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nord_285_5 | Diagnosis of Coffin Siris Syndrome | CSS should be suspected in newborns with underdeveloped nails and short fifth fingers and distinctive facial features. The facial features may become more apparent as the child grows. A diagnosis is based upon a thorough clinical evaluation and characteristic physical findings. However, physical features of CSS may be more variable as more individuals are diagnosed. Specialized testing may be conducted to detect certain findings that may be associated with the disorder. Diagnostic criteria were proposed in 2012 noting that most affected individuals have short fifth fingers with absent or underdeveloped nails, developmental and/or cognitive delays, and facial features such as a wide mouth and broad nose. Given the recent discovery of the genetic mutations causing CSS, diagnostic criteria will likely evolve to include clinical evaluations and molecular testing.It is possible that a diagnosis of CSS may be suggested before birth (prenatally) based upon specialized tests such as ultrasound. During fetal ultrasonography, reflected sound waves are used to generate an image of the developing fetus. Ultrasound studies may reveal characteristic findings such as cardiac or kidney malformations and intrauterine growth retardation, which may be associated with the disorder.If a disease-causing mutation has been identified in an affected family member, molecular testing can be done on the fetus. This involves the removal of fetal cells through chorionic villus sampling (performed at 10 to 12 weeks gestation with cells removed from the placenta) or amniocentesis (performed at 15 to 18 weeks gestation with cells removed from the amniotic fluid). DNA extracted from the fetal cells is then examined to see if the mutation is present in the fetus.Clinical Testing and WorkupIf indicated, further examinations and specialized imaging techniques are recommended to establish the extent of the disorder. For example, an MRI (magnetic resonance imaging) may be used to detect structural abnormalities, such as in the brain. During an MRI, radio waves and a magnetic field are used to generate an image. X-rays of the hands can be performed to confirm the underdevelopment or absence of the end bones in the fifth fingers. Echocardiograms, which are a type of ultrasound, can be used to generate images of the heart to detect any cardiac abnormalities that may be present. Other examinations can include developmental examinations, dietary evaluations and eye and hearing examinations.Once diagnosed, individuals with CSS should have yearly follow-up exams. This includes evaluation by a pediatrician to assess developmental progress and to determine the need for any educational or therapeutic interventions and follow-ups with other specialists to track any feeding, gastrointestinal, vision or hearing abnormalities | Diagnosis of Coffin Siris Syndrome. CSS should be suspected in newborns with underdeveloped nails and short fifth fingers and distinctive facial features. The facial features may become more apparent as the child grows. A diagnosis is based upon a thorough clinical evaluation and characteristic physical findings. However, physical features of CSS may be more variable as more individuals are diagnosed. Specialized testing may be conducted to detect certain findings that may be associated with the disorder. Diagnostic criteria were proposed in 2012 noting that most affected individuals have short fifth fingers with absent or underdeveloped nails, developmental and/or cognitive delays, and facial features such as a wide mouth and broad nose. Given the recent discovery of the genetic mutations causing CSS, diagnostic criteria will likely evolve to include clinical evaluations and molecular testing.It is possible that a diagnosis of CSS may be suggested before birth (prenatally) based upon specialized tests such as ultrasound. During fetal ultrasonography, reflected sound waves are used to generate an image of the developing fetus. Ultrasound studies may reveal characteristic findings such as cardiac or kidney malformations and intrauterine growth retardation, which may be associated with the disorder.If a disease-causing mutation has been identified in an affected family member, molecular testing can be done on the fetus. This involves the removal of fetal cells through chorionic villus sampling (performed at 10 to 12 weeks gestation with cells removed from the placenta) or amniocentesis (performed at 15 to 18 weeks gestation with cells removed from the amniotic fluid). DNA extracted from the fetal cells is then examined to see if the mutation is present in the fetus.Clinical Testing and WorkupIf indicated, further examinations and specialized imaging techniques are recommended to establish the extent of the disorder. For example, an MRI (magnetic resonance imaging) may be used to detect structural abnormalities, such as in the brain. During an MRI, radio waves and a magnetic field are used to generate an image. X-rays of the hands can be performed to confirm the underdevelopment or absence of the end bones in the fifth fingers. Echocardiograms, which are a type of ultrasound, can be used to generate images of the heart to detect any cardiac abnormalities that may be present. Other examinations can include developmental examinations, dietary evaluations and eye and hearing examinations.Once diagnosed, individuals with CSS should have yearly follow-up exams. This includes evaluation by a pediatrician to assess developmental progress and to determine the need for any educational or therapeutic interventions and follow-ups with other specialists to track any feeding, gastrointestinal, vision or hearing abnormalities | 285 | Coffin Siris Syndrome |
nord_285_6 | Therapies of Coffin Siris Syndrome | TreatmentThe treatment of CSS is directed toward the specific features of 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 child’s treatment. These professionals may include pediatricians; physicians who specialize in disorders of the skeleton, joints, muscles, and related tissues (orthopedists); physicians who diagnose and treat heart abnormalities (cardiologists); physicians who specialize in digestive abnormalities; physical therapists; geneticists and/or other health care professionals.Treatment may include surgical repair of certain craniofacial, skeletal, cardiac or other abnormalities that may be present. The surgical procedures performed will depend upon the severity of the anatomical abnormalities, their associated symptoms and other factors.In addition, in those with choanal atresia, surgery or other appropriate methods may be required to decrease the airway obstruction or correct the malformation. If Dandy-Walker malformation is present, treatment may include surgical implantation of a specialized device (shunt) to drain excess cerebrospinal fluid (CSF) away from the brain and into another part of the body where the CSF can be absorbed. During infancy, treatment may also require measures to help prevent or aggressively treat respiratory infections.Early intervention may be important in ensuring that affected children reach their potential. Special services that may be benefit developmental outcomes include special education, physical, speech or occupational therapy, or other social, and/or vocational services. Additional treatments to assist affected children can include eyeglasses, hearing aids and nutritional supplements. If needed, the placement of a gastrostomy tube (a tube inserted through the abdomen to deliver nutrition directly to the stomach) can help with feeding difficulties.Genetic counseling is recommended for individuals with CSS and their families. Other treatment is symptomatic and supportive. | Therapies of Coffin Siris Syndrome. TreatmentThe treatment of CSS is directed toward the specific features of 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 child’s treatment. These professionals may include pediatricians; physicians who specialize in disorders of the skeleton, joints, muscles, and related tissues (orthopedists); physicians who diagnose and treat heart abnormalities (cardiologists); physicians who specialize in digestive abnormalities; physical therapists; geneticists and/or other health care professionals.Treatment may include surgical repair of certain craniofacial, skeletal, cardiac or other abnormalities that may be present. The surgical procedures performed will depend upon the severity of the anatomical abnormalities, their associated symptoms and other factors.In addition, in those with choanal atresia, surgery or other appropriate methods may be required to decrease the airway obstruction or correct the malformation. If Dandy-Walker malformation is present, treatment may include surgical implantation of a specialized device (shunt) to drain excess cerebrospinal fluid (CSF) away from the brain and into another part of the body where the CSF can be absorbed. During infancy, treatment may also require measures to help prevent or aggressively treat respiratory infections.Early intervention may be important in ensuring that affected children reach their potential. Special services that may be benefit developmental outcomes include special education, physical, speech or occupational therapy, or other social, and/or vocational services. Additional treatments to assist affected children can include eyeglasses, hearing aids and nutritional supplements. If needed, the placement of a gastrostomy tube (a tube inserted through the abdomen to deliver nutrition directly to the stomach) can help with feeding difficulties.Genetic counseling is recommended for individuals with CSS and their families. Other treatment is symptomatic and supportive. | 285 | Coffin Siris Syndrome |
nord_286_0 | Overview of Cogan Reese Syndrome | Cogan-Reese syndrome is an extremely rare eye disorder characterized by a matted or smudged appearance to the surface of the iris; the development of small colored lumps on the iris (nodular iris nevi); the attachment of portions of the iris to the cornea (peripheral anterior synechiae); and/or increased pressure in the eye (glaucoma). Secondary glaucoma may lead to vision loss. This disorder most frequently appears in young and middle-aged females, usually affecting only one eye (unilateral) and developing slowly over time.Cogan-Reese syndrome is one of the iridocorneal endothelial (ICE) syndromes, all of which usually affect one eye of young to middle-aged women. The ICE syndromes (essential iris atrophy, Chandler’s syndrome, and Cogan-Reese syndrome) are distinct from one another. However, since these disorders all affect the eye and some of their symptoms overlap, it may be difficult to distinguish between them. These variants may represent different stages of one disease. (For more information on Chandler’s syndrome and essential iris atrophy, see the Related Disorders section of this article.) | Overview of Cogan Reese Syndrome. Cogan-Reese syndrome is an extremely rare eye disorder characterized by a matted or smudged appearance to the surface of the iris; the development of small colored lumps on the iris (nodular iris nevi); the attachment of portions of the iris to the cornea (peripheral anterior synechiae); and/or increased pressure in the eye (glaucoma). Secondary glaucoma may lead to vision loss. This disorder most frequently appears in young and middle-aged females, usually affecting only one eye (unilateral) and developing slowly over time.Cogan-Reese syndrome is one of the iridocorneal endothelial (ICE) syndromes, all of which usually affect one eye of young to middle-aged women. The ICE syndromes (essential iris atrophy, Chandler’s syndrome, and Cogan-Reese syndrome) are distinct from one another. However, since these disorders all affect the eye and some of their symptoms overlap, it may be difficult to distinguish between them. These variants may represent different stages of one disease. (For more information on Chandler’s syndrome and essential iris atrophy, see the Related Disorders section of this article.) | 286 | Cogan Reese Syndrome |
nord_286_1 | Symptoms of Cogan Reese Syndrome | Major characteristics of Cogan-Reese syndrome include a matted or smudged appearance to the surface of the iris (nevus), yellow or brown lumps or nodules on the iris (nodular iris nevi), the attachment of portions of the iris to the cornea (peripheral anterior synechiae), and increased pressure in the eye (glaucoma). The development of Cogan-Reese syndrome is gradual, and may be preceded by symptoms of essential iris atrophy and/or Chandler’s syndrome. The matted appearance of the iris and development of nodules on the iris distinguish Cogan-Reese syndrome from the other iridocorneal endothelial syndromes.Other features of Cogan-Reese syndrome may include swelling of the cornea (corneal edema) and/or abnormalities in the cells lining the cornea (corneal endothelium). These changes may be responsible for the glaucoma that is characteristic of this disorder. Glaucoma may lead to vision loss. The edge of the pupil may turn outward (ectropion uveae) and/or a transparent membrane may appear across the surface of the iris. | Symptoms of Cogan Reese Syndrome. Major characteristics of Cogan-Reese syndrome include a matted or smudged appearance to the surface of the iris (nevus), yellow or brown lumps or nodules on the iris (nodular iris nevi), the attachment of portions of the iris to the cornea (peripheral anterior synechiae), and increased pressure in the eye (glaucoma). The development of Cogan-Reese syndrome is gradual, and may be preceded by symptoms of essential iris atrophy and/or Chandler’s syndrome. The matted appearance of the iris and development of nodules on the iris distinguish Cogan-Reese syndrome from the other iridocorneal endothelial syndromes.Other features of Cogan-Reese syndrome may include swelling of the cornea (corneal edema) and/or abnormalities in the cells lining the cornea (corneal endothelium). These changes may be responsible for the glaucoma that is characteristic of this disorder. Glaucoma may lead to vision loss. The edge of the pupil may turn outward (ectropion uveae) and/or a transparent membrane may appear across the surface of the iris. | 286 | Cogan Reese Syndrome |
nord_286_2 | Causes of Cogan Reese Syndrome | The cause of Cogan-Reese syndrome is not known. Some researchers suspect that inflammation or chronic infection may be the cause of the disease. Others suggest that the primary disorder involves the cells that line the cornea (corneal endothelium), with the impact on the iris as a secondary or associated disorder. Some scientists suggest that the three iridocorneal (ICE) syndromes may represent different stages of one disease process.There is a hypothesis that ICE syndromes stem from an in-vitro herpes infection localized in the endothelial layer. According to this theory, one eye is infected first and the second eye develops immunity before it can be affected. | Causes of Cogan Reese Syndrome. The cause of Cogan-Reese syndrome is not known. Some researchers suspect that inflammation or chronic infection may be the cause of the disease. Others suggest that the primary disorder involves the cells that line the cornea (corneal endothelium), with the impact on the iris as a secondary or associated disorder. Some scientists suggest that the three iridocorneal (ICE) syndromes may represent different stages of one disease process.There is a hypothesis that ICE syndromes stem from an in-vitro herpes infection localized in the endothelial layer. According to this theory, one eye is infected first and the second eye develops immunity before it can be affected. | 286 | Cogan Reese Syndrome |
nord_286_3 | Affects of Cogan Reese Syndrome | Cogan-Reese syndrome is a very rare disorder that predominantly affects females in the middle adult years, although cases have been reported in children. Most affected individuals are white. The male to female ratio ranges from 1:2 to 1:5. A family history usually shows no other affected family members. | Affects of Cogan Reese Syndrome. Cogan-Reese syndrome is a very rare disorder that predominantly affects females in the middle adult years, although cases have been reported in children. Most affected individuals are white. The male to female ratio ranges from 1:2 to 1:5. A family history usually shows no other affected family members. | 286 | Cogan Reese Syndrome |
nord_286_4 | Related disorders of Cogan Reese Syndrome | Symptoms of the following disorders can be similar to those of Cogan-Reese syndrome. Comparisons may be useful for a differential diagnosis:Chandler's syndrome (CS) is a rare eye disorder in which the endothelium, the single layer of cells lining the inner surface of the cornea, proliferates causing corneal edema, distortion of the iris, and unusually high pressure in the eye (glaucoma). CS is one of three syndromes affecting the eyes (progressive iris atrophy and Cogan-Reese syndrome are the other two) that make up the iridocorneal endothelial syndrome (ICE syndrome). The spectrum is an acquired, unilateral disorder, which typically occurs in early to middle adulthood and predominantly affects women. Chandler's syndrome is the most commonly encountered clinical variant of this spectrum. (For more information on this disorder, choose “Chandler” as your search term in the Rare Disease Database.)Essential iris atrophy is a very rare, progressive disorder of the eye characterized by a pupil that is out of place and/or distorted, areas of degeneration on the iris (atrophy), and/or holes in the iris. Attachment of portions of the iris to the cornea (peripheral anterior synechiae) and subsequent closure of the drainage angle may lead to secondary glaucoma and vision loss. The colored nodules characteristic of Cogan-Reese Syndrome do not usually appear in essential iris atrophy. (For more information on this disorder, choose “Essential Iris Atrophy” as your search term in the Rare Disease Database.)Axenfeld’s anomaly is characterized by attachment of portions of the iris to the cornea (peripheral anterior synechiae). Axenfeld’s anomaly is considered to be an inherited, developmental defect, while the iridocorneal syndromes (Cogan-Reese syndrome, Chandler’s syndrome, and essential iris atrophy) are thought to be acquired disorders.Rieger’s anomaly is characterized by attachment of portions of the iris to the cornea, a distorted pupil, clouding of the edges of the cornea (peripheral corneal opacification), displacement of iris tissue (hypoplasia), and/or secondary glaucoma. When Rieger’s anomaly occurs in association with dental abnormalities (i.e., a decrease in the number of teeth, small teeth, or anodontia) and facial malformations (i.e., displacement of the jaw, flattening of the midface, a receding upper lip and prominent lower lip) it is referred to as Rieger’s syndrome. Rieger anomaly is considered to be an inherited, developmental defect, while the iridocorneal syndromes (Cogan-Reese syndrome, Chandler’s syndrome, and essential iris atrophy) are thought to be acquired disorders. There is some confusion in the medical literature as to whether Axenfeld’s and Rieger’s anomalies are separate disorders or whether they occur together in what is called the Axenfeld-Rieger (A-R) syndrome Of note, A-R syndrome is a bilateral condition, whereas ICE syndrome is usually unilateral. | Related disorders of Cogan Reese Syndrome. Symptoms of the following disorders can be similar to those of Cogan-Reese syndrome. Comparisons may be useful for a differential diagnosis:Chandler's syndrome (CS) is a rare eye disorder in which the endothelium, the single layer of cells lining the inner surface of the cornea, proliferates causing corneal edema, distortion of the iris, and unusually high pressure in the eye (glaucoma). CS is one of three syndromes affecting the eyes (progressive iris atrophy and Cogan-Reese syndrome are the other two) that make up the iridocorneal endothelial syndrome (ICE syndrome). The spectrum is an acquired, unilateral disorder, which typically occurs in early to middle adulthood and predominantly affects women. Chandler's syndrome is the most commonly encountered clinical variant of this spectrum. (For more information on this disorder, choose “Chandler” as your search term in the Rare Disease Database.)Essential iris atrophy is a very rare, progressive disorder of the eye characterized by a pupil that is out of place and/or distorted, areas of degeneration on the iris (atrophy), and/or holes in the iris. Attachment of portions of the iris to the cornea (peripheral anterior synechiae) and subsequent closure of the drainage angle may lead to secondary glaucoma and vision loss. The colored nodules characteristic of Cogan-Reese Syndrome do not usually appear in essential iris atrophy. (For more information on this disorder, choose “Essential Iris Atrophy” as your search term in the Rare Disease Database.)Axenfeld’s anomaly is characterized by attachment of portions of the iris to the cornea (peripheral anterior synechiae). Axenfeld’s anomaly is considered to be an inherited, developmental defect, while the iridocorneal syndromes (Cogan-Reese syndrome, Chandler’s syndrome, and essential iris atrophy) are thought to be acquired disorders.Rieger’s anomaly is characterized by attachment of portions of the iris to the cornea, a distorted pupil, clouding of the edges of the cornea (peripheral corneal opacification), displacement of iris tissue (hypoplasia), and/or secondary glaucoma. When Rieger’s anomaly occurs in association with dental abnormalities (i.e., a decrease in the number of teeth, small teeth, or anodontia) and facial malformations (i.e., displacement of the jaw, flattening of the midface, a receding upper lip and prominent lower lip) it is referred to as Rieger’s syndrome. Rieger anomaly is considered to be an inherited, developmental defect, while the iridocorneal syndromes (Cogan-Reese syndrome, Chandler’s syndrome, and essential iris atrophy) are thought to be acquired disorders. There is some confusion in the medical literature as to whether Axenfeld’s and Rieger’s anomalies are separate disorders or whether they occur together in what is called the Axenfeld-Rieger (A-R) syndrome Of note, A-R syndrome is a bilateral condition, whereas ICE syndrome is usually unilateral. | 286 | Cogan Reese Syndrome |
nord_286_5 | Diagnosis of Cogan Reese Syndrome | Diagnosis of Cogan Reese Syndrome. | 286 | Cogan Reese Syndrome |
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nord_286_6 | Therapies of Cogan Reese Syndrome | Secondary Glaucoma and Treatment:In general, glaucoma is one of the leading causes of blindness in the world.. Glaucoma is characterized by increased pressure within the eye. If left untreated, the increased pressure affects the optic nerve, resulting in eventual blindness. The etiology of glaucoma in unclear and remains an active area of research. The American Academy of Ophthalmology recommends a complete eye exam by the age of 40 or earlier for those at increased risk. Important elements of the examination include visual acuity test, tonometry to measure intraocular pressure, gonioscopy to assess if the drainage angle is open or closed, slit lamp examination to assess the anterior segment of the eye, use of special lenses to examine the optic nerve and posterior segment of the eye, and visual field test to assess the loss of peripheral or central vision. Glaucoma may occur as a secondary disorder to Cogan-Reese syndrome. The mechanism of glaucoma in ICE syndrome (all three variants) is believed to be related to a cellular membrane secreted by the abnormal endothelial cells. This membrane covers the trabecular meshwork of the drainage angle, thereby obstructing aqueous outflow facility and elevating intraocular pressure. In the early stages, the angle may appear open clinically although it is covered by this transparent membrane. Over time, contraction of this membrane leads to peripheral anterior synechiae and secondary angle closure glaucoma. Treatment of Cogan-Reese syndrome usually involves the use of drops in the eyes to control the glaucoma and swelling (edema). Mild cases or corneal edema are often managed with soft contact lenses and hypertonic saline solutions. In advanced cases penetrating or endothelial keratoplasty may be required, although the failure rate is high with need for repeat corneal grafts. In some individuals, the corneal edema may be improved with reduction in intraocular pressure. Medical therapy for glaucoma is usually initiated with aqueous suppressants, including beta blockers, alpha-2 agonists and carbonic anhydrase inhibitors. Prostaglandin analogues may be helpful in some cases. Surgical intervention for glaucoma is eventually required in a high percentage of patients with ICE syndrome. The most commonly performed procedure is trabeculectomy, with variable success rates. Glaucoma drainage devices have shown favorable outcomes in a small number of patients, but further studies are warranted to validate these results in a large series. Laser surgery is rarely effective. | Therapies of Cogan Reese Syndrome. Secondary Glaucoma and Treatment:In general, glaucoma is one of the leading causes of blindness in the world.. Glaucoma is characterized by increased pressure within the eye. If left untreated, the increased pressure affects the optic nerve, resulting in eventual blindness. The etiology of glaucoma in unclear and remains an active area of research. The American Academy of Ophthalmology recommends a complete eye exam by the age of 40 or earlier for those at increased risk. Important elements of the examination include visual acuity test, tonometry to measure intraocular pressure, gonioscopy to assess if the drainage angle is open or closed, slit lamp examination to assess the anterior segment of the eye, use of special lenses to examine the optic nerve and posterior segment of the eye, and visual field test to assess the loss of peripheral or central vision. Glaucoma may occur as a secondary disorder to Cogan-Reese syndrome. The mechanism of glaucoma in ICE syndrome (all three variants) is believed to be related to a cellular membrane secreted by the abnormal endothelial cells. This membrane covers the trabecular meshwork of the drainage angle, thereby obstructing aqueous outflow facility and elevating intraocular pressure. In the early stages, the angle may appear open clinically although it is covered by this transparent membrane. Over time, contraction of this membrane leads to peripheral anterior synechiae and secondary angle closure glaucoma. Treatment of Cogan-Reese syndrome usually involves the use of drops in the eyes to control the glaucoma and swelling (edema). Mild cases or corneal edema are often managed with soft contact lenses and hypertonic saline solutions. In advanced cases penetrating or endothelial keratoplasty may be required, although the failure rate is high with need for repeat corneal grafts. In some individuals, the corneal edema may be improved with reduction in intraocular pressure. Medical therapy for glaucoma is usually initiated with aqueous suppressants, including beta blockers, alpha-2 agonists and carbonic anhydrase inhibitors. Prostaglandin analogues may be helpful in some cases. Surgical intervention for glaucoma is eventually required in a high percentage of patients with ICE syndrome. The most commonly performed procedure is trabeculectomy, with variable success rates. Glaucoma drainage devices have shown favorable outcomes in a small number of patients, but further studies are warranted to validate these results in a large series. Laser surgery is rarely effective. | 286 | Cogan Reese Syndrome |
nord_287_0 | Overview of Cohen Syndrome | Cohen syndrome is a variable genetic disorder characterized by diminished muscle tone (hypotonia), abnormalities of the head, face, hands and feet, eye abnormalities, and non-progressive intellectual disability. Affected individuals usually have microcephaly, a condition that indicates that head circumference is smaller than would be expected for an infant’s age and sex. In many older patients, obesity is present, especially around the torso and is associated with slender arms and legs. A lowered level of certain white blood cells known as neutrophils (neutropenia) is present from birth in some affected individuals. Cohen syndrome is an autosomal recessive genetic disease caused by changes (variants or mutations) in the VPS13B/COH1 gene. | Overview of Cohen Syndrome. Cohen syndrome is a variable genetic disorder characterized by diminished muscle tone (hypotonia), abnormalities of the head, face, hands and feet, eye abnormalities, and non-progressive intellectual disability. Affected individuals usually have microcephaly, a condition that indicates that head circumference is smaller than would be expected for an infant’s age and sex. In many older patients, obesity is present, especially around the torso and is associated with slender arms and legs. A lowered level of certain white blood cells known as neutrophils (neutropenia) is present from birth in some affected individuals. Cohen syndrome is an autosomal recessive genetic disease caused by changes (variants or mutations) in the VPS13B/COH1 gene. | 287 | Cohen Syndrome |
nord_287_1 | Symptoms of Cohen Syndrome | The signs and symptoms of Cohen syndrome may vary from one individual to another. Although researchers have been able to establish a clear syndrome with characteristic or “core” features, much about the disorder is not fully understood. Several factors including the small number of identified cases and the lack of large clinical studies, prevent physicians from developing a complete picture of associated symptoms and prognosis. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below. Parents should talk to their children’s physician and medical team about their specific case, associated symptoms and overall prognosis.Newborns with Cohen syndrome usually have diminished muscle tone (hypotonia). Feeding and breathing difficulties due to hypotonia may be present in the first few days of life. Some newborns may have a weak or high-pitched cry. Some infants may exhibit a failure to gain weight and grow as would otherwise be expected based upon sex and age (failure to thrive). An infant’s joints may be ‘loose’, meaning that they have an abnormally large range of motion (joint hypermobility). Mild to moderate microcephaly often develops within the first year of life and continues into adulthood.As infants grow older, they may exhibit delays in reaching normal developmental milestones such as sitting up or rolling over (developmental delays). The degree of such delays is highly variable, even among members of the same family. Walking is often delayed until 2-5 years of age. Speech delays are also common; an infant’s or child’s first words or ability to speak in sentences are often delayed.Mild to moderate intellectual disability is non-progressive and affected individuals show an ability to learn new concepts. Most children are described as sociable with a cheerful disposition. In some instances, children may exhibit behavioral issues that fall within the autistic spectrum. Although rare, seizures have been reported in a minority of individuals.During childhood, often around the age of 5, distinctive facial features may become apparent. Such features include large ears; a prominent root of the nose (the part of nose between the eyes); a low hairline; highly arched or wave-shaped eyelids; long, thick eyelashes; thick eyebrows; a high, narrow roof of the mouth (palate); an abnormally short groove in the middle of the upper lip (philtrum); and prominent upper central incisors. Some individuals may develop recurrent, small, rounded ulcers in the mouth (aphthous ulcers) and inflammation or infection of the gums (gingivitis) may occur. In the medical literature, the range of distinctive facial features is highly variable and specific features appear to be more likely to occur in individuals of specific ethnic backgrounds.Affected individuals often develop a variety of abnormalities affecting the eyes and may experience vision problems early in childhood. Such abnormalities include decreased clarity of vision (visual acuity), nearsightedness (myopia) and crossed eyes (strabismus). Myopia usually becomes progressively worse throughout childhood.Affected individuals may also have chorioretinal dystrophy, a condition characterized by abnormalities affecting the choroid and retina including degeneration of the retina. The choroid is the middle layer of the eye that consists of blood vessels that supply blood to the retina. The retina is a membranous layer of light-sensing cells in the back of the eye that converts light to specific nerve signals, which are then transmitted to the brain to form images. Chorioretinal dystrophy is progressive and can cause poor vision in dim light and eventually night blindness (nyctalopia) and a decreased field of vision with a decreased ability to see to the left or right when looking straight ahead (constriction of the peripheral field of vision; sometimes referred to as tunnel vision). Loss of peripheral vision may cause individuals to trip or fall easily.Less often, additional abnormalities of the eyes are associated with Cohen syndrome including abnormal curvature of the cornea (astigmatism), reduced size of the cornea (microcornea), abnormally small eyeballs (microphthalmia), clouding (opacity) of the lenses, degeneration of the iris (iris atrophy), degeneration of the optic nerve, which carries impulses from the eyes to the brain (optic atrophy) and a cleft of missing tissue (colobomas) in the retina or eyelids.Some individuals develop obesity of the trunk or torso of the body that occurs during mid-childhood. The arms and legs can remain slender or thin. Individuals may be below average height for their age and gender (short stature). Some individuals may also have small, narrow hands and feet. Delayed puberty has also been reported and some males exhibit undescended testicles (cryptorchidism).Abnormal curvature of the spine is common. Affected individuals may develop abnormal front-to-back curvature of the spine (kyphosis), or a combination of kyphosis with abnormal sideways curvature of the spine (scoliosis).Individuals with Cohen syndrome may have a condition called neutropenia, in which there are abnormally low levels of certain white blood cells called neutrophils. Neutrophils are essential in helping the body to fight off infection by surrounding and destroying bacteria that enter the body. Neutropenia is usually mild or moderate. Some individuals may experience repeated infections such as respiratory infections or minor skin infections. Children with Cohen syndrome may be prone to developing middle ear infections (otitis media). Chronic development of aphthous ulcers and gingivitis may be partly due to neutropenia.Individuals with Cohen syndrome appear to be at an increased risk of developing autoimmune disorders, especially diabetes mellitus, but also thyroid disorders and celiac disease. Autoimmune disorders occur when the body’s immune system mistakenly attacks healthy tissue. | Symptoms of Cohen Syndrome. The signs and symptoms of Cohen syndrome may vary from one individual to another. Although researchers have been able to establish a clear syndrome with characteristic or “core” features, much about the disorder is not fully understood. Several factors including the small number of identified cases and the lack of large clinical studies, prevent physicians from developing a complete picture of associated symptoms and prognosis. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below. Parents should talk to their children’s physician and medical team about their specific case, associated symptoms and overall prognosis.Newborns with Cohen syndrome usually have diminished muscle tone (hypotonia). Feeding and breathing difficulties due to hypotonia may be present in the first few days of life. Some newborns may have a weak or high-pitched cry. Some infants may exhibit a failure to gain weight and grow as would otherwise be expected based upon sex and age (failure to thrive). An infant’s joints may be ‘loose’, meaning that they have an abnormally large range of motion (joint hypermobility). Mild to moderate microcephaly often develops within the first year of life and continues into adulthood.As infants grow older, they may exhibit delays in reaching normal developmental milestones such as sitting up or rolling over (developmental delays). The degree of such delays is highly variable, even among members of the same family. Walking is often delayed until 2-5 years of age. Speech delays are also common; an infant’s or child’s first words or ability to speak in sentences are often delayed.Mild to moderate intellectual disability is non-progressive and affected individuals show an ability to learn new concepts. Most children are described as sociable with a cheerful disposition. In some instances, children may exhibit behavioral issues that fall within the autistic spectrum. Although rare, seizures have been reported in a minority of individuals.During childhood, often around the age of 5, distinctive facial features may become apparent. Such features include large ears; a prominent root of the nose (the part of nose between the eyes); a low hairline; highly arched or wave-shaped eyelids; long, thick eyelashes; thick eyebrows; a high, narrow roof of the mouth (palate); an abnormally short groove in the middle of the upper lip (philtrum); and prominent upper central incisors. Some individuals may develop recurrent, small, rounded ulcers in the mouth (aphthous ulcers) and inflammation or infection of the gums (gingivitis) may occur. In the medical literature, the range of distinctive facial features is highly variable and specific features appear to be more likely to occur in individuals of specific ethnic backgrounds.Affected individuals often develop a variety of abnormalities affecting the eyes and may experience vision problems early in childhood. Such abnormalities include decreased clarity of vision (visual acuity), nearsightedness (myopia) and crossed eyes (strabismus). Myopia usually becomes progressively worse throughout childhood.Affected individuals may also have chorioretinal dystrophy, a condition characterized by abnormalities affecting the choroid and retina including degeneration of the retina. The choroid is the middle layer of the eye that consists of blood vessels that supply blood to the retina. The retina is a membranous layer of light-sensing cells in the back of the eye that converts light to specific nerve signals, which are then transmitted to the brain to form images. Chorioretinal dystrophy is progressive and can cause poor vision in dim light and eventually night blindness (nyctalopia) and a decreased field of vision with a decreased ability to see to the left or right when looking straight ahead (constriction of the peripheral field of vision; sometimes referred to as tunnel vision). Loss of peripheral vision may cause individuals to trip or fall easily.Less often, additional abnormalities of the eyes are associated with Cohen syndrome including abnormal curvature of the cornea (astigmatism), reduced size of the cornea (microcornea), abnormally small eyeballs (microphthalmia), clouding (opacity) of the lenses, degeneration of the iris (iris atrophy), degeneration of the optic nerve, which carries impulses from the eyes to the brain (optic atrophy) and a cleft of missing tissue (colobomas) in the retina or eyelids.Some individuals develop obesity of the trunk or torso of the body that occurs during mid-childhood. The arms and legs can remain slender or thin. Individuals may be below average height for their age and gender (short stature). Some individuals may also have small, narrow hands and feet. Delayed puberty has also been reported and some males exhibit undescended testicles (cryptorchidism).Abnormal curvature of the spine is common. Affected individuals may develop abnormal front-to-back curvature of the spine (kyphosis), or a combination of kyphosis with abnormal sideways curvature of the spine (scoliosis).Individuals with Cohen syndrome may have a condition called neutropenia, in which there are abnormally low levels of certain white blood cells called neutrophils. Neutrophils are essential in helping the body to fight off infection by surrounding and destroying bacteria that enter the body. Neutropenia is usually mild or moderate. Some individuals may experience repeated infections such as respiratory infections or minor skin infections. Children with Cohen syndrome may be prone to developing middle ear infections (otitis media). Chronic development of aphthous ulcers and gingivitis may be partly due to neutropenia.Individuals with Cohen syndrome appear to be at an increased risk of developing autoimmune disorders, especially diabetes mellitus, but also thyroid disorders and celiac disease. Autoimmune disorders occur when the body’s immune system mistakenly attacks healthy tissue. | 287 | Cohen Syndrome |
nord_287_2 | Causes of Cohen Syndrome | Cohen syndrome is caused by changes (variants or mutations) in the COH1 gene. This gene is also known as the VPS13B gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When an alteration of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the protein, this can affect many organ systems of the body.Researchers have determined that the protein product of the COH1 gene is involved in glycosylation, the process by which sugar ‘trees’ (glycans) are created, altered and chemically attached to certain proteins or fats (lipids). When these sugar molecules are attached to proteins, they form glycoproteins; when they are attached to lipids, they form glycolipids. Glycoproteins and glycolipids have numerous important functions in all tissues and organs. Glycosylation involves many different genes, encoding many different proteins such as enzymes. A deficiency or lack of one of these enzymes can lead to a variety of symptoms potentially affecting multiple organ systems, and there is nearly always an important neurological component. Symptoms can vary in severity.Cohen syndrome is inherited in an autosomal recessive manner. Recessive genetic disorders occur when an individual inherits a mutated gene from each parent. If an individual receives one normal gene and one mutated 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 mutated gene and have an affected child is 25% with each pregnancy. The risk of having 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. | Causes of Cohen Syndrome. Cohen syndrome is caused by changes (variants or mutations) in the COH1 gene. This gene is also known as the VPS13B gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When an alteration of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the protein, this can affect many organ systems of the body.Researchers have determined that the protein product of the COH1 gene is involved in glycosylation, the process by which sugar ‘trees’ (glycans) are created, altered and chemically attached to certain proteins or fats (lipids). When these sugar molecules are attached to proteins, they form glycoproteins; when they are attached to lipids, they form glycolipids. Glycoproteins and glycolipids have numerous important functions in all tissues and organs. Glycosylation involves many different genes, encoding many different proteins such as enzymes. A deficiency or lack of one of these enzymes can lead to a variety of symptoms potentially affecting multiple organ systems, and there is nearly always an important neurological component. Symptoms can vary in severity.Cohen syndrome is inherited in an autosomal recessive manner. Recessive genetic disorders occur when an individual inherits a mutated gene from each parent. If an individual receives one normal gene and one mutated 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 mutated gene and have an affected child is 25% with each pregnancy. The risk of having 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. | 287 | Cohen Syndrome |
nord_287_3 | Affects of Cohen Syndrome | Cohen syndrome affects males and females in about equal numbers. It appears to occur more frequently in people of Finnish, Amish, Greek/Mediterranean and Irish ancestry. More than 150 cases have been reported in the medical literature and an estimated over 1,000 individuals have been diagnosed with the disorder worldwide. However, instances of Cohen syndrome often go undiagnosed or misdiagnosed, making it difficult to determine the true frequency of the disorder in the general population. | Affects of Cohen Syndrome. Cohen syndrome affects males and females in about equal numbers. It appears to occur more frequently in people of Finnish, Amish, Greek/Mediterranean and Irish ancestry. More than 150 cases have been reported in the medical literature and an estimated over 1,000 individuals have been diagnosed with the disorder worldwide. However, instances of Cohen syndrome often go undiagnosed or misdiagnosed, making it difficult to determine the true frequency of the disorder in the general population. | 287 | Cohen Syndrome |
nord_287_4 | Related disorders of Cohen Syndrome | Symptoms of the following disorders can be similar to those of Cohen syndrome. Comparisons may be useful for a differential diagnosis:Prader-Willi syndrome (PWS) is a genetic multisystem disorder characterized during infancy by lethargy, diminished muscle tone (hypotonia), feeding difficulties and poor weight gain. In childhood, features of this disorder include short stature, small genitals and an excessive appetite because affected individuals do not feel satisfied after completing a meal (satiety). Without intervention, this can lead to overeating and the gradual onset of obesity. Food compulsion requires constant supervision. Individuals with severe obesity may have an increased risk of cardiac insufficiency, sleep apnea, diabetes and other serious conditions that can cause life-threatening complications. All individuals with PWS have some cognitive impairment that ranges from low normal intelligence with learning disabilities to mild to moderate intellectual disability. Behavioral problems are common and can include temper tantrums, obsessive/compulsive behavior and skin picking. Motor milestones and language development are often delayed. PWS occurs due to alterations affecting certain genes in a specific region of chromosome 15. These abnormalities usually result from random (sporadic) errors in development but are sometimes inherited. (For more information on this disorder, choose “Prader-Willi” as your search term in the Rare Disease Database.)Angelman syndrome (AS) is a rare genetic neurological disorder characterized by severe developmental delays and learning disabilities; the absence or near absence of speech; an inability to coordinate voluntary movements (ataxia) and tremulous, jerky movements of the arms and legs and a distinct behavioral pattern characterized by a happy disposition and unprovoked episodes of laughter and smiling, often at inappropriate times. Although affected individuals may be unable to speak, many gradually learn to communicate through other means such as gesturing. In addition, children may have enough receptive language ability to understand language to understand simple commands. Additional symptoms may occur in some children inluding seizures, sleep disorders and feeding difficulties. Some affected children may have distinctive facial features. Angelman syndrome is caused by deletion of or abnormal expression of the UBE3A gene that is located on the long arm (q) of chromosome 15 (15q11-q13), the PWS/AS region. (For more information on this disorder, choose “Angelman” as your search term in the Rare Disease Database.)Several other genetic disorders can have signs and symptoms that are similar to or overlap with those seen in Cohen syndrome. These disorders include Alstrom syndrome, Cri-du-chat syndrome, Williams syndrome, Bardet-Biedl syndrome and hypothyroidism. (For more information, choose the specific disorder name as your search term in the Rare Disease Database.) | Related disorders of Cohen Syndrome. Symptoms of the following disorders can be similar to those of Cohen syndrome. Comparisons may be useful for a differential diagnosis:Prader-Willi syndrome (PWS) is a genetic multisystem disorder characterized during infancy by lethargy, diminished muscle tone (hypotonia), feeding difficulties and poor weight gain. In childhood, features of this disorder include short stature, small genitals and an excessive appetite because affected individuals do not feel satisfied after completing a meal (satiety). Without intervention, this can lead to overeating and the gradual onset of obesity. Food compulsion requires constant supervision. Individuals with severe obesity may have an increased risk of cardiac insufficiency, sleep apnea, diabetes and other serious conditions that can cause life-threatening complications. All individuals with PWS have some cognitive impairment that ranges from low normal intelligence with learning disabilities to mild to moderate intellectual disability. Behavioral problems are common and can include temper tantrums, obsessive/compulsive behavior and skin picking. Motor milestones and language development are often delayed. PWS occurs due to alterations affecting certain genes in a specific region of chromosome 15. These abnormalities usually result from random (sporadic) errors in development but are sometimes inherited. (For more information on this disorder, choose “Prader-Willi” as your search term in the Rare Disease Database.)Angelman syndrome (AS) is a rare genetic neurological disorder characterized by severe developmental delays and learning disabilities; the absence or near absence of speech; an inability to coordinate voluntary movements (ataxia) and tremulous, jerky movements of the arms and legs and a distinct behavioral pattern characterized by a happy disposition and unprovoked episodes of laughter and smiling, often at inappropriate times. Although affected individuals may be unable to speak, many gradually learn to communicate through other means such as gesturing. In addition, children may have enough receptive language ability to understand language to understand simple commands. Additional symptoms may occur in some children inluding seizures, sleep disorders and feeding difficulties. Some affected children may have distinctive facial features. Angelman syndrome is caused by deletion of or abnormal expression of the UBE3A gene that is located on the long arm (q) of chromosome 15 (15q11-q13), the PWS/AS region. (For more information on this disorder, choose “Angelman” as your search term in the Rare Disease Database.)Several other genetic disorders can have signs and symptoms that are similar to or overlap with those seen in Cohen syndrome. These disorders include Alstrom syndrome, Cri-du-chat syndrome, Williams syndrome, Bardet-Biedl syndrome and hypothyroidism. (For more information, choose the specific disorder name as your search term in the Rare Disease Database.) | 287 | Cohen Syndrome |
nord_287_5 | Diagnosis of Cohen Syndrome | Diagnosis of Cohen Syndrome. | 287 | Cohen Syndrome |
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nord_287_6 | Therapies of Cohen Syndrome | The treatment of Cohen syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, pediatric neurologists, orthopedists, ophthalmologists, psychiatrists, speech pathologists and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Genetic counseling is recommended for affected individuals and their families.Treatment options that may be used to treat individuals with Cohen syndrome are complex and varied. The specific treatment plan will need to be highly individualized. Decisions concerning the use of specific treatments should be made by physicians and other members of the health care team in careful consultation with an affected child’s parents or with an adult patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.Early developmental intervention is important to ensure that affected children reach their potential. Most affected children will benefit from occupational, physical and speech therapy. Various methods of rehabilitative and behavioral therapy may be beneficial. Additional medical, social and/or vocational services including special remedial education may be necessary. Psychosocial support for the entire family is essential as well.Genetic counseling is recommended for families with an affected child.Specific treatments for Cohen syndrome include spectacles and eyeglasses to help with vision. In later years, low vision training as needed in individuals with visual impairment. Recurrent infections can be treated with standard therapies including antibiotics.
