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nord_671_3
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Affects of Keratolytic Winter Erythema
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In South Africa, families with KWE are scattered throughout the country and some families have emigrated to the UK and to other countries. The condition is much more common in South Africa owing to the founder effect. It affects families of both the white population and those of mixed racial descent. The patients in Germany, Denmark, Norway and the USA do not share the same ancestry.
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Affects of Keratolytic Winter Erythema. In South Africa, families with KWE are scattered throughout the country and some families have emigrated to the UK and to other countries. The condition is much more common in South Africa owing to the founder effect. It affects families of both the white population and those of mixed racial descent. The patients in Germany, Denmark, Norway and the USA do not share the same ancestry.
| 671 |
Keratolytic Winter Erythema
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nord_671_4
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Related disorders of Keratolytic Winter Erythema
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Conditions causing peeling of the palms and soles include both acquired conditions as well as other familial conditions. In some circumstances, palmoplantar peeling may be an acute phenomenon related to infections or drug reactions and such transient conditions will not be considered further.Keratolysis exfoliative (KE) is characterized by delicate superficial peeling rings seen on palms and soles. The initial lesion is a small air-filled vesicle which flakes off from the edges. The number of lesions seen is variable. When the tips of the fingers are involved, the peeled skin may be sensitive. The condition may vary with the season, often worsening in the summer. While most cases are sporadic, some families may be affected. Genetic studies are lacking but one study failed to find causative gene variants in the TGM5 gene. Acral peeling skin syndrome (peeling syndrome 2) has onset at birth or early childhood and persists thoughout life. The superficial peeling is limited to skin on the hands and feet (acral skin). It is bilateral but mostly asymmetric in distribution. This condition is caused by variants in the TGM5 gene.Peeling syndrome 5 has onset of symptoms between 3-6 months of age. It is characterized by superficial peeling of small areas of dorsal and palmar surfaces of hands and feet with underlying painless erythema. In some patients there is also superficial scaling of forearms and legs as well as diffuse, yellowish, hyperkeratotic thickenings on the palms and soles. The condition is exacerbated by heat, humidity and friction. Mutations in the SERPINB8 gene on chromosome 18q22 have been identified in some patients.
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Related disorders of Keratolytic Winter Erythema. Conditions causing peeling of the palms and soles include both acquired conditions as well as other familial conditions. In some circumstances, palmoplantar peeling may be an acute phenomenon related to infections or drug reactions and such transient conditions will not be considered further.Keratolysis exfoliative (KE) is characterized by delicate superficial peeling rings seen on palms and soles. The initial lesion is a small air-filled vesicle which flakes off from the edges. The number of lesions seen is variable. When the tips of the fingers are involved, the peeled skin may be sensitive. The condition may vary with the season, often worsening in the summer. While most cases are sporadic, some families may be affected. Genetic studies are lacking but one study failed to find causative gene variants in the TGM5 gene. Acral peeling skin syndrome (peeling syndrome 2) has onset at birth or early childhood and persists thoughout life. The superficial peeling is limited to skin on the hands and feet (acral skin). It is bilateral but mostly asymmetric in distribution. This condition is caused by variants in the TGM5 gene.Peeling syndrome 5 has onset of symptoms between 3-6 months of age. It is characterized by superficial peeling of small areas of dorsal and palmar surfaces of hands and feet with underlying painless erythema. In some patients there is also superficial scaling of forearms and legs as well as diffuse, yellowish, hyperkeratotic thickenings on the palms and soles. The condition is exacerbated by heat, humidity and friction. Mutations in the SERPINB8 gene on chromosome 18q22 have been identified in some patients.
| 671 |
Keratolytic Winter Erythema
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nord_671_5
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Diagnosis of Keratolytic Winter Erythema
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The diagnosis of KWE is based on the clinical findings of cyclical peeling of skin on the palms and soles and a family history of this condition. In most patients, skin biopsies are not required for the diagnosis. Genetic testing is limited to research laboratories.
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Diagnosis of Keratolytic Winter Erythema. The diagnosis of KWE is based on the clinical findings of cyclical peeling of skin on the palms and soles and a family history of this condition. In most patients, skin biopsies are not required for the diagnosis. Genetic testing is limited to research laboratories.
| 671 |
Keratolytic Winter Erythema
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nord_671_6
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Therapies of Keratolytic Winter Erythema
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TreatmentThere is currently no effective treatment for KWE. Topical steroids (anti-inflammatory preparation used to control many skin conditions) and retinoids (chemical compounds that are analogs of vitamin A) might help a little, but they can also aggravate it. Topical calciprotriol (a form of vitamin D) might also have minimal effect. Systemic steroids (anti-inflammatory derivatives of cortisol) have temporally resolved the circular lesions in a single patient. Measures to control sweating may be helpful. Photodynamic therapy has been used successfully in one patient.
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Therapies of Keratolytic Winter Erythema. TreatmentThere is currently no effective treatment for KWE. Topical steroids (anti-inflammatory preparation used to control many skin conditions) and retinoids (chemical compounds that are analogs of vitamin A) might help a little, but they can also aggravate it. Topical calciprotriol (a form of vitamin D) might also have minimal effect. Systemic steroids (anti-inflammatory derivatives of cortisol) have temporally resolved the circular lesions in a single patient. Measures to control sweating may be helpful. Photodynamic therapy has been used successfully in one patient.
| 671 |
Keratolytic Winter Erythema
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nord_672_0
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Overview of Keratomalacia
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Keratomalacia is an eye (ocular) condition, usually affecting both eyes (bilateral), that results from severe deficiency of vitamin A. That deficiency may be dietary (i.e., intake) or metabolic (i.e., absorption). Vitamin A is essential for normal vision as well as proper bone growth, healthy skin, and protection of the mucous membranes of the digestive, respiratory, and urinary tracts against infection.Early symptoms may include poor vision at night or in dim light (night blindness) and extreme dryness of the eyes (i.e., xerophthalmia), followed by wrinkling, progressive cloudiness, and increasing softening of the corneas (i.e., keratomalacia). With advancing vitamin A deficiency, dry, “foamy,” silver-gray deposits (Bitot spots) may appear on the delicate membranes covering the whites of the eyes. Without adequate treatment, increasing softening of the corneas may lead to corneal infection, rupture (perforation), and degenerative tissue changes, resulting in blindness. In addition, in some cases, vitamin A deficiency may have additional effects, particularly during infancy and childhood.In some developing countries, vitamin A deficiency in the diet and associated keratomalacia are a major cause of childhood blindness. In such regions, vitamin A deficiency often occurs as part of nonselective general malnutrition in infants and young children. Although rare in developed countries, vitamin A deficiency and keratomalacia may occur secondary to conditions associated with impaired absorption, storage, or transport of vitamin A, such as celiac disease, ulcerative colitis, cystic fibrosis, liver disease, or intestinal bypass surgery and any condition that affects absorption of fat-soluble vitamins.
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Overview of Keratomalacia. Keratomalacia is an eye (ocular) condition, usually affecting both eyes (bilateral), that results from severe deficiency of vitamin A. That deficiency may be dietary (i.e., intake) or metabolic (i.e., absorption). Vitamin A is essential for normal vision as well as proper bone growth, healthy skin, and protection of the mucous membranes of the digestive, respiratory, and urinary tracts against infection.Early symptoms may include poor vision at night or in dim light (night blindness) and extreme dryness of the eyes (i.e., xerophthalmia), followed by wrinkling, progressive cloudiness, and increasing softening of the corneas (i.e., keratomalacia). With advancing vitamin A deficiency, dry, “foamy,” silver-gray deposits (Bitot spots) may appear on the delicate membranes covering the whites of the eyes. Without adequate treatment, increasing softening of the corneas may lead to corneal infection, rupture (perforation), and degenerative tissue changes, resulting in blindness. In addition, in some cases, vitamin A deficiency may have additional effects, particularly during infancy and childhood.In some developing countries, vitamin A deficiency in the diet and associated keratomalacia are a major cause of childhood blindness. In such regions, vitamin A deficiency often occurs as part of nonselective general malnutrition in infants and young children. Although rare in developed countries, vitamin A deficiency and keratomalacia may occur secondary to conditions associated with impaired absorption, storage, or transport of vitamin A, such as celiac disease, ulcerative colitis, cystic fibrosis, liver disease, or intestinal bypass surgery and any condition that affects absorption of fat-soluble vitamins.
| 672 |
Keratomalacia
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nord_672_1
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Symptoms of Keratomalacia
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Keratomalacia is an eye condition characterized by distinctive ocular changes due to severe vitamin A deficiency. In some affected individuals, additional effects may result from vitamin A deficiency, the severity of which tends to be inversely related to age. Initial ocular findings commonly include impaired adjustment of the eyes to vision in the dark or dim light (impaired dark adaptation) and associated night blindness due to retinal* (i.e., rod) dysfunction. (*The retina is the light sensitive membrane upon which images are focused at the back of the eye. It contains specialized nerve cells [photoreceptors] that convert light into nerve impulses. Photoreceptors include “rods” that are sensitive to low-intensity light and thus required for night vision, and “cones” that respond to high-intensity light and colors. “Dark adaptation” is the normal increase in sensitivity of the rods to detect light available for vision in dark or dimly lit areas.)Vitamin A deficiency leads to abnormalities in the structure and function of certain cells covering the surface of the eyes (i.e., epithelial cells). Due to such epithelial changes and inadequate tear production, affected individuals develop extreme dryness of the delicate membranes (i.e., conjunctivae) covering the whites of the eyes and inner lining of the lids (xerosis conjunctivae) and the corneas (xerosis corneae). (The cornea is the thin-walled, “dome-shaped” transparent region forming the front of the eyeball; it serves as a protective covering and helps to focus or bend [refract] light waves onto the retina at the back of the eye.) Due to abnormal dryness of the conjunctivae and the corneas (i.e., a condition known as “xerophthalmia”), there is unusual thickening and wrinkling of the conjunctivae, as well as increasing cloudiness, haziness, wrinkling, and softening of the corneas. In addition, in advanced vitamin A deficiency, foamy, silver-gray, triangular patches (Bitot spots) appear that consist of abnormal deposits of epithelial debris and secretions on the conjunctivae. Evidence suggests that Bitot spots are most likely to develop in young children with other manifestations of vitamin A deficiency.Without adequate treatment, increasing softening of all or part of the corneas (keratomalacia) may lead to chronic infection, ulceration, and rupture (perforation) of the corneas and degenerative tissue changes (e.g., corneal protrusion and ocular shrinking [phthisis bulbi]), resulting in blindness.As noted above, in some affected individuals, vitamin A deficiency may have additional effects. For example, retardation of mental and physical growth is a common sign in children. Vitamin A deficiency may also be associated with dryness and scaliness of the skin; decreased levels of the oxygen-carrying component of red blood cells (anemia); abnormal enlargement of the liver and spleen (hepatosplenomegaly); an increased susceptibility to certain infections (e.g., due to epithelial changes of the digestive, respiratory, and urinary tracts); and/or other findings. Evidence suggests that children with vitamin A deficiency are particularly susceptible to potential complications associated with measles.
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Symptoms of Keratomalacia. Keratomalacia is an eye condition characterized by distinctive ocular changes due to severe vitamin A deficiency. In some affected individuals, additional effects may result from vitamin A deficiency, the severity of which tends to be inversely related to age. Initial ocular findings commonly include impaired adjustment of the eyes to vision in the dark or dim light (impaired dark adaptation) and associated night blindness due to retinal* (i.e., rod) dysfunction. (*The retina is the light sensitive membrane upon which images are focused at the back of the eye. It contains specialized nerve cells [photoreceptors] that convert light into nerve impulses. Photoreceptors include “rods” that are sensitive to low-intensity light and thus required for night vision, and “cones” that respond to high-intensity light and colors. “Dark adaptation” is the normal increase in sensitivity of the rods to detect light available for vision in dark or dimly lit areas.)Vitamin A deficiency leads to abnormalities in the structure and function of certain cells covering the surface of the eyes (i.e., epithelial cells). Due to such epithelial changes and inadequate tear production, affected individuals develop extreme dryness of the delicate membranes (i.e., conjunctivae) covering the whites of the eyes and inner lining of the lids (xerosis conjunctivae) and the corneas (xerosis corneae). (The cornea is the thin-walled, “dome-shaped” transparent region forming the front of the eyeball; it serves as a protective covering and helps to focus or bend [refract] light waves onto the retina at the back of the eye.) Due to abnormal dryness of the conjunctivae and the corneas (i.e., a condition known as “xerophthalmia”), there is unusual thickening and wrinkling of the conjunctivae, as well as increasing cloudiness, haziness, wrinkling, and softening of the corneas. In addition, in advanced vitamin A deficiency, foamy, silver-gray, triangular patches (Bitot spots) appear that consist of abnormal deposits of epithelial debris and secretions on the conjunctivae. Evidence suggests that Bitot spots are most likely to develop in young children with other manifestations of vitamin A deficiency.Without adequate treatment, increasing softening of all or part of the corneas (keratomalacia) may lead to chronic infection, ulceration, and rupture (perforation) of the corneas and degenerative tissue changes (e.g., corneal protrusion and ocular shrinking [phthisis bulbi]), resulting in blindness.As noted above, in some affected individuals, vitamin A deficiency may have additional effects. For example, retardation of mental and physical growth is a common sign in children. Vitamin A deficiency may also be associated with dryness and scaliness of the skin; decreased levels of the oxygen-carrying component of red blood cells (anemia); abnormal enlargement of the liver and spleen (hepatosplenomegaly); an increased susceptibility to certain infections (e.g., due to epithelial changes of the digestive, respiratory, and urinary tracts); and/or other findings. Evidence suggests that children with vitamin A deficiency are particularly susceptible to potential complications associated with measles.
| 672 |
Keratomalacia
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nord_672_2
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Causes of Keratomalacia
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The human body stores vitamin A mainly in the liver. Vitamin A plays a prime role in reconstituting a visual pigment (rhodopsin) within rods of the retinas that is required for night vision. It is also essential for the formation and maturation of epithelial cells and proper bone and tooth development. Sources of dietary vitamin A include fish-liver oils, liver, whole cow's milk, other dairy products (e.g., butter, cheese), egg yolks, green leafy vegetables, and yellow vegetables and fruits.Keratomalacia is most frequently caused by prolonged dietary deprivation of vitamin A (i.e., primary vitamin A deficiency). Primary vitamin A deficiency is common in certain regions where rice is a major component of the diet (e.g., eastern and southern Asia); rice does not contain beta-carotene, which is converted by the body into vitamin A.In addition, keratomalacia is common with certain malnutrition disorders resulting from insufficient consumption of protein and energy (i.e., protein-calorie malnutrition, such as kwashiorkor). In such cases, vitamin A deficiency may result from dietary deprivation as well as defective storage and transport of vitamin A.Infants and children who are allergic to milk or are given dilute formula may also be at risk for vitamin A deficiency and associated keratomalacia. (Whole cow's milk and breast milk are adequate sources of vitamin A.)Vitamin A deficiency and keratomalacia may also occur secondary to certain diseases or conditions characterized by insufficient conversion of beta-carotene to vitamin A or impaired storage, absorption, or transport of vitamin A (secondary vitamin A deficiency). For example, impaired vitamin A absorption or storage may occur with chronic intestinal disorders, such as ulcerative colitis; sprue or celiac disease; cystic fibrosis or other disorders characterized by pancreatic insufficiency and associated malabsorption; or intestinal bypass surgery (duodenal bypass). Impaired storage or absorption of vitamin A may also be associated with infection of the small intestine (giardiasis); partial obstruction of the small intestine at birth; obstruction of the bile ducts; or liver disease, such as internal scarring and impaired functioning of the liver (cirrhosis). (For further information on such conditions, please choose “colitis,” “celiac,” “cystic fibrosis,” or “giardiasis” as your search term in the Rare Disease Database.)
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Causes of Keratomalacia. The human body stores vitamin A mainly in the liver. Vitamin A plays a prime role in reconstituting a visual pigment (rhodopsin) within rods of the retinas that is required for night vision. It is also essential for the formation and maturation of epithelial cells and proper bone and tooth development. Sources of dietary vitamin A include fish-liver oils, liver, whole cow's milk, other dairy products (e.g., butter, cheese), egg yolks, green leafy vegetables, and yellow vegetables and fruits.Keratomalacia is most frequently caused by prolonged dietary deprivation of vitamin A (i.e., primary vitamin A deficiency). Primary vitamin A deficiency is common in certain regions where rice is a major component of the diet (e.g., eastern and southern Asia); rice does not contain beta-carotene, which is converted by the body into vitamin A.In addition, keratomalacia is common with certain malnutrition disorders resulting from insufficient consumption of protein and energy (i.e., protein-calorie malnutrition, such as kwashiorkor). In such cases, vitamin A deficiency may result from dietary deprivation as well as defective storage and transport of vitamin A.Infants and children who are allergic to milk or are given dilute formula may also be at risk for vitamin A deficiency and associated keratomalacia. (Whole cow's milk and breast milk are adequate sources of vitamin A.)Vitamin A deficiency and keratomalacia may also occur secondary to certain diseases or conditions characterized by insufficient conversion of beta-carotene to vitamin A or impaired storage, absorption, or transport of vitamin A (secondary vitamin A deficiency). For example, impaired vitamin A absorption or storage may occur with chronic intestinal disorders, such as ulcerative colitis; sprue or celiac disease; cystic fibrosis or other disorders characterized by pancreatic insufficiency and associated malabsorption; or intestinal bypass surgery (duodenal bypass). Impaired storage or absorption of vitamin A may also be associated with infection of the small intestine (giardiasis); partial obstruction of the small intestine at birth; obstruction of the bile ducts; or liver disease, such as internal scarring and impaired functioning of the liver (cirrhosis). (For further information on such conditions, please choose “colitis,” “celiac,” “cystic fibrosis,” or “giardiasis” as your search term in the Rare Disease Database.)
| 672 |
Keratomalacia
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nord_672_3
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Affects of Keratomalacia
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Keratomalacia occurs most commonly in developing countries due to prolonged dietary deprivation of vitamin A or protein-calorie malnutrition. As noted above, keratomalacia is a major cause of blindness in young children in such areas. In developed countries, vitamin A deficiency most frequently occurs when there is interference with vitamin A intake, absorption, or transport.
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Affects of Keratomalacia. Keratomalacia occurs most commonly in developing countries due to prolonged dietary deprivation of vitamin A or protein-calorie malnutrition. As noted above, keratomalacia is a major cause of blindness in young children in such areas. In developed countries, vitamin A deficiency most frequently occurs when there is interference with vitamin A intake, absorption, or transport.
| 672 |
Keratomalacia
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nord_672_4
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Related disorders of Keratomalacia
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Related disorders of Keratomalacia.
| 672 |
Keratomalacia
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nord_672_5
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Diagnosis of Keratomalacia
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Keratomalacia may be diagnosed based upon a complete patient history; thorough clinical evaluation, including eye examination; blood studies (e.g., assessment of beta-carotene and vitamin A levels); and additional specialized tests. Eye examination should include evaluation of the external appearance of the eyes, visual acuity, eye movements, and visual fields; the use of an illuminated microscope to view the conjunctivae, corneas, and other regions of the eyes (slit-lamp examination); measures of dark adaptation to help to detect night blindness; and/or additional diagnostic assessments (e.g., to exclude other possible causes of night blindness). In addition, evaluation may include microscopic examination of scrapings of surface cells from the eyes.In some cases, other diagnostic studies may also be conducted to help exclude or confirm possible secondary causes of vitamin A deficiency and keratomalacia. In addition, in some instances, a trial with appropriate therapeutic doses of vitamin A may confirm a diagnosis.
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Diagnosis of Keratomalacia. Keratomalacia may be diagnosed based upon a complete patient history; thorough clinical evaluation, including eye examination; blood studies (e.g., assessment of beta-carotene and vitamin A levels); and additional specialized tests. Eye examination should include evaluation of the external appearance of the eyes, visual acuity, eye movements, and visual fields; the use of an illuminated microscope to view the conjunctivae, corneas, and other regions of the eyes (slit-lamp examination); measures of dark adaptation to help to detect night blindness; and/or additional diagnostic assessments (e.g., to exclude other possible causes of night blindness). In addition, evaluation may include microscopic examination of scrapings of surface cells from the eyes.In some cases, other diagnostic studies may also be conducted to help exclude or confirm possible secondary causes of vitamin A deficiency and keratomalacia. In addition, in some instances, a trial with appropriate therapeutic doses of vitamin A may confirm a diagnosis.
| 672 |
Keratomalacia
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nord_672_6
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Therapies of Keratomalacia
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TreatmentThe treatment of vitamin A deficiency and associated keratomalacia includes vitamin A supplementation, with dose levels and length of treatment determined by the severity of the deficiency and other factors. However, prolonged daily administration of high doses must be avoided, particularly for infants, since toxicity (i.e., hypervitaminosis A) may result. (In infants and young children, manifestations of acute vitamin A toxicity due to large doses may include increased intracranial pressure, drowsiness, nausea, vomiting, and other abnormalities. Chronic hypervitaminosis A, which may result from excessive doses for several weeks or months, may be characterized by irritability; lack of appetite; dry, itchy skin; hair loss; cracked lips; generalized weakness; tender swelling of the bones; increased intracranial pressure; liver enlargement; and/or other abnormalities.. In addition, because vitamin A may cause birth defects if given in high doses during pregnancy, extreme caution must be taken in treating women in their childbearing years. Experts advise that vitamin A doses should not exceed two times the recommended daily allowance (RDA) for women who are pregnant or breastfeeding (i.e., lactating).In addition, in cases in which keratomalacia occurs secondary to impaired vitamin A absorption, storage, or transport, treatment also includes appropriate therapeutic measures to help manage or correct the underlying disorder or condition.In some cases, the treatment of keratomalacia may include the administration of antibiotic drops or ointments to treat secondary infections, the use of other appropriate eyedrops, and/or additional measures. Other treatment for this disorder is symptomatic and supportive.PreventionMeasures to prevent vitamin A deficiency and keratomalacia include ensuring proper nutrition through a balanced diet that contains adequate protein and vitamin A or carotenes. In some cases, routine preventive (prophylactic) vitamin A supplementation may also be required, such as for individuals with impaired vitamin A absorption, storage, or transport. In developing countries where keratomalacia is a major cause of blindness, regular prophylactic vitamin A supplementation is recommended for children at appropriate doses as determined by age and other factors.In addition, infants who are allergic to milk should be provided with adequate vitamin A within substitute formulas. (Parents should speak with pediatricians concerning appropriate measures to ensure that their children are receiving sufficient levels of vitamin A and other necessary nutrients within their diets.)Experts also advise administration of appropriate doses of vitamin A for children who are at risk for vitamin A deficiency and who develop certain viral infections, such as measles.
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Therapies of Keratomalacia. TreatmentThe treatment of vitamin A deficiency and associated keratomalacia includes vitamin A supplementation, with dose levels and length of treatment determined by the severity of the deficiency and other factors. However, prolonged daily administration of high doses must be avoided, particularly for infants, since toxicity (i.e., hypervitaminosis A) may result. (In infants and young children, manifestations of acute vitamin A toxicity due to large doses may include increased intracranial pressure, drowsiness, nausea, vomiting, and other abnormalities. Chronic hypervitaminosis A, which may result from excessive doses for several weeks or months, may be characterized by irritability; lack of appetite; dry, itchy skin; hair loss; cracked lips; generalized weakness; tender swelling of the bones; increased intracranial pressure; liver enlargement; and/or other abnormalities.. In addition, because vitamin A may cause birth defects if given in high doses during pregnancy, extreme caution must be taken in treating women in their childbearing years. Experts advise that vitamin A doses should not exceed two times the recommended daily allowance (RDA) for women who are pregnant or breastfeeding (i.e., lactating).In addition, in cases in which keratomalacia occurs secondary to impaired vitamin A absorption, storage, or transport, treatment also includes appropriate therapeutic measures to help manage or correct the underlying disorder or condition.In some cases, the treatment of keratomalacia may include the administration of antibiotic drops or ointments to treat secondary infections, the use of other appropriate eyedrops, and/or additional measures. Other treatment for this disorder is symptomatic and supportive.PreventionMeasures to prevent vitamin A deficiency and keratomalacia include ensuring proper nutrition through a balanced diet that contains adequate protein and vitamin A or carotenes. In some cases, routine preventive (prophylactic) vitamin A supplementation may also be required, such as for individuals with impaired vitamin A absorption, storage, or transport. In developing countries where keratomalacia is a major cause of blindness, regular prophylactic vitamin A supplementation is recommended for children at appropriate doses as determined by age and other factors.In addition, infants who are allergic to milk should be provided with adequate vitamin A within substitute formulas. (Parents should speak with pediatricians concerning appropriate measures to ensure that their children are receiving sufficient levels of vitamin A and other necessary nutrients within their diets.)Experts also advise administration of appropriate doses of vitamin A for children who are at risk for vitamin A deficiency and who develop certain viral infections, such as measles.
| 672 |
Keratomalacia
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nord_673_0
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Overview of Keratosis Follicularis
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Keratosis follicularis, also known as Darier disease, is a rare, genetic skin disorder. Affected individuals develop skin lesions that consist of thickened, rough bumps (papules) or plaques that may also be greasy or have a brown or yellow crust. These hardened, scaly lesions may gradually grow bigger or spread. The nails and mucous membranes are also affected in most patients. Individuals may have periods of time when signs improve (remission), but the lesions usually recur (relapse). The specific problems vary from one individual to another. Keratosis follicularis is inherited in an autosomal dominant pattern.
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Overview of Keratosis Follicularis. Keratosis follicularis, also known as Darier disease, is a rare, genetic skin disorder. Affected individuals develop skin lesions that consist of thickened, rough bumps (papules) or plaques that may also be greasy or have a brown or yellow crust. These hardened, scaly lesions may gradually grow bigger or spread. The nails and mucous membranes are also affected in most patients. Individuals may have periods of time when signs improve (remission), but the lesions usually recur (relapse). The specific problems vary from one individual to another. Keratosis follicularis is inherited in an autosomal dominant pattern.
| 673 |
Keratosis Follicularis
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nord_673_1
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Symptoms of Keratosis Follicularis
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The symptoms of keratosis follicularis usually become apparent during the teen-age years often around puberty. Symptoms may develop in younger or older individuals, but rarely develop after the third or fourth decade of life. The severity of the disorder and the specific symptoms that develop vary, even among individuals within the same family.The initial lesions in keratosis follicularis are usually small, firm, greasy bumps (papules) that are often skin-colored, brown or yellow brown in color. The lesions usually affect the areas of the body near sebaceous glands (sebaceous glands secrete oily grease) including the chest, back, forehead and scalp. Darier disease may also affect skin creases e.g., groin.The skin lesions associated with keratosis follicularis generally develop a brown, greasy crust and become thickened and warty (hyperkeratotic), scaly and darkened. The lesions will slowly grow bigger eventually coming together (coalescing) to form discolored, warty plaques that may cover extensive areas of the body particularly on the trunk. In extremely rare, severe cases, almost the entire body may be affected. The lesions may cause persistent itchiness (pruritus). Some patients have fragile skin that blisters or becomes raw (erosions) and painful.The skin may develop bacterial, viral or fungal infections (secondary infections) that worsen (exacerbate) the condition. Infected skin lesions may give off a distinct, unpleasant (malodorous) smell. The herpes simplex virus may be prone to infecting the lesions and causes pain. Heat, exercise and sunlight may also worsen keratosis follicularis or cause a new outbreak of lesions.Individuals with keratosis follicularis may have periods when few lesions are present (remission). However, the lesions tend to recur (relapse). Keratosis follicularis is usually worse in the summer and may improve in the winter. Heat or sun often causes an outbreak.Another common finding associated with keratosis follicularis is the development of multiple, small, yellow brown, flattened wart-like (verrucous) bumps (papules) on backs of the hands or feet. These bumps may be the first sign of keratosis follicularis. Many affected individuals develop small horny bumps called punctate keratoses or depressions (pits) on the palms and soles.Most individuals with keratosis follicularis have abnormalities affecting the nails including fragile nails with splits along the length of the nail or red or white streaks that run up and down the nail with V-shaped notching at the free edge.Sometimes the mucous membranes within the mouth develop small bumps (papules). The roof of the mouth (palate) is most often affected. The gums, larynx and esophagus may also be affected. Darier disease can also affect the ducts of the salivary glands causing salivary gland obstruction. In some people, Darier disease has developed on the mucous membranes of the anus and rectum.Although in most people Darier disease is limited to the skin, additional symptoms have been reported in some cases including seizures, bipolar disorder and learning disabilities.Keratosis follicularis may be restricted to a band of skin on one side of the body (segmental or linear keratosis follicularis) and in these linear cases the disease is most unlikely to be passed on to the next generation.
