itch (pruritis) and be red (erythroderma). Babies born with some forms of the disorder may be born covered in a parchment-like membrane called a collodion membrane.The appearance of the scales may vary; in some forms the scales may be fine and white, while in others the scales may be dark and brown and separated by deep cracks. The more severe forms of ichthyosis can cause other problems. When the skin loses moisture, it becomes dry, tight and inelastic. This rigidity can make moving uncomfortable and can cause the skin to crack and fissure. Thickening of the skin on the soles of the feet can make walking difficult and cracking around the fingers can make even simple tasks painful. In some types of ichthyosis the skin is very fragile and will rub off with the slightest abrasion. Cracks and abrasions then leave the skin open to infection. Severe scaling on the scalp may interfere with normal hair growth. Thick scales can block pores, making sweating difficult and increasing the risk of overheating. Although the outer skin is thicker in ichthyosis, it is less effective in preventing water and calorie loss by diffusion across the surface of the skin. The rapid turnover of the outer layers of the skin, in some forms of ichthyosis, requires additional energy. Because of greater energy needs, some children with severe ichthyosis may require additional calories to grow normally.Some people with ichthyosis have trouble closing their eyes completely because the surrounding skin is so tight. This condition, called ectropion, causes the eyelids to flip outward, exposing the red inner lid and causing irritation. If it is left untreated, damage to the cornea may develop leading to impaired vision.
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Symptoms of Ichthyosis. Ichthyosis is characterized by scaly and dry skin usually over large areas of the body. The skin may also itch (pruritis) and be red (erythroderma). Babies born with some forms of the disorder may be born covered in a parchment-like membrane called a collodion membrane.The appearance of the scales may vary; in some forms the scales may be fine and white, while in others the scales may be dark and brown and separated by deep cracks. The more severe forms of ichthyosis can cause other problems. When the skin loses moisture, it becomes dry, tight and inelastic. This rigidity can make moving uncomfortable and can cause the skin to crack and fissure. Thickening of the skin on the soles of the feet can make walking difficult and cracking around the fingers can make even simple tasks painful. In some types of ichthyosis the skin is very fragile and will rub off with the slightest abrasion. Cracks and abrasions then leave the skin open to infection. Severe scaling on the scalp may interfere with normal hair growth. Thick scales can block pores, making sweating difficult and increasing the risk of overheating. Although the outer skin is thicker in ichthyosis, it is less effective in preventing water and calorie loss by diffusion across the surface of the skin. The rapid turnover of the outer layers of the skin, in some forms of ichthyosis, requires additional energy. Because of greater energy needs, some children with severe ichthyosis may require additional calories to grow normally.Some people with ichthyosis have trouble closing their eyes completely because the surrounding skin is so tight. This condition, called ectropion, causes the eyelids to flip outward, exposing the red inner lid and causing irritation. If it is left untreated, damage to the cornea may develop leading to impaired vision.
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Ichthyosis
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Causes of Ichthyosis
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Most known forms of ichthyosis are hereditary disorders. Some forms are caused by dominant genes; some are caused by recessive genes.In some forms of ichthyosis, the skin cells are produced at the normal rate, but they do not separate normally at the surface of the outermost layer of skin (stratum corneum) and are not shed as quickly as they should be. In other forms, there is an overproduction of skin cells in the epidermis. The cells reach the stratum corneum in as few as four days, compared to the normal fourteen. New cells are made faster than the old cells are shed and build up in the stratum corneum and underlying layers. The result in both instances is a build up of scale.
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Causes of Ichthyosis. Most known forms of ichthyosis are hereditary disorders. Some forms are caused by dominant genes; some are caused by recessive genes.In some forms of ichthyosis, the skin cells are produced at the normal rate, but they do not separate normally at the surface of the outermost layer of skin (stratum corneum) and are not shed as quickly as they should be. In other forms, there is an overproduction of skin cells in the epidermis. The cells reach the stratum corneum in as few as four days, compared to the normal fourteen. New cells are made faster than the old cells are shed and build up in the stratum corneum and underlying layers. The result in both instances is a build up of scale.
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Ichthyosis
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Affects of Ichthyosis
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All the ichthyoses are rare disorders. Incidences vary according to disease type. The ichthyoses occur in all populations. Most forms are not bounded by gender, race or ethnicity.
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Affects of Ichthyosis. All the ichthyoses are rare disorders. Incidences vary according to disease type. The ichthyoses occur in all populations. Most forms are not bounded by gender, race or ethnicity.
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Ichthyosis
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Related disorders of Ichthyosis
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Ichthyosis congenita (collodion baby; congenital ichthyosiform erythroderma; xeroderma; desquamation of the newborn) is an inherited skin disorder. It is characterized by generalized, abnormally red, dry, and rough skin with large coarse and fine white scales. Itchiness (pruritus) usually also develops. Skin on the palms of the hands and soles of the feet can be abnormally thick. (For more information, choose “Ichthyosis Congenita” as your search term in the Rare Disease Database.)X-linked ichthyosis is an inherited skin disorder that affects males. It is caused by a deficiency of the enzyme steroid sulfatase. It is characterized by brownish scales on the back of the neck, back and legs.
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Related disorders of Ichthyosis. Ichthyosis congenita (collodion baby; congenital ichthyosiform erythroderma; xeroderma; desquamation of the newborn) is an inherited skin disorder. It is characterized by generalized, abnormally red, dry, and rough skin with large coarse and fine white scales. Itchiness (pruritus) usually also develops. Skin on the palms of the hands and soles of the feet can be abnormally thick. (For more information, choose “Ichthyosis Congenita” as your search term in the Rare Disease Database.)X-linked ichthyosis is an inherited skin disorder that affects males. It is caused by a deficiency of the enzyme steroid sulfatase. It is characterized by brownish scales on the back of the neck, back and legs.
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Ichthyosis
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nord_622_5
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Diagnosis of Ichthyosis
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Diagnosis of Ichthyosis.
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Ichthyosis
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Therapies of Ichthyosis
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The dry skin of ichthyosis is treating by applying skin softening emollients. This can be particularly effective after bathing while the skin is still moist. Lotions containing alpha-hydroxy acids, urea, or propylene glycol can also be effective. Skin barrier repair formulas containing ceramides or cholesterol may also improve scaling.Severe cases of ichthyosis may be treated systemically with oral synthetic retinoids (synthetic derivatives of Vitamin A). Retinoids are used only in severe cases due to their known bone toxicity and other complications.
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Therapies of Ichthyosis. The dry skin of ichthyosis is treating by applying skin softening emollients. This can be particularly effective after bathing while the skin is still moist. Lotions containing alpha-hydroxy acids, urea, or propylene glycol can also be effective. Skin barrier repair formulas containing ceramides or cholesterol may also improve scaling.Severe cases of ichthyosis may be treated systemically with oral synthetic retinoids (synthetic derivatives of Vitamin A). Retinoids are used only in severe cases due to their known bone toxicity and other complications.
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Ichthyosis
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nord_623_0
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Overview of Ichthyosis Hystrix, Curth Macklin Type
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Ichthyosis hystrix, Curth-Macklin type is a rare inherited skin disorder. It is characterized by scaling skin (ichthyosis) ranging from mild to severe. The patches of scaly, thickened skin range from spotty to severe, and may appear on almost any part of the body.
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Overview of Ichthyosis Hystrix, Curth Macklin Type. Ichthyosis hystrix, Curth-Macklin type is a rare inherited skin disorder. It is characterized by scaling skin (ichthyosis) ranging from mild to severe. The patches of scaly, thickened skin range from spotty to severe, and may appear on almost any part of the body.