In some instances, neutropenia may be treated with the administration of granulocyte-colony stimulating factors (G-CSF). G-CSF is a manufactured version of the natural hormones that stimulate the bone marrow to produce neutrophils. G-CSF increases the number of neutrophils generated by the bone marrow and improves the efficacy of their bacteria-killing ability. | Therapies of Cohen Syndrome. The treatment of Cohen syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, pediatric neurologists, orthopedists, ophthalmologists, psychiatrists, speech pathologists and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Genetic counseling is recommended for affected individuals and their families.Treatment options that may be used to treat individuals with Cohen syndrome are complex and varied. The specific treatment plan will need to be highly individualized. Decisions concerning the use of specific treatments should be made by physicians and other members of the health care team in careful consultation with an affected child’s parents or with an adult patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.Early developmental intervention is important to ensure that affected children reach their potential. Most affected children will benefit from occupational, physical and speech therapy. Various methods of rehabilitative and behavioral therapy may be beneficial. Additional medical, social and/or vocational services including special remedial education may be necessary. Psychosocial support for the entire family is essential as well.Genetic counseling is recommended for families with an affected child.Specific treatments for Cohen syndrome include spectacles and eyeglasses to help with vision. In later years, low vision training as needed in individuals with visual impairment. Recurrent infections can be treated with standard therapies including antibiotics.
In some instances, neutropenia may be treated with the administration of granulocyte-colony stimulating factors (G-CSF). G-CSF is a manufactured version of the natural hormones that stimulate the bone marrow to produce neutrophils. G-CSF increases the number of neutrophils generated by the bone marrow and improves the efficacy of their bacteria-killing ability. | 287 | Cohen Syndrome |
nord_288_0 | Overview of COL4A1/A2-Related Disorders | SummaryCOL4A1/A2-related disorders are rare, genetic, multi-system disorders. They are typically characterized by abnormal blood vessels in the brain (cerebral vasculature defects), eye development defects (ocular dysgenesis), muscle disease (myopathy), and kidney abnormalities (renal pathology); however, many other aspects of the syndrome including abnormalities affecting the structure of the brain (cerebral cortical abnormalities) and lung (pulmonary) abnormalities continue to emerge and the full spectrum is still uncharacterized. There are notable differences in the specific signs and symptoms (clinical heterogeneity), and different organs are affected to different degrees between patients – even among members of a family who carry the same gene mutation. Abnormal blood vessels in the brain are a major consequence of COL4A1 and COL4A2 gene mutations. The outcomes are highly variable ranging from brain hemorrhage before birth (in utero) leading to cavities in the brain (porencephaly) to mild age-related brain abnormalities that can only be observed on a specialized x-ray called magnetic resonance imaging (MRI). Mice with Col4a1 and Col4a2 gene mutations have pathology in many organs and the presence and severity of pathology in a given organ appears to depend on the location of the mutation, genetic context, and environmental interactions. COL4A1/A2-related disorders follow an autosomal dominant pattern of inheritance.OverviewCollagen type IV alpha 1 (COL4A1) and 2 (COL4A2) are extracellular matrix proteins that together constitute a major component of nearly all basement membranes. The two genes that code for these proteins are tightly linked on chromosome 13 and dominant COL4A1 and COL4A2 gene mutations cause a highly variable, multisystem disorder. | Overview of COL4A1/A2-Related Disorders. SummaryCOL4A1/A2-related disorders are rare, genetic, multi-system disorders. They are typically characterized by abnormal blood vessels in the brain (cerebral vasculature defects), eye development defects (ocular dysgenesis), muscle disease (myopathy), and kidney abnormalities (renal pathology); however, many other aspects of the syndrome including abnormalities affecting the structure of the brain (cerebral cortical abnormalities) and lung (pulmonary) abnormalities continue to emerge and the full spectrum is still uncharacterized. There are notable differences in the specific signs and symptoms (clinical heterogeneity), and different organs are affected to different degrees between patients – even among members of a family who carry the same gene mutation. Abnormal blood vessels in the brain are a major consequence of COL4A1 and COL4A2 gene mutations. The outcomes are highly variable ranging from brain hemorrhage before birth (in utero) leading to cavities in the brain (porencephaly) to mild age-related brain abnormalities that can only be observed on a specialized x-ray called magnetic resonance imaging (MRI). Mice with Col4a1 and Col4a2 gene mutations have pathology in many organs and the presence and severity of pathology in a given organ appears to depend on the location of the mutation, genetic context, and environmental interactions. COL4A1/A2-related disorders follow an autosomal dominant pattern of inheritance.OverviewCollagen type IV alpha 1 (COL4A1) and 2 (COL4A2) are extracellular matrix proteins that together constitute a major component of nearly all basement membranes. The two genes that code for these proteins are tightly linked on chromosome 13 and dominant COL4A1 and COL4A2 gene mutations cause a highly variable, multisystem disorder. | 288 | COL4A1/A2-Related Disorders |
nord_288_1 | Symptoms of COL4A1/A2-Related Disorders | The signs and symptoms can manifest at almost any age from before birth to old age. Some individuals do not have any observable symptoms (asymptomatic); others can develop severe, even life-threatening complications. Some may only develop specific symptoms such as isolated migraines or strokes in childhood or adulthood. The variability and severity of symptoms is significant and how COL4A1/A2-related disorders will potentially affect an individual can be unique. Clinical case reports suggest a syndrome with characteristic core findings; however, much about the disorder is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of other genes or factors influencing the disorder make it challenging to develop a complete picture of associated symptoms and prognosis. Therefore, it is important to note that there is a very broad spectrum of clinical presentations with different organs affected to different degrees between patients. Autosomal Dominant Familial Porencephaly Type IThe first reports of human COL4A1 mutations were in patients with autosomal dominant porencephaly and a more recent study found that COL4A1 mutations were found in ~16% of patients with porencephaly. Porencephaly refers to the formation of fluid-filled cysts or cavities within of the brain. The size and location of cerebral cavities contributes to clinical variability. In some people, serious, life-threatening complications may occur in infancy; in others, only minor complications may occur and intelligence is unaffected. Still other individuals may not develop any symptoms until well into adulthood. Symptoms that may occur in individuals with autosomal dominant type I porencephaly include migraines, weakness or paralysis of one side of the body (hemiparesis or hemiplegia), seizures, stroke, and dystonia, a group of neurological disorders characterized by involuntary muscle contractions that force the body into abnormal, sometimes painful, movements and positions. Migraines can occur with or without aura. Aura refers to additional neurological symptoms that occur with, or sometimes before, the development of the migraine headache. Affected infants and children can exhibit delays in reaching developmental milestones and varying degrees of intellectual disability. Additional features include poor or absent speech development, facial paralysis (paresis), involuntary muscle spasms (spasticity) that result in slow, stiff, rigid movements, visual field defects, and hydrocephalus, a condition in which accumulation of excessive cerebrospinal fluid in the skull causes pressure on the tissues of the brain, resulting in a variety of symptoms.Autosomal Dominant Brain Small Vessel DiseaseIn a retrospective study of 52 patients with COL4A1 mutations, stroke occurred in 17.3% of subjects and MRI showed white matter abnormalities (63.5%), subcortical microbleeds (52.9%), porencephaly (46%), enlarged spaces around blood vessels, (19.2%), and small infarctions (13.5%). This study clearly demonstrates that COL4A1 and COL4A2 mutations cause clinically variable cerebrovascular disease that includes characteristic features of cerebral small vessel disease. Cerebral small vessel disease with hemorrhage is likely milder continuum from porencephaly and exhibits many of the same symptoms (with the exception of the brain cavities). Affected individuals may have no observable symptoms or only isolated migraines with aura. Some affected individuals may develop weakness or paralysis of one side of the body (hemiparesis or hemiplegia) and have seizures. The main symptom is single or repeated bleeding inside the skull (intracranial hemorrhaging) that can occur without cause (spontaneously), after trauma, or when taking drugs that slow blood clotting (anticoagulants). In addition to the effects of a clear COL4A1 or COL4A2 mutation, large genetic studies reported associations for COL4A1/A2 with intracranial aneurysms, myocardial infarction, arterial calcification, arterial stiffness, deep intracerebral hemorrhages, lacunar ischemic stroke, reduced white matter volume and vascular leukoencephalopathy. Together, these studies suggest that certain unknown variants of COL4A1 and COL4A2 might contribute to chronic vascular dysfunction. Additional Signs and SymptomsMany patients with COL4A1 and COL4A2 mutations have additional signs and symptoms that do not include the cerebral vasculature. Some of these patients have been described as having HANAC syndrome, which is an acronym for hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. Affected individuals have kidney disease (nephropathy) causing blood in the urine (hematuria) that can either be seen by the naked eye (gross hematuria) or only visible when tested (microscopic hematuria). Some individuals develop cysts on the kidney. Aneurysms are bulges or enlargements of a blood vessel caused by weakening of the wall of the blood vessel. In most people, small vessel disease in the brain does not cause symptoms. Painful muscle cramps can occur and can develop before three years of age. Various muscles can be affected and muscle strength can become weakened. However, these findings can be observed independently or in combinations, in many patients with COL4A1 and COL4A2 mutations.COL4A1/A2-related disorders can also be associated with a variety of abnormalities affecting the front or back of the eyes. In the front of the eye, patients can have abnormally small eyes (microphthalmia), cataracts (cloudy lenses), and anterior segment dysgenesis (Axenfeld-Rieger). Cataracts, which are a clouding of the lenses of the eyes, are often present from birth (congenital) and may be one of the first identifiable signs of the syndrome. Axenfeld-Rieger is a collection of abnormalities affecting the front of the eye including the iris (colored part of the eye) and cornea (abnormally small corneas called microcornea), which is the transparent membrane that covers the eyes. Developmental defects to the front of the eye, which also includes the ocular drainage structures between the iris and cornea, can lead to increased pressure in the eye (elevated intraocular pressure, or IOP). Acute or chronic IOP elevation can lead to glaucoma where the increased pressure damages the optic nerve causing progressive and irreversible vision loss. In the back of the eye, affected individuals have also twisting or distortion (tortuosity) of arteries in the retina (bilateral retinal arterial tortuosity) as part of the syndrome or as an isolated finding. The retina is the light-sensitive membrane that lines the inside of the eyes. The cells of the retina trigger nerve impulses that run from the optic nerve to the brain to form sight. Abnormal retinal arteries are prone to rupture causing bleeding associated with temporary loss of vision or even retinal detachments that can cause permanent vision loss. A variety of additional signs and symptoms have been reported in individuals with COL4A1/A2-related disorders including childhood-onset epilepsy, hemolytic anemia ¬(a condition characterized by low levels of circulating red blood cells due to their premature destruction leading to fatigue, weakness, lightheadedness, dizziness, irritability, headaches, and pale skin color), mitral valve prolapse (flaps of the valve located between the upper and lower left heart chambers bulge or collapse during contraction allowing leakage of blood back into the left atrium).Other patients have been reported with cysts on the liver, irregular heartbeats (supraventricular arrhythmia), and Raynaud phenomenon, which is in which the fingers or toes become numb or have a prickly sensation in response to cold due to narrowing of blood vessels.Congenital Cephalic Disorders
In addition to porencephaly there can be other forms of damage to the brain present at birth. Individuals with COL4A1 or COL4A2 mutations can also develop formation of clefts or slits in the two halves of the brain (schizencephaly) in which cerebral hemispheres are missing and replaced with sacs filled with cerebrospinal fluid (hydranencephaly), abnormal folds in the brain surface (polymicrogyria) or abnormalities in the normal laying of the neuronal cells in the brain (cortical lamination defects). | Symptoms of COL4A1/A2-Related Disorders. The signs and symptoms can manifest at almost any age from before birth to old age. Some individuals do not have any observable symptoms (asymptomatic); others can develop severe, even life-threatening complications. Some may only develop specific symptoms such as isolated migraines or strokes in childhood or adulthood. The variability and severity of symptoms is significant and how COL4A1/A2-related disorders will potentially affect an individual can be unique. Clinical case reports suggest a syndrome with characteristic core findings; however, much about the disorder is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of other genes or factors influencing the disorder make it challenging to develop a complete picture of associated symptoms and prognosis. Therefore, it is important to note that there is a very broad spectrum of clinical presentations with different organs affected to different degrees between patients. Autosomal Dominant Familial Porencephaly Type IThe first reports of human COL4A1 mutations were in patients with autosomal dominant porencephaly and a more recent study found that COL4A1 mutations were found in ~16% of patients with porencephaly. Porencephaly refers to the formation of fluid-filled cysts or cavities within of the brain. The size and location of cerebral cavities contributes to clinical variability. In some people, serious, life-threatening complications may occur in infancy; in others, only minor complications may occur and intelligence is unaffected. Still other individuals may not develop any symptoms until well into adulthood. Symptoms that may occur in individuals with autosomal dominant type I porencephaly include migraines, weakness or paralysis of one side of the body (hemiparesis or hemiplegia), seizures, stroke, and dystonia, a group of neurological disorders characterized by involuntary muscle contractions that force the body into abnormal, sometimes painful, movements and positions. Migraines can occur with or without aura. Aura refers to additional neurological symptoms that occur with, or sometimes before, the development of the migraine headache. Affected infants and children can exhibit delays in reaching developmental milestones and varying degrees of intellectual disability. Additional features include poor or absent speech development, facial paralysis (paresis), involuntary muscle spasms (spasticity) that result in slow, stiff, rigid movements, visual field defects, and hydrocephalus, a condition in which accumulation of excessive cerebrospinal fluid in the skull causes pressure on the tissues of the brain, resulting in a variety of symptoms.Autosomal Dominant Brain Small Vessel DiseaseIn a retrospective study of 52 patients with COL4A1 mutations, stroke occurred in 17.3% of subjects and MRI showed white matter abnormalities (63.5%), subcortical microbleeds (52.9%), porencephaly (46%), enlarged spaces around blood vessels, (19.2%), and small infarctions (13.5%). This study clearly demonstrates that COL4A1 and COL4A2 mutations cause clinically variable cerebrovascular disease that includes characteristic features of cerebral small vessel disease. Cerebral small vessel disease with hemorrhage is likely milder continuum from porencephaly and exhibits many of the same symptoms (with the exception of the brain cavities). Affected individuals may have no observable symptoms or only isolated migraines with aura. Some affected individuals may develop weakness or paralysis of one side of the body (hemiparesis or hemiplegia) and have seizures. The main symptom is single or repeated bleeding inside the skull (intracranial hemorrhaging) that can occur without cause (spontaneously), after trauma, or when taking drugs that slow blood clotting (anticoagulants). In addition to the effects of a clear COL4A1 or COL4A2 mutation, large genetic studies reported associations for COL4A1/A2 with intracranial aneurysms, myocardial infarction, arterial calcification, arterial stiffness, deep intracerebral hemorrhages, lacunar ischemic stroke, reduced white matter volume and vascular leukoencephalopathy. Together, these studies suggest that certain unknown variants of COL4A1 and COL4A2 might contribute to chronic vascular dysfunction. Additional Signs and SymptomsMany patients with COL4A1 and COL4A2 mutations have additional signs and symptoms that do not include the cerebral vasculature. Some of these patients have been described as having HANAC syndrome, which is an acronym for hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. Affected individuals have kidney disease (nephropathy) causing blood in the urine (hematuria) that can either be seen by the naked eye (gross hematuria) or only visible when tested (microscopic hematuria). Some individuals develop cysts on the kidney. Aneurysms are bulges or enlargements of a blood vessel caused by weakening of the wall of the blood vessel. In most people, small vessel disease in the brain does not cause symptoms. Painful muscle cramps can occur and can develop before three years of age. Various muscles can be affected and muscle strength can become weakened. However, these findings can be observed independently or in combinations, in many patients with COL4A1 and COL4A2 mutations.COL4A1/A2-related disorders can also be associated with a variety of abnormalities affecting the front or back of the eyes. In the front of the eye, patients can have abnormally small eyes (microphthalmia), cataracts (cloudy lenses), and anterior segment dysgenesis (Axenfeld-Rieger). Cataracts, which are a clouding of the lenses of the eyes, are often present from birth (congenital) and may be one of the first identifiable signs of the syndrome. Axenfeld-Rieger is a collection of abnormalities affecting the front of the eye including the iris (colored part of the eye) and cornea (abnormally small corneas called microcornea), which is the transparent membrane that covers the eyes. Developmental defects to the front of the eye, which also includes the ocular drainage structures between the iris and cornea, can lead to increased pressure in the eye (elevated intraocular pressure, or IOP). Acute or chronic IOP elevation can lead to glaucoma where the increased pressure damages the optic nerve causing progressive and irreversible vision loss. In the back of the eye, affected individuals have also twisting or distortion (tortuosity) of arteries in the retina (bilateral retinal arterial tortuosity) as part of the syndrome or as an isolated finding. The retina is the light-sensitive membrane that lines the inside of the eyes. The cells of the retina trigger nerve impulses that run from the optic nerve to the brain to form sight. Abnormal retinal arteries are prone to rupture causing bleeding associated with temporary loss of vision or even retinal detachments that can cause permanent vision loss. A variety of additional signs and symptoms have been reported in individuals with COL4A1/A2-related disorders including childhood-onset epilepsy, hemolytic anemia ¬(a condition characterized by low levels of circulating red blood cells due to their premature destruction leading to fatigue, weakness, lightheadedness, dizziness, irritability, headaches, and pale skin color), mitral valve prolapse (flaps of the valve located between the upper and lower left heart chambers bulge or collapse during contraction allowing leakage of blood back into the left atrium).Other patients have been reported with cysts on the liver, irregular heartbeats (supraventricular arrhythmia), and Raynaud phenomenon, which is in which the fingers or toes become numb or have a prickly sensation in response to cold due to narrowing of blood vessels.Congenital Cephalic Disorders
In addition to porencephaly there can be other forms of damage to the brain present at birth. Individuals with COL4A1 or COL4A2 mutations can also develop formation of clefts or slits in the two halves of the brain (schizencephaly) in which cerebral hemispheres are missing and replaced with sacs filled with cerebrospinal fluid (hydranencephaly), abnormal folds in the brain surface (polymicrogyria) or abnormalities in the normal laying of the neuronal cells in the brain (cortical lamination defects). | 288 | COL4A1/A2-Related Disorders |
nord_288_2 | Causes of COL4A1/A2-Related Disorders | COL4A1/A2-related disorders are caused by dominant mutations in the COL4A1 or COL4A2 genes. These genes are the blueprints for two proteins that wind together like a long rope inside cells. When these ‘ropes' are secreted, they assemble into net-like structures outside the cells. When a mutation occurs in one of these genes, the rope does not wind up properly and it stays inside the cell. This can lead to problems 1) if too much of the misfolded protein accumulates within cells, 2) if not enough of the protein exits the cells to form networks, and 3) occasionally, the presence of the mutant proteins outside the cells can interfere with the structure of the network.The networks formed by the COL4A1 and COL4A2 proteins are called basement membranes and are present in every organ of the body. In addition to providing strength and support to tissues, basement membranes provide instructional cues to cells. For example, networks of COL4A1 and COL4A2 are present in the basement membranes of blood vessels. It is possible that insufficient collagen in the basement membrane predisposes blood vessels in the brain to leak or rupture. However, it is also very likely that basement membrane defects also contribute to abnormal signaling and function of cells that form blood vessels in the brain and elsewhere. This can manifest as porencephaly if the vessels rupture in utero, hemorrhagic stroke postnatally or in adults, or even small cerebral microbleeds that might go unnoticed except on MRI. The latest research shows that insufficient COL4A1/A2 in basement membranes damages different tissues in very different ways.Children inherit a full complement of chromosomes from each of their parent and so we carry two copies of each gene. COL4A1/A2-related disorders are dominant genetic disorders. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual (called sporadic or de novo). The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females. However, there are exceptions that depend on precisely when and where the mutation arose. These exceptions are nuanced and should be discussed with a genetic counselor. For example, if the mutation arises during the formation of the sperm or the egg, then all of the cells that make up the child will carry the mutation. If the mutation arises after fertilization, then some cells will carry the mutation and others will not – this is called mosaicism. Depending on the cell type that acquires the mutation and when the mutation arises, the individual may have many or few cells with the mutation. It is not uncommon for an unaffected parent to have a severely affected child. While there are other explanations, parental mosaicism should be considered. Mosaic individuals are likely less severely affected, or even asymptomatic, because they have many cells that secrete COL4A1 normally and that can compensate for those cells that cannot. When an individual tests positive for a mutation but does not manifest the effects, it is referred to as having incomplete or reduced penetrance. A similar term, variable expressivity, describes when affected individuals have widely varying signs and symptoms. Mosaicism can contribute to both reduced penetrance or variable expressivity but other factors do as well. For example, an individual may carry genetic variants elsewhere in their genome that confers protection or susceptibly to the mutation and environmental experiences (trauma, anticoagulant use, physical exertion etc.) can also contribute. With genetic disorders, the type of mutation, or its location in the gene can sometimes be associated with varying outcomes. This is called genotype-phenotype correlation. Researchers are still trying to determine whether there are any specific genotype-phenotype correlations in COL4A1/A2-related disorders. Research in mice with Col4a1 mutations suggests that the position of the mutation is very important. For example, the position of the mutation along the length of the protein can influence the severity of cerebrovascular disease and mutations in ‘functional subdomains’ can influence the likelihood of tissue-specific involvement (for example, muscle). These types of correlations can be difficult to detect in patients because of the broad genetic variability in humans. | Causes of COL4A1/A2-Related Disorders. COL4A1/A2-related disorders are caused by dominant mutations in the COL4A1 or COL4A2 genes. These genes are the blueprints for two proteins that wind together like a long rope inside cells. When these ‘ropes' are secreted, they assemble into net-like structures outside the cells. When a mutation occurs in one of these genes, the rope does not wind up properly and it stays inside the cell. This can lead to problems 1) if too much of the misfolded protein accumulates within cells, 2) if not enough of the protein exits the cells to form networks, and 3) occasionally, the presence of the mutant proteins outside the cells can interfere with the structure of the network.The networks formed by the COL4A1 and COL4A2 proteins are called basement membranes and are present in every organ of the body. In addition to providing strength and support to tissues, basement membranes provide instructional cues to cells. For example, networks of COL4A1 and COL4A2 are present in the basement membranes of blood vessels. It is possible that insufficient collagen in the basement membrane predisposes blood vessels in the brain to leak or rupture. However, it is also very likely that basement membrane defects also contribute to abnormal signaling and function of cells that form blood vessels in the brain and elsewhere. This can manifest as porencephaly if the vessels rupture in utero, hemorrhagic stroke postnatally or in adults, or even small cerebral microbleeds that might go unnoticed except on MRI. The latest research shows that insufficient COL4A1/A2 in basement membranes damages different tissues in very different ways.Children inherit a full complement of chromosomes from each of their parent and so we carry two copies of each gene. COL4A1/A2-related disorders are dominant genetic disorders. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual (called sporadic or de novo). The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females. However, there are exceptions that depend on precisely when and where the mutation arose. These exceptions are nuanced and should be discussed with a genetic counselor. For example, if the mutation arises during the formation of the sperm or the egg, then all of the cells that make up the child will carry the mutation. If the mutation arises after fertilization, then some cells will carry the mutation and others will not – this is called mosaicism. Depending on the cell type that acquires the mutation and when the mutation arises, the individual may have many or few cells with the mutation. It is not uncommon for an unaffected parent to have a severely affected child. While there are other explanations, parental mosaicism should be considered. Mosaic individuals are likely less severely affected, or even asymptomatic, because they have many cells that secrete COL4A1 normally and that can compensate for those cells that cannot. When an individual tests positive for a mutation but does not manifest the effects, it is referred to as having incomplete or reduced penetrance. A similar term, variable expressivity, describes when affected individuals have widely varying signs and symptoms. Mosaicism can contribute to both reduced penetrance or variable expressivity but other factors do as well. For example, an individual may carry genetic variants elsewhere in their genome that confers protection or susceptibly to the mutation and environmental experiences (trauma, anticoagulant use, physical exertion etc.) can also contribute. With genetic disorders, the type of mutation, or its location in the gene can sometimes be associated with varying outcomes. This is called genotype-phenotype correlation. Researchers are still trying to determine whether there are any specific genotype-phenotype correlations in COL4A1/A2-related disorders. Research in mice with Col4a1 mutations suggests that the position of the mutation is very important. For example, the position of the mutation along the length of the protein can influence the severity of cerebrovascular disease and mutations in ‘functional subdomains’ can influence the likelihood of tissue-specific involvement (for example, muscle). These types of correlations can be difficult to detect in patients because of the broad genetic variability in humans. | 288 | COL4A1/A2-Related Disorders |
nord_288_3 | Affects of COL4A1/A2-Related Disorders | COL4A1/A2-related disorders are believed to affect females and males in equal numbers. Over 100 families have been identified with these disorders in the medical literature and many more cases are known that are not in the published literature. Rare disorders often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. Given the variable expressivity of these mutations, COL4A1/A2-related disorders are likely under diagnosed and the exact number of people who have these disorders is unknown. Interestingly, COL4A1 and COL4A2 mutations appear to lead to generally similar outcomes although COL4A2 mutations occur less frequently. | Affects of COL4A1/A2-Related Disorders. COL4A1/A2-related disorders are believed to affect females and males in equal numbers. Over 100 families have been identified with these disorders in the medical literature and many more cases are known that are not in the published literature. Rare disorders often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. Given the variable expressivity of these mutations, COL4A1/A2-related disorders are likely under diagnosed and the exact number of people who have these disorders is unknown. Interestingly, COL4A1 and COL4A2 mutations appear to lead to generally similar outcomes although COL4A2 mutations occur less frequently. | 288 | COL4A1/A2-Related Disorders |
nord_288_4 | Related disorders of COL4A1/A2-Related Disorders | Symptoms of the following disorders can be similar to those of COL4A1/A2-related disorders. Comparisons may be useful for a differential diagnosis:CADASIL is a rare genetic disorder affecting the small blood vessels in the brain. The age of onset, severity, specific symptoms and disease progression varies greatly from one person to another, even among members of the same family. CADASIL is an acronym that stands for: (C)erebral – relating to the brain (A)utosomal (D)ominant – a form of inheritance in which one copy of an abnormal gene is necessary for the development of a disorder (A)rteriopathy – disease of the arteries (blood vessels that carry blood away from the heart) (S)ubcortical – relating to specific areas of the brain supplied by deep small arteries (I)nfarcts – tissue loss in the brain caused by lack of blood flow to the brain, which occurs when circulation through the small arteries is severely reduced or interrupted (L)eukoencephalopathy – lesions in the brain white matter caused by the disease and observed on MRI. CADASIL patients can experience progressive memory loss, deterioration of intellectual abilities and loss of balance with a progressive worsening of these symptoms, but symptoms are usually less severe and occur later in life. (For more information on this disorder, choose “cadasil” as your search term in the Rare Disease Database.)A variety of rare genetic disorders may have symptoms similar to those found in COL4A1/A2-related disorders. These disorders include autosomal dominant retinal vasculopathy with cerebral leukodystrophy (RVCL), hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS), cerebral autosomal recessive arteriopathy with subcortical infarcts and leukodystrophy (CARASIL), mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), Fabry disease, and a variety of leukodystrophies, rare progressive metabolic disorders that affect the brain, spinal cord and often the peripheral nerves. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | Related disorders of COL4A1/A2-Related Disorders. Symptoms of the following disorders can be similar to those of COL4A1/A2-related disorders. Comparisons may be useful for a differential diagnosis:CADASIL is a rare genetic disorder affecting the small blood vessels in the brain. The age of onset, severity, specific symptoms and disease progression varies greatly from one person to another, even among members of the same family. CADASIL is an acronym that stands for: (C)erebral – relating to the brain (A)utosomal (D)ominant – a form of inheritance in which one copy of an abnormal gene is necessary for the development of a disorder (A)rteriopathy – disease of the arteries (blood vessels that carry blood away from the heart) (S)ubcortical – relating to specific areas of the brain supplied by deep small arteries (I)nfarcts – tissue loss in the brain caused by lack of blood flow to the brain, which occurs when circulation through the small arteries is severely reduced or interrupted (L)eukoencephalopathy – lesions in the brain white matter caused by the disease and observed on MRI. CADASIL patients can experience progressive memory loss, deterioration of intellectual abilities and loss of balance with a progressive worsening of these symptoms, but symptoms are usually less severe and occur later in life. (For more information on this disorder, choose “cadasil” as your search term in the Rare Disease Database.)A variety of rare genetic disorders may have symptoms similar to those found in COL4A1/A2-related disorders. These disorders include autosomal dominant retinal vasculopathy with cerebral leukodystrophy (RVCL), hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS), cerebral autosomal recessive arteriopathy with subcortical infarcts and leukodystrophy (CARASIL), mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), Fabry disease, and a variety of leukodystrophies, rare progressive metabolic disorders that affect the brain, spinal cord and often the peripheral nerves. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | 288 | COL4A1/A2-Related Disorders |
nord_288_5 | Diagnosis of COL4A1/A2-Related Disorders | A diagnosis of COL4A1/A2-related disorders is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests including advanced imaging techniques. A diagnosis can be confirmed through molecular genetic testing. Molecular genetic testing can detect variations in the COL4A1 and COL4A2 genes that cause these disorders, but is available only as a diagnostic service at specialized laboratories.Clinical Testing and Workup
Advanced imaging techniques can include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues, including the brain. Individuals with COL4A1/A2-related disorders have characteristic patterns of brain disease when viewed under advanced imaging techniques.If individuals have muscle cramps, blood tests can reveal elevated levels creatine kinase, which is a muscle enzyme. When this enzyme is elevated, it is a sign of muscle damage. This is not specific to COL4A1/A2-related disorders, and is a sign of many different types of muscle disease. Urine analysis to test for blood or excess protein can be used to evaluate renal function and identify if the kidneys might be affected. | Diagnosis of COL4A1/A2-Related Disorders. A diagnosis of COL4A1/A2-related disorders is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests including advanced imaging techniques. A diagnosis can be confirmed through molecular genetic testing. Molecular genetic testing can detect variations in the COL4A1 and COL4A2 genes that cause these disorders, but is available only as a diagnostic service at specialized laboratories.Clinical Testing and Workup
Advanced imaging techniques can include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues, including the brain. Individuals with COL4A1/A2-related disorders have characteristic patterns of brain disease when viewed under advanced imaging techniques.If individuals have muscle cramps, blood tests can reveal elevated levels creatine kinase, which is a muscle enzyme. When this enzyme is elevated, it is a sign of muscle damage. This is not specific to COL4A1/A2-related disorders, and is a sign of many different types of muscle disease. Urine analysis to test for blood or excess protein can be used to evaluate renal function and identify if the kidneys might be affected. | 288 | COL4A1/A2-Related Disorders |
nord_288_6 | Therapies of COL4A1/A2-Related Disorders | Treatment
The management of COL4A1/A2-related disorders may require the coordinated efforts of a team of specialists. Pediatricians are physicians who specialize in the childhood disorders and are often the first to detect patients with COL4A1/A2-related disorders. The team may eventually include pediatric neurologists (diagnose and treat disorders of the brain, nerves and nervous system in children); ophthalmologists (who specialize in eye disorders) hematologists (who specialize in blood disorders); cardiologists (who specialize in heart disorders, nephrologists (who specialize in kidney disorders) and other healthcare professionals may need to systematically and comprehensively plan treatment. Additionally, consultation with a genetic counselor is strongly recommended for affected individuals and their families and psychosocial support for the entire family is essential. Some of the patient advocacy organizations listed in the Resources section below provide support and information to affected individuals and their families. 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 critical to determine the long-term safety and effectiveness of specific medications and treatments for individuals with COL4A1/A2-related disorders. Therapies are based on the specific symptoms in each individual. For example, treatment may include physical therapy, speech therapy, anti-convulsant medications for seizures, and a shunt to treat hydrocephalus by draining excess fluid from the skull. Individuals with high blood pressure (hypertension) must receive appropriate therapy because of the increased risk of stroke. Surgery may be necessary for individuals with severe cataracts. Glaucoma is initially treated with topical medications and, if medical therapy is unsuccessful, surgery. Drugs that prevent irregular heartbeats (anti-arrhythmic medications) are used to treat supraventricular arrythmia. Surgery or endovascular therapy can be used to treat intracranial hemorrhage. Endovascular therapy is a minimally-invasive procedure in which a long, thin tube called a catheter is passed into the blood vessel to repair or strengthen the blood vessel.
Early intervention is important in ensuring that children with reach their highest potential. Services that may be beneficial for some affected individuals include medical, social, and/or vocational services such as special remedial education.Smoking, which also increases the risk of stroke, physical activities that can cause head trauma such as contact sports, and the use of anti-clotting (anticoagulant) medications, should be avoided. | Therapies of COL4A1/A2-Related Disorders. Treatment
The management of COL4A1/A2-related disorders may require the coordinated efforts of a team of specialists. Pediatricians are physicians who specialize in the childhood disorders and are often the first to detect patients with COL4A1/A2-related disorders. The team may eventually include pediatric neurologists (diagnose and treat disorders of the brain, nerves and nervous system in children); ophthalmologists (who specialize in eye disorders) hematologists (who specialize in blood disorders); cardiologists (who specialize in heart disorders, nephrologists (who specialize in kidney disorders) and other healthcare professionals may need to systematically and comprehensively plan treatment. Additionally, consultation with a genetic counselor is strongly recommended for affected individuals and their families and psychosocial support for the entire family is essential. Some of the patient advocacy organizations listed in the Resources section below provide support and information to affected individuals and their families. 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 critical to determine the long-term safety and effectiveness of specific medications and treatments for individuals with COL4A1/A2-related disorders. Therapies are based on the specific symptoms in each individual. For example, treatment may include physical therapy, speech therapy, anti-convulsant medications for seizures, and a shunt to treat hydrocephalus by draining excess fluid from the skull. Individuals with high blood pressure (hypertension) must receive appropriate therapy because of the increased risk of stroke. Surgery may be necessary for individuals with severe cataracts. Glaucoma is initially treated with topical medications and, if medical therapy is unsuccessful, surgery. Drugs that prevent irregular heartbeats (anti-arrhythmic medications) are used to treat supraventricular arrythmia. Surgery or endovascular therapy can be used to treat intracranial hemorrhage. Endovascular therapy is a minimally-invasive procedure in which a long, thin tube called a catheter is passed into the blood vessel to repair or strengthen the blood vessel.