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Symptoms of Keratosis Follicularis. The symptoms of keratosis follicularis usually become apparent during the teen-age years often around puberty. Symptoms may develop in younger or older individuals, but rarely develop after the third or fourth decade of life. The severity of the disorder and the specific symptoms that develop vary, even among individuals within the same family.The initial lesions in keratosis follicularis are usually small, firm, greasy bumps (papules) that are often skin-colored, brown or yellow brown in color. The lesions usually affect the areas of the body near sebaceous glands (sebaceous glands secrete oily grease) including the chest, back, forehead and scalp. Darier disease may also affect skin creases e.g., groin.The skin lesions associated with keratosis follicularis generally develop a brown, greasy crust and become thickened and warty (hyperkeratotic), scaly and darkened. The lesions will slowly grow bigger eventually coming together (coalescing) to form discolored, warty plaques that may cover extensive areas of the body particularly on the trunk. In extremely rare, severe cases, almost the entire body may be affected. The lesions may cause persistent itchiness (pruritus). Some patients have fragile skin that blisters or becomes raw (erosions) and painful.The skin may develop bacterial, viral or fungal infections (secondary infections) that worsen (exacerbate) the condition. Infected skin lesions may give off a distinct, unpleasant (malodorous) smell. The herpes simplex virus may be prone to infecting the lesions and causes pain. Heat, exercise and sunlight may also worsen keratosis follicularis or cause a new outbreak of lesions.Individuals with keratosis follicularis may have periods when few lesions are present (remission). However, the lesions tend to recur (relapse). Keratosis follicularis is usually worse in the summer and may improve in the winter. Heat or sun often causes an outbreak.Another common finding associated with keratosis follicularis is the development of multiple, small, yellow brown, flattened wart-like (verrucous) bumps (papules) on backs of the hands or feet. These bumps may be the first sign of keratosis follicularis. Many affected individuals develop small horny bumps called punctate keratoses or depressions (pits) on the palms and soles.Most individuals with keratosis follicularis have abnormalities affecting the nails including fragile nails with splits along the length of the nail or red or white streaks that run up and down the nail with V-shaped notching at the free edge.Sometimes the mucous membranes within the mouth develop small bumps (papules). The roof of the mouth (palate) is most often affected. The gums, larynx and esophagus may also be affected. Darier disease can also affect the ducts of the salivary glands causing salivary gland obstruction. In some people, Darier disease has developed on the mucous membranes of the anus and rectum.Although in most people Darier disease is limited to the skin, additional symptoms have been reported in some cases including seizures, bipolar disorder and learning disabilities.Keratosis follicularis may be restricted to a band of skin on one side of the body (segmental or linear keratosis follicularis) and in these linear cases the disease is most unlikely to be passed on to the next generation.
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Keratosis Follicularis
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Causes of Keratosis Follicularis
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Keratosis follicularis is a genetic disorder that occurs randomly as the result of a spontaneous genetic change (i.e., new pathogenic variant or mutation) or the variant is inherited in an autosomal dominant pattern.Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent or can be the result of a new variant (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy. The risk is the same for males and females.Keratosis follicularis occurs due to pathogenic variants in the ATP2A2 gene. The ATP2A2 gene contains instructions for creating (encoding) a protein that acts as a calcium pump in the cell. This protein known as SERCA2 is responsible for carrying calcium ions from the semi-transparent fluid (cytoplasm) found in the interior of a cell into the extensive membrane network of a cell (endoplasmic reticulum) where proteins are processed. The exact process by which loss or improper function of the SERCA2 protein causes keratosis follicularis is unknown but SERCA2 is active (expressed) in keratinocytes, the main cell type of the outermost layer of the skin (epidermis). Calcium ions in the endoplasmic reticulum play an essential role in the formation of the proteins in the sticky junctions known as a desmosomes that hold the keratinocytes together. When the calcium pumps fail, the desmosomes do not hold cells together properly and the keratinocytes separate (acantholysis). Failure of keratinocytes to stick together also leads to abnormal maturation of the keratinocytes (abnormal keratinization) with the formation of the horny bumps. For this reason, keratosis follicularis is sometimes referred to as a disorder of abnormal keratinization or dyskeratosis.The linear or segmental forms of keratosis follicularis are caused by genetic mosaicism meaning that the ATP2A2 gene variant is only present in some of the cells in one part of the skin but most of the skin is not affected. Mosaicism is caused by a variant in a single cell after fertilization (postzygotic mutation) and is not inherited.
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Causes of Keratosis Follicularis. Keratosis follicularis is a genetic disorder that occurs randomly as the result of a spontaneous genetic change (i.e., new pathogenic variant or mutation) or the variant is inherited in an autosomal dominant pattern.Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent or can be the result of a new variant (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy. The risk is the same for males and females.Keratosis follicularis occurs due to pathogenic variants in the ATP2A2 gene. The ATP2A2 gene contains instructions for creating (encoding) a protein that acts as a calcium pump in the cell. This protein known as SERCA2 is responsible for carrying calcium ions from the semi-transparent fluid (cytoplasm) found in the interior of a cell into the extensive membrane network of a cell (endoplasmic reticulum) where proteins are processed. The exact process by which loss or improper function of the SERCA2 protein causes keratosis follicularis is unknown but SERCA2 is active (expressed) in keratinocytes, the main cell type of the outermost layer of the skin (epidermis). Calcium ions in the endoplasmic reticulum play an essential role in the formation of the proteins in the sticky junctions known as a desmosomes that hold the keratinocytes together. When the calcium pumps fail, the desmosomes do not hold cells together properly and the keratinocytes separate (acantholysis). Failure of keratinocytes to stick together also leads to abnormal maturation of the keratinocytes (abnormal keratinization) with the formation of the horny bumps. For this reason, keratosis follicularis is sometimes referred to as a disorder of abnormal keratinization or dyskeratosis.The linear or segmental forms of keratosis follicularis are caused by genetic mosaicism meaning that the ATP2A2 gene variant is only present in some of the cells in one part of the skin but most of the skin is not affected. Mosaicism is caused by a variant in a single cell after fertilization (postzygotic mutation) and is not inherited.
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Keratosis Follicularis
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Affects of Keratosis Follicularis
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Keratosis follicularis affects males and females in equal numbers. It is estimated to occur in 1 in 36,000 to 100,000 individuals in the general population. The disorder usually becomes apparent during the second decade in life but has developed in individuals as young 4 and older than 70. Keratosis follicularis was first described in the medical literature in 1889.
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Affects of Keratosis Follicularis. Keratosis follicularis affects males and females in equal numbers. It is estimated to occur in 1 in 36,000 to 100,000 individuals in the general population. The disorder usually becomes apparent during the second decade in life but has developed in individuals as young 4 and older than 70. Keratosis follicularis was first described in the medical literature in 1889.
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Keratosis Follicularis
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Related disorders of Keratosis Follicularis
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Symptoms of the following disorders can be similar to those of keratosis follicularis. Comparisons may be useful for a differential diagnosis.Hailey-Hailey disease, also known as benign familial chronic pemphigus, is another rare genetic skin disorder. Hailey-Hailey disease is characterized by blistering, erosive skin lesions that most often form on the neck, chest, armpits and groin. The skin may itch or burn. Secondary infection is common. Most individuals develop symptoms in the third or fourth decade of life. The lesions may disappear on their own but can recur. Heat, friction, sunlight and trauma may cause an outbreak or worsen existing symptoms. Hailey-Hailey disease is caused by variants in the ATP2C1 gene, a gene that encodes another calcium pump, and Hailey-Hailey disease is also inherited in an autosomal dominant pattern. The desmosomes do not function correctly in Hailey- Hailey disease. (For more information on this disorder, choose “Hailey-Hailey” as your search term in the Rare Disease Database.)Acrokeratosis verruciformis of Hopf is another rare genetic skin disorder. Symptoms of the disorder include flat-topped or slightly convex, smooth, firm, elevated spots (papules) usually distributed symmetrically on the back of the hands, feet, wrists and/or ankles. Spots may be few or numerous; they may range in size from 1/16 to 1/4 inch. Spots are mostly flesh-colored, some are light brown. The palms of the hands and the soles of the feet may be hardened (hyperkeratotic). The nails may be opaque and brittle. Acrokeratosis verruciformis of Hopf may be allelic to keratosis follicularis, which means that the two disorders are caused by different variants of the same gene (ATP2A2).Grover disease, also known as transient acantholytic dermatosis, is an acquired skin disorder (i.e., not inherited) characterized by the sudden appearance of small, firm, raised itchy red bumps, most often on sun-damaged skin of the chest and back. The desmosomes fail to hold the keratinocytes together in Grover disease as they do in Darier disease. The bumps may disappear after six to 12 months or persist for years. Grover disease is mainly seen in men older than forty or fifty. The cause is uncertain, but heat, sweating and sun damage seem to play a part. (For more information on this disorder, choose “Grover disease” as your search term in the Rare Disease Database.)
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Related disorders of Keratosis Follicularis. Symptoms of the following disorders can be similar to those of keratosis follicularis. Comparisons may be useful for a differential diagnosis.Hailey-Hailey disease, also known as benign familial chronic pemphigus, is another rare genetic skin disorder. Hailey-Hailey disease is characterized by blistering, erosive skin lesions that most often form on the neck, chest, armpits and groin. The skin may itch or burn. Secondary infection is common. Most individuals develop symptoms in the third or fourth decade of life. The lesions may disappear on their own but can recur. Heat, friction, sunlight and trauma may cause an outbreak or worsen existing symptoms. Hailey-Hailey disease is caused by variants in the ATP2C1 gene, a gene that encodes another calcium pump, and Hailey-Hailey disease is also inherited in an autosomal dominant pattern. The desmosomes do not function correctly in Hailey- Hailey disease. (For more information on this disorder, choose “Hailey-Hailey” as your search term in the Rare Disease Database.)Acrokeratosis verruciformis of Hopf is another rare genetic skin disorder. Symptoms of the disorder include flat-topped or slightly convex, smooth, firm, elevated spots (papules) usually distributed symmetrically on the back of the hands, feet, wrists and/or ankles. Spots may be few or numerous; they may range in size from 1/16 to 1/4 inch. Spots are mostly flesh-colored, some are light brown. The palms of the hands and the soles of the feet may be hardened (hyperkeratotic). The nails may be opaque and brittle. Acrokeratosis verruciformis of Hopf may be allelic to keratosis follicularis, which means that the two disorders are caused by different variants of the same gene (ATP2A2).Grover disease, also known as transient acantholytic dermatosis, is an acquired skin disorder (i.e., not inherited) characterized by the sudden appearance of small, firm, raised itchy red bumps, most often on sun-damaged skin of the chest and back. The desmosomes fail to hold the keratinocytes together in Grover disease as they do in Darier disease. The bumps may disappear after six to 12 months or persist for years. Grover disease is mainly seen in men older than forty or fifty. The cause is uncertain, but heat, sweating and sun damage seem to play a part. (For more information on this disorder, choose “Grover disease” as your search term in the Rare Disease Database.)
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Keratosis Follicularis
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Diagnosis of Keratosis Follicularis
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A diagnosis of keratosis follicularis is made based upon a thorough clinical evaluation, a detailed history from the affected individual including the family history, identification of characteristic findings and microscopic examination (biopsy) of affected skin tissue. A biopsy may reveal abnormal formation of keratin tissue (keratinization) and failure of cell-to-cell adhesion (acantholysis).
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Diagnosis of Keratosis Follicularis. A diagnosis of keratosis follicularis is made based upon a thorough clinical evaluation, a detailed history from the affected individual including the family history, identification of characteristic findings and microscopic examination (biopsy) of affected skin tissue. A biopsy may reveal abnormal formation of keratin tissue (keratinization) and failure of cell-to-cell adhesion (acantholysis).
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Keratosis Follicularis
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Therapies of Keratosis Follicularis
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Treatment
The treatment of keratosis follicularis is directed toward the specific symptoms that are apparent in each individual. For some individuals, sunscreen, loose clothing, moisturizing creams and avoiding excessive heat may reduce the severity of the disease.Synthetic derivatives of vitamin A (retinoids) applied directly to the affected areas (topically) may help reduce scaly thickening of the skin (hyperkeratosis) but may be uncomfortable to use because they irritate the skin. Therapy that helps soften and shed hardened, abnormal skin (keratolytics) such as treatment with salicylic acid in propylene glycol gel may also help treat hyperkeratosis. Topical corticosteroids and substances that soothe and soften the skin (emollients) have also been used to alleviate inflammation in localized keratosis follicularis.Retinoids taken by mouth (orally) have been effective in treating individuals with keratosis follicularis and are the drugs most often used to treat severe cases. Oral retinoids such as acitretin and isotretinoin affect the entire body (systemic therapy). Oral retinoids are associated with side effects. Women must not become pregnant when taking a retinoid because these drugs could damage the baby and pregnancy should be avoided for some time after stopping the drug (the exact time depends on which retinoid was prescribed). Retinoids should only be used under the supervision of a physician.Antibiotics may be necessary to treat individuals with secondary bacterial infection. Antiviral agents such as acyclovir have been used to treat associated infection with the herpes simplex virus.Genetic counseling is recommended for affected individuals and their families.
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Therapies of Keratosis Follicularis. Treatment
The treatment of keratosis follicularis is directed toward the specific symptoms that are apparent in each individual. For some individuals, sunscreen, loose clothing, moisturizing creams and avoiding excessive heat may reduce the severity of the disease.Synthetic derivatives of vitamin A (retinoids) applied directly to the affected areas (topically) may help reduce scaly thickening of the skin (hyperkeratosis) but may be uncomfortable to use because they irritate the skin. Therapy that helps soften and shed hardened, abnormal skin (keratolytics) such as treatment with salicylic acid in propylene glycol gel may also help treat hyperkeratosis. Topical corticosteroids and substances that soothe and soften the skin (emollients) have also been used to alleviate inflammation in localized keratosis follicularis.Retinoids taken by mouth (orally) have been effective in treating individuals with keratosis follicularis and are the drugs most often used to treat severe cases. Oral retinoids such as acitretin and isotretinoin affect the entire body (systemic therapy). Oral retinoids are associated with side effects. Women must not become pregnant when taking a retinoid because these drugs could damage the baby and pregnancy should be avoided for some time after stopping the drug (the exact time depends on which retinoid was prescribed). Retinoids should only be used under the supervision of a physician.Antibiotics may be necessary to treat individuals with secondary bacterial infection. Antiviral agents such as acyclovir have been used to treat associated infection with the herpes simplex virus.Genetic counseling is recommended for affected individuals and their families.
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Keratosis Follicularis
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Overview of Keratosis Follicularis Spinulosa Decalvans
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Keratosis follicularis spinulosa decalvans (KFSD) is a rare, inherited, skin disorder. KFSD is characterized by hardening of the skin (keratosis) on several parts of the body. Most frequently, the face, neck, and forearms are involved. The thickening of the skin is accompanied by the loss of eyebrows, eyelashes and beard. Baldness (alopecia) usually occurs. People with KFSD may have reduced tolerance to bright light (photophobia), inflammation of the eyelids (blepharitis), and inflammation of the outer membrane of the eyeball and the inner eyelid (conjunctivitis, also known as pink eye). Some have abnormal accumulation of material in the clear outer layer of the eye (corneal dystrophy), which may cause loss of vision or blurred vision. Some may also have poor fingernail formation.Most affected families with KFSD demonstrate an X-linked recessive inheritance pattern. This form of KFSD is called X-linked keratosis follicularis spinulosa decalvans (KFSDX). KFSDX affects predominately men in the family, while women have much milder symptoms. KFSD in these families is caused by an alternation in the MBTPS2 gene. Some studies suggest that an alternation in the SAT1 gene causes this form of KFSD as well.
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Overview of Keratosis Follicularis Spinulosa Decalvans. Keratosis follicularis spinulosa decalvans (KFSD) is a rare, inherited, skin disorder. KFSD is characterized by hardening of the skin (keratosis) on several parts of the body. Most frequently, the face, neck, and forearms are involved. The thickening of the skin is accompanied by the loss of eyebrows, eyelashes and beard. Baldness (alopecia) usually occurs. People with KFSD may have reduced tolerance to bright light (photophobia), inflammation of the eyelids (blepharitis), and inflammation of the outer membrane of the eyeball and the inner eyelid (conjunctivitis, also known as pink eye). Some have abnormal accumulation of material in the clear outer layer of the eye (corneal dystrophy), which may cause loss of vision or blurred vision. Some may also have poor fingernail formation.Most affected families with KFSD demonstrate an X-linked recessive inheritance pattern. This form of KFSD is called X-linked keratosis follicularis spinulosa decalvans (KFSDX). KFSDX affects predominately men in the family, while women have much milder symptoms. KFSD in these families is caused by an alternation in the MBTPS2 gene. Some studies suggest that an alternation in the SAT1 gene causes this form of KFSD as well.
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Keratosis Follicularis Spinulosa Decalvans
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Symptoms of Keratosis Follicularis Spinulosa Decalvans
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KFSD is a type of ichthyoses, a group of inherited disorders of the skin in which the skin tends to be thick and rough and has a scaly appearance. Hardening of the skin around the hair follicles leads to scarring and baldness. This condition begins in infancy, initially appearing on the face and neck, and then progresses to the chest, back, abdomen, arms and legs. Hair loss of the eyebrows and scalp caused by the scarring become evident in childhood and progress until teenage years.Allergic reactions (atopy), photophobia, and inflammation of the eye’s cornea (keratitis) may also occur. Some people have itchy and red eyeballs and eyelids. Some people affected with KFSD have corneal dystrophy. The cornea must remain clear to be able to focus incoming light. Therefore, corneal dystrophy may cause blurred vision or loss of vision. Occasionally, the teeth become stained and fingernails are poorly formed.The word decalvans comes from the Greek for snake and alludes to the whorls and winding streaks characteristic of the pattern of baldness in this disorder. The name is often accompanied by the phrase “cum ophiasi” which simply means baldness.
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Symptoms of Keratosis Follicularis Spinulosa Decalvans. KFSD is a type of ichthyoses, a group of inherited disorders of the skin in which the skin tends to be thick and rough and has a scaly appearance. Hardening of the skin around the hair follicles leads to scarring and baldness. This condition begins in infancy, initially appearing on the face and neck, and then progresses to the chest, back, abdomen, arms and legs. Hair loss of the eyebrows and scalp caused by the scarring become evident in childhood and progress until teenage years.Allergic reactions (atopy), photophobia, and inflammation of the eye’s cornea (keratitis) may also occur. Some people have itchy and red eyeballs and eyelids. Some people affected with KFSD have corneal dystrophy. The cornea must remain clear to be able to focus incoming light. Therefore, corneal dystrophy may cause blurred vision or loss of vision. Occasionally, the teeth become stained and fingernails are poorly formed.The word decalvans comes from the Greek for snake and alludes to the whorls and winding streaks characteristic of the pattern of baldness in this disorder. The name is often accompanied by the phrase “cum ophiasi” which simply means baldness.
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Keratosis Follicularis Spinulosa Decalvans
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Causes of Keratosis Follicularis Spinulosa Decalvans
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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.KFSD is usually caused by an alternation in the MBTPS2 gene. Some studies suggest that an alternation in the SAT1 gene causes this form of KFSD as well. This form of KFSD is called X-linked keratosis follicularis spinulosa decalvans (KFSDX) and follows an X-linked recessive inheritance pattern.X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and manifest mostly in males. Females that have an abnormal gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the abnormal gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains an abnormal gene he will develop the disease.Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son. If a male with an X-linked disorder is able to reproduce, he will pass the abnormal gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Some families with KFSD are reported to have male to male transmission, which suggests autosomal dominant inheritance. In these families, sons inherited KFSD from their father. All males in the family are affected by KFSD. All females do not have KFSD. The gene that causes KFSD in these families is not known. Rarely, patients with KFSD do not have any family history of KFSD. More research is needed to understand what gene causes KFSD in these families.
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Causes of Keratosis Follicularis Spinulosa Decalvans. 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.KFSD is usually caused by an alternation in the MBTPS2 gene. Some studies suggest that an alternation in the SAT1 gene causes this form of KFSD as well. This form of KFSD is called X-linked keratosis follicularis spinulosa decalvans (KFSDX) and follows an X-linked recessive inheritance pattern.X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and manifest mostly in males. Females that have an abnormal gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the abnormal gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains an abnormal gene he will develop the disease.Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son. If a male with an X-linked disorder is able to reproduce, he will pass the abnormal gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Some families with KFSD are reported to have male to male transmission, which suggests autosomal dominant inheritance. In these families, sons inherited KFSD from their father. All males in the family are affected by KFSD. All females do not have KFSD. The gene that causes KFSD in these families is not known. Rarely, patients with KFSD do not have any family history of KFSD. More research is needed to understand what gene causes KFSD in these families.
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Keratosis Follicularis Spinulosa Decalvans
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Affects of Keratosis Follicularis Spinulosa Decalvans
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KFSD is a rare disorder affecting males more severely than females. Because some people with KFSD may go unrecognized or undiagnosed, determining the true frequency of these disorders in the general population is difficult. KFSD is estimated to affect about less than 1 in 1,000, 000 people in the general population.
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Affects of Keratosis Follicularis Spinulosa Decalvans. KFSD is a rare disorder affecting males more severely than females. Because some people with KFSD may go unrecognized or undiagnosed, determining the true frequency of these disorders in the general population is difficult. KFSD is estimated to affect about less than 1 in 1,000, 000 people in the general population.
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Keratosis Follicularis Spinulosa Decalvans
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Related disorders of Keratosis Follicularis Spinulosa Decalvans
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Symptoms of the following disorders may be similar to those of keratosis follicularis spinulosa decalvans. Comparisons can be useful for a differential diagnosis:Tinea capitis (scalp ringworm) is a fungal infection of the scalp caused by different species of fungus. It is not inherited. Most cases occur between the ages of 3-7 years. It presents as numerous scaly macules and patches of broken hairs and alopecia on the scalp. More severe forms are associated with inflammatory papules, pustules, and plaques as well as systemic symptoms such as fever and malaise.Folliculitis decalvans is a form of alopecia (hair loss) that involves scarring. It is not inherited. It is characterized by redness and swelling around the hair follicle (folliculitis) that leads to destruction of the follicle. A hair follicle is part of the skin that grows hair. Therefore, destruction of the follicle leads to permanent hair loss. It most commonly occurs in middle-aged adults of both sexes but can arise any time after the onset of puberty. The crown is the most frequently affected area.Ichthyosis or “disorders of cornification” are general terms describing a group of disorders that are characterized by dry, rough and thick skin, giving a scaly appearance. The scaly appearance is due to 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. (For more information see “ichthyosis” in the Rare Disease Database.)Ichthyosis congenita is an inherited skin disorder. It is 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 congenita” as your search term in the Rare Disease Database.)X-Linked ichthyosis is an X-linked skin disorder affecting males which is caused by a deficiency of the enzyme steroid sulfatase. In this condition, the skin cells are produced at a normal rate but they do not separate normally at the outermost layer of the skin, and are not shed as quickly as they should be. The result is a build-up of scales, which is often dark and usually covers only a portion of the body. The back of the neck is almost always affected. (For more information, choose “X-linked ichthyosis” as your search term in the Rare Disease Database.)Keratitis ichthyosis deafness (KID) syndrome is a very rare disorder which follows an autosomal recessive inheritance pattern. People with KID have keratitis, fixed hardened skin scales (plaques) on the extremities and face, thick hardened skin on the palms of the hands and the soles of the feet, and small and malformed nails. KID is also characterized by hearing loss at birth. (For more information, choose “keratitis” as your search term in the Rare Disease Database.)Erythrokeratodermia variabilis (EKV) is an inherited skin disorder which is most often inherited in an autosomal dominant pattern. Symptoms are present at birth or become apparent in infancy. It is characterized by rough and thickened skin (hyperkeratosis). The reddish-brown patches and can either be widespread over many parts of the body or occur only in a small area. It is also characterized by redness (erythema), which can be triggered by sudden changes in temperature, emotional stress, or trauma or irritation to the area. It usually fades within hours to days. Hair, nails and teeth are not involved.Other forms of ichthyosis include Sjogren-Larsson syndrome, Netherton syndrome, ichthyosis hystrix, lamellar ichthyosis, Refsum syndrome, Darier disease, Conradi-Hunermann syndrome, 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 Keratosis Follicularis Spinulosa Decalvans. Symptoms of the following disorders may be similar to those of keratosis follicularis spinulosa decalvans. Comparisons can be useful for a differential diagnosis:Tinea capitis (scalp ringworm) is a fungal infection of the scalp caused by different species of fungus. It is not inherited. Most cases occur between the ages of 3-7 years. It presents as numerous scaly macules and patches of broken hairs and alopecia on the scalp. More severe forms are associated with inflammatory papules, pustules, and plaques as well as systemic symptoms such as fever and malaise.Folliculitis decalvans is a form of alopecia (hair loss) that involves scarring. It is not inherited. It is characterized by redness and swelling around the hair follicle (folliculitis) that leads to destruction of the follicle. A hair follicle is part of the skin that grows hair. Therefore, destruction of the follicle leads to permanent hair loss. It most commonly occurs in middle-aged adults of both sexes but can arise any time after the onset of puberty. The crown is the most frequently affected area.Ichthyosis or “disorders of cornification” are general terms describing a group of disorders that are characterized by dry, rough and thick skin, giving a scaly appearance. The scaly appearance is due to 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. (For more information see “ichthyosis” in the Rare Disease Database.)Ichthyosis congenita is an inherited skin disorder. It is 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 congenita” as your search term in the Rare Disease Database.)X-Linked ichthyosis is an X-linked skin disorder affecting males which is caused by a deficiency of the enzyme steroid sulfatase. In this condition, the skin cells are produced at a normal rate but they do not separate normally at the outermost layer of the skin, and are not shed as quickly as they should be. The result is a build-up of scales, which is often dark and usually covers only a portion of the body. The back of the neck is almost always affected. (For more information, choose “X-linked ichthyosis” as your search term in the Rare Disease Database.)Keratitis ichthyosis deafness (KID) syndrome is a very rare disorder which follows an autosomal recessive inheritance pattern. People with KID have keratitis, fixed hardened skin scales (plaques) on the extremities and face, thick hardened skin on the palms of the hands and the soles of the feet, and small and malformed nails. KID is also characterized by hearing loss at birth. (For more information, choose “keratitis” as your search term in the Rare Disease Database.)Erythrokeratodermia variabilis (EKV) is an inherited skin disorder which is most often inherited in an autosomal dominant pattern. Symptoms are present at birth or become apparent in infancy. It is characterized by rough and thickened skin (hyperkeratosis). The reddish-brown patches and can either be widespread over many parts of the body or occur only in a small area. It is also characterized by redness (erythema), which can be triggered by sudden changes in temperature, emotional stress, or trauma or irritation to the area. It usually fades within hours to days. Hair, nails and teeth are not involved.Other forms of ichthyosis include Sjogren-Larsson syndrome, Netherton syndrome, ichthyosis hystrix, lamellar ichthyosis, Refsum syndrome, Darier disease, Conradi-Hunermann syndrome, 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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Keratosis Follicularis Spinulosa Decalvans
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Diagnosis of Keratosis Follicularis Spinulosa Decalvans
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In most instances, the appearance of the skin determines the diagnosis, but a family history and physical examination are often required to rule out other possible causes of scaly, dry skin. Some physicians may examine skin tissue under a light microscope or even under an electron microscope.Molecular genetic testing can confirm a diagnosis of KFSDX. Molecular genetic testing looks for changes or alterations in the MBTPS2 and SAT1 genes known to cause KFSDX. A negative genetic test result does not rule out KFSD.