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Ichthyosis Hystrix, Curth Macklin Type
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Symptoms of Ichthyosis Hystrix, Curth Macklin Type
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Ichthyosis hystrix, Curth-Macklin type is characterized by patches of abnormally thick, hard skin that may appear almost anywhere on the body. Some clinicians describe the skin as “horn-like”. With treatment, the patches may be considerably reduced. Under examination by electron microscopy, numerous cells (keratinocytes) with two nuclei are found. Frequently, the nuclei are surrounded by shells of a primitive, precursor protein of the skin.
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Symptoms of Ichthyosis Hystrix, Curth Macklin Type. Ichthyosis hystrix, Curth-Macklin type is characterized by patches of abnormally thick, hard skin that may appear almost anywhere on the body. Some clinicians describe the skin as “horn-like”. With treatment, the patches may be considerably reduced. Under examination by electron microscopy, numerous cells (keratinocytes) with two nuclei are found. Frequently, the nuclei are surrounded by shells of a primitive, precursor protein of the skin.
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Ichthyosis Hystrix, Curth Macklin Type
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nord_623_2
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Causes of Ichthyosis Hystrix, Curth Macklin Type
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The cause of ichthyosis hystrix, Curth Macklin type is a defect in the development of the precursor, structural protein (tonofilaments). The defect occurs as a result of a change (mutation) in the gene that produces (codes for) these proteins. The faulty gene has been mapped to chromosome 12q13.Ichthyosis Hystrix, Curth-Macklin type is an inherited disorder, 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 12q13” refers to band 13 on the long arm of chromosome 12. The numbered bands specify the location of the thousands of genes that are present on each chromosome.Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. All individuals carry 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. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.
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Causes of Ichthyosis Hystrix, Curth Macklin Type. The cause of ichthyosis hystrix, Curth Macklin type is a defect in the development of the precursor, structural protein (tonofilaments). The defect occurs as a result of a change (mutation) in the gene that produces (codes for) these proteins. The faulty gene has been mapped to chromosome 12q13.Ichthyosis Hystrix, Curth-Macklin type is an inherited disorder, 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 12q13” refers to band 13 on the long arm of chromosome 12. The numbered bands specify the location of the thousands of genes that are present on each chromosome.Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. All individuals carry 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. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.
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Ichthyosis Hystrix, Curth Macklin Type
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Affects of Ichthyosis Hystrix, Curth Macklin Type
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Ichthyosis hystrix, Curth Macklin type is a rare disorder present at birth. It affects males and females in equal numbers.
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Affects of Ichthyosis Hystrix, Curth Macklin Type. Ichthyosis hystrix, Curth Macklin type is a rare disorder present at birth. It affects males and females in equal numbers.
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Related disorders of Ichthyosis Hystrix, Curth Macklin Type
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Symptoms of the following disorders may be similar to those of Ichthyosis hystrix, Curth Macklin type. Comparisons can be useful for a differential diagnosis:“Ichthyoses” or “Disorders of Cornification” are general terms describing a group of scaly skin disorders. They are characterized by an abnormal accumulation of large amounts of dead skin cells (squames) in the top layer of the skin. The conversion of an abnormally large number of epidermal cells into squamous cells is thought to be caused by a defect in the metabolism of the skin cells known as “corneocytes” or of the fat-rich matrix around these cells. The cells can be thought of as bricks, while the matrix would be the mortar holding these cells together. (See “Ichthyosis” in the Rare Disease Database.)Lamellar ichthyosis is an inherited skin disorder characterized by generalized, abnormally red, dry and rough skin, with large, coarse scales. Itchiness (pruritus) usually also develops. Skin on the palms of the hands and soles of the feet is abnormally thick. (For more information, choose “Ichthyosis, Lamellar” as your search term in the Rare Disease Database.)X-Linked ichthyosis is an inherited skin disorder caused by a deficiency of the enzyme steroid sulfatase. This enzyme deficiency leads to biochemical alterations in the steroid sex hormone metabolism. Cholesterol sulfate may accumulate in the blood and skin. (For more information, choose “X-Linked Ichthyosis” as your search term in the Rare Disease Database.)Other forms of ichthyosis include Sjogren-Larsson syndrome, Netherton syndrome, Refsum syndrome, Darier disease, Conradi- Hunermann syndrome, Chanarin-Dorfman syndrome, and Epidermolytic hyperkeratosis. (Search under each name for more information on that disorder in the Rare Disease Database.)
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Related disorders of Ichthyosis Hystrix, Curth Macklin Type. Symptoms of the following disorders may be similar to those of Ichthyosis hystrix, Curth Macklin type. Comparisons can be useful for a differential diagnosis:“Ichthyoses” or “Disorders of Cornification” are general terms describing a group of scaly skin disorders. They are characterized by an abnormal accumulation of large amounts of dead skin cells (squames) in the top layer of the skin. The conversion of an abnormally large number of epidermal cells into squamous cells is thought to be caused by a defect in the metabolism of the skin cells known as “corneocytes” or of the fat-rich matrix around these cells. The cells can be thought of as bricks, while the matrix would be the mortar holding these cells together. (See “Ichthyosis” in the Rare Disease Database.)Lamellar ichthyosis is an inherited skin disorder characterized by generalized, abnormally red, dry and rough skin, with large, coarse scales. Itchiness (pruritus) usually also develops. Skin on the palms of the hands and soles of the feet is abnormally thick. (For more information, choose “Ichthyosis, Lamellar” as your search term in the Rare Disease Database.)X-Linked ichthyosis is an inherited skin disorder caused by a deficiency of the enzyme steroid sulfatase. This enzyme deficiency leads to biochemical alterations in the steroid sex hormone metabolism. Cholesterol sulfate may accumulate in the blood and skin. (For more information, choose “X-Linked Ichthyosis” as your search term in the Rare Disease Database.)Other forms of ichthyosis include Sjogren-Larsson syndrome, Netherton syndrome, Refsum syndrome, Darier disease, Conradi- Hunermann syndrome, Chanarin-Dorfman syndrome, and Epidermolytic hyperkeratosis. (Search under each name for more information on that disorder in the Rare Disease Database.)
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Ichthyosis Hystrix, Curth Macklin Type
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Diagnosis of Ichthyosis Hystrix, Curth Macklin Type
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Diagnosis of Ichthyosis Hystrix, Curth Macklin Type.
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Therapies of Ichthyosis Hystrix, Curth Macklin Type
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Ichthyosis hystrix, Curth-Macklin type is treated by applying skin softening (emollient) ointments, preferably plain petroleum jelly. This can be especially effective after bathing while the skin is still moist. Salicylic acid gel is another particularly effective ointment. The skin should be covered at night with an airtight, waterproof dressing when this ointment is used. Lactate lotion can also be an effective treatment for this disorder.
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Therapies of Ichthyosis Hystrix, Curth Macklin Type. Ichthyosis hystrix, Curth-Macklin type is treated by applying skin softening (emollient) ointments, preferably plain petroleum jelly. This can be especially effective after bathing while the skin is still moist. Salicylic acid gel is another particularly effective ointment. The skin should be covered at night with an airtight, waterproof dressing when this ointment is used. Lactate lotion can also be an effective treatment for this disorder.
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Ichthyosis Hystrix, Curth Macklin Type
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Overview of Ichthyosis Vulgaris
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In ichthyosis vulgaris, the skin cells are produced at a normal rate, but they do not shed normally at the surface of the outermost layer of skin (stratum corneum) and are not shed as quickly as they should be. The result is a build-up of scale. Fine scales usually develop on the back and over muscles near the joints, such as an elbow or knee (extensor muscles). Ichthyosis is usually most common and severe over the lower legs.
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Overview of Ichthyosis Vulgaris. In ichthyosis vulgaris, the skin cells are produced at a normal rate, but they do not shed normally at the surface of the outermost layer of skin (stratum corneum) and are not shed as quickly as they should be. The result is a build-up of scale. Fine scales usually develop on the back and over muscles near the joints, such as an elbow or knee (extensor muscles). Ichthyosis is usually most common and severe over the lower legs.