Early intervention is important in ensuring that children with reach their highest potential. Services that may be beneficial for some affected individuals include medical, social, and/or vocational services such as special remedial education.Smoking, which also increases the risk of stroke, physical activities that can cause head trauma such as contact sports, and the use of anti-clotting (anticoagulant) medications, should be avoided. | 288 | COL4A1/A2-Related Disorders |
nord_289_0 | Overview of Cold Agglutinin Disease | Cold agglutinin disease (CAD) is a rare autoimmune disorder characterized by the premature destruction of red blood cells (hemolysis). Autoimmune diseases occur when one’s own immune system attacks healthy tissue. More specifically, CAD is a subtype of autoimmune hemolytic anemia. In this type of disorder, red blood cells are “tagged” by antibodies and are then destroyed by other types of immune cells. The disease is termed “cold” because the antibodies are active and cause hemolysis at cold temperatures, usually 3 to 4oC (37 to 39oF), which is not necessarily the case in other types of autoimmune hemolytic anemia. CAD affects about one person per million every year, and mostly develops between the ages of 40 and 80 years. Normally, the red blood cells have a life span of approximately 120 days before they are destroyed by the spleen. In individuals with CAD, the red blood cells are destroyed prematurely and the rate of production of new cells in the bone marrow can no longer compensate for their loss. A decreased number of red blood cells (anemia) may cause fatigue, weakness, a pale skin color (pallor), dizziness, palpitations, and shortness of breath (dyspnea). Hemolysis leads to an increased release from red blood cells of hemoglobin, a protein responsible for carrying oxygen in the blood. Degradation of hemoglobin into bilirubin can result in yellowing of the skin and whites of the eyes (jaundice). Hemoglobin can also pass in the urine and give it a dark brown color. Other symptoms that can be triggered by exposure to cold include sweating and coldness of the fingers and/or toes (digits) and painful bluish or reddish discoloration of the skin of the digits, ankles, and wrists (acrocyanosis or Raynaud sign). Treatment of CAD includes avoidance of cold temperatures, treating anemia and hemolysis (if needed) and medications that modulate the immune system to decrease the production of antibodies against red blood cells. If applicable, the underlying disease that caused CAD should be treated. | Overview of Cold Agglutinin Disease. Cold agglutinin disease (CAD) is a rare autoimmune disorder characterized by the premature destruction of red blood cells (hemolysis). Autoimmune diseases occur when one’s own immune system attacks healthy tissue. More specifically, CAD is a subtype of autoimmune hemolytic anemia. In this type of disorder, red blood cells are “tagged” by antibodies and are then destroyed by other types of immune cells. The disease is termed “cold” because the antibodies are active and cause hemolysis at cold temperatures, usually 3 to 4oC (37 to 39oF), which is not necessarily the case in other types of autoimmune hemolytic anemia. CAD affects about one person per million every year, and mostly develops between the ages of 40 and 80 years. Normally, the red blood cells have a life span of approximately 120 days before they are destroyed by the spleen. In individuals with CAD, the red blood cells are destroyed prematurely and the rate of production of new cells in the bone marrow can no longer compensate for their loss. A decreased number of red blood cells (anemia) may cause fatigue, weakness, a pale skin color (pallor), dizziness, palpitations, and shortness of breath (dyspnea). Hemolysis leads to an increased release from red blood cells of hemoglobin, a protein responsible for carrying oxygen in the blood. Degradation of hemoglobin into bilirubin can result in yellowing of the skin and whites of the eyes (jaundice). Hemoglobin can also pass in the urine and give it a dark brown color. Other symptoms that can be triggered by exposure to cold include sweating and coldness of the fingers and/or toes (digits) and painful bluish or reddish discoloration of the skin of the digits, ankles, and wrists (acrocyanosis or Raynaud sign). Treatment of CAD includes avoidance of cold temperatures, treating anemia and hemolysis (if needed) and medications that modulate the immune system to decrease the production of antibodies against red blood cells. If applicable, the underlying disease that caused CAD should be treated. | 289 | Cold Agglutinin Disease |
nord_289_1 | Symptoms of Cold Agglutinin Disease | CAD typically develops in individuals between the age of 40 and 80, and is more common in elderly individuals. The symptoms associated with the disease are mostly the result of either hemolysis or circulatory symptoms, both of which are triggered by exposure to cold temperatures. Some individuals, especially those with mild hemolysis and a gradual onset of anemia, may not have any obvious symptoms (asymptomatic). Symptoms of anemia include paleness of the skin (pallor), fatigue, shortness of breath (dyspnea), dizziness and palpitations. In cases of brisk and severe hemolysis, chest pain, decreased alertness (lethargy), confusion, transient loss of consciousness (syncope), and deregulation of heart rate and blood pressure (hemodynamic instability) might occur. Hemolysis also leads to increased release of hemoglobin (an oxygen-carrying protein) in the blood and urine, which can result in darkly pigmented urine. Hemoglobin is degraded into a yellow compound called bilirubin, which can accumulate and lead to yellowing of the skin and whites of the eyes (jaundice). Circulatory symptoms seen in CAD include coldness of the fingers and/or toes (digits) and painful bluish or reddish discoloration of the skin of the digits, ankles, and wrists (acrocyanosis or Raynaud phenomenon). In severe cases, ulcers may develop on the extremities of digits. There is a possibility that people living with CAD are at a higher risk of developing blood clots, although more studies are needed to clarify this potential association. CAD can be a long-standing (chronic) disease, but can be self-limited and clinically silent, especially when associated with infectious diseases (see below); although it can be caused by severe diseases, CAD itself does not seem to be associated with a significantly decreased life expectancy. | Symptoms of Cold Agglutinin Disease. CAD typically develops in individuals between the age of 40 and 80, and is more common in elderly individuals. The symptoms associated with the disease are mostly the result of either hemolysis or circulatory symptoms, both of which are triggered by exposure to cold temperatures. Some individuals, especially those with mild hemolysis and a gradual onset of anemia, may not have any obvious symptoms (asymptomatic). Symptoms of anemia include paleness of the skin (pallor), fatigue, shortness of breath (dyspnea), dizziness and palpitations. In cases of brisk and severe hemolysis, chest pain, decreased alertness (lethargy), confusion, transient loss of consciousness (syncope), and deregulation of heart rate and blood pressure (hemodynamic instability) might occur. Hemolysis also leads to increased release of hemoglobin (an oxygen-carrying protein) in the blood and urine, which can result in darkly pigmented urine. Hemoglobin is degraded into a yellow compound called bilirubin, which can accumulate and lead to yellowing of the skin and whites of the eyes (jaundice). Circulatory symptoms seen in CAD include coldness of the fingers and/or toes (digits) and painful bluish or reddish discoloration of the skin of the digits, ankles, and wrists (acrocyanosis or Raynaud phenomenon). In severe cases, ulcers may develop on the extremities of digits. There is a possibility that people living with CAD are at a higher risk of developing blood clots, although more studies are needed to clarify this potential association. CAD can be a long-standing (chronic) disease, but can be self-limited and clinically silent, especially when associated with infectious diseases (see below); although it can be caused by severe diseases, CAD itself does not seem to be associated with a significantly decreased life expectancy. | 289 | Cold Agglutinin Disease |
nord_289_2 | Causes of Cold Agglutinin Disease | CAD occurs when antibodies produced by the immune system bind to red blood cells and identify them as targets. Antibodies are specialized proteins that bind to invading organisms and contribute to their destruction. There are five main classes of antibodies -IgA, IgD, IgE, IgG, and IgM. Most cases of CAD are due to IgM antibodies. When antibodies attack healthy tissue, they may be referred to as autoantibodies. In the case of CAD, these autoantibodies are active and can trigger hemolysis when they are exposed to cold temperatures. Once red blood cells are “tagged” by a cold-induced antibody, they can clump (agglutinate) and are then bound by another component of the immune system known as complements. Once red blood cells are bound to complements, they are attacked and destroyed by different types of immune cells, such as macrophages.CAD may also occur as a secondary disorder in association with a number of different underlying disorders such as certain infectious diseases (e.g., mycoplasma infection, mumps, cytomegalovirus, infectious mononucleosis), immunoproliferative diseases (e.g., non-Hodgkin's lymphoma, chronic lymphocytic leukemia, monoclonal gammopathy of unknown significance), or connective tissue disorders (e.g., rheumatoid arthritis, systemic lupus erythematosus). A secondary cause of CAD might be present in up to 70% of affected individuals. | Causes of Cold Agglutinin Disease. CAD occurs when antibodies produced by the immune system bind to red blood cells and identify them as targets. Antibodies are specialized proteins that bind to invading organisms and contribute to their destruction. There are five main classes of antibodies -IgA, IgD, IgE, IgG, and IgM. Most cases of CAD are due to IgM antibodies. When antibodies attack healthy tissue, they may be referred to as autoantibodies. In the case of CAD, these autoantibodies are active and can trigger hemolysis when they are exposed to cold temperatures. Once red blood cells are “tagged” by a cold-induced antibody, they can clump (agglutinate) and are then bound by another component of the immune system known as complements. Once red blood cells are bound to complements, they are attacked and destroyed by different types of immune cells, such as macrophages.CAD may also occur as a secondary disorder in association with a number of different underlying disorders such as certain infectious diseases (e.g., mycoplasma infection, mumps, cytomegalovirus, infectious mononucleosis), immunoproliferative diseases (e.g., non-Hodgkin's lymphoma, chronic lymphocytic leukemia, monoclonal gammopathy of unknown significance), or connective tissue disorders (e.g., rheumatoid arthritis, systemic lupus erythematosus). A secondary cause of CAD might be present in up to 70% of affected individuals. | 289 | Cold Agglutinin Disease |
nord_289_3 | Affects of Cold Agglutinin Disease | CAD most commonly affects people between the ages of 40 and 80. The median age at symptom onset is around 65 years, meaning that half of affected individuals develop symptoms before this age, and the other half after this age. The disease is present in about 16 people per million (prevalence), and develops in one person per million every year (incidence). The disease is almost twice as common in women compared to men. Those living with conditions associated with CAD (see “causes” section above) are more likely to develop the disease. CAD is also potentially more common, or at least more recognized, in colder climates. | Affects of Cold Agglutinin Disease. CAD most commonly affects people between the ages of 40 and 80. The median age at symptom onset is around 65 years, meaning that half of affected individuals develop symptoms before this age, and the other half after this age. The disease is present in about 16 people per million (prevalence), and develops in one person per million every year (incidence). The disease is almost twice as common in women compared to men. Those living with conditions associated with CAD (see “causes” section above) are more likely to develop the disease. CAD is also potentially more common, or at least more recognized, in colder climates. | 289 | Cold Agglutinin Disease |
nord_289_4 | Related disorders of Cold Agglutinin Disease | Symptoms of the following disorders can be similar to those of CAD. Comparisons may be useful for a differential diagnosis:Paroxysmal cold hemoglobinuria (PCH) is a type of cold-induced autoimmune hemolytic anemia. The hemolysis is usually brisk and can be associated with severe pain in the back and legs, headache, vomiting, diarrhea and passage of dark brown urine (hemoglobinuria). There may be temporary enlargement of the liver and spleen. This disorder is frequently associated with viral infections such as chickenpox and mumps. (For more information on this disorder, choose “paroxysmal cold hemoglobinuria” as your search term in the Rare Disease Database.)Warm autoimmune hemolytic anemia (WAHA) is a type of autoimmune hemolytic anemia in which autoantibodies are triggered at body temperature. Symptoms are those of hemolysis and anemia, in addition to an enlarged spleen in some cases and an increased risk of developing blood clots. WAHA may arise without a clear cause (primary WAHA) or it may be caused by an underlying condition (secondary WAHA). The list of causes of secondary WAHA is extensive but notably includes medications, autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis, deficiency of the immune system (immunodeficiency), leukemias and lymphomas, infections, and pregnancy. (For more information on this disorders, choose “warm autoimmune hemolytic anemia” as your search term in the Rare Disease Database.)Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired stem cell disorder. The classic finding is hemolysis, resulting in repeated episodes of hemoglobin in the urine (hemoglobinuria). Individuals with hemoglobinuria may exhibit dark-colored or bloody urine. This finding is most prominent in the morning. In addition to hemolysis, individuals with PNH are also susceptible to developing repeated, potentially life-threatening blood clots (thromboses). Affected individuals also have some degree of underlying bone marrow dysfunction. Severe bone marrow dysfunction potentially results in low values of red and white blood cells and platelets (pancytopenia). The specific symptoms of PNH vary greatly and affected individuals usually do not exhibit all of the symptoms associated with the disorder. (For more information on this disorder, choose “paroxysmal nocturnal hemoglobinuria” as your search term in the Rare Disease Database.) | Related disorders of Cold Agglutinin Disease. Symptoms of the following disorders can be similar to those of CAD. Comparisons may be useful for a differential diagnosis:Paroxysmal cold hemoglobinuria (PCH) is a type of cold-induced autoimmune hemolytic anemia. The hemolysis is usually brisk and can be associated with severe pain in the back and legs, headache, vomiting, diarrhea and passage of dark brown urine (hemoglobinuria). There may be temporary enlargement of the liver and spleen. This disorder is frequently associated with viral infections such as chickenpox and mumps. (For more information on this disorder, choose “paroxysmal cold hemoglobinuria” as your search term in the Rare Disease Database.)Warm autoimmune hemolytic anemia (WAHA) is a type of autoimmune hemolytic anemia in which autoantibodies are triggered at body temperature. Symptoms are those of hemolysis and anemia, in addition to an enlarged spleen in some cases and an increased risk of developing blood clots. WAHA may arise without a clear cause (primary WAHA) or it may be caused by an underlying condition (secondary WAHA). The list of causes of secondary WAHA is extensive but notably includes medications, autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis, deficiency of the immune system (immunodeficiency), leukemias and lymphomas, infections, and pregnancy. (For more information on this disorders, choose “warm autoimmune hemolytic anemia” as your search term in the Rare Disease Database.)Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired stem cell disorder. The classic finding is hemolysis, resulting in repeated episodes of hemoglobin in the urine (hemoglobinuria). Individuals with hemoglobinuria may exhibit dark-colored or bloody urine. This finding is most prominent in the morning. In addition to hemolysis, individuals with PNH are also susceptible to developing repeated, potentially life-threatening blood clots (thromboses). Affected individuals also have some degree of underlying bone marrow dysfunction. Severe bone marrow dysfunction potentially results in low values of red and white blood cells and platelets (pancytopenia). The specific symptoms of PNH vary greatly and affected individuals usually do not exhibit all of the symptoms associated with the disorder. (For more information on this disorder, choose “paroxysmal nocturnal hemoglobinuria” as your search term in the Rare Disease Database.) | 289 | Cold Agglutinin Disease |
nord_289_5 | Diagnosis of Cold Agglutinin Disease | A diagnosis of hemolytic anemia may be suspected based on a thorough clinical evaluation, a detailed patient history, identification of characteristic symptoms and a variety of tests such as blood tests that measure values of hemoglobin and the percentage of the total blood volume occupied by red blood cells (hematocrit). Blood tests may also show an elevated value of immature red blood cells (reticulocytes), which occurs when the body is forced to produce extra red blood cells to make up for those that are destroyed prematurely. Some individuals with hemolytic anemia have elevated values of bilirubin in the blood (hyperbilirubinemia). Hemolytic anemia also leads to increased values of lactate dehydrogenase (LDH) in the blood, as it is released when red blood cells are destroyed. Haptoglobin is a hemoglobin scavenger that gets consumed when hemoglobin is released in the blood due to hemolysis. Haptoglobin values are therefore low in hemolytic anemia. When hemolytic anemia is suspected to be autoimmune in origin, specialized tests such as a Coombs test may be performed. This test is used to detect antibodies bound to red blood cells or other biological mediators, like complement (component 3, C3), which accompanies the binding of immunoglobulin to their targets. A sample of blood is taken and then exposed to the Coombs reagent. A positive test is indicated when the red blood cells clump in the presence of the reagent. In CAD, the immunoglobulin may not be picked up with the Coombs test, but this test most often picks-up the presence of C3 on the red cells, A thermal amplitude test then has to be performed to measure the reactivity of the detected antibodies at different temperatures. It is important to know how much of this cold agglutinin is present in each patient, especially to determine how it changes with treatment. This is done by determining the titer for the cold agglutinin, which is done by progressively diluting the serum of the patient until the agglutination of the red cells disappears. After a diagnosis of CAD is made, patients should be evaluated to attempt to identify a possible underlying condition such as an infection, autoimmune disease, or another blood disorder. The tests that will be performed depend on the clinical situation and the affected individual. In summary, the following sequence allows the diagnosis of CAD: 1) detection of anemia, 2) determination that the anemia is caused by hemolysis, based on elevated bilirubin and LDH and low haptoglobin, 3) determination that CAD is the cause of hemolytic anemia with a Coombs test and a cold agglutinin titer, and 4) investigation for a secondary cause of CAD. | Diagnosis of Cold Agglutinin Disease. A diagnosis of hemolytic anemia may be suspected based on a thorough clinical evaluation, a detailed patient history, identification of characteristic symptoms and a variety of tests such as blood tests that measure values of hemoglobin and the percentage of the total blood volume occupied by red blood cells (hematocrit). Blood tests may also show an elevated value of immature red blood cells (reticulocytes), which occurs when the body is forced to produce extra red blood cells to make up for those that are destroyed prematurely. Some individuals with hemolytic anemia have elevated values of bilirubin in the blood (hyperbilirubinemia). Hemolytic anemia also leads to increased values of lactate dehydrogenase (LDH) in the blood, as it is released when red blood cells are destroyed. Haptoglobin is a hemoglobin scavenger that gets consumed when hemoglobin is released in the blood due to hemolysis. Haptoglobin values are therefore low in hemolytic anemia. When hemolytic anemia is suspected to be autoimmune in origin, specialized tests such as a Coombs test may be performed. This test is used to detect antibodies bound to red blood cells or other biological mediators, like complement (component 3, C3), which accompanies the binding of immunoglobulin to their targets. A sample of blood is taken and then exposed to the Coombs reagent. A positive test is indicated when the red blood cells clump in the presence of the reagent. In CAD, the immunoglobulin may not be picked up with the Coombs test, but this test most often picks-up the presence of C3 on the red cells, A thermal amplitude test then has to be performed to measure the reactivity of the detected antibodies at different temperatures. It is important to know how much of this cold agglutinin is present in each patient, especially to determine how it changes with treatment. This is done by determining the titer for the cold agglutinin, which is done by progressively diluting the serum of the patient until the agglutination of the red cells disappears. After a diagnosis of CAD is made, patients should be evaluated to attempt to identify a possible underlying condition such as an infection, autoimmune disease, or another blood disorder. The tests that will be performed depend on the clinical situation and the affected individual. In summary, the following sequence allows the diagnosis of CAD: 1) detection of anemia, 2) determination that the anemia is caused by hemolysis, based on elevated bilirubin and LDH and low haptoglobin, 3) determination that CAD is the cause of hemolytic anemia with a Coombs test and a cold agglutinin titer, and 4) investigation for a secondary cause of CAD. | 289 | Cold Agglutinin Disease |
nord_289_6 | Therapies of Cold Agglutinin Disease | Treatment
Avoidance of cold exposure, particularly to the head, face, and extremities, is important to decrease hemolysis and circulatory symptoms. Other measures have to be taken in certain circumstances, such as prewarming of infusions (e.g. intravenous fluids) in hospitalized patients. If symptoms are mild or if destruction of red blood cells seems to be slowing of its own accord, usually no treatment is needed. If the rate at which red blood cells are being destroyed appears to be increasing, medication might be needed. Rituximab is an artificially-created antibody (monoclonal antibody) that targets certain white blood cells that create the antibodies which prematurely destroy red blood cells. It is considered first-line therapy in CAD and can be combined with the chemotherapy agents fludarabine or bendamustine or with prednisone. Although patients tend to respond well to rituximab, relapses are common. Rituximab can also be used to treat relapses of CAD. If an underlying condition is identified as the cause of CAD, it should be treated. In the case a patient develops rapid hemolysis or is severely anemic, blood transfusions or plasma exchange might be required. Plasma is the component of the blood in which antibodies circulate, so plasma exchange can momentarily decrease the autoantibody burden in a patient. However, these two measures do not treat the cause of the anemia and provide only temporary relief. In cases in which blood transfusions are necessary, certain guidelines must be followed because of the temperature sensitivities involved.In 2022, sutimlimab (Enjaymo) was approved by the U.S. Food and Drug Administration (FDA) to decrease the need for red blood cell transfusion due to hemolysis in adults with CAD. | Therapies of Cold Agglutinin Disease. Treatment
Avoidance of cold exposure, particularly to the head, face, and extremities, is important to decrease hemolysis and circulatory symptoms. Other measures have to be taken in certain circumstances, such as prewarming of infusions (e.g. intravenous fluids) in hospitalized patients. If symptoms are mild or if destruction of red blood cells seems to be slowing of its own accord, usually no treatment is needed. If the rate at which red blood cells are being destroyed appears to be increasing, medication might be needed. Rituximab is an artificially-created antibody (monoclonal antibody) that targets certain white blood cells that create the antibodies which prematurely destroy red blood cells. It is considered first-line therapy in CAD and can be combined with the chemotherapy agents fludarabine or bendamustine or with prednisone. Although patients tend to respond well to rituximab, relapses are common. Rituximab can also be used to treat relapses of CAD. If an underlying condition is identified as the cause of CAD, it should be treated. In the case a patient develops rapid hemolysis or is severely anemic, blood transfusions or plasma exchange might be required. Plasma is the component of the blood in which antibodies circulate, so plasma exchange can momentarily decrease the autoantibody burden in a patient. However, these two measures do not treat the cause of the anemia and provide only temporary relief. In cases in which blood transfusions are necessary, certain guidelines must be followed because of the temperature sensitivities involved.In 2022, sutimlimab (Enjaymo) was approved by the U.S. Food and Drug Administration (FDA) to decrease the need for red blood cell transfusion due to hemolysis in adults with CAD. | 289 | Cold Agglutinin Disease |
nord_290_0 | Overview of Collagen Type VI-Related Disorders | Collagen type VI-related disorders encompass two genetic muscle disorders formerly thought to be separate entities: Bethlem myopathy and Ullrich congenital muscular dystrophy. Researchers have determined that these disorders represent a disease spectrum associated with disruptions or changes (mutations) in genes that contain instructions to produce (encode) collagen type VI proteins. Bethlem myopathy represents the milder form of this spectrum and Ullrich congenital muscular dystrophy represents the severe end. Common symptoms include progressive muscle weakness and degeneration (atrophy) and abnormally fixed joints that occur when thickening and shortening of tissue such as muscle fibers and tendons cause deformity and restrict the movement of an affected area (contractures). Both Bethlem myopathy and Ullrich CMD can be inherited as autosomal dominant or autosomal recessive traits. | Overview of Collagen Type VI-Related Disorders. Collagen type VI-related disorders encompass two genetic muscle disorders formerly thought to be separate entities: Bethlem myopathy and Ullrich congenital muscular dystrophy. Researchers have determined that these disorders represent a disease spectrum associated with disruptions or changes (mutations) in genes that contain instructions to produce (encode) collagen type VI proteins. Bethlem myopathy represents the milder form of this spectrum and Ullrich congenital muscular dystrophy represents the severe end. Common symptoms include progressive muscle weakness and degeneration (atrophy) and abnormally fixed joints that occur when thickening and shortening of tissue such as muscle fibers and tendons cause deformity and restrict the movement of an affected area (contractures). Both Bethlem myopathy and Ullrich CMD can be inherited as autosomal dominant or autosomal recessive traits. | 290 | Collagen Type VI-Related Disorders |
nord_290_1 | Symptoms of Collagen Type VI-Related Disorders | The symptoms, severity, and age of onset of collagen type VI-related disorders vary greatly. In most cases, affected individuals have muscle weakness and degeneration and skeletal abnormalities such as curvature of the spine (scoliosis) and contractures.
Bethlem Myopathy (Benign Congenital Myopathy with Contractures)
Bethlem myopathy is a disorder characterized by mild weakness of the proximal muscles. Proximal muscles are the muscles that are closest to the center of the body such as the muscles of the shoulder, pelvis, and upper arms and legs. Muscle weakness may eventually affect the distal muscles to a lesser degree. Distal muscles are those farther from the center of the body and include the muscles of the lower arms and legs and the hands and feet.The symptoms of Bethlem myopathy may be apparent before birth (prenatally), shortly after birth (neonatally), or during adolescence or adulthood. In addition to muscle weakness, newborns and infants with Bethlem myopathy may develop diminished muscle tone (hypotonia), repeated mild contractures of certain joints especially the fingers, elbows, ankles, and knees, a twisted or tilted neck (torticollis), and delays in achieving motor milestones.Bethlem myopathy is slowly progressive. In some adults, noticeable muscle weakness may not occur until after 40 years of age. Many individuals with Bethlem retain the ability to walk either independently or with assistance (e.g., cane or crutches) throughout life. Some individuals may eventually require a wheelchair.In rare cases, breathing (respiratory) difficulties may occur late in life due to weakness of the diaphragm muscles. Heart (cardiac) function, which may become impaired in other forms of myopathy, is usually unaffected in individuals with Bethlem myopathy.In some cases, a skin condition may occur that is characterized by thickening and hardening (hyperkeratosis) of hair follicles, resulting in the development of rough, elevated growths (papules) on the skin.Ullrich Congenital Muscular Dystrophy (UCMD)
Ullrich CMD is characterized by diminished muscle tone (hypotonia), weakness and degeneration of the proximal muscles, and abnormally flexible (hyperelastic) joints of the wrists and ankles. Additional early symptoms of Ullrich CMD include the failure to gain weight and grow at the expected rate (failure to thrive), abnormal front-to-back and side-to-side curvature of the spine (kyphoscoliosis), a twisted or tilted neck (torticollis), congenital dislocation of the hip, contractures of the joints, and stiffness (rigidity) of the spine.
Intelligence is normal in most cases. The amount of motor development varies from case to case. Some children are able to walk independently; others require assistance to walk. In some cases, affected children may never be able to walk. In addition, some children who develop the ability to walk independently lose that ability because of the progression of the disease (e.g., worsening contractures, rigidity of spine).Additional symptoms may occur including breathing (respiratory) difficulties and frequent chest infections. Breathing difficulties can result in life-threatening complications and may require respiratory support, especially at night.As the disorder progress, previously flexible (lax) joints such as those of the wrists and ankles may stiffen. Some affected individuals may exhibit a skin condition characterized by thickening and hardening (hyperkeratosis) of hair follicles, resulting in the development of rough, elevated growths (papules). In some cases, scars may heal slowly or affected individuals may develop hardened, raised bumps at the site of an injury (hypertrophic keloid scars).Some individuals with Ullrich CMD may have a distinctive facial appearance with a rounded face with prominent ears. | Symptoms of Collagen Type VI-Related Disorders. The symptoms, severity, and age of onset of collagen type VI-related disorders vary greatly. In most cases, affected individuals have muscle weakness and degeneration and skeletal abnormalities such as curvature of the spine (scoliosis) and contractures.
Bethlem Myopathy (Benign Congenital Myopathy with Contractures)
Bethlem myopathy is a disorder characterized by mild weakness of the proximal muscles. Proximal muscles are the muscles that are closest to the center of the body such as the muscles of the shoulder, pelvis, and upper arms and legs. Muscle weakness may eventually affect the distal muscles to a lesser degree. Distal muscles are those farther from the center of the body and include the muscles of the lower arms and legs and the hands and feet.The symptoms of Bethlem myopathy may be apparent before birth (prenatally), shortly after birth (neonatally), or during adolescence or adulthood. In addition to muscle weakness, newborns and infants with Bethlem myopathy may develop diminished muscle tone (hypotonia), repeated mild contractures of certain joints especially the fingers, elbows, ankles, and knees, a twisted or tilted neck (torticollis), and delays in achieving motor milestones.Bethlem myopathy is slowly progressive. In some adults, noticeable muscle weakness may not occur until after 40 years of age. Many individuals with Bethlem retain the ability to walk either independently or with assistance (e.g., cane or crutches) throughout life. Some individuals may eventually require a wheelchair.In rare cases, breathing (respiratory) difficulties may occur late in life due to weakness of the diaphragm muscles. Heart (cardiac) function, which may become impaired in other forms of myopathy, is usually unaffected in individuals with Bethlem myopathy.In some cases, a skin condition may occur that is characterized by thickening and hardening (hyperkeratosis) of hair follicles, resulting in the development of rough, elevated growths (papules) on the skin.Ullrich Congenital Muscular Dystrophy (UCMD)
Ullrich CMD is characterized by diminished muscle tone (hypotonia), weakness and degeneration of the proximal muscles, and abnormally flexible (hyperelastic) joints of the wrists and ankles. Additional early symptoms of Ullrich CMD include the failure to gain weight and grow at the expected rate (failure to thrive), abnormal front-to-back and side-to-side curvature of the spine (kyphoscoliosis), a twisted or tilted neck (torticollis), congenital dislocation of the hip, contractures of the joints, and stiffness (rigidity) of the spine.