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Diagnosis of Keratosis Follicularis Spinulosa Decalvans. In most instances, the appearance of the skin determines the diagnosis, but a family history and physical examination are often required to rule out other possible causes of scaly, dry skin. Some physicians may examine skin tissue under a light microscope or even under an electron microscope.Molecular genetic testing can confirm a diagnosis of KFSDX. Molecular genetic testing looks for changes or alterations in the MBTPS2 and SAT1 genes known to cause KFSDX. A negative genetic test result does not rule out KFSD.
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Keratosis Follicularis Spinulosa Decalvans
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Therapies of Keratosis Follicularis Spinulosa Decalvans
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TreatmentThe dry scaly skin of KFSD is relieved by applying skin softening (emollient) ointments to soften add moisture the skin. This can be especially effective after bathing while the skin is still moist. Plain petroleum jelly is preferable. Lactate lotion can also be effective. 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. Drugs derived from vitamin A (retinoids) such as tretinoin, motretinide, and etretinate are often effective against symptoms of ichthyosis. They are help produce a thinner outermost layer of the skin and smooth the skin. Retinoids should never be taken except under the supervision of a doctor, and under strict guidelines, as outlined by the FDA and the drug manufacturers. This is because it can cause toxic effects on the bones in some patients. A synthetic derivative of vitamin A, isotretinoin, when taken orally by pregnant women, can cause severe birth defects in the fetus. The decision to treat with systemic retinoids requires consultation with a physician experienced in their use for these conditions. People with KFSD should follow-up with an eye doctor (ophthalmologist) for monitoring and treating symptoms of eye problems and watch for symptoms of pink eye and blurred or declining vision. In general, dietary changes have little or no effect on the ichthyoses. Although retinoids are used to treat ichthyosis, taking vitamin A in excess of normal daily requirements is not recommended. Excess vitamin A is toxic and can result in cerebral edema (swelling of the brain) and damage to the liver. Children can be particularly sensitive to toxic amounts of vitamin A.
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Therapies of Keratosis Follicularis Spinulosa Decalvans. TreatmentThe dry scaly skin of KFSD is relieved by applying skin softening (emollient) ointments to soften add moisture the skin. This can be especially effective after bathing while the skin is still moist. Plain petroleum jelly is preferable. Lactate lotion can also be effective. 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. Drugs derived from vitamin A (retinoids) such as tretinoin, motretinide, and etretinate are often effective against symptoms of ichthyosis. They are help produce a thinner outermost layer of the skin and smooth the skin. Retinoids should never be taken except under the supervision of a doctor, and under strict guidelines, as outlined by the FDA and the drug manufacturers. This is because it can cause toxic effects on the bones in some patients. A synthetic derivative of vitamin A, isotretinoin, when taken orally by pregnant women, can cause severe birth defects in the fetus. The decision to treat with systemic retinoids requires consultation with a physician experienced in their use for these conditions. People with KFSD should follow-up with an eye doctor (ophthalmologist) for monitoring and treating symptoms of eye problems and watch for symptoms of pink eye and blurred or declining vision. In general, dietary changes have little or no effect on the ichthyoses. Although retinoids are used to treat ichthyosis, taking vitamin A in excess of normal daily requirements is not recommended. Excess vitamin A is toxic and can result in cerebral edema (swelling of the brain) and damage to the liver. Children can be particularly sensitive to toxic amounts of vitamin A.
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Keratosis Follicularis Spinulosa Decalvans
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Overview of Kernicterus
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Kernicterus is a rare neurological disorder characterized by excessive levels of bilirubin in the blood (hyperbilirubinemia) during infancy. Bilirubin is an orange-yellow bile pigment that is a byproduct of the natural breakdown of hemoglobin in red blood cells (hemolysis). Toxic levels of bilirubin may accumulate in the brain, potentially resulting in a variety of symptoms and physical findings. These symptoms may include lack of energy (lethargy), poor feeding habits, fever, and vomiting. Affected infants may also experience the absence of certain reflexes (e.g., Moro reflex, etc.); mild to severe muscle spasms including those in which the head and heels are bent backward and the body bows forward (opisthotonus); and/or uncontrolled involuntary muscle movements (spasticity). In some cases, infants with kernicterus may develop life-threatening complications.
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Overview of Kernicterus. Kernicterus is a rare neurological disorder characterized by excessive levels of bilirubin in the blood (hyperbilirubinemia) during infancy. Bilirubin is an orange-yellow bile pigment that is a byproduct of the natural breakdown of hemoglobin in red blood cells (hemolysis). Toxic levels of bilirubin may accumulate in the brain, potentially resulting in a variety of symptoms and physical findings. These symptoms may include lack of energy (lethargy), poor feeding habits, fever, and vomiting. Affected infants may also experience the absence of certain reflexes (e.g., Moro reflex, etc.); mild to severe muscle spasms including those in which the head and heels are bent backward and the body bows forward (opisthotonus); and/or uncontrolled involuntary muscle movements (spasticity). In some cases, infants with kernicterus may develop life-threatening complications.
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Kernicterus
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Symptoms of Kernicterus
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In some cases, symptoms and physical findings of kernicterus appear two to five days after birth. Within the first few days of life, affected infants develop abnormally high levels of bilirubin in the blood (hyperbilirubinemia) and persistent yellowing of the skin, mucous membranes, and whites of the eyes (jaundice). Toxic levels of bilirubin may accumulate in certain areas of the brain (i.e., the basal ganglia and the brainstem), potentially resulting in a variety of symptoms and physical findings that, in some cases, may cause life-threatening complications. Initial findings associated with kernicterus may vary from case to case, but often include lack of energy (lethargy) or drowsiness, poor feeding habits, fever, a shrill high-pitched cry, and/or absence of certain reflexes (e.g., Moro reflex, etc.). Affected infants may eventually experience respiratory distress, mild to severe muscle spasms including those in which the head and heels are bent backward and the body bows forward (opisthotonus), and/or diminished muscle tone (hypotonia). As an affected infants ages, other symptoms and physical findings may develop including delayed and/or abnormal motions or motor development; convulsions or seizures; impaired ability to coordinate voluntary movements (ataxia); abnormal muscle rigidity resulting in muscle spasms (dystonia); slow, continuous, involuntary, writhing movements (athetosis) of the arms and legs (limbs) and/or entire body; problems with sensory perception; lack of upward gaze; and/or hearing loss. In some cases, affected infants may exhibit mental retardation and difficulty speaking (dysarthria). In most cases, the syndrome characteristic of kernicterus develops by three to four years of age.
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Symptoms of Kernicterus. In some cases, symptoms and physical findings of kernicterus appear two to five days after birth. Within the first few days of life, affected infants develop abnormally high levels of bilirubin in the blood (hyperbilirubinemia) and persistent yellowing of the skin, mucous membranes, and whites of the eyes (jaundice). Toxic levels of bilirubin may accumulate in certain areas of the brain (i.e., the basal ganglia and the brainstem), potentially resulting in a variety of symptoms and physical findings that, in some cases, may cause life-threatening complications. Initial findings associated with kernicterus may vary from case to case, but often include lack of energy (lethargy) or drowsiness, poor feeding habits, fever, a shrill high-pitched cry, and/or absence of certain reflexes (e.g., Moro reflex, etc.). Affected infants may eventually experience respiratory distress, mild to severe muscle spasms including those in which the head and heels are bent backward and the body bows forward (opisthotonus), and/or diminished muscle tone (hypotonia). As an affected infants ages, other symptoms and physical findings may develop including delayed and/or abnormal motions or motor development; convulsions or seizures; impaired ability to coordinate voluntary movements (ataxia); abnormal muscle rigidity resulting in muscle spasms (dystonia); slow, continuous, involuntary, writhing movements (athetosis) of the arms and legs (limbs) and/or entire body; problems with sensory perception; lack of upward gaze; and/or hearing loss. In some cases, affected infants may exhibit mental retardation and difficulty speaking (dysarthria). In most cases, the syndrome characteristic of kernicterus develops by three to four years of age.
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Causes of Kernicterus
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Some cases of kernicterus occur randomly, for no apparent reason (sporadically). According to the medical literature, excess levels of bilirubin (hyperbilirubinemia) alone is not sufficient to produce kernicterus. Potential causes may include Rh disease and/or unknown factors. Rh Disease, also known as isoimmunization or Erythroblastosis Fetalis, can also cause jaundice during infancy that may lead to kernicterus. In Rh Disease, red blood cells from the fetus may cross the placenta and enter into the mother's bloodstream. This stimulates maternal antibody formation against these “foreign” blood cells. These antibodies eventually reach the fetus via the placenta and cause destruction of fetal red blood cells (hemolysis), resulting in low levels of circulating red blood cells (anemia) in the fetus. In response, the fetal bone marrow releases immature red blood cells (erythroblasts) into the fetal bloodstream. The hemoglobin from the destroyed red blood cells is broken down into bilirubin, a yellow-orange bile pigment. Bilirubin is cleared from the fetal bloodstream by crossing the placenta into the mother's bloodstream. However, after birth abnormally high levels of bilirubin (hyperbilirubinemia) may accumulate in the newborn's bloodstream and brain. This disease is now almost non-existent due to the availability of anti-Rh globulin, which prevents isoimmunization. (For more information on this disorder, choose “Rh Disease” as your search term in the Rare Disease Database.)In some rare cases, kernicterus may result from a rare disorder known as Crigler-Najjar Syndrome Type I. (For more information on this disorder, choose “Crigler Najjar” as your search term in the Rare Disease Database.)
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Causes of Kernicterus. Some cases of kernicterus occur randomly, for no apparent reason (sporadically). According to the medical literature, excess levels of bilirubin (hyperbilirubinemia) alone is not sufficient to produce kernicterus. Potential causes may include Rh disease and/or unknown factors. Rh Disease, also known as isoimmunization or Erythroblastosis Fetalis, can also cause jaundice during infancy that may lead to kernicterus. In Rh Disease, red blood cells from the fetus may cross the placenta and enter into the mother's bloodstream. This stimulates maternal antibody formation against these “foreign” blood cells. These antibodies eventually reach the fetus via the placenta and cause destruction of fetal red blood cells (hemolysis), resulting in low levels of circulating red blood cells (anemia) in the fetus. In response, the fetal bone marrow releases immature red blood cells (erythroblasts) into the fetal bloodstream. The hemoglobin from the destroyed red blood cells is broken down into bilirubin, a yellow-orange bile pigment. Bilirubin is cleared from the fetal bloodstream by crossing the placenta into the mother's bloodstream. However, after birth abnormally high levels of bilirubin (hyperbilirubinemia) may accumulate in the newborn's bloodstream and brain. This disease is now almost non-existent due to the availability of anti-Rh globulin, which prevents isoimmunization. (For more information on this disorder, choose “Rh Disease” as your search term in the Rare Disease Database.)In some rare cases, kernicterus may result from a rare disorder known as Crigler-Najjar Syndrome Type I. (For more information on this disorder, choose “Crigler Najjar” as your search term in the Rare Disease Database.)
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Kernicterus
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Affects of Kernicterus
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Kernicterus is a rare neurological disorder that affects newborn infants of both sexes in equal numbers. Kernicterus occurs more often in premature infants than full-term infants.
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Affects of Kernicterus. Kernicterus is a rare neurological disorder that affects newborn infants of both sexes in equal numbers. Kernicterus occurs more often in premature infants than full-term infants.
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Kernicterus
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Related disorders of Kernicterus
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Related disorders of Kernicterus.
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Kernicterus
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Diagnosis of Kernicterus
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Kernicterus may be suspected within the first days of life. The diagnosis may be based upon a thorough clinical evaluation and identification of characteristic physical findings (e.g., jaundice, abnormal cry, loss of Moro reflex, etc.). In most cases, persistent yellowing of the skin, mucous membranes, and whites of the eyes (jaundice) is apparent within the first few days of life.
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Diagnosis of Kernicterus. Kernicterus may be suspected within the first days of life. The diagnosis may be based upon a thorough clinical evaluation and identification of characteristic physical findings (e.g., jaundice, abnormal cry, loss of Moro reflex, etc.). In most cases, persistent yellowing of the skin, mucous membranes, and whites of the eyes (jaundice) is apparent within the first few days of life.
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Kernicterus
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Therapies of Kernicterus
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TreatmentTreatment for Kernicterus focuses on decreasing the amount of unconjugated bilirubin in the blood. Early treatment is imperative in the attempt to prevent the symptoms and physical findings associated with kernicterus durint the first months of life. Such treatments may include exchange blood transfusions in which small amounts of blood are withdrawn repeatedly and replaced with blood from a donor until most of the blood has been exchanged. In another procedure known as plasmapheresis, unwanted substances (toxins, metabolic substances and plasma parts) are removed from the blood. During this procedure, blood is removed from the affected individual and blood cells are separated from plasma. The plasma is then replaced with other human plasma and the blood is transfused into the affected individual.In addition, phototherapy is used for disease management purposes. During this procedure, intense fluorescent light is focused on the bare skin, while the eyes are shielded. This helps to speed up the excretion of bilirubin from the skin and aids in its decomposition. As an affected individual ages, body mass increases and the skin thickens; phototherapy becomes less effective against preventing the symptoms and physical findings associated with kernicterus. Therefore, liver transplantation may be performed. Some researchers believe that liver transplantation should be performed at an early age, before brain damage potentially associated with kernicterus can develop.Other treatment is symptomatic and supportive.
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Therapies of Kernicterus. TreatmentTreatment for Kernicterus focuses on decreasing the amount of unconjugated bilirubin in the blood. Early treatment is imperative in the attempt to prevent the symptoms and physical findings associated with kernicterus durint the first months of life. Such treatments may include exchange blood transfusions in which small amounts of blood are withdrawn repeatedly and replaced with blood from a donor until most of the blood has been exchanged. In another procedure known as plasmapheresis, unwanted substances (toxins, metabolic substances and plasma parts) are removed from the blood. During this procedure, blood is removed from the affected individual and blood cells are separated from plasma. The plasma is then replaced with other human plasma and the blood is transfused into the affected individual.In addition, phototherapy is used for disease management purposes. During this procedure, intense fluorescent light is focused on the bare skin, while the eyes are shielded. This helps to speed up the excretion of bilirubin from the skin and aids in its decomposition. As an affected individual ages, body mass increases and the skin thickens; phototherapy becomes less effective against preventing the symptoms and physical findings associated with kernicterus. Therefore, liver transplantation may be performed. Some researchers believe that liver transplantation should be performed at an early age, before brain damage potentially associated with kernicterus can develop.Other treatment is symptomatic and supportive.
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Kernicterus
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Overview of Kienböck Disease
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Kienböck Disease is an acquired bone disorder. Abnormalities of the lunate bone in the wrist develops following an injury or inflammation. Recurrent pain and stiffness occur in conjunction with thickening, swelling and tenderness in soft tissue overlying the lunate bone. The range of motion in the wrist may become limited.
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Overview of Kienböck Disease. Kienböck Disease is an acquired bone disorder. Abnormalities of the lunate bone in the wrist develops following an injury or inflammation. Recurrent pain and stiffness occur in conjunction with thickening, swelling and tenderness in soft tissue overlying the lunate bone. The range of motion in the wrist may become limited.
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Kienböck Disease
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Symptoms of Kienböck Disease
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Kienböck Disease is characterized by degenerative changes in the lunate bone of the wrist. Softening, deterioration, fragmentation or compression of the affected bone can occur. These changes may produce pain, swelling, tenderness, thickening and/or stiffness in the overlying tissues of the wrist. The range of motion may become restricted. Many individuals with Kienböck Disease have a shorter ulna than radius (negative ulnar variance). Healing occurs through formation of new bone in some cases.
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Symptoms of Kienböck Disease. Kienböck Disease is characterized by degenerative changes in the lunate bone of the wrist. Softening, deterioration, fragmentation or compression of the affected bone can occur. These changes may produce pain, swelling, tenderness, thickening and/or stiffness in the overlying tissues of the wrist. The range of motion may become restricted. Many individuals with Kienböck Disease have a shorter ulna than radius (negative ulnar variance). Healing occurs through formation of new bone in some cases.
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Kienböck Disease
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Causes of Kienböck Disease
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The exact cause of Kienböck Disease is not known. However, it is believed to be caused by inflammation or injury of the wrist.
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Causes of Kienböck Disease. The exact cause of Kienböck Disease is not known. However, it is believed to be caused by inflammation or injury of the wrist.
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Kienböck Disease
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Affects of Kienböck Disease
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Kienböck Disease usually begins during childhood and seems to affect females more often than males.
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Affects of Kienböck Disease. Kienböck Disease usually begins during childhood and seems to affect females more often than males.
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Kienböck Disease
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Related disorders of Kienböck Disease
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Symptoms of the following disorders can be similar to those of Kienböck Disease. Comparisons may be useful for a differential diagnosis:Carpal Tunnel Syndrome is a condition caused by compression of peripheral nerves in the wrist, affecting one or both hands. It is characterized by a sensation of numbness, tingling, burning and/or pain in the hand and wrist. Persons affected by this disorder may be awakened at night with the feeling that the hand has “gone to sleep”. Various other diseases may occur in conjunction with this condition. With timely treatment, the prognosis in most cases is favorable. (For more information on this disorder, please choose “Carpal Tunnel” as your search term online.)Sudeck's Atrophy, also known as post-traumatic osteoporosis, is marked by an acute atrophy of the bones. The wrist and ankle bones are most commonly affected, following a slight injury such as a sprain.Juvenile Osteoporosis is marked by a porous condition or atrophy of bone tissue beginning before puberty. The exact cause has not been identified. This condition can lead to pain or fractures in many bones of the body including the wrist. Spontaneous remission may occur within several years.
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Related disorders of Kienböck Disease. Symptoms of the following disorders can be similar to those of Kienböck Disease. Comparisons may be useful for a differential diagnosis:Carpal Tunnel Syndrome is a condition caused by compression of peripheral nerves in the wrist, affecting one or both hands. It is characterized by a sensation of numbness, tingling, burning and/or pain in the hand and wrist. Persons affected by this disorder may be awakened at night with the feeling that the hand has “gone to sleep”. Various other diseases may occur in conjunction with this condition. With timely treatment, the prognosis in most cases is favorable. (For more information on this disorder, please choose “Carpal Tunnel” as your search term online.)Sudeck's Atrophy, also known as post-traumatic osteoporosis, is marked by an acute atrophy of the bones. The wrist and ankle bones are most commonly affected, following a slight injury such as a sprain.Juvenile Osteoporosis is marked by a porous condition or atrophy of bone tissue beginning before puberty. The exact cause has not been identified. This condition can lead to pain or fractures in many bones of the body including the wrist. Spontaneous remission may occur within several years.
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Kienböck Disease
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Diagnosis of Kienböck Disease
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Arthroscopic procedures, CT scan and/or x-ray imaging may be used for diagnosis.
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Diagnosis of Kienböck Disease. Arthroscopic procedures, CT scan and/or x-ray imaging may be used for diagnosis.
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Kienböck Disease
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Therapies of Kienböck Disease
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TreatmentThe treatment of Kienböck's Disease may involve surgery of the lunate bone, shortening of the radial bone, lengthening of the ulna or the stiffening of the joints through an operation (arthrodesis). Cutting off the nerve supply of the wrist (wrist denervation) has been used in conjunction with some of the other procedures. Surgical options depend on how far the disease has progressed and the best option will differ for each individual.If inflammation of the wrist has occurred, drug treatment may be recommended. Other treatment is symptomatic and supportive.
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Therapies of Kienböck Disease. TreatmentThe treatment of Kienböck's Disease may involve surgery of the lunate bone, shortening of the radial bone, lengthening of the ulna or the stiffening of the joints through an operation (arthrodesis). Cutting off the nerve supply of the wrist (wrist denervation) has been used in conjunction with some of the other procedures. Surgical options depend on how far the disease has progressed and the best option will differ for each individual.If inflammation of the wrist has occurred, drug treatment may be recommended. Other treatment is symptomatic and supportive.
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Kienböck Disease
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Overview of KIF1A-Related Disorder
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SummaryKIF1A-related disorder is a group of genetic disorders caused by one or more variations (pathogenic variants or mutations) in the KIF1A gene. Researchers have determined that different variations of this gene have been associated with different signs and symptoms, progression and severity of disease. Although different variations lead to many of the same signs and symptoms, the specific symptoms that develop, the progression of the symptoms and the overall severity can vary greatly. This is true for people in different families with the same genetic variation and members within the same family with the same variation in the KIF1A gene. The differences are based, in part, on where in the gene the variation occurs and the type of variation that occurs. KIF1A-related disorder can be inherited as an autosomal dominant condition or due to a single new (de novo) variant and, in other families, can be inherited in an autosomal recessive pattern. KIF1A-related disorder can best be thought of as a spectrum of disease that can range from mild symptoms to severe and life-threatening. Treatment for these disorders is focused on treatment of symptoms.Introduction
Originally, changes in the KIF1A gene were thought to lead to three different disorders: nonsyndromic intellectual disability 9 (MRD9), currently known as NESCAV syndrome, hereditary sensory neuropathy type IIC (HSNIIC) and hereditary spastic paraplegia 30 (SPG30). Some affected individuals may have symptoms and inheritance patterns that fit neatly into these categories, but others do not.
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Overview of KIF1A-Related Disorder. SummaryKIF1A-related disorder is a group of genetic disorders caused by one or more variations (pathogenic variants or mutations) in the KIF1A gene. Researchers have determined that different variations of this gene have been associated with different signs and symptoms, progression and severity of disease. Although different variations lead to many of the same signs and symptoms, the specific symptoms that develop, the progression of the symptoms and the overall severity can vary greatly. This is true for people in different families with the same genetic variation and members within the same family with the same variation in the KIF1A gene. The differences are based, in part, on where in the gene the variation occurs and the type of variation that occurs. KIF1A-related disorder can be inherited as an autosomal dominant condition or due to a single new (de novo) variant and, in other families, can be inherited in an autosomal recessive pattern. KIF1A-related disorder can best be thought of as a spectrum of disease that can range from mild symptoms to severe and life-threatening. Treatment for these disorders is focused on treatment of symptoms.Introduction
Originally, changes in the KIF1A gene were thought to lead to three different disorders: nonsyndromic intellectual disability 9 (MRD9), currently known as NESCAV syndrome, hereditary sensory neuropathy type IIC (HSNIIC) and hereditary spastic paraplegia 30 (SPG30). Some affected individuals may have symptoms and inheritance patterns that fit neatly into these categories, but others do not.
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Symptoms of KIF1A-Related Disorder
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The signs and symptoms of KIF1A-related disorder can vary greatly from one person to another depending on the specific variation in the gene that is present, the inheritance pattern and other factors. Much about KIF1A-related disorder is not fully understood. Several factors including the small number of identified patients prevent physicians from developing a complete picture of associated symptoms and prognosis. Therefore, it is important to note that affected individuals most likely will not have all of the symptoms discussed below and that every person is unique. Parents and patients should talk to their physician and medical team about their specific situation, associated symptoms and overall prognosis.AUTOSOMAL DOMINANT FORMS OF KIF1A-RELATED DISORDERS
Some affected individuals have an autosomal dominant form of the disorder that has been associated with a variety of symptoms. These symptoms include intellectual disability, delays in reaching developmental milestones (developmental delays) and diminished muscle tone (hypotonia). Additional symptoms include exaggerated reflexes (hyperreflexia) and, as infants or children age, increased muscle tone (hypertonia). Eventually, affected children may develop spastic paraplegia, a condition in which people have difficulty walking due to muscle weakness and muscle tightness (spasticity) in the legs. Spastic paraplegia can become progressively worse, significantly affecting the ability walk and get around.Spastic paraplegia is classified as “uncomplicated” or “pure” when symptoms are confined to leg weakness and tightness. Spastic paraplegia is classified as “complicated” when leg weakness and tightness (spasticity) are accompanied by other neurologic disturbances. Some individuals eventually develop contractures. A contracture is a condition in which a joint becomes permanently fixed in a bent or straightened position, completely or partially restricting the movement of the affected joint.Some affected individuals have optic nerve atrophy, which is degeneration of the main nerve that carries nerve impulses from the eyes to the brain. Sometimes, the field of vision can be reduced. Some affected individuals experience progressive deterioration of the nerve cells of cerebellum (cerebellar atrophy) and other parts of the brain, which can cause problem with balance and coordination, seizures, and brain function generally. Peripheral neuropathy is a condition that occurs when nerves that carry messages to and from the brain and spinal cord to the rest of the body are damaged. Those affected may experience tingling, burning, numbness, and stabbing pain in the affected extremities.Other symptoms that have been reported include poor coordination (ataxia), rapid, involuntary eye movements (nystagmus), crossed eyes (strabismus), drooping of the upper eyelid (ptosis), weakness or paralysis of half of the facial muscles (facial diplegia), clumsiness when trying to use their hands to manipulate or hold objects and tremors that occur when attempting to make deliberate actions (intention tremors). A variety of different seizure types have also been described and seizures during sleep can be a particular problem. Some individuals have abnormal electrical activity in the brain that is not a seizure but is not normal. Some individuals have developed abnormal curvature of the spine (scoliosis). Some infants have microcephaly, a condition in which the head is smaller than would otherwise be expected based on age and sex. Some infants and children experience backflow or regurgitation of the contents of the stomach into the esophagus (gastroesophageal reflux). Some males have had small testes or penis, or there is failure of the testes to descend into the scrotum (cryptorchidism).Genetic variants in KIF1A have also been associated with amyotrophic lateral sclerosis (ALS).AUTOSOMAL RECESSIVE FORMS OF KIF1A-RELATED DISORDERS
Individuals with recessive forms of KIF1A-related disorder may have symptoms that fit neatly into the categories described or may have symptoms that look more like the autosomal dominant form of the condition described above.HEREDITARY SENSORY NEUROPATHY IIC
Some individuals with variations in the KIF1A gene develop a form of hereditary sensory and autonomic neuropathy, specifically type IIC. Hereditary sensory neuropathies are a group of rare neurological disorders characterized by degeneration of the nervous system that frequently progresses to loss of feeling, especially in the hands and feet. Symptoms usually start with inflamed fingers or toes, especially around the nails. Numbness and tingling sensations in the hands and feet may also occur. Eventually, affected individuals lose feeling (sensation) in the hands and feet. This sensory loss is due to abnormal functioning of the sensory nerves that control responses to pain and temperature and may also affect the autonomic nervous system that controls other involuntary or automatic body processes. Chronic infection of the affected areas is common and worsens as ulcers form on the fingers or the soles of the hands and feet. NORD has a separate report on hereditary sensory and autonomic neuropathy type II. For more information, choose the exact disorder name as your search term in the Rare Disease Database.HEREDITARY SPASTIC PARAPLEGIA 30
Some individuals with variations in the KIF1A gene develop a form of hereditary spastic paraplegia, specifically hereditary spastic paraplegia type 30, or autosomal recessive spastic paraplegia 30, or SP30. The hereditary spastic paraplegias (HSP) are a large group of inherited neurologic disorders that share the primary symptom of difficulty walking due to muscle weakness and muscle tightness (spasticity) in the legs. There are more than 80 different genetic types of HSP. There may be significant variation in the severity of leg weakness (varying from none to marked), the degree of spasticity (varying from minimal to severe) and the occurrence of other neurologic symptoms between different genetic types of HSP; as well differences in the nature and severity of symptoms between individuals who have exactly the same genetic type of HSP. NORD has a separate report on hereditary spastic paraplegia. For more information, choose “hereditary spastic paraplegia” as your search term in the Rare Disease Database.