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Ichthyosis Vulgaris
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Symptoms of Ichthyosis Vulgaris
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Ichthyosis vulgaris is an inherited skin disorder, which begins during the first year of life, although it is usually not present at birth. Symptoms in different patients vary in severity, from mild to severe. The scale is usually fine and white. Only a portion of the body may be involved, but scaling is most common and most severe on the lower legs. Scaling on the torso is less severe and the face is usually unaffected. If the face is affected, the scaling is usually limited to the cheeks and forehead. The sides of the neck and the flexural areas are usually spared. Often, the skin on the palms of the hands and soles of the feet is thickened and may have exaggerated lines.A skin allergy or eczema (atopic dermatitis) may accompany symptoms in approximately half of patients with this disorder. This disorder tends to improve with age. Symptoms can also improve in warm humid climates or during the summer months.
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Symptoms of Ichthyosis Vulgaris. Ichthyosis vulgaris is an inherited skin disorder, which begins during the first year of life, although it is usually not present at birth. Symptoms in different patients vary in severity, from mild to severe. The scale is usually fine and white. Only a portion of the body may be involved, but scaling is most common and most severe on the lower legs. Scaling on the torso is less severe and the face is usually unaffected. If the face is affected, the scaling is usually limited to the cheeks and forehead. The sides of the neck and the flexural areas are usually spared. Often, the skin on the palms of the hands and soles of the feet is thickened and may have exaggerated lines.A skin allergy or eczema (atopic dermatitis) may accompany symptoms in approximately half of patients with this disorder. This disorder tends to improve with age. Symptoms can also improve in warm humid climates or during the summer months.
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Ichthyosis Vulgaris
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Causes of Ichthyosis Vulgaris
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Ichthyosis vulgaris is an inherited disorder transmitted through an autosomal dominant inheritance. The specific genetic defect that causes ichthyosis vulgaris is not yet identified. Human traits, including classic genetic diseases, are the product of the interaction of two genes for that condition, one received from the father and one from the mother. In dominant disorders, a single copy of the disease gene (received from either the mother or the father) will be expressed, dominating the other normal gene and resulting in the appearance of the disease. In the case of ichthyosis vulgaris, the gene for the disease overrides the gene for normal skin and the individual shows the disease. The risk of transmitting the disorder from an affected parent to offspring is 50 percent for each pregnancy, regardless of the sex of the child.
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Causes of Ichthyosis Vulgaris. Ichthyosis vulgaris is an inherited disorder transmitted through an autosomal dominant inheritance. The specific genetic defect that causes ichthyosis vulgaris is not yet identified. Human traits, including classic genetic diseases, are the product of the interaction of two genes for that condition, one received from the father and one from the mother. In dominant disorders, a single copy of the disease gene (received from either the mother or the father) will be expressed, dominating the other normal gene and resulting in the appearance of the disease. In the case of ichthyosis vulgaris, the gene for the disease overrides the gene for normal skin and the individual shows the disease. The risk of transmitting the disorder from an affected parent to offspring is 50 percent for each pregnancy, regardless of the sex of the child.
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Ichthyosis Vulgaris
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Affects of Ichthyosis Vulgaris
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Ichthyosis vulgaris is a fairly common disorder that affects approximately one in 250 persons in the United States. Males and females are affected in equal numbers.
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Affects of Ichthyosis Vulgaris. Ichthyosis vulgaris is a fairly common disorder that affects approximately one in 250 persons in the United States. Males and females are affected in equal numbers.
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Ichthyosis Vulgaris
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Related disorders of Ichthyosis Vulgaris
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Symptoms of the following disorders may be similar to those of ichthyosis vulgaris. Comparisons can be useful for a differential diagnosis.“Ichthyoses” or “disorders of cornification” are general terms describing a group of scaly skin disorders. They are characterized by an abnormal accumulation of large amounts of dead skin cells (squames) in the top layer of the skin. The conversion of an abnormally large number of epidermal cells into squamous cells is thought to be caused by a defect in the metabolism of the skin cells known as “corneocytes” or the fat-rich matrix around these cells. These cells can be thought of as bricks, while the matrix would be the mortar holding these cells together. (See “Ichthyosis” in the Rare Disease Database.)Ichthyosis congenita (collodion baby; congenital ichthyosiform erythroderma; xeroderma; desquamation of the newborn) is an inherited skin disorder. It is characterized by generalized, abnormally red, dry, and rough skin with large coarse and fine white scales. Itchiness (pruritus) usually also develops. Skin on the palms of the hands and soles of the feet can be abnormally thick. (For more information, choose “Ichthyosis Congenita” as your search term in the Rare Disease Database.)X-linked ichthyosis is an inherited skin disorder that affects males. It is caused by a deficiency of the enzyme steroid sulfatase. It is characterized by brownish scales on the back of the neck, back and legs.
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Related disorders of Ichthyosis Vulgaris. Symptoms of the following disorders may be similar to those of ichthyosis vulgaris. Comparisons can be useful for a differential diagnosis.“Ichthyoses” or “disorders of cornification” are general terms describing a group of scaly skin disorders. They are characterized by an abnormal accumulation of large amounts of dead skin cells (squames) in the top layer of the skin. The conversion of an abnormally large number of epidermal cells into squamous cells is thought to be caused by a defect in the metabolism of the skin cells known as “corneocytes” or the fat-rich matrix around these cells. These cells can be thought of as bricks, while the matrix would be the mortar holding these cells together. (See “Ichthyosis” in the Rare Disease Database.)Ichthyosis congenita (collodion baby; congenital ichthyosiform erythroderma; xeroderma; desquamation of the newborn) is an inherited skin disorder. It is characterized by generalized, abnormally red, dry, and rough skin with large coarse and fine white scales. Itchiness (pruritus) usually also develops. Skin on the palms of the hands and soles of the feet can be abnormally thick. (For more information, choose “Ichthyosis Congenita” as your search term in the Rare Disease Database.)X-linked ichthyosis is an inherited skin disorder that affects males. It is caused by a deficiency of the enzyme steroid sulfatase. It is characterized by brownish scales on the back of the neck, back and legs.
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Ichthyosis Vulgaris
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Diagnosis of Ichthyosis Vulgaris
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Diagnosis of Ichthyosis Vulgaris.
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Ichthyosis Vulgaris
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Therapies of Ichthyosis Vulgaris
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Ichthyosis vulgaris is treated topically with moisturizers containing urea or glycerol. Lotions containing alpha-hydroxy acids may help. However, some individuals with ichthyosis vulgaris also may experience atopic dermatitis (red, itchy patches of skin) and the alpha-hydroxy acids may irritate their skin.
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Therapies of Ichthyosis Vulgaris. Ichthyosis vulgaris is treated topically with moisturizers containing urea or glycerol. Lotions containing alpha-hydroxy acids may help. However, some individuals with ichthyosis vulgaris also may experience atopic dermatitis (red, itchy patches of skin) and the alpha-hydroxy acids may irritate their skin.
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Ichthyosis Vulgaris
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Overview of Ichthyosis, CHILD Syndrome
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CHILD syndrome (an acronym for congenital hemidysplasia with ichthyosiform erythroderma and limb defects) is an inherited disorder, affecting primarily women, that is characterized by ichthyosis-like skin abnormalities and limb defects on one side of the body. Other abnormalities may be present, as well.If defects of other body organs are present, they are usually on the same side of the body as the skin and limb abnormalities.
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Overview of Ichthyosis, CHILD Syndrome. CHILD syndrome (an acronym for congenital hemidysplasia with ichthyosiform erythroderma and limb defects) is an inherited disorder, affecting primarily women, that is characterized by ichthyosis-like skin abnormalities and limb defects on one side of the body. Other abnormalities may be present, as well.If defects of other body organs are present, they are usually on the same side of the body as the skin and limb abnormalities.
