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nord_314_2 | Causes of Congenital Myopathy | There is still emerging research on the causes of CM and mutations in more than twenty genes have been associated with CM. Genes responsible for calcium ion balance in muscle cells have been implicated in some inherited forms of the disease. Calcium ion balance is important in muscle cells because calcium is a signal for muscle cells to contract. Other mutations described in CM patients occur in genes that lead to malformed filaments in muscle cells. These filaments are normally responsible for the contraction of muscles.Most types of CM follow an autosomal recessive pattern of inheritance. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females. Structural defects such as rods or protein accumulation are common in nemaline myopathies, core-rod myopathy, and other types of CM are associated with mutations in genes such as ACTA1, CFL2, KBTBD13, KLHL40, KLHL41, LMOD3, NEB, RYR1, TNNT1, TPM2, and TPM3. The most common cause of nemaline myopathies is autosomal recessive mutations in the NEB gene which accounts for up to 50% of cases, followed by ACTA1 (~25%). Structural defects in cores seen in central core and multiminicore disease have been shown to be associated with mutations in the RYR1, MEGF10, MYH7, and SEPN1 genes. An overwhelming majority of patients with CCD (>90%) have a RYR1 mutation. Those with two RYR1 mutations have a more severe presentation than patients with a single RYR1 mutation or mutations in other genes. Most MmD is caused by recessive mutations in the SEPN1 gene. Structural defects in central nuclei of centronuclear myopathy are associated with mutations in genes such as BIN1, CCDC78, DNM2, MTM1, RYR1, SPEG, and TTN.X-linked myotubular myopathy is the most common and severe type with prenatal or neonatal onset. Autosomal recessive forms have a typical onset in infancy or childhood and autosomal dominant forms have the mildest symptoms and may present in adulthood. Most patients with centronuclear myopathy have mutations in the MTM1 gene which leads to X-linked myotubular myopathy, a type of CNM. DNM2 gene mutations are the second most common cause and result in milder symptoms. Mutations in the RYR1, TTN, and BIN1 genes have been identified in recessive forms and have highly variable symptom presentation.Structural defects that lead to fiber size variation are commonly seen in congenital fiber-type disproportion CM and have been shown to involve genes including ACTA1, MYH7, RYR1, SEPN1, TPM2, and TPM3. Most CFTD CM are associated with mutations in the TPM3 gene and some patients have been identified with ACTA1, MYH1, SEPN1, and TPM2 mutations. Mutation in the LMNA gene have been found in several Japanese patients and could be related to a subset of CFTD CM patients at risk for cardiac disease.Known genes have been found in 50-70% of families with CM, so other genetic causes remain to be identified. | Causes of Congenital Myopathy. There is still emerging research on the causes of CM and mutations in more than twenty genes have been associated with CM. Genes responsible for calcium ion balance in muscle cells have been implicated in some inherited forms of the disease. Calcium ion balance is important in muscle cells because calcium is a signal for muscle cells to contract. Other mutations described in CM patients occur in genes that lead to malformed filaments in muscle cells. These filaments are normally responsible for the contraction of muscles.Most types of CM follow an autosomal recessive pattern of inheritance. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females. Structural defects such as rods or protein accumulation are common in nemaline myopathies, core-rod myopathy, and other types of CM are associated with mutations in genes such as ACTA1, CFL2, KBTBD13, KLHL40, KLHL41, LMOD3, NEB, RYR1, TNNT1, TPM2, and TPM3. The most common cause of nemaline myopathies is autosomal recessive mutations in the NEB gene which accounts for up to 50% of cases, followed by ACTA1 (~25%). Structural defects in cores seen in central core and multiminicore disease have been shown to be associated with mutations in the RYR1, MEGF10, MYH7, and SEPN1 genes. An overwhelming majority of patients with CCD (>90%) have a RYR1 mutation. Those with two RYR1 mutations have a more severe presentation than patients with a single RYR1 mutation or mutations in other genes. Most MmD is caused by recessive mutations in the SEPN1 gene. Structural defects in central nuclei of centronuclear myopathy are associated with mutations in genes such as BIN1, CCDC78, DNM2, MTM1, RYR1, SPEG, and TTN.X-linked myotubular myopathy is the most common and severe type with prenatal or neonatal onset. Autosomal recessive forms have a typical onset in infancy or childhood and autosomal dominant forms have the mildest symptoms and may present in adulthood. Most patients with centronuclear myopathy have mutations in the MTM1 gene which leads to X-linked myotubular myopathy, a type of CNM. DNM2 gene mutations are the second most common cause and result in milder symptoms. Mutations in the RYR1, TTN, and BIN1 genes have been identified in recessive forms and have highly variable symptom presentation.Structural defects that lead to fiber size variation are commonly seen in congenital fiber-type disproportion CM and have been shown to involve genes including ACTA1, MYH7, RYR1, SEPN1, TPM2, and TPM3. Most CFTD CM are associated with mutations in the TPM3 gene and some patients have been identified with ACTA1, MYH1, SEPN1, and TPM2 mutations. Mutation in the LMNA gene have been found in several Japanese patients and could be related to a subset of CFTD CM patients at risk for cardiac disease.Known genes have been found in 50-70% of families with CM, so other genetic causes remain to be identified. | 314 | Congenital Myopathy |
nord_314_3 | Affects of Congenital Myopathy | Congenital myopathy is an extremely rare disorder that generally affects males and females in equal numbers. There are subsets of centronuclear myopathy, i.e. XLMTM that affect males more than females. | Affects of Congenital Myopathy. Congenital myopathy is an extremely rare disorder that generally affects males and females in equal numbers. There are subsets of centronuclear myopathy, i.e. XLMTM that affect males more than females. | 314 | Congenital Myopathy |
nord_314_4 | Related disorders of Congenital Myopathy | Symptoms of the following disorders can be similar to those of congenital myopathy. Comparisons may be useful for a differential diagnosis:Congenital hypotonia is a non-progressive neuromuscular disorder that is present at birth. This condition is characterized by decreased muscle tone or floppiness with no known cause or may be a symptom of another disorder. Newborns with this disorder have muscle weakness and generalized weakness. In many children, the symptoms improve as the child ages.Congenital hypotonia may occur in association with many other disorders. Generalized muscle weakness and floppiness may be symptoms of these disorders. A variety of other symptoms or unusual facial or physical characteristics may also occur. These other disorders include, but are not limited to, congenital hypomyelination neuropathy, Aicardi syndrome, cri du chat syndrome, multiple carboxylase deficiency, De Barsy syndrome, Down syndrome, FG syndrome type 1, neonatal herpes, non-ketotic hyperglycinemia, and Tay-Sachs disease.Spinal muscular atrophy type 1 (Werdnig-Hoffmann disease) is a rare inherited neuromuscular disorder of childhood characterized by generalized muscle weakness and the progressive loss of muscle mass (atrophy). Symptoms may also include hypermobility of the joints, absent tendon reflexes, and rapid twitching (fasciculations) of the tongue. SMA type 1 is a progressive disorder and affected children may develop breathing problems or kidney impairment. (For more information on this disorder, choose “Werdnig-Hoffman” as your search term in the Rare Disease Database.)Canavan disease is a rare inherited disorder that is characterized by the progressive degeneration of the central nervous system. The early symptoms of this disorder include a general lack of energy, floppiness, and the loss of previously acquired motor skills. Symptoms appear in early infancy and are rapidly progressive. Other symptoms may include jerky motions of the arms and legs, poor head control, and/or hearing loss. (For more information on this disorder, choose “Canavan” as your search term in the Rare Disease Database.) | Related disorders of Congenital Myopathy. Symptoms of the following disorders can be similar to those of congenital myopathy. Comparisons may be useful for a differential diagnosis:Congenital hypotonia is a non-progressive neuromuscular disorder that is present at birth. This condition is characterized by decreased muscle tone or floppiness with no known cause or may be a symptom of another disorder. Newborns with this disorder have muscle weakness and generalized weakness. In many children, the symptoms improve as the child ages.Congenital hypotonia may occur in association with many other disorders. Generalized muscle weakness and floppiness may be symptoms of these disorders. A variety of other symptoms or unusual facial or physical characteristics may also occur. These other disorders include, but are not limited to, congenital hypomyelination neuropathy, Aicardi syndrome, cri du chat syndrome, multiple carboxylase deficiency, De Barsy syndrome, Down syndrome, FG syndrome type 1, neonatal herpes, non-ketotic hyperglycinemia, and Tay-Sachs disease.Spinal muscular atrophy type 1 (Werdnig-Hoffmann disease) is a rare inherited neuromuscular disorder of childhood characterized by generalized muscle weakness and the progressive loss of muscle mass (atrophy). Symptoms may also include hypermobility of the joints, absent tendon reflexes, and rapid twitching (fasciculations) of the tongue. SMA type 1 is a progressive disorder and affected children may develop breathing problems or kidney impairment. (For more information on this disorder, choose “Werdnig-Hoffman” as your search term in the Rare Disease Database.)Canavan disease is a rare inherited disorder that is characterized by the progressive degeneration of the central nervous system. The early symptoms of this disorder include a general lack of energy, floppiness, and the loss of previously acquired motor skills. Symptoms appear in early infancy and are rapidly progressive. Other symptoms may include jerky motions of the arms and legs, poor head control, and/or hearing loss. (For more information on this disorder, choose “Canavan” as your search term in the Rare Disease Database.) | 314 | Congenital Myopathy |
nord_314_5 | Diagnosis of Congenital Myopathy | A diagnosis of congenital myopathy may be suspected upon a thorough clinical evaluation, detailed patient and family history, and identification of characteristic physical findings. A specific diagnosis can be made to confirm disease, track disease progression, and connect affected families with the relevant resources. The significant number of factors involved in CM makes a strict clinical, histopathological, or genetic diagnosis more complicated. Traditional clinical work-ups for myopathies use metabolic tests, electrocardiograms, and electromyography to identify which specific disease is suspected in the patient. In addition, clinical diagnosis based on symptom presentation can also assist in identifying the disease in patients. Metabolic tests can be used to look for abnormal elevations of creatine kinase levels. Electrocardiograms are done to observe the heart’s electrical activity and see if any disruptions are present that are common to specific subtypes such as congenital fiber-type disproportion CM. Electromyography are conducted to measure electrical activity within muscles. If these tests cannot identify the subtype of CM, a muscle biopsy can be done for a closer examination of the microscopic characteristics of the tissue to best characterize which exact subtype of CM an individual might have. Molecular testing of known genes implicated in CM can assist in narrowing down a diagnosis.Nemaline Myopathy
NM displays characteristic rod bodies in muscle that appear threadlike in longitudinal sections. In nemaline myopathy, creatine kinase levels are usually normal or slightly elevated. Electromyography may show changes in action potentials, indicative of a myopathy. If other tests are unsuccessful a muscle biopsy can confirm a diagnosis of nemaline myopathy.Core Myopathy
Clinical features of core myopathy include presentation in the neonatal period but it may not be identified until later in infancy. It is characterized by hypotonia and muscle weakness, predominantly in the proximal extremities (i.e. biceps, thighs). Clinical progression of weakness can occur but those with core myopathy generally do not have progressive disease. Laboratory studies are not useful in diagnosis and the diagnosis must be confirmed by muscle biopsy.Centronuclear Myopathy
Centronuclear myopathy subtypes are characterized by muscle fibers with central nuclei. One of two major clinical presentations can identify centronuclear myopathy. Certain symptoms can be indicative of centronuclear myopathy subtypes.The more common form, also the most severe, is X-linked myotubular myopathy that occurs predominantly in males. The signs in infants include hypotonia, skeletal muscle weakness and respiratory muscle impairment leading to respiratory failure, which are components of the most severe clinical presentations. Impaired bulbar muscle function can lead to facial weakness, which can be associated with difficulty feeding, or to extraocular muscle weakness. Female carriers can present with limb girdle weakness as well as marked facial weakness.A less common presentation of CNM occurs with autosomal dominant or recessive inheritance, presenting with mild weakness and hypotonia, which may be unrecognizable in infants. Unlike the more severe form (XLMTM), this type can be present in both males and females. Laboratory testing of creatine kinase often reveals normal levels although it is occasionally mildly elevated. The use of electromyography can be useful in detecting action potential changes however; diagnosis is confirmed by muscle biopsy or molecular genetic testing.Congenital Fiber Type Disproportion
Clinical presentations of this myopathy include disproportions in the number and size of fast and slow twitch muscles, along with weakness of the limbs, neck, and trunk and facial muscles. Most infants are severely affected, but the degree of weakness can vary. Infants with congenital fiber type disproportion can have improvements in respiratory function as they age. The only definitive diagnosis for congenital fiber type disproportion is muscle biopsy. | Diagnosis of Congenital Myopathy. A diagnosis of congenital myopathy may be suspected upon a thorough clinical evaluation, detailed patient and family history, and identification of characteristic physical findings. A specific diagnosis can be made to confirm disease, track disease progression, and connect affected families with the relevant resources. The significant number of factors involved in CM makes a strict clinical, histopathological, or genetic diagnosis more complicated. Traditional clinical work-ups for myopathies use metabolic tests, electrocardiograms, and electromyography to identify which specific disease is suspected in the patient. In addition, clinical diagnosis based on symptom presentation can also assist in identifying the disease in patients. Metabolic tests can be used to look for abnormal elevations of creatine kinase levels. Electrocardiograms are done to observe the heart’s electrical activity and see if any disruptions are present that are common to specific subtypes such as congenital fiber-type disproportion CM. Electromyography are conducted to measure electrical activity within muscles. If these tests cannot identify the subtype of CM, a muscle biopsy can be done for a closer examination of the microscopic characteristics of the tissue to best characterize which exact subtype of CM an individual might have. Molecular testing of known genes implicated in CM can assist in narrowing down a diagnosis.Nemaline Myopathy
NM displays characteristic rod bodies in muscle that appear threadlike in longitudinal sections. In nemaline myopathy, creatine kinase levels are usually normal or slightly elevated. Electromyography may show changes in action potentials, indicative of a myopathy. If other tests are unsuccessful a muscle biopsy can confirm a diagnosis of nemaline myopathy.Core Myopathy
Clinical features of core myopathy include presentation in the neonatal period but it may not be identified until later in infancy. It is characterized by hypotonia and muscle weakness, predominantly in the proximal extremities (i.e. biceps, thighs). Clinical progression of weakness can occur but those with core myopathy generally do not have progressive disease. Laboratory studies are not useful in diagnosis and the diagnosis must be confirmed by muscle biopsy.Centronuclear Myopathy
Centronuclear myopathy subtypes are characterized by muscle fibers with central nuclei. One of two major clinical presentations can identify centronuclear myopathy. Certain symptoms can be indicative of centronuclear myopathy subtypes.The more common form, also the most severe, is X-linked myotubular myopathy that occurs predominantly in males. The signs in infants include hypotonia, skeletal muscle weakness and respiratory muscle impairment leading to respiratory failure, which are components of the most severe clinical presentations. Impaired bulbar muscle function can lead to facial weakness, which can be associated with difficulty feeding, or to extraocular muscle weakness. Female carriers can present with limb girdle weakness as well as marked facial weakness.A less common presentation of CNM occurs with autosomal dominant or recessive inheritance, presenting with mild weakness and hypotonia, which may be unrecognizable in infants. Unlike the more severe form (XLMTM), this type can be present in both males and females. Laboratory testing of creatine kinase often reveals normal levels although it is occasionally mildly elevated. The use of electromyography can be useful in detecting action potential changes however; diagnosis is confirmed by muscle biopsy or molecular genetic testing.Congenital Fiber Type Disproportion
Clinical presentations of this myopathy include disproportions in the number and size of fast and slow twitch muscles, along with weakness of the limbs, neck, and trunk and facial muscles. Most infants are severely affected, but the degree of weakness can vary. Infants with congenital fiber type disproportion can have improvements in respiratory function as they age. The only definitive diagnosis for congenital fiber type disproportion is muscle biopsy. | 314 | Congenital Myopathy |
nord_314_6 | Therapies of Congenital Myopathy | Adults with congenital myopathy should be encouraged to get adequate exercise and to avoid unhealthy dietary and sedentary habits that may lead to obesity. Affected adults may experience episodes of mild muscle weakness, but generally there are no major physical disabilities.Medications, nutritional and respiratory support, orthopedic support, physical, occupational, or speech therapy may also be necessary to recover quality of life in affected patients. Genetic counseling is recommended for affected families. | Therapies of Congenital Myopathy. Adults with congenital myopathy should be encouraged to get adequate exercise and to avoid unhealthy dietary and sedentary habits that may lead to obesity. Affected adults may experience episodes of mild muscle weakness, but generally there are no major physical disabilities.Medications, nutritional and respiratory support, orthopedic support, physical, occupational, or speech therapy may also be necessary to recover quality of life in affected patients. Genetic counseling is recommended for affected families. | 314 | Congenital Myopathy |
nord_315_0 | Overview of Congenital Plasminogen Deficiency | SummaryCongenital type 1 plasminogen deficiency is a rare genetic disorder. Affected individuals develop thick growths, sometimes referred to as woody lesions or pseudomembranes, on the mucous membranes of the body. The mucous membranes are a moist layer of tissue that serves as a protective barrier that keeps these surfaces of the body from drying out. The mucous membranes most often affected in this disorder are those lining the inside of the eyelids and the front of the eye (called the conjunctiva) and the inside of the mouth. Other mucous membranes can be affected, including those lining the nose, middle ear, stomach and intestines (gastrointestinal tract), respiratory tract and the female genital tract. The disorder can also affect the kidneys and the brain. Without treatment, the abnormal growths that form on these surfaces can cause significant complications and they usually recur if they are removed without replacement of plasminogen. The overall severity of the disorder can vary greatly from one person to another and depends on the location and duration of lesions. The disorder is caused by alterations in the PLG gene, which leads to a deficiency of the plasminogen enzyme.IntroductionTwo types of plasminogen deficiency are described in the medical literature. Congenital type 1 plasminogen deficiency is a quantitative disorder with parallel reductions in both the level of immunoreactive and functional plasminogen; type1 plasminogen deficiency is also called hypoplasminogenemia, and is a severe disorder and the condition primarily discussed in this report. Congenital type II plasminogen deficiency is a qualitative deficiency with a normal or near normal plasminogen immunoreactive plasminogen level with decreased activity and is also called dysplasminogenemia; type II plasminogen deficiency is not associated with the development of pseudomembranes and is therefore not discussed. | Overview of Congenital Plasminogen Deficiency. SummaryCongenital type 1 plasminogen deficiency is a rare genetic disorder. Affected individuals develop thick growths, sometimes referred to as woody lesions or pseudomembranes, on the mucous membranes of the body. The mucous membranes are a moist layer of tissue that serves as a protective barrier that keeps these surfaces of the body from drying out. The mucous membranes most often affected in this disorder are those lining the inside of the eyelids and the front of the eye (called the conjunctiva) and the inside of the mouth. Other mucous membranes can be affected, including those lining the nose, middle ear, stomach and intestines (gastrointestinal tract), respiratory tract and the female genital tract. The disorder can also affect the kidneys and the brain. Without treatment, the abnormal growths that form on these surfaces can cause significant complications and they usually recur if they are removed without replacement of plasminogen. The overall severity of the disorder can vary greatly from one person to another and depends on the location and duration of lesions. The disorder is caused by alterations in the PLG gene, which leads to a deficiency of the plasminogen enzyme.IntroductionTwo types of plasminogen deficiency are described in the medical literature. Congenital type 1 plasminogen deficiency is a quantitative disorder with parallel reductions in both the level of immunoreactive and functional plasminogen; type1 plasminogen deficiency is also called hypoplasminogenemia, and is a severe disorder and the condition primarily discussed in this report. Congenital type II plasminogen deficiency is a qualitative deficiency with a normal or near normal plasminogen immunoreactive plasminogen level with decreased activity and is also called dysplasminogenemia; type II plasminogen deficiency is not associated with the development of pseudomembranes and is therefore not discussed. | 315 | Congenital Plasminogen Deficiency |