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Symptoms of KIF1A-Related Disorder. The signs and symptoms of KIF1A-related disorder can vary greatly from one person to another depending on the specific variation in the gene that is present, the inheritance pattern and other factors. Much about KIF1A-related disorder is not fully understood. Several factors including the small number of identified patients prevent physicians from developing a complete picture of associated symptoms and prognosis. Therefore, it is important to note that affected individuals most likely will not have all of the symptoms discussed below and that every person is unique. Parents and patients should talk to their physician and medical team about their specific situation, associated symptoms and overall prognosis.AUTOSOMAL DOMINANT FORMS OF KIF1A-RELATED DISORDERS
Some affected individuals have an autosomal dominant form of the disorder that has been associated with a variety of symptoms. These symptoms include intellectual disability, delays in reaching developmental milestones (developmental delays) and diminished muscle tone (hypotonia). Additional symptoms include exaggerated reflexes (hyperreflexia) and, as infants or children age, increased muscle tone (hypertonia). Eventually, affected children may develop spastic paraplegia, a condition in which people have difficulty walking due to muscle weakness and muscle tightness (spasticity) in the legs. Spastic paraplegia can become progressively worse, significantly affecting the ability walk and get around.Spastic paraplegia is classified as “uncomplicated” or “pure” when symptoms are confined to leg weakness and tightness. Spastic paraplegia is classified as “complicated” when leg weakness and tightness (spasticity) are accompanied by other neurologic disturbances. Some individuals eventually develop contractures. A contracture is a condition in which a joint becomes permanently fixed in a bent or straightened position, completely or partially restricting the movement of the affected joint.Some affected individuals have optic nerve atrophy, which is degeneration of the main nerve that carries nerve impulses from the eyes to the brain. Sometimes, the field of vision can be reduced. Some affected individuals experience progressive deterioration of the nerve cells of cerebellum (cerebellar atrophy) and other parts of the brain, which can cause problem with balance and coordination, seizures, and brain function generally. Peripheral neuropathy is a condition that occurs when nerves that carry messages to and from the brain and spinal cord to the rest of the body are damaged. Those affected may experience tingling, burning, numbness, and stabbing pain in the affected extremities.Other symptoms that have been reported include poor coordination (ataxia), rapid, involuntary eye movements (nystagmus), crossed eyes (strabismus), drooping of the upper eyelid (ptosis), weakness or paralysis of half of the facial muscles (facial diplegia), clumsiness when trying to use their hands to manipulate or hold objects and tremors that occur when attempting to make deliberate actions (intention tremors). A variety of different seizure types have also been described and seizures during sleep can be a particular problem. Some individuals have abnormal electrical activity in the brain that is not a seizure but is not normal. Some individuals have developed abnormal curvature of the spine (scoliosis). Some infants have microcephaly, a condition in which the head is smaller than would otherwise be expected based on age and sex. Some infants and children experience backflow or regurgitation of the contents of the stomach into the esophagus (gastroesophageal reflux). Some males have had small testes or penis, or there is failure of the testes to descend into the scrotum (cryptorchidism).Genetic variants in KIF1A have also been associated with amyotrophic lateral sclerosis (ALS).AUTOSOMAL RECESSIVE FORMS OF KIF1A-RELATED DISORDERS
Individuals with recessive forms of KIF1A-related disorder may have symptoms that fit neatly into the categories described or may have symptoms that look more like the autosomal dominant form of the condition described above.HEREDITARY SENSORY NEUROPATHY IIC
Some individuals with variations in the KIF1A gene develop a form of hereditary sensory and autonomic neuropathy, specifically type IIC. Hereditary sensory neuropathies are a group of rare neurological disorders characterized by degeneration of the nervous system that frequently progresses to loss of feeling, especially in the hands and feet. Symptoms usually start with inflamed fingers or toes, especially around the nails. Numbness and tingling sensations in the hands and feet may also occur. Eventually, affected individuals lose feeling (sensation) in the hands and feet. This sensory loss is due to abnormal functioning of the sensory nerves that control responses to pain and temperature and may also affect the autonomic nervous system that controls other involuntary or automatic body processes. Chronic infection of the affected areas is common and worsens as ulcers form on the fingers or the soles of the hands and feet. NORD has a separate report on hereditary sensory and autonomic neuropathy type II. For more information, choose the exact disorder name as your search term in the Rare Disease Database.HEREDITARY SPASTIC PARAPLEGIA 30
Some individuals with variations in the KIF1A gene develop a form of hereditary spastic paraplegia, specifically hereditary spastic paraplegia type 30, or autosomal recessive spastic paraplegia 30, or SP30. The hereditary spastic paraplegias (HSP) are a large group of inherited neurologic disorders that share the primary symptom of difficulty walking due to muscle weakness and muscle tightness (spasticity) in the legs. There are more than 80 different genetic types of HSP. There may be significant variation in the severity of leg weakness (varying from none to marked), the degree of spasticity (varying from minimal to severe) and the occurrence of other neurologic symptoms between different genetic types of HSP; as well differences in the nature and severity of symptoms between individuals who have exactly the same genetic type of HSP. NORD has a separate report on hereditary spastic paraplegia. For more information, choose “hereditary spastic paraplegia” as your search term in the Rare Disease Database.
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Causes of KIF1A-Related Disorder
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KIF1A-related disorders are caused by changes (mutations or variants) in the KIF1A gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a variation in a gene occurs, the protein product may be faulty, inefficient, absent or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.The KIF1A gene produces a protein that is expressed solely in the brain and nerves. The protein has a role in transporting or carrying substances within cells (intracellular transport), specifically these protein helps to transport substances through a tubular structure in nerve fibers (axonal microtubules). Some studies suggest that this protein is essential for the function and survival of sensory nerve cells (neurons). Sensory neurons are the nerves cells that respond to stimuli like pain or temperature.Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease, while recessive disorders occur when an individual inherits two copies of an abnormal gene, one from each parent. In dominant disorders, the abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. Some people with a KIF1A-related disorder have a variation in the KIF1A gene have a new (sporadic or de novo) mutation, which means that in nearly all families the gene mutation has occurred at the time of the formation of the egg or sperm for that child only, and no other family member will be affected. The disorder is usually not inherited from or “carried” by a healthy parent. The genetic variant can then be passed on by the affected person in an autosomal dominant pattern. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.At least two distinct disorders are associated with variations in the KIF1A gene that are inherited in an autosomal recessive pattern. These disorders are hereditary sensory and autonomic neuropathy IIC and hereditary spastic paraplegia 30. Disorders inherited in a recessive pattern occur when an individual inherits two variants in a gene for the same trait, one from each parent. If an individual receives one normal gene and one gene variant for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the abnormal gene variant and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.Some affected individuals are compound heterozygotes, which means that they have inherited two different autosomal recessive mutations that have the combined effect of causing disease.
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Causes of KIF1A-Related Disorder. KIF1A-related disorders are caused by changes (mutations or variants) in the KIF1A gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a variation in a gene occurs, the protein product may be faulty, inefficient, absent or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.The KIF1A gene produces a protein that is expressed solely in the brain and nerves. The protein has a role in transporting or carrying substances within cells (intracellular transport), specifically these protein helps to transport substances through a tubular structure in nerve fibers (axonal microtubules). Some studies suggest that this protein is essential for the function and survival of sensory nerve cells (neurons). Sensory neurons are the nerves cells that respond to stimuli like pain or temperature.Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease, while recessive disorders occur when an individual inherits two copies of an abnormal gene, one from each parent. In dominant disorders, the abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. Some people with a KIF1A-related disorder have a variation in the KIF1A gene have a new (sporadic or de novo) mutation, which means that in nearly all families the gene mutation has occurred at the time of the formation of the egg or sperm for that child only, and no other family member will be affected. The disorder is usually not inherited from or “carried” by a healthy parent. The genetic variant can then be passed on by the affected person in an autosomal dominant pattern. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.At least two distinct disorders are associated with variations in the KIF1A gene that are inherited in an autosomal recessive pattern. These disorders are hereditary sensory and autonomic neuropathy IIC and hereditary spastic paraplegia 30. Disorders inherited in a recessive pattern occur when an individual inherits two variants in a gene for the same trait, one from each parent. If an individual receives one normal gene and one gene variant for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the abnormal gene variant and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.Some affected individuals are compound heterozygotes, which means that they have inherited two different autosomal recessive mutations that have the combined effect of causing disease.
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Affects of KIF1A-Related Disorder
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KIF1A-related disorder is extremely rare. The number of people affected by these disorders is unknown. Rare disorders often go undiagnosed or misdiagnosed, making it extremely difficult to determine their true frequency in the general population. As of November 2022, according to KIF1A.org, there are approximately 500 people known to have a disease-causing variation in the KIF1A gene.
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Affects of KIF1A-Related Disorder. KIF1A-related disorder is extremely rare. The number of people affected by these disorders is unknown. Rare disorders often go undiagnosed or misdiagnosed, making it extremely difficult to determine their true frequency in the general population. As of November 2022, according to KIF1A.org, there are approximately 500 people known to have a disease-causing variation in the KIF1A gene.
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Related disorders of KIF1A-Related Disorder
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Symptoms of the following disorders can be similar to those of KIF1A-related disorder. Comparisons may be useful for a differential diagnosis.There are many disorders that can cause signs and symptoms similar to those seen in people with KIF1A-related disorder. Some of these disorders are other forms of hereditary spastic paraplegia, other forms of hereditary sensory and autonomic neuropathy (HSAN), some forms of Charcot-Marie-Tooth disease, immune-mediated neuropathies, metabolic disorders like Fabry disease, amyloidosis, motor neuron disorders, leukodystrophies, spinocerebellar ataxias, cerebral palsy and disorders that cause structural abnormalities in the brain or spinal cord. Some affected individuals have symptoms that are consistent with those for individuals with an autism spectrum disorder. (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 KIF1A-Related Disorder. Symptoms of the following disorders can be similar to those of KIF1A-related disorder. Comparisons may be useful for a differential diagnosis.There are many disorders that can cause signs and symptoms similar to those seen in people with KIF1A-related disorder. Some of these disorders are other forms of hereditary spastic paraplegia, other forms of hereditary sensory and autonomic neuropathy (HSAN), some forms of Charcot-Marie-Tooth disease, immune-mediated neuropathies, metabolic disorders like Fabry disease, amyloidosis, motor neuron disorders, leukodystrophies, spinocerebellar ataxias, cerebral palsy and disorders that cause structural abnormalities in the brain or spinal cord. Some affected individuals have symptoms that are consistent with those for individuals with an autism spectrum disorder. (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 KIF1A-Related Disorder
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A diagnosis of a KIF1A-related disorder is suspected based upon the identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation, and a variety of specialized tests. A diagnosis is confirmed through molecular genetic testing on a blood sample, which can detect variants in the KIFA1 gene, but is available only as a diagnostic service at specialized laboratories.Some individuals will have tests that cover a subset of genes related to the individual’s symptoms (panel testing) while others will have exome sequencing. Sometimes blood from the parents is requested for comparison as part of exome sequencing. Exome sequencing is a molecular genetic testing method that examines the genes in humans that contain instructions for creating proteins (protein-encoding genes). This is called the exome. Genetic sequencing can detect genetic variations in the KIF1A gene that are known to cause disease, or variations in other genes known to cause symptoms similar to KIF1A-related disorder.Clinical Testing and Workup
Affected individuals may undergo additional tests to assess the extent of the disease. Two of the more common symptoms of the condition are problems with vision due to issues with the nerves of the eye (optic nerve atrophy) and seizures. Optic nerve atrophy can be difficult to detect so individuals may be referred to see an eye doctor specializing in neurological conditions that affect the eyes (neuro-ophthalmologist). Since seizures and abnormal brain activity during sleep are common, longer electroencephalograms (EEG) that last 24-48 hours may be recommended. An EEG records the brain’s electrical activity and can detect seizures that might not be obvious, as well as detect abnormal brain activity that is not a seizure.Neurologic examination is important for individuals with the symptoms of a KIF1A-related disorder. Neurologic examination helps identify the specific features affecting a person. Laboratory tests, neurophysiologic testing, and neuroimaging; routine laboratory studies (such as blood counts, serum electrolytes and tests of kidney, liver, and endocrine functions); and analysis of cerebrospinal fluid (obtained by “spinal tap”) may be conducted to help exclude alternate and co-existing diagnoses.
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Diagnosis of KIF1A-Related Disorder. A diagnosis of a KIF1A-related disorder is suspected based upon the identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation, and a variety of specialized tests. A diagnosis is confirmed through molecular genetic testing on a blood sample, which can detect variants in the KIFA1 gene, but is available only as a diagnostic service at specialized laboratories.Some individuals will have tests that cover a subset of genes related to the individual’s symptoms (panel testing) while others will have exome sequencing. Sometimes blood from the parents is requested for comparison as part of exome sequencing. Exome sequencing is a molecular genetic testing method that examines the genes in humans that contain instructions for creating proteins (protein-encoding genes). This is called the exome. Genetic sequencing can detect genetic variations in the KIF1A gene that are known to cause disease, or variations in other genes known to cause symptoms similar to KIF1A-related disorder.Clinical Testing and Workup
Affected individuals may undergo additional tests to assess the extent of the disease. Two of the more common symptoms of the condition are problems with vision due to issues with the nerves of the eye (optic nerve atrophy) and seizures. Optic nerve atrophy can be difficult to detect so individuals may be referred to see an eye doctor specializing in neurological conditions that affect the eyes (neuro-ophthalmologist). Since seizures and abnormal brain activity during sleep are common, longer electroencephalograms (EEG) that last 24-48 hours may be recommended. An EEG records the brain’s electrical activity and can detect seizures that might not be obvious, as well as detect abnormal brain activity that is not a seizure.Neurologic examination is important for individuals with the symptoms of a KIF1A-related disorder. Neurologic examination helps identify the specific features affecting a person. Laboratory tests, neurophysiologic testing, and neuroimaging; routine laboratory studies (such as blood counts, serum electrolytes and tests of kidney, liver, and endocrine functions); and analysis of cerebrospinal fluid (obtained by “spinal tap”) may be conducted to help exclude alternate and co-existing diagnoses.
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Therapies of KIF1A-Related Disorder
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Treatment
The treatment of KIF1A-related disorder is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, physicians who specialize in the diagnosis and treatment of neurological disorders in children (pediatric neurologists), neurologists, physicians who specialize in the diagnosis and treatment of eye disorders (ophthalmologists), speech pathologists, physical therapists, and other healthcare professionals may need to systematically and comprehensively plan treatment.Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well.There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials will be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with KIF1A-related disorder.Following an initial diagnosis, a developmental assessment may be performed and appropriate occupational, physical, speech and feeding therapies be instituted. Periodic reassessments and adjustment of services should be provided with all children. Additional medical, social, and/or vocational services including specialized learning programs may be necessary.Medications may be tried to treat seizures, spasticity neuropathy, and certain neurological aspects of KIF1A-related disorder. Orthopedic devies including braces, gait trainers, and other devices may help children walk. Additional treatment is symptomatic and supportive.
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Therapies of KIF1A-Related Disorder. Treatment
The treatment of KIF1A-related disorder is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, physicians who specialize in the diagnosis and treatment of neurological disorders in children (pediatric neurologists), neurologists, physicians who specialize in the diagnosis and treatment of eye disorders (ophthalmologists), speech pathologists, physical therapists, and other healthcare professionals may need to systematically and comprehensively plan treatment.Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well.There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials will be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with KIF1A-related disorder.Following an initial diagnosis, a developmental assessment may be performed and appropriate occupational, physical, speech and feeding therapies be instituted. Periodic reassessments and adjustment of services should be provided with all children. Additional medical, social, and/or vocational services including specialized learning programs may be necessary.Medications may be tried to treat seizures, spasticity neuropathy, and certain neurological aspects of KIF1A-related disorder. Orthopedic devies including braces, gait trainers, and other devices may help children walk. Additional treatment is symptomatic and supportive.
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Overview of Kikuchi-Fujimoto Disease
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Kikuchi-Fujimoto disease (KFD), also known as histiocytic necrotizing lymphadenopathy, is a rare, benign (noncancerous, nonmalignant) disorder of the lymph nodes, predominantly of young adults and school aged children. While slightly more common in females, it is also seen in males. This disorder presents with similar signs and symptoms as lymphoma, including enlarged lymph nodes (lymphadenopathy) The exact cause is not known. KFD shows up as painful swelling of lymph nodes, often in the neck, along with general symptoms like fever and fatigue.KFD is similar to a type of inflammatory response called granulomatous response. When the lymph nodes are examined under a microscope, specific changes may be seen such as tissue necrosis (cell death) and an absence of a particular type of immune cell called neutrophils. Instead, the necrotic areas mainly contain remnants of cells undergoing apoptosis, where the cell nucleus breaks down. In simpler terms, KFD is a unique condition where the affected tissue shows signs of cell death, but the immune cells generally associated with that kind of reaction are missing. This unusual pattern makes it distinct from other diseases with similar symptoms. Usually, this disease does not cause severe problems and gets better on its own. However, in some people, it can be associated with autoimmune disorders, conditions where the immune system mistakenly attacks the body’s cells and tissues.
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Overview of Kikuchi-Fujimoto Disease. Kikuchi-Fujimoto disease (KFD), also known as histiocytic necrotizing lymphadenopathy, is a rare, benign (noncancerous, nonmalignant) disorder of the lymph nodes, predominantly of young adults and school aged children. While slightly more common in females, it is also seen in males. This disorder presents with similar signs and symptoms as lymphoma, including enlarged lymph nodes (lymphadenopathy) The exact cause is not known. KFD shows up as painful swelling of lymph nodes, often in the neck, along with general symptoms like fever and fatigue.KFD is similar to a type of inflammatory response called granulomatous response. When the lymph nodes are examined under a microscope, specific changes may be seen such as tissue necrosis (cell death) and an absence of a particular type of immune cell called neutrophils. Instead, the necrotic areas mainly contain remnants of cells undergoing apoptosis, where the cell nucleus breaks down. In simpler terms, KFD is a unique condition where the affected tissue shows signs of cell death, but the immune cells generally associated with that kind of reaction are missing. This unusual pattern makes it distinct from other diseases with similar symptoms. Usually, this disease does not cause severe problems and gets better on its own. However, in some people, it can be associated with autoimmune disorders, conditions where the immune system mistakenly attacks the body’s cells and tissues.
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Symptoms of Kikuchi-Fujimoto Disease
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KFD is a rare nonmalignant disorder that affects the lymph nodes. Lymph nodes are present throughout the body as small oval or kidney bean shaped structures that filter lymph fluid, fight infection and form white blood cells and blood plasma cells. Enlarged and painful lymph nodes are commonly in the neck region, but supraclavicular, axillary, thoracic, intraparotid, abdominal and pelvic lymph nodes may also be involved. Affected individuals may develop a mild fever, night sweats, muscle pain (myalgia) and a rash. Less common symptoms include headaches, fatigue, joint pain (arthralgia), nausea and vomiting. Some affected individuals may experience liver or spleen enlargement (hepatosplenomegaly). The symptoms of KFD may develop slowly over two to three weeks. In summary, the clinical features of KFD are the presence of enlarged lymph nodes associated with signs and symptoms such as:• Fever
• Fatigue
• Night sweats
• Body aches
• Weight loss (in some people)
• Loss of appetite
• HepatosplenomegalyThe abnormal tissue growth and inflammation in KFD usually clears up spontaneously within a few weeks or months without further therapy (self-limited disease).
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Symptoms of Kikuchi-Fujimoto Disease. KFD is a rare nonmalignant disorder that affects the lymph nodes. Lymph nodes are present throughout the body as small oval or kidney bean shaped structures that filter lymph fluid, fight infection and form white blood cells and blood plasma cells. Enlarged and painful lymph nodes are commonly in the neck region, but supraclavicular, axillary, thoracic, intraparotid, abdominal and pelvic lymph nodes may also be involved. Affected individuals may develop a mild fever, night sweats, muscle pain (myalgia) and a rash. Less common symptoms include headaches, fatigue, joint pain (arthralgia), nausea and vomiting. Some affected individuals may experience liver or spleen enlargement (hepatosplenomegaly). The symptoms of KFD may develop slowly over two to three weeks. In summary, the clinical features of KFD are the presence of enlarged lymph nodes associated with signs and symptoms such as:• Fever
• Fatigue
• Night sweats
• Body aches
• Weight loss (in some people)
• Loss of appetite
• HepatosplenomegalyThe abnormal tissue growth and inflammation in KFD usually clears up spontaneously within a few weeks or months without further therapy (self-limited disease).
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Causes of Kikuchi-Fujimoto Disease
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The exact cause of KFD is not known (idiopathic). It is thought that an abnormal immune response, possibly influenced by viral infection or genetic factors, may play a role. It is thought to be related to viral infections like HIV, HSV, VZV and EBV, as well as autoimmune conditions such as lupus, sarcoidosis, lymphoma and Sjogren’s syndrome. Another theory is that KFD is a self-limited autoimmune condition. Autoimmune disorders are caused when the body’s natural defenses against “foreign” or invading organisms begin to attack healthy tissue for unknown reasons. Our bodies have a normal protective response to infection from viruses. Small proteins called Interferon create signals to help protect the body against infections, including infection from viruses. KFD has been shown to be associated with an increase in interferon response (aberrant type I interferon response).
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Causes of Kikuchi-Fujimoto Disease. The exact cause of KFD is not known (idiopathic). It is thought that an abnormal immune response, possibly influenced by viral infection or genetic factors, may play a role. It is thought to be related to viral infections like HIV, HSV, VZV and EBV, as well as autoimmune conditions such as lupus, sarcoidosis, lymphoma and Sjogren’s syndrome. Another theory is that KFD is a self-limited autoimmune condition. Autoimmune disorders are caused when the body’s natural defenses against “foreign” or invading organisms begin to attack healthy tissue for unknown reasons. Our bodies have a normal protective response to infection from viruses. Small proteins called Interferon create signals to help protect the body against infections, including infection from viruses. KFD has been shown to be associated with an increase in interferon response (aberrant type I interferon response).
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Affects of Kikuchi-Fujimoto Disease
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KFD, first identified in Japan in 1972, is extremely rare.In 2014, after conducting a PubMed search, 590 articles were found that described KFD. Among them, 22 cases have been thoroughly documented in the United States. Of the 22 patients, 10 (45%) were male and 12 (55%) were female. The ethnic distribution of the cases was as follows: 20% Caucasian, 20% Asian American, and the remaining 60% represented various other ethnic backgrounds. It appears to affect young adults particularly but can occur at any age. From the literature, a total of 335 cases of KFD were reviewed with a distribution of cases among different age groups. Among these cases, in 2020, it was reported that 14 (4.2%) occurred in children under six years of age, while the majority, 321 (95.8%) of cases were reported in school-age children (6-20 years). School-age children were more commonly affected by KFD and the characteristic presentation in this group included pyrexia, leukopenia and cervical lymphadenopathy with tenderness. In contrast, children under six years of age with KFD had different significant symptoms. Three cases were associated with lung lesions, six had leukocytosis and eight presented with generalized lymphadenopathy, which differed from the symptom profile observed in school-age children. It is noteworthy that leukocytosis, generalized lymphadenopathy in locations other than cervical lymph nodes and lung lesions are characteristic symptoms of severe KFD in patients under six years old, an age group in which KFD occurs infrequently. For instance, in 2022, a 7-year-old African American girl who was previously healthy presented to an academic-affiliated community hospital pediatric emergency department (ED) for a rapid, enlarged postauricular lymph node along with fever. However, it primarily affects young adults (Age<40), which is more commonly seen in females than males. In 2022, a rare case of KFD was documented in a patient with coexisting Crohn’s disease. The patient, a 23-year-old African American female with a significant past medical history of Crohn’s disease, presented to the clinic due to a painless lump on the right side of her neck, which had been present for the past 3 weeks. KFD may be more prevalent than previously recognized since swollen glands are common and frequently ignored. This, combined with the self-limiting nature of the disorder, has led some clinicians to speculate that KFD is more common than initially thought. Since diagnosis of this disorder can only be confirmed by biopsy of the tissue in the affected lymph nodes, many affected people may be undiagnosed.
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Affects of Kikuchi-Fujimoto Disease. KFD, first identified in Japan in 1972, is extremely rare.In 2014, after conducting a PubMed search, 590 articles were found that described KFD. Among them, 22 cases have been thoroughly documented in the United States. Of the 22 patients, 10 (45%) were male and 12 (55%) were female. The ethnic distribution of the cases was as follows: 20% Caucasian, 20% Asian American, and the remaining 60% represented various other ethnic backgrounds. It appears to affect young adults particularly but can occur at any age. From the literature, a total of 335 cases of KFD were reviewed with a distribution of cases among different age groups. Among these cases, in 2020, it was reported that 14 (4.2%) occurred in children under six years of age, while the majority, 321 (95.8%) of cases were reported in school-age children (6-20 years). School-age children were more commonly affected by KFD and the characteristic presentation in this group included pyrexia, leukopenia and cervical lymphadenopathy with tenderness. In contrast, children under six years of age with KFD had different significant symptoms. Three cases were associated with lung lesions, six had leukocytosis and eight presented with generalized lymphadenopathy, which differed from the symptom profile observed in school-age children. It is noteworthy that leukocytosis, generalized lymphadenopathy in locations other than cervical lymph nodes and lung lesions are characteristic symptoms of severe KFD in patients under six years old, an age group in which KFD occurs infrequently. For instance, in 2022, a 7-year-old African American girl who was previously healthy presented to an academic-affiliated community hospital pediatric emergency department (ED) for a rapid, enlarged postauricular lymph node along with fever. However, it primarily affects young adults (Age<40), which is more commonly seen in females than males. In 2022, a rare case of KFD was documented in a patient with coexisting Crohn’s disease. The patient, a 23-year-old African American female with a significant past medical history of Crohn’s disease, presented to the clinic due to a painless lump on the right side of her neck, which had been present for the past 3 weeks. KFD may be more prevalent than previously recognized since swollen glands are common and frequently ignored. This, combined with the self-limiting nature of the disorder, has led some clinicians to speculate that KFD is more common than initially thought. Since diagnosis of this disorder can only be confirmed by biopsy of the tissue in the affected lymph nodes, many affected people may be undiagnosed.
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Related disorders of Kikuchi-Fujimoto Disease
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KFD may resemble other conditions that cause swollen lymph nodes such as lymphoma, tuberculosis, systemic lupus erythematosus (SLE) and infectious mononucleosis. Whether KFD is present at the start of SLE, coexists with SLE, or evolves into SLE depends on the patient’s condition. Symptoms of the following disorders can be similar to those of KFD. Comparisons may be valid for a differential diagnosis:
Burkitt’s lymphoma is a cancer of the lymphatic system that affects the lymph nodes as well as other areas of the body. Tumors may occur in the kidneys, sex glands, jaw, bone marrow, central nervous system and lymph nodes. Burkitt’s lymphoma may be infectious. This disorder often occurs in children living in Central Africa and is associated with the Epstein-Barr virus.Hodgkin’s disease is a form of lymphatic cancer associated with tumors in lymph nodes. Fever, night sweats and weight loss may occur along with swollen lymph nodes. The diagnosis of Hodgkin’s disease is confirmed if an expert pathological examination shows the presence of so-called Reed-Sternberg cells. The exact cause of Hodgkin’s disease is not known. (For more information on this disorder, choose “Hodgkin” as your search term in the Rare Disease Database.)Malignant lymphoma describes a malignant tumor of lymph tissue that is cancerous. A type of white blood cell (lymphocyte) circulates within the lymph system. Although the structure of these white blood cells may vary with the type of lymphoma present, the effects are usually similar. The appearance of large lymph nodes in the neck and or additional regions, such as the armpits or groin is usually followed by fever, weakness, weight loss and anemia. When there is widespread involvement of the lymphoid tissue, the spleen and liver may also enlarge.
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Related disorders of Kikuchi-Fujimoto Disease. KFD may resemble other conditions that cause swollen lymph nodes such as lymphoma, tuberculosis, systemic lupus erythematosus (SLE) and infectious mononucleosis. Whether KFD is present at the start of SLE, coexists with SLE, or evolves into SLE depends on the patient’s condition. Symptoms of the following disorders can be similar to those of KFD. Comparisons may be valid for a differential diagnosis:
Burkitt’s lymphoma is a cancer of the lymphatic system that affects the lymph nodes as well as other areas of the body. Tumors may occur in the kidneys, sex glands, jaw, bone marrow, central nervous system and lymph nodes. Burkitt’s lymphoma may be infectious. This disorder often occurs in children living in Central Africa and is associated with the Epstein-Barr virus.Hodgkin’s disease is a form of lymphatic cancer associated with tumors in lymph nodes. Fever, night sweats and weight loss may occur along with swollen lymph nodes. The diagnosis of Hodgkin’s disease is confirmed if an expert pathological examination shows the presence of so-called Reed-Sternberg cells. The exact cause of Hodgkin’s disease is not known. (For more information on this disorder, choose “Hodgkin” as your search term in the Rare Disease Database.)Malignant lymphoma describes a malignant tumor of lymph tissue that is cancerous. A type of white blood cell (lymphocyte) circulates within the lymph system. Although the structure of these white blood cells may vary with the type of lymphoma present, the effects are usually similar. The appearance of large lymph nodes in the neck and or additional regions, such as the armpits or groin is usually followed by fever, weakness, weight loss and anemia. When there is widespread involvement of the lymphoid tissue, the spleen and liver may also enlarge.