Intelligence is normal in most cases. The amount of motor development varies from case to case. Some children are able to walk independently; others require assistance to walk. In some cases, affected children may never be able to walk. In addition, some children who develop the ability to walk independently lose that ability because of the progression of the disease (e.g., worsening contractures, rigidity of spine).Additional symptoms may occur including breathing (respiratory) difficulties and frequent chest infections. Breathing difficulties can result in life-threatening complications and may require respiratory support, especially at night.As the disorder progress, previously flexible (lax) joints such as those of the wrists and ankles may stiffen. Some affected individuals may exhibit a skin condition characterized by thickening and hardening (hyperkeratosis) of hair follicles, resulting in the development of rough, elevated growths (papules). In some cases, scars may heal slowly or affected individuals may develop hardened, raised bumps at the site of an injury (hypertrophic keloid scars).Some individuals with Ullrich CMD may have a distinctive facial appearance with a rounded face with prominent ears. | 290 | Collagen Type VI-Related Disorders |
nord_290_2 | Causes of Collagen Type VI-Related Disorders | Bethlem myopathy and Ullrich CMD are caused by mutations in one of three genes that carry the instructions to produce (encode) various parts of collagen VI. Collagen VI is a protein that plays an essential role in the proper function and health of muscle cells.Two of the genes are located on the long arm of chromosome 21 (21q22.3) and the other is found on the long arm of chromosome 2 (2q37). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 21q22.3” refers to band 22.3 on the long arm of chromosome 21. The numbered bands specify the location of the thousands of genes that are present on each chromosome.Both Bethlem myopathy and Ullrich CMD can be inherited as autosomal dominant or autosomal recessive traits. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. 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. If an affected parent has a dominant mutation the risk of passing the abnormal gene from parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child. If the disorder is the result of a new mutation in the affected individual then the chance of the parents having another affected child is very low.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 on 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. | Causes of Collagen Type VI-Related Disorders. Bethlem myopathy and Ullrich CMD are caused by mutations in one of three genes that carry the instructions to produce (encode) various parts of collagen VI. Collagen VI is a protein that plays an essential role in the proper function and health of muscle cells.Two of the genes are located on the long arm of chromosome 21 (21q22.3) and the other is found on the long arm of chromosome 2 (2q37). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 21q22.3” refers to band 22.3 on the long arm of chromosome 21. The numbered bands specify the location of the thousands of genes that are present on each chromosome.Both Bethlem myopathy and Ullrich CMD can be inherited as autosomal dominant or autosomal recessive traits. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. 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. If an affected parent has a dominant mutation the risk of passing the abnormal gene from parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child. If the disorder is the result of a new mutation in the affected individual then the chance of the parents having another affected child is very low.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 on 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. | 290 | Collagen Type VI-Related Disorders |
nord_290_3 | Affects of Collagen Type VI-Related Disorders | Collagen type VI-related disorders affect males and females in equal numbers. The incidence and prevalence of these disorders are unknown. Because these disorders often go unrecognized, they may be underdiagnosed making it difficult to determine their true frequency in the general population.Bethlem myopathy was first described in the medical literature in 1976. Ullrich CMD was first described in the medical literature in 1930. The disorders have been described in individuals of varied ethnic backgrounds. | Affects of Collagen Type VI-Related Disorders. Collagen type VI-related disorders affect males and females in equal numbers. The incidence and prevalence of these disorders are unknown. Because these disorders often go unrecognized, they may be underdiagnosed making it difficult to determine their true frequency in the general population.Bethlem myopathy was first described in the medical literature in 1976. Ullrich CMD was first described in the medical literature in 1930. The disorders have been described in individuals of varied ethnic backgrounds. | 290 | Collagen Type VI-Related Disorders |
nord_290_4 | Related disorders of Collagen Type VI-Related Disorders | Symptoms of the following disorders can be similar to those of collagen type VI-related disorders. Comparisons may be useful for a differential diagnosis.Limb-girdle muscular dystrophy (LGMD) is a generic term for a group of rare progressive genetic disorders that are characterized by wasting (atrophy) and weakness of the voluntary muscles of the hip and shoulder areas (limb-girdle area). Muscle weakness and atrophy are progressive and may spread to affect other muscles of the body. Approximately 15 different subtypes have been identified based upon abnormal changes (mutations) of certain genes. The age of onset, severity, and progression of symptoms of these subtypes varies greatly even among individuals in the same family. Some individuals may have a mild, slowly progressive form of the disorders; other may have a rapidly progressive form of the disorder that causes severe disability. The term limb-girdle muscular dystrophy is a general term encompasses several disorders. These disorders can now be distinguished by genetic and protein analysis. At least 15 subtypes have been identified. The various forms of LGMD may be inherited as an autosomal dominant or recessive trait. Autosomal dominant LGMD is known as LGMD1 and has five subtypes (LGMDA-E). Autosomal recessive LGMD is known as LGMD2 and has 10 subtypes (LGMDA-J). (For more information on this disorder, choose “limb-girdle muscular dystrophy” as your search term in the Rare Disease Database.)Emery-Dreifuss muscular dystrophy (EDMD) is a rare, often slowly progressive genetic disorder affecting the muscles of the arms, legs, face, neck, spine and heart. The disorder consists of the clinical triad of weakness and degeneration (atrophy) of certain muscles, joints that are fixed in a flexed or extended position (contractures), and abnormalities affecting the heart (cardiomyopathy). Major symptoms may include muscle wasting and weakness particularly in arms and lower legs (humeroperoneal regions) and contractures of the elbows, Achilles tendons, and upper back muscles. In some cases, additional abnormalities may be present. In most cases, EDMD is inherited as an X-linked recessive or autosomal dominant trait. In extremely rare cases, autosomal recessive inheritance has been reported. Although EDMD has different modes of inheritance, the symptoms are nearly the same. (For more information on this disorder, choose “Emery-Dreifuss” as your search term in the Rare Disease Database.)Congenital muscular dystrophy (CMD) is a general term for a group of genetic muscle diseases that are present at birth (congenital) or develop early during infancy. CMDs are generally characterized by diminished muscle tone (hypotonia), which is sometimes referred to as “floppy baby”; progressive muscle weakness and degeneration (atrophy); abnormally fixed joints that occur when thickening and shortening of tissue such as muscle fibers and tendons cause deformity and restrict the movement of an affected area (contractures); and delays in reaching motor milestones such as sitting or standing unassisted. Some forms of CMD may be associated with structural brain defects and, potentially, intellectual disability. The severity, specific symptoms, and progression of these disorders vary greatly. Almost all known forms of CMD are inherited as autosomal recessive traits. (For more information on this disorder, choose “congenital muscular dystrophy” as your search term in the Rare Disease Database.)Spinal muscular atrophy (SMA) that is caused by a deletion of the SMN gene on chromosome 5 is an inherited progressive neuromuscular disorder characterized by degeneration of groups of nerve cells (motor nuclei) within the lowest region of the brain (lower brainstem) and certain motor neurons in the spinal cord (anterior horn cells). Motor neurons are nerve cells that transmit nerve impulses from the spinal cord or brain (central nervous system) to muscle or glandular tissue. Typical symptoms are a slowly progressive muscle weakness and muscle wasting (atrophy). Affected individuals have poor muscle tone, muscle weakness on both sides of the body without, or with minimal, involvement of the face muscles, twitching tongue and a lack of deep tendon reflexes. SMA is divided into subtypes based on age of onset of symptoms and maximum function achieved. (For more information on this disorder, choose “spinal muscular atrophy” as your search term in the Rare Disease Database.) | Related disorders of Collagen Type VI-Related Disorders. Symptoms of the following disorders can be similar to those of collagen type VI-related disorders. Comparisons may be useful for a differential diagnosis.Limb-girdle muscular dystrophy (LGMD) is a generic term for a group of rare progressive genetic disorders that are characterized by wasting (atrophy) and weakness of the voluntary muscles of the hip and shoulder areas (limb-girdle area). Muscle weakness and atrophy are progressive and may spread to affect other muscles of the body. Approximately 15 different subtypes have been identified based upon abnormal changes (mutations) of certain genes. The age of onset, severity, and progression of symptoms of these subtypes varies greatly even among individuals in the same family. Some individuals may have a mild, slowly progressive form of the disorders; other may have a rapidly progressive form of the disorder that causes severe disability. The term limb-girdle muscular dystrophy is a general term encompasses several disorders. These disorders can now be distinguished by genetic and protein analysis. At least 15 subtypes have been identified. The various forms of LGMD may be inherited as an autosomal dominant or recessive trait. Autosomal dominant LGMD is known as LGMD1 and has five subtypes (LGMDA-E). Autosomal recessive LGMD is known as LGMD2 and has 10 subtypes (LGMDA-J). (For more information on this disorder, choose “limb-girdle muscular dystrophy” as your search term in the Rare Disease Database.)Emery-Dreifuss muscular dystrophy (EDMD) is a rare, often slowly progressive genetic disorder affecting the muscles of the arms, legs, face, neck, spine and heart. The disorder consists of the clinical triad of weakness and degeneration (atrophy) of certain muscles, joints that are fixed in a flexed or extended position (contractures), and abnormalities affecting the heart (cardiomyopathy). Major symptoms may include muscle wasting and weakness particularly in arms and lower legs (humeroperoneal regions) and contractures of the elbows, Achilles tendons, and upper back muscles. In some cases, additional abnormalities may be present. In most cases, EDMD is inherited as an X-linked recessive or autosomal dominant trait. In extremely rare cases, autosomal recessive inheritance has been reported. Although EDMD has different modes of inheritance, the symptoms are nearly the same. (For more information on this disorder, choose “Emery-Dreifuss” as your search term in the Rare Disease Database.)Congenital muscular dystrophy (CMD) is a general term for a group of genetic muscle diseases that are present at birth (congenital) or develop early during infancy. CMDs are generally characterized by diminished muscle tone (hypotonia), which is sometimes referred to as “floppy baby”; progressive muscle weakness and degeneration (atrophy); abnormally fixed joints that occur when thickening and shortening of tissue such as muscle fibers and tendons cause deformity and restrict the movement of an affected area (contractures); and delays in reaching motor milestones such as sitting or standing unassisted. Some forms of CMD may be associated with structural brain defects and, potentially, intellectual disability. The severity, specific symptoms, and progression of these disorders vary greatly. Almost all known forms of CMD are inherited as autosomal recessive traits. (For more information on this disorder, choose “congenital muscular dystrophy” as your search term in the Rare Disease Database.)Spinal muscular atrophy (SMA) that is caused by a deletion of the SMN gene on chromosome 5 is an inherited progressive neuromuscular disorder characterized by degeneration of groups of nerve cells (motor nuclei) within the lowest region of the brain (lower brainstem) and certain motor neurons in the spinal cord (anterior horn cells). Motor neurons are nerve cells that transmit nerve impulses from the spinal cord or brain (central nervous system) to muscle or glandular tissue. Typical symptoms are a slowly progressive muscle weakness and muscle wasting (atrophy). Affected individuals have poor muscle tone, muscle weakness on both sides of the body without, or with minimal, involvement of the face muscles, twitching tongue and a lack of deep tendon reflexes. SMA is divided into subtypes based on age of onset of symptoms and maximum function achieved. (For more information on this disorder, choose “spinal muscular atrophy” as your search term in the Rare Disease Database.) | 290 | Collagen Type VI-Related Disorders |
nord_290_5 | Diagnosis of Collagen Type VI-Related Disorders | A diagnosis of Bethlem myopathy or Ullrich CMD is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic symptoms (e.g., specific distribution of muscle weakness and atrophy), and a variety of specialized tests including surgical removal and microscopic examination (biopsy) of affected muscle tissue that may reveal characteristic changes to muscle fibers; a test that assesses the health of muscles and the nerves that control muscles (electromyography); specialized blood tests; and tests that evaluate the presence and number of certain muscle proteins (immunohistochemistry).During an electromyography, a needle electrode is inserted through the skin into an affected muscle. The electrode records the electrical activity of the muscle. This record shows how well a muscle responds to the nerves and can determine whether muscle weakness is caused by the muscle themselves or by the nerves that control the muscles. An electromyography can rule out nerve disorders such as motor neuron disease and peripheral neuropathy.Blood tests may reveal slightly elevated levels of the creatine kinase (CK), an enzyme that is often found in abnormally high levels when muscle is damaged. Slightly elevated CK levels occur in some, but not all cases of collagen type VI-related disorders. The detection of elevated CK levels can confirm that muscle is damaged or inflamed, but cannot confirm a diagnosis.In some cases of Ullrich CMD, a specialized test can be performed on muscle biopsy samples that can determine the presence and levels of specific muscle proteins within muscle cells or tissue (immunolabeling). Various techniques such as immunostaining, immunofluorescence or Western blot (immunoblot) can be used. These tests involve the use of certain antibodies that react to certain muscle proteins. Samples from muscle biopsies are exposed to these antibodies and the results can determine whether a specific muscle protein is present and in what quantity. In Ullrich CMD, collagen VI can be markedly reduced or absent or show abnormal localization in the muscle. In Bethlem myopathy, immunolabeling usually only shows subtle changes or normal collagen VI, therefore the test cannot usually aid in diagnosis.Increasingly, a new genetic test called exome sequencing is being offered as the front line diagnostic test. This test uses DNA isolated from blood or a cheek swap and examines all the genes known to cause inherited neuromuscular disorders. | Diagnosis of Collagen Type VI-Related Disorders. A diagnosis of Bethlem myopathy or Ullrich CMD is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic symptoms (e.g., specific distribution of muscle weakness and atrophy), and a variety of specialized tests including surgical removal and microscopic examination (biopsy) of affected muscle tissue that may reveal characteristic changes to muscle fibers; a test that assesses the health of muscles and the nerves that control muscles (electromyography); specialized blood tests; and tests that evaluate the presence and number of certain muscle proteins (immunohistochemistry).During an electromyography, a needle electrode is inserted through the skin into an affected muscle. The electrode records the electrical activity of the muscle. This record shows how well a muscle responds to the nerves and can determine whether muscle weakness is caused by the muscle themselves or by the nerves that control the muscles. An electromyography can rule out nerve disorders such as motor neuron disease and peripheral neuropathy.Blood tests may reveal slightly elevated levels of the creatine kinase (CK), an enzyme that is often found in abnormally high levels when muscle is damaged. Slightly elevated CK levels occur in some, but not all cases of collagen type VI-related disorders. The detection of elevated CK levels can confirm that muscle is damaged or inflamed, but cannot confirm a diagnosis.In some cases of Ullrich CMD, a specialized test can be performed on muscle biopsy samples that can determine the presence and levels of specific muscle proteins within muscle cells or tissue (immunolabeling). Various techniques such as immunostaining, immunofluorescence or Western blot (immunoblot) can be used. These tests involve the use of certain antibodies that react to certain muscle proteins. Samples from muscle biopsies are exposed to these antibodies and the results can determine whether a specific muscle protein is present and in what quantity. In Ullrich CMD, collagen VI can be markedly reduced or absent or show abnormal localization in the muscle. In Bethlem myopathy, immunolabeling usually only shows subtle changes or normal collagen VI, therefore the test cannot usually aid in diagnosis.Increasingly, a new genetic test called exome sequencing is being offered as the front line diagnostic test. This test uses DNA isolated from blood or a cheek swap and examines all the genes known to cause inherited neuromuscular disorders. | 290 | Collagen Type VI-Related Disorders |
nord_290_6 | Therapies of Collagen Type VI-Related Disorders | Treatment
The treatment of collagen type VI-related disorders is directed toward the specific symptoms that are apparent in each individual. Treatment varies based upon the specific symptoms present, their severity, and the age of onset.In individuals with Ullrich CMD, early intervention is essential to promote mobility and independence. The use of a standing frame may be necessary to achieve an upright posture and protect against the development of scoliosis and contractures. Physical and occupational therapy to improve muscle strength and prevent contractures is beneficial to individuals with Ullrich CMD or Bethlem myopathy. Surgery may be necessary to correct contractures or scoliosis, especially in individuals with Ullrich CMD.Regular monitoring of breathing (respiratory function) is recommended. Individuals with Ullrich CMD may need respiratory support such as (nocturnal ventilation). Individuals with Bethlem myopathy may develop respiratory difficulties later in life and may eventually require respiratory support such as mask ventilation. Antibiotics, vaccinations, and physiotherapy may be beneficial in preventing or treating repeated chest infections and preventing additional respiratory problems.Feeding difficulties that may occur in individuals with Ullrich CMD may require seeing a nutritionist to create a plan to ensure proper caloric intake. In severe cases, it may be necessary to use a gastrostomy tube, in which a tube is inserted into a surgical opening in the stomach to provide direct nutritional support.Individuals with Ullrich CMD may need various devices (e.g., canes, braces, walkers, wheelchairs) to assist with walking (ambulation) and mobility. Such assistive devices are necessary for approximately two-thirds of individuals with Bethlem myopathy over 50 years of age.Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive. | Therapies of Collagen Type VI-Related Disorders. Treatment
The treatment of collagen type VI-related disorders is directed toward the specific symptoms that are apparent in each individual. Treatment varies based upon the specific symptoms present, their severity, and the age of onset.In individuals with Ullrich CMD, early intervention is essential to promote mobility and independence. The use of a standing frame may be necessary to achieve an upright posture and protect against the development of scoliosis and contractures. Physical and occupational therapy to improve muscle strength and prevent contractures is beneficial to individuals with Ullrich CMD or Bethlem myopathy. Surgery may be necessary to correct contractures or scoliosis, especially in individuals with Ullrich CMD.Regular monitoring of breathing (respiratory function) is recommended. Individuals with Ullrich CMD may need respiratory support such as (nocturnal ventilation). Individuals with Bethlem myopathy may develop respiratory difficulties later in life and may eventually require respiratory support such as mask ventilation. Antibiotics, vaccinations, and physiotherapy may be beneficial in preventing or treating repeated chest infections and preventing additional respiratory problems.Feeding difficulties that may occur in individuals with Ullrich CMD may require seeing a nutritionist to create a plan to ensure proper caloric intake. In severe cases, it may be necessary to use a gastrostomy tube, in which a tube is inserted into a surgical opening in the stomach to provide direct nutritional support.Individuals with Ullrich CMD may need various devices (e.g., canes, braces, walkers, wheelchairs) to assist with walking (ambulation) and mobility. Such assistive devices are necessary for approximately two-thirds of individuals with Bethlem myopathy over 50 years of age.Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive. | 290 | Collagen Type VI-Related Disorders |
nord_291_0 | Overview of Colorado Tick Fever | Colorado Tick Fever is a rare viral disease transmitted by ticks that commonly inhabit the western United States. Major symptoms may include fever, headaches, muscle aches, and/or generalized discomfort (myalgia). The symptoms usually last for about a week and resolve on their own. | Overview of Colorado Tick Fever. Colorado Tick Fever is a rare viral disease transmitted by ticks that commonly inhabit the western United States. Major symptoms may include fever, headaches, muscle aches, and/or generalized discomfort (myalgia). The symptoms usually last for about a week and resolve on their own. | 291 | Colorado Tick Fever |
nord_291_1 | Symptoms of Colorado Tick Fever | Colorado Tick Fever typically has a sudden onset about five days after a tick bite. It usually occurs at moderate altitudes during spring or early summer. The symptoms are flu-like and may include chills, headache, increased sensitivity to light (photophobia), fatigue, nausea, vomiting, and a lack of appetite. Muscle pain occurs, especially in the legs and back. There may be a slight, reddish rash, and the spleen can become enlarged (splenomegaly). Fever may rise sharply for two or three days and then subside only to return after a day or two (biphasic fever). The second fever typically subsides after 2 to 4 days.In very rare childhood cases, severe illness involving the central nervous system may occur. Symptoms may include acute inflammation of the membranes around the brain (aseptic meningitis) and/or spinal cord (encephalitis). | Symptoms of Colorado Tick Fever. Colorado Tick Fever typically has a sudden onset about five days after a tick bite. It usually occurs at moderate altitudes during spring or early summer. The symptoms are flu-like and may include chills, headache, increased sensitivity to light (photophobia), fatigue, nausea, vomiting, and a lack of appetite. Muscle pain occurs, especially in the legs and back. There may be a slight, reddish rash, and the spleen can become enlarged (splenomegaly). Fever may rise sharply for two or three days and then subside only to return after a day or two (biphasic fever). The second fever typically subsides after 2 to 4 days.In very rare childhood cases, severe illness involving the central nervous system may occur. Symptoms may include acute inflammation of the membranes around the brain (aseptic meningitis) and/or spinal cord (encephalitis). | 291 | Colorado Tick Fever |
nord_291_2 | Causes of Colorado Tick Fever | Colorado Tick Fever is a rare viral disease caused by a virus belonging to the Coltivirus family. It is transmitted to humans through the bite of the wood tick (Dermacentor andersoni). | Causes of Colorado Tick Fever. Colorado Tick Fever is a rare viral disease caused by a virus belonging to the Coltivirus family. It is transmitted to humans through the bite of the wood tick (Dermacentor andersoni). | 291 | Colorado Tick Fever |
nord_291_3 | Affects of Colorado Tick Fever | Colorado Tick Fever is a rare viral disease that affects males and females in equal numbers. Most reported cases have occurred in the Rocky Mountain area of the United States and the western provinces of Canada. Several hundred cases of this disease are reported each year in these areas where the wood tick lives (endemic). However, it is possible that many additional cases are misdiagnosed or undiagnosed. | Affects of Colorado Tick Fever. Colorado Tick Fever is a rare viral disease that affects males and females in equal numbers. Most reported cases have occurred in the Rocky Mountain area of the United States and the western provinces of Canada. Several hundred cases of this disease are reported each year in these areas where the wood tick lives (endemic). However, it is possible that many additional cases are misdiagnosed or undiagnosed. | 291 | Colorado Tick Fever |
nord_291_4 | Related disorders of Colorado Tick Fever | Symptoms of the following disorders can be similar to those of Colorado Tick Fever. Comparisons may be useful for a differential diagnosis:Lyme Disease is an infectious inflammatory disease transmitted by a tick (Borrelia burgdorferi). The early symptoms may include a characteristic red, round skin lesion (bull-eye rash), fever, muscle pain, chills, headache, nausea, and/or vomiting. Swollen and/or painful joints may also occur. Neurological abnormalities may develop (e.g., meningitis, facial paralysis, involuntary muscle movements) but usually resolve completely without treatment. (For more information on this disorder, choose “Lyme” as your search term in the Rare Disease Database.)Rocky Mountain Spotted Fever is an acute disease caused by bacterium (Rickettsia) and transmitted by ticks. Initially, symptoms begin suddenly and may include fever, severe headache, and muscle pain. Nausea, vomiting, and abdominal pain may also occur. A rash typically begins on the wrists and ankles and spreads toward the center of the body. Early diagnosis and treatment are vital to avoid serious complications. (For more information on this disorder, choose “Rocky Mountain Spotted Fever” as your search term in the Rare Disease Database.) | Related disorders of Colorado Tick Fever. Symptoms of the following disorders can be similar to those of Colorado Tick Fever. Comparisons may be useful for a differential diagnosis:Lyme Disease is an infectious inflammatory disease transmitted by a tick (Borrelia burgdorferi). The early symptoms may include a characteristic red, round skin lesion (bull-eye rash), fever, muscle pain, chills, headache, nausea, and/or vomiting. Swollen and/or painful joints may also occur. Neurological abnormalities may develop (e.g., meningitis, facial paralysis, involuntary muscle movements) but usually resolve completely without treatment. (For more information on this disorder, choose “Lyme” as your search term in the Rare Disease Database.)Rocky Mountain Spotted Fever is an acute disease caused by bacterium (Rickettsia) and transmitted by ticks. Initially, symptoms begin suddenly and may include fever, severe headache, and muscle pain. Nausea, vomiting, and abdominal pain may also occur. A rash typically begins on the wrists and ankles and spreads toward the center of the body. Early diagnosis and treatment are vital to avoid serious complications. (For more information on this disorder, choose “Rocky Mountain Spotted Fever” as your search term in the Rare Disease Database.) | 291 | Colorado Tick Fever |
nord_291_5 | Diagnosis of Colorado Tick Fever | Diagnosis of Colorado Tick Fever. | 291 | Colorado Tick Fever |
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nord_291_6 | Therapies of Colorado Tick Fever | The diagnosis of Colorado Tick Fever is confirmed by isolation of the virus from the blood. Treatment for Colorado Tick Fever is symptomatic and may include acetaminophen to relieve headaches and muscle pain.The most effective means of preventing Colorado Tick Fever is the use of protective clothing or chemical tick repellents when visiting endemic areas during the spring and summer. Individuals should inspect themselves frequently for ticks and quickly remove them when found. | Therapies of Colorado Tick Fever. The diagnosis of Colorado Tick Fever is confirmed by isolation of the virus from the blood. Treatment for Colorado Tick Fever is symptomatic and may include acetaminophen to relieve headaches and muscle pain.The most effective means of preventing Colorado Tick Fever is the use of protective clothing or chemical tick repellents when visiting endemic areas during the spring and summer. Individuals should inspect themselves frequently for ticks and quickly remove them when found. | 291 | Colorado Tick Fever |
nord_292_0 | Overview of Common Variable Immune Deficiency | Common variable immune deficiency (CVID) is a type of primary immunodeficiency, which is defined as an immune system dysfunction typically caused by a mutation in a gene or genes. The World Health Organization (WHO) recognizes more than 400 primary immunodeficiencies ranging from relatively common to quite rare.CVID is one of the most prevalent of the symptomatic primary immunodeficiencies and manifests a wide variability of symptoms and range of severity. While considered a genetic condition, the syndrome consists of a group of diseases, and most of the causes are still unknown. CVID is characterized by low levels of specific proteins (immunoglobulins) in the fluid portion of the blood. This results in a loss of antibodies and a decreased ability to fight invading microorganisms, toxins, or other foreign substances. These immunoglobulins are produced by specialized white blood cells (B cells) as they mature into plasma cells.The cause of CVID is unknown in at least 80% of affected individuals, as a genetic cause has been identified in about 20%. Sporadic cases, with no apparent history of the disorder in the family, are the commonest form. These may be caused by a complex interaction of environmental and genetic components (multifactorial inheritance), but genes that are involved in the development and function of immune cells have now been shown to be the primary cause. | Overview of Common Variable Immune Deficiency. Common variable immune deficiency (CVID) is a type of primary immunodeficiency, which is defined as an immune system dysfunction typically caused by a mutation in a gene or genes. The World Health Organization (WHO) recognizes more than 400 primary immunodeficiencies ranging from relatively common to quite rare.CVID is one of the most prevalent of the symptomatic primary immunodeficiencies and manifests a wide variability of symptoms and range of severity. While considered a genetic condition, the syndrome consists of a group of diseases, and most of the causes are still unknown. CVID is characterized by low levels of specific proteins (immunoglobulins) in the fluid portion of the blood. This results in a loss of antibodies and a decreased ability to fight invading microorganisms, toxins, or other foreign substances. These immunoglobulins are produced by specialized white blood cells (B cells) as they mature into plasma cells.The cause of CVID is unknown in at least 80% of affected individuals, as a genetic cause has been identified in about 20%. Sporadic cases, with no apparent history of the disorder in the family, are the commonest form. These may be caused by a complex interaction of environmental and genetic components (multifactorial inheritance), but genes that are involved in the development and function of immune cells have now been shown to be the primary cause. | 292 | Common Variable Immune Deficiency |
nord_292_1 | Symptoms of Common Variable Immune Deficiency | The clinical course and symptoms of CVID vary widely from mild to severe. The immunoglobulins affected also vary. For example, some patients have a deficiency in all three major types of immunoglobulins: immunoglobulin G (IgG), immunoglobulin A (IgA), and immunoglobulin M (IgM) while others have a shortage of just IgG and IgA. The diagnosis is made by finding that functional antibodies are very low or absent.Onset of symptoms, including frequent and unusual infections, may first occur during childhood and adolescence; however, for many patients, the diagnosis may not be made until the third to fourth decade of life.People with CVID have trouble fighting off infections because of a lack of antibodies which are normally made to resist invading microbes. As antibody production is impaired, vaccines are not effective. Recurrent bacterial infections, particularly affecting the upper and lower respiratory tracts, such as in the lungs, sinuses, or ears, are common. Recurrent lung infections can lead to chronic lung disease and potentially life-threatening complications.Gastrointestinal complications, such as infections or inflammation, are also prevalent. Some patients report abdominal pain, bloating, nausea, vomiting, diarrhea and weight loss. Affected individuals may also have an impaired ability to absorb nutrients such as vitamins, minerals, fat and certain sugars from the digestive tract. Individuals with CVID may also experience recurrent or chronic infections (giardiasis) of the small intestine caused by the single-celled parasite called Giardia lamblia. Individuals with CVID also have an increased susceptibility to certain bacterial gastrointestinal infections (e.g., Campylobacter, etc.) or more recently, norovirus that causes symptoms similar to those associated with giardiasis.Due to abnormalities in the maturation of B cells, and dysregulation of the immune system, some individuals with CVID may have abnormal accumulations of lymphocytes in lymphoid tissues such as lymph nodes (lymphadenopathy) or spleen (splenomegaly). In some cases, abnormal growth of small nodules of lymphoid tissue in the gastrointestinal tract (nodular lymphoid hyperplasia) may occur. In addition, an increased percent of individuals with CVID are more prone to developing certain forms of cancer than the general population such as malignancies of lymphatic tissue (lymphoma) and possibly stomach cancer). The risk of gastric carcinoma is almost 50 times greater in patients with CVID than in other individuals.In addition, some individuals with CVID may develop granular, inflammatory nodules (noncaseating granulomas) within tissue of the skin, lungs, spleen, and/or liver.Twenty to twenty-five percent of patients with CVID are prone to developing certain autoimmune disorders. Immune thrombocytopenia (ITP) and autoimmune hemolytic anemia (AIHA) anemia are the most frequently diagnosed ones. (For more information on these disorders, choose “ITP” and “Anemia, Hemolytic, Acquired Autoimmune” as your search terms in the Rare Disease Database.)It is not fully understood why CVID patients are at risk for autoimmune disorders. While one would assume that CVID suppresses the immune response, in fact, loss of normal controls in CVID leads to autoimmunity due to an overactive or unrestrained portion of the immune system. This then leads to an attack on the body’s healthy tissues and organs. This phenomenon has long shown that more complex defects in the immune system, beyond qualitative and quantitative defects in antibody production, underlie the diverse clinical manifestations of CVID. | Symptoms of Common Variable Immune Deficiency. The clinical course and symptoms of CVID vary widely from mild to severe. The immunoglobulins affected also vary. For example, some patients have a deficiency in all three major types of immunoglobulins: immunoglobulin G (IgG), immunoglobulin A (IgA), and immunoglobulin M (IgM) while others have a shortage of just IgG and IgA. The diagnosis is made by finding that functional antibodies are very low or absent.Onset of symptoms, including frequent and unusual infections, may first occur during childhood and adolescence; however, for many patients, the diagnosis may not be made until the third to fourth decade of life.People with CVID have trouble fighting off infections because of a lack of antibodies which are normally made to resist invading microbes. As antibody production is impaired, vaccines are not effective. Recurrent bacterial infections, particularly affecting the upper and lower respiratory tracts, such as in the lungs, sinuses, or ears, are common. Recurrent lung infections can lead to chronic lung disease and potentially life-threatening complications.Gastrointestinal complications, such as infections or inflammation, are also prevalent. Some patients report abdominal pain, bloating, nausea, vomiting, diarrhea and weight loss. Affected individuals may also have an impaired ability to absorb nutrients such as vitamins, minerals, fat and certain sugars from the digestive tract. Individuals with CVID may also experience recurrent or chronic infections (giardiasis) of the small intestine caused by the single-celled parasite called Giardia lamblia. Individuals with CVID also have an increased susceptibility to certain bacterial gastrointestinal infections (e.g., Campylobacter, etc.) or more recently, norovirus that causes symptoms similar to those associated with giardiasis.Due to abnormalities in the maturation of B cells, and dysregulation of the immune system, some individuals with CVID may have abnormal accumulations of lymphocytes in lymphoid tissues such as lymph nodes (lymphadenopathy) or spleen (splenomegaly). In some cases, abnormal growth of small nodules of lymphoid tissue in the gastrointestinal tract (nodular lymphoid hyperplasia) may occur. In addition, an increased percent of individuals with CVID are more prone to developing certain forms of cancer than the general population such as malignancies of lymphatic tissue (lymphoma) and possibly stomach cancer). The risk of gastric carcinoma is almost 50 times greater in patients with CVID than in other individuals.In addition, some individuals with CVID may develop granular, inflammatory nodules (noncaseating granulomas) within tissue of the skin, lungs, spleen, and/or liver.Twenty to twenty-five percent of patients with CVID are prone to developing certain autoimmune disorders. Immune thrombocytopenia (ITP) and autoimmune hemolytic anemia (AIHA) anemia are the most frequently diagnosed ones. (For more information on these disorders, choose “ITP” and “Anemia, Hemolytic, Acquired Autoimmune” as your search terms in the Rare Disease Database.)It is not fully understood why CVID patients are at risk for autoimmune disorders. While one would assume that CVID suppresses the immune response, in fact, loss of normal controls in CVID leads to autoimmunity due to an overactive or unrestrained portion of the immune system. This then leads to an attack on the body’s healthy tissues and organs. This phenomenon has long shown that more complex defects in the immune system, beyond qualitative and quantitative defects in antibody production, underlie the diverse clinical manifestations of CVID. | 292 | Common Variable Immune Deficiency |
nord_292_2 | Causes of Common Variable Immune Deficiency | The cause of CVID is unknown for most patients but a genetic cause has been identified in about 20%. Autosomal dominant (mostly) and autosomal recessive inheritance has been reported in CVID. More commonly, sporadic cases, with no apparent history of the disorder in their family, may still be caused by either rare autosomal defects or complex interactions of environmental and genetic causes (multifactorial inheritance). Mutations in genes that are involved in the development and function of B cells are only a small part of the genes that lead to CVID, as most the causal genes identified are those that are involved in regulation of immune responses. B cells are specialized white blood cells that, as they mature into their final stage of plasma cells, produce special proteins called antibodies (immunoglobulins). These antibodies help protect the body against infection by attaching to specific invading microorganisms, toxins, or other foreign substances (antigens), marking them for destruction. Individuals with CVID usually have a deficiency of all major immunoglobulin classes (panhypogammaglobulinemia). However, in some cases, affected individuals may have severely reduced levels of some immunoglobulins (i.e., IgG and IgA) and relatively normal levels of IgM.Researchers have found that, in addition to defective B cells, errors in other immune cells (the T cell system) may either contribute to or be responsible for the irregularities in immunoglobulin production. Lack of T cell maturational influence on the developing B cell may lead to poor B cell development.Previous research suggested that, in certain cases, CVID and selective IgA deficiency are somewhat related conditions. In multigenerational families (kindreds) some have CVID while other members of the same families have selective IgA deficiency. (For more information on selective IgA deficiency, refer to the Related Disorders section below.)Dominant genetic disorders occur when a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual 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 have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, similar to 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.Mutations in many genes have now been associated with CVID. Approximately 8% of affected individuals have mutations in the TNFRSF13B gene but since mutations in this gene can be found in unaffected relatives and blood bank normal donors, it is not considered a direct cause of CVID. The second most common gene associated with CVID is an autosomal dominant gene, NFKB1, but not all family members with a mutation in this gene are affected. Other dominant genes associated with CVID include: NFKB2, CLTA4, PI3KCD, IKZF1 and STAT3. As for recessive genes, mutations in LRBA are common in some groups. Much more rarely, mutations in CD19, CD81, ICOS CD20, CD21, and TNFRSF13C have been identified. | Causes of Common Variable Immune Deficiency. The cause of CVID is unknown for most patients but a genetic cause has been identified in about 20%. Autosomal dominant (mostly) and autosomal recessive inheritance has been reported in CVID. More commonly, sporadic cases, with no apparent history of the disorder in their family, may still be caused by either rare autosomal defects or complex interactions of environmental and genetic causes (multifactorial inheritance). Mutations in genes that are involved in the development and function of B cells are only a small part of the genes that lead to CVID, as most the causal genes identified are those that are involved in regulation of immune responses. B cells are specialized white blood cells that, as they mature into their final stage of plasma cells, produce special proteins called antibodies (immunoglobulins). These antibodies help protect the body against infection by attaching to specific invading microorganisms, toxins, or other foreign substances (antigens), marking them for destruction. Individuals with CVID usually have a deficiency of all major immunoglobulin classes (panhypogammaglobulinemia). However, in some cases, affected individuals may have severely reduced levels of some immunoglobulins (i.e., IgG and IgA) and relatively normal levels of IgM.Researchers have found that, in addition to defective B cells, errors in other immune cells (the T cell system) may either contribute to or be responsible for the irregularities in immunoglobulin production. Lack of T cell maturational influence on the developing B cell may lead to poor B cell development.Previous research suggested that, in certain cases, CVID and selective IgA deficiency are somewhat related conditions. In multigenerational families (kindreds) some have CVID while other members of the same families have selective IgA deficiency. (For more information on selective IgA deficiency, refer to the Related Disorders section below.)Dominant genetic disorders occur when a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual 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 have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, similar to 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.Mutations in many genes have now been associated with CVID. Approximately 8% of affected individuals have mutations in the TNFRSF13B gene but since mutations in this gene can be found in unaffected relatives and blood bank normal donors, it is not considered a direct cause of CVID. The second most common gene associated with CVID is an autosomal dominant gene, NFKB1, but not all family members with a mutation in this gene are affected. Other dominant genes associated with CVID include: NFKB2, CLTA4, PI3KCD, IKZF1 and STAT3. As for recessive genes, mutations in LRBA are common in some groups. Much more rarely, mutations in CD19, CD81, ICOS CD20, CD21, and TNFRSF13C have been identified. | 292 | Common Variable Immune Deficiency |
nord_292_3 | Affects of Common Variable Immune Deficiency | CVID equally affects males and females. The prevalence of CVID is approximately 1 in 30,000 people. The diagnosis of CVID is not made in children under the age of 4, because until that time, it may be confused with other genetic defects that must be excluded. In addition, it can be confused with physiologic immaturity. However, most patients have symptoms later and are not diagnosed until ages 20-40. | Affects of Common Variable Immune Deficiency. CVID equally affects males and females. The prevalence of CVID is approximately 1 in 30,000 people. The diagnosis of CVID is not made in children under the age of 4, because until that time, it may be confused with other genetic defects that must be excluded. In addition, it can be confused with physiologic immaturity. However, most patients have symptoms later and are not diagnosed until ages 20-40. | 292 | Common Variable Immune Deficiency |
nord_292_4 | Related disorders of Common Variable Immune Deficiency | Symptoms of the following disorders may be similar to those of common variable immunodeficiency. Comparisons may be useful for a differential diagnosis:Agammaglobulinemia is a group of inherited immune deficiencies characterized by a low concentration of antibodies in the blood due to the lack of particular lymphocytes (B cells) in the blood and lymph. The types of agammaglobulinemia are: X-linked agammaglobulinemia (XLA), the much rarer X-linked agammaglobulinemia with growth hormone deficiency (about 10 cases reported), and autosomal recessive agammaglobulinemia. All of these disorders are characterized by a weakened immune system that must be strengthened by the administration of gammaglobulin in order to fight off infections. (For more information on this disorder, choose “agammaglobulinemia” as your search term in the Rare Disease Database.)Hyper-IgM Syndrome (HIGM) is a rare primary immunodeficiency disorder that is usually inherited as an X-linked recessive condition. People with this disorder have low levels of IgG, IgA and IgE antibodies. Levels of IgM antibodies may be high or in the normal range. Symptoms and physical findings usually become apparent in the first or second year of life. HIGM is characterized by recurrent bacterial infections of the middle ear, sinuses, lungs, the membrane that lines the eyelid and the white portion of the eyes, the skin, and/or other areas. Affected children may have an impaired absorption of nutrients, chronic diarrhea and failure to gain weight (failure to thrive) and enlargement of the tonsils and/or enlargement of the liver and spleen (hepatosplenomegaly). In addition, affected individuals are prone to the development of autoimmune disorders of the blood such as neutropenia, in which there is a decreased level of certain white blood cells. Because approximately 70 percent of reported cases of HIGM are X-linked, the vast majority of affected individuals are male. However, autosomal recessive and autosomal dominant forms of the disorder have also been described. (For more information on this disorder, choose “Hyper IgM” as your search term in the Rare Disease Database.)X-linked lymphoproliferative (XLP) syndrome is an extremely rare inherited primary immunodeficiency disorder characterized by a defective immune response to infection with the Epstein-Barr virus (EBV). This virus is common among the general population and is relatively well-known because it is the cause of infectious mononucleosis (IM), usually with no long-lasting effects. However, in individuals with XLP, exposure to EBV may result in severe, life-threatening fulminant hepatitis; abnormally low levels of antibodies in the blood and body secretions (hypogammaglobulinemia), resulting in increased susceptibility to various infections; malignancies of certain types of lymphoid tissue (B-cell lymphomas); and/or other abnormalities. The range of symptoms and findings associated with XLP may vary considerably from person to person. In addition, the range of effects may change in an affected individual over time. In most cases, individuals with XLP experience an onset of symptoms anytime from ages about 6 months to 10 years of age. XLP is caused by mutations in the SH2D1A and XIAP genes.The WAS-related disorders are a spectrum of conditions affecting the immune system that are caused by mutations in the WAS gene. These disorders include Wiskott-Aldrich syndrome, X-linked thrombocytopenia and X-linked congenital neutropenia. The WAS gene abnormality results in a deficiency in the WASP protein that leads to a low platelet count (thrombocytopenia). WAS-related disorders usually present in infancy and are characterized by bloody diarrhea, recurrent infections, scaling, itchy, skin rashes (eczema), and the appearance of small purple spots on the skin (petechia). The development of Pneumocystis carinii pneumonia (PCP) and intracranial bleeding are possible early, life-threatening complications. Later potential complications include destruction of red blood cells (hemolytic anemia), arthritis, vasculitis and kidney and liver damage. Affected individuals have an increased risk of developing lymphomas, especially after exposure to Epstein-Barr virus. WAS-related disorders are extremely variable, even in individuals in the same family. (For more information on this disorder, choose “WAS related disorders” as your search term in the Rare Disease Database.) | Related disorders of Common Variable Immune Deficiency. Symptoms of the following disorders may be similar to those of common variable immunodeficiency. Comparisons may be useful for a differential diagnosis:Agammaglobulinemia is a group of inherited immune deficiencies characterized by a low concentration of antibodies in the blood due to the lack of particular lymphocytes (B cells) in the blood and lymph. The types of agammaglobulinemia are: X-linked agammaglobulinemia (XLA), the much rarer X-linked agammaglobulinemia with growth hormone deficiency (about 10 cases reported), and autosomal recessive agammaglobulinemia. All of these disorders are characterized by a weakened immune system that must be strengthened by the administration of gammaglobulin in order to fight off infections. (For more information on this disorder, choose “agammaglobulinemia” as your search term in the Rare Disease Database.)Hyper-IgM Syndrome (HIGM) is a rare primary immunodeficiency disorder that is usually inherited as an X-linked recessive condition. People with this disorder have low levels of IgG, IgA and IgE antibodies. Levels of IgM antibodies may be high or in the normal range. Symptoms and physical findings usually become apparent in the first or second year of life. HIGM is characterized by recurrent bacterial infections of the middle ear, sinuses, lungs, the membrane that lines the eyelid and the white portion of the eyes, the skin, and/or other areas. Affected children may have an impaired absorption of nutrients, chronic diarrhea and failure to gain weight (failure to thrive) and enlargement of the tonsils and/or enlargement of the liver and spleen (hepatosplenomegaly). In addition, affected individuals are prone to the development of autoimmune disorders of the blood such as neutropenia, in which there is a decreased level of certain white blood cells. Because approximately 70 percent of reported cases of HIGM are X-linked, the vast majority of affected individuals are male. However, autosomal recessive and autosomal dominant forms of the disorder have also been described. (For more information on this disorder, choose “Hyper IgM” as your search term in the Rare Disease Database.)X-linked lymphoproliferative (XLP) syndrome is an extremely rare inherited primary immunodeficiency disorder characterized by a defective immune response to infection with the Epstein-Barr virus (EBV). This virus is common among the general population and is relatively well-known because it is the cause of infectious mononucleosis (IM), usually with no long-lasting effects. However, in individuals with XLP, exposure to EBV may result in severe, life-threatening fulminant hepatitis; abnormally low levels of antibodies in the blood and body secretions (hypogammaglobulinemia), resulting in increased susceptibility to various infections; malignancies of certain types of lymphoid tissue (B-cell lymphomas); and/or other abnormalities. The range of symptoms and findings associated with XLP may vary considerably from person to person. In addition, the range of effects may change in an affected individual over time. In most cases, individuals with XLP experience an onset of symptoms anytime from ages about 6 months to 10 years of age. XLP is caused by mutations in the SH2D1A and XIAP genes.The WAS-related disorders are a spectrum of conditions affecting the immune system that are caused by mutations in the WAS gene. These disorders include Wiskott-Aldrich syndrome, X-linked thrombocytopenia and X-linked congenital neutropenia. The WAS gene abnormality results in a deficiency in the WASP protein that leads to a low platelet count (thrombocytopenia). WAS-related disorders usually present in infancy and are characterized by bloody diarrhea, recurrent infections, scaling, itchy, skin rashes (eczema), and the appearance of small purple spots on the skin (petechia). The development of Pneumocystis carinii pneumonia (PCP) and intracranial bleeding are possible early, life-threatening complications. Later potential complications include destruction of red blood cells (hemolytic anemia), arthritis, vasculitis and kidney and liver damage. Affected individuals have an increased risk of developing lymphomas, especially after exposure to Epstein-Barr virus. WAS-related disorders are extremely variable, even in individuals in the same family. (For more information on this disorder, choose “WAS related disorders” as your search term in the Rare Disease Database.) | 292 | Common Variable Immune Deficiency |
nord_292_5 | Diagnosis of Common Variable Immune Deficiency | In most patients, CVIDis diagnosed based upon a thorough clinical evaluation, identification of characteristic symptoms and physical findings, a detailed patient and family history, and a pattern of immune system defects confirmed by laboratory testing.Confirmation of certain immunologic abnormalities plays an essential role in establishing the diagnosis of CVID. The diagnosis of CVID is primarily established by testing for low blood (serum) IgG immunoglobulin concentrations ranging from severely reduced (<100 mg/dL) to just below adult normal range (500-1200 mg/dL). In addition, laboratory testing may reveal normal or, in some cases, reduced numbers of circulating B cells. Failure of certain B cells to appropriately mature into antibody-producing plasma cells may also be detected. Specialized laboratory tests may also help to determine the exact nature of the immune defect (e.g., B cell, helper T cell, suppressor T cell, or B and T cell defects). In many cases, x-ray, examination of the small intestine (enteroscopy), or surgical removal (biopsy) of small samples of tissue from lymph nodes may reveal certain abnormalities (e.g., nodular lymphoid hyperplasia). In addition, in some cases, specialized imaging tests followed by biopsy and microscopic examination may confirm the presence of granular, inflammatory nodules (noncaseating granulomas) within tissue of the skin, lungs, spleen, and/or liver.
| Diagnosis of Common Variable Immune Deficiency. In most patients, CVIDis diagnosed based upon a thorough clinical evaluation, identification of characteristic symptoms and physical findings, a detailed patient and family history, and a pattern of immune system defects confirmed by laboratory testing.Confirmation of certain immunologic abnormalities plays an essential role in establishing the diagnosis of CVID. The diagnosis of CVID is primarily established by testing for low blood (serum) IgG immunoglobulin concentrations ranging from severely reduced (<100 mg/dL) to just below adult normal range (500-1200 mg/dL). In addition, laboratory testing may reveal normal or, in some cases, reduced numbers of circulating B cells. Failure of certain B cells to appropriately mature into antibody-producing plasma cells may also be detected. Specialized laboratory tests may also help to determine the exact nature of the immune defect (e.g., B cell, helper T cell, suppressor T cell, or B and T cell defects). In many cases, x-ray, examination of the small intestine (enteroscopy), or surgical removal (biopsy) of small samples of tissue from lymph nodes may reveal certain abnormalities (e.g., nodular lymphoid hyperplasia). In addition, in some cases, specialized imaging tests followed by biopsy and microscopic examination may confirm the presence of granular, inflammatory nodules (noncaseating granulomas) within tissue of the skin, lungs, spleen, and/or liver.