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Ichthyosis, CHILD Syndrome
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Symptoms of Ichthyosis, CHILD Syndrome
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CHILD syndrome is usually present at birth. It may first become apparent at some point during the first month of life. The skin is usually dry, itchy, red and scaly (ichthyosiform erythroderma) on one side of the body, although minor skin involvement in the shape of lines or segments may occur on the opposite side of the body. Bands of normal skin may be found on the affected side as well. Patients with CHILD syndrome may be bald on one side of the head and have clawlike nails. Limb defects usually occur on the same side of the body as the major skin symptoms. These defects may range from underdevelopment of fingers and toes to complete absence of a limb. Some of the types of skeletal defects that might occur include abnormal ribs, anomalies of the shoulder blades (scapula), webbing of the skin between joints, and absence of muscles of the breast (pectoral).Heart defects sometimes associated with this syndrome include defects in the walls between auricles and/or ventricles, as well as complex heart disease in which less than adequate amounts of oxygen get to the organ (cyanosis). Abnormalities of the central nervous system, blood vessels, kidneys, thyroid, lungs and adrenal glands, and of the reproductive and urinary system, may also occur. Most of these abnormalities result from underdevelopment of the affected side of the body.
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Symptoms of Ichthyosis, CHILD Syndrome. CHILD syndrome is usually present at birth. It may first become apparent at some point during the first month of life. The skin is usually dry, itchy, red and scaly (ichthyosiform erythroderma) on one side of the body, although minor skin involvement in the shape of lines or segments may occur on the opposite side of the body. Bands of normal skin may be found on the affected side as well. Patients with CHILD syndrome may be bald on one side of the head and have clawlike nails. Limb defects usually occur on the same side of the body as the major skin symptoms. These defects may range from underdevelopment of fingers and toes to complete absence of a limb. Some of the types of skeletal defects that might occur include abnormal ribs, anomalies of the shoulder blades (scapula), webbing of the skin between joints, and absence of muscles of the breast (pectoral).Heart defects sometimes associated with this syndrome include defects in the walls between auricles and/or ventricles, as well as complex heart disease in which less than adequate amounts of oxygen get to the organ (cyanosis). Abnormalities of the central nervous system, blood vessels, kidneys, thyroid, lungs and adrenal glands, and of the reproductive and urinary system, may also occur. Most of these abnormalities result from underdevelopment of the affected side of the body.
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Ichthyosis, CHILD Syndrome
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Causes of Ichthyosis, CHILD Syndrome
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CHILD syndrome is a hereditary disorder transmitted as an X-linked dominant trait. The faulty gene is on the long arm of the X chromosome (Xq28). The protein/enzyme product coded by the gene has been identified as NSDHL and governs an essential step in the biosynthesis of cholesterol.Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome Xq28” refers to band 28 on the long arm of the X-chromosome. The numbered bands specify the location of the thousands of genes that are present on each chromosome.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.X-linked dominant disorders are caused by an abnormal gene on the X chromosome, but in these rare conditions, females with an abnormal gene are affected with the disease. Males with an abnormal gene are more severely affected than females, and many of these males do not survive.
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Causes of Ichthyosis, CHILD Syndrome. CHILD syndrome is a hereditary disorder transmitted as an X-linked dominant trait. The faulty gene is on the long arm of the X chromosome (Xq28). The protein/enzyme product coded by the gene has been identified as NSDHL and governs an essential step in the biosynthesis of cholesterol.Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome Xq28” refers to band 28 on the long arm of the X-chromosome. The numbered bands specify the location of the thousands of genes that are present on each chromosome.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.X-linked dominant disorders are caused by an abnormal gene on the X chromosome, but in these rare conditions, females with an abnormal gene are affected with the disease. Males with an abnormal gene are more severely affected than females, and many of these males do not survive.
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Ichthyosis, CHILD Syndrome
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Affects of Ichthyosis, CHILD Syndrome
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Only about 30 cases have been reported in the United States and of these 29 involved infant girls and only 1 involved a boy. Of these 30 cases, only 6 cases involved organs or systems on the left side of the body.
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Affects of Ichthyosis, CHILD Syndrome. Only about 30 cases have been reported in the United States and of these 29 involved infant girls and only 1 involved a boy. Of these 30 cases, only 6 cases involved organs or systems on the left side of the body.
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Ichthyosis, CHILD Syndrome
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Related disorders of Ichthyosis, CHILD Syndrome
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Symptoms of the following disorders may resemble those of CHILD Syndrome. Comparisons may be useful for a differential diagnosis:Conradi-Hunermann Syndrome is a form of Chondrodysplasia Punctata. It is a rare inherited disorder affecting infants and young children. This disorder is characterized by mild to moderate growth deficiencies including a shortened neck and slowed growth of arms or legs. Unusual facial characteristics, large skin pores and sparse hair that tends to be coarse may also occur. (For more information, choose “Conradi-Hunermann Syndrome” as your search term in the Rare Disease Database.)“Ichthyoses” or “Disorders of Cornification” are general terms describing a group of scaly skin disorders. They are characterized by an abnormal accumulation of large amounts of dead skin cells (squames) in the top layer of the skin. The conversion of an abnormally large number of epidermal cells into squamous cells is thought to be caused by a defect in the metabolism of skin cells known as “corneocytes” or of the fat-rich matrix around these cells. The cells can be thought of as bricks, while the matrix would be the mortar holding these cells together. (See “Ichthyosis” in the Rare Disease Database.)Other forms of Ichthyosis include Sjogren-Larsson Syndrome, Netherton Syndrome, Ichthyosis Hystrix, Lamellar Ichthyosis, Refsum Syndrome, Darier Disease, Chanarin-Dorfman Syndrome, and Epidermolytic Hyperkeratosis. (Choose the appropriate name as your search term for more information on that disorder in the Rare Disease Database.
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Related disorders of Ichthyosis, CHILD Syndrome. Symptoms of the following disorders may resemble those of CHILD Syndrome. Comparisons may be useful for a differential diagnosis:Conradi-Hunermann Syndrome is a form of Chondrodysplasia Punctata. It is a rare inherited disorder affecting infants and young children. This disorder is characterized by mild to moderate growth deficiencies including a shortened neck and slowed growth of arms or legs. Unusual facial characteristics, large skin pores and sparse hair that tends to be coarse may also occur. (For more information, choose “Conradi-Hunermann Syndrome” as your search term in the Rare Disease Database.)“Ichthyoses” or “Disorders of Cornification” are general terms describing a group of scaly skin disorders. They are characterized by an abnormal accumulation of large amounts of dead skin cells (squames) in the top layer of the skin. The conversion of an abnormally large number of epidermal cells into squamous cells is thought to be caused by a defect in the metabolism of skin cells known as “corneocytes” or of the fat-rich matrix around these cells. The cells can be thought of as bricks, while the matrix would be the mortar holding these cells together. (See “Ichthyosis” in the Rare Disease Database.)Other forms of Ichthyosis include Sjogren-Larsson Syndrome, Netherton Syndrome, Ichthyosis Hystrix, Lamellar Ichthyosis, Refsum Syndrome, Darier Disease, Chanarin-Dorfman Syndrome, and Epidermolytic Hyperkeratosis. (Choose the appropriate name as your search term for more information on that disorder in the Rare Disease Database.
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Ichthyosis, CHILD Syndrome
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Diagnosis of Ichthyosis, CHILD Syndrome
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A thorough physical exam may be sufficient for the diagnosis.
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Diagnosis of Ichthyosis, CHILD Syndrome. A thorough physical exam may be sufficient for the diagnosis.