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Diagnosis of Kikuchi-Fujimoto Disease
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Diagnosis requires proper evaluation by a healthcare professional and pathologist, including a thorough medical history, physical examination and sometimes a biopsy of the affected lymph node.In some people, the histological and immunohistochemical characteristics of the lymph nodes in SLE and KFD can be similar. However, there are differences, and careful analysis is needed to distinguish between the two. Practically, KFD affects the lymph nodes, causing them to become swollen and possibly enlarged. A part or all of an enlarged lymph node is removed and examined under a microscope to diagnose the condition. The characteristic features include tissue necrosis and the presence of certain types of cells. Immunohistochemistry is used to identify specific markers that help confirm the diagnosis.The following conditions have been associated with Kikuchi disease in some patients. They are not necessary for a diagnosis:Pancytopenia – a reduction in the number of red and white blood cells and platelets in the circulating blood.Splenomegaly – an abnormal enlargement of the spleen.Still’s disease – also called juvenile rheumatoid arthritis or rheumatic arthritis, is a form of arthritis that usually, but not exclusively, affects the larger joints of children. In addition to occasional high fever and rash, patients have inflammation of several thin layers of tissue that line certain body areas (serous membranes) and enlarged lymph nodes. Post Vaccination
Post-vaccinal lymphadenitis, a reactive response to vaccination, can occur following the administration of various vaccines, including those against smallpox, influenza, varicella zoster, BCG and pneumococcal infections. Rarely, KFD has been reported after human papillomavirus and influenza vaccinations. Temporary lymphadenopathy on the same side as vaccination, including after COVID-19 vaccine may be seen, and may involve the armpit or neck nodes. There have been very rare, reported cases of KFD following COVID-19 vaccinations. The mechanism by which a vaccine may lead to the development of KFD remains unknown, but it is hypothesized that viral or other antigens in the vaccine could trigger an abnormal immune response in some people, resulting in the development of KFD. Sometimes, reactions in lymph nodes after vaccination can last for a while. If a patient has a high fever that persists for a long time, even up to three to four months after vaccination, a doctor might consider the possibility of KFD, especially if signs and symptoms like swollen lymph nodes, abnormal lymphocyte counts and liver issues are also present.
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Diagnosis of Kikuchi-Fujimoto Disease. Diagnosis requires proper evaluation by a healthcare professional and pathologist, including a thorough medical history, physical examination and sometimes a biopsy of the affected lymph node.In some people, the histological and immunohistochemical characteristics of the lymph nodes in SLE and KFD can be similar. However, there are differences, and careful analysis is needed to distinguish between the two. Practically, KFD affects the lymph nodes, causing them to become swollen and possibly enlarged. A part or all of an enlarged lymph node is removed and examined under a microscope to diagnose the condition. The characteristic features include tissue necrosis and the presence of certain types of cells. Immunohistochemistry is used to identify specific markers that help confirm the diagnosis.The following conditions have been associated with Kikuchi disease in some patients. They are not necessary for a diagnosis:Pancytopenia – a reduction in the number of red and white blood cells and platelets in the circulating blood.Splenomegaly – an abnormal enlargement of the spleen.Still’s disease – also called juvenile rheumatoid arthritis or rheumatic arthritis, is a form of arthritis that usually, but not exclusively, affects the larger joints of children. In addition to occasional high fever and rash, patients have inflammation of several thin layers of tissue that line certain body areas (serous membranes) and enlarged lymph nodes. Post Vaccination
Post-vaccinal lymphadenitis, a reactive response to vaccination, can occur following the administration of various vaccines, including those against smallpox, influenza, varicella zoster, BCG and pneumococcal infections. Rarely, KFD has been reported after human papillomavirus and influenza vaccinations. Temporary lymphadenopathy on the same side as vaccination, including after COVID-19 vaccine may be seen, and may involve the armpit or neck nodes. There have been very rare, reported cases of KFD following COVID-19 vaccinations. The mechanism by which a vaccine may lead to the development of KFD remains unknown, but it is hypothesized that viral or other antigens in the vaccine could trigger an abnormal immune response in some people, resulting in the development of KFD. Sometimes, reactions in lymph nodes after vaccination can last for a while. If a patient has a high fever that persists for a long time, even up to three to four months after vaccination, a doctor might consider the possibility of KFD, especially if signs and symptoms like swollen lymph nodes, abnormal lymphocyte counts and liver issues are also present.
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Therapies of Kikuchi-Fujimoto Disease
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Treatment of KFD is symptomatic and supportive. Usually, the disorder resolves spontaneously within a few weeks or months. Analgesics-antipyretics and nonsteroidal anti-inflammatory (NSAIDs) may be used to treat pain, tenderness and lymphadenopathy-related fever. In extremely rare cases, KFD may recur.There is no specific treatment for KFD as it is a self-limited disorder which can be resolved in less than 4 months. Management focuses on relieving symptoms (e.g., pain and fever) with nonsteroidal anti-inflammatory drugs (NSAIDs) or other symptomatic treatments. Fever tends to subside after removal of the affected lymph node, indicating the potential therapeutic benefit of excisional biopsy as both a diagnostic and treatment measure. Patients with prolonged fever, severe symptoms lasting over two weeks, or recurrent disease may require treatment with immunomodulators and systemic corticosteroids (prednisolone 1-2 mg/kg body weight), either alone or in combination. Corticosteroids and intravenous immune globulin (IVIg) are commonly used in the treatment of KFD, particularly in patients with the severe or generalized disease, extra nodal involvement or hemophagocytic syndrome, and have shown positive therapeutic outcomes. Hydroxychloroquine alone or combined with systemic corticosteroids has been reported as a successful treatment option for recurrent or steroid-resistant KFD. One study achieved a rapid response in a KFD patient with systemic symptoms by administering chloroquine, leading to significant improvement within four days. In one case, anakinra, an IL-1 inhibitor, demonstrated effectiveness in a patient unresponsive to steroid therapy. The potential benefit of ciprofloxacin, minocycline and ofloxacin in managing KFD requires further evaluation, despite some anecdotal evidence suggesting their effective doses of glucocorticoids are often required to control the disease. In some people, hydroxychloroquine is used, which may have a critical role in avoiding disease recurrence in flared patients, although the current research study has not thoroughly investigated this condition. It is worth noting that antibiotics do not impact the progression of KFD in the studied patients. Currently, there is a lack of literature outlining the optimal approach for long-term follow-up of KFD patients, particularly regarding potential complications and associations with diseases such as SLE. It appears reasonable to conduct an SLE screening upon the initial diagnosis of KFD, followed by annual screenings for several years. Additionally, monitoring erythrocyte sedimentation rate (ESR) can help identify any autoimmune, infectious or malignant developments. KFD generally has an excellent prognosis, with most cases resolving within six months.
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Therapies of Kikuchi-Fujimoto Disease. Treatment of KFD is symptomatic and supportive. Usually, the disorder resolves spontaneously within a few weeks or months. Analgesics-antipyretics and nonsteroidal anti-inflammatory (NSAIDs) may be used to treat pain, tenderness and lymphadenopathy-related fever. In extremely rare cases, KFD may recur.There is no specific treatment for KFD as it is a self-limited disorder which can be resolved in less than 4 months. Management focuses on relieving symptoms (e.g., pain and fever) with nonsteroidal anti-inflammatory drugs (NSAIDs) or other symptomatic treatments. Fever tends to subside after removal of the affected lymph node, indicating the potential therapeutic benefit of excisional biopsy as both a diagnostic and treatment measure. Patients with prolonged fever, severe symptoms lasting over two weeks, or recurrent disease may require treatment with immunomodulators and systemic corticosteroids (prednisolone 1-2 mg/kg body weight), either alone or in combination. Corticosteroids and intravenous immune globulin (IVIg) are commonly used in the treatment of KFD, particularly in patients with the severe or generalized disease, extra nodal involvement or hemophagocytic syndrome, and have shown positive therapeutic outcomes. Hydroxychloroquine alone or combined with systemic corticosteroids has been reported as a successful treatment option for recurrent or steroid-resistant KFD. One study achieved a rapid response in a KFD patient with systemic symptoms by administering chloroquine, leading to significant improvement within four days. In one case, anakinra, an IL-1 inhibitor, demonstrated effectiveness in a patient unresponsive to steroid therapy. The potential benefit of ciprofloxacin, minocycline and ofloxacin in managing KFD requires further evaluation, despite some anecdotal evidence suggesting their effective doses of glucocorticoids are often required to control the disease. In some people, hydroxychloroquine is used, which may have a critical role in avoiding disease recurrence in flared patients, although the current research study has not thoroughly investigated this condition. It is worth noting that antibiotics do not impact the progression of KFD in the studied patients. Currently, there is a lack of literature outlining the optimal approach for long-term follow-up of KFD patients, particularly regarding potential complications and associations with diseases such as SLE. It appears reasonable to conduct an SLE screening upon the initial diagnosis of KFD, followed by annual screenings for several years. Additionally, monitoring erythrocyte sedimentation rate (ESR) can help identify any autoimmune, infectious or malignant developments. KFD generally has an excellent prognosis, with most cases resolving within six months.
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Overview of Kleefstra Syndrome
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SummaryKleefstra syndrome is a rare genetic condition that affects multiple organ systems and has specific developmental and behavioral symptoms. Children with Kleefstra syndrome may have specific facial features including a small head size (microcephaly), a broad forehead, widely spaced eyes (hypertelorism), distinctive eyebrows and large tongue (macroglossia). Low muscle tone (hypotonia) along with a large birth weight and childhood obesity are also common. Additionally, heart (cardiac), kidney (renal), genital and brain abnormalities may be seen. Most people with Kleefstra syndrome will have some form of intellectual disability which may occur with autistic-like features, speech delay and the development of extreme apathy and/or lack of movement and communication (catatonia) after puberty. Additional symptoms that can occur include epilepsy (seizures) and/or febrile seizures (seizures in the setting of a fever), hearing loss, stomach (gastrointestinal) issues, respiratory infections and farsightedness (hyperopia). Fewer than 1,000 people have been diagnosed with Kleefstra syndrome in the U.S. IntroductionKleefstra syndrome was initially known as “9q subtelomeric deletion syndrome” because it is caused by changes in a specific region of chromosome 9, known as 9q34.3. It was renamed in honor of Dr. Tjitske Kleefstra, a clinical geneticist who was one of the first to describe the syndrome in scientific publications. This renaming occurred in the early 2000s.
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Overview of Kleefstra Syndrome. SummaryKleefstra syndrome is a rare genetic condition that affects multiple organ systems and has specific developmental and behavioral symptoms. Children with Kleefstra syndrome may have specific facial features including a small head size (microcephaly), a broad forehead, widely spaced eyes (hypertelorism), distinctive eyebrows and large tongue (macroglossia). Low muscle tone (hypotonia) along with a large birth weight and childhood obesity are also common. Additionally, heart (cardiac), kidney (renal), genital and brain abnormalities may be seen. Most people with Kleefstra syndrome will have some form of intellectual disability which may occur with autistic-like features, speech delay and the development of extreme apathy and/or lack of movement and communication (catatonia) after puberty. Additional symptoms that can occur include epilepsy (seizures) and/or febrile seizures (seizures in the setting of a fever), hearing loss, stomach (gastrointestinal) issues, respiratory infections and farsightedness (hyperopia). Fewer than 1,000 people have been diagnosed with Kleefstra syndrome in the U.S. IntroductionKleefstra syndrome was initially known as “9q subtelomeric deletion syndrome” because it is caused by changes in a specific region of chromosome 9, known as 9q34.3. It was renamed in honor of Dr. Tjitske Kleefstra, a clinical geneticist who was one of the first to describe the syndrome in scientific publications. This renaming occurred in the early 2000s.
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Symptoms of Kleefstra Syndrome
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Kleefstra syndrome has a wide range of symptoms that include physical, developmental and behavioral characteristics. While some physical features are apparent from birth (congenital), other symptoms, particularly behavioral, often develop during early childhood.People with Kleefstra syndrome have distinctive facial features including a small head size (microcephaly), flattening of the back of the skull (brachycephaly), broad forehead, arched or connected eyebrows (synophrys), widely spaced (hypertelorism) and up-slanting eyes, nostrils that open to the front instead of downwards (anteverted nares), a flatter appearance of the midface (midface hypoplasia), large tongue (macroglossia), full bottom lip (everted lower vermilion), protruding jaw (prognathism) and thickened outer-ear (thickened helix). As children get older, their facial characteristics become more defined and noticeable.Low muscle tone (hypotonia) is a common symptom. About half of babies with Kleefstra syndrome are born with a large birth weight and may develop childhood obesity.Other physical symptoms include heart (cardiac) defects such as a hole in the wall between the heart’s chambers (atrial septal defect and/or ventral septal defect), narrowing of the heart vessels (aortic coarctation and/or pulmonic stenosis) and a malformed heart valve (bicuspid aortic valve). These symptoms have been seen in about half (50%) of people diagnosed with Kleefstra syndrome.Kidney (renal) issues, including abnormal flow of urine (vesicoureteral reflux), stretching and swelling of the kidney (hydronephrosis), development of fluid-filled pouches (renal cysts) and chronic renal failure (insufficiency) are found in approximately 10%-30% of people with Kleefstra syndrome.Genital differences, including the failure of the testicles to descend into the scrotum (cryptorchidism), the opening of the urethra not being located at the tip of the penis (hypospadias) and small penis, are reported in 30% of affected males.Brain abnormalities can include underdevelopment (hypoplasia) of the connection between the left and right side of the brain (corpus callosum) and outer layer of brain (cortex).Most people with Kleefstra syndrome will have some form of intellectual disability which is typically moderate to severe. Autism spectrum disorder along with expressive speech delay is also common. People with Kleefstra syndrome may develop a lack of interest/difficulty in communicating or moving (catatonia) and extreme apathy after puberty. Psychiatric and sleep problems are also associated with the condition.Other symptoms include epilepsy (seizures) and/or febrile seizures (seizures in the setting of a fever), hearing loss, stomach (gastrointestinal) issues, respiratory infection and farsightedness (hyperopia).
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Symptoms of Kleefstra Syndrome. Kleefstra syndrome has a wide range of symptoms that include physical, developmental and behavioral characteristics. While some physical features are apparent from birth (congenital), other symptoms, particularly behavioral, often develop during early childhood.People with Kleefstra syndrome have distinctive facial features including a small head size (microcephaly), flattening of the back of the skull (brachycephaly), broad forehead, arched or connected eyebrows (synophrys), widely spaced (hypertelorism) and up-slanting eyes, nostrils that open to the front instead of downwards (anteverted nares), a flatter appearance of the midface (midface hypoplasia), large tongue (macroglossia), full bottom lip (everted lower vermilion), protruding jaw (prognathism) and thickened outer-ear (thickened helix). As children get older, their facial characteristics become more defined and noticeable.Low muscle tone (hypotonia) is a common symptom. About half of babies with Kleefstra syndrome are born with a large birth weight and may develop childhood obesity.Other physical symptoms include heart (cardiac) defects such as a hole in the wall between the heart’s chambers (atrial septal defect and/or ventral septal defect), narrowing of the heart vessels (aortic coarctation and/or pulmonic stenosis) and a malformed heart valve (bicuspid aortic valve). These symptoms have been seen in about half (50%) of people diagnosed with Kleefstra syndrome.Kidney (renal) issues, including abnormal flow of urine (vesicoureteral reflux), stretching and swelling of the kidney (hydronephrosis), development of fluid-filled pouches (renal cysts) and chronic renal failure (insufficiency) are found in approximately 10%-30% of people with Kleefstra syndrome.Genital differences, including the failure of the testicles to descend into the scrotum (cryptorchidism), the opening of the urethra not being located at the tip of the penis (hypospadias) and small penis, are reported in 30% of affected males.Brain abnormalities can include underdevelopment (hypoplasia) of the connection between the left and right side of the brain (corpus callosum) and outer layer of brain (cortex).Most people with Kleefstra syndrome will have some form of intellectual disability which is typically moderate to severe. Autism spectrum disorder along with expressive speech delay is also common. People with Kleefstra syndrome may develop a lack of interest/difficulty in communicating or moving (catatonia) and extreme apathy after puberty. Psychiatric and sleep problems are also associated with the condition.Other symptoms include epilepsy (seizures) and/or febrile seizures (seizures in the setting of a fever), hearing loss, stomach (gastrointestinal) issues, respiratory infection and farsightedness (hyperopia).
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Causes of Kleefstra Syndrome
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Kleefstra syndrome is a genetic condition caused by changes in a specific region of chromosome 9, known as 9q34.3. The genetic changes that lead to Kleefstra syndrome can take different forms, including deletions (missing pieces) of the chromosome or pathogenic variants (previously known as mutations) within a specific gene called EHMT1.The EHMT1 gene provides the instructions for making an enzyme called euchromatin histone methyl transferase 1, which is involved in a cellular process called histone methylation. This enzyme plays an essential role in controlling how genes work by stopping specific genes from being active, which is crucial for proper growth and body functions. Genetic changes (deletions or pathogenic variants) within the EHMT1 gene result in a loss of function of this enzyme, which can disrupt the normal regulation of other genes and lead to the symptoms of Kleefstra syndrome.In most people with Kleefstra syndrome, the genetic change that causes the disorder is not inherited from a parent but occurs spontaneously (de novo) in the individual with Kleefstra syndrome. However, in a small number of patients reported in the medical literature, Kleefstra syndrome was inherited (passed down) from a parent with no symptoms to a child. This type of inheritance is called autosomal dominant. Dominant genetic disorders occur when only a single copy of a mutated gene is necessary to cause the disease.
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Causes of Kleefstra Syndrome. Kleefstra syndrome is a genetic condition caused by changes in a specific region of chromosome 9, known as 9q34.3. The genetic changes that lead to Kleefstra syndrome can take different forms, including deletions (missing pieces) of the chromosome or pathogenic variants (previously known as mutations) within a specific gene called EHMT1.The EHMT1 gene provides the instructions for making an enzyme called euchromatin histone methyl transferase 1, which is involved in a cellular process called histone methylation. This enzyme plays an essential role in controlling how genes work by stopping specific genes from being active, which is crucial for proper growth and body functions. Genetic changes (deletions or pathogenic variants) within the EHMT1 gene result in a loss of function of this enzyme, which can disrupt the normal regulation of other genes and lead to the symptoms of Kleefstra syndrome.In most people with Kleefstra syndrome, the genetic change that causes the disorder is not inherited from a parent but occurs spontaneously (de novo) in the individual with Kleefstra syndrome. However, in a small number of patients reported in the medical literature, Kleefstra syndrome was inherited (passed down) from a parent with no symptoms to a child. This type of inheritance is called autosomal dominant. Dominant genetic disorders occur when only a single copy of a mutated gene is necessary to cause the disease.
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Affects of Kleefstra Syndrome
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Kleefstra Syndrome affects both males and females equally. It occurs in people from all ancestral backgrounds. How often it occurs is not well understood. Many people with Kleefstra syndrome may be undiagnosed, making it challenging to accurately gauge the frequency of the disorder in the general population.
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Affects of Kleefstra Syndrome. Kleefstra Syndrome affects both males and females equally. It occurs in people from all ancestral backgrounds. How often it occurs is not well understood. Many people with Kleefstra syndrome may be undiagnosed, making it challenging to accurately gauge the frequency of the disorder in the general population.
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Related disorders of Kleefstra Syndrome
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Symptoms of the following disorders can be similar to those of Kleefstra syndrome.
Comparisons may be useful for a differential diagnosis.Smith-Magenis syndrome (SMS) is a complex developmental disorder that affects multiple organ systems of the body. The disorder is characterized by a pattern of abnormalities that are present at birth (congenital) as well as behavioral and cognitive problems. Common symptoms include distinctive facial features, skeletal malformations, varying degrees of intellectual disability, speech and motor delays, sleep disturbances and self-injurious or attention-seeking behaviors. The specific symptoms present in each patient can vary dramatically from one individual to another. Approximately 90% of cases are caused when a portion of chromosome 17 is missing or deleted (monosomic). This deleted portion within chromosome 17p11.2 includes the RAI1 gene, which is believed to play a major role in the development of the disorder. In the remaining cases, there is no deleted material on chromosome 17; these cases are caused by pathogenic variants in the RAI1 gene. Other genes within the deleted segment may also play a role in variable features in the syndrome, but it is not fully understood how significant a role they play in the development of SMS. Unlike Kleefstra syndrome, people with SMS often have tooth agenesis, which means they are born without certain teeth or have fewer teeth than expected. They are also at a higher risk of developing sinopulmonary infections such as otitis media, pneumonia and sinusitis. Individuals with Smith-Magenis syndrome may exhibit aggression and self-injurious behaviors at a higher rate. (For more information on this disorder, choose “Smith Magenis Syndrome” as your search term in the Rare Disease Database.)Pitt-Hopkins syndrome (PTHS) is a rare, genetic, neurological disorder. Affected individuals typically have distinctive facial features, intellectual disability, delays in reaching developmental milestones, impaired ability to speak, and can have recurrent seizures and breathing pattern abnormalities. Additional symptoms that can occur include poor coordination (ataxia), repetitive nonfunctional hand movements, constipation, sleep disturbances and severe nearsightedness (myopia). Behavioral abnormalities are common, although children are often described as social and having happy dispositions. Some affected children meet the criteria for autism spectrum disorder. The specific signs and symptoms of the disorder and their severity can vary from one affected individual to another. Pitt-Hopkins syndrome is caused by a pathogenic variant in the TCF4 gene. This variant occurs spontaneously and in almost all patients and does not run in a family. (For more information on this disorder, choose “Pitt-Hopkins Syndrome” as your search term in the Rare Disease Database.)KMT2C-associated syndrome, also known as “Kleefstra syndrome-2,” is a rare neurodevelopmental disorder inherited in an autosomal dominant pattern. The main symptoms of the syndrome include intellectual disability and developmental delay. In addition, individuals with this syndrome may also have specific facial features such as a flattened midface (midface hypoplasia), prominent eyebrows (synophrys) and everted lower lip. This condition has been observed in individuals with de novo variants in the KMT2C gene.MBD5 haploinsufficiency is a neurological condition that results in developmental delay, intellectual disability; speech, language, and sleeping difficulties; seizures and autistic-like and self-injurious behaviors. This condition can be diagnosed in individuals who have a deletion in the 2q23.1 region of chromosome 2, which may affect the entire MBD5 gene or only a portion of it, or who have a pathogenic variant in the MBD5 gene.
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Related disorders of Kleefstra Syndrome. Symptoms of the following disorders can be similar to those of Kleefstra syndrome.
Comparisons may be useful for a differential diagnosis.Smith-Magenis syndrome (SMS) is a complex developmental disorder that affects multiple organ systems of the body. The disorder is characterized by a pattern of abnormalities that are present at birth (congenital) as well as behavioral and cognitive problems. Common symptoms include distinctive facial features, skeletal malformations, varying degrees of intellectual disability, speech and motor delays, sleep disturbances and self-injurious or attention-seeking behaviors. The specific symptoms present in each patient can vary dramatically from one individual to another. Approximately 90% of cases are caused when a portion of chromosome 17 is missing or deleted (monosomic). This deleted portion within chromosome 17p11.2 includes the RAI1 gene, which is believed to play a major role in the development of the disorder. In the remaining cases, there is no deleted material on chromosome 17; these cases are caused by pathogenic variants in the RAI1 gene. Other genes within the deleted segment may also play a role in variable features in the syndrome, but it is not fully understood how significant a role they play in the development of SMS. Unlike Kleefstra syndrome, people with SMS often have tooth agenesis, which means they are born without certain teeth or have fewer teeth than expected. They are also at a higher risk of developing sinopulmonary infections such as otitis media, pneumonia and sinusitis. Individuals with Smith-Magenis syndrome may exhibit aggression and self-injurious behaviors at a higher rate. (For more information on this disorder, choose “Smith Magenis Syndrome” as your search term in the Rare Disease Database.)Pitt-Hopkins syndrome (PTHS) is a rare, genetic, neurological disorder. Affected individuals typically have distinctive facial features, intellectual disability, delays in reaching developmental milestones, impaired ability to speak, and can have recurrent seizures and breathing pattern abnormalities. Additional symptoms that can occur include poor coordination (ataxia), repetitive nonfunctional hand movements, constipation, sleep disturbances and severe nearsightedness (myopia). Behavioral abnormalities are common, although children are often described as social and having happy dispositions. Some affected children meet the criteria for autism spectrum disorder. The specific signs and symptoms of the disorder and their severity can vary from one affected individual to another. Pitt-Hopkins syndrome is caused by a pathogenic variant in the TCF4 gene. This variant occurs spontaneously and in almost all patients and does not run in a family. (For more information on this disorder, choose “Pitt-Hopkins Syndrome” as your search term in the Rare Disease Database.)KMT2C-associated syndrome, also known as “Kleefstra syndrome-2,” is a rare neurodevelopmental disorder inherited in an autosomal dominant pattern. The main symptoms of the syndrome include intellectual disability and developmental delay. In addition, individuals with this syndrome may also have specific facial features such as a flattened midface (midface hypoplasia), prominent eyebrows (synophrys) and everted lower lip. This condition has been observed in individuals with de novo variants in the KMT2C gene.MBD5 haploinsufficiency is a neurological condition that results in developmental delay, intellectual disability; speech, language, and sleeping difficulties; seizures and autistic-like and self-injurious behaviors. This condition can be diagnosed in individuals who have a deletion in the 2q23.1 region of chromosome 2, which may affect the entire MBD5 gene or only a portion of it, or who have a pathogenic variant in the MBD5 gene.
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Diagnosis of Kleefstra Syndrome
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Kleefstra Syndrome may first be suspected based on characteristic features of the condition and tests done in a clinical evaluation. Often, a person with Kleefstra syndrome will be the only person with the condition in their family history. Molecular genetic testing that identifies the characteristic deletion in chromosome 9 or identifies a variant in the EHMT1 gene can confirm the diagnosis. Molecular genetic testing for the parents might also be recommended. A genetic counselor can explain what type of testing is most appropriate for the child and family. Clinical Testing and Work-UpA clinical work up should include a physical examination including evaluation of the height, weight and head circumference, with particular attention to facial features.An echocardiogram and electrocardiogram (EKG) may be done to look for any potential heart defects and rhythm disturbances. The echocardiogram provides information about the structure of the heart and the EKG uses electrical currents to evaluate the rhythm of the heart.A neurology evaluation might be suggested, including an electroencephalogram (EEG) and magnetic resonance imaging (MRI) for the brain, in children who have had recorded or suspected seizures. An EEG measures electrical activity in the brain to detect seizures and a brain MRI creates a cross sectional image of the brain. MRIs can also be utilized in children with movement disorders, regression of psychomotor development or extreme catatonia.The workup might also include a renal ultrasound to evaluate the kidneys, an assessment for sleep disturbances, hearing evaluation for hearing loss, a psychiatric evaluation and a developmental assessment including motor, speech, cognitive and vocational skills.
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Diagnosis of Kleefstra Syndrome. Kleefstra Syndrome may first be suspected based on characteristic features of the condition and tests done in a clinical evaluation. Often, a person with Kleefstra syndrome will be the only person with the condition in their family history. Molecular genetic testing that identifies the characteristic deletion in chromosome 9 or identifies a variant in the EHMT1 gene can confirm the diagnosis. Molecular genetic testing for the parents might also be recommended. A genetic counselor can explain what type of testing is most appropriate for the child and family. Clinical Testing and Work-UpA clinical work up should include a physical examination including evaluation of the height, weight and head circumference, with particular attention to facial features.An echocardiogram and electrocardiogram (EKG) may be done to look for any potential heart defects and rhythm disturbances. The echocardiogram provides information about the structure of the heart and the EKG uses electrical currents to evaluate the rhythm of the heart.A neurology evaluation might be suggested, including an electroencephalogram (EEG) and magnetic resonance imaging (MRI) for the brain, in children who have had recorded or suspected seizures. An EEG measures electrical activity in the brain to detect seizures and a brain MRI creates a cross sectional image of the brain. MRIs can also be utilized in children with movement disorders, regression of psychomotor development or extreme catatonia.The workup might also include a renal ultrasound to evaluate the kidneys, an assessment for sleep disturbances, hearing evaluation for hearing loss, a psychiatric evaluation and a developmental assessment including motor, speech, cognitive and vocational skills.