| 292 | Common Variable Immune Deficiency |
nord_292_6 | Therapies of Common Variable Immune Deficiency | TreatmentThe treatment of CVID requires the coordinated efforts of a team of specialists who may need to systematically and comprehensively plan an affected individual’s treatment. Such specialists may include physicians who diagnose and treat disorders of the blood (hematologists), the digestive tract (gastroenterologists), and/or the lungs (pulmonologists); specialists in the treatment of immune system disorders (immunologists); and/or other health care professionals.The primary treatment for CVID consists of regular immunoglobulin (gammaglobulin) therapy, which is administered by intravenous or subcutaneous infusion with antibodies obtained from the fluid portion of the blood (gammaglobulin). Such therapy may help to prevent the recurrent infections characteristic of CVID as well as treat the disorder’s associated symptoms.Individuals with CVID who experience adverse reactions to intravenous gammaglobulin may benefit from the subcutaneous delivery of this medication. In some, the administration of medications that block the effects of the chemical histamine (antihistamines), which is released during allergic reactions, or nonsteroidal anti-inflammatory agents (NSAIDs) are used. Rarely, hydrocortisone, a corticosteroid medication, may be needed prior to gammaglobulin therapy. Because corticosteroids may actually suppress an already weakened immune system, NSAIDs may be helpful in controlling autoimmune-like symptoms while avoiding the use of corticosteroids. However, after being immunoglobulin therapy for several months, most patients no longer require any premedication.Some researchers have recommended that when a patient is diagnosed with an autoimmune disease, the possibility of an underlying CVID should be evaluated before the administration of immunosuppressive drugs for the autoimmune disease.Antibiotic medications often prove beneficial for the treatment of various bacterial infections associated with CVID. Patients with irregularities involving the malabsorption of vitamin B12 may also benefit from monthly B12 injections.Affected individuals with severely low levels of circulating platelets may be cautioned to avoid the use of aspirin, since this medication may interfere with the ability of platelets to assist in the blood-clotting process. In addition, as is the case with individuals affected by many other primary immunodeficiency disorders, individuals with CVID should not receive live virus vaccines since there is the remote possibility that the vaccine strains of virus may cause disease as a result of their defective immune systems.Surveillance for complications include periodic complete blood count (CBC), and differential white blood counts to detect lymphoma, annual thyroid examination and thyroid function testing, annual lung (pulmonary) function testing beginning about age eight to ten years, biopsy of enlarged lymphoid tissue, and other imaging techniques for assessment of granulomatous disease and gastrointestinal complications.Genetic counseling is recommended for affected individuals and their family members if a genetic type of CVID is suspected or confirmed. Other treatment is symptomatic and supportive. | Therapies of Common Variable Immune Deficiency. TreatmentThe treatment of CVID requires the coordinated efforts of a team of specialists who may need to systematically and comprehensively plan an affected individual’s treatment. Such specialists may include physicians who diagnose and treat disorders of the blood (hematologists), the digestive tract (gastroenterologists), and/or the lungs (pulmonologists); specialists in the treatment of immune system disorders (immunologists); and/or other health care professionals.The primary treatment for CVID consists of regular immunoglobulin (gammaglobulin) therapy, which is administered by intravenous or subcutaneous infusion with antibodies obtained from the fluid portion of the blood (gammaglobulin). Such therapy may help to prevent the recurrent infections characteristic of CVID as well as treat the disorder’s associated symptoms.Individuals with CVID who experience adverse reactions to intravenous gammaglobulin may benefit from the subcutaneous delivery of this medication. In some, the administration of medications that block the effects of the chemical histamine (antihistamines), which is released during allergic reactions, or nonsteroidal anti-inflammatory agents (NSAIDs) are used. Rarely, hydrocortisone, a corticosteroid medication, may be needed prior to gammaglobulin therapy. Because corticosteroids may actually suppress an already weakened immune system, NSAIDs may be helpful in controlling autoimmune-like symptoms while avoiding the use of corticosteroids. However, after being immunoglobulin therapy for several months, most patients no longer require any premedication.Some researchers have recommended that when a patient is diagnosed with an autoimmune disease, the possibility of an underlying CVID should be evaluated before the administration of immunosuppressive drugs for the autoimmune disease.Antibiotic medications often prove beneficial for the treatment of various bacterial infections associated with CVID. Patients with irregularities involving the malabsorption of vitamin B12 may also benefit from monthly B12 injections.Affected individuals with severely low levels of circulating platelets may be cautioned to avoid the use of aspirin, since this medication may interfere with the ability of platelets to assist in the blood-clotting process. In addition, as is the case with individuals affected by many other primary immunodeficiency disorders, individuals with CVID should not receive live virus vaccines since there is the remote possibility that the vaccine strains of virus may cause disease as a result of their defective immune systems.Surveillance for complications include periodic complete blood count (CBC), and differential white blood counts to detect lymphoma, annual thyroid examination and thyroid function testing, annual lung (pulmonary) function testing beginning about age eight to ten years, biopsy of enlarged lymphoid tissue, and other imaging techniques for assessment of granulomatous disease and gastrointestinal complications.Genetic counseling is recommended for affected individuals and their family members if a genetic type of CVID is suspected or confirmed. Other treatment is symptomatic and supportive. | 292 | Common Variable Immune Deficiency |
nord_293_0 | Overview of Complete DiGeorge Syndrome | SummaryComplete DiGeorge syndrome is a rare disorder in which children have no detectable thymus (athymia). The thymus is a gland located on top of the heart. The thymus produces specialized white blood cells called T cells that fight infections, especially viral infections. The T cell count is the highest in infants in the first 2 years of life and then slowly decreases with time. In older adults over the age of 60, the thymus is mostly replaced by fat. Children with complete DiGeorge syndrome are born without a thymus and are therefore profoundly deficient in T cells and extremely susceptible to infections. Without treatment, the disorder is usually fatal by two or three years of age.IntroductionSome individuals have DiGeorge syndrome as part of a larger disorder, specifically chromosome 22q11.2 deletion syndrome or CHARGE syndrome. Both of these disorders have symptoms affecting multiple systems of the body. DiGeorge syndrome typically refers to individuals who have T cell counts less than the 10th percentile for age, plus they have heart defects and/or low calcium levels. Many but not all of infants with 22q11.2 deletion syndrome and CHARGE syndrome have T cell counts less than the 10th percentile for age and are often referred to as having DiGeorge syndrome. (Children with 22q11.2 deletion syndrome or CHARGE syndrome who have normal T cell counts are not considered as having DiGeorge syndrome.)Only about 1% of children with DiGeorge syndrome have absence of the thymus. To determine that a child had no thymus, blood testing must not detect T cells emerging from the thymus. Newly developed T cells emerging from the thymus have special proteins on the cell surface. Those T cells are called “naïve” T cells. Children with 22q11.2 deletion syndrome or CHARGE syndrome who have very low naïve T cells counts (less than 50 per mm3 in the blood) are said to have complete DiGeorge syndrome. Children with complete DiGeorge syndrome are all athymic by definition. NORD has individual reports on both 22q11.2 deletion syndrome and CHARGE syndrome patients with athymia. These reports are accessible through the NORD Rare Disease Database. Lastly, for affected infants who are infants of diabetic mothers and other infants with no identifiable genetic defects or syndromes, the cause of athymia remains unknown. | Overview of Complete DiGeorge Syndrome. SummaryComplete DiGeorge syndrome is a rare disorder in which children have no detectable thymus (athymia). The thymus is a gland located on top of the heart. The thymus produces specialized white blood cells called T cells that fight infections, especially viral infections. The T cell count is the highest in infants in the first 2 years of life and then slowly decreases with time. In older adults over the age of 60, the thymus is mostly replaced by fat. Children with complete DiGeorge syndrome are born without a thymus and are therefore profoundly deficient in T cells and extremely susceptible to infections. Without treatment, the disorder is usually fatal by two or three years of age.IntroductionSome individuals have DiGeorge syndrome as part of a larger disorder, specifically chromosome 22q11.2 deletion syndrome or CHARGE syndrome. Both of these disorders have symptoms affecting multiple systems of the body. DiGeorge syndrome typically refers to individuals who have T cell counts less than the 10th percentile for age, plus they have heart defects and/or low calcium levels. Many but not all of infants with 22q11.2 deletion syndrome and CHARGE syndrome have T cell counts less than the 10th percentile for age and are often referred to as having DiGeorge syndrome. (Children with 22q11.2 deletion syndrome or CHARGE syndrome who have normal T cell counts are not considered as having DiGeorge syndrome.)Only about 1% of children with DiGeorge syndrome have absence of the thymus. To determine that a child had no thymus, blood testing must not detect T cells emerging from the thymus. Newly developed T cells emerging from the thymus have special proteins on the cell surface. Those T cells are called “naïve” T cells. Children with 22q11.2 deletion syndrome or CHARGE syndrome who have very low naïve T cells counts (less than 50 per mm3 in the blood) are said to have complete DiGeorge syndrome. Children with complete DiGeorge syndrome are all athymic by definition. NORD has individual reports on both 22q11.2 deletion syndrome and CHARGE syndrome patients with athymia. These reports are accessible through the NORD Rare Disease Database. Lastly, for affected infants who are infants of diabetic mothers and other infants with no identifiable genetic defects or syndromes, the cause of athymia remains unknown. | 293 | Complete DiGeorge Syndrome |
nord_293_1 | Symptoms of Complete DiGeorge Syndrome | By definition, complete DiGeorge syndrome is characterized by absence or underdevelopment (hypoplasia) of the thymus resulting in very low T cell counts. Absence or underdevelopment of the thymus results in an increased susceptibility to viral, fungal and bacterial infections (immunodeficiency). The degree of susceptibility can vary. Specific symptoms will vary depending upon the type of infection, overall health of the infant, and other factors. Respiratory infections are common often leading to respiratory distress. Opportunistic infections are also common. Opportunistic infection refers either to infections caused by microorganisms that usually do not cause disease in individuals with fully functioning immune systems or to widespread (systemic) overwhelming disease by microorganisms that typically cause only localized, mild infections. Not only are affected infants more susceptible to infections, but their bodies cannot effectively fight off the infections either. Infants with complete DiGeorge syndrome have additional symptoms including congenital heart defects and/or hypoparathyroidism. These complications can be significant. Congenital health defects are problems with the structure of the heart. This include the walls, valves, and arteries and veins of the heart. Over 50 percent of infants with complete DiGeorge syndrome require surgery to fix the heart defects. Hypoparathyroidism is a rare condition in which the parathyroid glands, that are located in the neck, fail to produce sufficient amounts of parathyroid hormone. Parathyroid hormone plays a role in regulating the levels of calcium and phosphorus in the blood. Due to a deficiency of parathyroid hormone, individuals with hypoparathyroidism may exhibit abnormally low levels of calcium in the blood (hypocalcemia) and high levels of phosphorus. Low levels of calcium in the blood can result in seizures. Management of calcium levels can be difficult in infants with complete DiGeorge syndrome. Although infants with partial DiGeorge syndrome usually outgrow the hypoparathyroidism in approximately 12 months, approximately 80% of infants with complete DiGeorge syndrome have long term problems maintaining safe calcium levels. Some infants have softening of the tissues of the voice box (larynx), a condition called laryngomalacia. This can cause noisy breathing. Sometimes, it can cause difficulties eating. Infants with chromosome 22q11.2 deletion syndrome and CHARGE syndrome will have additional symptoms that are associated with their specific diagnosis. Infants with complete DiGeorge syndrome who are born to diabetic mothers may also have only one kidney (renal agenesis). Researchers have identified an atypical form of complete DiGeorge syndrome. Affected infants, in addition to immunodeficiency, have a red, often itchy, rash and enlargement of the lymph nodes (lymphadenopathy). They develop oligoclonal T cells. To understand this process, it can be helpful to think of the thymus as a schoolhouse. In normal children, stem cells from the bone marrow go to the thymus (the “schoolhouse”) to develop into T cells. The developing T cells learn to not attack the infant’s body (self) and to fight infections. If the developing T cells are successful learning these two lessons, they “graduate,” and leave the schoolhouse. The graduates have special proteins on the surface of the cell and are called “naïve” T cells. After the naïve T cells fight an infection, they lose the special markers and are called memory T cells. Memory T cells can quickly fight an infection if it recurs. In atypical complete DiGeorge syndrome, there is no thymus (no schoolhouse). However, stem cells in the bone marrow develop into a cell that looks like a T cell, but is missing the “naïve” T cell markers. These “atypical” T cells have not gone to “school” and have not learned what is “self.” The atypical T cells then attack the body causing rash, and often also diarrhea or liver damage. The diagnosis of atypical DiGeorge syndrome is made when a patient has the rash and high numbers of T cells but no, or very few, naïve T cells in the blood. | Symptoms of Complete DiGeorge Syndrome. By definition, complete DiGeorge syndrome is characterized by absence or underdevelopment (hypoplasia) of the thymus resulting in very low T cell counts. Absence or underdevelopment of the thymus results in an increased susceptibility to viral, fungal and bacterial infections (immunodeficiency). The degree of susceptibility can vary. Specific symptoms will vary depending upon the type of infection, overall health of the infant, and other factors. Respiratory infections are common often leading to respiratory distress. Opportunistic infections are also common. Opportunistic infection refers either to infections caused by microorganisms that usually do not cause disease in individuals with fully functioning immune systems or to widespread (systemic) overwhelming disease by microorganisms that typically cause only localized, mild infections. Not only are affected infants more susceptible to infections, but their bodies cannot effectively fight off the infections either. Infants with complete DiGeorge syndrome have additional symptoms including congenital heart defects and/or hypoparathyroidism. These complications can be significant. Congenital health defects are problems with the structure of the heart. This include the walls, valves, and arteries and veins of the heart. Over 50 percent of infants with complete DiGeorge syndrome require surgery to fix the heart defects. Hypoparathyroidism is a rare condition in which the parathyroid glands, that are located in the neck, fail to produce sufficient amounts of parathyroid hormone. Parathyroid hormone plays a role in regulating the levels of calcium and phosphorus in the blood. Due to a deficiency of parathyroid hormone, individuals with hypoparathyroidism may exhibit abnormally low levels of calcium in the blood (hypocalcemia) and high levels of phosphorus. Low levels of calcium in the blood can result in seizures. Management of calcium levels can be difficult in infants with complete DiGeorge syndrome. Although infants with partial DiGeorge syndrome usually outgrow the hypoparathyroidism in approximately 12 months, approximately 80% of infants with complete DiGeorge syndrome have long term problems maintaining safe calcium levels. Some infants have softening of the tissues of the voice box (larynx), a condition called laryngomalacia. This can cause noisy breathing. Sometimes, it can cause difficulties eating. Infants with chromosome 22q11.2 deletion syndrome and CHARGE syndrome will have additional symptoms that are associated with their specific diagnosis. Infants with complete DiGeorge syndrome who are born to diabetic mothers may also have only one kidney (renal agenesis). Researchers have identified an atypical form of complete DiGeorge syndrome. Affected infants, in addition to immunodeficiency, have a red, often itchy, rash and enlargement of the lymph nodes (lymphadenopathy). They develop oligoclonal T cells. To understand this process, it can be helpful to think of the thymus as a schoolhouse. In normal children, stem cells from the bone marrow go to the thymus (the “schoolhouse”) to develop into T cells. The developing T cells learn to not attack the infant’s body (self) and to fight infections. If the developing T cells are successful learning these two lessons, they “graduate,” and leave the schoolhouse. The graduates have special proteins on the surface of the cell and are called “naïve” T cells. After the naïve T cells fight an infection, they lose the special markers and are called memory T cells. Memory T cells can quickly fight an infection if it recurs. In atypical complete DiGeorge syndrome, there is no thymus (no schoolhouse). However, stem cells in the bone marrow develop into a cell that looks like a T cell, but is missing the “naïve” T cell markers. These “atypical” T cells have not gone to “school” and have not learned what is “self.” The atypical T cells then attack the body causing rash, and often also diarrhea or liver damage. The diagnosis of atypical DiGeorge syndrome is made when a patient has the rash and high numbers of T cells but no, or very few, naïve T cells in the blood. | 293 | Complete DiGeorge Syndrome |
nord_293_2 | Causes of Complete DiGeorge Syndrome | Complete DiGeorge syndrome is characterized by the absence of the thymus in an infant. There are several causes of this condition. In some infants, complete DiGeorge syndrome occurs as part of a larger syndrome such as chromosome 22q11.2 deletion syndrome or CHARGE syndrome. Chromosome 22q11.2 deletion syndrome is characterized by the absence of a small piece of chromosome 22. Chromosome 22q11.2DS is associated with a range of problems including: congenital heart disease, palate abnormalities, immune system dysfunction including autoimmune disease, low calcium (hypocalcemia) and other endocrine abnormalities such as thyroid problems and growth hormone deficiency, gastrointestinal problems, feeding difficulties, kidney abnormalities, hearing loss, seizures, skeletal abnormalities, minor facial differences, and learning and behavioral differences. CHARGE is an acronym that stands for [C]oloboma, congenital [H]eart defects, choanal [A]tresia, growth [R]etardation, [G]enital hypoplasia and [E]ar anomalies or deafness. Some infants who do not have a thymus or have an underdeveloped thymus have mothers who are diabetic. The mothers can have type I or type II or gestational diabetes. At this time, it is not known that the diabetes is causing DiGeorge syndrome in these patients. However, many patients with DiGeorge syndrome have mothers with diabetes. In a small percentage of children with complete DiGeorge syndrome, there is no identifiable genetic cause for the disorder, and no symptoms indicative of a larger syndrome. In these children, the underlying cause of complete DiGeorge syndrome is unknown. | Causes of Complete DiGeorge Syndrome. Complete DiGeorge syndrome is characterized by the absence of the thymus in an infant. There are several causes of this condition. In some infants, complete DiGeorge syndrome occurs as part of a larger syndrome such as chromosome 22q11.2 deletion syndrome or CHARGE syndrome. Chromosome 22q11.2 deletion syndrome is characterized by the absence of a small piece of chromosome 22. Chromosome 22q11.2DS is associated with a range of problems including: congenital heart disease, palate abnormalities, immune system dysfunction including autoimmune disease, low calcium (hypocalcemia) and other endocrine abnormalities such as thyroid problems and growth hormone deficiency, gastrointestinal problems, feeding difficulties, kidney abnormalities, hearing loss, seizures, skeletal abnormalities, minor facial differences, and learning and behavioral differences. CHARGE is an acronym that stands for [C]oloboma, congenital [H]eart defects, choanal [A]tresia, growth [R]etardation, [G]enital hypoplasia and [E]ar anomalies or deafness. Some infants who do not have a thymus or have an underdeveloped thymus have mothers who are diabetic. The mothers can have type I or type II or gestational diabetes. At this time, it is not known that the diabetes is causing DiGeorge syndrome in these patients. However, many patients with DiGeorge syndrome have mothers with diabetes. In a small percentage of children with complete DiGeorge syndrome, there is no identifiable genetic cause for the disorder, and no symptoms indicative of a larger syndrome. In these children, the underlying cause of complete DiGeorge syndrome is unknown. | 293 | Complete DiGeorge Syndrome |
nord_293_3 | Affects of Complete DiGeorge Syndrome | Complete DiGeorge syndrome affects both boys and girls. The exact incidence or prevalence of this disorder is unknown. | Affects of Complete DiGeorge Syndrome. Complete DiGeorge syndrome affects both boys and girls. The exact incidence or prevalence of this disorder is unknown. | 293 | Complete DiGeorge Syndrome |
nord_293_4 | Related disorders of Complete DiGeorge Syndrome | Symptoms of the following disorders can be similar to those of complete DiGeorge syndrome. Comparisons may be useful for a differential diagnosis.Researchers have identified several genes that, when altered (mutated), can cause absence of the thymus. These genes include the FOXN1, TBX1, TBX2, and the PAX1 genes. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation 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. | Related disorders of Complete DiGeorge Syndrome. Symptoms of the following disorders can be similar to those of complete DiGeorge syndrome. Comparisons may be useful for a differential diagnosis.Researchers have identified several genes that, when altered (mutated), can cause absence of the thymus. These genes include the FOXN1, TBX1, TBX2, and the PAX1 genes. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation 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. | 293 | Complete DiGeorge Syndrome |
nord_293_5 | Diagnosis of Complete DiGeorge Syndrome | A diagnosis of complete DiGeorge syndrome is based upon identification of characteristic symptoms, a detailed patient and family history, and a thorough clinical evaluation. Some infants are diagnosed via newborn screening. All 50 states have added newborn screening for severe combined immunodeficiency. Some states, however, do not require that every hospital include the newborn screening for SCID. Newborn screening identifies infants with low levels of T cells, which can lead to identification of newborns with complete DiGeorge syndrome. In such instances, the infants are kept in isolation right away. Clinical Testing and Workup
Physicians may use a technique called flow cytometry to diagnose complete DiGeorge syndrome. Flow cytometry of the peripheral blood means that the peripheral blood (the blood that is circulating through the body) is studied using a machine called a flow cytometer. The flow cytometer can determine the number and percentage of various cell types in the blood sample. A diagnosis cannot be made with a chest x-ray (radiography) or computerized tomography (CAT) scan, or during heart surgery because the thymus can be small or may be found in a different part of the body such as in the neck (ectopic thymus). | Diagnosis of Complete DiGeorge Syndrome. A diagnosis of complete DiGeorge syndrome is based upon identification of characteristic symptoms, a detailed patient and family history, and a thorough clinical evaluation. Some infants are diagnosed via newborn screening. All 50 states have added newborn screening for severe combined immunodeficiency. Some states, however, do not require that every hospital include the newborn screening for SCID. Newborn screening identifies infants with low levels of T cells, which can lead to identification of newborns with complete DiGeorge syndrome. In such instances, the infants are kept in isolation right away. Clinical Testing and Workup
Physicians may use a technique called flow cytometry to diagnose complete DiGeorge syndrome. Flow cytometry of the peripheral blood means that the peripheral blood (the blood that is circulating through the body) is studied using a machine called a flow cytometer. The flow cytometer can determine the number and percentage of various cell types in the blood sample. A diagnosis cannot be made with a chest x-ray (radiography) or computerized tomography (CAT) scan, or during heart surgery because the thymus can be small or may be found in a different part of the body such as in the neck (ectopic thymus). | 293 | Complete DiGeorge Syndrome |
nord_293_6 | Therapies of Complete DiGeorge Syndrome | Treatment
Treatment may require the coordinated efforts of a team of specialists. Pediatricians, physicians who specialize in diagnosing and treating immune system disorders (immunologists), physicians who specialize in diagnosing and treating blood disorders (hematologists), physicians who specialize in diagnosing and treating endocrine disorders (endocrinologists), and other healthcare professionals may need to systematically and comprehensively plan treatment. Additional healthcare professionals are necessary for affected infants with chromosome 22q11.2 deletion syndrome or CHARGE syndrome.Antibiotic and anti-viral medications are used for infections until an investigational cultured thymus tissue transplant can be undergone. Congenital heart defects may require surgery. Some infants require supplementation with calcium or a synthetic version of vitamin D3 called calcitriol for hypoparathyroidism.Affected infants with laryngomalacia or aspiration may require a tracheostomy. This is the creation of a surgical opening in the neck to gain access to the windpipe (trachea). A tube is placed into this opening to allow for breathing. Other children may require a gastrostomy tube (a tube going into the stomach) for feeding the child.In 2021, the U.S. Food and Drug Administration (FDA) approved Rethymic for the treatment of pediatric patients with congenital athymia. It is composed of processed and cultured thymus tissue from donors and implanted into athymic patients to help improve immune function. | Therapies of Complete DiGeorge Syndrome. Treatment
Treatment may require the coordinated efforts of a team of specialists. Pediatricians, physicians who specialize in diagnosing and treating immune system disorders (immunologists), physicians who specialize in diagnosing and treating blood disorders (hematologists), physicians who specialize in diagnosing and treating endocrine disorders (endocrinologists), and other healthcare professionals may need to systematically and comprehensively plan treatment. Additional healthcare professionals are necessary for affected infants with chromosome 22q11.2 deletion syndrome or CHARGE syndrome.Antibiotic and anti-viral medications are used for infections until an investigational cultured thymus tissue transplant can be undergone. Congenital heart defects may require surgery. Some infants require supplementation with calcium or a synthetic version of vitamin D3 called calcitriol for hypoparathyroidism.Affected infants with laryngomalacia or aspiration may require a tracheostomy. This is the creation of a surgical opening in the neck to gain access to the windpipe (trachea). A tube is placed into this opening to allow for breathing. Other children may require a gastrostomy tube (a tube going into the stomach) for feeding the child.In 2021, the U.S. Food and Drug Administration (FDA) approved Rethymic for the treatment of pediatric patients with congenital athymia. It is composed of processed and cultured thymus tissue from donors and implanted into athymic patients to help improve immune function. | 293 | Complete DiGeorge Syndrome |
nord_294_0 | Overview of Complex Regional Pain Syndrome | SummaryComplex regional pain syndrome (CRPS) is a disorder in which pain, occurring spontaneously or from a sensory stimulus, is disproportionately far more painful than it should be. An example of this would be light touching of the skin, which normally is not painful, yet is perceived as extremely painful in CRPS patients. The disproportionate pain is also reflected in normally painful stimuli, such as a pinprick, hurting more than it should (hyperalgesia). CRPS usually affects one limb after a limb injury or surgery. Usually, patients with CRPS will experience limited use of their affected limbs due to the pain. Besides increased perception of pain, other signs and symptoms that are seen with CRPS particularly in its early stages are a warm, red and swollen extremity on the affected side. In its later stages, a cool, bluish and sweaty limb is common. CRPS is often treated with physical and occupational therapy, and the patient will typically require medications or other interventions to manage the pain.IntroductionCRPS has traditionally been subdivided into 2 categories: type I and type II CRPS. In CRPS type I, there are no nerve injuries or lesions identified. CRPS type I is also known as “reflex sympathetic dystrophy,” and it comprises about 90 percent of all cases of CRPS. CRPS type II (causalgia), on the other hand, is diagnosed when there is evidence of nerve damage. A new CRPS subdivision has recently been added: CRPS with remission of some features. This label applies to patients who have met the full CRPS diagnostic criteria detailed below in the past, but who currently display insufficient CRPS features to meet the full criteria (i.e., ongoing CRPS-related pain and features but with some improvement). | Overview of Complex Regional Pain Syndrome. SummaryComplex regional pain syndrome (CRPS) is a disorder in which pain, occurring spontaneously or from a sensory stimulus, is disproportionately far more painful than it should be. An example of this would be light touching of the skin, which normally is not painful, yet is perceived as extremely painful in CRPS patients. The disproportionate pain is also reflected in normally painful stimuli, such as a pinprick, hurting more than it should (hyperalgesia). CRPS usually affects one limb after a limb injury or surgery. Usually, patients with CRPS will experience limited use of their affected limbs due to the pain. Besides increased perception of pain, other signs and symptoms that are seen with CRPS particularly in its early stages are a warm, red and swollen extremity on the affected side. In its later stages, a cool, bluish and sweaty limb is common. CRPS is often treated with physical and occupational therapy, and the patient will typically require medications or other interventions to manage the pain.IntroductionCRPS has traditionally been subdivided into 2 categories: type I and type II CRPS. In CRPS type I, there are no nerve injuries or lesions identified. CRPS type I is also known as “reflex sympathetic dystrophy,” and it comprises about 90 percent of all cases of CRPS. CRPS type II (causalgia), on the other hand, is diagnosed when there is evidence of nerve damage. A new CRPS subdivision has recently been added: CRPS with remission of some features. This label applies to patients who have met the full CRPS diagnostic criteria detailed below in the past, but who currently display insufficient CRPS features to meet the full criteria (i.e., ongoing CRPS-related pain and features but with some improvement). | 294 | Complex Regional Pain Syndrome |
nord_294_1 | Symptoms of Complex Regional Pain Syndrome | The most common and prominent symptom of CRPS is the pain that affected individuals will feel. The pain is often deep inside the limbs with a burning, stinging or tearing sensation. Sensory changes are also common, and may include increased sensitivity to painful stimuli, feeling pain from stimuli that are usually non-painful and, in some instances, sensory loss (e.g., numbness).In addition to pain, patients commonly experience an affected extremity that is warm, red and swollen, at least initially. In many patients, as CRPS continues, the affected extremity may more often feel cool with dark or bluish skin. Swelling, resulting from fluid build-up in the limb (edema), can be present regardless of the color and temperature of the skin, but is typically more prominent with the early clinical picture (red and warm skin). Skin color and temperature may sometimes change even over short periods of time inconsistently. In addition to the changes above, CRPS patients may experience skin that becomes thin and shiny and may experience either increased or decreased hair and nail growth in the affected extremity.Most patients will experience motor impairment, which is the decrease in the ability to use the limbs for movement, with weakness or limited range of motion being the most common impairments. The impairments may be seen in a reduction in strength in handgrip or during tiptoe-standing. Some patients may develop spasms or even uncontrollable muscle contractions (dystonia). | Symptoms of Complex Regional Pain Syndrome. The most common and prominent symptom of CRPS is the pain that affected individuals will feel. The pain is often deep inside the limbs with a burning, stinging or tearing sensation. Sensory changes are also common, and may include increased sensitivity to painful stimuli, feeling pain from stimuli that are usually non-painful and, in some instances, sensory loss (e.g., numbness).In addition to pain, patients commonly experience an affected extremity that is warm, red and swollen, at least initially. In many patients, as CRPS continues, the affected extremity may more often feel cool with dark or bluish skin. Swelling, resulting from fluid build-up in the limb (edema), can be present regardless of the color and temperature of the skin, but is typically more prominent with the early clinical picture (red and warm skin). Skin color and temperature may sometimes change even over short periods of time inconsistently. In addition to the changes above, CRPS patients may experience skin that becomes thin and shiny and may experience either increased or decreased hair and nail growth in the affected extremity.Most patients will experience motor impairment, which is the decrease in the ability to use the limbs for movement, with weakness or limited range of motion being the most common impairments. The impairments may be seen in a reduction in strength in handgrip or during tiptoe-standing. Some patients may develop spasms or even uncontrollable muscle contractions (dystonia). | 294 | Complex Regional Pain Syndrome |
nord_294_2 | Causes of Complex Regional Pain Syndrome | The exact causes of CRPS are unclear, but it is likely that there are multiple factors that contribute to its development.Immobilization (e.g., casting) to keep a limb from moving in order to allow it heal is a common treatment for injuries such as broken bones or fractures in the limb. In adults and pediatric patients, CRPS type I was commonly seen in those who have a history of immobilization, and this was associated with a worsening of symptoms. Immobilization of limbs in patients after fractures or surgery results in an increase in sensitivity to pain, edema and temperature increase in the affected limb. This suggests that immobilization may play a role in the development of the disease.CRPS may also be caused in part by alterations to the nervous system of the body. One part of the nervous system is the sympathetic nervous system. The sympathetic nervous system is activated in “fight or flight” situations, which are times when the body is in high level of stress and requires alertness. During times of stress, the sympathetic nervous system constricts blood vessels to reduce blood flow to the extremities. In contrast, low sympathetic nervous system activity increases blood flow to the extremities. In CRPS, sympathetic function may initially be decreased, which could contribute to warm, red and swollen limbs. The sympathetic nervous system may also play a role in contributing to the pain associated with CRPS. Although it is believed that the sympathetic nervous system in CRPS may become linked to pain receptors, it is still unclear exactly how the sympathetic nervous system causes pain in patients with CRPS.Inflammation may also play a significant role in the development of the syndrome. In CRPS, particularly in its early stages, it is found that patients have increased levels of inflammation-causing substances (cytokines) released by the body. Along with the inflammatory cytokines, there are pain-enhancing substances in the nerves that are released. The increased inflammatory and pain-producing substances in CRPS are a possible explanation for why a person with CRPS may experience pain from a stimulus that normally should not cause pain.It is possible that genetic factors may contribute to CRPS; however, there is no clear genetic risk pattern known at this time. There are a few genes that may contribute to CRPS, but the ones most frequently identified are in genes that influence the immune system and inflammation. It is possible that particular genetic variants that a person is born with might increase the risk of developing CRPS after injury, but there is no evidence that CRPS is a disease that can be caused by genetic factors alone.Psychological factors, such as anxiety, depression and anger, may worsen the symptoms of CRPS. In children, psychological issues are often assumed to play a greater role in CRPS than in adults, but this belief remains unproven. | Causes of Complex Regional Pain Syndrome. The exact causes of CRPS are unclear, but it is likely that there are multiple factors that contribute to its development.Immobilization (e.g., casting) to keep a limb from moving in order to allow it heal is a common treatment for injuries such as broken bones or fractures in the limb. In adults and pediatric patients, CRPS type I was commonly seen in those who have a history of immobilization, and this was associated with a worsening of symptoms. Immobilization of limbs in patients after fractures or surgery results in an increase in sensitivity to pain, edema and temperature increase in the affected limb. This suggests that immobilization may play a role in the development of the disease.CRPS may also be caused in part by alterations to the nervous system of the body. One part of the nervous system is the sympathetic nervous system. The sympathetic nervous system is activated in “fight or flight” situations, which are times when the body is in high level of stress and requires alertness. During times of stress, the sympathetic nervous system constricts blood vessels to reduce blood flow to the extremities. In contrast, low sympathetic nervous system activity increases blood flow to the extremities. In CRPS, sympathetic function may initially be decreased, which could contribute to warm, red and swollen limbs. The sympathetic nervous system may also play a role in contributing to the pain associated with CRPS. Although it is believed that the sympathetic nervous system in CRPS may become linked to pain receptors, it is still unclear exactly how the sympathetic nervous system causes pain in patients with CRPS.Inflammation may also play a significant role in the development of the syndrome. In CRPS, particularly in its early stages, it is found that patients have increased levels of inflammation-causing substances (cytokines) released by the body. Along with the inflammatory cytokines, there are pain-enhancing substances in the nerves that are released. The increased inflammatory and pain-producing substances in CRPS are a possible explanation for why a person with CRPS may experience pain from a stimulus that normally should not cause pain.It is possible that genetic factors may contribute to CRPS; however, there is no clear genetic risk pattern known at this time. There are a few genes that may contribute to CRPS, but the ones most frequently identified are in genes that influence the immune system and inflammation. It is possible that particular genetic variants that a person is born with might increase the risk of developing CRPS after injury, but there is no evidence that CRPS is a disease that can be caused by genetic factors alone.Psychological factors, such as anxiety, depression and anger, may worsen the symptoms of CRPS. In children, psychological issues are often assumed to play a greater role in CRPS than in adults, but this belief remains unproven. | 294 | Complex Regional Pain Syndrome |
nord_294_3 | Affects of Complex Regional Pain Syndrome | CRPS occurs 3 to 4 times more often in women than men. Although CRPS can occur at any age, it is rare in children and adolescents. In the pediatric population, the onset of CRPS usually occurs in early adolescence with the lower end of the range falling between 7 to 9 years. In adults, the age of onset is highly variable from 37 to 70 years of age. CRPS occurs most frequently in people of European ancestry (in about 66 to 80 percent of cases). In a study done in the United States, it was found that CRPS type I developed in 5.46 persons out of every 100,000 per year. It is estimated that CRPS affects nearly 200,000 patients annually in the United States. | Affects of Complex Regional Pain Syndrome. CRPS occurs 3 to 4 times more often in women than men. Although CRPS can occur at any age, it is rare in children and adolescents. In the pediatric population, the onset of CRPS usually occurs in early adolescence with the lower end of the range falling between 7 to 9 years. In adults, the age of onset is highly variable from 37 to 70 years of age. CRPS occurs most frequently in people of European ancestry (in about 66 to 80 percent of cases). In a study done in the United States, it was found that CRPS type I developed in 5.46 persons out of every 100,000 per year. It is estimated that CRPS affects nearly 200,000 patients annually in the United States. | 294 | Complex Regional Pain Syndrome |
nord_294_4 | Related disorders of Complex Regional Pain Syndrome | Symptoms of some disorders may be similar to CRPS, and it is important to be able to be able to recognize them during the process of diagnosing CRPS.Infection of the skin, muscle, or bone can cause redness, swelling and pain much like CRPS. Laboratory values that indicate inflammation and measure white blood cell count are usually elevated with infections, but they are no significant changes to those values in CRPS.Diseases that affect the blood vessels (vascular diseases) may also present the same symptoms as in the early stages of CRPS. Clotting of the veins in the legs and feet can produce redness, swelling, and pain in the affected extremity. Those clots can also cause the feet to become discolored and cold due to the reduced blood flow to the area. This can be distinguished from CRPS by using a form of ultrasound test to identify the decreased blood flow resulting from the clots.Another type of vascular disease is called Raynaud’s disease. It is a condition in which the blood vessels in the hands and fingers overreact and constrict in response to cold temperature and emotional stress. Raynaud’s phenomenon can be diagnosed by examining the hands to see if they are unusually sensitive to cold temperature, which is marked by a skin color change of blue and/or white.Rheumatoid arthritis is a chronic inflammatory disease that affects the joints, which can cause pain. What makes rheumatoid arthritis different from CRPS is that rheumatoid arthritis affects the joints, while CRPS affects an entire region of an extremity.Factitious disorder is a psychological disorder in which a patient will describe non-existent physical or psychological problems and has a need to pretend to be sick. These cases may be difficult to identify and diagnose, but close observation and psychiatric support can help properly diagnose factitious disorder. In such cases, patients often report symptoms of CRPS in the absence of objective CRPS signs on physical examination. | Related disorders of Complex Regional Pain Syndrome. Symptoms of some disorders may be similar to CRPS, and it is important to be able to be able to recognize them during the process of diagnosing CRPS.Infection of the skin, muscle, or bone can cause redness, swelling and pain much like CRPS. Laboratory values that indicate inflammation and measure white blood cell count are usually elevated with infections, but they are no significant changes to those values in CRPS.Diseases that affect the blood vessels (vascular diseases) may also present the same symptoms as in the early stages of CRPS. Clotting of the veins in the legs and feet can produce redness, swelling, and pain in the affected extremity. Those clots can also cause the feet to become discolored and cold due to the reduced blood flow to the area. This can be distinguished from CRPS by using a form of ultrasound test to identify the decreased blood flow resulting from the clots.Another type of vascular disease is called Raynaud’s disease. It is a condition in which the blood vessels in the hands and fingers overreact and constrict in response to cold temperature and emotional stress. Raynaud’s phenomenon can be diagnosed by examining the hands to see if they are unusually sensitive to cold temperature, which is marked by a skin color change of blue and/or white.Rheumatoid arthritis is a chronic inflammatory disease that affects the joints, which can cause pain. What makes rheumatoid arthritis different from CRPS is that rheumatoid arthritis affects the joints, while CRPS affects an entire region of an extremity.Factitious disorder is a psychological disorder in which a patient will describe non-existent physical or psychological problems and has a need to pretend to be sick. These cases may be difficult to identify and diagnose, but close observation and psychiatric support can help properly diagnose factitious disorder. In such cases, patients often report symptoms of CRPS in the absence of objective CRPS signs on physical examination. | 294 | Complex Regional Pain Syndrome |