nord_315_1 | Symptoms of Congenital Plasminogen Deficiency | The signs and symptoms of type 1 plasminogen deficiency can vary from one person to another, even among members of the same family with the same genetic variants and levels. Oftentimes, initial signs present in infants or young children. Symptoms may be persistent and lifelong, may wax and wane or be intermittent or may not appear until later in life. Some individuals appear to remain asymptomatic and may be diagnosed based upon testing of clinically apparent family members. Lesions may develop spontaneously or be ‘triggered’ by infection, trauma or injury and may be localized to one area of the body or affect multiple body systems.The most common and well recognized symptom is ligneous conjunctivitis. Conjunctivitis refers to inflammation of the conjunctiva, the membrane that lines the eyes. Ligneous is a term that means ‘resembling wood’. People with ligneous conjunctivitis have growths or lesions on the conjunctiva that are yellow, white or red and have a texture that resembles wood. These growths most often appear on the inside of the eyelid and may be preceded by redness of the conjunctiva. Sometimes, the cornea (the thin, transparent membrane that covers the front of the eye) may become be damaged by the lesions and cause scarring. Ultimately, a loss of vision can occur.The second most common symptom is ligneous gingivitis, where ligneous growths appear on the gums and cause inflammation. They are usually not painful but can lead to a loss tissue and ultimately of teeth.Growths can also form in the mucous membranes of the middle ear, nose, throat, vocal cords, larynx, respiratory tract, gastrointestinal tract and the female genital tract. Growths in the middle ear can lead to what appears as chronic middle ear infection (otitis media) and hearing loss. Growths in the gastrointestinal tract may result in ulcers or what appears as an inflammatory bowel disease. Growths in the respiratory tract can lead to serious complications, including recurrent pneumonia and obstruction of the airways, which can be life-threatening, especially in small children. Growths can occur in the renal tubules of the kidney and lead to obstruction and poor kidney function. When growths occur in the female genital tract, they can lead to pain with menses, intercourse and infertility.When growths affect the skin, the condition is called juvenile colloid milium and is characterized by small, translucent, yellow-brown bumps (papules). These growths usually occur on areas of the skin that are most exposed to the sun.Some children with congenital type I plasminogen deficiency can develop a condition called occlusive hydrocephalus when lesions obstruct the flow of cerebral spinal fluid (CSF) in the central nervous system. This results in the accumulation of CSF in the skull because the fluid cannot drain properly. This causes pressure on the tissues of the brain.In earlier reports in the medical literature, physicians speculated that affected individuals were at risk for the development of blood clots (thrombosis). However, most evidence suggests that congenital type I plasminogen deficiency does not increase the risk of developing a blood clot.Type I congenital plasminogen deficiency is life-long disorder that without adequate therapy can be associated with significant morbidity and disability and in some cases may be life threatening. | Symptoms of Congenital Plasminogen Deficiency. The signs and symptoms of type 1 plasminogen deficiency can vary from one person to another, even among members of the same family with the same genetic variants and levels. Oftentimes, initial signs present in infants or young children. Symptoms may be persistent and lifelong, may wax and wane or be intermittent or may not appear until later in life. Some individuals appear to remain asymptomatic and may be diagnosed based upon testing of clinically apparent family members. Lesions may develop spontaneously or be ‘triggered’ by infection, trauma or injury and may be localized to one area of the body or affect multiple body systems.The most common and well recognized symptom is ligneous conjunctivitis. Conjunctivitis refers to inflammation of the conjunctiva, the membrane that lines the eyes. Ligneous is a term that means ‘resembling wood’. People with ligneous conjunctivitis have growths or lesions on the conjunctiva that are yellow, white or red and have a texture that resembles wood. These growths most often appear on the inside of the eyelid and may be preceded by redness of the conjunctiva. Sometimes, the cornea (the thin, transparent membrane that covers the front of the eye) may become be damaged by the lesions and cause scarring. Ultimately, a loss of vision can occur.The second most common symptom is ligneous gingivitis, where ligneous growths appear on the gums and cause inflammation. They are usually not painful but can lead to a loss tissue and ultimately of teeth.Growths can also form in the mucous membranes of the middle ear, nose, throat, vocal cords, larynx, respiratory tract, gastrointestinal tract and the female genital tract. Growths in the middle ear can lead to what appears as chronic middle ear infection (otitis media) and hearing loss. Growths in the gastrointestinal tract may result in ulcers or what appears as an inflammatory bowel disease. Growths in the respiratory tract can lead to serious complications, including recurrent pneumonia and obstruction of the airways, which can be life-threatening, especially in small children. Growths can occur in the renal tubules of the kidney and lead to obstruction and poor kidney function. When growths occur in the female genital tract, they can lead to pain with menses, intercourse and infertility.When growths affect the skin, the condition is called juvenile colloid milium and is characterized by small, translucent, yellow-brown bumps (papules). These growths usually occur on areas of the skin that are most exposed to the sun.Some children with congenital type I plasminogen deficiency can develop a condition called occlusive hydrocephalus when lesions obstruct the flow of cerebral spinal fluid (CSF) in the central nervous system. This results in the accumulation of CSF in the skull because the fluid cannot drain properly. This causes pressure on the tissues of the brain.In earlier reports in the medical literature, physicians speculated that affected individuals were at risk for the development of blood clots (thrombosis). However, most evidence suggests that congenital type I plasminogen deficiency does not increase the risk of developing a blood clot.Type I congenital plasminogen deficiency is life-long disorder that without adequate therapy can be associated with significant morbidity and disability and in some cases may be life threatening. | 315 | Congenital Plasminogen Deficiency |
nord_315_2 | Causes of Congenital Plasminogen Deficiency | Type I congenital plasminogen deficiency is an autosomal recessive genetic disorder caused by alterations in the plasminogen (PLG) gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a pathogenic genetic variant of a gene occurs, the protein product may be faulty, inefficient or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.The PLG gene contains instructions for creating the protein plasminogen. Alterations in the PLG gene may result in a quantitative deficiency of plasminogen (type I plasminogen deficiency). Plasminogen is activated by other enzymes into plasmin, the main enzyme involved in fibrinolysis. Plasmin has several functions in the body. For example, plasmin breaks down another protein called fibrin through the process known as fibrinolysis. Fibrin is an important protein in blood clotting and wound healing. Because of the lack of plasminogen, fibrin abnormally accumulates in the body, causing local inflammation and the development of ligneous growths that characterize type I congenital plasminogen deficiency.A variety of pathogenic variants in the PLG gene can lead to type I congenital plasminogen deficiency. Research is underway to develop severity levels that may help predict clinical course. This in turn will help determine the best treatment approaches. At this time, the specific PLG mutations do not predict clinical course; however the K38E variant appears to be associated with a more mild disease course.Type I congenital plasminogen deficiency is inherited in an autosomal recessive pattern. Recessive disorders occur when an individual inherits two copies of a pathogenic gene variant for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. Affected individuals may have two copies of the same pathogenic variant (homozygous) or two different pathogenic variants in the gene (compound heterozygous). | Causes of Congenital Plasminogen Deficiency. Type I congenital plasminogen deficiency is an autosomal recessive genetic disorder caused by alterations in the plasminogen (PLG) gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a pathogenic genetic variant of a gene occurs, the protein product may be faulty, inefficient or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.The PLG gene contains instructions for creating the protein plasminogen. Alterations in the PLG gene may result in a quantitative deficiency of plasminogen (type I plasminogen deficiency). Plasminogen is activated by other enzymes into plasmin, the main enzyme involved in fibrinolysis. Plasmin has several functions in the body. For example, plasmin breaks down another protein called fibrin through the process known as fibrinolysis. Fibrin is an important protein in blood clotting and wound healing. Because of the lack of plasminogen, fibrin abnormally accumulates in the body, causing local inflammation and the development of ligneous growths that characterize type I congenital plasminogen deficiency.A variety of pathogenic variants in the PLG gene can lead to type I congenital plasminogen deficiency. Research is underway to develop severity levels that may help predict clinical course. This in turn will help determine the best treatment approaches. At this time, the specific PLG mutations do not predict clinical course; however the K38E variant appears to be associated with a more mild disease course.Type I congenital plasminogen deficiency is inherited in an autosomal recessive pattern. Recessive disorders occur when an individual inherits two copies of a pathogenic gene variant for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. Affected individuals may have two copies of the same pathogenic variant (homozygous) or two different pathogenic variants in the gene (compound heterozygous). | 315 | Congenital Plasminogen Deficiency |
nord_315_3 | Affects of Congenital Plasminogen Deficiency | Type 1 congenital plasminogen deficiency is a rare disorder that occurs worldwide. Slightly more females have been identified than males. The exact incidence or prevalence of the disorder is not completely established, but the current best estimate places the incidence at 1.6 people per 1,000,000 in the general population. Incidence is the rate of new or newly diagnosed people with a disorder. Prevalence is the overall number of people who have the disorder at a given time. People with no symptoms or a mild case with localized symptoms may remain undiagnosed. | Affects of Congenital Plasminogen Deficiency. Type 1 congenital plasminogen deficiency is a rare disorder that occurs worldwide. Slightly more females have been identified than males. The exact incidence or prevalence of the disorder is not completely established, but the current best estimate places the incidence at 1.6 people per 1,000,000 in the general population. Incidence is the rate of new or newly diagnosed people with a disorder. Prevalence is the overall number of people who have the disorder at a given time. People with no symptoms or a mild case with localized symptoms may remain undiagnosed. | 315 | Congenital Plasminogen Deficiency |
nord_315_4 | Related disorders of Congenital Plasminogen Deficiency | Related disorders of Congenital Plasminogen Deficiency. | 315 | Congenital Plasminogen Deficiency |
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nord_315_5 | Diagnosis of Congenital Plasminogen Deficiency | A diagnosis of congenital plasminogen deficiency is based upon identification of characteristic symptoms, family medical history, detailed patient history and a thorough clinical evaluation. Some affected individuals may be identified due to another family member’s diagnosis even if they are without symptoms. Diagnosis is confirmed by specific laboratory tests that measure the activity and immunoreactive level (also called the antigen level) of plasminogen; the activity level is decreased while the immunoreactive level is normal or near normal. These tests are available in most clinical coagulation laboratories.Molecular genetic testing can confirm the diagnosis. Molecular genetic testing can detect alterations in the PLG gene known to cause the disorder but is available as a diagnostic service only at specialized laboratories. | Diagnosis of Congenital Plasminogen Deficiency. A diagnosis of congenital plasminogen deficiency is based upon identification of characteristic symptoms, family medical history, detailed patient history and a thorough clinical evaluation. Some affected individuals may be identified due to another family member’s diagnosis even if they are without symptoms. Diagnosis is confirmed by specific laboratory tests that measure the activity and immunoreactive level (also called the antigen level) of plasminogen; the activity level is decreased while the immunoreactive level is normal or near normal. These tests are available in most clinical coagulation laboratories.Molecular genetic testing can confirm the diagnosis. Molecular genetic testing can detect alterations in the PLG gene known to cause the disorder but is available as a diagnostic service only at specialized laboratories. | 315 | Congenital Plasminogen Deficiency |
nord_315_6 | Therapies of Congenital Plasminogen Deficiency | TreatmentIn 2021, the U.S. Food and Drug Administration (FDA) approved Ryplazim (generic name plasminogen, human-tvmh), the first treatment for patients with type I plasminogen deficiency. Ryplazim is a plasminogen concentrate purified from human plasma and administered as an IV infusion. Treatment with Ryplazim increases the plasma level of plasminogen, temporarily correcting the deficiency and reducing or resolving lesions. It has been found to be effective in patients who haven't responded to other treatments. Various other therapies have been tried to treat individuals with type I congenital plasminogen deficiency. Surgical removal of the growths may be beneficial initially, but the growths usually recur if the patient is not treated with some form of plasminogen. Several medications have been tried, including high-dose intravenous corticosteroid treatment, heparin, cyclosporine, azathioprine, hyaluronidase and α-chymotrypsin. There is a report of oral contraceptives leading to an increase of plasminogen level in one woman. These therapies have shown no or only limited benefit, or have been reported to be beneficial in only single cases.Fresh frozen plasma has also been used as a treatment for plasminogen deficiency. Plasma is a component of blood that's been separated from red and white blood cells and contains water, salt, proteins and enzymes, including plasminogen. It has been administered as an IV infusion when multiple body systems are affected or as eye drops and eye injections for ligneous conjunctivitis. When administered intravenously, fluid overload, or too much water in the body, may become a concern. Fluid overload (hypervolemia) can affect the lungs and heart, making breathing difficult and damaging heart muscles. In addition, some people develop reactions to fresh frozen plasma, usually to some other protein component of the plasma that also may make infusions difficult. Treatment with plasminogen concentrate is a better treatment option.Some children with hydrocephalus may require surgical implantation of a shunt to drain away excess cerebrospinal fluid. Treatment should be coordinated by a hematologist who is knowledgeable about the disorder. There is a network of hemophilia treatment centers in the United States that is skilled in the treatment of coagulation factor deficiencies and the use of replacement therapies. In addition, these physicians will coordinate efforts of a team of needed specialists depending upon the specific organ system involved. For example, pediatricians, ophthalmologists, dental specialists, lung specialists (pulmonologists) and other health care professionals may need to systematically and comprehensively plan an affected child’s treatment. Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well. | Therapies of Congenital Plasminogen Deficiency. TreatmentIn 2021, the U.S. Food and Drug Administration (FDA) approved Ryplazim (generic name plasminogen, human-tvmh), the first treatment for patients with type I plasminogen deficiency. Ryplazim is a plasminogen concentrate purified from human plasma and administered as an IV infusion. Treatment with Ryplazim increases the plasma level of plasminogen, temporarily correcting the deficiency and reducing or resolving lesions. It has been found to be effective in patients who haven't responded to other treatments. Various other therapies have been tried to treat individuals with type I congenital plasminogen deficiency. Surgical removal of the growths may be beneficial initially, but the growths usually recur if the patient is not treated with some form of plasminogen. Several medications have been tried, including high-dose intravenous corticosteroid treatment, heparin, cyclosporine, azathioprine, hyaluronidase and α-chymotrypsin. There is a report of oral contraceptives leading to an increase of plasminogen level in one woman. These therapies have shown no or only limited benefit, or have been reported to be beneficial in only single cases.Fresh frozen plasma has also been used as a treatment for plasminogen deficiency. Plasma is a component of blood that's been separated from red and white blood cells and contains water, salt, proteins and enzymes, including plasminogen. It has been administered as an IV infusion when multiple body systems are affected or as eye drops and eye injections for ligneous conjunctivitis. When administered intravenously, fluid overload, or too much water in the body, may become a concern. Fluid overload (hypervolemia) can affect the lungs and heart, making breathing difficult and damaging heart muscles. In addition, some people develop reactions to fresh frozen plasma, usually to some other protein component of the plasma that also may make infusions difficult. Treatment with plasminogen concentrate is a better treatment option.Some children with hydrocephalus may require surgical implantation of a shunt to drain away excess cerebrospinal fluid. Treatment should be coordinated by a hematologist who is knowledgeable about the disorder. There is a network of hemophilia treatment centers in the United States that is skilled in the treatment of coagulation factor deficiencies and the use of replacement therapies. In addition, these physicians will coordinate efforts of a team of needed specialists depending upon the specific organ system involved. For example, pediatricians, ophthalmologists, dental specialists, lung specialists (pulmonologists) and other health care professionals may need to systematically and comprehensively plan an affected child’s treatment. Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well. | 315 | Congenital Plasminogen Deficiency |
nord_316_0 | Overview of Congenital Pulmonary Lymphangiectasia | Congenital pulmonary lymphangiectasia (CPL) is a rare developmental disorder that is present at birth (congenital). Affected infants have abnormally widened (dilated) lymphatic vessels within the lungs. The lymphatic system helps the immune system in protecting the body against infection and disease. It consists of a network of tubular channels (lymph vessels) that drain a thin watery fluid known as lymph from different areas of the body into the bloodstream. Lymph accumulates in the tiny spaces between tissue cells and contains proteins, fats, and certain white blood cells known as lymphocytes.Infants with CPL often develop severe, potentially life-threatening, respiratory distress shortly after birth. Affected infants may also develop cyanosis, a condition marked by abnormal bluish discoloration of the skin that occurs because of low levels of circulating oxygen in the blood. The exact cause of CPL is unknown.CPL can occur as a primary or secondary disorder. Primary pulmonary lymphangiectasia can occur as isolated congenital defect within the lungs or as part of a generalized form of lymphatic vessel malformation (lymphangiectasia) that affects the entire body, usually associated with generalized lymphedema. Secondary CPL occurs secondary to a variety of heart (cardiac) abnormalities, and/or lymphatic obstructive forms. | Overview of Congenital Pulmonary Lymphangiectasia. Congenital pulmonary lymphangiectasia (CPL) is a rare developmental disorder that is present at birth (congenital). Affected infants have abnormally widened (dilated) lymphatic vessels within the lungs. The lymphatic system helps the immune system in protecting the body against infection and disease. It consists of a network of tubular channels (lymph vessels) that drain a thin watery fluid known as lymph from different areas of the body into the bloodstream. Lymph accumulates in the tiny spaces between tissue cells and contains proteins, fats, and certain white blood cells known as lymphocytes.Infants with CPL often develop severe, potentially life-threatening, respiratory distress shortly after birth. Affected infants may also develop cyanosis, a condition marked by abnormal bluish discoloration of the skin that occurs because of low levels of circulating oxygen in the blood. The exact cause of CPL is unknown.CPL can occur as a primary or secondary disorder. Primary pulmonary lymphangiectasia can occur as isolated congenital defect within the lungs or as part of a generalized form of lymphatic vessel malformation (lymphangiectasia) that affects the entire body, usually associated with generalized lymphedema. Secondary CPL occurs secondary to a variety of heart (cardiac) abnormalities, and/or lymphatic obstructive forms. | 316 | Congenital Pulmonary Lymphangiectasia |
nord_316_1 | Symptoms of Congenital Pulmonary Lymphangiectasia | Much of the older medical literature suggests that CPL has an extremely high mortality rate. However, recent studies suggest that the disorder does not have as poor a prognosis as described and that symptoms may improve with age in some cases. Symptoms associated with CPL often develop during the newborn (neonatal) period shortly after birth. During intrauterine period, the occurrence of non-immune hydrops fetalis associated with pleural effusion may be linked to CPL. In some cases, symptoms develop later during infancy. The symptoms of CPL vary in severity from case to case; in most cases, the earlier the presentation the more severe the symptoms. Affected infants often develop severe respiratory failure and abnormal bluish discoloration of the skin that occurs because of low levels of circulating oxygen in the blood (cyanosis). Infants with CPL may also exhibit coughing or wheezing, progressive difficulty breathing (dyspnea), coughing up blood (hemoptysis), and swelling due to accumulation of lymphatic fluid (lymphedema). Affected infants may exhibit growth failure during infancy. Additional symptoms eventually develop including an abnormally rapid rate of breathing (tachypnea), chylous pleural effusion, known as chylothorax and recurrent respiratory infections. Chyle is a fat-laden cloudy fluid that is absorbed during digestion by the lymphatic vessels located around the intestine. Chylothorax is the accumulation of chyle or lymph fluid in the pleural cavity. Chyle is composed by fats (mainly phospholipids), proteins (albumin in particular), and a significant amount of lymphocytes. Chyle normally flows through lymphatic vessels into the upper chest (thoracic duct) and is then deposited into veins, where it mixes with blood. In some cases, chyle may accumulate in the abdomen causing chylous ascites. Some infants with CPL may develop heart abnormalities including a limited ability to circulate blood to the lungs and the rest of the body resulting in fluid buildup in the heart, lung and various body tissues (congestive heart failure).Some infants with CPL develop gastroesophageal reflux, a digestive disorder characterized by the passage or flowing back (reflux) of the contents of the stomach or small intestines (duodenum) into the esophagus. The esophagus is the tube that carries food from the mouth to the stomach (esophagus). Symptoms of gastroesophageal reflux may include a sensation of warmth or burning rising up to the neck area (heartburn or pyrosis), swallowing difficulties (dysphagia), and chest pain. This problem is a possible complication of CPL, but not a direct consequence or typical symptom. | Symptoms of Congenital Pulmonary Lymphangiectasia. Much of the older medical literature suggests that CPL has an extremely high mortality rate. However, recent studies suggest that the disorder does not have as poor a prognosis as described and that symptoms may improve with age in some cases. Symptoms associated with CPL often develop during the newborn (neonatal) period shortly after birth. During intrauterine period, the occurrence of non-immune hydrops fetalis associated with pleural effusion may be linked to CPL. In some cases, symptoms develop later during infancy. The symptoms of CPL vary in severity from case to case; in most cases, the earlier the presentation the more severe the symptoms. Affected infants often develop severe respiratory failure and abnormal bluish discoloration of the skin that occurs because of low levels of circulating oxygen in the blood (cyanosis). Infants with CPL may also exhibit coughing or wheezing, progressive difficulty breathing (dyspnea), coughing up blood (hemoptysis), and swelling due to accumulation of lymphatic fluid (lymphedema). Affected infants may exhibit growth failure during infancy. Additional symptoms eventually develop including an abnormally rapid rate of breathing (tachypnea), chylous pleural effusion, known as chylothorax and recurrent respiratory infections. Chyle is a fat-laden cloudy fluid that is absorbed during digestion by the lymphatic vessels located around the intestine. Chylothorax is the accumulation of chyle or lymph fluid in the pleural cavity. Chyle is composed by fats (mainly phospholipids), proteins (albumin in particular), and a significant amount of lymphocytes. Chyle normally flows through lymphatic vessels into the upper chest (thoracic duct) and is then deposited into veins, where it mixes with blood. In some cases, chyle may accumulate in the abdomen causing chylous ascites. Some infants with CPL may develop heart abnormalities including a limited ability to circulate blood to the lungs and the rest of the body resulting in fluid buildup in the heart, lung and various body tissues (congestive heart failure).Some infants with CPL develop gastroesophageal reflux, a digestive disorder characterized by the passage or flowing back (reflux) of the contents of the stomach or small intestines (duodenum) into the esophagus. The esophagus is the tube that carries food from the mouth to the stomach (esophagus). Symptoms of gastroesophageal reflux may include a sensation of warmth or burning rising up to the neck area (heartburn or pyrosis), swallowing difficulties (dysphagia), and chest pain. This problem is a possible complication of CPL, but not a direct consequence or typical symptom. | 316 | Congenital Pulmonary Lymphangiectasia |