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Therapies of Kleefstra Syndrome
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TreatmentAn interdisciplinary team should work together to care for these patients under the coordination of a pediatrician or medical geneticist. Members of this team, depending on the specific symptoms unique to the individual, can include a pediatric neurologist (a physician who specializes in the diagnosis and treatment of disorders of the brain, nerves and nervous system in children), an ophthalmologist (a physician who specializes in the diagnosis and treatment of disorders of the eye), an audiologist (a healthcare provider who specializes in the diagnosis and treatment of disorders of the ears), a cardiologist ( a physician who specializes in the diagnosis and treatment of disorders of the heart), a gastroenterologist (a physician who specializes in the diagnosis and treatment of disorders of the gastrointestinal tract), a urologist and/or nephrologist (a physician who specializes in the diagnosis and treatment of disorders of the genitals and/or kidneys), a speech therapist, occupational therapist, physical therapist and a psychiatrist. The addition of a specialist for adults with intellectual disability may be considered in adulthood.Genetic counseling in encouraged and can be beneficial to both the patient and their family.A developmental assessment can determine appropriate therapies, such as occupational, speech, physical and feeding therapies to help with the difficulties in motor control. Medical equipment such as wheelchairs and walkers might be considered for some patients. Medications like baclofen, Botox, and anti-parkinsonian prescriptions or orthopedic procedures that can help with symptoms of hypotonia and dystonia should be managed by the appropriate specialist.To address communication and behavioral concerns, augmentative and alternative communications (AAC) can provide care for those with difficulties in expressive language, and an applied behavior analysis (ABA) can be implemented as treatment for autism spectrum disorder. ABA adapts to the strengths and weaknesses of each child. A developmental pediatrician can provide guidance in behavior management as well as prescriptions when appropriate. Early intervention programs, developmental preschools and individualized education plans (IEPs) are all beneficial for social, cognitive and intellectual development.
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Therapies of Kleefstra Syndrome. TreatmentAn interdisciplinary team should work together to care for these patients under the coordination of a pediatrician or medical geneticist. Members of this team, depending on the specific symptoms unique to the individual, can include a pediatric neurologist (a physician who specializes in the diagnosis and treatment of disorders of the brain, nerves and nervous system in children), an ophthalmologist (a physician who specializes in the diagnosis and treatment of disorders of the eye), an audiologist (a healthcare provider who specializes in the diagnosis and treatment of disorders of the ears), a cardiologist ( a physician who specializes in the diagnosis and treatment of disorders of the heart), a gastroenterologist (a physician who specializes in the diagnosis and treatment of disorders of the gastrointestinal tract), a urologist and/or nephrologist (a physician who specializes in the diagnosis and treatment of disorders of the genitals and/or kidneys), a speech therapist, occupational therapist, physical therapist and a psychiatrist. The addition of a specialist for adults with intellectual disability may be considered in adulthood.Genetic counseling in encouraged and can be beneficial to both the patient and their family.A developmental assessment can determine appropriate therapies, such as occupational, speech, physical and feeding therapies to help with the difficulties in motor control. Medical equipment such as wheelchairs and walkers might be considered for some patients. Medications like baclofen, Botox, and anti-parkinsonian prescriptions or orthopedic procedures that can help with symptoms of hypotonia and dystonia should be managed by the appropriate specialist.To address communication and behavioral concerns, augmentative and alternative communications (AAC) can provide care for those with difficulties in expressive language, and an applied behavior analysis (ABA) can be implemented as treatment for autism spectrum disorder. ABA adapts to the strengths and weaknesses of each child. A developmental pediatrician can provide guidance in behavior management as well as prescriptions when appropriate. Early intervention programs, developmental preschools and individualized education plans (IEPs) are all beneficial for social, cognitive and intellectual development.
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Overview of Kleine-Levin Syndrome
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Kleine-Levin syndrome is a rare disorder characterized by the need for excessive amounts of sleep (hypersomnolence), (i.e., up to 20 hours a day); excessive food intake (compulsive hyperphagia); and behavioral changes such as an abnormally uninhibited sexual drive. The disorder primarily affects adolescent males. When awake, affected individuals may exhibit irritability, lack of energy (lethargy), and/or lack of emotions (apathy). They may also appear confused (disoriented) and experience hallucinations. Symptoms of Kleine-Levin syndrome are cyclical. An affected individual may go for weeks or months without experiencing symptoms. When present, symptoms may persist for days to weeks. In some cases, the symptoms associated with Kleine-Levin syndrome eventually disappear with advancing age. However, episodes may recur later during life.The exact cause of Kleine-Levin syndrome is not known. However, researchers believe that in some cases, hereditary factors may cause some individuals to have a genetic predisposition to developing the disorder. It is thought that symptoms of Kleine-Levin syndrome may be related to malfunction of the portion of the brain that helps to regulate functions such as sleep, appetite, and body temperature (hypothalamus). Some researchers speculate that Kleine-Levin syndrome may be an autoimmune disorder.
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Overview of Kleine-Levin Syndrome. Kleine-Levin syndrome is a rare disorder characterized by the need for excessive amounts of sleep (hypersomnolence), (i.e., up to 20 hours a day); excessive food intake (compulsive hyperphagia); and behavioral changes such as an abnormally uninhibited sexual drive. The disorder primarily affects adolescent males. When awake, affected individuals may exhibit irritability, lack of energy (lethargy), and/or lack of emotions (apathy). They may also appear confused (disoriented) and experience hallucinations. Symptoms of Kleine-Levin syndrome are cyclical. An affected individual may go for weeks or months without experiencing symptoms. When present, symptoms may persist for days to weeks. In some cases, the symptoms associated with Kleine-Levin syndrome eventually disappear with advancing age. However, episodes may recur later during life.The exact cause of Kleine-Levin syndrome is not known. However, researchers believe that in some cases, hereditary factors may cause some individuals to have a genetic predisposition to developing the disorder. It is thought that symptoms of Kleine-Levin syndrome may be related to malfunction of the portion of the brain that helps to regulate functions such as sleep, appetite, and body temperature (hypothalamus). Some researchers speculate that Kleine-Levin syndrome may be an autoimmune disorder.
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Symptoms of Kleine-Levin Syndrome
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Kleine-Levin syndrome is an extremely rare disorder characterized by the need for excessive amounts of sleep (hypersomnolence), excessive eating (compulsive hyperphagia), and behavioral abnormalities. Onset of symptoms associated with this disorder is extremely rapid. Such symptoms may persist for days to weeks. Affected individuals may have approximately two to 12 episodes per year. In most cases, no symptoms of Kleine-Levin syndrome are exhibited between episodes. Episodes become less frequent with age and may eventually disappear (spontaneous remission). However, episodes have been reported to occur in individuals well into the fourth and fifth decades of life. Individuals with Kleine-Levin syndrome may sleep for 18 to 20 hours per day and wake only to eat, urinate, and defecate. Although affected individuals can be awakened, they may be irritable or listless (lethargic) and/or lack emotion (apathy). They may also appear confused (disoriented), or have difficulties speaking such as slurred speech. In some cases, affected individuals may experience hallucinations or sense of distorted reality in which they feel detached from their surroundings or have disconnected thinking. In addition, individuals with Kleine-Levin syndrome may have an uncontrollable urge to eat excessively (compulsive hyperphagia). Affected individuals generally do not complain of being excessively hungry but will typically consume available food, regardless of the food's condition, quality, or appeal to their preferences. Most individuals with Kleine-Levin syndrome may experience weight gain associated with episodes of compulsive hyperphagia. In some cases, individuals with Kleine-Levin syndrome also exhibit an abnormal sexual drive. They may be sexually uninhibited or have an abnormally increased sex drive (hypersexuality). In addition, in some cases, episodes of Kleine-Levin syndrome may be characterized by other behavioral abnormalities such as memory problems, inattentiveness, absentmindedness, and/or difficulties with concentration. Some affected individuals may show signs of depression, aggression, and/or anxiety. (For more information on Depression, see the Related Disorders section of this report.)
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Symptoms of Kleine-Levin Syndrome. Kleine-Levin syndrome is an extremely rare disorder characterized by the need for excessive amounts of sleep (hypersomnolence), excessive eating (compulsive hyperphagia), and behavioral abnormalities. Onset of symptoms associated with this disorder is extremely rapid. Such symptoms may persist for days to weeks. Affected individuals may have approximately two to 12 episodes per year. In most cases, no symptoms of Kleine-Levin syndrome are exhibited between episodes. Episodes become less frequent with age and may eventually disappear (spontaneous remission). However, episodes have been reported to occur in individuals well into the fourth and fifth decades of life. Individuals with Kleine-Levin syndrome may sleep for 18 to 20 hours per day and wake only to eat, urinate, and defecate. Although affected individuals can be awakened, they may be irritable or listless (lethargic) and/or lack emotion (apathy). They may also appear confused (disoriented), or have difficulties speaking such as slurred speech. In some cases, affected individuals may experience hallucinations or sense of distorted reality in which they feel detached from their surroundings or have disconnected thinking. In addition, individuals with Kleine-Levin syndrome may have an uncontrollable urge to eat excessively (compulsive hyperphagia). Affected individuals generally do not complain of being excessively hungry but will typically consume available food, regardless of the food's condition, quality, or appeal to their preferences. Most individuals with Kleine-Levin syndrome may experience weight gain associated with episodes of compulsive hyperphagia. In some cases, individuals with Kleine-Levin syndrome also exhibit an abnormal sexual drive. They may be sexually uninhibited or have an abnormally increased sex drive (hypersexuality). In addition, in some cases, episodes of Kleine-Levin syndrome may be characterized by other behavioral abnormalities such as memory problems, inattentiveness, absentmindedness, and/or difficulties with concentration. Some affected individuals may show signs of depression, aggression, and/or anxiety. (For more information on Depression, see the Related Disorders section of this report.)
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Causes of Kleine-Levin Syndrome
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The exact cause of Kleine-Levin syndrome is unknown. It is speculated that symptoms may develop due to malfunction or damage to the portion of the brain that helps to regulate functions such as sleep, appetite, and body temperature (hypothalamus). As with most diseases with no known cause, some researchers have speculated that, in some cases, symptoms may develop as a result of a head injury or an infectious disease affecting the hypothalamus; however, this is unproven. In some cases, the development of Kleine-Levin syndrome follows a flu-like illness indicating an infection leading some researchers to speculate that an underlying autoimmune process may play a role in the development of the disorder. Autoimmune disorders are caused when the body's natural defenses against “foreign” or invading organisms (e.g., antibodies) begin to attack healthy tissue for unknown reasons. A Stanford University study in 2005 determined that 72 percent of the cases studied were preceded by symptoms of infection.In extremely rare cases, more than one family member has been affected (familial Kleine-Levin syndrome). These rare cases and the possible role of infection in the development of Kleine-Levin syndrome suggest that genetic factors may cause some individuals to have a predisposition to developing the disorder.
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Causes of Kleine-Levin Syndrome. The exact cause of Kleine-Levin syndrome is unknown. It is speculated that symptoms may develop due to malfunction or damage to the portion of the brain that helps to regulate functions such as sleep, appetite, and body temperature (hypothalamus). As with most diseases with no known cause, some researchers have speculated that, in some cases, symptoms may develop as a result of a head injury or an infectious disease affecting the hypothalamus; however, this is unproven. In some cases, the development of Kleine-Levin syndrome follows a flu-like illness indicating an infection leading some researchers to speculate that an underlying autoimmune process may play a role in the development of the disorder. Autoimmune disorders are caused when the body's natural defenses against “foreign” or invading organisms (e.g., antibodies) begin to attack healthy tissue for unknown reasons. A Stanford University study in 2005 determined that 72 percent of the cases studied were preceded by symptoms of infection.In extremely rare cases, more than one family member has been affected (familial Kleine-Levin syndrome). These rare cases and the possible role of infection in the development of Kleine-Levin syndrome suggest that genetic factors may cause some individuals to have a predisposition to developing the disorder.
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Affects of Kleine-Levin Syndrome
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Kleine-Levin syndrome is a rare sleep disorder that primarily affects adolescent males, usually around the age of 16 years. However, there have been cases involving females and older men. Males appear to be affected three times as often as females (M3:F1). On average, women had a longer disease course than men. More than 500 cases have been reported in the medical literature. However, because cases of Kleine-Levin syndrome often go unrecognized, the disorder is under-diagnosed, making it difficult to determine its true frequency in the general population.Symptoms associated with the disorder usually become apparent during adolescence. Individuals with Kleine-Levin syndrome may have episodes that last for a few days or up to several weeks. Episodes occur approximately two to 12 times per year. Most affected individuals exhibit no symptoms of Kleine-Levin syndrome between episodes. In some cases, symptoms subside with advancing age (spontaneous remission), most often by early adult life. However, in other cases, the disorder persists throughout adulthood.
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Affects of Kleine-Levin Syndrome. Kleine-Levin syndrome is a rare sleep disorder that primarily affects adolescent males, usually around the age of 16 years. However, there have been cases involving females and older men. Males appear to be affected three times as often as females (M3:F1). On average, women had a longer disease course than men. More than 500 cases have been reported in the medical literature. However, because cases of Kleine-Levin syndrome often go unrecognized, the disorder is under-diagnosed, making it difficult to determine its true frequency in the general population.Symptoms associated with the disorder usually become apparent during adolescence. Individuals with Kleine-Levin syndrome may have episodes that last for a few days or up to several weeks. Episodes occur approximately two to 12 times per year. Most affected individuals exhibit no symptoms of Kleine-Levin syndrome between episodes. In some cases, symptoms subside with advancing age (spontaneous remission), most often by early adult life. However, in other cases, the disorder persists throughout adulthood.
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Related disorders of Kleine-Levin Syndrome
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Symptoms of the following disorders can be similar to those of Kleine-Levin syndrome. Comparisons may be useful for a differential diagnosis: Narcolepsy is a sleep disorder characterized by abnormal sleepiness during the day, sudden extreme muscle weakness (cataplexy), hallucinations, paralysis while sleeping, and disrupted sleep during the night. Excessive daytime sleepiness is usually the first symptom of narcolepsy. People with narcolepsy may also experience lack of energy (lethargy), an irresistible urge to sleep (“sleep attack”), and/or an inability to resist sleep. The symptoms of narcolepsy generally begin between the ages of 10 to 20 years. The exact cause of narcolepsy is not known. (For more information on this disorder, choose “Narcolepsy” as your search term in the Rare Disease Database.) Numerous disorders in addition to narcolepsy are involved with disturbed sleeping patterns. A partial list of these disorders includes cataplexy, sleep apnea, delayed sleep phase syndrome, excessive daytime sleepiness, and African sleeping sickness. A recently described disorder known as idiopathic hypersomnia is characterized by excessive sleepiness (hypersomnia) that occurs for unknown reasons (idiopathic). The following disorder may be associated with Kleine-Levin syndrome as secondary a characteristic. It is not necessary for a differential diagnosis: Depression is a common psychiatric disorder characterized by prolonged feelings of profound sadness, unhappiness, and discouragement. Affected individuals may be irritable, have difficulty concentrating, and/or experience confusion and/or hallucinations. Some affected individuals may also experience extremes in eating behaviors: they may refuse to eat or may eat enormous amounts of food. In addition, affected individuals may sleep excessively or may be unable to sleep (insomnia). Some researchers believe that depression may be caused by a variety of factors, including diet, family history, and the interaction of many genes (polygenic inheritance), possibly in combination with environmental factors (multifactorial inheritance). (For more information on this disorder, choose “Depression” as your search term in the Rare Disease Database.)
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Related disorders of Kleine-Levin Syndrome. Symptoms of the following disorders can be similar to those of Kleine-Levin syndrome. Comparisons may be useful for a differential diagnosis: Narcolepsy is a sleep disorder characterized by abnormal sleepiness during the day, sudden extreme muscle weakness (cataplexy), hallucinations, paralysis while sleeping, and disrupted sleep during the night. Excessive daytime sleepiness is usually the first symptom of narcolepsy. People with narcolepsy may also experience lack of energy (lethargy), an irresistible urge to sleep (“sleep attack”), and/or an inability to resist sleep. The symptoms of narcolepsy generally begin between the ages of 10 to 20 years. The exact cause of narcolepsy is not known. (For more information on this disorder, choose “Narcolepsy” as your search term in the Rare Disease Database.) Numerous disorders in addition to narcolepsy are involved with disturbed sleeping patterns. A partial list of these disorders includes cataplexy, sleep apnea, delayed sleep phase syndrome, excessive daytime sleepiness, and African sleeping sickness. A recently described disorder known as idiopathic hypersomnia is characterized by excessive sleepiness (hypersomnia) that occurs for unknown reasons (idiopathic). The following disorder may be associated with Kleine-Levin syndrome as secondary a characteristic. It is not necessary for a differential diagnosis: Depression is a common psychiatric disorder characterized by prolonged feelings of profound sadness, unhappiness, and discouragement. Affected individuals may be irritable, have difficulty concentrating, and/or experience confusion and/or hallucinations. Some affected individuals may also experience extremes in eating behaviors: they may refuse to eat or may eat enormous amounts of food. In addition, affected individuals may sleep excessively or may be unable to sleep (insomnia). Some researchers believe that depression may be caused by a variety of factors, including diet, family history, and the interaction of many genes (polygenic inheritance), possibly in combination with environmental factors (multifactorial inheritance). (For more information on this disorder, choose “Depression” as your search term in the Rare Disease Database.)
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Diagnosis of Kleine-Levin Syndrome
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Diagnosis of Kleine-Levin Syndrome.
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Therapies of Kleine-Levin Syndrome
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Kleine-Levin syndrome may be suspected based upon a thorough clinical evaluation and a detailed patient history. Kleine-Levin syndrome may be confirmed based upon excessive sleep requirements (hypersomnolence); the desire to eat all available food (compulsive hyperphagia); and hypersexuality. Certain medical tests may be performed to rule out other conditions such as epilepsy, brain lesions, meningitis or encephalitis.The treatment of Kleine-Levin syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, psychiatrists, psychologists, neurologists, and other health care professionals may need to systematically and comprehensively plan an affected adolescent's treatment.Specific therapies for the treatment of Kleine-Levin syndrome are symptomatic and supportive. In some cases, stimulants may provide temporary relief from the need for excessive amounts of sleep. Amphetamines were most successful in reducing sleepiness in affected individuals, but had no effect on other associated symptoms (e.g., behavioral changes).
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Therapies of Kleine-Levin Syndrome. Kleine-Levin syndrome may be suspected based upon a thorough clinical evaluation and a detailed patient history. Kleine-Levin syndrome may be confirmed based upon excessive sleep requirements (hypersomnolence); the desire to eat all available food (compulsive hyperphagia); and hypersexuality. Certain medical tests may be performed to rule out other conditions such as epilepsy, brain lesions, meningitis or encephalitis.The treatment of Kleine-Levin syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, psychiatrists, psychologists, neurologists, and other health care professionals may need to systematically and comprehensively plan an affected adolescent's treatment.Specific therapies for the treatment of Kleine-Levin syndrome are symptomatic and supportive. In some cases, stimulants may provide temporary relief from the need for excessive amounts of sleep. Amphetamines were most successful in reducing sleepiness in affected individuals, but had no effect on other associated symptoms (e.g., behavioral changes).
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Overview of Klippel-Feil Syndrome
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SummaryKlippel-Feil syndrome (KFS) is a rare skeletal disorder characterized by the congenital fusion of two or more vertebrae of the cervical spine within the neck. Some affected individuals may also have an abnormally short neck, restricted movement of the head and neck and a low hairline at the back of the head (posterior hairline). The disorder is present at birth (congenital), but mild cases may go undiagnosed until later life when symptoms worsen or first become apparent. In some individuals, KFS can be associated with a variety of additional symptoms and physical abnormalities. These may include abnormal curvature of the spine (scoliosis) and/or vertebral instability, spina bifida occulta, raised scapula (Sprengel’s deformity), absent rib(s) and other rib defects including cervical ribs, other skeletal abnormalities including skeletal malformations of the ear, nose, mouth and larynx including hearing impairment and cleft palate, malformations of the head and facial (craniofacial) area; anomalies of the urinary tract and/or kidney including absent or horse-shoe kidney; or structural abnormalities of the heart (congenital heart defects), mirror movements, webbing of the digits and digital hypoplasia. In addition, in some cases, neurological complications may result due to associated spinal cord injury. KFS may occur as an isolated abnormality (Klippel-Feil anomaly) or as a syndrome with associated anomalies.In many individuals with KFS, the condition appears to occur randomly for unknown reasons (sporadically). In other cases, KFS may be inherited in an autosomal dominant or autosomal recessive pattern. Researchers had determined that some cases of KFS were associated with changes (variants or mutations) of the GDF6 gene. Variants in the GDF6 gene also cause multiple synostosis syndrome type 4 (SYSN4) which is very difficult to distinguish from KFS because SYSN4 is also congenital and progressive with vertebral fusion from a very early age. Some people were wrongly diagnosed with KFS but in fact have SYSN4.IntroductionKFS was originally described in the medical literature in 1912 by doctors Maurice Klippel and Andre Feil.
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Overview of Klippel-Feil Syndrome. SummaryKlippel-Feil syndrome (KFS) is a rare skeletal disorder characterized by the congenital fusion of two or more vertebrae of the cervical spine within the neck. Some affected individuals may also have an abnormally short neck, restricted movement of the head and neck and a low hairline at the back of the head (posterior hairline). The disorder is present at birth (congenital), but mild cases may go undiagnosed until later life when symptoms worsen or first become apparent. In some individuals, KFS can be associated with a variety of additional symptoms and physical abnormalities. These may include abnormal curvature of the spine (scoliosis) and/or vertebral instability, spina bifida occulta, raised scapula (Sprengel’s deformity), absent rib(s) and other rib defects including cervical ribs, other skeletal abnormalities including skeletal malformations of the ear, nose, mouth and larynx including hearing impairment and cleft palate, malformations of the head and facial (craniofacial) area; anomalies of the urinary tract and/or kidney including absent or horse-shoe kidney; or structural abnormalities of the heart (congenital heart defects), mirror movements, webbing of the digits and digital hypoplasia. In addition, in some cases, neurological complications may result due to associated spinal cord injury. KFS may occur as an isolated abnormality (Klippel-Feil anomaly) or as a syndrome with associated anomalies.In many individuals with KFS, the condition appears to occur randomly for unknown reasons (sporadically). In other cases, KFS may be inherited in an autosomal dominant or autosomal recessive pattern. Researchers had determined that some cases of KFS were associated with changes (variants or mutations) of the GDF6 gene. Variants in the GDF6 gene also cause multiple synostosis syndrome type 4 (SYSN4) which is very difficult to distinguish from KFS because SYSN4 is also congenital and progressive with vertebral fusion from a very early age. Some people were wrongly diagnosed with KFS but in fact have SYSN4.IntroductionKFS was originally described in the medical literature in 1912 by doctors Maurice Klippel and Andre Feil.
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Symptoms of Klippel-Feil Syndrome
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KFS is a rare skeletal condition in which there is abnormal union and fusion of two or more vertebrae within the neck. The spinal column or backbone is made up of 33 irregularly shaped bones known as vertebrae. These bones are divided into different categories. The first seven vertebrae, beginning at the base of the skull, are known as the cervical vertebrae. KFS primarily affects the cervical vertebrae.The specific symptoms associated with KFS vary greatly from one person to another. Historically, KFS was associated with a classic triad of symptoms, specifically abnormally short neck, restricted movement of the head and neck, and a low hairline at the back of the head (posterior hairline). However, researchers have determined that these symptoms may define one class of KFS, which accounts for less than 50 percent of affected individuals.In addition to the fusion of certain vertebrae, KFS can be associated with a wide variety of additional anomalies affecting many different organ systems of the body. The progression and severity of KFS can vary greatly depending upon the specific associated complications and the Class of KFS. Some cases may be mild; others may cause serious, life-long complications.It is important to note that affected individuals will not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.Approximately 30 percent of affected individuals have additional skeletal abnormalities, such as fusion of certain ribs or other rib defects; abnormal sideways curvature of the spine (scoliosis); or a condition known as Sprengel’s deformity. This condition is characterized by elevation and/or underdevelopment of the shoulder blade (scapula), limited movement of the arm on the affected side, and the development of a lump at the base of the neck due to elevation of the shoulder blade. Also, in some individuals with KFS, a portion of the spinal cord may be exposed due to incomplete closure of certain vertebrae (spina bifida occulta). Associated findings may include the presence of a tuft of hair or dimple over the underlying abnormality and, in some cases, leg weakness, an inability to control urination (urinary incontinence), or other findings. As mentioned above, KFS type II may be associated with incomplete development of one half of certain vertebrae (hemivertebrae) and fusion of the first vertebra of the neck (atlas) with the bone at the back of the skull (occipital bone).Approximately 25 to 50 percent of individuals with KFS also have hearing impairment. Such hearing loss may result from impaired transmission of sound from the outer or middle ear to the inner ear (conductive hearing loss); failed transmission of sound impulses from the inner ear to the brain (sensorineural hearing loss); or both (mixed hearing loss). Conductive hearing loss in association with vertebral fusion is also present in individuals with multiple synostosis syndrome type 4 (SYSN4).Various eye (ocular) abnormalities may also be associated with KFS, such as deviation of one eye toward the other (cross-eye or convergent strabismus); involuntary, rapid eye movements (nystagmus); or absence or defects of ocular tissue (colobomas). In addition, some affected individuals may have other abnormalities of the head and facial (craniofacial) area including facial asymmetry, in which one side of the face appears dissimilar from other side, with one eye higher than the other. There may also be abnormal twisting of the neck (torticollis), causing the head to be rotated into an abnormal position. According to some reports, approximately 17 percent of individuals with KFS also have incomplete closure of the roof of the mouth (cleft palate).KFS may sometimes be associated with additional physical abnormalities. These may include structural malformations of the heart (congenital heart defects), particularly ventricular septal defects (VSDs). VSDs are characterized by the presence of an abnormal opening in the fibrous partition (septum) that separates the two lower chambers of the heart. Some individuals may also have kidney (renal) defects, such as underdevelopment (hypoplasia) or absence (agenesis) of one or both kidneys; abnormal renal rotation or placement (ectopia); or swelling of the kidneys with urine (hydronephrosis) due to blockage or narrowing of the tubes (ureters) that carry urine to the bladder.Some individuals with the disorder may also develop neurological complications due to associated spinal cord injury. Such injury may result from instability of cervical vertebrae. For example, unfused vertebral segments adjacent to fused cervical vertebrae may be abnormally mobile (hypermobile), making them vulnerable to increased stress, which in turn may lead to vertebral instability or degenerative changes. Associated neurological complications tend to develop between the second and third decades of life and may occur spontaneously or following minor trauma. Such complications may include pain; abnormal sensations (paresthesia), such as tingling, prickling, or burning; or involuntary muscle movements accompanying certain voluntary actions (synkinesia or mirror movements). In addition, some individuals may develop increased reflex reactions (hyperreflexia); weakness or paralysis of one side of the body (hemiplegia) or of the legs and the lower part of the body (paraplegia); or impairment of certain nerves that emerge from the brain (cranial nerve palsies).