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Ichthyosis, CHILD Syndrome
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Therapies of Ichthyosis, CHILD Syndrome
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TreatmentSkin (dermatologic) symptoms of CHILD syndrome are treated by applying skin softening (emollient) ointments, preferably plain petroleum jelly. This can be especially effective after bathing while the skin is still moist. Salicylic acid gel is another particularly effective ointment. The skin should be covered at night with an airtight, waterproof dressing when this ointment is used. Lactate lotion can also be an effective treatment for the skin symptoms of this disorder.Drugs derived from Vitamin A (retinoids) such as tretinoin, motretinide, and etretinate can be effective against dermatologic symptoms of CHILD syndrome. but can cause toxic effects on the bones in some cases. A synthetic derivative of Vitamin A, isotretinoin (accutane), when taken by pregnant women, can cause severe birth defects to the fetus. These Vitamin A compounds have not yet been approved by the Food and Drug Administration (FDA) for treatment of Ichthyosis.Other treatment is symptomatic and supportive. Genetic counseling may be helpful to families of patients with CHILD syndrome.
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Therapies of Ichthyosis, CHILD Syndrome. TreatmentSkin (dermatologic) symptoms of CHILD syndrome are treated by applying skin softening (emollient) ointments, preferably plain petroleum jelly. This can be especially effective after bathing while the skin is still moist. Salicylic acid gel is another particularly effective ointment. The skin should be covered at night with an airtight, waterproof dressing when this ointment is used. Lactate lotion can also be an effective treatment for the skin symptoms of this disorder.Drugs derived from Vitamin A (retinoids) such as tretinoin, motretinide, and etretinate can be effective against dermatologic symptoms of CHILD syndrome. but can cause toxic effects on the bones in some cases. A synthetic derivative of Vitamin A, isotretinoin (accutane), when taken by pregnant women, can cause severe birth defects to the fetus. These Vitamin A compounds have not yet been approved by the Food and Drug Administration (FDA) for treatment of Ichthyosis.Other treatment is symptomatic and supportive. Genetic counseling may be helpful to families of patients with CHILD syndrome.
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Ichthyosis, CHILD Syndrome
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Overview of Ichthyosis, Netherton Syndrome
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Netherton syndrome is a rare hereditary disorder characterized by scaling skin, hair anomalies, increased susceptibility to atopic eczema (a skin condition that can result in dry, red and flaky skin), elevated IgE levels, and other related symptoms. Netherton syndrome is inherited as an autosomal recessive trait.
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Overview of Ichthyosis, Netherton Syndrome. Netherton syndrome is a rare hereditary disorder characterized by scaling skin, hair anomalies, increased susceptibility to atopic eczema (a skin condition that can result in dry, red and flaky skin), elevated IgE levels, and other related symptoms. Netherton syndrome is inherited as an autosomal recessive trait.
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Ichthyosis, Netherton Syndrome
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Symptoms of Ichthyosis, Netherton Syndrome
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Newborns with Netherton syndrome have reddened skin (erythroderma) and sometimes a thick parchment-like covering of skin (collodion membrane). The skin is red and scaly all over. Hair shafts are fragile and break easily due to trichorrhexis or “bamboo hair”, resulting in short sparse hair. In older children and adults the scaling may have a distinctive circular pattern (ichthyosis linearis circumflexa). Another characteristic of Netherton syndrome is a predisposition to allergies, asthma, and eczema.Babies with Netherton syndrome may be born prematurely. Trouble gaining weight in infancy and childhood is common and can be severe. Infants may also have recurrent skin infections and septicemia. They may develop hypernatremia (elevated sodium levels in the blood) due to excessive loss of fluid from the skin surface. Because hairs may not be affected at birth, and then may be sparse in all babies in the first months of life, the characteristic hair defect that is diagnostic of Netherton syndrome may not be detected initially.Infants with Netherton syndrome may be misdiagnosed as having CIE (congenital ichthyosiform erythroderma), atopic dermatitis or psoriasis. Atopic dermatitis (red, itchy patches of skin) may be present and a cradle cap-like scale and redness may appear on the face, scalp and eyebrows.
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Symptoms of Ichthyosis, Netherton Syndrome. Newborns with Netherton syndrome have reddened skin (erythroderma) and sometimes a thick parchment-like covering of skin (collodion membrane). The skin is red and scaly all over. Hair shafts are fragile and break easily due to trichorrhexis or “bamboo hair”, resulting in short sparse hair. In older children and adults the scaling may have a distinctive circular pattern (ichthyosis linearis circumflexa). Another characteristic of Netherton syndrome is a predisposition to allergies, asthma, and eczema.Babies with Netherton syndrome may be born prematurely. Trouble gaining weight in infancy and childhood is common and can be severe. Infants may also have recurrent skin infections and septicemia. They may develop hypernatremia (elevated sodium levels in the blood) due to excessive loss of fluid from the skin surface. Because hairs may not be affected at birth, and then may be sparse in all babies in the first months of life, the characteristic hair defect that is diagnostic of Netherton syndrome may not be detected initially.Infants with Netherton syndrome may be misdiagnosed as having CIE (congenital ichthyosiform erythroderma), atopic dermatitis or psoriasis. Atopic dermatitis (red, itchy patches of skin) may be present and a cradle cap-like scale and redness may appear on the face, scalp and eyebrows.
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Ichthyosis, Netherton Syndrome
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nord_626_2
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Causes of Ichthyosis, Netherton Syndrome
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The mutation that causes Netherton syndrome has been pinpointed to the gene SPINK5 located on the long arm (q) of chromosome 5 (5q32). This mutation is transmitted by autosomal recessive inheritance. Individuals must inherit two recessive genes in order to show the disorder, with each parent donating one mutated gene. The parents (carriers) show no evidence of Netherton syndrome.The SPINK5 gene encodes a protein that serves as the brake on the activity of certain proteases (enzymes that digest proteins) in the skin protein. Increased protease action in the skin results in too few layers of the outer skin (stratum corneum), not in too many layers as in other forms of ichthyosis.
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Causes of Ichthyosis, Netherton Syndrome. The mutation that causes Netherton syndrome has been pinpointed to the gene SPINK5 located on the long arm (q) of chromosome 5 (5q32). This mutation is transmitted by autosomal recessive inheritance. Individuals must inherit two recessive genes in order to show the disorder, with each parent donating one mutated gene. The parents (carriers) show no evidence of Netherton syndrome.The SPINK5 gene encodes a protein that serves as the brake on the activity of certain proteases (enzymes that digest proteins) in the skin protein. Increased protease action in the skin results in too few layers of the outer skin (stratum corneum), not in too many layers as in other forms of ichthyosis.
| 626 |
Ichthyosis, Netherton Syndrome
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nord_626_3
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Affects of Ichthyosis, Netherton Syndrome
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Netherton syndrome is a rare hereditary disorder. There are approximately 150 cases reported in the medical literature, but the true number of affected individuals may be much higher due to diagnostic difficulties and overlapping symptoms with common atopic dermatitis and other congenital ichthyoses.
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Affects of Ichthyosis, Netherton Syndrome. Netherton syndrome is a rare hereditary disorder. There are approximately 150 cases reported in the medical literature, but the true number of affected individuals may be much higher due to diagnostic difficulties and overlapping symptoms with common atopic dermatitis and other congenital ichthyoses.