nord_316_2 | Causes of Congenital Pulmonary Lymphangiectasia | The exact cause of CPL is unknown. Most cases occur randomly, for no apparent reason (sporadically). The disorder may be caused by a congenital defect in the development of the lung or result from obstruction of the lymph vessels in the lungs (pulmonary lymphatics). Some cases have been associated with genetic multisystem disorders including Noonan syndrome, Turner syndrome, Hennekam syndrome or Fryns syndrome. CPL may be inherited as dominant, recessive, or X-linked inheritance pattern. 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 like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary 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.X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and manifest mostly in males. Females that have a defective gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the defective gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a defective gene he will develop the disease.Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son. If a male with X-linked disorders is able to reproduce, he will pass the defective 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. Pulmonary lymphangiectasia may occur as a secondary condition to a variety of heart (cardiac) disorders including hypoplastic left heart syndrome, cor triatum, and congenital mitral valve stenosis. Infectious agents have also been suggested as a possible cause of this disorder. | Causes of Congenital Pulmonary Lymphangiectasia. The exact cause of CPL is unknown. Most cases occur randomly, for no apparent reason (sporadically). The disorder may be caused by a congenital defect in the development of the lung or result from obstruction of the lymph vessels in the lungs (pulmonary lymphatics). Some cases have been associated with genetic multisystem disorders including Noonan syndrome, Turner syndrome, Hennekam syndrome or Fryns syndrome. CPL may be inherited as dominant, recessive, or X-linked inheritance pattern. 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 like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary 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.X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and manifest mostly in males. Females that have a defective gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the defective gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a defective gene he will develop the disease.Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son. If a male with X-linked disorders is able to reproduce, he will pass the defective 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. Pulmonary lymphangiectasia may occur as a secondary condition to a variety of heart (cardiac) disorders including hypoplastic left heart syndrome, cor triatum, and congenital mitral valve stenosis. Infectious agents have also been suggested as a possible cause of this disorder. | 316 | Congenital Pulmonary Lymphangiectasia |
nord_316_3 | Affects of Congenital Pulmonary Lymphangiectasia | According to some reports CPL occurs more often in males than females. However, the data is not conclusive and CPL may occur in males and females in equal numbers. The exact number of cases of CPL is unknown. In the past, the disorder was associated with high mortality in the newborn period. CPL was first described in the medical literature in 1856. | Affects of Congenital Pulmonary Lymphangiectasia. According to some reports CPL occurs more often in males than females. However, the data is not conclusive and CPL may occur in males and females in equal numbers. The exact number of cases of CPL is unknown. In the past, the disorder was associated with high mortality in the newborn period. CPL was first described in the medical literature in 1856. | 316 | Congenital Pulmonary Lymphangiectasia |
nord_316_4 | Related disorders of Congenital Pulmonary Lymphangiectasia | Symptoms of the following disorders can be similar to those of CPL. Comparisons may be useful for a differential diagnosis.There are many disorders or conditions that cause respiratory distress syndrome is infants including lung infections, interstitial lung disease, idiopathic interstitial lung pneumonitis, follicular bronchiolitis, pulmonary alveolar proteinosis, idiopathic pulmonary hemosiderosis and lymphangiomatosis. (For more information, choose the specific disease name as your search term in the Rare Disease Database.)Pulmonary lymphangiectasia may occur as part of a specific syndrome including Noonan syndrome, yellow nail syndrome, intestinal lymphangiectasia, Hennekam syndrome, Turner syndrome, Fryns syndrome, PEHO syndrome, and idiopathic hydrops fetalis. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | Related disorders of Congenital Pulmonary Lymphangiectasia. Symptoms of the following disorders can be similar to those of CPL. Comparisons may be useful for a differential diagnosis.There are many disorders or conditions that cause respiratory distress syndrome is infants including lung infections, interstitial lung disease, idiopathic interstitial lung pneumonitis, follicular bronchiolitis, pulmonary alveolar proteinosis, idiopathic pulmonary hemosiderosis and lymphangiomatosis. (For more information, choose the specific disease name as your search term in the Rare Disease Database.)Pulmonary lymphangiectasia may occur as part of a specific syndrome including Noonan syndrome, yellow nail syndrome, intestinal lymphangiectasia, Hennekam syndrome, Turner syndrome, Fryns syndrome, PEHO syndrome, and idiopathic hydrops fetalis. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | 316 | Congenital Pulmonary Lymphangiectasia |
nord_316_5 | Diagnosis of Congenital Pulmonary Lymphangiectasia | A diagnosis of CPL may be made based upon a thorough clinical evaluation, identification of characteristic symptoms and a variety of specialized imaging tests. These may include high resolution helical chest computed tomography (CT) scans. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of an organ's tissue structure. In individuals with CPL, CT scans may reveal fluid build up in the chest cavity or lung tissue, showing the characteristic diffuse thickening of the interstitium. An imaging procedure called lymphoscintigraphy may be used to provide pictures of the lymphatic system, and it is very useful to detect diffuse aspects of congenital lymphatic dysplasia, such as lymphedema.If pleural effusion is present, bronchoscopy and lung biopsy may be considered. During bronchoscopy, a thin, flexible tube (bronchoscope) is inserted through the nose or mouth, allowing a physician to examine the throat, larynx, trachea and lower airways. Lung biopsy involves the surgical removal and microscopic evaluation of affected lung tissue. | Diagnosis of Congenital Pulmonary Lymphangiectasia. A diagnosis of CPL may be made based upon a thorough clinical evaluation, identification of characteristic symptoms and a variety of specialized imaging tests. These may include high resolution helical chest computed tomography (CT) scans. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of an organ's tissue structure. In individuals with CPL, CT scans may reveal fluid build up in the chest cavity or lung tissue, showing the characteristic diffuse thickening of the interstitium. An imaging procedure called lymphoscintigraphy may be used to provide pictures of the lymphatic system, and it is very useful to detect diffuse aspects of congenital lymphatic dysplasia, such as lymphedema.If pleural effusion is present, bronchoscopy and lung biopsy may be considered. During bronchoscopy, a thin, flexible tube (bronchoscope) is inserted through the nose or mouth, allowing a physician to examine the throat, larynx, trachea and lower airways. Lung biopsy involves the surgical removal and microscopic evaluation of affected lung tissue. | 316 | Congenital Pulmonary Lymphangiectasia |
nord_316_6 | Therapies of Congenital Pulmonary Lymphangiectasia | TreatmentThe treatment of CPL is symptomatic and supportive. Newborns with serious complications may require a variety of procedures shortly after birth including the use of a machine that creates a controlled flow of air (continuous positive airway pressure, CPAP) to an affected individual's airways to support spontaneous breathing or the placement of a tube into the windpipe (trachea) to assist breathing performing mechanical ventilation (tracheal intubation). In some cases, at birth the immediate drainage of excess fluid from the chest cavity (pleural effusion) with assisted ventilation may improve respiratory distress. A chest tube may be inserted to drain fluid in some cases.As affected infants age supplemental oxygen may be necessary. Symptomatic treatment for associated conditions such as coughing, wheezing and recurrent infections may also be necessary. Affected children should be monitored for the development of bronchitis. Since nutritional considerations can play a role in limiting lymphatic production, nutritional supplementation may also be recommended.Since nutritional considerations can play a role in limiting lymphatic production, nutritional supplementation with Medium Chain Triglycerides (MCT) may also be recommended | Therapies of Congenital Pulmonary Lymphangiectasia. TreatmentThe treatment of CPL is symptomatic and supportive. Newborns with serious complications may require a variety of procedures shortly after birth including the use of a machine that creates a controlled flow of air (continuous positive airway pressure, CPAP) to an affected individual's airways to support spontaneous breathing or the placement of a tube into the windpipe (trachea) to assist breathing performing mechanical ventilation (tracheal intubation). In some cases, at birth the immediate drainage of excess fluid from the chest cavity (pleural effusion) with assisted ventilation may improve respiratory distress. A chest tube may be inserted to drain fluid in some cases.As affected infants age supplemental oxygen may be necessary. Symptomatic treatment for associated conditions such as coughing, wheezing and recurrent infections may also be necessary. Affected children should be monitored for the development of bronchitis. Since nutritional considerations can play a role in limiting lymphatic production, nutritional supplementation may also be recommended.Since nutritional considerations can play a role in limiting lymphatic production, nutritional supplementation with Medium Chain Triglycerides (MCT) may also be recommended | 316 | Congenital Pulmonary Lymphangiectasia |
nord_317_0 | Overview of Congenital Sucrase-Isomaltase Deficiency | Congenital sucrase-isomaltase deficiency (CSID) is a rare inherited metabolic disorder characterized by the deficiency or absence of the enzymes sucrase and isomaltase. This enzyme complex (sucrase-isomaltase) assists in the breakdown of a certain sugars (i.e., sucrose) and certain products of starch digestion (dextrins). The sucrase-isomaltase enzyme complex is normally found within the tiny, finger-like projections (microvilli or brush border) lining the small intestine. When this enzyme complex is deficient, nutrients based on ingested sucrose and starch cannot be absorbed properly from the gut.
Symptoms of this disorder become evident soon after sucrose or starches, as found in modified milk formulas with sucrose or polycose, are ingested by an affected infant. Breast-fed infants or those on lactose-only formula manifest no symptoms until such time as sucrose (found in fruit juices, solid foods, and/or some medications) is introduced into the diet. Symptoms are variable among affected individuals but usually include watery diarrhea, abdominal swelling (distension) and/or discomfort, among others. Intolerance to starch often disappears within the first few years of life and the symptoms of sucrose intolerance usually improve as the affected child ages. CSID is inherited as an autosomal recessive genetic trait. | Overview of Congenital Sucrase-Isomaltase Deficiency. Congenital sucrase-isomaltase deficiency (CSID) is a rare inherited metabolic disorder characterized by the deficiency or absence of the enzymes sucrase and isomaltase. This enzyme complex (sucrase-isomaltase) assists in the breakdown of a certain sugars (i.e., sucrose) and certain products of starch digestion (dextrins). The sucrase-isomaltase enzyme complex is normally found within the tiny, finger-like projections (microvilli or brush border) lining the small intestine. When this enzyme complex is deficient, nutrients based on ingested sucrose and starch cannot be absorbed properly from the gut.
Symptoms of this disorder become evident soon after sucrose or starches, as found in modified milk formulas with sucrose or polycose, are ingested by an affected infant. Breast-fed infants or those on lactose-only formula manifest no symptoms until such time as sucrose (found in fruit juices, solid foods, and/or some medications) is introduced into the diet. Symptoms are variable among affected individuals but usually include watery diarrhea, abdominal swelling (distension) and/or discomfort, among others. Intolerance to starch often disappears within the first few years of life and the symptoms of sucrose intolerance usually improve as the affected child ages. CSID is inherited as an autosomal recessive genetic trait. | 317 | Congenital Sucrase-Isomaltase Deficiency |
nord_317_1 | Symptoms of Congenital Sucrase-Isomaltase Deficiency | CSID is a rare inherited metabolic disorder characterized by the deficiency or absence of the enzymes sucrase and isomaltase. When the concentration of this enzyme complex is low or absent, the breakdown of the disaccharide sucrose and starch and the subsequent absorption of smaller molecular components cannot take place.Affected infants develop symptoms soon after they first ingest sucrose, as found in modified milk formulas, fruits, or starches. Symptoms may include explosive, watery diarrhea resulting in abnormally low levels of body fluids (dehydration), abdominal swelling (distension), and/or abdominal discomfort. In addition, some affected infants may experience malnutrition, resulting from malabsorption of essential nutrients, and/or a delay in growth and weight gain (failure to thrive), resulting from nutritional deficiencies. In some cases, individuals may exhibit irritability; colic; abrasion and/or irritation (excoriation) of the skin on the buttocks as a result of prolonged diarrhea episodes; and/or vomiting. Symptoms of this disorder vary among affected individuals. Symptoms are usually more severe in infants and young children than in adults.Symptoms of CSID may be absent in an affected infant who is breast-fed or who is on a lactose-only formula; however, as soon as sucrose is introduced into the diet through fruit juices, solid food, medications, and/or other sources, symptoms may rapidly develop. Intolerance to starch may disappear within the first few months or years of life while sucrose intolerance, responsible for most of the symptoms of this disorder, often improves as the affected child ages, exhibiting only occasional or mild symptoms in adulthood. In some cases, symptoms may not be manifested until the onset of puberty.Symptoms exhibited in infants and young children are usually more pronounced than those of the affected adults because the diet of younger individuals often includes a higher carbohydrate intake. In addition, the time it takes for intestinal digestion is less in infants or young children.
In some cases, the development of kidney stones (renal calculi) may be associated with CSID. | Symptoms of Congenital Sucrase-Isomaltase Deficiency. CSID is a rare inherited metabolic disorder characterized by the deficiency or absence of the enzymes sucrase and isomaltase. When the concentration of this enzyme complex is low or absent, the breakdown of the disaccharide sucrose and starch and the subsequent absorption of smaller molecular components cannot take place.Affected infants develop symptoms soon after they first ingest sucrose, as found in modified milk formulas, fruits, or starches. Symptoms may include explosive, watery diarrhea resulting in abnormally low levels of body fluids (dehydration), abdominal swelling (distension), and/or abdominal discomfort. In addition, some affected infants may experience malnutrition, resulting from malabsorption of essential nutrients, and/or a delay in growth and weight gain (failure to thrive), resulting from nutritional deficiencies. In some cases, individuals may exhibit irritability; colic; abrasion and/or irritation (excoriation) of the skin on the buttocks as a result of prolonged diarrhea episodes; and/or vomiting. Symptoms of this disorder vary among affected individuals. Symptoms are usually more severe in infants and young children than in adults.Symptoms of CSID may be absent in an affected infant who is breast-fed or who is on a lactose-only formula; however, as soon as sucrose is introduced into the diet through fruit juices, solid food, medications, and/or other sources, symptoms may rapidly develop. Intolerance to starch may disappear within the first few months or years of life while sucrose intolerance, responsible for most of the symptoms of this disorder, often improves as the affected child ages, exhibiting only occasional or mild symptoms in adulthood. In some cases, symptoms may not be manifested until the onset of puberty.Symptoms exhibited in infants and young children are usually more pronounced than those of the affected adults because the diet of younger individuals often includes a higher carbohydrate intake. In addition, the time it takes for intestinal digestion is less in infants or young children.
In some cases, the development of kidney stones (renal calculi) may be associated with CSID. | 317 | Congenital Sucrase-Isomaltase Deficiency |
nord_317_2 | Causes of Congenital Sucrase-Isomaltase Deficiency | CSID is inherited as an autosomal recessive genetic trait. The faulty gene has been tracked to chromosome 3 (3q25-q26).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 3q25-q26” refers to a region between band 25 and band 26 on the long arm of chromosome 3. The numbered bands specify the location of the thousands of genes that are present on each chromosome.Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.Parents of some children with CSID may exhibit some defects in sucrase-isomaltase absorption, but do not display symptoms of this disorder. These parents are said to be heterozygous for the defective sucrase-isomaltase gene. Heterozygous is the term used to describe a person who has two different genes for a particular trait, one inherited form each parent. A person heterozygous for a genetic disease caused by a dominant gene will be affected with the disease. An individual heterozygous for a genetic disorder produced by a recessive gene will not usually be affected by the disease, or will have a milder form of it.In addition, researchers have reported in the medical literature that parents of some individuals affected with CSID have been closely related by blood (consanguineous). If both parents carry the same disease gene, there is a higher than normal risk that their children may inherit the two genes necessary for the development of the disease. | Causes of Congenital Sucrase-Isomaltase Deficiency. CSID is inherited as an autosomal recessive genetic trait. The faulty gene has been tracked to chromosome 3 (3q25-q26).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 3q25-q26” refers to a region between band 25 and band 26 on the long arm of chromosome 3. The numbered bands specify the location of the thousands of genes that are present on each chromosome.Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.Parents of some children with CSID may exhibit some defects in sucrase-isomaltase absorption, but do not display symptoms of this disorder. These parents are said to be heterozygous for the defective sucrase-isomaltase gene. Heterozygous is the term used to describe a person who has two different genes for a particular trait, one inherited form each parent. A person heterozygous for a genetic disease caused by a dominant gene will be affected with the disease. An individual heterozygous for a genetic disorder produced by a recessive gene will not usually be affected by the disease, or will have a milder form of it.In addition, researchers have reported in the medical literature that parents of some individuals affected with CSID have been closely related by blood (consanguineous). If both parents carry the same disease gene, there is a higher than normal risk that their children may inherit the two genes necessary for the development of the disease. | 317 | Congenital Sucrase-Isomaltase Deficiency |
nord_317_3 | Affects of Congenital Sucrase-Isomaltase Deficiency | CSID is a metabolic disorder that affects males and females in equal numbers and is diagnosed in approximately 0.2 percent of North Americans. This disorder has a higher frequency among Greenland and Canadian Inuit populations, with a reported incidence of approximately 10 percent. In addition, researchers report a higher degree of homozygosity among these more frequently affected groups than among other groups. Also, as a diagnosis may be easily missed, especially in those individuals with mild symptoms, many researchers suspect there may be a higher incidence of this disorder than is actually reported in the medical literature. | Affects of Congenital Sucrase-Isomaltase Deficiency. CSID is a metabolic disorder that affects males and females in equal numbers and is diagnosed in approximately 0.2 percent of North Americans. This disorder has a higher frequency among Greenland and Canadian Inuit populations, with a reported incidence of approximately 10 percent. In addition, researchers report a higher degree of homozygosity among these more frequently affected groups than among other groups. Also, as a diagnosis may be easily missed, especially in those individuals with mild symptoms, many researchers suspect there may be a higher incidence of this disorder than is actually reported in the medical literature. | 317 | Congenital Sucrase-Isomaltase Deficiency |
nord_317_4 | Related disorders of Congenital Sucrase-Isomaltase Deficiency | Symptoms of the following disorders can be similar to those of CSID. Comparisons may be useful for a differential diagnosis:Congenital lactase deficiency (lactose intolerance) is an extremely rare metabolic disorder characterized by the severe deficiency or absence of the enzyme lactase. This enzyme, found in the brush border membrane of the intestine, aids in the breakdown of the disaccharide lactose, found in mother’s milk. Symptoms appear within a few hours or days of birth and may include severe diarrhea with dehydration, malnutrition, undigested lactose in the stool, and/or excoriation of the skin of the buttocks. Research has shown that affected children exhibit normal progress in growth and development when kept on a lactose-free diet. In addition, an adult form of inherited lactase deficiency is quite common among the world’s population. Symptoms of this adult-onset disorder may include abdominal pain, abnormal amounts of gas or air in the digestive system (flatulence), and/or diarrhea. Both congenital and adult-onset lactase deficiency are inherited as autosomal recessive genetic traits.There are several other malabsorption disorders that are characterized by severe diarrhea, abdominal distension, dehydration, and/or other symptoms similar to those of CSID. (For more information on these disorders, choose “malabsorption” as your search term in the Rare Disease Database.) | Related disorders of Congenital Sucrase-Isomaltase Deficiency. Symptoms of the following disorders can be similar to those of CSID. Comparisons may be useful for a differential diagnosis:Congenital lactase deficiency (lactose intolerance) is an extremely rare metabolic disorder characterized by the severe deficiency or absence of the enzyme lactase. This enzyme, found in the brush border membrane of the intestine, aids in the breakdown of the disaccharide lactose, found in mother’s milk. Symptoms appear within a few hours or days of birth and may include severe diarrhea with dehydration, malnutrition, undigested lactose in the stool, and/or excoriation of the skin of the buttocks. Research has shown that affected children exhibit normal progress in growth and development when kept on a lactose-free diet. In addition, an adult form of inherited lactase deficiency is quite common among the world’s population. Symptoms of this adult-onset disorder may include abdominal pain, abnormal amounts of gas or air in the digestive system (flatulence), and/or diarrhea. Both congenital and adult-onset lactase deficiency are inherited as autosomal recessive genetic traits.There are several other malabsorption disorders that are characterized by severe diarrhea, abdominal distension, dehydration, and/or other symptoms similar to those of CSID. (For more information on these disorders, choose “malabsorption” as your search term in the Rare Disease Database.) | 317 | Congenital Sucrase-Isomaltase Deficiency |
nord_317_5 | Diagnosis of Congenital Sucrase-Isomaltase Deficiency | CSID may be suspected in any newborn infant exhibiting severe watery diarrhea after ingestion of milk-modified or glucose-polymer formula. The diagnosis of this disorder may be confirmed through clinical evaluation, characteristic findings, detailed patient history, and/or specialized testing. For example, after deliberate feeding of measured doses of sucrose, isomaltose, or its substitute, palatinose, for tolerance testing purposes, blood serum tests of an affected individual may reveal a flat serum glucose curve. In addition, blood and urine samples may reveal the presence of the disaccharide sucrose, isomaltose, or palatinose if used as a substitute during tolerance testing. The feces may exhibit sucrose, the monosaccharides glucose and fructose, and an acid ph level of below 5.0 or 6.0.Diagnostic procedures may also include enzyme tests (assays) that measure the activity of sucrase-isomaltase in the intestine. This procedure usually involves the removal of a small sample of tissue (biopsy) from a certain area or areas of the small intestine. Other tests may include a sucrose hydrogen breath test in which an abnormally high level of hydrogen will be detected in the breath of an affected individual after sucrose ingestion. | Diagnosis of Congenital Sucrase-Isomaltase Deficiency. CSID may be suspected in any newborn infant exhibiting severe watery diarrhea after ingestion of milk-modified or glucose-polymer formula. The diagnosis of this disorder may be confirmed through clinical evaluation, characteristic findings, detailed patient history, and/or specialized testing. For example, after deliberate feeding of measured doses of sucrose, isomaltose, or its substitute, palatinose, for tolerance testing purposes, blood serum tests of an affected individual may reveal a flat serum glucose curve. In addition, blood and urine samples may reveal the presence of the disaccharide sucrose, isomaltose, or palatinose if used as a substitute during tolerance testing. The feces may exhibit sucrose, the monosaccharides glucose and fructose, and an acid ph level of below 5.0 or 6.0.Diagnostic procedures may also include enzyme tests (assays) that measure the activity of sucrase-isomaltase in the intestine. This procedure usually involves the removal of a small sample of tissue (biopsy) from a certain area or areas of the small intestine. Other tests may include a sucrose hydrogen breath test in which an abnormally high level of hydrogen will be detected in the breath of an affected individual after sucrose ingestion. | 317 | Congenital Sucrase-Isomaltase Deficiency |