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Symptoms of Klippel-Feil Syndrome. KFS is a rare skeletal condition in which there is abnormal union and fusion of two or more vertebrae within the neck. The spinal column or backbone is made up of 33 irregularly shaped bones known as vertebrae. These bones are divided into different categories. The first seven vertebrae, beginning at the base of the skull, are known as the cervical vertebrae. KFS primarily affects the cervical vertebrae.The specific symptoms associated with KFS vary greatly from one person to another. Historically, KFS was associated with a classic triad of symptoms, specifically abnormally short neck, restricted movement of the head and neck, and a low hairline at the back of the head (posterior hairline). However, researchers have determined that these symptoms may define one class of KFS, which accounts for less than 50 percent of affected individuals.In addition to the fusion of certain vertebrae, KFS can be associated with a wide variety of additional anomalies affecting many different organ systems of the body. The progression and severity of KFS can vary greatly depending upon the specific associated complications and the Class of KFS. Some cases may be mild; others may cause serious, life-long complications.It is important to note that affected individuals will not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.Approximately 30 percent of affected individuals have additional skeletal abnormalities, such as fusion of certain ribs or other rib defects; abnormal sideways curvature of the spine (scoliosis); or a condition known as Sprengel’s deformity. This condition is characterized by elevation and/or underdevelopment of the shoulder blade (scapula), limited movement of the arm on the affected side, and the development of a lump at the base of the neck due to elevation of the shoulder blade. Also, in some individuals with KFS, a portion of the spinal cord may be exposed due to incomplete closure of certain vertebrae (spina bifida occulta). Associated findings may include the presence of a tuft of hair or dimple over the underlying abnormality and, in some cases, leg weakness, an inability to control urination (urinary incontinence), or other findings. As mentioned above, KFS type II may be associated with incomplete development of one half of certain vertebrae (hemivertebrae) and fusion of the first vertebra of the neck (atlas) with the bone at the back of the skull (occipital bone).Approximately 25 to 50 percent of individuals with KFS also have hearing impairment. Such hearing loss may result from impaired transmission of sound from the outer or middle ear to the inner ear (conductive hearing loss); failed transmission of sound impulses from the inner ear to the brain (sensorineural hearing loss); or both (mixed hearing loss). Conductive hearing loss in association with vertebral fusion is also present in individuals with multiple synostosis syndrome type 4 (SYSN4).Various eye (ocular) abnormalities may also be associated with KFS, such as deviation of one eye toward the other (cross-eye or convergent strabismus); involuntary, rapid eye movements (nystagmus); or absence or defects of ocular tissue (colobomas). In addition, some affected individuals may have other abnormalities of the head and facial (craniofacial) area including facial asymmetry, in which one side of the face appears dissimilar from other side, with one eye higher than the other. There may also be abnormal twisting of the neck (torticollis), causing the head to be rotated into an abnormal position. According to some reports, approximately 17 percent of individuals with KFS also have incomplete closure of the roof of the mouth (cleft palate).KFS may sometimes be associated with additional physical abnormalities. These may include structural malformations of the heart (congenital heart defects), particularly ventricular septal defects (VSDs). VSDs are characterized by the presence of an abnormal opening in the fibrous partition (septum) that separates the two lower chambers of the heart. Some individuals may also have kidney (renal) defects, such as underdevelopment (hypoplasia) or absence (agenesis) of one or both kidneys; abnormal renal rotation or placement (ectopia); or swelling of the kidneys with urine (hydronephrosis) due to blockage or narrowing of the tubes (ureters) that carry urine to the bladder.Some individuals with the disorder may also develop neurological complications due to associated spinal cord injury. Such injury may result from instability of cervical vertebrae. For example, unfused vertebral segments adjacent to fused cervical vertebrae may be abnormally mobile (hypermobile), making them vulnerable to increased stress, which in turn may lead to vertebral instability or degenerative changes. Associated neurological complications tend to develop between the second and third decades of life and may occur spontaneously or following minor trauma. Such complications may include pain; abnormal sensations (paresthesia), such as tingling, prickling, or burning; or involuntary muscle movements accompanying certain voluntary actions (synkinesia or mirror movements). In addition, some individuals may develop increased reflex reactions (hyperreflexia); weakness or paralysis of one side of the body (hemiplegia) or of the legs and the lower part of the body (paraplegia); or impairment of certain nerves that emerge from the brain (cranial nerve palsies).
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Klippel-Feil Syndrome
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nord_681_2
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Causes of Klippel-Feil Syndrome
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In most individuals with KFS, the condition appears to occur randomly for unknown reasons (sporadically). However, in other cases, familial patterns have been reported that indicate autosomal dominant or autosomal recessive inheritance. Most likely, KFS is multifactorial, which means that several different factors including genetic factors all play some causative role. In addition, different genetic changes can cause KFS (genetic heterogeneity) in different people.Researchers have determined that some familial cases of KFS are associated with autosomal dominant transmission. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. For autosomal dominant inheritance the risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy. The risk is the same for males and females.In 2008, researchers determined that some cases of autosomal dominant and sporadic KFS are caused by mutations of the GDF6 gene. The GDF6 gene produces a growth factor that is involved in the production and function of cartilage in the developing embryo. Cartilage is the specialized tissue that serves as a buffer or cushion at joints. Most of the skeleton of an embryo consists of cartilage, which is slowly converted to bone. Researchers have determined that the growth factor produced by the GDF6 gene is essential to the proper function of the spinal discs found between the vertebrae. These discs provide flexibility and protection for the spinal cord. How mutations of the GDF6 gene contribute to the full spectrum of symptoms and physical findings associated with KFS is not yet known. Multiple synostosis 4 (SYNS4) is also associated with the mutations in the GDF gene. Some cases of KFS have been reported that seem to suggest autosomal recessive inheritance. 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 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent 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 percent. The risk is the same for males and females.The specific underlying causes and mechanisms that are associated with KFS are not fully understood. However, the condition appears to result from failure of the proper division (segmentation) of embryonic tissue that normally develops into vertebrae. As explained above, some cases are linked to mutations of the GDF6 gene which regulates the ossification of cartilage which can affect both congenital bone formation and progressive ossification after birth. Other cases may be due to mutations in other genes or other causes. Further research is needed to learn more about the various underlying mechanisms that may be responsible for KFS, and the exact roles genetic and other factors ultimately play in the development of the disorder.
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Causes of Klippel-Feil Syndrome. In most individuals with KFS, the condition appears to occur randomly for unknown reasons (sporadically). However, in other cases, familial patterns have been reported that indicate autosomal dominant or autosomal recessive inheritance. Most likely, KFS is multifactorial, which means that several different factors including genetic factors all play some causative role. In addition, different genetic changes can cause KFS (genetic heterogeneity) in different people.Researchers have determined that some familial cases of KFS are associated with autosomal dominant transmission. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. For autosomal dominant inheritance the risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy. The risk is the same for males and females.In 2008, researchers determined that some cases of autosomal dominant and sporadic KFS are caused by mutations of the GDF6 gene. The GDF6 gene produces a growth factor that is involved in the production and function of cartilage in the developing embryo. Cartilage is the specialized tissue that serves as a buffer or cushion at joints. Most of the skeleton of an embryo consists of cartilage, which is slowly converted to bone. Researchers have determined that the growth factor produced by the GDF6 gene is essential to the proper function of the spinal discs found between the vertebrae. These discs provide flexibility and protection for the spinal cord. How mutations of the GDF6 gene contribute to the full spectrum of symptoms and physical findings associated with KFS is not yet known. Multiple synostosis 4 (SYNS4) is also associated with the mutations in the GDF gene. Some cases of KFS have been reported that seem to suggest autosomal recessive inheritance. 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 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent 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 percent. The risk is the same for males and females.The specific underlying causes and mechanisms that are associated with KFS are not fully understood. However, the condition appears to result from failure of the proper division (segmentation) of embryonic tissue that normally develops into vertebrae. As explained above, some cases are linked to mutations of the GDF6 gene which regulates the ossification of cartilage which can affect both congenital bone formation and progressive ossification after birth. Other cases may be due to mutations in other genes or other causes. Further research is needed to learn more about the various underlying mechanisms that may be responsible for KFS, and the exact roles genetic and other factors ultimately play in the development of the disorder.
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Affects of Klippel-Feil Syndrome
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The exact incidence of the disorder is unknown, although reports estimate that the condition occurs in approximately one in 42,000-50,000 live births. KFS affects females more frequently than males. More specifically, approximately 65 percent of affected individuals are female. According to reports in the medical literature, KFS type II appears to be the most common form of the condition.
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Affects of Klippel-Feil Syndrome. The exact incidence of the disorder is unknown, although reports estimate that the condition occurs in approximately one in 42,000-50,000 live births. KFS affects females more frequently than males. More specifically, approximately 65 percent of affected individuals are female. According to reports in the medical literature, KFS type II appears to be the most common form of the condition.
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Klippel-Feil Syndrome
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Related disorders of Klippel-Feil Syndrome
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Symptoms of the following disorder may be similar to those of KFS. Comparisons may be useful for a differential diagnosis:Multiple synostosis (SYNS) is also associated with the fusion of cervical vertebrae. Multiple synostosis 4 (SYNS4) is caused by variants in the GDF6 gene. SYSN4 is very difficult to distinguish from KFS because SYSN4 is also congenital and progressive with vertebral fusion from a very early age. Some people were wrongly diagnosed with KFS but in fact have SYSN4. Ankylosing spondylitis is a progressive inflammatory disease that typically becomes evident during early to mid-adulthood. The disease is characterized by inflammation (arthritis), stiffness, and pain of various joints of the spine and potential loss of spinal mobility. It may involve joints between the spine and the pelvis, known as the sacroiliac joints; joints within the spinal column of the lower back (lumbar spine), the upper back (thoracic spine), and the neck (cervical spine) to varying degrees; as well as joints of the limbs, particularly the legs. Progression may spontaneously subside at any stage of involvement; however, in some individuals, all regions of the spinal column may eventually become involved. Many affected individuals develop lower back and hip pain that may be more severe at night and after rest. In addition, there is often associated stiffness of affected regions in the morning. In some cases, those with involvement of joints joining the ribs with the spine (costovertebral joints) may have a limited ability to expand the chest to take a deep breath. In addition, in some affected individuals, other associated findings may include recurrent inflammation of the colored region of the eyes (acute iritis), leakage of the aortic valve resulting in a backflow of blood into the lower left chamber (ventricle) of the heart (aortic insufficiency or regurgitation), and/or other abnormalities. The exact cause of ankylosing spondylitis is not known. However, researchers suggest that genetic, immunologic and/or environmental factors may play some role.Juvenile rheumatoid arthritis (JRA) is a rheumatic disease characterized by chronic inflammation (arthritis) of one or more joints in a child aged 16 years or younger. Associated symptoms typically include swelling, abnormal warmth, tenderness or pain, and/or stiffness of affected joints that tends to be worse in the mornings. In severe cases, destructive changes may eventually result in limited mobility and possible deformity of affected joints. Some children with JRA may also have generalized symptoms and findings, such as fever, lack of appetite (anorexia), enlargement of the liver and spleen (hepatosplenomegaly) and/or other abnormalities. In addition, some forms of JRA are associated with an increased risk for inflammation of certain regions of the eyes (iridocyclitis). The range and severity of associated symptoms and findings may vary, depending upon the specific form of the disease present. The exact cause of JRA is not known. Wildervanck syndrome, also known as cervicooculoacoustic syndrome, is a rare genetic disorder that may be detected during infancy. The disorder is characterized by KFS; hearing impairment due to failed transmission of sound impulses from the inner ear to the brain (sensorineural deafness); and a condition known as Duane syndrome in which there are abnormalities of certain eye (ocular) movements. Duane syndrome is primarily characterized by limitation or absence of certain horizontal eye movements; retraction or “drawing back” of the eyeball into the eye cavity (orbit) upon looking inward; and, in some patients, abnormal deviation of one eye in relation to the other (strabismus). In addition, in some individuals with Wildervanck syndrome, the face may appear dissimilar from one side to the other (facial asymmetry). According to reports in the medical literature, Wildervanck syndrome primarily affects females. The disorder has appeared to occur randomly for unknown reasons (sporadically). Some researchers suggest that Wildervanck syndrome may result from the interaction of several different genes (polygenic). (For further information, please choose “Wildervanck” as your search term in the Rare Disease Database.)There are a number of additional syndromes in which KFS may occur in association with other characteristic physical findings. Such syndromes include MURCS association; fetal alcohol syndrome; Goldenhar syndrome, also known as oculo-auriculo-vertebral (OAV) spectrum; and other disorders. (For further information, choose the exact disease name in question as your search term in the Rare Disease Database.)
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Related disorders of Klippel-Feil Syndrome. Symptoms of the following disorder may be similar to those of KFS. Comparisons may be useful for a differential diagnosis:Multiple synostosis (SYNS) is also associated with the fusion of cervical vertebrae. Multiple synostosis 4 (SYNS4) is caused by variants in the GDF6 gene. SYSN4 is very difficult to distinguish from KFS because SYSN4 is also congenital and progressive with vertebral fusion from a very early age. Some people were wrongly diagnosed with KFS but in fact have SYSN4. Ankylosing spondylitis is a progressive inflammatory disease that typically becomes evident during early to mid-adulthood. The disease is characterized by inflammation (arthritis), stiffness, and pain of various joints of the spine and potential loss of spinal mobility. It may involve joints between the spine and the pelvis, known as the sacroiliac joints; joints within the spinal column of the lower back (lumbar spine), the upper back (thoracic spine), and the neck (cervical spine) to varying degrees; as well as joints of the limbs, particularly the legs. Progression may spontaneously subside at any stage of involvement; however, in some individuals, all regions of the spinal column may eventually become involved. Many affected individuals develop lower back and hip pain that may be more severe at night and after rest. In addition, there is often associated stiffness of affected regions in the morning. In some cases, those with involvement of joints joining the ribs with the spine (costovertebral joints) may have a limited ability to expand the chest to take a deep breath. In addition, in some affected individuals, other associated findings may include recurrent inflammation of the colored region of the eyes (acute iritis), leakage of the aortic valve resulting in a backflow of blood into the lower left chamber (ventricle) of the heart (aortic insufficiency or regurgitation), and/or other abnormalities. The exact cause of ankylosing spondylitis is not known. However, researchers suggest that genetic, immunologic and/or environmental factors may play some role.Juvenile rheumatoid arthritis (JRA) is a rheumatic disease characterized by chronic inflammation (arthritis) of one or more joints in a child aged 16 years or younger. Associated symptoms typically include swelling, abnormal warmth, tenderness or pain, and/or stiffness of affected joints that tends to be worse in the mornings. In severe cases, destructive changes may eventually result in limited mobility and possible deformity of affected joints. Some children with JRA may also have generalized symptoms and findings, such as fever, lack of appetite (anorexia), enlargement of the liver and spleen (hepatosplenomegaly) and/or other abnormalities. In addition, some forms of JRA are associated with an increased risk for inflammation of certain regions of the eyes (iridocyclitis). The range and severity of associated symptoms and findings may vary, depending upon the specific form of the disease present. The exact cause of JRA is not known. Wildervanck syndrome, also known as cervicooculoacoustic syndrome, is a rare genetic disorder that may be detected during infancy. The disorder is characterized by KFS; hearing impairment due to failed transmission of sound impulses from the inner ear to the brain (sensorineural deafness); and a condition known as Duane syndrome in which there are abnormalities of certain eye (ocular) movements. Duane syndrome is primarily characterized by limitation or absence of certain horizontal eye movements; retraction or “drawing back” of the eyeball into the eye cavity (orbit) upon looking inward; and, in some patients, abnormal deviation of one eye in relation to the other (strabismus). In addition, in some individuals with Wildervanck syndrome, the face may appear dissimilar from one side to the other (facial asymmetry). According to reports in the medical literature, Wildervanck syndrome primarily affects females. The disorder has appeared to occur randomly for unknown reasons (sporadically). Some researchers suggest that Wildervanck syndrome may result from the interaction of several different genes (polygenic). (For further information, please choose “Wildervanck” as your search term in the Rare Disease Database.)There are a number of additional syndromes in which KFS may occur in association with other characteristic physical findings. Such syndromes include MURCS association; fetal alcohol syndrome; Goldenhar syndrome, also known as oculo-auriculo-vertebral (OAV) spectrum; and other disorders. (For further information, choose the exact disease name in question as your search term in the Rare Disease Database.)
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Klippel-Feil Syndrome
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Diagnosis of Klippel-Feil Syndrome
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KFS may be diagnosed at birth based upon a thorough clinical evaluation, identification of characteristic physical findings, and specialized tests. Diagnostic studies may include advanced imaging techniques, such as magnetic resonance imaging (MRI), to help characterize the open spaces (interspaces) between certain cervical and other vertebrae, the extent of abnormal vertebral union or fusion, and possible impingement of vertebrae on the spinal cord. During MRI, a magnetic field and radio waves form detailed cross-sectional images of internal structures. Additional specialized tests may also be conducted to help detect and/or characterize other abnormalities that may be associated with KFS (e.g., hearing impairment, congenital heart defects, renal abnormalities, eye defects, etc.).
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Diagnosis of Klippel-Feil Syndrome. KFS may be diagnosed at birth based upon a thorough clinical evaluation, identification of characteristic physical findings, and specialized tests. Diagnostic studies may include advanced imaging techniques, such as magnetic resonance imaging (MRI), to help characterize the open spaces (interspaces) between certain cervical and other vertebrae, the extent of abnormal vertebral union or fusion, and possible impingement of vertebrae on the spinal cord. During MRI, a magnetic field and radio waves form detailed cross-sectional images of internal structures. Additional specialized tests may also be conducted to help detect and/or characterize other abnormalities that may be associated with KFS (e.g., hearing impairment, congenital heart defects, renal abnormalities, eye defects, etc.).
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Klippel-Feil Syndrome
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Therapies of Klippel-Feil Syndrome
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Treatment
The treatment of KFS is directed toward the specific symptoms and associated physical findings that are apparent in each individual. Such treatment may require the coordinated efforts of a team of medical professionals who may need to systematically and comprehensively plan an affected individual’s treatment. These professionals may include pediatricians; surgeons; physicians who diagnose and treat disorders of the skeleton, muscles, joints, and related tissues (orthopedists); physicians who specialize in neurological disorders (neurologists); physicians who diagnose and treat heart abnormalities (cardiologists); specialists who assess and treat hearing problems (audiologists); eye specialists (ophthalmologists); and/or other health care professionals.Therapy for KFS can include a variety of conservative measures including the use of cervical collars, braces, traction, non-steroidal anti-inflammatory drugs (NSAIDs) and various pain medications (analgesics).Because some affected individuals may have an increased risk of neurological complications, they should be regularly monitored by physicians. In addition, they should avoid activities that could lead to trauma or injury to cervical vertebrae.In some individuals with KFS, treatment may include surgical repair of certain skeletal, auditory, ocular, cardiac, renal or other abnormalities potentially associated with the disorder. For example, in those with cervical spinal cord compression, surgery may be conducted to correct such compression or associated vertebral instability. The surgical procedures performed will depend upon the severity of the anatomical abnormalities, their associated symptoms, and other factors.In addition, some individuals with hearing impairment may benefit from the use of specialized hearing aids. Genetic counseling may also be of benefit for individuals with KFS and their families.
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Therapies of Klippel-Feil Syndrome. Treatment
The treatment of KFS is directed toward the specific symptoms and associated physical findings that are apparent in each individual. Such treatment may require the coordinated efforts of a team of medical professionals who may need to systematically and comprehensively plan an affected individual’s treatment. These professionals may include pediatricians; surgeons; physicians who diagnose and treat disorders of the skeleton, muscles, joints, and related tissues (orthopedists); physicians who specialize in neurological disorders (neurologists); physicians who diagnose and treat heart abnormalities (cardiologists); specialists who assess and treat hearing problems (audiologists); eye specialists (ophthalmologists); and/or other health care professionals.Therapy for KFS can include a variety of conservative measures including the use of cervical collars, braces, traction, non-steroidal anti-inflammatory drugs (NSAIDs) and various pain medications (analgesics).Because some affected individuals may have an increased risk of neurological complications, they should be regularly monitored by physicians. In addition, they should avoid activities that could lead to trauma or injury to cervical vertebrae.In some individuals with KFS, treatment may include surgical repair of certain skeletal, auditory, ocular, cardiac, renal or other abnormalities potentially associated with the disorder. For example, in those with cervical spinal cord compression, surgery may be conducted to correct such compression or associated vertebral instability. The surgical procedures performed will depend upon the severity of the anatomical abnormalities, their associated symptoms, and other factors.In addition, some individuals with hearing impairment may benefit from the use of specialized hearing aids. Genetic counseling may also be of benefit for individuals with KFS and their families.
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Klippel-Feil Syndrome
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Overview of Klippel-Trenaunay Syndrome
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Summary
Klippel-Trenaunay syndrome (KTS) is a rare vascular disorder that is present at birth (congenital) and characterized by three features: cutaneous capillary malformation (“port-wine stain”), lymphatic anomalies and abnormal veins in association with variable overgrowth of soft tissue and bone. KTS occurs most frequently in the lower limb and less commonly in the upper extremity.Introduction
The eponym KTS generated controversy in the medical literature since the first report of the condition in the early 20th century. The French physicians, Klippel and Trenaunay, described patients with capillary stains (improperly called “hemangiomas” at that time), venous varicosities and overgrowth. In the same era, the English dermatologist, Parkes Weber, reported the combination of “hemangiomas” and overgrowth of a limb. For many years, the names of all three physicians were linked as a confusing (and incorrect) term “Klippel-Weber-Trenaunay syndrome,” which unfortunately is sometimes used to this day.Since the latter 20th century, it is well-recognized that Parkes Weber and Klippel-Trenaunay syndromes are entirely different. Parkes Weber syndrome consists of fast-flow, multiple microscopic arteriovenous connections with variable capillary staining of an enlarged limb (usually the lower extremity). In contrast, KTS is a slow flow combined vascular disorder involving abnormal capillaries (C), lymphatics (L) and veins (V). Therefore, many investigators use the abbreviation CLVM, rather than KTS, and restrict the designation for patients who have all three anomalous vascular components. Other authors apply the KTS term more broadly and include patients with only capillary stain (CM) or combined capillary and venous anomalies (CVM) in the lower limb in the absence of lymphatic abnormalities. Now that genetic testing is available, it is possible to more precisely diagnose patients with these various combinations of vascular anomalies.
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Overview of Klippel-Trenaunay Syndrome. Summary
Klippel-Trenaunay syndrome (KTS) is a rare vascular disorder that is present at birth (congenital) and characterized by three features: cutaneous capillary malformation (“port-wine stain”), lymphatic anomalies and abnormal veins in association with variable overgrowth of soft tissue and bone. KTS occurs most frequently in the lower limb and less commonly in the upper extremity.Introduction
The eponym KTS generated controversy in the medical literature since the first report of the condition in the early 20th century. The French physicians, Klippel and Trenaunay, described patients with capillary stains (improperly called “hemangiomas” at that time), venous varicosities and overgrowth. In the same era, the English dermatologist, Parkes Weber, reported the combination of “hemangiomas” and overgrowth of a limb. For many years, the names of all three physicians were linked as a confusing (and incorrect) term “Klippel-Weber-Trenaunay syndrome,” which unfortunately is sometimes used to this day.Since the latter 20th century, it is well-recognized that Parkes Weber and Klippel-Trenaunay syndromes are entirely different. Parkes Weber syndrome consists of fast-flow, multiple microscopic arteriovenous connections with variable capillary staining of an enlarged limb (usually the lower extremity). In contrast, KTS is a slow flow combined vascular disorder involving abnormal capillaries (C), lymphatics (L) and veins (V). Therefore, many investigators use the abbreviation CLVM, rather than KTS, and restrict the designation for patients who have all three anomalous vascular components. Other authors apply the KTS term more broadly and include patients with only capillary stain (CM) or combined capillary and venous anomalies (CVM) in the lower limb in the absence of lymphatic abnormalities. Now that genetic testing is available, it is possible to more precisely diagnose patients with these various combinations of vascular anomalies.
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Klippel-Trenaunay Syndrome
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nord_682_1
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Symptoms of Klippel-Trenaunay Syndrome
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Capillary Malformation (CM)
At birth, KTS presents with scattered, geographic capillary stains. With age, the surface of the CM becomes studded with tiny lymphatic vesicles that often ooze clear fluid and turn black due to intralesional bleeding.Lymphatic Malformation (LM)
LM presents as localized or generalized overgrowth caused by micro- and macrocystic anomalies, sometimes in association with lymphedema. Often there is lymphatic swelling and fatty deposition on the opposite foot. The lymphatic anomalies can also occur in the pelvis, bladder and lower gastrointestinal tract. Lymphatic cysts in the spleen are also common. LM is documented by ultrasonography and/or MRI. Lymphography shows that lymphedema is the result of diminished number or absence of lymphatic channels.
Episodic infections (cellulitis) are common and probably related to poor lymphatic drainage in the limb.Venous Malformation (VM)
Venous abnormalities are always present but variable and involve the entire affected extremity. Typically, there are anomalous embryonic veins called the “marginal system.” Dilatation of superficial veins may not be apparent in infancy but becomes more prominent with age. LM and VM can also involve the pelvic or abdominal organs resulting in bleeding from the rectum, vagina or urinary bladder. Abnormal fatty deposits accompany the venous and lymphatic anomalies.Many patients with extensive abnormal veins have a low-grade hematologic condition called “localized intravascular coagulopathy” (LIC), this can be determined by measuring increased D-dimers in the blood. Stagnant blood in the dilated veins may clot and trigger a generalized bleeding disorder called “disseminated intravascular coagulopathy” (DIC).Overgrowth
Enlargement of the limb can be minimal to extremely distorted. Overgrowth in length often occurs; however, in some patients the affected limb is shorter than normal. Frequently there is enlargement of the opposite foot.
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Symptoms of Klippel-Trenaunay Syndrome. Capillary Malformation (CM)
At birth, KTS presents with scattered, geographic capillary stains. With age, the surface of the CM becomes studded with tiny lymphatic vesicles that often ooze clear fluid and turn black due to intralesional bleeding.Lymphatic Malformation (LM)
LM presents as localized or generalized overgrowth caused by micro- and macrocystic anomalies, sometimes in association with lymphedema. Often there is lymphatic swelling and fatty deposition on the opposite foot. The lymphatic anomalies can also occur in the pelvis, bladder and lower gastrointestinal tract. Lymphatic cysts in the spleen are also common. LM is documented by ultrasonography and/or MRI. Lymphography shows that lymphedema is the result of diminished number or absence of lymphatic channels.
Episodic infections (cellulitis) are common and probably related to poor lymphatic drainage in the limb.Venous Malformation (VM)
Venous abnormalities are always present but variable and involve the entire affected extremity. Typically, there are anomalous embryonic veins called the “marginal system.” Dilatation of superficial veins may not be apparent in infancy but becomes more prominent with age. LM and VM can also involve the pelvic or abdominal organs resulting in bleeding from the rectum, vagina or urinary bladder. Abnormal fatty deposits accompany the venous and lymphatic anomalies.Many patients with extensive abnormal veins have a low-grade hematologic condition called “localized intravascular coagulopathy” (LIC), this can be determined by measuring increased D-dimers in the blood. Stagnant blood in the dilated veins may clot and trigger a generalized bleeding disorder called “disseminated intravascular coagulopathy” (DIC).Overgrowth
Enlargement of the limb can be minimal to extremely distorted. Overgrowth in length often occurs; however, in some patients the affected limb is shorter than normal. Frequently there is enlargement of the opposite foot.
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Klippel-Trenaunay Syndrome
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nord_682_2
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Causes of Klippel-Trenaunay Syndrome
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KTS is caused by a change (variant or mutation) in the PIK3CA gene. This mutation does not occur in the germ cells (egg and sperm) but only in the body cells after fertilization. Therefore, KTS is not an inherited condition and is not passed on in a family.
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Causes of Klippel-Trenaunay Syndrome. KTS is caused by a change (variant or mutation) in the PIK3CA gene. This mutation does not occur in the germ cells (egg and sperm) but only in the body cells after fertilization. Therefore, KTS is not an inherited condition and is not passed on in a family.
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Klippel-Trenaunay Syndrome
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nord_682_3
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Affects of Klippel-Trenaunay Syndrome
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Klippel-Trenaunay syndrome is a rare disorder affecting males and females in equal numbers. The disorder occurs worldwide.
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Affects of Klippel-Trenaunay Syndrome. Klippel-Trenaunay syndrome is a rare disorder affecting males and females in equal numbers. The disorder occurs worldwide.
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Klippel-Trenaunay Syndrome
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Related disorders of Klippel-Trenaunay Syndrome
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KTS can be confused with other combined vascular disorders.Parkes Weber syndrome
Tiny arteriovenous shunts in the thigh region have been found in KTS; however, these are not clinically important. In contrast, multiple arteriovenous shunts and increased blood flow in the upper or lower limb are the hallmarks of Parkes Weber syndrome. This is an autosomal dominant genetic condition caused by a mutation in the RASA1 gene and genetic testing is available to confirm the diagnosis.CLOVES syndrome
In the past, patients with CLVM of the trunk were usually diagnosed as having KTS. It is now recognized that many of these patients have another, specific disorder of combined vascular anomalies and enlarged tissues designated by the acronym CLOVES = congenital lipomatous overgrowth with vascular anomalies, epidermal nevus and skeletal anomalies. CLOVES is considered to be KTS of the trunk. It is caused by a somatic mutation in the PIK3CA gene and also not inherited.