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Ichthyosis, Netherton Syndrome
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nord_626_4
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Related disorders of Ichthyosis, Netherton Syndrome
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Symptoms of the following disorders may be similar to those of Netherton syndrome. Comparisons can be useful for a differential diagnosis.Ichthyoses or “disorders of cornification” are general terms describing a group of scaly skin disorders. They are characterized by an abnormal accumulation of large amounts of dead skin cells (squames) in the top layer of the skin. The conversion of an abnormally large number of epidermal cells into squamous cells is thought to be caused by a defect in the metabolism of the skin cells known as “corneocytes” or the fat-rich matrix around these cells. These cells can be thought of as bricks, while the matrix would be the mortar holding these cells together. (See “Ichthyosis” in the Rare Disease Database.)Ichthyosis congenita (collodion baby; congenital ichthyosiform erythroderma; xeroderma; desquamation of the newborn) is an inherited skin disorder. It is characterized by generalized, abnormally red, dry, and rough skin with large coarse and fine white scales. Itchiness (pruritus) usually also develops. Skin on the palms of the hands and soles of the feet can be abnormally thick. (For more information, choose “Ichthyosis Congenita” as your search term in the Rare Disease Database.)X-linked ichthyosis is an inherited skin disorder that affects males. It is caused by a deficiency of the enzyme steroid sulfatase. It is characterized by brownish scales on the back of the neck, back and legs.
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Related disorders of Ichthyosis, Netherton Syndrome. Symptoms of the following disorders may be similar to those of Netherton syndrome. Comparisons can be useful for a differential diagnosis.Ichthyoses or “disorders of cornification” are general terms describing a group of scaly skin disorders. They are characterized by an abnormal accumulation of large amounts of dead skin cells (squames) in the top layer of the skin. The conversion of an abnormally large number of epidermal cells into squamous cells is thought to be caused by a defect in the metabolism of the skin cells known as “corneocytes” or the fat-rich matrix around these cells. These cells can be thought of as bricks, while the matrix would be the mortar holding these cells together. (See “Ichthyosis” in the Rare Disease Database.)Ichthyosis congenita (collodion baby; congenital ichthyosiform erythroderma; xeroderma; desquamation of the newborn) is an inherited skin disorder. It is characterized by generalized, abnormally red, dry, and rough skin with large coarse and fine white scales. Itchiness (pruritus) usually also develops. Skin on the palms of the hands and soles of the feet can be abnormally thick. (For more information, choose “Ichthyosis Congenita” as your search term in the Rare Disease Database.)X-linked ichthyosis is an inherited skin disorder that affects males. It is caused by a deficiency of the enzyme steroid sulfatase. It is characterized by brownish scales on the back of the neck, back and legs.
| 626 |
Ichthyosis, Netherton Syndrome
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nord_626_5
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Diagnosis of Ichthyosis, Netherton Syndrome
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Diagnosis of Ichthyosis, Netherton Syndrome.
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Ichthyosis, Netherton Syndrome
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nord_626_6
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Therapies of Ichthyosis, Netherton Syndrome
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The treatment of Netherton syndrome is symptomatic, often difficult, and should be tailored to the patient's specific needs. Recommendations include the regular use of emollients and moisturizing creams and lotions. Other topical agents should be used with caution because the skin in Netherton syndrome may allow ingredients from some topically applied medications to be absorbed into the blood, which may pose a danger to the child. Topical keratolytic agents such as urea or lactic acid derivatives may be limited by skin irritation and should generally be reserved for older children. The base line treatment also includes oral antihistamines, which can help to control the itchy, eczematous component, and topical or systemic antibiotics as needed. To treat the scaling of the scalp, mild dandruff shampoos and topical steroids might be helpful. Oral and topical steroids are beneficial in reducing inflammation and the eczematous component of the disease. However, the well-documented side effects of long-term steroid use need to be considered. Oral retinoids have been used with varying success, leading to dramatic improvement in some patients and severe worsening of the disease in others.Molecular Diagnostic testing for Netherton syndrome is offered by:Gabriele Richard, MDAssociate Professor, Department of Dermatology and Cutaneous Biology andDepartment of Medicine / Division of Medical GeneticsThomas Jefferson Unversity233 S. 10th. Street, BLSB Suite 409Philadelphia, PA 19107Telephone: ( 215) 503-8259 (lab)Fax: (215) 503-5788Email. [email protected]
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Therapies of Ichthyosis, Netherton Syndrome. The treatment of Netherton syndrome is symptomatic, often difficult, and should be tailored to the patient's specific needs. Recommendations include the regular use of emollients and moisturizing creams and lotions. Other topical agents should be used with caution because the skin in Netherton syndrome may allow ingredients from some topically applied medications to be absorbed into the blood, which may pose a danger to the child. Topical keratolytic agents such as urea or lactic acid derivatives may be limited by skin irritation and should generally be reserved for older children. The base line treatment also includes oral antihistamines, which can help to control the itchy, eczematous component, and topical or systemic antibiotics as needed. To treat the scaling of the scalp, mild dandruff shampoos and topical steroids might be helpful. Oral and topical steroids are beneficial in reducing inflammation and the eczematous component of the disease. However, the well-documented side effects of long-term steroid use need to be considered. Oral retinoids have been used with varying success, leading to dramatic improvement in some patients and severe worsening of the disease in others.Molecular Diagnostic testing for Netherton syndrome is offered by:Gabriele Richard, MDAssociate Professor, Department of Dermatology and Cutaneous Biology andDepartment of Medicine / Division of Medical GeneticsThomas Jefferson Unversity233 S. 10th. Street, BLSB Suite 409Philadelphia, PA 19107Telephone: ( 215) 503-8259 (lab)Fax: (215) 503-5788Email. [email protected]
| 626 |
Ichthyosis, Netherton Syndrome
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nord_627_0
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Overview of Ichthyosis, X Linked
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X-linked ichthyosis is a genetic skin disorder that affects males. It is an inborn error of metabolism characterized by a deficiency of the enzyme steroid sulfatase. Under normal conditions, this enzyme breaks down (metabolizes) cholesterol sulfate, a member of the chemical family of steroids. Cholesterol sulfate plays a role in maintaining the integrity of the skin. If steroid metabolism is interrupted and cholesterol sulfate accumulates in the skin cells, the skin cells stick together more strongly than usual. The normal shedding of dead skin cells is inhibited and the skin cells build up and clump into scales.
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Overview of Ichthyosis, X Linked. X-linked ichthyosis is a genetic skin disorder that affects males. It is an inborn error of metabolism characterized by a deficiency of the enzyme steroid sulfatase. Under normal conditions, this enzyme breaks down (metabolizes) cholesterol sulfate, a member of the chemical family of steroids. Cholesterol sulfate plays a role in maintaining the integrity of the skin. If steroid metabolism is interrupted and cholesterol sulfate accumulates in the skin cells, the skin cells stick together more strongly than usual. The normal shedding of dead skin cells is inhibited and the skin cells build up and clump into scales.
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Ichthyosis, X Linked
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nord_627_1
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Symptoms of Ichthyosis, X Linked
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Boys with X-linked ichthyosis appear normal at birth. The skin symptoms generally appear within the first year of life. Brownish scales that adhere to the skin are among the first signs of the disorder. The back and legs are most frequently involved early. The face, scalp, palms and soles, and hollows of the elbows and knees are usually spared.In about half of adult males, comma-shaped corneal opacities occur in the eyes (seen on exam by an ophthalmologist), but they do not interfere with vision. Symptoms can improve markedly in the summer months and warm humid climates. A small percentage of males may experience undescended testes (crytpchordism). These men may be at increased risk for contracting malignancies of the testes.Women who are carriers of X-linked ichthyosis and give birth to sons with the disorder may experience a delay in labor or failure of labor to initiate. The enzyme defect can cause a decrease in production of maternal estriol in late pregnancy, which may affect labor and delivery. Low serum estriol levels detected by prenatal screening suggest the presence of a fetus with X-linked ichthyosis.