nord_294_5 | Diagnosis of Complex Regional Pain Syndrome | Diagnosis of CRPS is suspected when a patient’s symptoms develop 4 to 6 weeks after limb trauma, symptoms cannot be fully explained by the initial trauma and the symptoms are regional (affecting an entire limb). Actual diagnosis of CRPS is made solely based on a history and physical examination to determine whether a patient meets CRPS diagnostic criteria (often called the “Budapest criteria”).The Budapest criteria has 4 components. First, the patient has continuing pain of an intensity disproportionate to any event that provokes it. Second, the patient must report symptoms in at least 3 of the 4 following categories: sensory (increased in sensitivity), vasomotor (temperature or color changes in the skin of affected limb), sudomotor/edema (sweating changes or swelling) and motor/trophic (motor impairment or changes in the hair/nails/skin). Third, the patient must also exhibit signs, which are observable by the health care provider, in at least 2 of the 4 categories above (sensory, vasomotor, sudomotor/edema, motor/trophic). The last component of the Budapest criteria is that no other diagnosis can better explain the signs and symptoms. The Budapest criteria have recently been incorporated into the new ICD-11 international diagnostic coding system. There is no “gold standard” test for diagnosing CRPS, and the diagnosis can be made with no testing at all other than the examination by a medical professional. Bone scans (bone scintigraphy) are sometimes used to support a CRPS diagnosis, but they are not required. Diagnostic sympathetic blocks, while also not required for diagnosis, are sometimes used to help determine the degree to which sympathetic nerve activity is contributing to the CRPS pain. | Diagnosis of Complex Regional Pain Syndrome. Diagnosis of CRPS is suspected when a patient’s symptoms develop 4 to 6 weeks after limb trauma, symptoms cannot be fully explained by the initial trauma and the symptoms are regional (affecting an entire limb). Actual diagnosis of CRPS is made solely based on a history and physical examination to determine whether a patient meets CRPS diagnostic criteria (often called the “Budapest criteria”).The Budapest criteria has 4 components. First, the patient has continuing pain of an intensity disproportionate to any event that provokes it. Second, the patient must report symptoms in at least 3 of the 4 following categories: sensory (increased in sensitivity), vasomotor (temperature or color changes in the skin of affected limb), sudomotor/edema (sweating changes or swelling) and motor/trophic (motor impairment or changes in the hair/nails/skin). Third, the patient must also exhibit signs, which are observable by the health care provider, in at least 2 of the 4 categories above (sensory, vasomotor, sudomotor/edema, motor/trophic). The last component of the Budapest criteria is that no other diagnosis can better explain the signs and symptoms. The Budapest criteria have recently been incorporated into the new ICD-11 international diagnostic coding system. There is no “gold standard” test for diagnosing CRPS, and the diagnosis can be made with no testing at all other than the examination by a medical professional. Bone scans (bone scintigraphy) are sometimes used to support a CRPS diagnosis, but they are not required. Diagnostic sympathetic blocks, while also not required for diagnosis, are sometimes used to help determine the degree to which sympathetic nerve activity is contributing to the CRPS pain. | 294 | Complex Regional Pain Syndrome |
nord_294_6 | Therapies of Complex Regional Pain Syndrome | TreatmentCRPS is best treated using multiple approaches simultaneously, including physical therapy (PT), occupational therapy (OT), medications and interventional procedures and pain-focused psychological therapy. The goal of treatment is to manage the pain and to increase mobility of the affected limbs.Physical and Occupational TherapyPT and OT are considered first-line treatments for CRPS. Some available therapeutic methods that can be used include desensitization, strength and flexibility training, vocational support, coping skills training, postural control, gait retraining, enhancing ability to carry out daily activities and relaxation techniques. Another possible rehabilitation method that can be used is graded motor imagery. This method is used to train the brain to enhance motor coordination and function of the limbs that are affected. There are few downsides to PT and OT for CRPS, except for cost and convenience, and it is suggested that a patient newly diagnosed with CRPS should seek out PT and OT care.Pharmacologic TherapyPain is a major concern with CRPS, and this can be managed with a variety of medications that can reduce and control the pain. Pain management is important so that a patient with CRPS can undergo PT with minimal pain.Anticonvulsants may be useful in treating pain that is associated with damage or injury to nerves (neuropathic pain). Drugs such as gabapentin and pregabalin are options for treating neuropathic pain and are often used in management of CRPS. These drugs have modest effects for the reduction of pain. Topical creams containing lidocaine (a numbing agent) can also be used for neuropathic pain.Another standard treatment for CRPS is certain types of antidepressant drugs, even if a patient is not depressed. These drugs cause chemical changes in the brain that may help reduce pain and also improve sleep, a common problem among CRPS patients.Bisphosphonates may be beneficial in patients with CRPS. Bisphosphonates work by inhibiting the breakdown of bones by cells called osteoclasts; however, it is unlikely that bisphosphonates help with CRPS pain by this mechanism. Regardless of the mechanism of action, bisphosphonates, such as alendronate, have shown some signs of efficacy in reducing CRPS pain, particularly in its earlier stages, although they are not widely used in CRPS treatment at the present time.Glucocorticoids (steroid medications) are another treatment option for CRPS. There is some evidence that they may be effective at least in the early stages of CRPS (less than a year). In patients who have had CRPS for a longer duration (chronic CRPS), glucocorticoid treatments may have no beneficial effects.Opioids may also be used for CRPS; however, there are very few studies that have investigated the use of opioids for CRPS. The studies that have been done with opioids do not show that they are effective. The use of opioids may be considered if other options have failed, although opioid medications may carry significant risks.Interventional ProceduresCertain procedures may be required for those who find noninvasive treatments, such as medications and PT, ineffective.Sympathetic nerve blockade can be used to block the nerves of the sympathetic nervous system. With this nerve blockade, local anesthetics, such as lidocaine, are injected to block the nerves, which may result in a decrease in pain sensation for some patients. There is little research evidence to show its benefits for CRPS as a whole, but it has been reported to work and be life-changing in some patients.Spinal cord stimulation (SCS) may be beneficial for patients who have not adequately responded to the interventions above. SCS uses an electric pulse stimulation to control the transmission of pain signals in the spinal cord. This treatment is relatively safe and reversible but may be expensive.Pain-Focused Psychological TherapyFor individuals in whom CRPS does not quickly resolve with the noninvasive treatments above, psychological issues frequently emerge resulting from life disruptions related to CRPS and the fact that psychological stress and emotional distress often exacerbate CRPS pain. Psychological therapy focused on addressing barriers to living with CRPS and learning strategies to manage symptoms (e.g., mindfulness techniques, relaxation and imagery training, biofeedback) may be useful for enhancing quality of life in those living with CRPS. This type of psychological therapy typically employs cognitive behavioral and/or mindfulness training techniques. | Therapies of Complex Regional Pain Syndrome. TreatmentCRPS is best treated using multiple approaches simultaneously, including physical therapy (PT), occupational therapy (OT), medications and interventional procedures and pain-focused psychological therapy. The goal of treatment is to manage the pain and to increase mobility of the affected limbs.Physical and Occupational TherapyPT and OT are considered first-line treatments for CRPS. Some available therapeutic methods that can be used include desensitization, strength and flexibility training, vocational support, coping skills training, postural control, gait retraining, enhancing ability to carry out daily activities and relaxation techniques. Another possible rehabilitation method that can be used is graded motor imagery. This method is used to train the brain to enhance motor coordination and function of the limbs that are affected. There are few downsides to PT and OT for CRPS, except for cost and convenience, and it is suggested that a patient newly diagnosed with CRPS should seek out PT and OT care.Pharmacologic TherapyPain is a major concern with CRPS, and this can be managed with a variety of medications that can reduce and control the pain. Pain management is important so that a patient with CRPS can undergo PT with minimal pain.Anticonvulsants may be useful in treating pain that is associated with damage or injury to nerves (neuropathic pain). Drugs such as gabapentin and pregabalin are options for treating neuropathic pain and are often used in management of CRPS. These drugs have modest effects for the reduction of pain. Topical creams containing lidocaine (a numbing agent) can also be used for neuropathic pain.Another standard treatment for CRPS is certain types of antidepressant drugs, even if a patient is not depressed. These drugs cause chemical changes in the brain that may help reduce pain and also improve sleep, a common problem among CRPS patients.Bisphosphonates may be beneficial in patients with CRPS. Bisphosphonates work by inhibiting the breakdown of bones by cells called osteoclasts; however, it is unlikely that bisphosphonates help with CRPS pain by this mechanism. Regardless of the mechanism of action, bisphosphonates, such as alendronate, have shown some signs of efficacy in reducing CRPS pain, particularly in its earlier stages, although they are not widely used in CRPS treatment at the present time.Glucocorticoids (steroid medications) are another treatment option for CRPS. There is some evidence that they may be effective at least in the early stages of CRPS (less than a year). In patients who have had CRPS for a longer duration (chronic CRPS), glucocorticoid treatments may have no beneficial effects.Opioids may also be used for CRPS; however, there are very few studies that have investigated the use of opioids for CRPS. The studies that have been done with opioids do not show that they are effective. The use of opioids may be considered if other options have failed, although opioid medications may carry significant risks.Interventional ProceduresCertain procedures may be required for those who find noninvasive treatments, such as medications and PT, ineffective.Sympathetic nerve blockade can be used to block the nerves of the sympathetic nervous system. With this nerve blockade, local anesthetics, such as lidocaine, are injected to block the nerves, which may result in a decrease in pain sensation for some patients. There is little research evidence to show its benefits for CRPS as a whole, but it has been reported to work and be life-changing in some patients.Spinal cord stimulation (SCS) may be beneficial for patients who have not adequately responded to the interventions above. SCS uses an electric pulse stimulation to control the transmission of pain signals in the spinal cord. This treatment is relatively safe and reversible but may be expensive.Pain-Focused Psychological TherapyFor individuals in whom CRPS does not quickly resolve with the noninvasive treatments above, psychological issues frequently emerge resulting from life disruptions related to CRPS and the fact that psychological stress and emotional distress often exacerbate CRPS pain. Psychological therapy focused on addressing barriers to living with CRPS and learning strategies to manage symptoms (e.g., mindfulness techniques, relaxation and imagery training, biofeedback) may be useful for enhancing quality of life in those living with CRPS. This type of psychological therapy typically employs cognitive behavioral and/or mindfulness training techniques. | 294 | Complex Regional Pain Syndrome |
nord_295_0 | Overview of Cone Dystrophy | SummaryCone dystrophy is a general term used to describe a group of rare eye disorders that affect the cone cells of the retina. Cone dystrophy can cause a variety of symptoms including decreased visual clarity (acuity), decreased color perception (dyschromatopsia), and increased sensitivity to light (photophobia). There are two main forms of cone dystrophy: stationary cone dystrophy and progressive cone dystrophy. In stationary cone dystrophy, symptoms tend to remain stable and are usually present at birth or early childhood. In progressive cone dystrophy, symptoms slowly worsen over time. The age of onset, progression and severity of cone dystrophy can vary greatly from one person to another, even among individuals with the same type of cone dystrophy. Some forms of cone dystrophy are inherited; other forms appear to occur by chance for no apparent reason (sporadically).A variety of different and confusing names have been used to describe the various forms of cone dystrophy. Some researchers limit the term “cone dystrophy” to the progressive forms of the disorder. Other researchers use cone dystrophy as an umbrella term for both the stationary and progressive forms of cone dystrophy – examples of which include achromatopsia, incomplete achromatopsia, blue cone monochromatism and X-linked progressive cone dystrophy. This report is a general overview of stationary and progressive cone dystrophy. For more specific information on an individual form of cone dystrophy, use the disorder's specific name as your search term in the Rare Disease Database or contact one of the organizations listed in the resources section of this report. | Overview of Cone Dystrophy. SummaryCone dystrophy is a general term used to describe a group of rare eye disorders that affect the cone cells of the retina. Cone dystrophy can cause a variety of symptoms including decreased visual clarity (acuity), decreased color perception (dyschromatopsia), and increased sensitivity to light (photophobia). There are two main forms of cone dystrophy: stationary cone dystrophy and progressive cone dystrophy. In stationary cone dystrophy, symptoms tend to remain stable and are usually present at birth or early childhood. In progressive cone dystrophy, symptoms slowly worsen over time. The age of onset, progression and severity of cone dystrophy can vary greatly from one person to another, even among individuals with the same type of cone dystrophy. Some forms of cone dystrophy are inherited; other forms appear to occur by chance for no apparent reason (sporadically).A variety of different and confusing names have been used to describe the various forms of cone dystrophy. Some researchers limit the term “cone dystrophy” to the progressive forms of the disorder. Other researchers use cone dystrophy as an umbrella term for both the stationary and progressive forms of cone dystrophy – examples of which include achromatopsia, incomplete achromatopsia, blue cone monochromatism and X-linked progressive cone dystrophy. This report is a general overview of stationary and progressive cone dystrophy. For more specific information on an individual form of cone dystrophy, use the disorder's specific name as your search term in the Rare Disease Database or contact one of the organizations listed in the resources section of this report. | 295 | Cone Dystrophy |
nord_295_1 | Symptoms of Cone Dystrophy | The symptoms of cone dystrophy may vary from one person to another, even among individuals with the same form of the disorder. The age of onset, specific symptoms, severity and progression (if any) can vary greatly. The amount of vision loss varies and is difficult to predict. Affected individuals should talk to their physician and medical team about their specific case and associated symptoms.Cone dystrophy results from damage to the cone cells of the retinas. The retinas are the thin layers of nerve cells that line the inner surface of the back of the eyes. The retinas sense light and convert it to nerve signals, which are then relayed to the brain through the optic nerve. The retina has two main types of cells: cones and rods. Cone and rod cells are called photoreceptors because they detect and respond to light stimuli.Cone cells are located throughout the retina. The highest concentration of cone cells is clustered in the oval-shaped, yellowish area near the center of the retina (macula). Cone cells are involved in the part of vision that enables a person to see fine details, read or recognize faces. Cone cells also play a role in the perception of color. Cone cells function best in bright light. Rod cells are found throughout the retina except in the center. Rod cells enable people to see in low or limited light.Cone dystrophy is sometimes broken down into two broad groups: stationary and progressive. Stationary cone dystrophy is usually present during infancy or early childhood and symptoms usually remain the same throughout life. In progressive cone dystrophy, associated symptoms become worse over time. Progressive cone dystrophy usually develops in late childhood or early during adulthood. However, the rate of progression and age of onset can vary greatly from one person to another.
Damage to cone cells can result in decreased clarity of vision (reduced visual acuity) when looking straight ahead (central vision), a reduced ability to see colors and an abnormal sensitivity to light (photophobia). Some affected individuals may not be able to see color at all and some may develop rapid, involuntary eye movements (nystagmus).In the progressive form of cone dystrophy, vision continues to deteriorate over time. In many cases vision may deteriorate so that a person is considered “legally” blind (i.e., vision that is 20/200 or worse). Complete blindness is uncommon in individuals with cone dystrophy. Side (peripheral) vision is usually unaffected as well. Individuals with cone dystrophy can usually see well at night or in low light situations because the rod cells are usually unaffected. In rare cases, late in the disease course, some rod cells may become involved. | Symptoms of Cone Dystrophy. The symptoms of cone dystrophy may vary from one person to another, even among individuals with the same form of the disorder. The age of onset, specific symptoms, severity and progression (if any) can vary greatly. The amount of vision loss varies and is difficult to predict. Affected individuals should talk to their physician and medical team about their specific case and associated symptoms.Cone dystrophy results from damage to the cone cells of the retinas. The retinas are the thin layers of nerve cells that line the inner surface of the back of the eyes. The retinas sense light and convert it to nerve signals, which are then relayed to the brain through the optic nerve. The retina has two main types of cells: cones and rods. Cone and rod cells are called photoreceptors because they detect and respond to light stimuli.Cone cells are located throughout the retina. The highest concentration of cone cells is clustered in the oval-shaped, yellowish area near the center of the retina (macula). Cone cells are involved in the part of vision that enables a person to see fine details, read or recognize faces. Cone cells also play a role in the perception of color. Cone cells function best in bright light. Rod cells are found throughout the retina except in the center. Rod cells enable people to see in low or limited light.Cone dystrophy is sometimes broken down into two broad groups: stationary and progressive. Stationary cone dystrophy is usually present during infancy or early childhood and symptoms usually remain the same throughout life. In progressive cone dystrophy, associated symptoms become worse over time. Progressive cone dystrophy usually develops in late childhood or early during adulthood. However, the rate of progression and age of onset can vary greatly from one person to another.
Damage to cone cells can result in decreased clarity of vision (reduced visual acuity) when looking straight ahead (central vision), a reduced ability to see colors and an abnormal sensitivity to light (photophobia). Some affected individuals may not be able to see color at all and some may develop rapid, involuntary eye movements (nystagmus).In the progressive form of cone dystrophy, vision continues to deteriorate over time. In many cases vision may deteriorate so that a person is considered “legally” blind (i.e., vision that is 20/200 or worse). Complete blindness is uncommon in individuals with cone dystrophy. Side (peripheral) vision is usually unaffected as well. Individuals with cone dystrophy can usually see well at night or in low light situations because the rod cells are usually unaffected. In rare cases, late in the disease course, some rod cells may become involved. | 295 | Cone Dystrophy |
nord_295_2 | Causes of Cone Dystrophy | Many cases of cone dystrophy occur randomly for no identifiable reason (sporadically). Some forms are inherited in an autosomal dominant, autosomal recessive or X-linked pattern. Inherited forms of cone dystrophy are due to changes (mutations) in one of several genes that have been linked to cone dystrophy. These genes contain instructions for making proteins that play vital roles in the development, function and overall health of cone cells. The exact underlying mechanisms that cause cone dystrophy are not fully understood.Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a changed (mutated) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.X-linked genetic disorders are conditions caused by a non-working gene on the X chromosome and manifest mostly in males. Females that have a non-working gene copy 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 non-working gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a non-working 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.A male with an X-linked disorder will pass the non-working gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Less often, cone dystrophy may be inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a non-working gene copy from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females. | Causes of Cone Dystrophy. Many cases of cone dystrophy occur randomly for no identifiable reason (sporadically). Some forms are inherited in an autosomal dominant, autosomal recessive or X-linked pattern. Inherited forms of cone dystrophy are due to changes (mutations) in one of several genes that have been linked to cone dystrophy. These genes contain instructions for making proteins that play vital roles in the development, function and overall health of cone cells. The exact underlying mechanisms that cause cone dystrophy are not fully understood.Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a changed (mutated) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.X-linked genetic disorders are conditions caused by a non-working gene on the X chromosome and manifest mostly in males. Females that have a non-working gene copy 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 non-working gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a non-working 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.A male with an X-linked disorder will pass the non-working gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Less often, cone dystrophy may be inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a non-working gene copy from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females. | 295 | Cone Dystrophy |
nord_295_3 | Affects of Cone Dystrophy | Cone dystrophy affects males and females in equal numbers when it occurs sporadically or is inherited in an autosomal dominant or recessive pattern. The X-linked form of cone dystrophy only affects males fully, although some females may have mild symptoms of the disorder. The exact incidence of cone dystrophy is unknown. Most sources estimate that the condition affects 1 in 30,000 individuals in the general population. | Affects of Cone Dystrophy. Cone dystrophy affects males and females in equal numbers when it occurs sporadically or is inherited in an autosomal dominant or recessive pattern. The X-linked form of cone dystrophy only affects males fully, although some females may have mild symptoms of the disorder. The exact incidence of cone dystrophy is unknown. Most sources estimate that the condition affects 1 in 30,000 individuals in the general population. | 295 | Cone Dystrophy |
nord_295_4 | Related disorders of Cone Dystrophy | Symptoms of the following disorders can be similar to those of cone dystrophy. Comparisons may be useful for a differential diagnosis.Cone-rod dystrophies are a group of rare eye disorders that affect both the cone and rod cells of the retina. In some cases, individuals experience deterioration of the cone cells more severely than the rod cells. In these cases, the initial symptoms are decreased clarity (acuity) of vision when looking straight ahead (central), loss of the ability to perceive color, and an abnormal sensitivity to light (photophobia). When the rod cells become more involved, affected individuals experience a decreased ability to see at night or in low light situations and may lose the ability to see clearly to the sides (peripheral vision). In rare cases, cone and rod cells deteriorate simultaneously and these symptoms occur at approximately the same time. Most cases of cone-rod dystrophies occur due to mutations of certain genes. Several different genes have been linked to cone-rod dystrophy. Cone-rod dystrophies can be inherited in an autosomal recessive, dominant, X-linked or mitochondrial pattern.Leber congenital amaurosis (LCA) is a rare genetic eye disorder. Affected infants are often blind at birth or lose their sight within the first few years of life. Other symptoms may include crossed eyes (strabismus); rapid, involuntary eye movements (nystagmus); unusual sensitivity to light (photophobia); clouding of the lenses of the eyes (cataracts); and/or abnormal protrusion of the front (anterior), clear portion of the eye through which light passes (cornea) (keratoconus). In addition, some infants with complicated syndromes from other genes may exhibit hearing loss, intellectual disability, and/or a delay in the acquisition of skills that require the coordination of mental and muscular activity (developmental delay). LCA is usually inherited in an autosomal recessive pattern. Several genes have been found to be involved in LCA. (For more information on this disorder, choose “Leber Congenital Amaurosis” as your search term in the Rare Disease Database.)Stargardt disease is a rare juvenile form of macular degeneration. Macular degeneration is a general term for a group of eyes disorders characterized by the deterioration of the oval-shaped yellow spot (macula) near the center of the retina. The macula is essential for proper vision when looking straight ahead (central vision) and with seeing fine details. Some individuals with Stargardt disease may experience symptoms during childhood, while other individuals with this condition may not experience symptoms until their 30s or 40s. Central vision is usually affected in most cases and affected individuals may have trouble reading or have spots in their field of vision. Later in the course of the disease, the ability to perceive color is affected. Affected individuals may also need more time than normal to adjust from moving between bright and dark environments. Peripheral vision and the ability to see at night or in low light environments are usually unaffected. Stargardt disease is inherited as an autosomal recessive trait. X-linked retinoschisis is a genetic disorder that affects the specialized light-sensitive tissue at the back of the eye (retina). Specifically, the cells in the center area of the retina (macula) are affected, which causes decreased clarity (acuity) of vision. X-linked retinoschisis may be diagnosed in infancy due to symptoms of squinting or at school age due to decreased clarity of vision. The condition is typically mild until age 40, at which point an individual’s clarity of vision decreases progressively. X-linked retinoschisis is inherited in an X-linked pattern, and almost exclusively occurs in males. In fact, X-linked retinoschisis is the leading cause of macular degeneration in young males. (For more information on this disorder, choose “X-linked retinoschisis” as your search term in the Rare Disease Database.)Choroideremia is a genetic disorder that causes progressive vision loss. Individuals with choroideremia experience a progressive loss of cells in the light-sensitive tissue at the back of the eye (retina) and in the network of blood vessels in the eye (choroid). Symptoms may begin in early childhood, typically starting with difficulty seeing in low light (night blindness). Later in life, the field of vision becomes progressively narrower (tunnel vision), and progressive decreased clarity (acuity) of vision occurs as well. Choroideremia is inherited in an X-linked pattern, and usually affects males. (For more information on this disorder, choose “Choroideremia” as your search term in the Rare Disease Database.)Syndromic cone dystrophy is a general term for a cone dystrophy that occurs as part of a larger syndrome. These syndromes include Bardet-Biedl syndrome, Refsum disease, Batten disease, NARP syndrome and spinocerebellar ataxia type 7. These disorders have additional symptoms unrelated to cone dystrophy. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | Related disorders of Cone Dystrophy. Symptoms of the following disorders can be similar to those of cone dystrophy. Comparisons may be useful for a differential diagnosis.Cone-rod dystrophies are a group of rare eye disorders that affect both the cone and rod cells of the retina. In some cases, individuals experience deterioration of the cone cells more severely than the rod cells. In these cases, the initial symptoms are decreased clarity (acuity) of vision when looking straight ahead (central), loss of the ability to perceive color, and an abnormal sensitivity to light (photophobia). When the rod cells become more involved, affected individuals experience a decreased ability to see at night or in low light situations and may lose the ability to see clearly to the sides (peripheral vision). In rare cases, cone and rod cells deteriorate simultaneously and these symptoms occur at approximately the same time. Most cases of cone-rod dystrophies occur due to mutations of certain genes. Several different genes have been linked to cone-rod dystrophy. Cone-rod dystrophies can be inherited in an autosomal recessive, dominant, X-linked or mitochondrial pattern.Leber congenital amaurosis (LCA) is a rare genetic eye disorder. Affected infants are often blind at birth or lose their sight within the first few years of life. Other symptoms may include crossed eyes (strabismus); rapid, involuntary eye movements (nystagmus); unusual sensitivity to light (photophobia); clouding of the lenses of the eyes (cataracts); and/or abnormal protrusion of the front (anterior), clear portion of the eye through which light passes (cornea) (keratoconus). In addition, some infants with complicated syndromes from other genes may exhibit hearing loss, intellectual disability, and/or a delay in the acquisition of skills that require the coordination of mental and muscular activity (developmental delay). LCA is usually inherited in an autosomal recessive pattern. Several genes have been found to be involved in LCA. (For more information on this disorder, choose “Leber Congenital Amaurosis” as your search term in the Rare Disease Database.)Stargardt disease is a rare juvenile form of macular degeneration. Macular degeneration is a general term for a group of eyes disorders characterized by the deterioration of the oval-shaped yellow spot (macula) near the center of the retina. The macula is essential for proper vision when looking straight ahead (central vision) and with seeing fine details. Some individuals with Stargardt disease may experience symptoms during childhood, while other individuals with this condition may not experience symptoms until their 30s or 40s. Central vision is usually affected in most cases and affected individuals may have trouble reading or have spots in their field of vision. Later in the course of the disease, the ability to perceive color is affected. Affected individuals may also need more time than normal to adjust from moving between bright and dark environments. Peripheral vision and the ability to see at night or in low light environments are usually unaffected. Stargardt disease is inherited as an autosomal recessive trait. X-linked retinoschisis is a genetic disorder that affects the specialized light-sensitive tissue at the back of the eye (retina). Specifically, the cells in the center area of the retina (macula) are affected, which causes decreased clarity (acuity) of vision. X-linked retinoschisis may be diagnosed in infancy due to symptoms of squinting or at school age due to decreased clarity of vision. The condition is typically mild until age 40, at which point an individual’s clarity of vision decreases progressively. X-linked retinoschisis is inherited in an X-linked pattern, and almost exclusively occurs in males. In fact, X-linked retinoschisis is the leading cause of macular degeneration in young males. (For more information on this disorder, choose “X-linked retinoschisis” as your search term in the Rare Disease Database.)Choroideremia is a genetic disorder that causes progressive vision loss. Individuals with choroideremia experience a progressive loss of cells in the light-sensitive tissue at the back of the eye (retina) and in the network of blood vessels in the eye (choroid). Symptoms may begin in early childhood, typically starting with difficulty seeing in low light (night blindness). Later in life, the field of vision becomes progressively narrower (tunnel vision), and progressive decreased clarity (acuity) of vision occurs as well. Choroideremia is inherited in an X-linked pattern, and usually affects males. (For more information on this disorder, choose “Choroideremia” as your search term in the Rare Disease Database.)Syndromic cone dystrophy is a general term for a cone dystrophy that occurs as part of a larger syndrome. These syndromes include Bardet-Biedl syndrome, Refsum disease, Batten disease, NARP syndrome and spinocerebellar ataxia type 7. These disorders have additional symptoms unrelated to cone dystrophy. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | 295 | Cone Dystrophy |
nord_295_5 | Diagnosis of Cone Dystrophy | A diagnosis of cone dystrophy is made based on identification of characteristic symptoms, a detailed family history, and a thorough clinical evaluation involving ophthalmological exams that measure visual acuity, the ability to perceive color and field of vision. An electroretinogram (ERG) is used to confirm the diagnosis of cone dystrophy.During an ERG, eye drops are used to numb the eye before placing a special contact lens-electrode on the eye. The patient then watches a set of flashing lights in order to stimulate the retina. Doctors can then measure the electrical signals made by the cone and rod cells. An ERG test is performed twice – once in a bright room and once in a dark room. The test can determine whether cone and rod cells are functioning properly. A weak or absent signal of cone cells indicates cone dystrophy. | Diagnosis of Cone Dystrophy. A diagnosis of cone dystrophy is made based on identification of characteristic symptoms, a detailed family history, and a thorough clinical evaluation involving ophthalmological exams that measure visual acuity, the ability to perceive color and field of vision. An electroretinogram (ERG) is used to confirm the diagnosis of cone dystrophy.During an ERG, eye drops are used to numb the eye before placing a special contact lens-electrode on the eye. The patient then watches a set of flashing lights in order to stimulate the retina. Doctors can then measure the electrical signals made by the cone and rod cells. An ERG test is performed twice – once in a bright room and once in a dark room. The test can determine whether cone and rod cells are functioning properly. A weak or absent signal of cone cells indicates cone dystrophy. | 295 | Cone Dystrophy |
nord_295_6 | Therapies of Cone Dystrophy | TreatmentThere is no cure for cone dystrophy. Treatment is directed toward the specific symptoms that are apparent in each individual. Treatment may include using tinted lenses or dark sunglass in bright environments and magnifying devices to assist in reading and other similar activities.Genetic counseling is recommended for affected individuals and their families. Genetic counselors help individuals and families assess the chance of inherited disease as well as understand and adapt to its implications. Other treatment is symptomatic and supportive. | Therapies of Cone Dystrophy. TreatmentThere is no cure for cone dystrophy. Treatment is directed toward the specific symptoms that are apparent in each individual. Treatment may include using tinted lenses or dark sunglass in bright environments and magnifying devices to assist in reading and other similar activities.Genetic counseling is recommended for affected individuals and their families. Genetic counselors help individuals and families assess the chance of inherited disease as well as understand and adapt to its implications. Other treatment is symptomatic and supportive. | 295 | Cone Dystrophy |
nord_296_0 | Overview of Congenital Adrenal Hyperplasia | Congenital adrenal hyperplasia (CAH) is a group of rare inherited autosomal recessive disorders characterized by a deficiency of one of the enzymes needed to make specific hormones. CAH affects the adrenal glands located at the top of each kidney. Normally, the adrenal glands are responsible for producing three different hormones: corticosteroids, which gauge the body’s response to illness or injury; mineralocorticoids, which regulate salt and water levels; and androgens, which are male sex hormones. An enzyme deficiency will make the body unable to produce one or more of these hormones, which in turn will result in the overproduction of another type of hormone precursor in order to compensate for the loss. The most common cause of CAH is the absence of the enzyme 21-hydroxylase. Different variants in the gene responsible for 21-hydroxylase result in different levels of the enzyme, producing a spectrum of effects. CAH due to 21-hydroxylase deficiency is responsible for 95% of all cases of CAH and is broken down further into two subcategories: classical CAH, which can be sub-divided into the salt-losing form or the simple-virilizing form, and non-classical CAH. Classical CAH is by far the more severe form and can result in adrenal crisis and death if not detected and treated. Non-classical CAH is milder and may or may not present symptoms. Since the absence of 21-hydroxylase makes these individuals unable to make the hormone cortisol and, in the case of salt-losing CAH, aldosterone, the body produces more androgens which cause a variety of symptoms such as atypical genital development in infant girls. There are other much rarer forms of CAH as well, including 11-Beta hydroxylase deficiency, 17a- hydroxylase deficiency, 3-Beta-hydroxysteroid dehydrogenase deficiency, congenital lipoid adrenal hyperplasia and p450 oxidoreductase deficiency which all present different symptoms. Although CAH is not curable, patients can go on to lead normal lives if they receive adequate care and treatment. | Overview of Congenital Adrenal Hyperplasia. Congenital adrenal hyperplasia (CAH) is a group of rare inherited autosomal recessive disorders characterized by a deficiency of one of the enzymes needed to make specific hormones. CAH affects the adrenal glands located at the top of each kidney. Normally, the adrenal glands are responsible for producing three different hormones: corticosteroids, which gauge the body’s response to illness or injury; mineralocorticoids, which regulate salt and water levels; and androgens, which are male sex hormones. An enzyme deficiency will make the body unable to produce one or more of these hormones, which in turn will result in the overproduction of another type of hormone precursor in order to compensate for the loss. The most common cause of CAH is the absence of the enzyme 21-hydroxylase. Different variants in the gene responsible for 21-hydroxylase result in different levels of the enzyme, producing a spectrum of effects. CAH due to 21-hydroxylase deficiency is responsible for 95% of all cases of CAH and is broken down further into two subcategories: classical CAH, which can be sub-divided into the salt-losing form or the simple-virilizing form, and non-classical CAH. Classical CAH is by far the more severe form and can result in adrenal crisis and death if not detected and treated. Non-classical CAH is milder and may or may not present symptoms. Since the absence of 21-hydroxylase makes these individuals unable to make the hormone cortisol and, in the case of salt-losing CAH, aldosterone, the body produces more androgens which cause a variety of symptoms such as atypical genital development in infant girls. There are other much rarer forms of CAH as well, including 11-Beta hydroxylase deficiency, 17a- hydroxylase deficiency, 3-Beta-hydroxysteroid dehydrogenase deficiency, congenital lipoid adrenal hyperplasia and p450 oxidoreductase deficiency which all present different symptoms. Although CAH is not curable, patients can go on to lead normal lives if they receive adequate care and treatment. | 296 | Congenital Adrenal Hyperplasia |
nord_296_1 | Symptoms of Congenital Adrenal Hyperplasia | Many individuals with CAH present with abnormally enlarged adrenal glands (hyperplastic adrenomegaly) that produce excessive amounts of androgens (male steroid hormones) leading to abnormal sexual development in females affected with the disease. Females with severe or classic virilizing CAH due to 21-hydroxylase deficiency will most likely have ambiguous or atypical external genitalia (masculinization or virilization), although they are genetically female and will have normal internal reproductive organs. Males with this type of CAH will not have ambiguous genitalia. Both genders can experience other symptoms such as early onset of puberty, fast body growth and premature completion of growth leading to short stature, if they are not diagnosed and treated in early life. About 75% of people with classical CAH due to 21-hydroxylase deficiency also have a deficiency of the hormone aldosterone, leading to the inability to retain salt and water (salt wasting). This results in excessive loss of water (dehydration), low circulating blood volume (hypovolemia) and abnormally low blood pressure (hypotension and shock). Without treatment, this severe form of CAH can lead to profound weakness, vomiting, diarrhea and circulatory collapse due to adrenal crisis. The remaining 25% are referred to as simple-virilizers and do not have a problem regulating salt and water levels. Fortunately, in the United States, and in many other developed countries, there is universal newborn screening for CAH due to 21-hydroxylase deficiency, and the vast majority of children are diagnosed and treated early to avoid these complications. The mild form of 21-hydroxylase deficiency (non-classical CAH) is not life-threatening and is due to a more common genetic variant. This mild form is not usually detected in our newborn screening programs, and it seldom requires early treatment. Symptoms in later childhood may include premature body hair or acne development. In adolescent females, the most common problems include excessive facial or body hair, menstrual irregularities, and pustular acne. Both genders have normal genitals. A small proportion of the non-classical CAH population has sub-fertility. Patients with CAH may or may not require treatment to improve their quality of life. Rare forms of CAH:
Patients affected with 11-Beta hydroxylase deficiency are protected from the symptoms associated with adrenal crisis, although they are subject to others such as hypertension due to salt retention and ambiguous genitalia in females. Steroid 17a-hydroxylase deficiency results in ambiguous external genitalia in males and lack of pubertal development or menstrual cycles (amenorrhea) in females. Steroid 3-Beta-hydroxysteroid dehydrogenase deficiency leads to ambiguous genitalia in males and females. In both genders it can lead to salt-wasting. Congenital lipoid adrenal hyperplasia may cause early death due to adrenal crisis. Males have ambiguous genitalia. Both males and females, if they survive, would likely be infertile. PORD (P450 oxidoreductase deficiency) presents with signs and symptoms that may resemble 21-hydroxylase deficiency, 17-hydroxylase deficiency, or a combination of the two enzyme deficiencies. Some cases have been associated with a skeletal disorder known as Antley-Bixler syndrome. | Symptoms of Congenital Adrenal Hyperplasia. Many individuals with CAH present with abnormally enlarged adrenal glands (hyperplastic adrenomegaly) that produce excessive amounts of androgens (male steroid hormones) leading to abnormal sexual development in females affected with the disease. Females with severe or classic virilizing CAH due to 21-hydroxylase deficiency will most likely have ambiguous or atypical external genitalia (masculinization or virilization), although they are genetically female and will have normal internal reproductive organs. Males with this type of CAH will not have ambiguous genitalia. Both genders can experience other symptoms such as early onset of puberty, fast body growth and premature completion of growth leading to short stature, if they are not diagnosed and treated in early life. About 75% of people with classical CAH due to 21-hydroxylase deficiency also have a deficiency of the hormone aldosterone, leading to the inability to retain salt and water (salt wasting). This results in excessive loss of water (dehydration), low circulating blood volume (hypovolemia) and abnormally low blood pressure (hypotension and shock). Without treatment, this severe form of CAH can lead to profound weakness, vomiting, diarrhea and circulatory collapse due to adrenal crisis. The remaining 25% are referred to as simple-virilizers and do not have a problem regulating salt and water levels. Fortunately, in the United States, and in many other developed countries, there is universal newborn screening for CAH due to 21-hydroxylase deficiency, and the vast majority of children are diagnosed and treated early to avoid these complications. The mild form of 21-hydroxylase deficiency (non-classical CAH) is not life-threatening and is due to a more common genetic variant. This mild form is not usually detected in our newborn screening programs, and it seldom requires early treatment. Symptoms in later childhood may include premature body hair or acne development. In adolescent females, the most common problems include excessive facial or body hair, menstrual irregularities, and pustular acne. Both genders have normal genitals. A small proportion of the non-classical CAH population has sub-fertility. Patients with CAH may or may not require treatment to improve their quality of life. Rare forms of CAH:
Patients affected with 11-Beta hydroxylase deficiency are protected from the symptoms associated with adrenal crisis, although they are subject to others such as hypertension due to salt retention and ambiguous genitalia in females. Steroid 17a-hydroxylase deficiency results in ambiguous external genitalia in males and lack of pubertal development or menstrual cycles (amenorrhea) in females. Steroid 3-Beta-hydroxysteroid dehydrogenase deficiency leads to ambiguous genitalia in males and females. In both genders it can lead to salt-wasting. Congenital lipoid adrenal hyperplasia may cause early death due to adrenal crisis. Males have ambiguous genitalia. Both males and females, if they survive, would likely be infertile. PORD (P450 oxidoreductase deficiency) presents with signs and symptoms that may resemble 21-hydroxylase deficiency, 17-hydroxylase deficiency, or a combination of the two enzyme deficiencies. Some cases have been associated with a skeletal disorder known as Antley-Bixler syndrome. | 296 | Congenital Adrenal Hyperplasia |