nord_317_6 | Therapies of Congenital Sucrase-Isomaltase Deficiency | Treatment
Treatment of CSID focuses on dietary management through a low-sucrose or sucrose-free diet. In addition, a low-starch or starch-free diet is advised in some cases, especially in the first few years of life. Some affected individuals may show signs of sucrose tolerance during the second decade of life, but many others may exhibit a life-long sucrose intolerance. Individuals affected with this disorder may benefit from ingesting fresh baker's yeast, which exhibits sucrase activity, after sucrose ingestion. Researchers suggest that the yeast be taken on a full stomach as sucrase activity is much more effective when the gastric juices are diluted.The orphan drug sacrosidase oral solution (Sucraid) has been approved by the FDA for the treatment of congenital sucrose isomaltose malabsorption. This oral solution is an enzyme replacement therapy that contains the enzyme sucrase (sacrosidase), obtained from baker's yeast and glycerin. Sucraid has been found to relieve many of the symptoms associated with sucrose ingestion by individuals with this disorder. Sacrosidase oral solution is manufactured by QOL Medical, LLC.Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive. For example, fluid and electrolyte replacement after episodes of diarrhea may be indicated to stave off dehydration and/or other associated symptoms.A team approach for infants with this disorder may be of benefit and may include pediatricians, physicians who diagnose and treat disorders of the digestive tract (gastroenterologists), specialists who will assess and plan a diet that best achieves proper growth and development (nutritionists), special social support, and other medical services. | Therapies of Congenital Sucrase-Isomaltase Deficiency. Treatment
Treatment of CSID focuses on dietary management through a low-sucrose or sucrose-free diet. In addition, a low-starch or starch-free diet is advised in some cases, especially in the first few years of life. Some affected individuals may show signs of sucrose tolerance during the second decade of life, but many others may exhibit a life-long sucrose intolerance. Individuals affected with this disorder may benefit from ingesting fresh baker's yeast, which exhibits sucrase activity, after sucrose ingestion. Researchers suggest that the yeast be taken on a full stomach as sucrase activity is much more effective when the gastric juices are diluted.The orphan drug sacrosidase oral solution (Sucraid) has been approved by the FDA for the treatment of congenital sucrose isomaltose malabsorption. This oral solution is an enzyme replacement therapy that contains the enzyme sucrase (sacrosidase), obtained from baker's yeast and glycerin. Sucraid has been found to relieve many of the symptoms associated with sucrose ingestion by individuals with this disorder. Sacrosidase oral solution is manufactured by QOL Medical, LLC.Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive. For example, fluid and electrolyte replacement after episodes of diarrhea may be indicated to stave off dehydration and/or other associated symptoms.A team approach for infants with this disorder may be of benefit and may include pediatricians, physicians who diagnose and treat disorders of the digestive tract (gastroenterologists), specialists who will assess and plan a diet that best achieves proper growth and development (nutritionists), special social support, and other medical services. | 317 | Congenital Sucrase-Isomaltase Deficiency |
nord_318_0 | Overview of Congenital Syphilis | Congenital syphilis is a chronic infectious disease caused by a spirochete (treponema pallidum) acquired by the fetus in the uterus before birth. Symptoms of this disease may not become apparent until several weeks or months after birth and, in some cases, may take years to appear. Congenital syphilis is passed on to the child from the mother who acquired the disease prior to or during pregnancy. The infant is more likely to have congenital syphilis when the mother has been infected during pregnancy although it is not uncommon for an infant to acquire congenital syphilis from a mother who was infected prior to pregnancy. Symptoms of early congenital syphilis include fever, skin problems and low birth weight. In late congenital syphilis, the symptoms of the disease do not usually become apparent until two to five years of age. In rare cases, the disease may remain latent for years with symptoms not being diagnosed until well into adulthood. | Overview of Congenital Syphilis. Congenital syphilis is a chronic infectious disease caused by a spirochete (treponema pallidum) acquired by the fetus in the uterus before birth. Symptoms of this disease may not become apparent until several weeks or months after birth and, in some cases, may take years to appear. Congenital syphilis is passed on to the child from the mother who acquired the disease prior to or during pregnancy. The infant is more likely to have congenital syphilis when the mother has been infected during pregnancy although it is not uncommon for an infant to acquire congenital syphilis from a mother who was infected prior to pregnancy. Symptoms of early congenital syphilis include fever, skin problems and low birth weight. In late congenital syphilis, the symptoms of the disease do not usually become apparent until two to five years of age. In rare cases, the disease may remain latent for years with symptoms not being diagnosed until well into adulthood. | 318 | Congenital Syphilis |
nord_318_1 | Symptoms of Congenital Syphilis | Congenital syphilis is acquired by the fetus when the treponema pallidum spirochete is present in the mother. Pregnant women with syphilis may have a reduction in estrogen while serum progesterone levels may increase. Symptoms of early congenital syphilis usually appear at three to fourteen weeks of age but may appear as late as age five years. Symptoms may include inflammation and hardening of the umbilical chord, rash, fever, low birth weight, high levels of cholesterol at birth, aseptic meningitis, anemia, monocytosis (an increase in the number of monocytes in the circulating blood), enlarged liver and spleen, jaundice (yellowish color of the skin), shedding of skin affecting the palms and soles, convulsions, mental retardation, periostitis (inflammation around the bones causing tender limbs and joints), rhinitis with an infectious nasal discharge, hair loss, inflammation of the eye's iris and pneumonia.Symptoms of late congenital syphilis usually present themselves after age five and may remain undiagnosed well into adulthood. The characteristics of late congenital syphilis may be bone pain, retinitis pigmentosa (a serious eye disease), Hutchinson's triad which is characterized by pegshaped upper central incisors (teeth), and interstitial keratitis which consists of blurred vision, abnormal tearing, eye pain and abnormal sensitivity to light, saddle nose, bony prominence of the forehead, high arched palate, short upper jawbone, nerve deafness and fissuring around the mouth and anus. | Symptoms of Congenital Syphilis. Congenital syphilis is acquired by the fetus when the treponema pallidum spirochete is present in the mother. Pregnant women with syphilis may have a reduction in estrogen while serum progesterone levels may increase. Symptoms of early congenital syphilis usually appear at three to fourteen weeks of age but may appear as late as age five years. Symptoms may include inflammation and hardening of the umbilical chord, rash, fever, low birth weight, high levels of cholesterol at birth, aseptic meningitis, anemia, monocytosis (an increase in the number of monocytes in the circulating blood), enlarged liver and spleen, jaundice (yellowish color of the skin), shedding of skin affecting the palms and soles, convulsions, mental retardation, periostitis (inflammation around the bones causing tender limbs and joints), rhinitis with an infectious nasal discharge, hair loss, inflammation of the eye's iris and pneumonia.Symptoms of late congenital syphilis usually present themselves after age five and may remain undiagnosed well into adulthood. The characteristics of late congenital syphilis may be bone pain, retinitis pigmentosa (a serious eye disease), Hutchinson's triad which is characterized by pegshaped upper central incisors (teeth), and interstitial keratitis which consists of blurred vision, abnormal tearing, eye pain and abnormal sensitivity to light, saddle nose, bony prominence of the forehead, high arched palate, short upper jawbone, nerve deafness and fissuring around the mouth and anus. | 318 | Congenital Syphilis |
nord_318_2 | Causes of Congenital Syphilis | Congenital syphilis is a chronic infectious disease caused by the spirochete treponema pallidum and transmitted by an infected mother to the fetus in the womb. Adults transmit syphilis through sexual contact. (For information on syphilis in adults choose “Syphilis” as your search term in the Rare Disease Database). | Causes of Congenital Syphilis. Congenital syphilis is a chronic infectious disease caused by the spirochete treponema pallidum and transmitted by an infected mother to the fetus in the womb. Adults transmit syphilis through sexual contact. (For information on syphilis in adults choose “Syphilis” as your search term in the Rare Disease Database). | 318 | Congenital Syphilis |
nord_318_3 | Affects of Congenital Syphilis | In 1998, the National Syphilis Elimination Plan went into effect. One of the goals of this plan was to reduce the incidence of congenital syphilis (CS) to fewer than 40 cases per 100,000 live births. The incidence of congenital syphilis in newborns under a year old rose in the United States from 180 cases in 1957 to 422 cases in 1972. More recently there has been a dramatic increase of congenital syphilis, especially in urban areas, that has been attributed in part to crack cocaine use. In the year 2000, the incidence rate was about 13.4 per 100,000 live births, which represented about 529 cases. | Affects of Congenital Syphilis. In 1998, the National Syphilis Elimination Plan went into effect. One of the goals of this plan was to reduce the incidence of congenital syphilis (CS) to fewer than 40 cases per 100,000 live births. The incidence of congenital syphilis in newborns under a year old rose in the United States from 180 cases in 1957 to 422 cases in 1972. More recently there has been a dramatic increase of congenital syphilis, especially in urban areas, that has been attributed in part to crack cocaine use. In the year 2000, the incidence rate was about 13.4 per 100,000 live births, which represented about 529 cases. | 318 | Congenital Syphilis |
nord_318_4 | Related disorders of Congenital Syphilis | Symptoms of the following disorders can be similar to those of Congenital Syphilis. Comparisons may be useful for a differential diagnosis:Bejel, or endemic syphilis, is an infectious disease caused by an organism (treponema pallidum II) related to and identical in appearance to that causing venereal syphilis. This infection causes lesions of the skin and bone and is common among children in the Mediterranean countries of the Middle East, northern Africa, parts of eastern Europe, Arabia, subsaharan Africa, and Southeast Asia. In the United States, however, it is rare. Bejel is transmitted by physical, non-sexual contact and the sharing of eating and drinking utensils. (For more information on this disease choose “Bejel” as your search term in the Rare Disease Database)Epidermolysis Bullosa is the name of a group of rare, hereditary skin diseases in which blisters (vesicles) develop usually following trauma. Severe forms of the disease may include involvement of the mucous membranes and may leave scars and contractures on healing. The shedding or absence of skin during infancy may be confused with the diagnosis of congenital syphilis. (For more information on Epidermolysis Bullosa choose “Epidermolysis” as your search term in the Rare Disease Database)Ectodermal Dysplasias are a group of hereditary, non-progressive skin diseases. The skin, it's derivatives, and some other organs are involved. A predisposition to respiratory infections, due to a somewhat depressed immune system, and to defective mucous glands in parts of the respiratory tract, is the most life threatening characteristic of this group of disorders. Symptoms include eczema, poorly functioning sweat glands, sparse or absent hair follicles, abnormal hair, disfigured nails, and difficulties with the nasal passages and ear canals. Skin is satiny smooth, prone to rashes, and slow to heal. Commonly, the teeth fail to develop properly. Other complications may include hearing deficit, loss of sight, mental retardation, limb abnormalities, cleft palate and lip, and urinary tract abnormalities. Allergies are common, as are bronchitis and pneumonia. (For more information on Ectodermal Dysplasias choose “Ectodermal” as your search term in the Rare Disease Database.)Jaundice is a yellow discoloration of the skin, tissues and certain body fluids caused by excess circulating bilirubin (reddish yellow pigment occuring in the urine, bile, blood and gallbladder). A wide range of liver disorders may cause jaundice. An evaluation based on physical examination, history, and routine laboratory tests will identify the cause of jaundice. Treatment of the underlying disorder is required. (For more information on diseases that cause Jaundice choose “Jaundice” as your search term in the Rare Disease Database.)Pinta is an infectious disease caused by the microorganism treponema carateum and is closely related to the microorganism which causes some venereal disease. This disease is transmitted nonsexually and is characterized by rashes and discoloration of the skin. Small bumps develop and within several months reddish, scaly areas appear most often on the face, hands, and feet. It is common in the hot lowlands of Central and South America, but is rare in the United States. (For more information on this disease choose “Pinta” as your search term in the Rare Disease Database)Yaws is a nonvenereal infectious disease caused by the microorganism treponema pertenue which is related to syphilis. This disorder is common in children and is characterized by skin and bone lesions. Yaws is rarely found in the United States but is common among children in the humid tropics of Africa, South and Central America, the West Indies, and the Far East. (For more information on this disease choose “Yaws” as your search term in the Rare Disease Database.) | Related disorders of Congenital Syphilis. Symptoms of the following disorders can be similar to those of Congenital Syphilis. Comparisons may be useful for a differential diagnosis:Bejel, or endemic syphilis, is an infectious disease caused by an organism (treponema pallidum II) related to and identical in appearance to that causing venereal syphilis. This infection causes lesions of the skin and bone and is common among children in the Mediterranean countries of the Middle East, northern Africa, parts of eastern Europe, Arabia, subsaharan Africa, and Southeast Asia. In the United States, however, it is rare. Bejel is transmitted by physical, non-sexual contact and the sharing of eating and drinking utensils. (For more information on this disease choose “Bejel” as your search term in the Rare Disease Database)Epidermolysis Bullosa is the name of a group of rare, hereditary skin diseases in which blisters (vesicles) develop usually following trauma. Severe forms of the disease may include involvement of the mucous membranes and may leave scars and contractures on healing. The shedding or absence of skin during infancy may be confused with the diagnosis of congenital syphilis. (For more information on Epidermolysis Bullosa choose “Epidermolysis” as your search term in the Rare Disease Database)Ectodermal Dysplasias are a group of hereditary, non-progressive skin diseases. The skin, it's derivatives, and some other organs are involved. A predisposition to respiratory infections, due to a somewhat depressed immune system, and to defective mucous glands in parts of the respiratory tract, is the most life threatening characteristic of this group of disorders. Symptoms include eczema, poorly functioning sweat glands, sparse or absent hair follicles, abnormal hair, disfigured nails, and difficulties with the nasal passages and ear canals. Skin is satiny smooth, prone to rashes, and slow to heal. Commonly, the teeth fail to develop properly. Other complications may include hearing deficit, loss of sight, mental retardation, limb abnormalities, cleft palate and lip, and urinary tract abnormalities. Allergies are common, as are bronchitis and pneumonia. (For more information on Ectodermal Dysplasias choose “Ectodermal” as your search term in the Rare Disease Database.)Jaundice is a yellow discoloration of the skin, tissues and certain body fluids caused by excess circulating bilirubin (reddish yellow pigment occuring in the urine, bile, blood and gallbladder). A wide range of liver disorders may cause jaundice. An evaluation based on physical examination, history, and routine laboratory tests will identify the cause of jaundice. Treatment of the underlying disorder is required. (For more information on diseases that cause Jaundice choose “Jaundice” as your search term in the Rare Disease Database.)Pinta is an infectious disease caused by the microorganism treponema carateum and is closely related to the microorganism which causes some venereal disease. This disease is transmitted nonsexually and is characterized by rashes and discoloration of the skin. Small bumps develop and within several months reddish, scaly areas appear most often on the face, hands, and feet. It is common in the hot lowlands of Central and South America, but is rare in the United States. (For more information on this disease choose “Pinta” as your search term in the Rare Disease Database)Yaws is a nonvenereal infectious disease caused by the microorganism treponema pertenue which is related to syphilis. This disorder is common in children and is characterized by skin and bone lesions. Yaws is rarely found in the United States but is common among children in the humid tropics of Africa, South and Central America, the West Indies, and the Far East. (For more information on this disease choose “Yaws” as your search term in the Rare Disease Database.) | 318 | Congenital Syphilis |
nord_318_5 | Diagnosis of Congenital Syphilis | The diagnosis of CS may be delayed because the symptoms are not always evident. However, any child of a mother infected with syphilis should be suspected for congenital syphilis. If the signs and symptoms are not obviously those of CS, then further testing will be required, including (1) the examination of blood samples for antibodies to the spirochete infection and (2) identification of the syphilis bacterium under a light microscope. | Diagnosis of Congenital Syphilis. The diagnosis of CS may be delayed because the symptoms are not always evident. However, any child of a mother infected with syphilis should be suspected for congenital syphilis. If the signs and symptoms are not obviously those of CS, then further testing will be required, including (1) the examination of blood samples for antibodies to the spirochete infection and (2) identification of the syphilis bacterium under a light microscope. | 318 | Congenital Syphilis |
nord_318_6 | Therapies of Congenital Syphilis | TreatmentCongenital syphilis is preventable. It occurs in infants whose mothers have not been treated for the disease prior to or during pregnancy. When the infection is very recent, the disease may not show up in the infant. Therefore, it is important to have the infant tested again later on if the mother has been diagnosed with syphilis.It is possible that blood tests (serologic tests) may be negative during pregnancy. Symptoms may then show up when the infant is 3-14 weeks of age. In these cases the mother probably acquired the infection during the later part of her pregnancy.The most effective treatment for syphilis in the mother, as well as congenital syphilis in the infant, is penicillin. In some cases other antibiotics may be used. Interstitial keratitis may be treated with corticosteroid drugs and atropine drops. An ophthalmologist should be consulted.If nerve deafness is present a combination of penicillin and corticosteroids may be prescribed. | Therapies of Congenital Syphilis. TreatmentCongenital syphilis is preventable. It occurs in infants whose mothers have not been treated for the disease prior to or during pregnancy. When the infection is very recent, the disease may not show up in the infant. Therefore, it is important to have the infant tested again later on if the mother has been diagnosed with syphilis.It is possible that blood tests (serologic tests) may be negative during pregnancy. Symptoms may then show up when the infant is 3-14 weeks of age. In these cases the mother probably acquired the infection during the later part of her pregnancy.The most effective treatment for syphilis in the mother, as well as congenital syphilis in the infant, is penicillin. In some cases other antibiotics may be used. Interstitial keratitis may be treated with corticosteroid drugs and atropine drops. An ophthalmologist should be consulted.If nerve deafness is present a combination of penicillin and corticosteroids may be prescribed. | 318 | Congenital Syphilis |
nord_319_0 | Overview of Congenital Tracheomalacia | SummaryCongenital tracheomalacia is a rare childhood form of tracheomalacia in which the cartilage around the windpipe (trachea) is weak at birth. As the infant breathes out, the trachea collapses making it difficult to breathe. Symptoms range from mild to severe shortness of breath (particularly during exercise and eating), loud breathing (stridor), bluish skin (cyanosis) and recurrent airway infections. Tracheomalacia is associated with many childhood syndromes (i.e. Ehlers Danlos syndrome, bronchopulmonary dysplasia) and congenital diseases (i.e. tracheoesophageal fistula, double aortic arch) that weaken or compress the trachea. A weakened or compressed airway may occur by itself or alongside other airway abnormalities.Children will have a harder time clearing mucus as the trachea collapses, which can lead to recurrent infections and difficulty breathing. If the trachea narrows >50% when exhaling, more symptoms will likely be present. These symptoms often resolve by themselves before the child turns 2 years old and can be managed by a team of clinicians. Treatment usually includes physical therapy, continuous positive pressure ventilation (CPAP) and monitoring for respiratory infections. More severe cases may need surgery to hold open the airway or relieve anything compressing it. Case severity may vary widely, but prognosis has continually improved with supportive measures. | Overview of Congenital Tracheomalacia. SummaryCongenital tracheomalacia is a rare childhood form of tracheomalacia in which the cartilage around the windpipe (trachea) is weak at birth. As the infant breathes out, the trachea collapses making it difficult to breathe. Symptoms range from mild to severe shortness of breath (particularly during exercise and eating), loud breathing (stridor), bluish skin (cyanosis) and recurrent airway infections. Tracheomalacia is associated with many childhood syndromes (i.e. Ehlers Danlos syndrome, bronchopulmonary dysplasia) and congenital diseases (i.e. tracheoesophageal fistula, double aortic arch) that weaken or compress the trachea. A weakened or compressed airway may occur by itself or alongside other airway abnormalities.Children will have a harder time clearing mucus as the trachea collapses, which can lead to recurrent infections and difficulty breathing. If the trachea narrows >50% when exhaling, more symptoms will likely be present. These symptoms often resolve by themselves before the child turns 2 years old and can be managed by a team of clinicians. Treatment usually includes physical therapy, continuous positive pressure ventilation (CPAP) and monitoring for respiratory infections. More severe cases may need surgery to hold open the airway or relieve anything compressing it. Case severity may vary widely, but prognosis has continually improved with supportive measures. | 319 | Congenital Tracheomalacia |
nord_319_1 | Symptoms of Congenital Tracheomalacia | Many patients with congenital tracheomalacia do not have symptoms. The most common symptoms include: | Symptoms of Congenital Tracheomalacia. Many patients with congenital tracheomalacia do not have symptoms. The most common symptoms include: | 319 | Congenital Tracheomalacia |
nord_319_2 | Causes of Congenital Tracheomalacia | Congenital tracheomalacia can be associated with: | Causes of Congenital Tracheomalacia. Congenital tracheomalacia can be associated with: | 319 | Congenital Tracheomalacia |