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Symptoms of Ichthyosis, X Linked. Boys with X-linked ichthyosis appear normal at birth. The skin symptoms generally appear within the first year of life. Brownish scales that adhere to the skin are among the first signs of the disorder. The back and legs are most frequently involved early. The face, scalp, palms and soles, and hollows of the elbows and knees are usually spared.In about half of adult males, comma-shaped corneal opacities occur in the eyes (seen on exam by an ophthalmologist), but they do not interfere with vision. Symptoms can improve markedly in the summer months and warm humid climates. A small percentage of males may experience undescended testes (crytpchordism). These men may be at increased risk for contracting malignancies of the testes.Women who are carriers of X-linked ichthyosis and give birth to sons with the disorder may experience a delay in labor or failure of labor to initiate. The enzyme defect can cause a decrease in production of maternal estriol in late pregnancy, which may affect labor and delivery. Low serum estriol levels detected by prenatal screening suggest the presence of a fetus with X-linked ichthyosis.
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Ichthyosis, X Linked
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nord_627_2
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Causes of Ichthyosis, X Linked
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X-linked recessive disorders are conditions that are coded on the X chromosome. Females have two X chromosomes; males have one X chromosome and one Y chromosome. Therefore, in females, the normal gene on one X chromosome can mask disease traits on the other X chromosome. Since males have only one X chromosome, if they inherit the gene for a disease present on the X they will express the disease. Men with X-linked disorders transmit the gene to all their daughters, who are carriers, but never to their sons. Women who are carriers of an X-linked disorder have a 50 percent chance of transmitting the carrier condition to their daughters and a 50 percent risk of transmitting the disease to their sons.
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Causes of Ichthyosis, X Linked. X-linked recessive disorders are conditions that are coded on the X chromosome. Females have two X chromosomes; males have one X chromosome and one Y chromosome. Therefore, in females, the normal gene on one X chromosome can mask disease traits on the other X chromosome. Since males have only one X chromosome, if they inherit the gene for a disease present on the X they will express the disease. Men with X-linked disorders transmit the gene to all their daughters, who are carriers, but never to their sons. Women who are carriers of an X-linked disorder have a 50 percent chance of transmitting the carrier condition to their daughters and a 50 percent risk of transmitting the disease to their sons.
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Ichthyosis, X Linked
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nord_627_3
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Affects of Ichthyosis, X Linked
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X-linked ichthyosis is a rare disorder affecting one in 6,000 males.
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Affects of Ichthyosis, X Linked. X-linked ichthyosis is a rare disorder affecting one in 6,000 males.
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Ichthyosis, X Linked
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nord_627_4
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Related disorders of Ichthyosis, X Linked
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Symptoms of the following disorders may be similar to those of X-linked ichthyosis. Comparisons can be useful for a differential diagnosis.“Ichthyoses” or “disorders of cornification” are general terms describing a group of scaly skin disorders. They are characterized by an abnormal accumulation of large amounts of dead skin cells (squames) in the top layer of the skin. The conversion of an abnormally large number of epidermal cells into squamous cells is thought to be caused by a defect in the metabolism of the skin cells known as “corneocytes” or the fat-rich matrix around these cells. These cells can be thought of as bricks, while the matrix would be the mortar holding these cells together. (See “Ichthyosis” in the Rare Disease Database.)Ichthyosis congenita (collodion baby; congenital ichthyosiform erythroderma; xeroderma; desquamation of the newborn) is an inherited skin disorder. It is characterized by generalized, abnormally red, dry, and rough skin with large coarse and fine white scales. Itchiness (pruritus) usually also develops. Skin on the palms of the hands and soles of the feet can be abnormally thick. (For more information, choose “Ichthyosis Congenita” as your search term in the Rare Disease Database.)Other forms of ichthyosis include Sjogren-Larsson syndrome, Netherton syndrome, ichthyosis hystrix, lamellar ichthyosis, Darier disease, and epidermolytic hyperkeratosis. (Search under each name for more information on that disorder in the Rare Disease Database.)
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Related disorders of Ichthyosis, X Linked. Symptoms of the following disorders may be similar to those of X-linked ichthyosis. Comparisons can be useful for a differential diagnosis.“Ichthyoses” or “disorders of cornification” are general terms describing a group of scaly skin disorders. They are characterized by an abnormal accumulation of large amounts of dead skin cells (squames) in the top layer of the skin. The conversion of an abnormally large number of epidermal cells into squamous cells is thought to be caused by a defect in the metabolism of the skin cells known as “corneocytes” or the fat-rich matrix around these cells. These cells can be thought of as bricks, while the matrix would be the mortar holding these cells together. (See “Ichthyosis” in the Rare Disease Database.)Ichthyosis congenita (collodion baby; congenital ichthyosiform erythroderma; xeroderma; desquamation of the newborn) is an inherited skin disorder. It is characterized by generalized, abnormally red, dry, and rough skin with large coarse and fine white scales. Itchiness (pruritus) usually also develops. Skin on the palms of the hands and soles of the feet can be abnormally thick. (For more information, choose “Ichthyosis Congenita” as your search term in the Rare Disease Database.)Other forms of ichthyosis include Sjogren-Larsson syndrome, Netherton syndrome, ichthyosis hystrix, lamellar ichthyosis, Darier disease, and epidermolytic hyperkeratosis. (Search under each name for more information on that disorder in the Rare Disease Database.)
| 627 |
Ichthyosis, X Linked
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nord_627_5
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Diagnosis of Ichthyosis, X Linked
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Diagnosis of Ichthyosis, X Linked.
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Ichthyosis, X Linked
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nord_627_6
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Therapies of Ichthyosis, X Linked
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X-linked ichthyosis can be diagnosed before birth by amniocentesis or chorionic villus sampling. Low maternal estriol levels can suggest the presence of X-linked ichthyosis.X-linked ichthyosis is treated by applying skin softening creams and lotions. This can be especially effective after bathing while the skin is still moist. X-linked ichthyosis responds relatively well to topical treatment with alpha-hydroxy acids, which accelerate the shedding of the dead skin cells. Cholesterol containing emollients may also improve the scaling. Alpha-hydroxy acids may sting the skin of babies and young children and should be used cautiously or in combination with another mild emollient product.
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Therapies of Ichthyosis, X Linked. X-linked ichthyosis can be diagnosed before birth by amniocentesis or chorionic villus sampling. Low maternal estriol levels can suggest the presence of X-linked ichthyosis.X-linked ichthyosis is treated by applying skin softening creams and lotions. This can be especially effective after bathing while the skin is still moist. X-linked ichthyosis responds relatively well to topical treatment with alpha-hydroxy acids, which accelerate the shedding of the dead skin cells. Cholesterol containing emollients may also improve the scaling. Alpha-hydroxy acids may sting the skin of babies and young children and should be used cautiously or in combination with another mild emollient product.
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Ichthyosis, X Linked
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nord_628_0
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Overview of Idiopathic Intracranial Hypertension
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Intracranial Hypertension (IH) is characterized by increased pressure inside the skull. Intracranial means inside the skull and hypertension means high fluid pressure. Intracranial hypertension means that the pressure of the fluid that surrounds the brain (cerebrospinal fluid or CSF) is too high. Elevated CSF pressure can cause two problems, severe headache and visual loss. If the elevated CSF pressure remains untreated, permanent visual loss or blindness may result. Pseudotumor cerebri and benign intracranial hypertension are both former names for IH, which are now considered inaccurate. These names do not adequately describe the disorder and downplay the seriousness of IH.There are two categories of IH: primary intracranial hypertension and secondary intracranial hypertension. Primary intracranial hypertension, now known as idiopathic intracranial hypertension (IIH), occurs without known cause. This form is known to occur in young, overweight, females in their reproductive years (ages 20-45). However, IH can develop in both males and females of all ages and body types. Secondary intracranial hypertension has an identifiable, causative agent, including drugs (such as tetracycline, lithium, Vitamin A-derived oral acne medications or excessive ingestion of Vitamin A, and oral or intrathecal steroids, growth hormone treatments), sleep apnea and certain systemic diseases such as lupus, leukemia, kidney failure (uremia), meningitis and dural venous sinus thrombosis. There is an association of IH and Chiari type I malformation. Many other causes have been suggested in the medical literature but have not yet been confirmed as true causes. It is critical in these patients to rule out an intracranial space occupying mass by neuro-imaging (CT or MRI). Although many factors are known to trigger the disease, the mechanism by which IH occurs, in either primary or secondary forms, is not known. In many cases, either type of IH may be chronic.