nord_296_2 | Causes of Congenital Adrenal Hyperplasia | Deletions and changes (mutations or variants) in the CYP21A2 gene account for all cases of the 21-hydroxylase deficiency form of CAH. Variants in the CYP11B1, CYP17A1, HSD3B2, CYP11A1, STAR and CYPOR genes are responsible, respectively, for 11-hydroxylase, 17-hydroxylase, 3-beta-hydroxysteroid dehydrogenase deficiencies, lipoid adrenal hyperplasia, and PORD, the other rarer forms of CAH. All forms of CAH are inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits an abnormal gene from each parent. If an individual receives one normal gene and one abnormal 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 abnormal gene and, therefore, have an affected child is 25% with each pregnancy. The risk of having 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. | Causes of Congenital Adrenal Hyperplasia. Deletions and changes (mutations or variants) in the CYP21A2 gene account for all cases of the 21-hydroxylase deficiency form of CAH. Variants in the CYP11B1, CYP17A1, HSD3B2, CYP11A1, STAR and CYPOR genes are responsible, respectively, for 11-hydroxylase, 17-hydroxylase, 3-beta-hydroxysteroid dehydrogenase deficiencies, lipoid adrenal hyperplasia, and PORD, the other rarer forms of CAH. All forms of CAH are inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits an abnormal gene from each parent. If an individual receives one normal gene and one abnormal 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 abnormal gene and, therefore, have an affected child is 25% with each pregnancy. The risk of having 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. | 296 | Congenital Adrenal Hyperplasia |
nord_296_3 | Affects of Congenital Adrenal Hyperplasia | The most common form of CAH, 21 hydroxylase deficiency, affects approximately 1:10,000 to 1:15,000 people in the United States and Europe. Among Yupik Eskimos, the occurrence of the salt-wasting form of this disorder may be as high as 1 in 282 individuals. Other forms of CAH are much rarer. In contrast, non-classical CAH affects approximately 1 in 100 to 1 in 200 individuals in the general population. | Affects of Congenital Adrenal Hyperplasia. The most common form of CAH, 21 hydroxylase deficiency, affects approximately 1:10,000 to 1:15,000 people in the United States and Europe. Among Yupik Eskimos, the occurrence of the salt-wasting form of this disorder may be as high as 1 in 282 individuals. Other forms of CAH are much rarer. In contrast, non-classical CAH affects approximately 1 in 100 to 1 in 200 individuals in the general population. | 296 | Congenital Adrenal Hyperplasia |
nord_296_4 | Related disorders of Congenital Adrenal Hyperplasia | Symptoms of the following disorders can be similar to those of congenital adrenal hyperplasia. Comparisons may be useful for a differential diagnosis: Addison disease is a rare disorder characterized by inadequate production of cortisol, aldosterone, and/or androgens by the outer layer of cells of the adrenal glands (adrenal cortex). The symptoms of classic Addison disease, also known as primary adrenal insufficiency, result from the insufficient production of these hormones. Major symptoms include fatigue, hypotension, salt-craving, abdominal pain, nausea or vomiting, darkened skin color and absence of body hair. Depressive behavior and mood changes may also occur in some individuals with Addison disease. The symptoms of Addison usually develop slowly, but sometimes can develop rapidly into a serious condition called acute adrenal failure. In most cases, Addison disease most often occurs when the body’s immune system mistakenly attacks the adrenal glands causing slowly progressive damage to the adrenal cortex. (For more information on this disorder, choose “Addison “as your search term in the Rare Disease Database.) Since autoimmune disorders often cluster in families and individual patients, people who themselves suffer, or who have family members who suffer from such diseases (e.g., type 1 diabetes, Graves' disease, lupus) should be screened for Addison disease if they have suggestive symptoms. There are other non-immune forms of adrenal dysfunction, including iatrogenic (caused by medications), inherited, infectious, cancerous and toxic adrenal diseases. Addison disease is not associated with female or male genital ambiguity, as it typically occurs in adults and older children or adolescents. Ovotesticular disorder of sex development (ovotesticular DSD) is a very rare disorder in which an infant is born with the internal reproductive organs (gonads) of both sexes (female ovaries and male testes). The gonads can be any combination of ovary, testes or combined ovary and testes (ovotestes). The external genitalia are usually ambiguous but can range from normal male to normal female. (For more information on this disorder, choose “Ovotesticular disorder of sex development” as your search term in the Rare Disease Database.) There are numerous other types of DSD. Virilization of female fetuses and children, or accelerated sexual maturity in males, may also result from androgen-producing tumors or exposure to androgenic substances. Genetic abnormalities affecting development of the placenta, pituitary, adrenal or gonads (testicles or ovaries) can also result in abnormal sexual development. | Related disorders of Congenital Adrenal Hyperplasia. Symptoms of the following disorders can be similar to those of congenital adrenal hyperplasia. Comparisons may be useful for a differential diagnosis: Addison disease is a rare disorder characterized by inadequate production of cortisol, aldosterone, and/or androgens by the outer layer of cells of the adrenal glands (adrenal cortex). The symptoms of classic Addison disease, also known as primary adrenal insufficiency, result from the insufficient production of these hormones. Major symptoms include fatigue, hypotension, salt-craving, abdominal pain, nausea or vomiting, darkened skin color and absence of body hair. Depressive behavior and mood changes may also occur in some individuals with Addison disease. The symptoms of Addison usually develop slowly, but sometimes can develop rapidly into a serious condition called acute adrenal failure. In most cases, Addison disease most often occurs when the body’s immune system mistakenly attacks the adrenal glands causing slowly progressive damage to the adrenal cortex. (For more information on this disorder, choose “Addison “as your search term in the Rare Disease Database.) Since autoimmune disorders often cluster in families and individual patients, people who themselves suffer, or who have family members who suffer from such diseases (e.g., type 1 diabetes, Graves' disease, lupus) should be screened for Addison disease if they have suggestive symptoms. There are other non-immune forms of adrenal dysfunction, including iatrogenic (caused by medications), inherited, infectious, cancerous and toxic adrenal diseases. Addison disease is not associated with female or male genital ambiguity, as it typically occurs in adults and older children or adolescents. Ovotesticular disorder of sex development (ovotesticular DSD) is a very rare disorder in which an infant is born with the internal reproductive organs (gonads) of both sexes (female ovaries and male testes). The gonads can be any combination of ovary, testes or combined ovary and testes (ovotestes). The external genitalia are usually ambiguous but can range from normal male to normal female. (For more information on this disorder, choose “Ovotesticular disorder of sex development” as your search term in the Rare Disease Database.) There are numerous other types of DSD. Virilization of female fetuses and children, or accelerated sexual maturity in males, may also result from androgen-producing tumors or exposure to androgenic substances. Genetic abnormalities affecting development of the placenta, pituitary, adrenal or gonads (testicles or ovaries) can also result in abnormal sexual development. | 296 | Congenital Adrenal Hyperplasia |
nord_296_5 | Diagnosis of Congenital Adrenal Hyperplasia | All newborns in the United States are screened for classic 21-hydroxylase deficiency. Non-classic CAH is frequently not detected in the newborn test and therefore, may not be diagnosed until childhood or early adulthood when the patient first starts showing symptoms. Genetic testing for the gene variants associated with the various forms of CAH is available but is most often performed when pre-pregnancy genetic counseling is indicated, after an endocrinologist confirms the diagnosis through blood hormone tests, or if results of hormone tests are not definitive. Prenatal diagnosis is available for couples at risk for having a child affected with CAH using first trimester chorionic villus sampling and testing the fetal DNA for a particular CAH gene variant known to occur in the family. Non-invasive determination of sex can be accomplished through testing fetal DNA in the mother’s blood. Non-invasive prenatal testing for variants in CYP21A2 (the gene causing this disorder) is not generally available at present. Clinical Evaluation
If CAH is detected in a fetus, prenatal treatment is a possibility, although it should be regarded as experimental. The oral drug dexamethasone can be given to pregnant women in a subsequent pregnancy if she has given birth to child with severe classical CAH. Such treatment does not prevent or cure the disease but may lessen the virilization of affected female fetuses. There is limited knowledge about the long-term safety of this procedure, and this should be done only under the supervision of experienced clinicians who report to an ethical review board for human studies. This treatment is not routinely recommended and is not curative [The Endocrine Society Clinical Practice Guidelines for CAH 2010, updated 2018]. Monitoring hormone levels in individuals with CAH is crucial throughout their post-natal life. Height and weight are important aspects that need to be monitored in order to know if treatment should be adjusted, particularly in children. Monitoring bone age is an additional tool to determine if the child is undergoing proper physical maturation. A simple x-ray of the hand can show the growth centers and provide an estimate of predicted adult height. As individuals mature, the growth centers change and have characteristic appearances at different ages. Too much sex hormone secretion can cause bones to age more rapidly, and treatment can slow this progression, if caught early. | Diagnosis of Congenital Adrenal Hyperplasia. All newborns in the United States are screened for classic 21-hydroxylase deficiency. Non-classic CAH is frequently not detected in the newborn test and therefore, may not be diagnosed until childhood or early adulthood when the patient first starts showing symptoms. Genetic testing for the gene variants associated with the various forms of CAH is available but is most often performed when pre-pregnancy genetic counseling is indicated, after an endocrinologist confirms the diagnosis through blood hormone tests, or if results of hormone tests are not definitive. Prenatal diagnosis is available for couples at risk for having a child affected with CAH using first trimester chorionic villus sampling and testing the fetal DNA for a particular CAH gene variant known to occur in the family. Non-invasive determination of sex can be accomplished through testing fetal DNA in the mother’s blood. Non-invasive prenatal testing for variants in CYP21A2 (the gene causing this disorder) is not generally available at present. Clinical Evaluation
If CAH is detected in a fetus, prenatal treatment is a possibility, although it should be regarded as experimental. The oral drug dexamethasone can be given to pregnant women in a subsequent pregnancy if she has given birth to child with severe classical CAH. Such treatment does not prevent or cure the disease but may lessen the virilization of affected female fetuses. There is limited knowledge about the long-term safety of this procedure, and this should be done only under the supervision of experienced clinicians who report to an ethical review board for human studies. This treatment is not routinely recommended and is not curative [The Endocrine Society Clinical Practice Guidelines for CAH 2010, updated 2018]. Monitoring hormone levels in individuals with CAH is crucial throughout their post-natal life. Height and weight are important aspects that need to be monitored in order to know if treatment should be adjusted, particularly in children. Monitoring bone age is an additional tool to determine if the child is undergoing proper physical maturation. A simple x-ray of the hand can show the growth centers and provide an estimate of predicted adult height. As individuals mature, the growth centers change and have characteristic appearances at different ages. Too much sex hormone secretion can cause bones to age more rapidly, and treatment can slow this progression, if caught early. | 296 | Congenital Adrenal Hyperplasia |
nord_296_6 | Therapies of Congenital Adrenal Hyperplasia | Treatment of CAH varies greatly depending on the type and severity. CAH cannot be cured, but it can be effectively treated. Treatment of classical CAH starts soon after birth and is needed throughout the patient’s life. People with classical CAH should have a team of healthcare providers, including specialists in pediatric endocrinology, uro-gynecologic surgery (for girls), psychology and genetics. People with classical CAH can have normal, fulfilling lives. Patients with non-classical CAH may not need any treatment, depending on their symptoms. Treatment must be individualized by doctors who have experience with this condition. The primary goal of treating classical CAH is to reduce the excess androgen production and replace the deficient hormones. Proper treatment with the correct dosage of these medications is crucial to preventing adrenal crisis and virilization. Daily tablets including glucocorticoids (usually as hydrocortisone to replace cortisol), mineralocorticoids (fludrocortisone to replace aldosterone) and salt supplements may be prescribed, the latter particularly in infancy. During times of high stress or illness adrenal glands are normally much more active. Therefore, when ill or after major surgery or stressful event, CAH patients must be closely monitored because their bodies will require more hormones to help the body recover and meet increased demands. Hormone levels need to be adjusted and monitored throughout the patient’s life. The dose of glucocorticoids should be adjusted to avoid development of Cushing’s syndrome, a disorder characterized by a variety of symptoms and physical abnormalities including weight gain; skin, muscle and bone changes. High dose mineralocorticoid supplements or salt should be avoided to prevent high blood pressure. Surgery may be considered to correct the appearance of ambiguous genitalia and/or relieve urethra-vaginal outlet obstruction that may lead to infection. Usually, surgery is thought to be easier when performed at about 6-12 months after birth. The choice to have the surgery should be reserved for infants with severe genital ambiguity and is most often a joint decision of the parents and medical-surgical teams. Some parents choose to wait until their daughter is old enough to have a say in her surgery. Others feel uncomfortable with waiting and may request early surgical intervention. If this is the case, finding a highly skilled pediatric urologic surgeon is of the utmost importance. Surgical techniques have changed over the past few decades, and cosmetic appearance and functionality have improved. It is also highly recommended that families of girls who undergo this surgery have expert psychological counseling and care. Non-classical CAH on the other hand, is not life-threatening and relatively mild. People who have no obvious symptoms of non-classical CAH do not require surgery or medical treatment. If a patient with non-classical CAH begins to enter puberty too early, has early maturation of bones, or is a female with excess facial or body hair or other masculine features, glucocorticoid treatment is often recommended. Fertility problems can also be corrected with glucocorticoids and/or fertility drugs. Women who do not wish to conceive may also be prescribed oral contraceptives. Unlike severe forms of CAH, non-classical CAH patients are free to taper and stop treatment when symptoms go away. Please refer to the Endocrine Society Clinical Practice Guidelines for additional information regarding diagnosis and treatment of CAH (listed below in the references). | Therapies of Congenital Adrenal Hyperplasia. Treatment of CAH varies greatly depending on the type and severity. CAH cannot be cured, but it can be effectively treated. Treatment of classical CAH starts soon after birth and is needed throughout the patient’s life. People with classical CAH should have a team of healthcare providers, including specialists in pediatric endocrinology, uro-gynecologic surgery (for girls), psychology and genetics. People with classical CAH can have normal, fulfilling lives. Patients with non-classical CAH may not need any treatment, depending on their symptoms. Treatment must be individualized by doctors who have experience with this condition. The primary goal of treating classical CAH is to reduce the excess androgen production and replace the deficient hormones. Proper treatment with the correct dosage of these medications is crucial to preventing adrenal crisis and virilization. Daily tablets including glucocorticoids (usually as hydrocortisone to replace cortisol), mineralocorticoids (fludrocortisone to replace aldosterone) and salt supplements may be prescribed, the latter particularly in infancy. During times of high stress or illness adrenal glands are normally much more active. Therefore, when ill or after major surgery or stressful event, CAH patients must be closely monitored because their bodies will require more hormones to help the body recover and meet increased demands. Hormone levels need to be adjusted and monitored throughout the patient’s life. The dose of glucocorticoids should be adjusted to avoid development of Cushing’s syndrome, a disorder characterized by a variety of symptoms and physical abnormalities including weight gain; skin, muscle and bone changes. High dose mineralocorticoid supplements or salt should be avoided to prevent high blood pressure. Surgery may be considered to correct the appearance of ambiguous genitalia and/or relieve urethra-vaginal outlet obstruction that may lead to infection. Usually, surgery is thought to be easier when performed at about 6-12 months after birth. The choice to have the surgery should be reserved for infants with severe genital ambiguity and is most often a joint decision of the parents and medical-surgical teams. Some parents choose to wait until their daughter is old enough to have a say in her surgery. Others feel uncomfortable with waiting and may request early surgical intervention. If this is the case, finding a highly skilled pediatric urologic surgeon is of the utmost importance. Surgical techniques have changed over the past few decades, and cosmetic appearance and functionality have improved. It is also highly recommended that families of girls who undergo this surgery have expert psychological counseling and care. Non-classical CAH on the other hand, is not life-threatening and relatively mild. People who have no obvious symptoms of non-classical CAH do not require surgery or medical treatment. If a patient with non-classical CAH begins to enter puberty too early, has early maturation of bones, or is a female with excess facial or body hair or other masculine features, glucocorticoid treatment is often recommended. Fertility problems can also be corrected with glucocorticoids and/or fertility drugs. Women who do not wish to conceive may also be prescribed oral contraceptives. Unlike severe forms of CAH, non-classical CAH patients are free to taper and stop treatment when symptoms go away. Please refer to the Endocrine Society Clinical Practice Guidelines for additional information regarding diagnosis and treatment of CAH (listed below in the references). | 296 | Congenital Adrenal Hyperplasia |
nord_297_0 | Overview of Congenital Afibrinogenemia | Summary
Congenital afibrinogenemia is a rare bleeding disorder characterized by absence of fibrinogen (also known as coagulation factor I) in the blood, a protein that is essential in the blood clotting (coagulation) process. Affected individuals may be susceptible to severe bleeding (hemorrhaging) episodes, particularly during infancy and childhood. Bleeding can occur anywhere in the body, including the skin, nose, oral cavity, gastrointestinal tract, liver, genital and urinary tract, joints, muscles and central nervous system. Bleeding can also happen in the skull (intracranial hemorrhage) and is a leading cause of death and disability in individuals with congenital afibrinogenemia.Women are at increased risk for vaginal bleeding and increased blood loss during menstruation and tend to have recurrent miscarriages. Other manifestations of the disease include risk of spontaneous spleen rupture, formation of painful bone cysts, poor wound healing and increased risk of formation of unstable clots that can lodge in blood vessels and occlude them (thromboembolic complications).Symptoms usually begin to show at birth with umbilical cord bleeding but can manifest later in life. Individuals with this disease can be treated with fibrinogen replacement therapy, which might require frequent injections and monitoring of blood fibrinogen levels. Treatment can be preventive (prophylaxis) or can be administered when the individual has episodes of bleeding (symptomatic treatment). Congenital afibrinogenemia is genetic disease that follows an autosomal recessive inheritance pattern.Introduction
Congenital afibrinogenemia is a hereditary fibrinogen abnormality, a rare category of bleeding disorder that can affect the quantity or quality of fibrinogen, a blood coagulation factor. Afibrinogenemia and hypofibrinogenemia respectively refer to the absence and reduced levels of fibrinogen in the blood.Dysfibrinogenemia and hypodysfibrinogenemia are fibrinogen abnormalities where the blood levels of fibrinogen are normal (in dysfibrinogenemia) or reduced (in hypodysfibrinogenemia), but the coagulation factor is modified in a way that it does not function normally or optimally. When symptomatic, hereditary fibrinogen abnormalities have similar symptoms. Congenital afibrinogenemia patients are more likely to have symptoms and to experience severe bleeding episodes. Diagnosis can often be made at birth because most affected infants have severe umbilical cord bleeding. Early diagnosis of congenital afibrinogenemia and early treatment can prevent severe bleeding episodes, particularly bleeding inside the skull (intracranial hemorrhage), which can lead to disability and death. | Overview of Congenital Afibrinogenemia. Summary
Congenital afibrinogenemia is a rare bleeding disorder characterized by absence of fibrinogen (also known as coagulation factor I) in the blood, a protein that is essential in the blood clotting (coagulation) process. Affected individuals may be susceptible to severe bleeding (hemorrhaging) episodes, particularly during infancy and childhood. Bleeding can occur anywhere in the body, including the skin, nose, oral cavity, gastrointestinal tract, liver, genital and urinary tract, joints, muscles and central nervous system. Bleeding can also happen in the skull (intracranial hemorrhage) and is a leading cause of death and disability in individuals with congenital afibrinogenemia.Women are at increased risk for vaginal bleeding and increased blood loss during menstruation and tend to have recurrent miscarriages. Other manifestations of the disease include risk of spontaneous spleen rupture, formation of painful bone cysts, poor wound healing and increased risk of formation of unstable clots that can lodge in blood vessels and occlude them (thromboembolic complications).Symptoms usually begin to show at birth with umbilical cord bleeding but can manifest later in life. Individuals with this disease can be treated with fibrinogen replacement therapy, which might require frequent injections and monitoring of blood fibrinogen levels. Treatment can be preventive (prophylaxis) or can be administered when the individual has episodes of bleeding (symptomatic treatment). Congenital afibrinogenemia is genetic disease that follows an autosomal recessive inheritance pattern.Introduction
Congenital afibrinogenemia is a hereditary fibrinogen abnormality, a rare category of bleeding disorder that can affect the quantity or quality of fibrinogen, a blood coagulation factor. Afibrinogenemia and hypofibrinogenemia respectively refer to the absence and reduced levels of fibrinogen in the blood.Dysfibrinogenemia and hypodysfibrinogenemia are fibrinogen abnormalities where the blood levels of fibrinogen are normal (in dysfibrinogenemia) or reduced (in hypodysfibrinogenemia), but the coagulation factor is modified in a way that it does not function normally or optimally. When symptomatic, hereditary fibrinogen abnormalities have similar symptoms. Congenital afibrinogenemia patients are more likely to have symptoms and to experience severe bleeding episodes. Diagnosis can often be made at birth because most affected infants have severe umbilical cord bleeding. Early diagnosis of congenital afibrinogenemia and early treatment can prevent severe bleeding episodes, particularly bleeding inside the skull (intracranial hemorrhage), which can lead to disability and death. | 297 | Congenital Afibrinogenemia |
nord_297_1 | Symptoms of Congenital Afibrinogenemia | The absence of fibrinogen in the circulating blood of individuals with congenital afibrinogenemia makes them unable to effectively coagulate their blood, leading to prolonged bleeding. Bleeding episodes can be spontaneous or due to minor trauma and can happen anywhere in the body, including the skin, nose, oral cavity, gastrointestinal tract, liver, genital and urinary tract and central nervous system. Symptoms begin to show at birth with umbilical cord bleeding in around 85% of individuals. Bleeding might also be noticed in the stools or vomit of newborns.Intracranial hemorrhage is a leading cause of death and disability in affected individuals. Signs of intracranial hemorrhage include vomiting, dizziness, headache, confusion and seizures. Patients can suffer from long term problems such as psychomotor impairment after an episode of bleeding inside the skull.Joint bleeding (hemarthrosis) might cause pain and limit movement. Severe cases of joint bleeding might require total joint replacement (arthroplasty). Pain and movement limitation can also happen from accumulation of blood (hematoma) in muscles. Some patients also experience bleeding in the bones (interosseous hemorrhage) after minimal trauma. Formation of bone cysts containing blood can happen, particularly in long bones, and cause bone pain.Women are at increased risk for vaginal bleeding and increased blood loss during menstruation (menometrorrhagia) and tend to have recurrent miscarriages. Women who receive treatment might be able to give birth but might suffer from prolonged bleeding after delivering (postpartum hemorrhage).Other symptoms related to congenital afibrinogenemia include an increased risk of spontaneous rupture of the spleen, poor wound healing, and formation of unstable clots that can lodge in blood vessels and occlude them (embolus). Even without fibrinogen in their blood, affected individuals can form clots via the action of other coagulation factors, namely von Willebrand factor and thrombin. However, these clots are loose and tend to disseminate in the body. They can then occlude the blood vessels in the lungs (pulmonary embolism), brain (ischemic stroke) or heart (coronary embolism) and cause severe consequences, including death. | Symptoms of Congenital Afibrinogenemia. The absence of fibrinogen in the circulating blood of individuals with congenital afibrinogenemia makes them unable to effectively coagulate their blood, leading to prolonged bleeding. Bleeding episodes can be spontaneous or due to minor trauma and can happen anywhere in the body, including the skin, nose, oral cavity, gastrointestinal tract, liver, genital and urinary tract and central nervous system. Symptoms begin to show at birth with umbilical cord bleeding in around 85% of individuals. Bleeding might also be noticed in the stools or vomit of newborns.Intracranial hemorrhage is a leading cause of death and disability in affected individuals. Signs of intracranial hemorrhage include vomiting, dizziness, headache, confusion and seizures. Patients can suffer from long term problems such as psychomotor impairment after an episode of bleeding inside the skull.Joint bleeding (hemarthrosis) might cause pain and limit movement. Severe cases of joint bleeding might require total joint replacement (arthroplasty). Pain and movement limitation can also happen from accumulation of blood (hematoma) in muscles. Some patients also experience bleeding in the bones (interosseous hemorrhage) after minimal trauma. Formation of bone cysts containing blood can happen, particularly in long bones, and cause bone pain.Women are at increased risk for vaginal bleeding and increased blood loss during menstruation (menometrorrhagia) and tend to have recurrent miscarriages. Women who receive treatment might be able to give birth but might suffer from prolonged bleeding after delivering (postpartum hemorrhage).Other symptoms related to congenital afibrinogenemia include an increased risk of spontaneous rupture of the spleen, poor wound healing, and formation of unstable clots that can lodge in blood vessels and occlude them (embolus). Even without fibrinogen in their blood, affected individuals can form clots via the action of other coagulation factors, namely von Willebrand factor and thrombin. However, these clots are loose and tend to disseminate in the body. They can then occlude the blood vessels in the lungs (pulmonary embolism), brain (ischemic stroke) or heart (coronary embolism) and cause severe consequences, including death. | 297 | Congenital Afibrinogenemia |
nord_297_2 | Causes of Congenital Afibrinogenemia | Absence of fibrinogen in the blood is caused by changes (pathogenic variants or mutations) in one of three genes, known as the fibrinogen alpha-chain (FGA), beta-chain (FGB), and gamma-chain (FGG).Variants in FGA, FGB and FGG can affect blood levels of fibrinogen in multiple ways. Some impair fibrinogen synthesis by preventing the DNA from being read properly. Others affect the fibrinogen protein itself, either by impairing its synthesis, its secretion, or the fusion of the different subunits of the protein. In all cases, the result is the same: fibrinogen is absent from the blood. As the conversion of fibrinogen to fibrin is one of the crucial steps of blood coagulation (coagulation cascade), its absence severely impairs clot formation and can lead to episodes of prolonged bleeding. Clot formation is still possible via other coagulation factors known as von Willebrand factor and thrombin, but these clots are loose and ineffective. They tend to detach and can lodge in blood vessels and occlude them (embolus), which can lead to major consequences (thromboembolic complications).Congenital afibrinogenemia follows an autosomal recessive inheritance pattern. Recessive genetic disorders occur when an individual inherits an altered gene from each parent. If an individual receives one normal gene and one abnormal gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and, 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. | Causes of Congenital Afibrinogenemia. Absence of fibrinogen in the blood is caused by changes (pathogenic variants or mutations) in one of three genes, known as the fibrinogen alpha-chain (FGA), beta-chain (FGB), and gamma-chain (FGG).Variants in FGA, FGB and FGG can affect blood levels of fibrinogen in multiple ways. Some impair fibrinogen synthesis by preventing the DNA from being read properly. Others affect the fibrinogen protein itself, either by impairing its synthesis, its secretion, or the fusion of the different subunits of the protein. In all cases, the result is the same: fibrinogen is absent from the blood. As the conversion of fibrinogen to fibrin is one of the crucial steps of blood coagulation (coagulation cascade), its absence severely impairs clot formation and can lead to episodes of prolonged bleeding. Clot formation is still possible via other coagulation factors known as von Willebrand factor and thrombin, but these clots are loose and ineffective. They tend to detach and can lodge in blood vessels and occlude them (embolus), which can lead to major consequences (thromboembolic complications).Congenital afibrinogenemia follows an autosomal recessive inheritance pattern. Recessive genetic disorders occur when an individual inherits an altered gene from each parent. If an individual receives one normal gene and one abnormal gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and, 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. | 297 | Congenital Afibrinogenemia |
nord_297_3 | Affects of Congenital Afibrinogenemia | Congenital afibrinogenemia is a very rare disorder that affects approximately one in a million people. Males and females are equally affected. There doesn’t seem to be any ethnic predisposition to this disease. However, as it is an autosomal recessive disorder, children whose parents are blood relatives (consanguineous) are more at risk. Indeed, individuals from the same family are more likely to have the same rare gene variant and can have an affected child if they inherit the pathogenic variant from both parents. Therefore, the disease is more common in areas with high rates of consanguineous marriage, such as the Middle East and Southern India. | Affects of Congenital Afibrinogenemia. Congenital afibrinogenemia is a very rare disorder that affects approximately one in a million people. Males and females are equally affected. There doesn’t seem to be any ethnic predisposition to this disease. However, as it is an autosomal recessive disorder, children whose parents are blood relatives (consanguineous) are more at risk. Indeed, individuals from the same family are more likely to have the same rare gene variant and can have an affected child if they inherit the pathogenic variant from both parents. Therefore, the disease is more common in areas with high rates of consanguineous marriage, such as the Middle East and Southern India. | 297 | Congenital Afibrinogenemia |
nord_297_4 | Related disorders of Congenital Afibrinogenemia | Symptoms of the following blood clotting disorders can be similar to those of congenital afibrinogenemia. Comparisons may be useful for a differential diagnosis:Factor XIII deficiency is a very rare inherited disorder that prevents the blood from clotting normally. The lack of clotting factor XIII can cause slow, oozing internal bleeding which may begin several days after even a mild trauma, such as a bump or bruise. The bleeding may persist so that large cysts form in the tissue spaces, destroying the surrounding bone and causing peripheral nerve damage. This typically occurs in the thigh and buttocks area. (For more information on this disorder, choose “Factor XIII Deficiency” as your search term in the Rare Disease Database.)Hemophilia is a hereditary blood clotting disorder which affects males almost exclusively. Hemophilia is caused by the inactivity of one of the blood proteins necessary for clotting (usually factor VIII in hemophilia A, factor IX in hemophilia B) and can be classified by its level of severity, mild, moderate and severe. Severity is determined by the percentage of active clotting factor in the blood. (For more information on these disorders, choose “Hemophilia” as your search term in the Rare Disease Database.)Von Willebrand disease is a hereditary blood clotting disorder characterized by prolonged bleeding. Blood clotting is slow due to a deficiency of the Von Willebrand factor protein and factor VIII protein (the factor VIII complex). Also, platelets do not stick normally causing excessively long clotting time. Increased risk of excessive bleeding following surgery, dental procedures or injury occurs in patients with this disorder. With proper treatment and appropriate precautions, few patients become seriously handicapped by Von Willebrand disease. The tendency to prolonged bleeding usually decreases with age. | Related disorders of Congenital Afibrinogenemia. Symptoms of the following blood clotting disorders can be similar to those of congenital afibrinogenemia. Comparisons may be useful for a differential diagnosis:Factor XIII deficiency is a very rare inherited disorder that prevents the blood from clotting normally. The lack of clotting factor XIII can cause slow, oozing internal bleeding which may begin several days after even a mild trauma, such as a bump or bruise. The bleeding may persist so that large cysts form in the tissue spaces, destroying the surrounding bone and causing peripheral nerve damage. This typically occurs in the thigh and buttocks area. (For more information on this disorder, choose “Factor XIII Deficiency” as your search term in the Rare Disease Database.)Hemophilia is a hereditary blood clotting disorder which affects males almost exclusively. Hemophilia is caused by the inactivity of one of the blood proteins necessary for clotting (usually factor VIII in hemophilia A, factor IX in hemophilia B) and can be classified by its level of severity, mild, moderate and severe. Severity is determined by the percentage of active clotting factor in the blood. (For more information on these disorders, choose “Hemophilia” as your search term in the Rare Disease Database.)Von Willebrand disease is a hereditary blood clotting disorder characterized by prolonged bleeding. Blood clotting is slow due to a deficiency of the Von Willebrand factor protein and factor VIII protein (the factor VIII complex). Also, platelets do not stick normally causing excessively long clotting time. Increased risk of excessive bleeding following surgery, dental procedures or injury occurs in patients with this disorder. With proper treatment and appropriate precautions, few patients become seriously handicapped by Von Willebrand disease. The tendency to prolonged bleeding usually decreases with age. | 297 | Congenital Afibrinogenemia |
nord_297_5 | Diagnosis of Congenital Afibrinogenemia | Diagnosis of congenital afibrinogenemia is made with a combination of blood coagulation tests, tests that measure blood levels of fibrinogen, and genetic testing. The disorder can be suspected in newborns with severe umbilical cord bleeding and in infants and children with severe and persistent bleeding episodes.In a patient with congenital afibrinogenemia, all the coagulation tests that rely on fibrin (the product of the conversion of fibrinogen) will be infinitely prolonged. These tests include thrombin time (TT), prothrombin time (PTT), activated partial thromboplastin time (aPTT) and reptilase time. Tests to measure levels of fibrinogen, including the Clauss method and ELISA, will not detect any fibrinogen in the circulating blood. Genetic testing of the parents and affected individual is used to detect disease-causing pathogenic variants in the FGA, FGB, and FGG genes. | Diagnosis of Congenital Afibrinogenemia. Diagnosis of congenital afibrinogenemia is made with a combination of blood coagulation tests, tests that measure blood levels of fibrinogen, and genetic testing. The disorder can be suspected in newborns with severe umbilical cord bleeding and in infants and children with severe and persistent bleeding episodes.In a patient with congenital afibrinogenemia, all the coagulation tests that rely on fibrin (the product of the conversion of fibrinogen) will be infinitely prolonged. These tests include thrombin time (TT), prothrombin time (PTT), activated partial thromboplastin time (aPTT) and reptilase time. Tests to measure levels of fibrinogen, including the Clauss method and ELISA, will not detect any fibrinogen in the circulating blood. Genetic testing of the parents and affected individual is used to detect disease-causing pathogenic variants in the FGA, FGB, and FGG genes. | 297 | Congenital Afibrinogenemia |
nord_297_6 | Therapies of Congenital Afibrinogenemia | Treatment
Individuals with congenital afibrinogenemia need to be treated with fibrinogen replacement therapy. Fresh frozen plasma and blood product made from plasma (cryoprecipitate) may be injected to replace fibrinogen. However, fibrinogen concentrates are the best option, as they have a faster onset, greater dosing flexibility, are easier to administrate and are safer, as they are less likely to be contaminated with viruses than fresh frozen plasma and cryoprecipitate. The goal of the treatment is to restore and maintain normal fibrinogen levels.Depending on the patient’s needs, treatment can be given weekly or bi-weekly in prevention of bleeding (primary prophylaxis), after bleeding episodes to prevent recurrence (secondary prophylaxis) or as soon as bleeding starts (on demand). Primary prophylaxis is essential for pregnant women to avoid miscarriage.In some patients, fibrinogen replacement therapy might provoke the formation of unstable clots that will detach and disseminate throughout the body, potentially occluding blood vessels (thromboembolic complications). These patients should be administered an anticoagulant with their treatment, preferably low-molecular-weight heparin.For less severe bleeding episodes, patients can be given amino acids that prevent clot dissolution (antifibrinolytic amino acids), namely epsilon-aminocaproic acid and tranexamic acid. The major advantage of this treatment is that it is non-injectable.Genetic counseling is recommended for patients and their families. Other treatment is symptomatic and supportive and includes joint replacement surgery (arthroplasty) after joint damage due to excessive bleeding (hemarthrosis) and neurosurgical interventions to control severe bleeding inside the skull (intracranial hemorrhage). | Therapies of Congenital Afibrinogenemia. Treatment
Individuals with congenital afibrinogenemia need to be treated with fibrinogen replacement therapy. Fresh frozen plasma and blood product made from plasma (cryoprecipitate) may be injected to replace fibrinogen. However, fibrinogen concentrates are the best option, as they have a faster onset, greater dosing flexibility, are easier to administrate and are safer, as they are less likely to be contaminated with viruses than fresh frozen plasma and cryoprecipitate. The goal of the treatment is to restore and maintain normal fibrinogen levels.Depending on the patient’s needs, treatment can be given weekly or bi-weekly in prevention of bleeding (primary prophylaxis), after bleeding episodes to prevent recurrence (secondary prophylaxis) or as soon as bleeding starts (on demand). Primary prophylaxis is essential for pregnant women to avoid miscarriage.In some patients, fibrinogen replacement therapy might provoke the formation of unstable clots that will detach and disseminate throughout the body, potentially occluding blood vessels (thromboembolic complications). These patients should be administered an anticoagulant with their treatment, preferably low-molecular-weight heparin.For less severe bleeding episodes, patients can be given amino acids that prevent clot dissolution (antifibrinolytic amino acids), namely epsilon-aminocaproic acid and tranexamic acid. The major advantage of this treatment is that it is non-injectable.Genetic counseling is recommended for patients and their families. Other treatment is symptomatic and supportive and includes joint replacement surgery (arthroplasty) after joint damage due to excessive bleeding (hemarthrosis) and neurosurgical interventions to control severe bleeding inside the skull (intracranial hemorrhage). | 297 | Congenital Afibrinogenemia |
nord_298_0 | Overview of Congenital Athymia | SummaryCongenital athymia is a rare disorder in which children have no detectable thymus (athymia). The thymus is a gland located on top of the heart. The thymus produces specialized white blood cells called T cells that fight infections, especially viral infections. The T cell count is the highest in infants in the first 2 years of life and then slowly decreases with time. In adults over the age of 60, the thymus is mostly replaced by fat. Children with congenital athymia are born without a thymus and are therefore profoundly deficient in T cells and extremely susceptible to infections. Without treatment, the disorder is usually fatal by two to three years of age.IntroductionThe following conditions can result in congenital athymia:• complete DiGeorge syndrome, also known as complete DiGeorge anomaly
• 22q11.2 deletion syndrome
• CHARGE syndrome
• infant of diabetic mother
• FOXN1 gene deficiency
• TBX1 gene mutation
• TBX2 gene mutation
• PAX1 gene deficiency
• SEMA3E gene mutationMost infants with congenital athymia have chromosome 22q11.2 deletion syndrome or CHARGE syndrome. Both disorders have symptoms affecting multiple systems of the body. These infants have a set of T cells called “naïve T cells” or “recent thymus emigrants” that are less than the 100/mm3. These T cells are critical for the health of the infant. These infants will die unless placed in permanent complete isolation.In the past, children with T cells below the 10th percentile for age were said to have DiGeorge syndrome (named after a medical student who first reported the condition). However, most of these patients did well. Only about 1% of children with DiGeorge syndrome have lower than 100 naïve T cells/mm3. This group of patients is the group with congenital athymia. NORD has individual reports on 22q11.2 deletion syndrome and CHARGE syndrome and these reports are accessible on the NORD website in the Rare Disease Database. | Overview of Congenital Athymia. SummaryCongenital athymia is a rare disorder in which children have no detectable thymus (athymia). The thymus is a gland located on top of the heart. The thymus produces specialized white blood cells called T cells that fight infections, especially viral infections. The T cell count is the highest in infants in the first 2 years of life and then slowly decreases with time. In adults over the age of 60, the thymus is mostly replaced by fat. Children with congenital athymia are born without a thymus and are therefore profoundly deficient in T cells and extremely susceptible to infections. Without treatment, the disorder is usually fatal by two to three years of age.IntroductionThe following conditions can result in congenital athymia:• complete DiGeorge syndrome, also known as complete DiGeorge anomaly
• 22q11.2 deletion syndrome
• CHARGE syndrome
• infant of diabetic mother
• FOXN1 gene deficiency
• TBX1 gene mutation
• TBX2 gene mutation
• PAX1 gene deficiency
• SEMA3E gene mutationMost infants with congenital athymia have chromosome 22q11.2 deletion syndrome or CHARGE syndrome. Both disorders have symptoms affecting multiple systems of the body. These infants have a set of T cells called “naïve T cells” or “recent thymus emigrants” that are less than the 100/mm3. These T cells are critical for the health of the infant. These infants will die unless placed in permanent complete isolation.In the past, children with T cells below the 10th percentile for age were said to have DiGeorge syndrome (named after a medical student who first reported the condition). However, most of these patients did well. Only about 1% of children with DiGeorge syndrome have lower than 100 naïve T cells/mm3. This group of patients is the group with congenital athymia. NORD has individual reports on 22q11.2 deletion syndrome and CHARGE syndrome and these reports are accessible on the NORD website in the Rare Disease Database. | 298 | Congenital Athymia |