nord_319_3 | Affects of Congenital Tracheomalacia | The prevalence of congenital tracheomalacia is roughly estimated to be around 1 in 2,100 livebirths. It is often associated with certain genetic conditions or structural birth defects (see Causes). | Affects of Congenital Tracheomalacia. The prevalence of congenital tracheomalacia is roughly estimated to be around 1 in 2,100 livebirths. It is often associated with certain genetic conditions or structural birth defects (see Causes). | 319 | Congenital Tracheomalacia |
nord_319_4 | Related disorders of Congenital Tracheomalacia | Tracheobronchomalacia – the cartilage of both the trachea and bronchi are weakened, causing them to collapse when exhalingBronchomalacia – the cartilage of the bronchus alone is weakened, causing it to collapse when exhalingExcessive dynamic airway collapse (EDAC) – the airway cartilage is normal, but the posterior wall is atrophied causing the trachea to collapse when exhalingLaryngomalacia – the cartilage of the voice box (larynx) is weak at birth, causing it to collapse when inhalingEpiglottitis – this is an inflammation of the epiglottis, causing the airway to close and requiring emergency surgeryCongenital vascular disorders – these include any malformed blood vessels which compress the windpipe and weaken it, including vascular rings, innominate arteries, and double aortic archesTracheoesophageal fistula – a rare birth defect where the esophagus forms incorrectly and connects to the windpipe rather than the stomach. Infants will have trouble breathing and swallowing and require surgery. | Related disorders of Congenital Tracheomalacia. Tracheobronchomalacia – the cartilage of both the trachea and bronchi are weakened, causing them to collapse when exhalingBronchomalacia – the cartilage of the bronchus alone is weakened, causing it to collapse when exhalingExcessive dynamic airway collapse (EDAC) – the airway cartilage is normal, but the posterior wall is atrophied causing the trachea to collapse when exhalingLaryngomalacia – the cartilage of the voice box (larynx) is weak at birth, causing it to collapse when inhalingEpiglottitis – this is an inflammation of the epiglottis, causing the airway to close and requiring emergency surgeryCongenital vascular disorders – these include any malformed blood vessels which compress the windpipe and weaken it, including vascular rings, innominate arteries, and double aortic archesTracheoesophageal fistula – a rare birth defect where the esophagus forms incorrectly and connects to the windpipe rather than the stomach. Infants will have trouble breathing and swallowing and require surgery. | 319 | Congenital Tracheomalacia |
nord_319_5 | Diagnosis of Congenital Tracheomalacia | Congenital tracheomalacia is diagnosed by bronchoscopy to visualize the airway collapsing as the patient breathes. The patient is awake but numbed so they can take deep breaths during the procedure. Additional imaging may include a CT scan, a chest x-ray and/or an MRI to determine if a blood vessel is compressing the airway.Clinical Testing and Work-upMany cases of congenital tracheomalacia are found incidentally if the symptoms are mild or absent. The clinician will take a thorough history from the patient and a respiratory physical exam. They may then order pulmonary function tests to indicate the degree that the patient’s breathing is affected. These tests are important to rule out other conditions such as asthma, a foreign body and pneumonia. The clinician will likely order imaging tests such as a CT scan, chest x-ray and/or MRI of the chest. A diagnosis is made by inserting a small camera into the airway (bronchoscopy) and seeing the weak trachea collapse as the patient breathes deeply. | Diagnosis of Congenital Tracheomalacia. Congenital tracheomalacia is diagnosed by bronchoscopy to visualize the airway collapsing as the patient breathes. The patient is awake but numbed so they can take deep breaths during the procedure. Additional imaging may include a CT scan, a chest x-ray and/or an MRI to determine if a blood vessel is compressing the airway.Clinical Testing and Work-upMany cases of congenital tracheomalacia are found incidentally if the symptoms are mild or absent. The clinician will take a thorough history from the patient and a respiratory physical exam. They may then order pulmonary function tests to indicate the degree that the patient’s breathing is affected. These tests are important to rule out other conditions such as asthma, a foreign body and pneumonia. The clinician will likely order imaging tests such as a CT scan, chest x-ray and/or MRI of the chest. A diagnosis is made by inserting a small camera into the airway (bronchoscopy) and seeing the weak trachea collapse as the patient breathes deeply. | 319 | Congenital Tracheomalacia |
nord_319_6 | Therapies of Congenital Tracheomalacia | Since many cases of congenital tracheomalacia resolve before two years of age, the objective is to manage any symptoms by a multidisciplinary team of professionals. These therapies may include:Standard TherapiesTreatment
Only severe cases which do not resolve on their own will need surgical treatment. A team of specialists including interventional pulmonologists, respiratory therapists, radiologists and surgeons work together to care for patients. Age and other conditions that the patient has are factored in as the treatment team considers advanced treatment. In some patients, treating the underlying condition improves the symptoms of congenital tracheomalacia. Depending on severity, treatment options for congenital tracheomalacia may include: | Therapies of Congenital Tracheomalacia. Since many cases of congenital tracheomalacia resolve before two years of age, the objective is to manage any symptoms by a multidisciplinary team of professionals. These therapies may include:Standard TherapiesTreatment
Only severe cases which do not resolve on their own will need surgical treatment. A team of specialists including interventional pulmonologists, respiratory therapists, radiologists and surgeons work together to care for patients. Age and other conditions that the patient has are factored in as the treatment team considers advanced treatment. In some patients, treating the underlying condition improves the symptoms of congenital tracheomalacia. Depending on severity, treatment options for congenital tracheomalacia may include: | 319 | Congenital Tracheomalacia |
nord_320_0 | Overview of Congenital Varicella Syndrome | Congenital Varicella Syndrome is an extremely rare disorder in which affected infants have distinctive abnormalities at birth (congenital) due to the mother's infection with chickenpox (maternal varicella zoster) early during pregnancy (i.e., up to 20 weeks gestation). Affected newborns may have a low birth weight and characteristic abnormalities of the skin; the arms, legs, hands, and/or feet (extremities); the brain; the eyes; and/or, in rare cases, other areas of the body. The range and severity of associated symptoms and physical findings may vary greatly from case to case depending upon when maternal varicella zoster infection occurred during fetal development.In many cases, newborns with Congenital Varicella Syndrome may be abnormally small and have a low birth weight due to abnormal growth delays during fetal development (intrauterine growth retardation). In addition, distinctive skin abnormalities are often present. Certain areas of the skin may consist of thickened, overgrown (hypertrophic) scar tissue (cicatrix), and surrounding skin may appear abnormally hardened (indurate), red, and inflamed (erythema). Such cicatrix scarring typically occurs on one or more of the arms and/or legs, which may also be malformed, underdeveloped (hypoplastic), and abnormally shortened (reduction deformities). Affected infants may also exhibit incomplete development (hypoplasia) of certain fingers and/or toes (rudimentary digits).In some cases, newborns with Congenital Varicella Syndrome may have abnormalities of the brain such as degeneration of the outer portion of the brain (cortical atrophy) and/or abnormal enlargement of cavities of the brain (dilated ventricles [ventriculomegaly]). There may also be abnormalities of the part of the nervous system that controls involuntary functions (autonomic nervous system) such as damage to or abnormalities of certain nerve fibers (sympathetic nerve fibers) that pass from the spinal cord to the neck and/or pelvic area. Some affected infants and children may also exhibit abnormal smallness of the head (microcephaly), delays in the acquisition of skills requiring the coordination of mental and physical activities (psychomotor retardation), varying degrees of mental retardation, and/or learning disabilities. In some cases, characteristic eye (ocular) abnormalities may also be present including loss of transparency of the lenses of the eyes (cataracts); abnormal smallness of one or both eyes (unilateral or bilateral microphthalmia); involuntary, rapid, side-to-side movements of the eyes (pendular nystagmus); and/or inflammation and scarring of certain membranes of the eyes (chorioretinitis and chorioretinal scarring). Such ocular abnormalities may result in varying degrees of visual impairment. In rare cases, newborns with Congenital Varicella Syndrome may have additional abnormalities associated with the disorder. | Overview of Congenital Varicella Syndrome. Congenital Varicella Syndrome is an extremely rare disorder in which affected infants have distinctive abnormalities at birth (congenital) due to the mother's infection with chickenpox (maternal varicella zoster) early during pregnancy (i.e., up to 20 weeks gestation). Affected newborns may have a low birth weight and characteristic abnormalities of the skin; the arms, legs, hands, and/or feet (extremities); the brain; the eyes; and/or, in rare cases, other areas of the body. The range and severity of associated symptoms and physical findings may vary greatly from case to case depending upon when maternal varicella zoster infection occurred during fetal development.In many cases, newborns with Congenital Varicella Syndrome may be abnormally small and have a low birth weight due to abnormal growth delays during fetal development (intrauterine growth retardation). In addition, distinctive skin abnormalities are often present. Certain areas of the skin may consist of thickened, overgrown (hypertrophic) scar tissue (cicatrix), and surrounding skin may appear abnormally hardened (indurate), red, and inflamed (erythema). Such cicatrix scarring typically occurs on one or more of the arms and/or legs, which may also be malformed, underdeveloped (hypoplastic), and abnormally shortened (reduction deformities). Affected infants may also exhibit incomplete development (hypoplasia) of certain fingers and/or toes (rudimentary digits).In some cases, newborns with Congenital Varicella Syndrome may have abnormalities of the brain such as degeneration of the outer portion of the brain (cortical atrophy) and/or abnormal enlargement of cavities of the brain (dilated ventricles [ventriculomegaly]). There may also be abnormalities of the part of the nervous system that controls involuntary functions (autonomic nervous system) such as damage to or abnormalities of certain nerve fibers (sympathetic nerve fibers) that pass from the spinal cord to the neck and/or pelvic area. Some affected infants and children may also exhibit abnormal smallness of the head (microcephaly), delays in the acquisition of skills requiring the coordination of mental and physical activities (psychomotor retardation), varying degrees of mental retardation, and/or learning disabilities. In some cases, characteristic eye (ocular) abnormalities may also be present including loss of transparency of the lenses of the eyes (cataracts); abnormal smallness of one or both eyes (unilateral or bilateral microphthalmia); involuntary, rapid, side-to-side movements of the eyes (pendular nystagmus); and/or inflammation and scarring of certain membranes of the eyes (chorioretinitis and chorioretinal scarring). Such ocular abnormalities may result in varying degrees of visual impairment. In rare cases, newborns with Congenital Varicella Syndrome may have additional abnormalities associated with the disorder. | 320 | Congenital Varicella Syndrome |
nord_320_1 | Symptoms of Congenital Varicella Syndrome | Affected newborns may have low birth weight and characteristic abnormalities of the skin; the arms, legs, hands, and/or feet (extremities); the brain; the eyes; and/or, in rare cases, other areas of the body. The range and severity of symptoms and physical findings may vary greatly from case to case depending upon when maternal chickenpox occurred during fetal development. For example, while some affected infants may exhibit only characteristic skin and limb malformations, others may have only specific eye abnormalities (e.g., cataracts) and/or may experience symptoms associated with brain involvement.In many cases of congenital varicella syndrome, abnormal growth delays occur during fetal development (intrauterine growth retardation). As a result, most affected newborns are abnormally small and have low birth weight.Many newborns with CVS also have distinctive skin abnormalities. In many cases, certain areas of the skin may consist of scar tissue (cicatricial) that is thickened and overgrown (hypertrophic). Such scarring may appear in a characteristic “zigzag” pattern, and the surrounding skin may be abnormally hardened (indurate) and appear red and inflamed (erythematic). In most cases, cicatrix scarring occurs on one or more of the arms and/or legs. Affected arms and/or legs and/or fingers or toes may also be malformed, underdeveloped (hypoplastic). Some newborns with CVS may have damage to the brain and/or other parts of the central nervous system. A small head (microcephaly) or uncontrolled electrical disturbances in the brain (seizures) are among the symptoms sometimes encountered. In some cases, cerebrospinal fluid may accumulate within the hollow spaces of the brain (ventricles) leading to an enlarged head (hydrocephalus). Developmental delays including varying degrees of mental retardation may be present.In some cases, affected infants may have Horner's syndrome, a condition resulting from damage to or abnormalities of nerve fibers (sympathetic nerve fibers) passing from the spinal cord to certain areas of the face, eyes, and eyelids. Associated symptoms, which affect one side of the face, may include “sinking in” of the eyeball, drooping of the upper eyelid (ptosis), raised lower eyelid, abnormal narrowing (constriction) of the pupil, and flushing and absence of sweating (anhidrosis) on the affected side of the face. (For more information on this condition, use “Horner” as your search term in the Rare Disease Database.)In addition, in some cases, due to damage to sympathic nerve fibers passing to the pelvic area, affected infants may experience impaired functioning of certain bands of muscle fibers (sphincters) that help ensure the proper passage of feces (anal sphincter dysfunction) and urine (urethral sphincter). As a result, affected children may experience an inability to voluntarily retain feces in the rectum (fecal incontinence) as well as involuntary, uncontrolled urination (urinary incontinence).Distinctive abnormalities of the eyes may also be present. These may include abnormally small eye(s) (unilateral or bilateral microphthalmia); abnormal clouding of the lenses of the eyes (cataracts); and/or involuntary, rapid, side-to-side movements of the eyes (pendular nystagmus). In addition, the nerve-rich membrane lining the inside of the back of the eyes (retina) and the thin membranous layer of blood vessels behind the retina (choroid) may exhibit inflammation (chorioretinitis) that may lead to scarring (chorioretinal scarring). Such inflammatory changes and chorioretinal scarring may, in turn, result in blurred vision and abnormal sensitivity to light (photophobia). Children with CVS may have an increased susceptibility to Herpes zoster infection within the first two years of life. Herpes zoster infection, usually a problem of older people, results from the reactivation of varicella zoster virus that has remained dormant in certain nerve tissues. (For more information on this condition, please see the “Related Disorders” section of this report below.) | Symptoms of Congenital Varicella Syndrome. Affected newborns may have low birth weight and characteristic abnormalities of the skin; the arms, legs, hands, and/or feet (extremities); the brain; the eyes; and/or, in rare cases, other areas of the body. The range and severity of symptoms and physical findings may vary greatly from case to case depending upon when maternal chickenpox occurred during fetal development. For example, while some affected infants may exhibit only characteristic skin and limb malformations, others may have only specific eye abnormalities (e.g., cataracts) and/or may experience symptoms associated with brain involvement.In many cases of congenital varicella syndrome, abnormal growth delays occur during fetal development (intrauterine growth retardation). As a result, most affected newborns are abnormally small and have low birth weight.Many newborns with CVS also have distinctive skin abnormalities. In many cases, certain areas of the skin may consist of scar tissue (cicatricial) that is thickened and overgrown (hypertrophic). Such scarring may appear in a characteristic “zigzag” pattern, and the surrounding skin may be abnormally hardened (indurate) and appear red and inflamed (erythematic). In most cases, cicatrix scarring occurs on one or more of the arms and/or legs. Affected arms and/or legs and/or fingers or toes may also be malformed, underdeveloped (hypoplastic). Some newborns with CVS may have damage to the brain and/or other parts of the central nervous system. A small head (microcephaly) or uncontrolled electrical disturbances in the brain (seizures) are among the symptoms sometimes encountered. In some cases, cerebrospinal fluid may accumulate within the hollow spaces of the brain (ventricles) leading to an enlarged head (hydrocephalus). Developmental delays including varying degrees of mental retardation may be present.In some cases, affected infants may have Horner's syndrome, a condition resulting from damage to or abnormalities of nerve fibers (sympathetic nerve fibers) passing from the spinal cord to certain areas of the face, eyes, and eyelids. Associated symptoms, which affect one side of the face, may include “sinking in” of the eyeball, drooping of the upper eyelid (ptosis), raised lower eyelid, abnormal narrowing (constriction) of the pupil, and flushing and absence of sweating (anhidrosis) on the affected side of the face. (For more information on this condition, use “Horner” as your search term in the Rare Disease Database.)In addition, in some cases, due to damage to sympathic nerve fibers passing to the pelvic area, affected infants may experience impaired functioning of certain bands of muscle fibers (sphincters) that help ensure the proper passage of feces (anal sphincter dysfunction) and urine (urethral sphincter). As a result, affected children may experience an inability to voluntarily retain feces in the rectum (fecal incontinence) as well as involuntary, uncontrolled urination (urinary incontinence).Distinctive abnormalities of the eyes may also be present. These may include abnormally small eye(s) (unilateral or bilateral microphthalmia); abnormal clouding of the lenses of the eyes (cataracts); and/or involuntary, rapid, side-to-side movements of the eyes (pendular nystagmus). In addition, the nerve-rich membrane lining the inside of the back of the eyes (retina) and the thin membranous layer of blood vessels behind the retina (choroid) may exhibit inflammation (chorioretinitis) that may lead to scarring (chorioretinal scarring). Such inflammatory changes and chorioretinal scarring may, in turn, result in blurred vision and abnormal sensitivity to light (photophobia). Children with CVS may have an increased susceptibility to Herpes zoster infection within the first two years of life. Herpes zoster infection, usually a problem of older people, results from the reactivation of varicella zoster virus that has remained dormant in certain nerve tissues. (For more information on this condition, please see the “Related Disorders” section of this report below.) | 320 | Congenital Varicella Syndrome |
nord_320_2 | Causes of Congenital Varicella Syndrome | Congenital varicella syndrome is an extremely rare disorder in which affected infants demonstrate distinctive abnormalities at birth due to the mother's infection with chickenpox (maternal varicella zoster) early during pregnancy. The varicella zoster virus (VZV) is one of several belonging to a family of viruses known as herpesviruses. A susceptible individual's initial exposure to the virus (i.e., through respiration or direct contact with vesicular fluid) usually results in chickenpox, a highly contagious infectious disease. Although most individuals contract chickenpox during childhood, those who do not will remain suspectible to the disorder during adulthood.If a woman who has not had the disorder contracts chickenpox during pregnancy, it is possible that the developing fetus may also become infected. In approximately two percent of such cases, fetal exposure to the virus during the first 20 weeks of pregnancy (particularly during the sixth to the 20th week of gestation) may result in congenital varicella syndrome. According to researchers, when VZV infection occurs later during pregnancy (i.e., in the middle of the second or in the third trimester), the developing fetus' defense mechanisms against infection (fetal immune system) may be able to mount a response to the invading organism, typically resulting in a benign course. However, when VZV infection occurs early during fetal development, the immature fetal immune system may be unable to fight the invading virus, potentially resulting in CVS.Many researchers believe that the symptoms and signs of CVS result from damage to the nervous system during early fetal development. The varicella zoster virus invades the fetal nerves (e.g., optic stalk, cervical cord, lumbosacral cord) leading to reduced development of nerve supply and/or damaged conduction of nerve signals (denervation) to certain tissues (e.g., within the eyes, extremities, etc.). This damage results in many of the abnormalities associated with the disorder. Although it is not fully understood why certain areas of the body seem particularly affected by fetal VZV infection, researchers speculate that the virus may affect those tissues undergoing rapid development such as those areas of the developing fetus that differentiate into the extremities (limb buds). | Causes of Congenital Varicella Syndrome. Congenital varicella syndrome is an extremely rare disorder in which affected infants demonstrate distinctive abnormalities at birth due to the mother's infection with chickenpox (maternal varicella zoster) early during pregnancy. The varicella zoster virus (VZV) is one of several belonging to a family of viruses known as herpesviruses. A susceptible individual's initial exposure to the virus (i.e., through respiration or direct contact with vesicular fluid) usually results in chickenpox, a highly contagious infectious disease. Although most individuals contract chickenpox during childhood, those who do not will remain suspectible to the disorder during adulthood.If a woman who has not had the disorder contracts chickenpox during pregnancy, it is possible that the developing fetus may also become infected. In approximately two percent of such cases, fetal exposure to the virus during the first 20 weeks of pregnancy (particularly during the sixth to the 20th week of gestation) may result in congenital varicella syndrome. According to researchers, when VZV infection occurs later during pregnancy (i.e., in the middle of the second or in the third trimester), the developing fetus' defense mechanisms against infection (fetal immune system) may be able to mount a response to the invading organism, typically resulting in a benign course. However, when VZV infection occurs early during fetal development, the immature fetal immune system may be unable to fight the invading virus, potentially resulting in CVS.Many researchers believe that the symptoms and signs of CVS result from damage to the nervous system during early fetal development. The varicella zoster virus invades the fetal nerves (e.g., optic stalk, cervical cord, lumbosacral cord) leading to reduced development of nerve supply and/or damaged conduction of nerve signals (denervation) to certain tissues (e.g., within the eyes, extremities, etc.). This damage results in many of the abnormalities associated with the disorder. Although it is not fully understood why certain areas of the body seem particularly affected by fetal VZV infection, researchers speculate that the virus may affect those tissues undergoing rapid development such as those areas of the developing fetus that differentiate into the extremities (limb buds). | 320 | Congenital Varicella Syndrome |
nord_320_3 | Affects of Congenital Varicella Syndrome | Congenital varicella syndrome is an extremely rare disorder that appears to affect male and female newborns in equal numbers. Symptoms and physical characteristics associated with the disorder are apparent at birth. CVS occurs in about 1-7 of 10,000 pregnancies. If CVS develops within the final days before delivery, or within a day or two afterward, there is a risk of neonatal varicella that can be severe and even life-threatening. | Affects of Congenital Varicella Syndrome. Congenital varicella syndrome is an extremely rare disorder that appears to affect male and female newborns in equal numbers. Symptoms and physical characteristics associated with the disorder are apparent at birth. CVS occurs in about 1-7 of 10,000 pregnancies. If CVS develops within the final days before delivery, or within a day or two afterward, there is a risk of neonatal varicella that can be severe and even life-threatening. | 320 | Congenital Varicella Syndrome |