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Overview of Idiopathic Intracranial Hypertension. Intracranial Hypertension (IH) is characterized by increased pressure inside the skull. Intracranial means inside the skull and hypertension means high fluid pressure. Intracranial hypertension means that the pressure of the fluid that surrounds the brain (cerebrospinal fluid or CSF) is too high. Elevated CSF pressure can cause two problems, severe headache and visual loss. If the elevated CSF pressure remains untreated, permanent visual loss or blindness may result. Pseudotumor cerebri and benign intracranial hypertension are both former names for IH, which are now considered inaccurate. These names do not adequately describe the disorder and downplay the seriousness of IH.There are two categories of IH: primary intracranial hypertension and secondary intracranial hypertension. Primary intracranial hypertension, now known as idiopathic intracranial hypertension (IIH), occurs without known cause. This form is known to occur in young, overweight, females in their reproductive years (ages 20-45). However, IH can develop in both males and females of all ages and body types. Secondary intracranial hypertension has an identifiable, causative agent, including drugs (such as tetracycline, lithium, Vitamin A-derived oral acne medications or excessive ingestion of Vitamin A, and oral or intrathecal steroids, growth hormone treatments), sleep apnea and certain systemic diseases such as lupus, leukemia, kidney failure (uremia), meningitis and dural venous sinus thrombosis. There is an association of IH and Chiari type I malformation. Many other causes have been suggested in the medical literature but have not yet been confirmed as true causes. It is critical in these patients to rule out an intracranial space occupying mass by neuro-imaging (CT or MRI). Although many factors are known to trigger the disease, the mechanism by which IH occurs, in either primary or secondary forms, is not known. In many cases, either type of IH may be chronic.
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Idiopathic Intracranial Hypertension
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nord_628_1
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Symptoms of Idiopathic Intracranial Hypertension
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The most common symptom is often an unbearably painful or frequent headache, sometimes associated with nausea and vomiting that is not relieved by medication. The headache often awakens the patient from sleep. Some patients are treated in the emergency room where a lumbar puncture (spinal tap) is done as a last resort, to temporarily ease the headache. Measurement of the opening pressure is encouraged during these procedures in order to assess for intracranial hypertension.The diagnosis is also confirmed by detecting a high spinal CSF pressure reading, usually greater than 250 mmH2O or 25 cmH2O (200-250 mmH2O or 20-25 cmH2O is considered borderline high) and normal laboratory and imaging studies including CT scans and MRIs. There is generally a normal neurological examination as well, although abnormal findings may be detected on eye examination. The eye findings may be subtle, and not noted in an emergency room evaluation. It is not uncommon to misdiagnose a patient with IH as simply having a refractory migraine headache, and be treated as such. Unlike primary IH, secondary IH patients may have abnormal scans and laboratory tests.The high CSF pressure may cause the optic nerves to swell (papilledema). The optic nerve connects the interior of each eye, the retina, to the vision centers of the brain. The optic nerve transmits impulses from the retina to these brain centers. The earliest sign of papilledema on a visual field test is known as an enlarged blind spot. Abnormal CSF pressure can also affect the eye muscles controlling eye movements producing double vision, but this is an infrequent event. (All patients with presumed IH should have a thorough eye examination including visual field tests by an ophthalmologist or neuro-ophthalmologist).Other common symptoms include transient altered vision, particularly on movement or bending over, intracranial noise (pulse synchronous tinnitus), stiff neck, back and arm pain, pain behind the eye, exercise intolerance, and memory difficulties.
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Symptoms of Idiopathic Intracranial Hypertension. The most common symptom is often an unbearably painful or frequent headache, sometimes associated with nausea and vomiting that is not relieved by medication. The headache often awakens the patient from sleep. Some patients are treated in the emergency room where a lumbar puncture (spinal tap) is done as a last resort, to temporarily ease the headache. Measurement of the opening pressure is encouraged during these procedures in order to assess for intracranial hypertension.The diagnosis is also confirmed by detecting a high spinal CSF pressure reading, usually greater than 250 mmH2O or 25 cmH2O (200-250 mmH2O or 20-25 cmH2O is considered borderline high) and normal laboratory and imaging studies including CT scans and MRIs. There is generally a normal neurological examination as well, although abnormal findings may be detected on eye examination. The eye findings may be subtle, and not noted in an emergency room evaluation. It is not uncommon to misdiagnose a patient with IH as simply having a refractory migraine headache, and be treated as such. Unlike primary IH, secondary IH patients may have abnormal scans and laboratory tests.The high CSF pressure may cause the optic nerves to swell (papilledema). The optic nerve connects the interior of each eye, the retina, to the vision centers of the brain. The optic nerve transmits impulses from the retina to these brain centers. The earliest sign of papilledema on a visual field test is known as an enlarged blind spot. Abnormal CSF pressure can also affect the eye muscles controlling eye movements producing double vision, but this is an infrequent event. (All patients with presumed IH should have a thorough eye examination including visual field tests by an ophthalmologist or neuro-ophthalmologist).Other common symptoms include transient altered vision, particularly on movement or bending over, intracranial noise (pulse synchronous tinnitus), stiff neck, back and arm pain, pain behind the eye, exercise intolerance, and memory difficulties.
| 628 |
Idiopathic Intracranial Hypertension
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nord_628_2
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Causes of Idiopathic Intracranial Hypertension
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In the idiopathic or primary type (IIH), obesity is considered a factor in young women. However, only a small fraction of obese individuals develop IH, so other unknown causes are yet to be determined.The many potential causes of secondary intracranial hypertension have been noted above. Note that in secondary IH, unlike IIH, obesity, gender, age and race are NOT risk factors, but may be present.The mechanism by which IH occurs is not known, but several possibilities have been suggested. Most research supports the theory that there is resistance or obstruction to CSF outflow through the normal existing pathways in the brain, leading to relative over-production of CSF.
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Causes of Idiopathic Intracranial Hypertension. In the idiopathic or primary type (IIH), obesity is considered a factor in young women. However, only a small fraction of obese individuals develop IH, so other unknown causes are yet to be determined.The many potential causes of secondary intracranial hypertension have been noted above. Note that in secondary IH, unlike IIH, obesity, gender, age and race are NOT risk factors, but may be present.The mechanism by which IH occurs is not known, but several possibilities have been suggested. Most research supports the theory that there is resistance or obstruction to CSF outflow through the normal existing pathways in the brain, leading to relative over-production of CSF.
| 628 |
Idiopathic Intracranial Hypertension
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nord_628_3
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Affects of Idiopathic Intracranial Hypertension
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The incidence of IIH in the general population is thought to be about 1 per 100,000. In obese young females the incidence of IIH is about 20 per 100,000. IIH occurs in men and children as well, but with substantially lower frequency. Weight is not usually a factor in men and in children under 10 years of age.The true incidence of secondary IH remains unknown because of the wide range of underlying causes and the lack of published surveys on the subject. Current statistics are not available on how many people have secondary intracranial hypertension.
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Affects of Idiopathic Intracranial Hypertension. The incidence of IIH in the general population is thought to be about 1 per 100,000. In obese young females the incidence of IIH is about 20 per 100,000. IIH occurs in men and children as well, but with substantially lower frequency. Weight is not usually a factor in men and in children under 10 years of age.The true incidence of secondary IH remains unknown because of the wide range of underlying causes and the lack of published surveys on the subject. Current statistics are not available on how many people have secondary intracranial hypertension.
| 628 |
Idiopathic Intracranial Hypertension
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