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Related disorders of Klippel-Trenaunay Syndrome. KTS can be confused with other combined vascular disorders.Parkes Weber syndrome
Tiny arteriovenous shunts in the thigh region have been found in KTS; however, these are not clinically important. In contrast, multiple arteriovenous shunts and increased blood flow in the upper or lower limb are the hallmarks of Parkes Weber syndrome. This is an autosomal dominant genetic condition caused by a mutation in the RASA1 gene and genetic testing is available to confirm the diagnosis.CLOVES syndrome
In the past, patients with CLVM of the trunk were usually diagnosed as having KTS. It is now recognized that many of these patients have another, specific disorder of combined vascular anomalies and enlarged tissues designated by the acronym CLOVES = congenital lipomatous overgrowth with vascular anomalies, epidermal nevus and skeletal anomalies. CLOVES is considered to be KTS of the trunk. It is caused by a somatic mutation in the PIK3CA gene and also not inherited.
| 682 |
Klippel-Trenaunay Syndrome
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nord_682_5
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Diagnosis of Klippel-Trenaunay Syndrome
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KTS is diagnosed based on physical signs and symptoms. Computed axial tomography (CAT) and magnetic resonance imaging (MRI) scans, and color doppler studies may be useful in determining the extent of the condition and how best to manage it.
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Diagnosis of Klippel-Trenaunay Syndrome. KTS is diagnosed based on physical signs and symptoms. Computed axial tomography (CAT) and magnetic resonance imaging (MRI) scans, and color doppler studies may be useful in determining the extent of the condition and how best to manage it.
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Klippel-Trenaunay Syndrome
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Therapies of Klippel-Trenaunay Syndrome
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Treatment
Recommended management for the following malformations associated with KTS:Capillary Malformation
The vesicles in the CM can be improved by laser therapy, sclerotherapy or sometimes
resection and closure of the skin or replacement with a split-thickness skin graft.
Lymphatic Malformation
Macrocystic LM can be deflated by sclerotherapy (injection of irritating solutions). Microcystic LM is less responsive to sclerotherapy and may require resection.Venous Malformation
Blood stagnates in large, dilated veins, and thus there is a risk for initiating a clotting disorder or thrombosis and pulmonary embolism. Anticoagulation with heparin (subcutaneously injected) is often necessary prior to radiologic or surgical intervention. Conversion to a direct oral anticoagulant (DOAC) may be considered. Large venous channels can be obliterated by sclerotherapy or endovascular laser. Chronic bleeding from the colon may require surgical resection. Bleeding lesions in the bladder can be controlled by laser through a cystoscope. An elastic compressive stocking is useful to minimize discomfort and swelling due to venous distension in the limb.Overgrowth
Enlarged toes may require amputation to narrow the foot and permit footwear. Discrepancy in leg length can be corrected by inserting a lift in the shoe on the normal foot to prevent compensatory curvature of the spine (scoliosis). Surgical closure of the growth plate at the knee (epiphysiodesis) is often needed to equalize leg length.
Staged contour resection is possible to diminish girth of the limb. These procedures are less effective if the abnormal fat and vasculature extends beneath the deep fascia of the leg into the muscle layer.
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Therapies of Klippel-Trenaunay Syndrome. Treatment
Recommended management for the following malformations associated with KTS:Capillary Malformation
The vesicles in the CM can be improved by laser therapy, sclerotherapy or sometimes
resection and closure of the skin or replacement with a split-thickness skin graft.
Lymphatic Malformation
Macrocystic LM can be deflated by sclerotherapy (injection of irritating solutions). Microcystic LM is less responsive to sclerotherapy and may require resection.Venous Malformation
Blood stagnates in large, dilated veins, and thus there is a risk for initiating a clotting disorder or thrombosis and pulmonary embolism. Anticoagulation with heparin (subcutaneously injected) is often necessary prior to radiologic or surgical intervention. Conversion to a direct oral anticoagulant (DOAC) may be considered. Large venous channels can be obliterated by sclerotherapy or endovascular laser. Chronic bleeding from the colon may require surgical resection. Bleeding lesions in the bladder can be controlled by laser through a cystoscope. An elastic compressive stocking is useful to minimize discomfort and swelling due to venous distension in the limb.Overgrowth
Enlarged toes may require amputation to narrow the foot and permit footwear. Discrepancy in leg length can be corrected by inserting a lift in the shoe on the normal foot to prevent compensatory curvature of the spine (scoliosis). Surgical closure of the growth plate at the knee (epiphysiodesis) is often needed to equalize leg length.
Staged contour resection is possible to diminish girth of the limb. These procedures are less effective if the abnormal fat and vasculature extends beneath the deep fascia of the leg into the muscle layer.
| 682 |
Klippel-Trenaunay Syndrome
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nord_683_0
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Overview of Klüver-Bucy Syndrome
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Klüver-Bucy syndrome is a very rare cerebral neurological disorder associated with damage to both temporal lobes resulting in abnormalities in memory, social and sexual functioning and idiosyncratic behaviors.
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Overview of Klüver-Bucy Syndrome. Klüver-Bucy syndrome is a very rare cerebral neurological disorder associated with damage to both temporal lobes resulting in abnormalities in memory, social and sexual functioning and idiosyncratic behaviors.
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Klüver-Bucy Syndrome
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nord_683_1
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Symptoms of Klüver-Bucy Syndrome
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Major symptoms may include excessive oral tendencies with an urge to put all kinds of objects into the mouth, hypermetamorophosis (a need to explore everything), memory loss, emotional changes, extreme sexual behavior, indifference, placidity, visual distractibility and visual agnosia (difficulty identifying and processing visual information). An almost uncontrollable appetite for food may also be noted. There may also be other symptoms associated with dementia (loss of reason) as well.
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Symptoms of Klüver-Bucy Syndrome. Major symptoms may include excessive oral tendencies with an urge to put all kinds of objects into the mouth, hypermetamorophosis (a need to explore everything), memory loss, emotional changes, extreme sexual behavior, indifference, placidity, visual distractibility and visual agnosia (difficulty identifying and processing visual information). An almost uncontrollable appetite for food may also be noted. There may also be other symptoms associated with dementia (loss of reason) as well.
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Klüver-Bucy Syndrome
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nord_683_2
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Causes of Klüver-Bucy Syndrome
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Klüver-Bucy syndrome is the result of damage to the temporal lobes of the brain. This may be the result of trauma to the brain itself, or the result of other degenerative brain diseases, tumors, or it can be caused by some brain infections, most commonly herpes simplex encephalitis (a viral brain infection).
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Causes of Klüver-Bucy Syndrome. Klüver-Bucy syndrome is the result of damage to the temporal lobes of the brain. This may be the result of trauma to the brain itself, or the result of other degenerative brain diseases, tumors, or it can be caused by some brain infections, most commonly herpes simplex encephalitis (a viral brain infection).
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Klüver-Bucy Syndrome
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nord_683_3
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Affects of Klüver-Bucy Syndrome
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Klüver-Bucy syndrome is a very rare disease that affects males and females equally.
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Affects of Klüver-Bucy Syndrome. Klüver-Bucy syndrome is a very rare disease that affects males and females equally.
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Klüver-Bucy Syndrome
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nord_683_4
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Related disorders of Klüver-Bucy Syndrome
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Symptoms of the following disorders can be similar to those of Klüver-Bucy syndrome. Comparisons may be useful for a differential diagnosis:Frontotemporal degeneration is a very rare progressive neurological disease initially predominately affecting the frontal and temporal lobes of the brain. It is characterized by progressive deterioration of intellect with changes in behavior and personality. The memory is usually intact in the early stages of the disease and there is less disorientation than in Alzheimer’s disease. However, in later stages there is loss of motor control as well as confusion and severe dementia. (For more information on this disorder, choose “frontotemporal degeneration” as your search term in the Rare Disease Database.)Alzheimer disease is a common progressive disorder of the brain affecting memory, thought and language. Groups of nerve endings in the cortex of the brains of people with Alzheimer’s degenerate and disrupt the passage of electrochemical signals between the cells. Affected individuals become increasingly forgetful. As memory losses increase, personality, mood and behavior also tend to change. Judgment, concentration, speech and physical coordination may also be affected. (For more information on this disorder, choose “Alzheimer” as your search term in the Rare Disease Database.)Korsakoff syndrome is a deficiency of vitamin B-1 that leads to cardiovascular, central and peripheral nervous system disturbances. Early symptoms of Korsakoff’s syndrome include fatigue, irritation, poor memory, difficulty sleeping, chest pain, abdominal discomfort, poor appetite and constipation. Later symptoms are principally cardiovascular and neurological. (For more information on this disorder, choose “Korsakoff” as your search term in the Rare Disease Database.)
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Related disorders of Klüver-Bucy Syndrome. Symptoms of the following disorders can be similar to those of Klüver-Bucy syndrome. Comparisons may be useful for a differential diagnosis:Frontotemporal degeneration is a very rare progressive neurological disease initially predominately affecting the frontal and temporal lobes of the brain. It is characterized by progressive deterioration of intellect with changes in behavior and personality. The memory is usually intact in the early stages of the disease and there is less disorientation than in Alzheimer’s disease. However, in later stages there is loss of motor control as well as confusion and severe dementia. (For more information on this disorder, choose “frontotemporal degeneration” as your search term in the Rare Disease Database.)Alzheimer disease is a common progressive disorder of the brain affecting memory, thought and language. Groups of nerve endings in the cortex of the brains of people with Alzheimer’s degenerate and disrupt the passage of electrochemical signals between the cells. Affected individuals become increasingly forgetful. As memory losses increase, personality, mood and behavior also tend to change. Judgment, concentration, speech and physical coordination may also be affected. (For more information on this disorder, choose “Alzheimer” as your search term in the Rare Disease Database.)Korsakoff syndrome is a deficiency of vitamin B-1 that leads to cardiovascular, central and peripheral nervous system disturbances. Early symptoms of Korsakoff’s syndrome include fatigue, irritation, poor memory, difficulty sleeping, chest pain, abdominal discomfort, poor appetite and constipation. Later symptoms are principally cardiovascular and neurological. (For more information on this disorder, choose “Korsakoff” as your search term in the Rare Disease Database.)
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Klüver-Bucy Syndrome
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nord_683_5
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Diagnosis of Klüver-Bucy Syndrome
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Diagnosis of Klüver-Bucy Syndrome.
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Klüver-Bucy Syndrome
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Therapies of Klüver-Bucy Syndrome
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Treatment of Klüver-Bucy syndrome is supportive and psychotropics that may be effective for some of the associated symptoms.
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Therapies of Klüver-Bucy Syndrome. Treatment of Klüver-Bucy syndrome is supportive and psychotropics that may be effective for some of the associated symptoms.
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Klüver-Bucy Syndrome
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nord_684_0
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Overview of Kniest Dysplasia
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Kniest dysplasia is one of several forms of dwarfism that is caused by a change (mutation) in a gene known as COL2A1. This gene is involved in the production of a particular protein that forms type 2 collagen, which is essential for the normal development of bones and other connective tissue. Changes in the composition of type 2 collagen lead to abnormal skeletal growth and, thus, to a variety of dwarfing conditions known as skeletal dysplasias.Some of the signs and symptoms of Kniest dysplasia, such as short stature, enlarged knees, and cleft palate, are usually present at birth. Other characteristics may not appear for two or three years.
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Overview of Kniest Dysplasia. Kniest dysplasia is one of several forms of dwarfism that is caused by a change (mutation) in a gene known as COL2A1. This gene is involved in the production of a particular protein that forms type 2 collagen, which is essential for the normal development of bones and other connective tissue. Changes in the composition of type 2 collagen lead to abnormal skeletal growth and, thus, to a variety of dwarfing conditions known as skeletal dysplasias.Some of the signs and symptoms of Kniest dysplasia, such as short stature, enlarged knees, and cleft palate, are usually present at birth. Other characteristics may not appear for two or three years.
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Kniest Dysplasia
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nord_684_1
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Symptoms of Kniest Dysplasia
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People with Kniest dysplasia are known to have an unusually short stature; short, deformed arms and legs; a chest that is “barrel-shaped” and abnormally short; and a relatively long trunk. Later in life, short trunk dwarfism develops due to curvature of the spine and enlargement of the joints.People with Kniest dysplasia have an unusually flat face with protruding eyes, and a low nasal bridge. A cleft palate may also be present, and speech impairment may occur. Involvement of the eyes may include nearsightedness (myopia) that can progress to retinal detachment and cataracts. Dislocated eye lenses, drooping of the eyelids (blepharoptosis), possible blindness with disease of the optic nerve, involvement of the spine or brain, and glaucoma may also occur. As the person matures, the joints may become enlarged causing limited movement and pain. Limbs are short, often bowed, and there may be irregularities of the ends of the long bones (epiphyses). Contracted hips may cause walking difficulties and there may be a congenital flattening of the vertebrae and a hump of the spine. Affected individuals may sometimes exhibit hernias of the groin (inguinal) and navel (umbilical), frequent ear infections, slowed motor development and hearing loss.Also characteristic of Kniest dysplasia are holes in the individual's cartilage, creating a “Swiss-cheese” appearance in cartilage that is significant for diagnostic purposes. One variant of Kniest dysplasia that is extremely rare is known as Kniest-like dysplasia with pursed lips and ectopia lentis or Burton disease. It is characterized by a small mouth (microstomia) and pursed lips. In this variant, the collagen does not have the holes mentioned above.
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Symptoms of Kniest Dysplasia. People with Kniest dysplasia are known to have an unusually short stature; short, deformed arms and legs; a chest that is “barrel-shaped” and abnormally short; and a relatively long trunk. Later in life, short trunk dwarfism develops due to curvature of the spine and enlargement of the joints.People with Kniest dysplasia have an unusually flat face with protruding eyes, and a low nasal bridge. A cleft palate may also be present, and speech impairment may occur. Involvement of the eyes may include nearsightedness (myopia) that can progress to retinal detachment and cataracts. Dislocated eye lenses, drooping of the eyelids (blepharoptosis), possible blindness with disease of the optic nerve, involvement of the spine or brain, and glaucoma may also occur. As the person matures, the joints may become enlarged causing limited movement and pain. Limbs are short, often bowed, and there may be irregularities of the ends of the long bones (epiphyses). Contracted hips may cause walking difficulties and there may be a congenital flattening of the vertebrae and a hump of the spine. Affected individuals may sometimes exhibit hernias of the groin (inguinal) and navel (umbilical), frequent ear infections, slowed motor development and hearing loss.Also characteristic of Kniest dysplasia are holes in the individual's cartilage, creating a “Swiss-cheese” appearance in cartilage that is significant for diagnostic purposes. One variant of Kniest dysplasia that is extremely rare is known as Kniest-like dysplasia with pursed lips and ectopia lentis or Burton disease. It is characterized by a small mouth (microstomia) and pursed lips. In this variant, the collagen does not have the holes mentioned above.
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Kniest Dysplasia
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nord_684_2
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Causes of Kniest Dysplasia
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Kniest dysplasia is the result of a change (mutation) in the gene known as COL2A1, which produces (codes for) the protein that forms collagen type 2. This gene has been mapped to the following gene map locus: 12q13.11-q13.20. The disorder is transmitted from parent to child as an autosomal dominant trait. In some instances, the mutation appears to be spontaneous, occurring for no apparent reason. 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, “12q13.11-q13.20” refers to a region between bands 13.11 and 13.20 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. 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.Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. All individuals carry a few abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females have two X chromosomes but one of the X chromosomes is “turned off” and all of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder because it is usually the X chromosome with the abnormal gene that is “turned off”. A male has one X chromosome and if he inherits an X chromosome that contains a disease gene, he will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease, and a 25% chance to have an unaffected son. X-linked dominant disorders are also 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 Kniest Dysplasia. Kniest dysplasia is the result of a change (mutation) in the gene known as COL2A1, which produces (codes for) the protein that forms collagen type 2. This gene has been mapped to the following gene map locus: 12q13.11-q13.20. The disorder is transmitted from parent to child as an autosomal dominant trait. In some instances, the mutation appears to be spontaneous, occurring for no apparent reason. 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, “12q13.11-q13.20” refers to a region between bands 13.11 and 13.20 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. 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.Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. All individuals carry a few abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females have two X chromosomes but one of the X chromosomes is “turned off” and all of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder because it is usually the X chromosome with the abnormal gene that is “turned off”. A male has one X chromosome and if he inherits an X chromosome that contains a disease gene, he will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease, and a 25% chance to have an unaffected son. X-linked dominant disorders are also 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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Kniest Dysplasia
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nord_684_3
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Affects of Kniest Dysplasia
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Kniest Syndrome is a rare disorder that affects males and females in equal numbers.
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Affects of Kniest Dysplasia. Kniest Syndrome is a rare disorder that affects males and females in equal numbers.
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Kniest Dysplasia
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nord_684_4
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Related disorders of Kniest Dysplasia
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Symptoms of the following disorders can be similar to those of Kniest dysplasia. Comparisons may be useful for a differential diagnosis:Hypochondrogenesis (underdevelopment or lack of development of cartilage) is characterized by short-limb dwarfism, swelling of the body and face, widely spaced eyes (hypertelorism), a flat face and cleft palate. Respiratory distress may develop, due to the small rib cage, and is a significant concern. This disorder is an autosomal dominant trait. The mutation may be spontaneous in many cases.Spondyloepiphyseal dysplasia congenita (SEDc) is characterized by short stature, clubfeet, and/or cleft palate. Other characteristics include a flat face, widely spaced eyes, barrel-shaped chest, and short neck, especially as the child grows older. The inheritance pattern is autosomal dominant. Spondyloepimetaphyseal dysplasia (SEMD) is a disorder that resembles Morquio syndrome, as aggravated by curvature of the spine and a pigeon-breast. As in SEDc, cleft palate and retinal detachment are not uncommon. Morquio syndrome is a metabolic disorder characterized by an accumulation of keratan sulfate. Bony abnormalities of the head, chest, hands, knees, and spine may occur as a result of this defect. Intelligence is usually normal. The bony abnormalities of the spine can result in spinal cord compression. Surgery to stabilize the upper cervical spine, usually by spinal fusion, can prevent severe paralysis. There may also be enlargement of the liver, curvature of the spine (thoracic kyphoscoliosis), a back flow of blood from the aortic valve of the heart into the left ventricle of the heart (aortic regurgitation), as well as loss of hearing. (For more information on this disorder, choose “Morquio” as your search term in the Rare Disease Database.) Metatropic dwarfism, type I, is a rare genetic disorder characterized by extremely small stature, with short and deformed arms and legs. Other characteristics of this disorder are a narrow thorax with short ribs, prominent joints with restricted mobility of the knees and hips, and unusual increased extension of the finger joints. There is also an unusually long torso, which later develops into short trunk dwarfism due to curvature of the spine and enlargement of the joints. This rare disorder is often recognized at birth because the spinal deformities tend to be severe during infancy. (For information about other forms of dwarfism choose “Dwarfism” as your search term in the Rare Disease Database.)
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Related disorders of Kniest Dysplasia. Symptoms of the following disorders can be similar to those of Kniest dysplasia. Comparisons may be useful for a differential diagnosis:Hypochondrogenesis (underdevelopment or lack of development of cartilage) is characterized by short-limb dwarfism, swelling of the body and face, widely spaced eyes (hypertelorism), a flat face and cleft palate. Respiratory distress may develop, due to the small rib cage, and is a significant concern. This disorder is an autosomal dominant trait. The mutation may be spontaneous in many cases.Spondyloepiphyseal dysplasia congenita (SEDc) is characterized by short stature, clubfeet, and/or cleft palate. Other characteristics include a flat face, widely spaced eyes, barrel-shaped chest, and short neck, especially as the child grows older. The inheritance pattern is autosomal dominant. Spondyloepimetaphyseal dysplasia (SEMD) is a disorder that resembles Morquio syndrome, as aggravated by curvature of the spine and a pigeon-breast. As in SEDc, cleft palate and retinal detachment are not uncommon. Morquio syndrome is a metabolic disorder characterized by an accumulation of keratan sulfate. Bony abnormalities of the head, chest, hands, knees, and spine may occur as a result of this defect. Intelligence is usually normal. The bony abnormalities of the spine can result in spinal cord compression. Surgery to stabilize the upper cervical spine, usually by spinal fusion, can prevent severe paralysis. There may also be enlargement of the liver, curvature of the spine (thoracic kyphoscoliosis), a back flow of blood from the aortic valve of the heart into the left ventricle of the heart (aortic regurgitation), as well as loss of hearing. (For more information on this disorder, choose “Morquio” as your search term in the Rare Disease Database.) Metatropic dwarfism, type I, is a rare genetic disorder characterized by extremely small stature, with short and deformed arms and legs. Other characteristics of this disorder are a narrow thorax with short ribs, prominent joints with restricted mobility of the knees and hips, and unusual increased extension of the finger joints. There is also an unusually long torso, which later develops into short trunk dwarfism due to curvature of the spine and enlargement of the joints. This rare disorder is often recognized at birth because the spinal deformities tend to be severe during infancy. (For information about other forms of dwarfism choose “Dwarfism” as your search term in the Rare Disease Database.)
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Kniest Dysplasia
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nord_684_5
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Diagnosis of Kniest Dysplasia
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Newborns with this disorder are clearly in distress so that x-rays may be ordered. Diagnosis may frequently be made on the basis of the radiographs developed, while a bone biopsy usually clarifies more ambiguous cases.
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Diagnosis of Kniest Dysplasia. Newborns with this disorder are clearly in distress so that x-rays may be ordered. Diagnosis may frequently be made on the basis of the radiographs developed, while a bone biopsy usually clarifies more ambiguous cases.
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Kniest Dysplasia
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nord_684_6
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Therapies of Kniest Dysplasia
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TreatmentTreatment of Kniest syndrome usually consists of stabilization of lax joints, surgery to prevent contractures, and repair of retinal detachments and cleft palate. Genetic counseling may be of benefit for patients and their families. Other treatment is symptomatic and supportive.
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Therapies of Kniest Dysplasia. TreatmentTreatment of Kniest syndrome usually consists of stabilization of lax joints, surgery to prevent contractures, and repair of retinal detachments and cleft palate. Genetic counseling may be of benefit for patients and their families. Other treatment is symptomatic and supportive.
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Kniest Dysplasia
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nord_685_0
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Overview of Kohler Disease
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Kohler disease is a rare bone disorder of the foot in children that may be the result of stress-related compression at a critical time during the period of growth. It is characterized by limping caused by pain and swelling in the foot. It most often occurs in children between the ages 3-7, and affects males five times more often than females. Usually, just one foot is affected so children typically walk on the side portion of the foot.Children appear to grow out of the disorder, and the affected bones usually regain their size, density and structure within three months. Rarely, symptoms may last as long as two years.
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Overview of Kohler Disease. Kohler disease is a rare bone disorder of the foot in children that may be the result of stress-related compression at a critical time during the period of growth. It is characterized by limping caused by pain and swelling in the foot. It most often occurs in children between the ages 3-7, and affects males five times more often than females. Usually, just one foot is affected so children typically walk on the side portion of the foot.Children appear to grow out of the disorder, and the affected bones usually regain their size, density and structure within three months. Rarely, symptoms may last as long as two years.
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Symptoms of Kohler Disease
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Kohler disease is a rare bone disorder characterized by a painful swollen foot. The foot is especially tender along the length of the arch. It may include redness of the affected area. Putting weight on the foot or walking is difficult, causing further discomfort and a limp. For reasons that are not understood, the flow of blood to one of the bones in the foot (navicular bone) is interrupted, resulting in progressive degeneration of that bone. In a relatively short time, however, the bone heals itself.Usually, symptoms will be mild, and patients may not seek treatment until the pain and swelling have persisted for a while.
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Symptoms of Kohler Disease. Kohler disease is a rare bone disorder characterized by a painful swollen foot. The foot is especially tender along the length of the arch. It may include redness of the affected area. Putting weight on the foot or walking is difficult, causing further discomfort and a limp. For reasons that are not understood, the flow of blood to one of the bones in the foot (navicular bone) is interrupted, resulting in progressive degeneration of that bone. In a relatively short time, however, the bone heals itself.Usually, symptoms will be mild, and patients may not seek treatment until the pain and swelling have persisted for a while.
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Causes of Kohler Disease
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The exact cause of Kohler disease is unknown.Some orthopedic specialists think that Kohler disease may be related to an injury in the area around the navicular bone in the foot and may be the result of delayed bone formation (ossification). Bone ossification usually begins at age 18-24 months in girls and at age 24 to 30 months in boys. Structural weakness might result from an increase in the ratio of cartilage to bone. Since the navicular bone is part of the mechanism by which the foot moves (articulation), it is subject to weight-bearing pressures and stresses from twisting and turning.Under normal circumstances, the navicular bone is served by a blood vessel from which smaller arteries supply blood to the regions of bone growth. At around the ages of 4-6, the blood supply to these regions of bone growth increases as other blood vessels reach them. If ossification is delayed and the child gains weight, the effect is to compress the blood vessels, thus causing tissue destruction (ischemia).It has been suggested that genetic factors may play a role in the development of Kohler disease, but a specific gene has not been found to be associated with this disease.
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Causes of Kohler Disease. The exact cause of Kohler disease is unknown.Some orthopedic specialists think that Kohler disease may be related to an injury in the area around the navicular bone in the foot and may be the result of delayed bone formation (ossification). Bone ossification usually begins at age 18-24 months in girls and at age 24 to 30 months in boys. Structural weakness might result from an increase in the ratio of cartilage to bone. Since the navicular bone is part of the mechanism by which the foot moves (articulation), it is subject to weight-bearing pressures and stresses from twisting and turning.Under normal circumstances, the navicular bone is served by a blood vessel from which smaller arteries supply blood to the regions of bone growth. At around the ages of 4-6, the blood supply to these regions of bone growth increases as other blood vessels reach them. If ossification is delayed and the child gains weight, the effect is to compress the blood vessels, thus causing tissue destruction (ischemia).It has been suggested that genetic factors may play a role in the development of Kohler disease, but a specific gene has not been found to be associated with this disease.
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Affects of Kohler Disease
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Kohler disease is a rare bone disorder of the foot that affects males more often than females. The disorder strikes children between the ages of 1 and 10 years with a peak occurring at ages 3 to 7 years. The center of bone growth that is affected in Kohler disease develops in young girls about one year before it appears in young boys. Nevertheless, the disorder is five times more prevalent in boys than girls.The incidence of the disorder in the population is estimated to be less than 2%.
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Affects of Kohler Disease. Kohler disease is a rare bone disorder of the foot that affects males more often than females. The disorder strikes children between the ages of 1 and 10 years with a peak occurring at ages 3 to 7 years. The center of bone growth that is affected in Kohler disease develops in young girls about one year before it appears in young boys. Nevertheless, the disorder is five times more prevalent in boys than girls.The incidence of the disorder in the population is estimated to be less than 2%.
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Related disorders of Kohler Disease
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Symptoms of the following disorders can be similar to those of Kohler disease. Comparisons may be useful for a differential diagnosis:Freiberg Disease is a rare bone disorder characterized by a pain in the area of the second or third metatarsals (long bones of the foot). Putting weight on the foot or walking can cause further discomfort and lead to a limp. This condition is usually diagnosed during adolescence or in the twenties. Grierson-Gopalan syndrome is characterized by burning sensations in the feet, and aching and cramp-like pains in the soles of the feet (and possibly palms of the hands. Patients often experience a sensation like pins and needles in the feet. This condition can be related to a vitamin B deficiency.
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Related disorders of Kohler Disease. Symptoms of the following disorders can be similar to those of Kohler disease. Comparisons may be useful for a differential diagnosis:Freiberg Disease is a rare bone disorder characterized by a pain in the area of the second or third metatarsals (long bones of the foot). Putting weight on the foot or walking can cause further discomfort and lead to a limp. This condition is usually diagnosed during adolescence or in the twenties. Grierson-Gopalan syndrome is characterized by burning sensations in the feet, and aching and cramp-like pains in the soles of the feet (and possibly palms of the hands. Patients often experience a sensation like pins and needles in the feet. This condition can be related to a vitamin B deficiency.
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