nord_320_4 | Related disorders of Congenital Varicella Syndrome | Symptoms of the following disorders may be similar to those of Congenital Varicella Syndrome. Comparisons may be useful for a differential diagnosis: Neonatal Chickenpox is characterized by infection with varicella zoster (chickenpox) shortly after birth. In most cases, affected infants exhibit varicella zoster infection due to the mother's infection with chickenpox (maternal varicella zoster) during the last weeks or days of pregnancy. In other cases, Neonatal Chickenpox may result due to an affected infant's exposure to the virus shortly after birth. Because of the time span that typically occurs between exposure to the virus and initial symptoms (i.e., approximate 10- to 14-day incubation period), if the mother initially contracted chickenpox more than a week before giving birth, the affected newborn may have received antibodies from the mother that help fight the virus (transplacental anti-VZV antibody). However, if the interval from maternal VZV infection to birth was less than a week, the newborn may not have received protective antibodies from the mother. In such cases, Neonatal Chickenpox may result in severe symptoms. In addition, throughout the first year of life, chickenpox tends to be a severe illness. Symptoms typically associated with chickenpox include a low fever, listlessness, lack of appetite (anorexia), and the appearance of an itchy (pruritic) rash. The rash consists of small, red spots that become fluid-filled blisters, which, in turn, eventually dry out, scab over, and drop off, potentially leaving small pits in the skin. Infants with Neonatal Chickenpox may be at an increased risk for the more serious complications that may be associated with varicella zoster infection such as inflammation of the liver (hepatitis), the lungs (pneumonia), and/or the brain (encephalitis). (For more information on this disorder, choose “Varicella Zoster” as your search term in the Rare Disease Database.) Herpes Zoster, also known as shingles, is a common infection caused by the reactivation of the varicella zoster virus in individuals who previously experienced chickenpox. In most cases, once individuals have contracted the varicella zoster virus (VZV), they are immune to future occurrences of chickenpox. However, though most of the viral organisms are destroyed, some survive and remain inactive (dormant) within certain sensory nerves (i.e., dorsal root ganglion). In some cases, particularly in older individuals and/or in those who experience declining efficiency of the immune system, the VZV virus “reactivates,” resulting in Herpes Zoster. The condition, which is an infection of nerves that supply (enervate) specific areas of the skin, initially causes sensitivity in certain skin areas, followed by pain. Within a few days, a rash appears in such areas, consisting of small, red, raised spots that soon become blisters. The blisters then dry, crust over, and drop off, potentially leaving small pits in the skin. The rash, which typically affects one side of the body, may appear on the skin over the ribs, the neck, the lower body, or in some cases, the upper half of the face, potentially affecting the eye (herpes zoster ophthalmicus). The skin of the eyelid and/or the eye itself may be affected, potentially resulting in inflammation of certain areas of the eye (uveitis) and/or ulceration of the transparent portion of the eye through which light passes (cornea). In some cases, affected individuals may continue to experience pain after Herpes Zoster infection due to nerve damage resulting from the condition. (For more information on this condition, choose “Varicella Zoster” as your search term in the Rare Disease Database.) There may be other disorders in which affected infants may have abnormalities at birth (congenital) similar to those occurring in association with Congenital Varicella Syndrome due to maternal exposure to certain infectious diseases or drug exposure during pregnancy. (For more information on such disorders, please choose the exact disease name in question as your search term in the Rare Disease Database.) | Related disorders of Congenital Varicella Syndrome. Symptoms of the following disorders may be similar to those of Congenital Varicella Syndrome. Comparisons may be useful for a differential diagnosis: Neonatal Chickenpox is characterized by infection with varicella zoster (chickenpox) shortly after birth. In most cases, affected infants exhibit varicella zoster infection due to the mother's infection with chickenpox (maternal varicella zoster) during the last weeks or days of pregnancy. In other cases, Neonatal Chickenpox may result due to an affected infant's exposure to the virus shortly after birth. Because of the time span that typically occurs between exposure to the virus and initial symptoms (i.e., approximate 10- to 14-day incubation period), if the mother initially contracted chickenpox more than a week before giving birth, the affected newborn may have received antibodies from the mother that help fight the virus (transplacental anti-VZV antibody). However, if the interval from maternal VZV infection to birth was less than a week, the newborn may not have received protective antibodies from the mother. In such cases, Neonatal Chickenpox may result in severe symptoms. In addition, throughout the first year of life, chickenpox tends to be a severe illness. Symptoms typically associated with chickenpox include a low fever, listlessness, lack of appetite (anorexia), and the appearance of an itchy (pruritic) rash. The rash consists of small, red spots that become fluid-filled blisters, which, in turn, eventually dry out, scab over, and drop off, potentially leaving small pits in the skin. Infants with Neonatal Chickenpox may be at an increased risk for the more serious complications that may be associated with varicella zoster infection such as inflammation of the liver (hepatitis), the lungs (pneumonia), and/or the brain (encephalitis). (For more information on this disorder, choose “Varicella Zoster” as your search term in the Rare Disease Database.) Herpes Zoster, also known as shingles, is a common infection caused by the reactivation of the varicella zoster virus in individuals who previously experienced chickenpox. In most cases, once individuals have contracted the varicella zoster virus (VZV), they are immune to future occurrences of chickenpox. However, though most of the viral organisms are destroyed, some survive and remain inactive (dormant) within certain sensory nerves (i.e., dorsal root ganglion). In some cases, particularly in older individuals and/or in those who experience declining efficiency of the immune system, the VZV virus “reactivates,” resulting in Herpes Zoster. The condition, which is an infection of nerves that supply (enervate) specific areas of the skin, initially causes sensitivity in certain skin areas, followed by pain. Within a few days, a rash appears in such areas, consisting of small, red, raised spots that soon become blisters. The blisters then dry, crust over, and drop off, potentially leaving small pits in the skin. The rash, which typically affects one side of the body, may appear on the skin over the ribs, the neck, the lower body, or in some cases, the upper half of the face, potentially affecting the eye (herpes zoster ophthalmicus). The skin of the eyelid and/or the eye itself may be affected, potentially resulting in inflammation of certain areas of the eye (uveitis) and/or ulceration of the transparent portion of the eye through which light passes (cornea). In some cases, affected individuals may continue to experience pain after Herpes Zoster infection due to nerve damage resulting from the condition. (For more information on this condition, choose “Varicella Zoster” as your search term in the Rare Disease Database.) There may be other disorders in which affected infants may have abnormalities at birth (congenital) similar to those occurring in association with Congenital Varicella Syndrome due to maternal exposure to certain infectious diseases or drug exposure during pregnancy. (For more information on such disorders, please choose the exact disease name in question as your search term in the Rare Disease Database.) | 320 | Congenital Varicella Syndrome |
nord_320_5 | Diagnosis of Congenital Varicella Syndrome | A diagnosis of congenital varicella syndrome is usually suggested by confirmation of maternal varicella zoster infection early during pregnancy and the presence of certain characteristic symptoms and physical findings in the developing fetus or newborn.In some cases, prenatal ultrasound studies may reveal distinctive limb malformations, craniofacial abnormalities, and/or other characteristic findings suggestive of the disorder. In other cases, a sample of fluid that surrounds the developing fetus (amniocentesis) and/or a tissue sample from a portion of the placenta (chorionic villus sampling [CVS]) may be removed and studied to confirm infection with varicella zoster virus (VZV).Several tests may be used to analyze the liquid portion of the blood (serum) for evidence of varicella zoster virus infection (serological tests) in affected infants. For example, serum tests may reveal the presence of antibodies (IgG, VZV-specific IgM) to varicella zoster virus (VZV) up to several months or more after birth. | Diagnosis of Congenital Varicella Syndrome. A diagnosis of congenital varicella syndrome is usually suggested by confirmation of maternal varicella zoster infection early during pregnancy and the presence of certain characteristic symptoms and physical findings in the developing fetus or newborn.In some cases, prenatal ultrasound studies may reveal distinctive limb malformations, craniofacial abnormalities, and/or other characteristic findings suggestive of the disorder. In other cases, a sample of fluid that surrounds the developing fetus (amniocentesis) and/or a tissue sample from a portion of the placenta (chorionic villus sampling [CVS]) may be removed and studied to confirm infection with varicella zoster virus (VZV).Several tests may be used to analyze the liquid portion of the blood (serum) for evidence of varicella zoster virus infection (serological tests) in affected infants. For example, serum tests may reveal the presence of antibodies (IgG, VZV-specific IgM) to varicella zoster virus (VZV) up to several months or more after birth. | 320 | Congenital Varicella Syndrome |
nord_320_6 | Therapies of Congenital Varicella Syndrome | TreatmentThe treatment of congenital varicella 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, infectious disease specialists, neurologists, eye specialists (ophthalmologists), surgeons, physical therapists, and/or other health care professionals may need to prepare systematic and comprehensive plans for an affected infant's treatment.If a non-immune pregnant woman is exposed to chickenpox, varicella zoster immunoglobulin (VZIG) should be administered as soon as possible after exposure. VZIG is apparently most effective if used within 72 hours of exposure. However, some studies show that there are benefits for mother and child to be gained from the administration of VZIG for up to 10 days following exposure.Newborn children of infected mothers should be given VZIG as soon as possible after birth. Such treatment seems to reduce the severity of the neonatal disease or, in some few cases, to prevent neonatal disease.In many cases, physicians may recommend that females of child-bearing age who have not contracted chickenpox (seronegative) be immunized with the chickenpox vaccine to help prevent the occurrence of VZV infection during pregnancy and thus to avoid potential congenital varicella syndrome. However, it is essential that such vaccination be received under the recommendations of women's personal physicians. Because the chickenpox vaccine contains live, weakened strains of the VZV virus (live attenuated varicella virus), vaccination may, in some rare cases, result in disease in certain females who may have weakened immune systems (e.g., due to primary immunodeficiency disease, treatment with immunosuppressant medications, etc.). | Therapies of Congenital Varicella Syndrome. TreatmentThe treatment of congenital varicella 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, infectious disease specialists, neurologists, eye specialists (ophthalmologists), surgeons, physical therapists, and/or other health care professionals may need to prepare systematic and comprehensive plans for an affected infant's treatment.If a non-immune pregnant woman is exposed to chickenpox, varicella zoster immunoglobulin (VZIG) should be administered as soon as possible after exposure. VZIG is apparently most effective if used within 72 hours of exposure. However, some studies show that there are benefits for mother and child to be gained from the administration of VZIG for up to 10 days following exposure.Newborn children of infected mothers should be given VZIG as soon as possible after birth. Such treatment seems to reduce the severity of the neonatal disease or, in some few cases, to prevent neonatal disease.In many cases, physicians may recommend that females of child-bearing age who have not contracted chickenpox (seronegative) be immunized with the chickenpox vaccine to help prevent the occurrence of VZV infection during pregnancy and thus to avoid potential congenital varicella syndrome. However, it is essential that such vaccination be received under the recommendations of women's personal physicians. Because the chickenpox vaccine contains live, weakened strains of the VZV virus (live attenuated varicella virus), vaccination may, in some rare cases, result in disease in certain females who may have weakened immune systems (e.g., due to primary immunodeficiency disease, treatment with immunosuppressant medications, etc.). | 320 | Congenital Varicella Syndrome |
nord_321_0 | Overview of Conradi Hünermann Syndrome | SummaryConradi-Hünermann syndrome is a rare genetic disorder that affects approximately 1:100,000 to 1:200,000 births. This syndrome typically presents with skeletal abnormalities, short stature, differences in the form of the skull bones (craniofacial), eye or vision differences, and skin, hair, and nail abnormalities. The specific symptoms and severity of the disorder may vary greatly in individuals with Conradi-Hünermann syndrome. Symptoms may manifest anytime between early life to adulthood. Conradi-Hünermann syndrome is classified as a form of chondrodysplasia punctata, a group of disorders characterized by the formation of small, hardened spots of calcium on the “growing portion” or heads of the long bones (stippled epiphyses), the bones of the spine (vertebrae), the windpipe (trachea) and parts of the ribs. Skeletal findings in Conradi-Hünermann syndrome present as asymmetric shortening of long bones, particularly those of the upper arms (humeri), thighs (femora) and of the hands and feet. Individuals with Conradi-Hünermann syndrome may also have abnormalities in the curvature of the spine as well as growth deficiency that can cause short stature. Individuals with Conradi-Hünermann syndrome can have differences in the way the skull bones are formed, and this can be seen as a face or head that is asymmetric, prominent forehead, flattened midfacial regions (midfacial hypoplasia) and a low nasal bridge. Eye findings in Conradi-Hünermann syndrome can include cataracts at birth or early in life, abnormally small eyeballs (microphthalmia), small corneas (microcornea) and loss of transparency of the lenses of the eyes (cataracts). Many individuals with Conradi-Hünermann syndrome also present with sparse, coarse scalp hair, flattened and split nail plates and/or abnormal thickening, dryness, and scaling of the skin. Conradi-Hünermann syndrome is inherited as an X-linked dominant manner; this means that the disorder primarily affects females and can lead to fetal death in males. Treatment is dependent on the individual’s symptoms and no cure exists for Conradi-Hünermann syndrome.IntroductionConradi-Hünermann syndrome is named after Dr. Conradi and Dr. Hünermann, who described this condition in medical literature in 1931. In the 1970’s, Dr. Happle contributed additional information about the signs and symptoms, inheritance and causes of this syndrome which is why this condition is also referred to as Conradi-Hünermann-Happle syndrome. | Overview of Conradi Hünermann Syndrome. SummaryConradi-Hünermann syndrome is a rare genetic disorder that affects approximately 1:100,000 to 1:200,000 births. This syndrome typically presents with skeletal abnormalities, short stature, differences in the form of the skull bones (craniofacial), eye or vision differences, and skin, hair, and nail abnormalities. The specific symptoms and severity of the disorder may vary greatly in individuals with Conradi-Hünermann syndrome. Symptoms may manifest anytime between early life to adulthood. Conradi-Hünermann syndrome is classified as a form of chondrodysplasia punctata, a group of disorders characterized by the formation of small, hardened spots of calcium on the “growing portion” or heads of the long bones (stippled epiphyses), the bones of the spine (vertebrae), the windpipe (trachea) and parts of the ribs. Skeletal findings in Conradi-Hünermann syndrome present as asymmetric shortening of long bones, particularly those of the upper arms (humeri), thighs (femora) and of the hands and feet. Individuals with Conradi-Hünermann syndrome may also have abnormalities in the curvature of the spine as well as growth deficiency that can cause short stature. Individuals with Conradi-Hünermann syndrome can have differences in the way the skull bones are formed, and this can be seen as a face or head that is asymmetric, prominent forehead, flattened midfacial regions (midfacial hypoplasia) and a low nasal bridge. Eye findings in Conradi-Hünermann syndrome can include cataracts at birth or early in life, abnormally small eyeballs (microphthalmia), small corneas (microcornea) and loss of transparency of the lenses of the eyes (cataracts). Many individuals with Conradi-Hünermann syndrome also present with sparse, coarse scalp hair, flattened and split nail plates and/or abnormal thickening, dryness, and scaling of the skin. Conradi-Hünermann syndrome is inherited as an X-linked dominant manner; this means that the disorder primarily affects females and can lead to fetal death in males. Treatment is dependent on the individual’s symptoms and no cure exists for Conradi-Hünermann syndrome.IntroductionConradi-Hünermann syndrome is named after Dr. Conradi and Dr. Hünermann, who described this condition in medical literature in 1931. In the 1970’s, Dr. Happle contributed additional information about the signs and symptoms, inheritance and causes of this syndrome which is why this condition is also referred to as Conradi-Hünermann-Happle syndrome. | 321 | Conradi Hünermann Syndrome |
nord_321_1 | Symptoms of Conradi Hünermann Syndrome | The symptoms, progression and severity of Conradi-Hünermann syndrome can vary dramatically, even among members of the same family. The disorder can cause serious complications at birth or be so mild that individuals may not be identified until adulthood (usually after having a child with Conradi-Hünermann syndrome). It is important to note that individuals with Conradi-Hünermann syndrome may not have all of the symptoms discussed below. Individuals with Conradi-Hünermann syndrome should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis. The classic symptoms of Conradi-Hünermann syndrome involve the skeleton, skin and eyes. Intelligence is usually unaffected.Growth Infants with Conradi-Hünermann syndrome may fail to grow and gain weight at the rate expected for their age and sex (failure to thrive). Growth deficiencies may ultimately result in a final adult height that is below normal (short stature). Some infants with Conradi-Hünermann syndrome are susceptible to recurrent infections.Skeletal FindingsInfants with Conradi-Hünermann syndrome have small, hardened spots of calcium on the “growing portion” or heads of the long bones (stippled epiphyses) as well as other areas of the cartilaginous skeleton. Cartilage is a tough, elastic type of connective tissue that provides cushion and structure within the body. When the skeleton begins to develop, it mostly consists of cartilage, which is gradually replaced by bone. The development of these abnormal calcified spots is also known as chondrodysplasia punctata. In infants with Conradi-Hünermann syndrome, punctate calcifications may develop throughout the spinal column, pelvis, front ends of the ribs (costal cartilages), breastbone, shoulder blades, collarbones, and, in rare cases, the voice-box (larynx) and windpipe (trachea). Chondrodysplasia punctata tends to resolve on its own within the first few years of life.Individuals with Conradi-Hünermann syndrome typically have additional skeletal abnormalities. This commonly includes asymmetric shortening of long bones of the limbs, particularly those of the upper arms (humeri) and the thigh bones (femora). This causes a disproportionate length of the arms and legs with one side typically more impacted than the other. Individuals with Conradi-Hünermann syndrome also frequently have abnormal sideways and front-to-back curvature of the spine (scoliosis or kyphoscoliosis). Abnormal stiffness of the joints or joints that are fixed or locked in a bent position (flexion contractures) may also occur. In some patients, other skeletal abnormalities have also been reported including malformation of the hips (hip dysplasia), defects of the spinal column and deformities in which the feet are abnormally twisted out of shape or position (clubbed feet).Eye findings Some individuals with Conradi-Hünermann syndrome have clouding of the lenses of the eye (cataracts). Cataracts may be present at birth (congenital) or may develop during infancy. Cataracts may affect one or both eyes and can cause blurred vision or decreased clarity of vision. Rarely, additional eye (ocular) abnormalities include abnormally small eyes (microphthalmos), abnormally small corneas (microcornea), down-slanting eyelid folds (palpebral fissures), rapid, involuntary eye movements (nystagmus) and degeneration of the main nerve that transmits nerve impulses from the retina to the brain (optic atrophy). In some patients, eye abnormalities can significantly reduce vision.Facial features Individuals with Conradi-Hünermann syndrome can have distinctive facial features which include an unusually prominent forehead (frontal bossing), flattened cheekbones (malar hypoplasia), a flattened bridge of the nose, upturned nostrils (anteverted nares) and malformed (dysplastic) ears. Hearing loss has been reported in some patients.Skin findingsIn the newborn period, many infants with Conradi-Hünermann syndrome can have redness (erythema) and unusual thickening, dryness and scaling of the skin (ichthyosiform erythroderma) distributed in a linear, blotchy pattern over the body. Although the eruption usually resolves during infancy, older children may subsequently develop inflammation and wasting (atrophy) of follicles (follicular atrophoderma), causing pores to appear unusually large. In some patients, areas of the skin may be darker or lighter than surrounding areas (hyper- and hypopigmentation). Patchy areas of hair loss and scarring may develop on the scalp (cicatricial alopecia). The sparse scalp hair may also be unusually coarse and lusterless.Other features reported in individuals with Conradi-Hünermann include abnormal calcifications and potential narrowing (stenosis) of the windpipe (trachea) and/or the larynx, which connects the throat and the trachea; an unusually short neck; abnormalities of the nails such as flattened or split nails; and/or other physical findings.Typically, individuals with Conradi-Hünermann syndrome have a life expectancy similar to that of the general population unless they have severe spine problems (scoliosis) that affect lung and heart function. The intelligence of individuals with Conradi-Hünermann syndrome is usually not affected. | Symptoms of Conradi Hünermann Syndrome. The symptoms, progression and severity of Conradi-Hünermann syndrome can vary dramatically, even among members of the same family. The disorder can cause serious complications at birth or be so mild that individuals may not be identified until adulthood (usually after having a child with Conradi-Hünermann syndrome). It is important to note that individuals with Conradi-Hünermann syndrome may not have all of the symptoms discussed below. Individuals with Conradi-Hünermann syndrome should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis. The classic symptoms of Conradi-Hünermann syndrome involve the skeleton, skin and eyes. Intelligence is usually unaffected.Growth Infants with Conradi-Hünermann syndrome may fail to grow and gain weight at the rate expected for their age and sex (failure to thrive). Growth deficiencies may ultimately result in a final adult height that is below normal (short stature). Some infants with Conradi-Hünermann syndrome are susceptible to recurrent infections.Skeletal FindingsInfants with Conradi-Hünermann syndrome have small, hardened spots of calcium on the “growing portion” or heads of the long bones (stippled epiphyses) as well as other areas of the cartilaginous skeleton. Cartilage is a tough, elastic type of connective tissue that provides cushion and structure within the body. When the skeleton begins to develop, it mostly consists of cartilage, which is gradually replaced by bone. The development of these abnormal calcified spots is also known as chondrodysplasia punctata. In infants with Conradi-Hünermann syndrome, punctate calcifications may develop throughout the spinal column, pelvis, front ends of the ribs (costal cartilages), breastbone, shoulder blades, collarbones, and, in rare cases, the voice-box (larynx) and windpipe (trachea). Chondrodysplasia punctata tends to resolve on its own within the first few years of life.Individuals with Conradi-Hünermann syndrome typically have additional skeletal abnormalities. This commonly includes asymmetric shortening of long bones of the limbs, particularly those of the upper arms (humeri) and the thigh bones (femora). This causes a disproportionate length of the arms and legs with one side typically more impacted than the other. Individuals with Conradi-Hünermann syndrome also frequently have abnormal sideways and front-to-back curvature of the spine (scoliosis or kyphoscoliosis). Abnormal stiffness of the joints or joints that are fixed or locked in a bent position (flexion contractures) may also occur. In some patients, other skeletal abnormalities have also been reported including malformation of the hips (hip dysplasia), defects of the spinal column and deformities in which the feet are abnormally twisted out of shape or position (clubbed feet).Eye findings Some individuals with Conradi-Hünermann syndrome have clouding of the lenses of the eye (cataracts). Cataracts may be present at birth (congenital) or may develop during infancy. Cataracts may affect one or both eyes and can cause blurred vision or decreased clarity of vision. Rarely, additional eye (ocular) abnormalities include abnormally small eyes (microphthalmos), abnormally small corneas (microcornea), down-slanting eyelid folds (palpebral fissures), rapid, involuntary eye movements (nystagmus) and degeneration of the main nerve that transmits nerve impulses from the retina to the brain (optic atrophy). In some patients, eye abnormalities can significantly reduce vision.Facial features Individuals with Conradi-Hünermann syndrome can have distinctive facial features which include an unusually prominent forehead (frontal bossing), flattened cheekbones (malar hypoplasia), a flattened bridge of the nose, upturned nostrils (anteverted nares) and malformed (dysplastic) ears. Hearing loss has been reported in some patients.Skin findingsIn the newborn period, many infants with Conradi-Hünermann syndrome can have redness (erythema) and unusual thickening, dryness and scaling of the skin (ichthyosiform erythroderma) distributed in a linear, blotchy pattern over the body. Although the eruption usually resolves during infancy, older children may subsequently develop inflammation and wasting (atrophy) of follicles (follicular atrophoderma), causing pores to appear unusually large. In some patients, areas of the skin may be darker or lighter than surrounding areas (hyper- and hypopigmentation). Patchy areas of hair loss and scarring may develop on the scalp (cicatricial alopecia). The sparse scalp hair may also be unusually coarse and lusterless.Other features reported in individuals with Conradi-Hünermann include abnormal calcifications and potential narrowing (stenosis) of the windpipe (trachea) and/or the larynx, which connects the throat and the trachea; an unusually short neck; abnormalities of the nails such as flattened or split nails; and/or other physical findings.Typically, individuals with Conradi-Hünermann syndrome have a life expectancy similar to that of the general population unless they have severe spine problems (scoliosis) that affect lung and heart function. The intelligence of individuals with Conradi-Hünermann syndrome is usually not affected. | 321 | Conradi Hünermann Syndrome |