nord_298_1 | Symptoms of Congenital Athymia | By definition, congenital athymia is characterized by absence or underdevelopment (hypoplasia) of the thymus resulting in very low T cell counts. Absence or underdevelopment of the thymus results in an increased susceptibility to viral, fungal and bacterial infections (immunodeficiency). The degree of susceptibility can vary. Specific symptoms will vary depending upon the type of infection, overall health of the infant and other factors. Respiratory infections are common, often leading to respiratory distress. Opportunistic infections are also common. The term “opportunistic infection” refers either to infections caused by microorganisms that usually do not cause disease in individuals with a fully functioning immune system or to widespread (systemic) overwhelming disease by microorganisms that typically cause only localized, mild infections. Not only are affected infants more susceptible to infections, but their bodies also cannot effectively fight off the infections.Infants with congenital athymia have additional symptoms including congenital heart defects and/or hypoparathyroidism. These complications can be significant. Congenital heart defects are problems with the structure of the heart. The defects in the heart may include the walls, valves, arteries and veins of the heart. Over 50% of infants with congenital athymia require surgery to fix heart defects.Hypoparathyroidism is a rare condition in which the parathyroid glands, that are in the neck, fail to produce enough parathyroid hormone. Parathyroid hormone plays a role in regulating the levels of calcium and phosphorus in the blood. Due to a deficiency of parathyroid hormone, individuals with hypoparathyroidism may exhibit abnormally low levels of calcium in the blood (hypocalcemia) and high levels of phosphorus. Low levels of calcium in the blood can result in seizures. Management of calcium levels can be difficult in infants with congenital athymia. Approximately 80% of infants with congenital athymia have long term problems maintaining safe calcium levels.Some infants have softening of the tissues of the voice box (larynx), a condition called laryngomalacia. This can cause noisy breathing. Sometimes, it can cause difficulties eating.Infants with chromosome 22q11.2 deletion syndrome and CHARGE syndrome have additional symptoms that are associated with their specific diagnosis. Infants with congenital athymia who are born to diabetic mothers may also have only one kidney (renal agenesis).Researchers have identified an atypical form of congenital athymia. Affected infants, in addition to immunodeficiency, develop a red, often itchy, rash and enlargement of the lymph nodes (lymphadenopathy). They develop oligoclonal T cells. To understand this process, it can be helpful to think of the thymus as a schoolhouse. In normal children, stem cells from the bone marrow go to the thymus (the “schoolhouse”) to develop into T cells. The developing T cells learn to not attack the infant’s body (self) and to fight infections. If the developing T cells are successful learning these two lessons, they “graduate,” and leave the schoolhouse. The graduates have special proteins on the surface of the cell; they are called “naïve” T cells. After the naïve T cells fight an infection, they lose the special markers and are called memory T cells. Memory T cells can quickly fight an infection if it recurs.In the atypical form of congenital athymia, there is no thymus (no schoolhouse). However, stem cells in the bone marrow develop into cells that look like T cells but are missing the “naïve” T cell markers. These “atypical” T cells have not gone to “school” and have not learned what is “self.” The atypical T cells then attack the body causing rash, and often also diarrhea or liver damage. The diagnosis of atypical congenital athymia is made when a patient has the rash and high numbers of T cells but no, or very few, naïve T cells in the blood. | Symptoms of Congenital Athymia. By definition, congenital athymia is characterized by absence or underdevelopment (hypoplasia) of the thymus resulting in very low T cell counts. Absence or underdevelopment of the thymus results in an increased susceptibility to viral, fungal and bacterial infections (immunodeficiency). The degree of susceptibility can vary. Specific symptoms will vary depending upon the type of infection, overall health of the infant and other factors. Respiratory infections are common, often leading to respiratory distress. Opportunistic infections are also common. The term “opportunistic infection” refers either to infections caused by microorganisms that usually do not cause disease in individuals with a fully functioning immune system or to widespread (systemic) overwhelming disease by microorganisms that typically cause only localized, mild infections. Not only are affected infants more susceptible to infections, but their bodies also cannot effectively fight off the infections.Infants with congenital athymia have additional symptoms including congenital heart defects and/or hypoparathyroidism. These complications can be significant. Congenital heart defects are problems with the structure of the heart. The defects in the heart may include the walls, valves, arteries and veins of the heart. Over 50% of infants with congenital athymia require surgery to fix heart defects.Hypoparathyroidism is a rare condition in which the parathyroid glands, that are in the neck, fail to produce enough parathyroid hormone. Parathyroid hormone plays a role in regulating the levels of calcium and phosphorus in the blood. Due to a deficiency of parathyroid hormone, individuals with hypoparathyroidism may exhibit abnormally low levels of calcium in the blood (hypocalcemia) and high levels of phosphorus. Low levels of calcium in the blood can result in seizures. Management of calcium levels can be difficult in infants with congenital athymia. Approximately 80% of infants with congenital athymia have long term problems maintaining safe calcium levels.Some infants have softening of the tissues of the voice box (larynx), a condition called laryngomalacia. This can cause noisy breathing. Sometimes, it can cause difficulties eating.Infants with chromosome 22q11.2 deletion syndrome and CHARGE syndrome have additional symptoms that are associated with their specific diagnosis. Infants with congenital athymia who are born to diabetic mothers may also have only one kidney (renal agenesis).Researchers have identified an atypical form of congenital athymia. Affected infants, in addition to immunodeficiency, develop a red, often itchy, rash and enlargement of the lymph nodes (lymphadenopathy). They develop oligoclonal T cells. To understand this process, it can be helpful to think of the thymus as a schoolhouse. In normal children, stem cells from the bone marrow go to the thymus (the “schoolhouse”) to develop into T cells. The developing T cells learn to not attack the infant’s body (self) and to fight infections. If the developing T cells are successful learning these two lessons, they “graduate,” and leave the schoolhouse. The graduates have special proteins on the surface of the cell; they are called “naïve” T cells. After the naïve T cells fight an infection, they lose the special markers and are called memory T cells. Memory T cells can quickly fight an infection if it recurs.In the atypical form of congenital athymia, there is no thymus (no schoolhouse). However, stem cells in the bone marrow develop into cells that look like T cells but are missing the “naïve” T cell markers. These “atypical” T cells have not gone to “school” and have not learned what is “self.” The atypical T cells then attack the body causing rash, and often also diarrhea or liver damage. The diagnosis of atypical congenital athymia is made when a patient has the rash and high numbers of T cells but no, or very few, naïve T cells in the blood. | 298 | Congenital Athymia |
nord_298_2 | Causes of Congenital Athymia | Congenital athymia is characterized by the absence of the thymus in an infant. There are several causes of this condition. In some infants, congenital athymia occurs secondarily to chromosome 22q11.2 deletion syndrome or CHARGE syndrome. Chromosome 22q11.2 deletion syndrome is characterized by the absence of a small piece of chromosome 22. This syndrome is associated with a range of problems including congenital heart disease, palate abnormalities, immune system dysfunction including autoimmune disease, low calcium (hypocalcemia) and other endocrine abnormalities such as thyroid problems and growth hormone deficiency, gastrointestinal problems, feeding difficulties, kidney abnormalities, hearing loss, seizures, skeletal abnormalities, minor facial differences and learning and behavioral differences.CHARGE is an acronym that stands for [C]oloboma, congenital [H]eart defects, choanal [A]tresia, growth [R]etardation, [G]enital hypoplasia and [E]ar anomalies or deafness.There are other causes of congenital athymia. Some infants who do not have a thymus or have an underdeveloped thymus have a mother who is diabetic. The mothers can have type I, type II or gestational diabetes. At this time, it is not known if the diabetes is causing congenital athymia in these patients. However, many patients with congenital athymia have mothers with diabetes.Congenital athymia can also be found in patients with changes (mutations) in the genes FOXN1, T-box transcription factor 1 (TBX1) and TBX2, paired box 1 (PAX1), and semaphorine 3 (SEMA3E). Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation in a gene occurs, the protein product may be faulty, inefficient, absent or overproduced. Depending upon the functions of the protein, this can affect many organ systems of the body.Lastly, congenital athymia can be found in a very small number of infants with no identifiable genetic mutations or syndromes. | Causes of Congenital Athymia. Congenital athymia is characterized by the absence of the thymus in an infant. There are several causes of this condition. In some infants, congenital athymia occurs secondarily to chromosome 22q11.2 deletion syndrome or CHARGE syndrome. Chromosome 22q11.2 deletion syndrome is characterized by the absence of a small piece of chromosome 22. This syndrome is associated with a range of problems including congenital heart disease, palate abnormalities, immune system dysfunction including autoimmune disease, low calcium (hypocalcemia) and other endocrine abnormalities such as thyroid problems and growth hormone deficiency, gastrointestinal problems, feeding difficulties, kidney abnormalities, hearing loss, seizures, skeletal abnormalities, minor facial differences and learning and behavioral differences.CHARGE is an acronym that stands for [C]oloboma, congenital [H]eart defects, choanal [A]tresia, growth [R]etardation, [G]enital hypoplasia and [E]ar anomalies or deafness.There are other causes of congenital athymia. Some infants who do not have a thymus or have an underdeveloped thymus have a mother who is diabetic. The mothers can have type I, type II or gestational diabetes. At this time, it is not known if the diabetes is causing congenital athymia in these patients. However, many patients with congenital athymia have mothers with diabetes.Congenital athymia can also be found in patients with changes (mutations) in the genes FOXN1, T-box transcription factor 1 (TBX1) and TBX2, paired box 1 (PAX1), and semaphorine 3 (SEMA3E). Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation in a gene occurs, the protein product may be faulty, inefficient, absent or overproduced. Depending upon the functions of the protein, this can affect many organ systems of the body.Lastly, congenital athymia can be found in a very small number of infants with no identifiable genetic mutations or syndromes. | 298 | Congenital Athymia |
nord_298_3 | Affects of Congenital Athymia | Congenital athymia affects both males and females. The exact incidence and prevalence of this disorder is unknown. | Affects of Congenital Athymia. Congenital athymia affects both males and females. The exact incidence and prevalence of this disorder is unknown. | 298 | Congenital Athymia |
nord_298_4 | Related disorders of Congenital Athymia | Related disorders of Congenital Athymia. | 298 | Congenital Athymia |
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nord_298_5 | Diagnosis of Congenital Athymia | A diagnosis of congenital athymia is based upon identification of characteristic symptoms, a detailed patient and family history and a thorough clinical evaluation.Some infants are diagnosed via newborn screening. All 50 states have added newborn screening for severe combined immunodeficiency (SCID). Some states, however, do not require that every hospital include the newborn screening for SCID. Newborn screening identifies infants with low levels of T cells, which can lead to identification of newborns with congenital athymia. In such instances, the infants are put in isolation right away. Clinical Testing and Workup Physicians may use a technique called flow cytometry to diagnose congenital athymia. Flow cytometry of the peripheral blood means that the peripheral blood (the blood that is circulating through the body) is studied using a machine called a flow cytometer. The flow cytometer can determine the number and percentage of various cell types in the blood sample. Very low T cell numbers shortly after birth are a sign of congenital athymia.The diagnosis of congenital athymia cannot be made with a chest x-ray (radiography) or computerized tomography (CT) scan, or by visualization during heart surgery because the thymus can be small or may be found in a different part of the body such as in the neck (ectopic thymus). | Diagnosis of Congenital Athymia. A diagnosis of congenital athymia is based upon identification of characteristic symptoms, a detailed patient and family history and a thorough clinical evaluation.Some infants are diagnosed via newborn screening. All 50 states have added newborn screening for severe combined immunodeficiency (SCID). Some states, however, do not require that every hospital include the newborn screening for SCID. Newborn screening identifies infants with low levels of T cells, which can lead to identification of newborns with congenital athymia. In such instances, the infants are put in isolation right away. Clinical Testing and Workup Physicians may use a technique called flow cytometry to diagnose congenital athymia. Flow cytometry of the peripheral blood means that the peripheral blood (the blood that is circulating through the body) is studied using a machine called a flow cytometer. The flow cytometer can determine the number and percentage of various cell types in the blood sample. Very low T cell numbers shortly after birth are a sign of congenital athymia.The diagnosis of congenital athymia cannot be made with a chest x-ray (radiography) or computerized tomography (CT) scan, or by visualization during heart surgery because the thymus can be small or may be found in a different part of the body such as in the neck (ectopic thymus). | 298 | Congenital Athymia |
nord_298_6 | Therapies of Congenital Athymia | TreatmentTreatment requires the coordinated efforts of a team of specialists. Pediatricians, physicians who specialize in diagnosing and treating immune system disorders (immunologists), physicians who specialize in diagnosing and treating blood disorders (hematologists), physicians who specialize in diagnosing and treating endocrine disorders (endocrinologists) and other healthcare professionals may need to plan treatment systematically and comprehensively for a patient with congenital athymia. Specialized healthcare professionals are necessary for infants with chromosome 22q11.2 deletion syndrome and CHARGE syndrome because these children have many other abnormalities and health problems (comorbidities).Antibiotic and anti-viral medications are used for infections. Congenital heart defects may require surgery. Some infants require supplementation with calcium or a synthetic version of vitamin D3 called calcitriol for hypoparathyroidism.Affected infants with laryngomalacia or aspiration may require a tracheostomy. This is the creation of a surgical opening in the neck to gain access to the windpipe (trachea). A tube is placed into this opening to allow for breathing. Other children may require a gastrostomy tube (a tube going into the stomach) for feeding the child. Therapy On October 8, 2021, the U.S. Food and Drug Administration approved the use of cultured thymus tissue (Rethymic) for treatment of pediatric patients with congenital athymia. Rethymic is composed of thymus tissue from infant donors that has been processed and cultured. Many tissue slices, after culture, are implanted into the thigh muscle of an athymic patient to help improve immune function. (The word “implant” is used in this report because the thymus tissue is processed in a laboratory for at least 12 days prior to use. The word “transplant” refers to an organ taken out of one individual in an operating room which is immediately brought to a neighboring operating room and placed into the recipient.)The research supporting this approval included 95 patients with congenital athymia previously treated under research studies with investigational cultured thymus tissue implants. The thymus tissue needed for this product is obtained during heart surgery on an infant. Thymus tissue may need to be removed during infant heart surgery to allow for the surgeon to access the heart. Instead of being discarded, it is put in a sterile container and sent to a laboratory. The tissue is processed into slices and maintained in culture for 12 to 21 days. The cultured tissue is then brought to the operating room and implanted into the child’s quadriceps muscle. That location was chosen because it has a good blood supply to get oxygen and nutrients to the thymus tissue slices. The implanted cultured thymus tissue slices will produce the T cells missing from the affected infant’s immune system. It takes approximately six months for the immune system to begin functioning. Over 6-9 months, infants will develop T cells that are able to fight infections.The most common adverse effect of this therapy is autoimmunity in the first year prior to development of diverse T cells. Autoimmunity is when the body’s immune system accidentally harms healthy tissue. Autoimmunity is treatable and is less frequent after the first year after implantation.Investigational cultured thymus tissue implants for congenital athymia have resulted in survival of approximately 72% of patients. More research and follow up is necessary to determine the long-term safety and effectiveness of this procedure. In the United States, Duke Children’s Hospital is the only medical center that performs this procedure. | Therapies of Congenital Athymia. TreatmentTreatment requires the coordinated efforts of a team of specialists. Pediatricians, physicians who specialize in diagnosing and treating immune system disorders (immunologists), physicians who specialize in diagnosing and treating blood disorders (hematologists), physicians who specialize in diagnosing and treating endocrine disorders (endocrinologists) and other healthcare professionals may need to plan treatment systematically and comprehensively for a patient with congenital athymia. Specialized healthcare professionals are necessary for infants with chromosome 22q11.2 deletion syndrome and CHARGE syndrome because these children have many other abnormalities and health problems (comorbidities).Antibiotic and anti-viral medications are used for infections. Congenital heart defects may require surgery. Some infants require supplementation with calcium or a synthetic version of vitamin D3 called calcitriol for hypoparathyroidism.Affected infants with laryngomalacia or aspiration may require a tracheostomy. This is the creation of a surgical opening in the neck to gain access to the windpipe (trachea). A tube is placed into this opening to allow for breathing. Other children may require a gastrostomy tube (a tube going into the stomach) for feeding the child. Therapy On October 8, 2021, the U.S. Food and Drug Administration approved the use of cultured thymus tissue (Rethymic) for treatment of pediatric patients with congenital athymia. Rethymic is composed of thymus tissue from infant donors that has been processed and cultured. Many tissue slices, after culture, are implanted into the thigh muscle of an athymic patient to help improve immune function. (The word “implant” is used in this report because the thymus tissue is processed in a laboratory for at least 12 days prior to use. The word “transplant” refers to an organ taken out of one individual in an operating room which is immediately brought to a neighboring operating room and placed into the recipient.)The research supporting this approval included 95 patients with congenital athymia previously treated under research studies with investigational cultured thymus tissue implants. The thymus tissue needed for this product is obtained during heart surgery on an infant. Thymus tissue may need to be removed during infant heart surgery to allow for the surgeon to access the heart. Instead of being discarded, it is put in a sterile container and sent to a laboratory. The tissue is processed into slices and maintained in culture for 12 to 21 days. The cultured tissue is then brought to the operating room and implanted into the child’s quadriceps muscle. That location was chosen because it has a good blood supply to get oxygen and nutrients to the thymus tissue slices. The implanted cultured thymus tissue slices will produce the T cells missing from the affected infant’s immune system. It takes approximately six months for the immune system to begin functioning. Over 6-9 months, infants will develop T cells that are able to fight infections.The most common adverse effect of this therapy is autoimmunity in the first year prior to development of diverse T cells. Autoimmunity is when the body’s immune system accidentally harms healthy tissue. Autoimmunity is treatable and is less frequent after the first year after implantation.Investigational cultured thymus tissue implants for congenital athymia have resulted in survival of approximately 72% of patients. More research and follow up is necessary to determine the long-term safety and effectiveness of this procedure. In the United States, Duke Children’s Hospital is the only medical center that performs this procedure. | 298 | Congenital Athymia |
nord_299_0 | Overview of Congenital Bilateral Perisylvian Syndrome | Congenital bilateral perisylvian syndrome (CBPS) is an extremely rare neurological disorder that may be apparent at birth (congenital), infancy, or later during childhood. It is characterized by partial paralysis of muscles on both sides (diplegia) of the face, tongue, jaws, and throat (pseudobulbar palsy); difficulties in speaking (dysarthria), chewing (mastication), and swallowing (dysphagia); and/or sudden episodes of uncontrolled electrical activity in the brain (epilepsy). In most cases, mild to severe intellectual disability is also present. Associated symptoms and findings are thought to be due to improper development of the outer surface of the brain (cerebral cortex) during embryonic growth (neuronal dysmigration). In most cases, the disorder appears to occur randomly for unknown reasons (sporadically). | Overview of Congenital Bilateral Perisylvian Syndrome. Congenital bilateral perisylvian syndrome (CBPS) is an extremely rare neurological disorder that may be apparent at birth (congenital), infancy, or later during childhood. It is characterized by partial paralysis of muscles on both sides (diplegia) of the face, tongue, jaws, and throat (pseudobulbar palsy); difficulties in speaking (dysarthria), chewing (mastication), and swallowing (dysphagia); and/or sudden episodes of uncontrolled electrical activity in the brain (epilepsy). In most cases, mild to severe intellectual disability is also present. Associated symptoms and findings are thought to be due to improper development of the outer surface of the brain (cerebral cortex) during embryonic growth (neuronal dysmigration). In most cases, the disorder appears to occur randomly for unknown reasons (sporadically). | 299 | Congenital Bilateral Perisylvian Syndrome |
nord_299_1 | Symptoms of Congenital Bilateral Perisylvian Syndrome | CBPS is characterized by partial paralysis of the muscles on both sides of the face (facial diplegia), seizures, and intellectual disability.In those with CBPS, impairment of certain nerves (cranial nerves) that emerge from the brain may result in sudden, involuntary spasms of facial muscles as well as partial paralysis of both sides (diplegia) of the face, jaws, tongue, and throat (pharynx). Impaired control of these muscles may cause difficulty chewing (mastication), swallowing (dysphagia), and/or pronouncing certain sounds and words (dysarthria). In some cases, affected individuals may be unable to speak.Most individuals with CBPS also experience seizures or sudden recurrent episodes in which uncontrolled electrical discharges from nerve cells (neurons) of the outer region of the brain (cerebral cortex) cause involuntary muscle contractions, sensory disturbances, loss of consciousness, and/or other associated findings (epilepsy). Several different types of seizures may occur in the same affected individual. However, reports indicate that the epileptic seizures are frequently generalized. (Epileptic seizures may be broadly categorized into generalized and focal-onset seizures. Generalized seizures appear to arise over a wide area or both sides or hemispheres of the cerebral cortex, while focal seizures have an onset limited to a part of one hemisphere.)In some cases, generalized seizures may be characterized by sudden breaks or momentary lapses of awareness or action; fluttering of the eyelids; twitching of facial muscles; and/or other findings (absence or petit mal seizures). In those with CBPS, the beginning and end of such seizure episodes may not be as distinct as often seen in absence seizures or they may be associated with loss of muscle tone or other atypical findings (i.e., atypical absence or petit mal seizures). Additional types of generalized seizures occur in some cases. Some affected individuals may have seizure episodes characterized by sustained muscle contraction or muscle jerks followed by sudden loss of muscle tone (atonic [astatic] seizures), potentially causing falls. In addition, some may have seizures characterized by an abrupt loss of consciousness, generalized stiffening of muscles, rhythmic contraction and relaxation of all muscle groups, and other findings (tonic-clonic or grand-mal seizures). In some cases, affected infants may first experience seizures characterized by sudden, brief, involuntary contractions of the neck, trunk, arms, and legs (infantile spasms). (For more information on these seizure types, use “Epilepsy” as your search terms in the Rare Disease Database.)Children with CBPS may also have delays in the development of certain physical, mental, and behavioral skills that are typically acquired at particular stages (developmental milestones), such as language and speech development and certain motor abilities. In addition, mild to severe intellectual disability is usually present. | Symptoms of Congenital Bilateral Perisylvian Syndrome. CBPS is characterized by partial paralysis of the muscles on both sides of the face (facial diplegia), seizures, and intellectual disability.In those with CBPS, impairment of certain nerves (cranial nerves) that emerge from the brain may result in sudden, involuntary spasms of facial muscles as well as partial paralysis of both sides (diplegia) of the face, jaws, tongue, and throat (pharynx). Impaired control of these muscles may cause difficulty chewing (mastication), swallowing (dysphagia), and/or pronouncing certain sounds and words (dysarthria). In some cases, affected individuals may be unable to speak.Most individuals with CBPS also experience seizures or sudden recurrent episodes in which uncontrolled electrical discharges from nerve cells (neurons) of the outer region of the brain (cerebral cortex) cause involuntary muscle contractions, sensory disturbances, loss of consciousness, and/or other associated findings (epilepsy). Several different types of seizures may occur in the same affected individual. However, reports indicate that the epileptic seizures are frequently generalized. (Epileptic seizures may be broadly categorized into generalized and focal-onset seizures. Generalized seizures appear to arise over a wide area or both sides or hemispheres of the cerebral cortex, while focal seizures have an onset limited to a part of one hemisphere.)In some cases, generalized seizures may be characterized by sudden breaks or momentary lapses of awareness or action; fluttering of the eyelids; twitching of facial muscles; and/or other findings (absence or petit mal seizures). In those with CBPS, the beginning and end of such seizure episodes may not be as distinct as often seen in absence seizures or they may be associated with loss of muscle tone or other atypical findings (i.e., atypical absence or petit mal seizures). Additional types of generalized seizures occur in some cases. Some affected individuals may have seizure episodes characterized by sustained muscle contraction or muscle jerks followed by sudden loss of muscle tone (atonic [astatic] seizures), potentially causing falls. In addition, some may have seizures characterized by an abrupt loss of consciousness, generalized stiffening of muscles, rhythmic contraction and relaxation of all muscle groups, and other findings (tonic-clonic or grand-mal seizures). In some cases, affected infants may first experience seizures characterized by sudden, brief, involuntary contractions of the neck, trunk, arms, and legs (infantile spasms). (For more information on these seizure types, use “Epilepsy” as your search terms in the Rare Disease Database.)Children with CBPS may also have delays in the development of certain physical, mental, and behavioral skills that are typically acquired at particular stages (developmental milestones), such as language and speech development and certain motor abilities. In addition, mild to severe intellectual disability is usually present. | 299 | Congenital Bilateral Perisylvian Syndrome |
nord_299_2 | Causes of Congenital Bilateral Perisylvian Syndrome | The exact cause of CBPS is not completely understood. Associated symptoms and findings are believed to be due to improper development of the outer surface of the brain (cerebral cortex) during embryonic growth. The cerebral cortex, which is responsible for conscious movement and thought, normally consists of several deep folds (gyri) and grooves (sulci). However, in cases of CBPS, newly developed embryonic cells (neuroblasts) fail to migrate to their destined locations in the outer portion of the brain (neuronal dysmigration). As a result, the cerebral cortex does not develop the normal number of cellular layers, and the deep grooves (sulci) that normally develop on the sides (lateral) of both cerebral hemispheres (sylvian fissures or sulcus lateralis cerebri) may form improperly, resulting in an abnormally increased number of folds (gyri) that are unusually small (bilateral perisylvian polymicrogyria). In some cases, the groove separating the front (frontal) and side (parietal) portions (lobes) of the brain (fissure of Rolando or sulcus centralis cerebri) may also be malformed.In most cases, CBPS appears to occur randomly for unknown reasons (sporadically) in the absence of a family history. However, a few families have been reported in which more than one member has been affected. In such cases, researchers suggest that the condition may potentially be due to an underlying genetic abnormality that may have autosomal recessive inheritance. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother.In recessive disorders, the condition does not appear unless a person inherits a defective, or mutated, gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy. | Causes of Congenital Bilateral Perisylvian Syndrome. The exact cause of CBPS is not completely understood. Associated symptoms and findings are believed to be due to improper development of the outer surface of the brain (cerebral cortex) during embryonic growth. The cerebral cortex, which is responsible for conscious movement and thought, normally consists of several deep folds (gyri) and grooves (sulci). However, in cases of CBPS, newly developed embryonic cells (neuroblasts) fail to migrate to their destined locations in the outer portion of the brain (neuronal dysmigration). As a result, the cerebral cortex does not develop the normal number of cellular layers, and the deep grooves (sulci) that normally develop on the sides (lateral) of both cerebral hemispheres (sylvian fissures or sulcus lateralis cerebri) may form improperly, resulting in an abnormally increased number of folds (gyri) that are unusually small (bilateral perisylvian polymicrogyria). In some cases, the groove separating the front (frontal) and side (parietal) portions (lobes) of the brain (fissure of Rolando or sulcus centralis cerebri) may also be malformed.In most cases, CBPS appears to occur randomly for unknown reasons (sporadically) in the absence of a family history. However, a few families have been reported in which more than one member has been affected. In such cases, researchers suggest that the condition may potentially be due to an underlying genetic abnormality that may have autosomal recessive inheritance. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother.In recessive disorders, the condition does not appear unless a person inherits a defective, or mutated, gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy. | 299 | Congenital Bilateral Perisylvian Syndrome |
nord_299_3 | Affects of Congenital Bilateral Perisylvian Syndrome | CBPS is a rare neurological disorder that was first recognized as a distinct syndrome in the early 1990s. The disorder is usually apparent at birth (congenital) or early in life, based upon characteristic physical findings and specialized imaging tests. In affected individuals who exhibit infantile spasms, onset of these sudden, involuntary contractions tends to occur within the first six months of life. Onset of other forms of epilepsy potentially associated with CBPS (e.g., atypical absence seizures, atonic-tonic seizures, and/or tonic-clonic seizures) may occur between two to 12 years of life. CBPS appears to affect males and females in equal numbers. Various subtypes have been described based on radiological features as seen on MRI; the prevalence is now known. In a recent review of 35 new cases of polymicrogyria, 22 had bilateral perisylvian distribution (Flotats-Bastardas et al 2012). | Affects of Congenital Bilateral Perisylvian Syndrome. CBPS is a rare neurological disorder that was first recognized as a distinct syndrome in the early 1990s. The disorder is usually apparent at birth (congenital) or early in life, based upon characteristic physical findings and specialized imaging tests. In affected individuals who exhibit infantile spasms, onset of these sudden, involuntary contractions tends to occur within the first six months of life. Onset of other forms of epilepsy potentially associated with CBPS (e.g., atypical absence seizures, atonic-tonic seizures, and/or tonic-clonic seizures) may occur between two to 12 years of life. CBPS appears to affect males and females in equal numbers. Various subtypes have been described based on radiological features as seen on MRI; the prevalence is now known. In a recent review of 35 new cases of polymicrogyria, 22 had bilateral perisylvian distribution (Flotats-Bastardas et al 2012). | 299 | Congenital Bilateral Perisylvian Syndrome |
nord_299_4 | Related disorders of Congenital Bilateral Perisylvian Syndrome | Symptoms of the following disorders may be similar to those of CBPS. Comparisons may be useful for a differential diagnosis:Pachygyria with mental retardation and seizures is a rare neurological disorder that is characterized by moderate intellectual disability; delays in the acquisition of skills requiring the coordination of physical and mental activities (psychomotor retardation); and/or sudden episodes of uncontrolled electrical activity in the brain (epilepsy). Several different types of epileptic seizures may occur in the same affected individual. Associated symptoms and findings are believed to result from abnormal development of the outer portion of the brain (cerebral cortex) during embryonic growth (neuronal dysmigration). In pachygyria with mental retardation and seizures, it is believed that there is a reduced number of folds in the cerebral cortex that are larger than normal (pachygria) or that the deep folds are abnormally numerous and small (polymicrogyria). In some cases, it is thought that the neuronal dysmigration may be due to an underlying genetic abnormality that may be transmitted as an autosomal recessive trait.In double cortex syndrome, an abnormal band of brain tissue is present under the outer region of the brain (subcortical band heterotopia); as a result, it may appear as if the brain has a “double” cerebral cortex. Symptoms may vary from case to case, depending upon the extent of cerebral cortex malformation. Most affected individuals have various forms of epilepsy and mild to moderate intellectual disability. Some researchers believe that, in some cases, the abnormal development of the cerebral cortex during embryonic growth (neuronal dysmigration) may be due to an underlying genetic abnormality that may be transmitted as an autosomal dominant trait.Lissencephaly is a rare brain malformation that may occur as an isolated condition or in association with certain underlying syndromes. The condition is characterized by incomplete development of the folds (gyri) of the cerebral cortex, causing the brain’s surface to appear unusually smooth (agyria). Affected infants may have an abnormally small head (microcephaly); seizures; severe or profound intellectual disability; growth retardation; and impaired motor abilities. If an underlying syndrome is present, there may be additional symptoms and physical findings, such as distinctive abnormalities of the skull and facial (craniofacial) region and/or other physical malformations. Lissencephaly may appear to occur randomly for unknown reasons (sporadically), be inherited, or occur in association with various underlying disorders. (For more information, choose “lissencephaly” as your search term in the Rare Disease Database.)Neuronal migration disorders are a category of rare neurological disorders, including CBPS, pachygyria with mental retardation and seizures, double cortex syndrome, and lissencephaly, that result from improper development of the cerebral cortex. During normal embryonic growth, newly developed embryonic cells that will later become nerve cells (neuroblasts) migrate to the surface of the brain (neuronal migration), forming several cellular layers. If these embryonic cells fail to migrate to their destined locations (dysmigration), the cerebral cortex may not develop the normal number of cellular layers; as a result, there may be structural abnormalities of the brain's two cerebral hemispheres, such as improper development of the deep grooves (sulci) and folds (gyri) that normally form within the cerebral cortex. Neuronal migration disorders are often characterized by seizures and mild to severe intellectual disability. (For more information on these disorders, use “neuronal migration” or “neuronal dysmigration” as your search terms in the Rare Disease Database.) | Related disorders of Congenital Bilateral Perisylvian Syndrome. Symptoms of the following disorders may be similar to those of CBPS. Comparisons may be useful for a differential diagnosis:Pachygyria with mental retardation and seizures is a rare neurological disorder that is characterized by moderate intellectual disability; delays in the acquisition of skills requiring the coordination of physical and mental activities (psychomotor retardation); and/or sudden episodes of uncontrolled electrical activity in the brain (epilepsy). Several different types of epileptic seizures may occur in the same affected individual. Associated symptoms and findings are believed to result from abnormal development of the outer portion of the brain (cerebral cortex) during embryonic growth (neuronal dysmigration). In pachygyria with mental retardation and seizures, it is believed that there is a reduced number of folds in the cerebral cortex that are larger than normal (pachygria) or that the deep folds are abnormally numerous and small (polymicrogyria). In some cases, it is thought that the neuronal dysmigration may be due to an underlying genetic abnormality that may be transmitted as an autosomal recessive trait.In double cortex syndrome, an abnormal band of brain tissue is present under the outer region of the brain (subcortical band heterotopia); as a result, it may appear as if the brain has a “double” cerebral cortex. Symptoms may vary from case to case, depending upon the extent of cerebral cortex malformation. Most affected individuals have various forms of epilepsy and mild to moderate intellectual disability. Some researchers believe that, in some cases, the abnormal development of the cerebral cortex during embryonic growth (neuronal dysmigration) may be due to an underlying genetic abnormality that may be transmitted as an autosomal dominant trait.Lissencephaly is a rare brain malformation that may occur as an isolated condition or in association with certain underlying syndromes. The condition is characterized by incomplete development of the folds (gyri) of the cerebral cortex, causing the brain’s surface to appear unusually smooth (agyria). Affected infants may have an abnormally small head (microcephaly); seizures; severe or profound intellectual disability; growth retardation; and impaired motor abilities. If an underlying syndrome is present, there may be additional symptoms and physical findings, such as distinctive abnormalities of the skull and facial (craniofacial) region and/or other physical malformations. Lissencephaly may appear to occur randomly for unknown reasons (sporadically), be inherited, or occur in association with various underlying disorders. (For more information, choose “lissencephaly” as your search term in the Rare Disease Database.)Neuronal migration disorders are a category of rare neurological disorders, including CBPS, pachygyria with mental retardation and seizures, double cortex syndrome, and lissencephaly, that result from improper development of the cerebral cortex. During normal embryonic growth, newly developed embryonic cells that will later become nerve cells (neuroblasts) migrate to the surface of the brain (neuronal migration), forming several cellular layers. If these embryonic cells fail to migrate to their destined locations (dysmigration), the cerebral cortex may not develop the normal number of cellular layers; as a result, there may be structural abnormalities of the brain's two cerebral hemispheres, such as improper development of the deep grooves (sulci) and folds (gyri) that normally form within the cerebral cortex. Neuronal migration disorders are often characterized by seizures and mild to severe intellectual disability. (For more information on these disorders, use “neuronal migration” or “neuronal dysmigration” as your search terms in the Rare Disease Database.) | 299 | Congenital Bilateral Perisylvian Syndrome |
nord_299_5 | Diagnosis of Congenital Bilateral Perisylvian Syndrome | Diagnosis of Congenital Bilateral Perisylvian Syndrome. | 299 | Congenital Bilateral Perisylvian Syndrome |
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nord_299_6 | Therapies of Congenital Bilateral Perisylvian Syndrome | CBPS may be diagnosed at birth or early in life, based upon a thorough clinical evaluation, a detailed patient history, and a complete neurological evaluation including advanced imaging techniques such as electroencephalography (EEG), computerized tomography (CT) scanning, or magnetic resonance imaging (MRI).During an EEG, the brain's electrical impulses are recorded; such studies may reveal brain wave patterns that are characteristic of certain types of epilepsy. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of the brain's tissue structure. During MRI, a magnetic field and radio waves are used to create cross-sectional images of the brain.CT and MRI images may confirm malformations of certain areas of the cerebral cortex (perisylvian and/or perirolandic malformations) and abnormalities of the brain's deep folds and grooves. In addition, analysis of speech abnormalities due to impaired muscle control (dysarthria) may reveal characteristic patterns among individuals with CBPS, such as difficulty with certain vowels or noise ranges.The treatment of CBPS is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, surgeons, physical therapists, and others may need to systematically and comprehensively plan an affected child's treatment.Treatment with anticonvulsant drugs may help prevent, reduce, or control various types of epilepsy associated with CBPS. In affected infants who exhibit sudden, involuntary contractions of the head, neck, and trunk and/or uncontrolled extension of the legs and/or arms in the first six months of life (infantile spasms or West Syndrome), treatment with adrenocorticotropic hormone (ACTH or corticotropin) has resolved the seizures in some cases. In cases when drug therapy is ineffective in preventing or controlling seizures (intractable epilepsy), surgical removal of tissue in certain areas of the brain (focal corticectomy) or surgical division (callosotomy) of the fibers joining the two cerebral hemispheres (corpus callosum) may result in seizure improvement.Early intervention is important in ensuring that children with CBPS reach their potential. Special services that may be beneficial to affected children may include physical therapy, special remedial education, speech therapy, and other medical, social, and/or vocational services.Genetic counseling will be of benefit for affected children and their families. Other treatment is symptomatic and supportive. | Therapies of Congenital Bilateral Perisylvian Syndrome. CBPS may be diagnosed at birth or early in life, based upon a thorough clinical evaluation, a detailed patient history, and a complete neurological evaluation including advanced imaging techniques such as electroencephalography (EEG), computerized tomography (CT) scanning, or magnetic resonance imaging (MRI).During an EEG, the brain's electrical impulses are recorded; such studies may reveal brain wave patterns that are characteristic of certain types of epilepsy. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of the brain's tissue structure. During MRI, a magnetic field and radio waves are used to create cross-sectional images of the brain.CT and MRI images may confirm malformations of certain areas of the cerebral cortex (perisylvian and/or perirolandic malformations) and abnormalities of the brain's deep folds and grooves. In addition, analysis of speech abnormalities due to impaired muscle control (dysarthria) may reveal characteristic patterns among individuals with CBPS, such as difficulty with certain vowels or noise ranges.The treatment of CBPS is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, surgeons, physical therapists, and others may need to systematically and comprehensively plan an affected child's treatment.Treatment with anticonvulsant drugs may help prevent, reduce, or control various types of epilepsy associated with CBPS. In affected infants who exhibit sudden, involuntary contractions of the head, neck, and trunk and/or uncontrolled extension of the legs and/or arms in the first six months of life (infantile spasms or West Syndrome), treatment with adrenocorticotropic hormone (ACTH or corticotropin) has resolved the seizures in some cases. In cases when drug therapy is ineffective in preventing or controlling seizures (intractable epilepsy), surgical removal of tissue in certain areas of the brain (focal corticectomy) or surgical division (callosotomy) of the fibers joining the two cerebral hemispheres (corpus callosum) may result in seizure improvement.Early intervention is important in ensuring that children with CBPS reach their potential. Special services that may be beneficial to affected children may include physical therapy, special remedial education, speech therapy, and other medical, social, and/or vocational services.Genetic counseling will be of benefit for affected children and their families. Other treatment is symptomatic and supportive. | 299 | Congenital Bilateral Perisylvian Syndrome |
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