nord_321_2 | Causes of Conradi Hünermann Syndrome | Conradi-Hünermann syndrome is caused by particular changes that disrupt the function of the emopamil-binding protein (EBP) gene. This gene codes for a substance called 3β-hydroxysteroid-∆8,∆7- isomerase or sterol-∆8-isomerase, that works to excite a reaction (enzyme). This enzyme is important in the final steps of the production of cholesterol. Cholesterol is a waxy, fat substance that is present in all the cells of the body. Cholesterol is produced by our cells and obtained by the food we consume. Although too much cholesterol increases our risk for heart disease, cholesterol plays an important role in development before and after birth. The lack of cholesterol has been shown to disrupt certain molecular signaling that impacts the development of the limbs of a fetus. As a result of the dysfunction of sterol-∆8-isomerase, there is an accumulation of substances that precede cholesterol (precursor compounds) called sterols that accumulate and are toxic. How exactly the disruption of cholesterol production results in the signs and symptoms associated with Conradi-Hünermann syndrome are not fully understood.Changes in the EBP gene that cause Conradi-Hünermann syndrome (pathogenic variants) can occur due to random chance (i.e., de novo) in the affected person or can be inherited in an X-linked dominant manner. X-linked dominant disorders are conditions caused by a non-working gene on the X chromosome. Females have two X chromosomes, whereas males have one X chromosome and one Y chromosome. In females, disease traits on the X chromosome can be masked by the normal gene on the other X chromosome. Since only one functioning X chromosome is required in males and females, one of the X chromosomes in each cell of a female is essentially “turned off”, usually in a random pattern (random X chromosome inactivation). Therefore, if the X chromosome with the gene mutation is activated in some cells, female carriers may manifest certain, typically more variable features of Conradi-Hünermann syndrome. Since males only have one X chromosome, if they inherit a disease gene present on the X chromosome, it will always be turned on. Males who inherit the disease-causing gene for EPB typically have more severe symptoms which may not be compatible with life and lead to loss of the pregnancy. However, males have been reported with Conradi-Hünermann syndrome. Typically these males have portions of the cells in their bodies that carry the affected EPB gene while other cells do not (mosaic) or they have an additional X chromosome (XXY chromosomal makeup). Males with a disease gene for an X-linked disorder transmit the gene to their all of daughters but not to their sons. Women with a copy of the disease gene have a 50 percent risk of transmitting the gene to their daughters and their sons.In some people with Conradi-Hünermann syndrome, where there is no apparent family history, the disorder may have occured due to differences in the genetic makeup of a person’s reproductive cells (gonadal mosaicism). This includes rare instances in which more than one child of apparently unaffected parents have the disorder. In gonadal mosaicism, some of a parent’s reproductive cells (germ cells) may carry the gene mutation while others contain a normal cell line (mosaicism). As a result, one or more of the parent’s children may inherit the gene mutation, potentially leading to the disorder, while the parent may have no apparent symptoms (asymptomatic carrier). Gonadal mosaicism may be suspected when apparently unaffected parents have more than one child with the same genetic abnormality. Within families, there is variation in the severity of the clinical picture between affected females, and this is largely secondary to differences in X-inactivation. | Causes of Conradi Hünermann Syndrome. Conradi-Hünermann syndrome is caused by particular changes that disrupt the function of the emopamil-binding protein (EBP) gene. This gene codes for a substance called 3β-hydroxysteroid-∆8,∆7- isomerase or sterol-∆8-isomerase, that works to excite a reaction (enzyme). This enzyme is important in the final steps of the production of cholesterol. Cholesterol is a waxy, fat substance that is present in all the cells of the body. Cholesterol is produced by our cells and obtained by the food we consume. Although too much cholesterol increases our risk for heart disease, cholesterol plays an important role in development before and after birth. The lack of cholesterol has been shown to disrupt certain molecular signaling that impacts the development of the limbs of a fetus. As a result of the dysfunction of sterol-∆8-isomerase, there is an accumulation of substances that precede cholesterol (precursor compounds) called sterols that accumulate and are toxic. How exactly the disruption of cholesterol production results in the signs and symptoms associated with Conradi-Hünermann syndrome are not fully understood.Changes in the EBP gene that cause Conradi-Hünermann syndrome (pathogenic variants) can occur due to random chance (i.e., de novo) in the affected person or can be inherited in an X-linked dominant manner. X-linked dominant disorders are conditions caused by a non-working gene on the X chromosome. Females have two X chromosomes, whereas males have one X chromosome and one Y chromosome. In females, disease traits on the X chromosome can be masked by the normal gene on the other X chromosome. Since only one functioning X chromosome is required in males and females, one of the X chromosomes in each cell of a female is essentially “turned off”, usually in a random pattern (random X chromosome inactivation). Therefore, if the X chromosome with the gene mutation is activated in some cells, female carriers may manifest certain, typically more variable features of Conradi-Hünermann syndrome. Since males only have one X chromosome, if they inherit a disease gene present on the X chromosome, it will always be turned on. Males who inherit the disease-causing gene for EPB typically have more severe symptoms which may not be compatible with life and lead to loss of the pregnancy. However, males have been reported with Conradi-Hünermann syndrome. Typically these males have portions of the cells in their bodies that carry the affected EPB gene while other cells do not (mosaic) or they have an additional X chromosome (XXY chromosomal makeup). Males with a disease gene for an X-linked disorder transmit the gene to their all of daughters but not to their sons. Women with a copy of the disease gene have a 50 percent risk of transmitting the gene to their daughters and their sons.In some people with Conradi-Hünermann syndrome, where there is no apparent family history, the disorder may have occured due to differences in the genetic makeup of a person’s reproductive cells (gonadal mosaicism). This includes rare instances in which more than one child of apparently unaffected parents have the disorder. In gonadal mosaicism, some of a parent’s reproductive cells (germ cells) may carry the gene mutation while others contain a normal cell line (mosaicism). As a result, one or more of the parent’s children may inherit the gene mutation, potentially leading to the disorder, while the parent may have no apparent symptoms (asymptomatic carrier). Gonadal mosaicism may be suspected when apparently unaffected parents have more than one child with the same genetic abnormality. Within families, there is variation in the severity of the clinical picture between affected females, and this is largely secondary to differences in X-inactivation. | 321 | Conradi Hünermann Syndrome |
nord_321_3 | Affects of Conradi Hünermann Syndrome | Conradi-Hünermann syndrome is a rare disorder that almost exclusively affects females. The exact incidence of the disorder in the general population is unknown, but one estimate is that 1 in 100,000 to 1 in 200,000 individuals are born with Conradi-Hünermann syndrome. The disorder is often apparent at birth (congenital), but some individuals with mild cases may not be identified until adulthood. | Affects of Conradi Hünermann Syndrome. Conradi-Hünermann syndrome is a rare disorder that almost exclusively affects females. The exact incidence of the disorder in the general population is unknown, but one estimate is that 1 in 100,000 to 1 in 200,000 individuals are born with Conradi-Hünermann syndrome. The disorder is often apparent at birth (congenital), but some individuals with mild cases may not be identified until adulthood. | 321 | Conradi Hünermann Syndrome |
nord_321_4 | Related disorders of Conradi Hünermann Syndrome | Symptoms of the following disorders can be similar to those of Conradi-Hünermann syndrome. Comparisons may be useful for a differential diagnosis.Male EBP disorder with neurologic defects (MEND) is a condition caused by a genetic alteration that does not completely disrupt the function of the EBP gene. Unlike Conradi-Hünermann syndrome, which causes the complete disruption of the EBP gene, males with MEND present with moderate-to-severe developmental delay, malformations such as the absence of a part of the brain that connects the hemispheres of the brain (agenesis of the corpus callosum) and abnormalities in the ridges of the cerebral cortex (major gyral). Males with MEND may have a large nasal bridge, ears that are lower than expected and a large front soft spot (anterior fontanelle). MEND in males can also present with other findings such as webbing of the fingers, extra fingers (polydactyly), failure of the testes descend from the abdomen to the scrotum (cryptorchidism) and an abnormality in the position of the opening at the tip of the penis (hypospadias). Males with MEND typically do not have epiphyseal stippling which is a characteristic finding in Conradi-Hünermann syndrome. Females with MEND have no clinical manifestations of the disorder. Rhizomelic chondrodysplasia punctata (RCDP) spectrum is a group of rare disorders that affect the function and structure of the peroxisomes. Peroxisomes are sac-like structures found inside cells that degrade certain compounds in cells and play a role in the production of fats that are necessary for the body. RCDP is characterized by bilateral and symmetric shortening of the upper long bone of the arms (humerus) and legs (femur), a condition known as rhizomelia. Additional findings include distinctive facial features, the formation of small, hardened spots of calcium (stippling) on the kneecap (patella) and long bones of the arms and legs (chondrodysplasia punctata), cataracts that are present at birth or shortly thereafter, profound growth deficiency after birth, intellectual disability and seizures. RCDP causes life-threatening complications during the first decade of life and in some children during the newborn (neonatal) period. Milder forms of RCDP present with less severe intellectual and developmental deficits and growth deficiency with often no rhizomelia. Many of these disorders are caused by changes in four genes PEX7 (type 1), GNPAT (type 2), AGPS (type 3), PEX5 (type 5). All of the genes that cause RCDP are inherited in an autosomal recessive pattern.X-linked recessive chondrodysplasia punctata is a form of chondrodysplasia punctata characterized by abnormal, symmetric, dotlike (punctate) calcifications within the growing ends of certain long bones (i.e., stippled epiphyses) and other regions; short stature; and underdevelopment (hypoplasia) of the bones at the ends of the fingers (distal phalanges). Additional characteristic findings may include sparse, unruly hair; ichthyosis, primarily over the neck, chest, under the arms and on the backs of the legs; and underdevelopment of the nose (nasal hypoplasia). The severity of the disorder can vary greatly from one person to another. Because the disorder is inherited in an X-linked recessive pattern, it is typically fully expressed only in males. X-linked recessive chondrodysplasia punctata is caused by deletions or genetic changes in the ARSL gene which eliminate the function of the gene. The ARSL gene produces a substance whose function is to excite a chemical reaction (enzyme) known as arylsulfatase E (ARSE). The specific function of this enzyme is still unknown. Changes in the ARSL gene have been identified in several individuals with the disorder, suggesting that altered ARSE activity plays a causative role in the development of X-linked recessive chondrodysplasia punctata.CHILD syndrome a rare genetic disorder that is apparent at birth (congenital) is characterized by distinctive skin abnormalities and limb defects affecting one side of the body (hemidysplasia). The right side of the body tends to be affected twice as much as the left side. The term “CHILD” is an acronym that stands for (C)ongenital (H)emidysplasia with (I)chthyosiform erythroderma and (L)imb (D)efects. The disorder is associated with mild growth deficiency before birth; stippled epiphyses; limb malformations on one side of the body (unilateral), which may range from underdevelopment (hypoplasia) of finger bones to absence of a limb; unilateral redness (erythema) and unusual thickening, dryness, and scaling of the skin (ichthyosiform erythroderma); and/or unilateral hair loss (alopecia). CHILD syndrome may also be characterized by underdevelopment or incomplete development (hypoplasia) of other tissues or organs on the affected side, such as other skeletal regions, the brain, spinal cord, thyroid, adrenal gland and/or lung. Additional features may include an abnormal opening in the partition that separates the upper or lower chambers of the heart (cardiac septal defects). The majority of cases are due to genetic change in the NSDHL gene on the X chromosome. The gene encodes a steroid dehydrogenase enzyme that also plays a role in cholesterol metabolism. CHILD syndrome is inherited in an X-linked dominant pattern. (For more information on this disorder, choose “CHILD” as your search term in the Rare Disease Database.)Fetal warfarin syndrome, which may also be referred to as coumarin embryopathy, is a characteristic pattern of birth defects in a newborn resulting from exposure to certain anti-clotting drugs (i.e., coumarin anticoagulants [vitamin K antagonists]), such as warfarin, during pregnancy. Evidence suggests that the greatest period of risk occurs from approximately six to nine weeks following conception. The most common feature is midfacial hypoplasia, with an unusually small, flattened nose; a deep groove between the “wings” of the nose (alae) and the tip; and abnormally small nostrils. Additional characteristic features may include stippled epiphyses, disproportionate short stature, intellectual disability, eye abnormalities, hearing loss, sudden episodes of uncontrolled electrical activity in the brain (seizures) and/or other abnormalities. Conradi-Hünermann syndrome and other forms of chondrodysplasia punctata must be differentiated from the fetal effects of warfarin or other coumarin anticoagulants.There are additional disorders that involve chondrodysplasia punctata or other skeletal symptoms similar to those found in Conradi-Hünermann syndrome. These disorders include Zellweger spectrum disorders, Smith-Lemli-Optiz syndrome, Keutel syndrome, Antley-Bixler syndrome, desmosterolosis, lathosterolosis, Greenberg dysplasia and chondrodysplasia punctata, tibia-metacarpal type, Astley-Kendall dysplasia, maternal autoimmune disease (systemic lupus, mixed connective tissue disease and scleroderma). There are other disorders that have skin abnormalities similar to those found in Conradi-Hünermann syndrome, including other forms of ichthyosis. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | Related disorders of Conradi Hünermann Syndrome. Symptoms of the following disorders can be similar to those of Conradi-Hünermann syndrome. Comparisons may be useful for a differential diagnosis.Male EBP disorder with neurologic defects (MEND) is a condition caused by a genetic alteration that does not completely disrupt the function of the EBP gene. Unlike Conradi-Hünermann syndrome, which causes the complete disruption of the EBP gene, males with MEND present with moderate-to-severe developmental delay, malformations such as the absence of a part of the brain that connects the hemispheres of the brain (agenesis of the corpus callosum) and abnormalities in the ridges of the cerebral cortex (major gyral). Males with MEND may have a large nasal bridge, ears that are lower than expected and a large front soft spot (anterior fontanelle). MEND in males can also present with other findings such as webbing of the fingers, extra fingers (polydactyly), failure of the testes descend from the abdomen to the scrotum (cryptorchidism) and an abnormality in the position of the opening at the tip of the penis (hypospadias). Males with MEND typically do not have epiphyseal stippling which is a characteristic finding in Conradi-Hünermann syndrome. Females with MEND have no clinical manifestations of the disorder. Rhizomelic chondrodysplasia punctata (RCDP) spectrum is a group of rare disorders that affect the function and structure of the peroxisomes. Peroxisomes are sac-like structures found inside cells that degrade certain compounds in cells and play a role in the production of fats that are necessary for the body. RCDP is characterized by bilateral and symmetric shortening of the upper long bone of the arms (humerus) and legs (femur), a condition known as rhizomelia. Additional findings include distinctive facial features, the formation of small, hardened spots of calcium (stippling) on the kneecap (patella) and long bones of the arms and legs (chondrodysplasia punctata), cataracts that are present at birth or shortly thereafter, profound growth deficiency after birth, intellectual disability and seizures. RCDP causes life-threatening complications during the first decade of life and in some children during the newborn (neonatal) period. Milder forms of RCDP present with less severe intellectual and developmental deficits and growth deficiency with often no rhizomelia. Many of these disorders are caused by changes in four genes PEX7 (type 1), GNPAT (type 2), AGPS (type 3), PEX5 (type 5). All of the genes that cause RCDP are inherited in an autosomal recessive pattern.X-linked recessive chondrodysplasia punctata is a form of chondrodysplasia punctata characterized by abnormal, symmetric, dotlike (punctate) calcifications within the growing ends of certain long bones (i.e., stippled epiphyses) and other regions; short stature; and underdevelopment (hypoplasia) of the bones at the ends of the fingers (distal phalanges). Additional characteristic findings may include sparse, unruly hair; ichthyosis, primarily over the neck, chest, under the arms and on the backs of the legs; and underdevelopment of the nose (nasal hypoplasia). The severity of the disorder can vary greatly from one person to another. Because the disorder is inherited in an X-linked recessive pattern, it is typically fully expressed only in males. X-linked recessive chondrodysplasia punctata is caused by deletions or genetic changes in the ARSL gene which eliminate the function of the gene. The ARSL gene produces a substance whose function is to excite a chemical reaction (enzyme) known as arylsulfatase E (ARSE). The specific function of this enzyme is still unknown. Changes in the ARSL gene have been identified in several individuals with the disorder, suggesting that altered ARSE activity plays a causative role in the development of X-linked recessive chondrodysplasia punctata.CHILD syndrome a rare genetic disorder that is apparent at birth (congenital) is characterized by distinctive skin abnormalities and limb defects affecting one side of the body (hemidysplasia). The right side of the body tends to be affected twice as much as the left side. The term “CHILD” is an acronym that stands for (C)ongenital (H)emidysplasia with (I)chthyosiform erythroderma and (L)imb (D)efects. The disorder is associated with mild growth deficiency before birth; stippled epiphyses; limb malformations on one side of the body (unilateral), which may range from underdevelopment (hypoplasia) of finger bones to absence of a limb; unilateral redness (erythema) and unusual thickening, dryness, and scaling of the skin (ichthyosiform erythroderma); and/or unilateral hair loss (alopecia). CHILD syndrome may also be characterized by underdevelopment or incomplete development (hypoplasia) of other tissues or organs on the affected side, such as other skeletal regions, the brain, spinal cord, thyroid, adrenal gland and/or lung. Additional features may include an abnormal opening in the partition that separates the upper or lower chambers of the heart (cardiac septal defects). The majority of cases are due to genetic change in the NSDHL gene on the X chromosome. The gene encodes a steroid dehydrogenase enzyme that also plays a role in cholesterol metabolism. CHILD syndrome is inherited in an X-linked dominant pattern. (For more information on this disorder, choose “CHILD” as your search term in the Rare Disease Database.)Fetal warfarin syndrome, which may also be referred to as coumarin embryopathy, is a characteristic pattern of birth defects in a newborn resulting from exposure to certain anti-clotting drugs (i.e., coumarin anticoagulants [vitamin K antagonists]), such as warfarin, during pregnancy. Evidence suggests that the greatest period of risk occurs from approximately six to nine weeks following conception. The most common feature is midfacial hypoplasia, with an unusually small, flattened nose; a deep groove between the “wings” of the nose (alae) and the tip; and abnormally small nostrils. Additional characteristic features may include stippled epiphyses, disproportionate short stature, intellectual disability, eye abnormalities, hearing loss, sudden episodes of uncontrolled electrical activity in the brain (seizures) and/or other abnormalities. Conradi-Hünermann syndrome and other forms of chondrodysplasia punctata must be differentiated from the fetal effects of warfarin or other coumarin anticoagulants.There are additional disorders that involve chondrodysplasia punctata or other skeletal symptoms similar to those found in Conradi-Hünermann syndrome. These disorders include Zellweger spectrum disorders, Smith-Lemli-Optiz syndrome, Keutel syndrome, Antley-Bixler syndrome, desmosterolosis, lathosterolosis, Greenberg dysplasia and chondrodysplasia punctata, tibia-metacarpal type, Astley-Kendall dysplasia, maternal autoimmune disease (systemic lupus, mixed connective tissue disease and scleroderma). There are other disorders that have skin abnormalities similar to those found in Conradi-Hünermann syndrome, including other forms of ichthyosis. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | 321 | Conradi Hünermann Syndrome |
nord_321_5 | Diagnosis of Conradi Hünermann Syndrome | A diagnosis of Conradi-Hünermann syndrome is based upon identification of characteristic symptoms, a detailed medical history, thorough clinical evaluation and a variety of specialized tests. X-ray (radiographic), eye (ophthalmologic), skin (dermatological), tissue examination (histological exam) and biochemical examinations may be performed to help diagnose Conradi-Hünermann syndrome.
X-ray evaluation looks for characteristic stippling of epiphyses, specked calcium deposits in the bones and other regions of the cartilaginous skeleton (See the “signs and symptoms” section for additional information on stippling of epiphyses). However, there is loss of distinctive epiphyseal stippling over time, potentially making diagnosis difficult.An important test to confirm a diagnosis of Conradi-Hünermann syndrome is a blood test that looks for elevated levels of substances called sterols. Genetic changes in the EBP gene result in higher levels of sterols (8(9)-cholesterol and 8-dehydrocholesterol) in the blood and certain tissues of the body.
In individuals with skin findings, affected areas of the skin can be analyzed under a microscope (histologic examination) to see if there is thickening and small opening of the outer layer (ostial hyperkeratosis) of the hair follicle with calcium deposits. This finding is common in Conradi-Hünermann syndrome but can also be found in a few other conditions. A diagnosis of Conradi-Hünermann syndrome can also be confirmed through molecular genetic testing, which may identify the characteristic genetic mutation that causes the disorder. Genetic testing for males may require additional tests to see whether they carry an additional X chromosome (46, XXY males) or if they are mosaic for a genetic change in the EBP gene (See the “causes” section for additional information on mosaic males).Clinical Testing and Work-UpInitial evaluation to establish a diagnosis typically requires the help of a multidisciplinary team of specialists. Individuals with suspected Conradi-Hünermann syndrome should have the following evaluations: | Diagnosis of Conradi Hünermann Syndrome. A diagnosis of Conradi-Hünermann syndrome is based upon identification of characteristic symptoms, a detailed medical history, thorough clinical evaluation and a variety of specialized tests. X-ray (radiographic), eye (ophthalmologic), skin (dermatological), tissue examination (histological exam) and biochemical examinations may be performed to help diagnose Conradi-Hünermann syndrome.
X-ray evaluation looks for characteristic stippling of epiphyses, specked calcium deposits in the bones and other regions of the cartilaginous skeleton (See the “signs and symptoms” section for additional information on stippling of epiphyses). However, there is loss of distinctive epiphyseal stippling over time, potentially making diagnosis difficult.An important test to confirm a diagnosis of Conradi-Hünermann syndrome is a blood test that looks for elevated levels of substances called sterols. Genetic changes in the EBP gene result in higher levels of sterols (8(9)-cholesterol and 8-dehydrocholesterol) in the blood and certain tissues of the body.
In individuals with skin findings, affected areas of the skin can be analyzed under a microscope (histologic examination) to see if there is thickening and small opening of the outer layer (ostial hyperkeratosis) of the hair follicle with calcium deposits. This finding is common in Conradi-Hünermann syndrome but can also be found in a few other conditions. A diagnosis of Conradi-Hünermann syndrome can also be confirmed through molecular genetic testing, which may identify the characteristic genetic mutation that causes the disorder. Genetic testing for males may require additional tests to see whether they carry an additional X chromosome (46, XXY males) or if they are mosaic for a genetic change in the EBP gene (See the “causes” section for additional information on mosaic males).Clinical Testing and Work-UpInitial evaluation to establish a diagnosis typically requires the help of a multidisciplinary team of specialists. Individuals with suspected Conradi-Hünermann syndrome should have the following evaluations: | 321 | Conradi Hünermann Syndrome |
nord_321_6 | Therapies of Conradi Hünermann Syndrome | TreatmentThe treatment of Conradi-Hünermann syndrome is directed toward the specific symptoms that each individual has. Such treatment may require the coordinated efforts of a team of medical professionals, such as pediatricians; physicians who diagnose and treat disorders of the skeleton, joints, muscles, and related tissues (orthopedists); skin specialists (dermatologists); eye specialists; and/or other health care professionals.Various orthopedic measures, including surgery, may be recommended to help prevent, treat, or correct certain skeletal abnormalities associated with the disorder. Surgery may also be advised for certain craniofacial malformations, scoliosis or other physical abnormalities. The surgical procedures performed will depend on the nature, severity, and combination of anatomical abnormalities, their associated symptoms and other factors.Recommended treatment for congenital cataracts may include early surgical removal of the cataracts (when they interfere with vision); implantation of artificial lenses in some patients; and/or certain measures following surgery, such as the use of corrective lenses, to help achieve good vision.For those individuals with ichthyosis and skin abnormalities, supportive measures may be recommended, such as bathing with bath oil and/or applying appropriate skin ointments and lubricants that soften and soothe the skin (emollients). Sun protection (sunscreen) is also recommended as well avoiding using emollients when exposed to the sun as that can lead to sunburn. For individuals with hearing loss, standard treatment is provided based on the recommendation of the physicians who specializes in ear conditions (otolaryngologist) and community services can be offered through early intervention services. Genetic counseling is recommended for affected individuals with and their families to coordinate genetic testing, talk about the risk to family members and discuss family planning. Social workers can help families identify local resources and arrange ongoing support (i.e., palliative care or home nursing). | Therapies of Conradi Hünermann Syndrome. TreatmentThe treatment of Conradi-Hünermann syndrome is directed toward the specific symptoms that each individual has. Such treatment may require the coordinated efforts of a team of medical professionals, such as pediatricians; physicians who diagnose and treat disorders of the skeleton, joints, muscles, and related tissues (orthopedists); skin specialists (dermatologists); eye specialists; and/or other health care professionals.Various orthopedic measures, including surgery, may be recommended to help prevent, treat, or correct certain skeletal abnormalities associated with the disorder. Surgery may also be advised for certain craniofacial malformations, scoliosis or other physical abnormalities. The surgical procedures performed will depend on the nature, severity, and combination of anatomical abnormalities, their associated symptoms and other factors.Recommended treatment for congenital cataracts may include early surgical removal of the cataracts (when they interfere with vision); implantation of artificial lenses in some patients; and/or certain measures following surgery, such as the use of corrective lenses, to help achieve good vision.For those individuals with ichthyosis and skin abnormalities, supportive measures may be recommended, such as bathing with bath oil and/or applying appropriate skin ointments and lubricants that soften and soothe the skin (emollients). Sun protection (sunscreen) is also recommended as well avoiding using emollients when exposed to the sun as that can lead to sunburn. For individuals with hearing loss, standard treatment is provided based on the recommendation of the physicians who specializes in ear conditions (otolaryngologist) and community services can be offered through early intervention services. Genetic counseling is recommended for affected individuals with and their families to coordinate genetic testing, talk about the risk to family members and discuss family planning. Social workers can help families identify local resources and arrange ongoing support (i.e., palliative care or home nursing). | 321 | Conradi Hünermann Syndrome |
nord_322_0 | Overview of COPA Syndrome | Summary COPA syndrome is a rare, genetic autoimmune disorder that can affect multiple systems of the body, especially the lungs, kidneys, and joints. Symptoms usually appear in childhood during the first or second decade of life. The signs and symptoms, and the severity of the disorder can be very different in one person when compared to another. This is true even for members of the same family. COPA syndrome is an immune-mediated disorder, which means that the characteristic inflammation results from abnormal functioning (dysregulation) of the immune system and the presence of specific autoantibodies. The disorder is caused by variations (mutations) in the COPA gene and occurs spontaneously as a new variation, or is inherited in an autosomal dominant pattern. COPA syndrome has been described as having features of both autoimmune disorders and autoinflammatory disorders. An autoimmune disorder is one in which the body’s adaptive immune system, which protects the body from infectious or other foreign substances, mistakenly attacks healthy tissue instead. Autoinflammatory syndromes are a group of disorders characterized by recurrent episodes of inflammation due to an abnormality of the innate immune system. | Overview of COPA Syndrome. Summary COPA syndrome is a rare, genetic autoimmune disorder that can affect multiple systems of the body, especially the lungs, kidneys, and joints. Symptoms usually appear in childhood during the first or second decade of life. The signs and symptoms, and the severity of the disorder can be very different in one person when compared to another. This is true even for members of the same family. COPA syndrome is an immune-mediated disorder, which means that the characteristic inflammation results from abnormal functioning (dysregulation) of the immune system and the presence of specific autoantibodies. The disorder is caused by variations (mutations) in the COPA gene and occurs spontaneously as a new variation, or is inherited in an autosomal dominant pattern. COPA syndrome has been described as having features of both autoimmune disorders and autoinflammatory disorders. An autoimmune disorder is one in which the body’s adaptive immune system, which protects the body from infectious or other foreign substances, mistakenly attacks healthy tissue instead. Autoinflammatory syndromes are a group of disorders characterized by recurrent episodes of inflammation due to an abnormality of the innate immune system. | 322 | COPA Syndrome |
nord_322_1 | Symptoms of COPA Syndrome | Although researchers have been able to establish a clear syndrome with characteristic or “core” symptoms, much about the disorder is not fully understood. Several factors including the small number of identified patients, the lack of large clinical studies, and the possibility of other genes or factors (e.g. environmental factors) influencing the disorder 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. Individuals and parents should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.Lung disease associated with COPA syndrome can be classified as interstitial lung disease (ILD), which is a general term for disorders that cause progressive scarring of the lungs. Lung disease may occur before the development of joint disease. General symptoms associated with lung disease include a chronic or persistent cough, shortness of breath, and abnormal, rapid breathing (tachypnea). Affected individuals may also develop inflammation of the air passages of the lungs (bronchitis) and lung cysts. Chronic wheezing and chest pain can also occur. There can be a slow, gradual decline in lung function. About half of individuals with COPA syndrome experience bleeding from the alveoli (alveolar hemorrhaging). The lungs contain millions of tiny air sacs called alveoli. When a person breathes in air, oxygen travels to the lungs and into the alveoli. It passes through the walls of the alveoli into tiny blood vessels called capillaries and then into the bloodstream to be carried throughout the body. Alveolar hemorrhaging is a severe complication that can cause coughing up of blood (hemoptysis) and low levels of circulating red blood cells (anemia). Anemia can cause fatigue, lightheadedness, pale skin color, dizziness, rapid heartbeat, and shortness of breath. Alveolar hemorrhaging is a potentially life-threatening complication that can lead to blood through the lungs (diffuse pulmonary infiltrates) and a rapid inability to breathe (acute respiratory failure). Many affected individuals will develop inflammation of the joints (arthritis). Affected joints have included large joints such as the shoulders and knees, and smaller joints like those found in the fingers. Affected individuals experience pain, swelling, and stiffness of the affected joints. Joint pain can potentially be severe and debilitating. Symptoms may be worse upon waking. Children can also experience severe arthritis. Arthritis can sometimes develop before symptoms of lung disease. Affected individuals may also develop inflammation of the kidneys (nephritis). Progressive damage to the kidneys can lead to blood in the urine (hematuria), abnormal levels of protein in the urine (proteinuria), and decreased urine output. Eventually, swelling due to fluid accumulation (edema) and reduced kidney function develop. Some individuals develop scarring (fibrosis) of the kidneys. Other conditions have been reported to occur in a few individuals with COPA syndrome include inflammation of the spinal cord and optic nerve (neuromyelitis optica) and the degeneration of the bone near where the long bone of the leg meets the hip (avascular necrosis). However, it is not known whether these are potential complications of the disorder, or coincidental findings. | Symptoms of COPA Syndrome. Although researchers have been able to establish a clear syndrome with characteristic or “core” symptoms, much about the disorder is not fully understood. Several factors including the small number of identified patients, the lack of large clinical studies, and the possibility of other genes or factors (e.g. environmental factors) influencing the disorder 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. Individuals and parents should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.Lung disease associated with COPA syndrome can be classified as interstitial lung disease (ILD), which is a general term for disorders that cause progressive scarring of the lungs. Lung disease may occur before the development of joint disease. General symptoms associated with lung disease include a chronic or persistent cough, shortness of breath, and abnormal, rapid breathing (tachypnea). Affected individuals may also develop inflammation of the air passages of the lungs (bronchitis) and lung cysts. Chronic wheezing and chest pain can also occur. There can be a slow, gradual decline in lung function. About half of individuals with COPA syndrome experience bleeding from the alveoli (alveolar hemorrhaging). The lungs contain millions of tiny air sacs called alveoli. When a person breathes in air, oxygen travels to the lungs and into the alveoli. It passes through the walls of the alveoli into tiny blood vessels called capillaries and then into the bloodstream to be carried throughout the body. Alveolar hemorrhaging is a severe complication that can cause coughing up of blood (hemoptysis) and low levels of circulating red blood cells (anemia). Anemia can cause fatigue, lightheadedness, pale skin color, dizziness, rapid heartbeat, and shortness of breath. Alveolar hemorrhaging is a potentially life-threatening complication that can lead to blood through the lungs (diffuse pulmonary infiltrates) and a rapid inability to breathe (acute respiratory failure). Many affected individuals will develop inflammation of the joints (arthritis). Affected joints have included large joints such as the shoulders and knees, and smaller joints like those found in the fingers. Affected individuals experience pain, swelling, and stiffness of the affected joints. Joint pain can potentially be severe and debilitating. Symptoms may be worse upon waking. Children can also experience severe arthritis. Arthritis can sometimes develop before symptoms of lung disease. Affected individuals may also develop inflammation of the kidneys (nephritis). Progressive damage to the kidneys can lead to blood in the urine (hematuria), abnormal levels of protein in the urine (proteinuria), and decreased urine output. Eventually, swelling due to fluid accumulation (edema) and reduced kidney function develop. Some individuals develop scarring (fibrosis) of the kidneys. Other conditions have been reported to occur in a few individuals with COPA syndrome include inflammation of the spinal cord and optic nerve (neuromyelitis optica) and the degeneration of the bone near where the long bone of the leg meets the hip (avascular necrosis). However, it is not known whether these are potential complications of the disorder, or coincidental findings. | 322 | COPA Syndrome |
nord_322_2 | Causes of COPA Syndrome | COPA is caused by a variation in the coatomer protein complex subunit alpha (COPA) gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body.The COPA gene creates (encodes) a protein complex that is involved in the trafficking of other proteins from the Golgi complex to the endoplasmic reticulum. The Golgi complex (or apparatus) is a structure found in most cells that changes, sorts, packages and transports proteins. The endoplasmic reticulum is an extensive membrane network of a cell where proteins are processed. The exact manner that disease-causing variations in the COPA gene contribute to or cause the specific signs and symptoms of COPA syndrome is not fully understood. COPA syndrome is an immune-mediated disorder, which means that the characteristic inflammation results from abnormal functioning (dysregulation) of the immune system and the presence of specific autoantibodies. Antibodies are part of the immune system; they are specialized proteins that target foreign or invading organisms. Autoantibodies are ones that mistakenly attack healthy tissue. Affected individuals often develop anti-neutrophil cytoplasmic antibodies and anti-nuclear antibodies. Some individuals may be positive for rheumatoid factor. The exact role these autoantibodies play in the development of COPA syndrome is not fully understood.COPA syndrome can be inherited from a parent or it can occur as a new (sporadic or de novo) variation, which means that the gene change has occurred at the time of the formation of the egg or sperm for that child only, and no other family member will be affected. Affected individuals can then pass on the altered gene in an autosomal dominant pattern. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.COPA syndrome is described as having incomplete or reduced penetrance and variable expressivity. These are genetic terms. Incomplete penetrance means that some individuals who inherit the gene for a dominant disorder will not be affected by the disorder. Variable expressivity in a dominant disorder means that widely varying signs and symptoms can occur among affected individuals. | Causes of COPA Syndrome. COPA is caused by a variation in the coatomer protein complex subunit alpha (COPA) gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body.The COPA gene creates (encodes) a protein complex that is involved in the trafficking of other proteins from the Golgi complex to the endoplasmic reticulum. The Golgi complex (or apparatus) is a structure found in most cells that changes, sorts, packages and transports proteins. The endoplasmic reticulum is an extensive membrane network of a cell where proteins are processed. The exact manner that disease-causing variations in the COPA gene contribute to or cause the specific signs and symptoms of COPA syndrome is not fully understood. COPA syndrome is an immune-mediated disorder, which means that the characteristic inflammation results from abnormal functioning (dysregulation) of the immune system and the presence of specific autoantibodies. Antibodies are part of the immune system; they are specialized proteins that target foreign or invading organisms. Autoantibodies are ones that mistakenly attack healthy tissue. Affected individuals often develop anti-neutrophil cytoplasmic antibodies and anti-nuclear antibodies. Some individuals may be positive for rheumatoid factor. The exact role these autoantibodies play in the development of COPA syndrome is not fully understood.COPA syndrome can be inherited from a parent or it can occur as a new (sporadic or de novo) variation, which means that the gene change has occurred at the time of the formation of the egg or sperm for that child only, and no other family member will be affected. Affected individuals can then pass on the altered gene in an autosomal dominant pattern. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.COPA syndrome is described as having incomplete or reduced penetrance and variable expressivity. These are genetic terms. Incomplete penetrance means that some individuals who inherit the gene for a dominant disorder will not be affected by the disorder. Variable expressivity in a dominant disorder means that widely varying signs and symptoms can occur among affected individuals. | 322 | COPA Syndrome |
nord_322_3 | Affects of COPA Syndrome | Initial reports have shown more females being affected than males. Larger groups of patients will need to be identified to confirm whether women are affected more often than men. Less than 100 families have been identified with this disorder in the medical literature, but the exact number of people who have this disorder is unknown. The low number of people identified with this disorder is because COPA syndrome was only first defined as a disorder in 2015, and genetic testing has only recently become available. In general, rare disorders often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. COPA syndrome is likely underrecognized and underdiagnosed. | Affects of COPA Syndrome. Initial reports have shown more females being affected than males. Larger groups of patients will need to be identified to confirm whether women are affected more often than men. Less than 100 families have been identified with this disorder in the medical literature, but the exact number of people who have this disorder is unknown. The low number of people identified with this disorder is because COPA syndrome was only first defined as a disorder in 2015, and genetic testing has only recently become available. In general, rare disorders often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. COPA syndrome is likely underrecognized and underdiagnosed. | 322 | COPA Syndrome |
nord_322_4 | Related disorders of COPA Syndrome | Symptoms of the following disorders can be similar to those of COPA syndrome. Comparisons may be useful for a differential diagnosis.A variety of disorders or conditions can present with signs and symptoms that are similar to those seen in COPA syndrome. This includes autoimmune pulmonary hemorrhage, granulomatosis with polyangiitis, systemic lupus erythematosus, and STING-associated vasculopathy with onset in infancy (SAVI) syndrome.Interstitial pneumonia can be seen in numerous disorders including common variable immunodeficiency, LRBA deficiency, Churg-Strauss syndrome, and Goodpasture syndrome. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | Related disorders of COPA Syndrome. Symptoms of the following disorders can be similar to those of COPA syndrome. Comparisons may be useful for a differential diagnosis.A variety of disorders or conditions can present with signs and symptoms that are similar to those seen in COPA syndrome. This includes autoimmune pulmonary hemorrhage, granulomatosis with polyangiitis, systemic lupus erythematosus, and STING-associated vasculopathy with onset in infancy (SAVI) syndrome.Interstitial pneumonia can be seen in numerous disorders including common variable immunodeficiency, LRBA deficiency, Churg-Strauss syndrome, and Goodpasture syndrome. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | 322 | COPA Syndrome |
nord_322_5 | Diagnosis of COPA Syndrome | A diagnosis of COPA syndrome is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. Molecular genetic testing can confirm a diagnosis. Two findings that are suggestive of COPA syndrome are diffuse alveolar hemorrhaging and follicular bronchiolitis. Follicular bronchiolitis is when there is an overgrowth (hyperplasia) of lymphoid tissue within the small airways (bronchioles) of the lungs causing inflammation of those airways. Lymphoid tissue is the tissue in the body that produces white blood cells and antibodies. Clinical Testing and Workup
Molecular genetic testing can detect variations in the COPA gene known to cause the disorder. Doctors will take a blood sample of individuals suspected of having COPA syndrome and the sample will undergo targeted sequencing of the region of the COPA gene that is known to cause the disease to assess for the presence of variations known to cause the disease. Additional tests may be run before or after molecular genetic testing to determine the extent of the disease or to rule out other conditions. Such tests can include plain chest x-rays (radiographs) or a specialized imaging technique such as computerized tomography (CT) scanning of the lungs. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. Affected individuals have distinctive changes in lung tissue that can be detected on x-rays. For example, a CT scan can show areas of haziness that resembles ground glass (ground glass opacity) or small bumps (nodules) in the lungs. Pulmonary function tests may be administered to determine how effectively or ineffectively the lungs are working. This can include having an individual breathe into a machine called a spirometer to measure how much air they can breathe out or take in, and can reveal reduced airflow and reduced air volume. Doctors may measure a person’s forced vital capacity, which is the amount of air that can be forcibly blown out after taking a deep breath. A similar test called forced expiratory volume may also be recommended. This test measures how much air a person can breathe out during a forced breath. Another test called a plethysmography measures the total among of air people can hold in their lungs, which is called total lung capacity. During this exam, patients will sit or stand in an airtight chamber that is similar to a phone booth. The nostrils will be clipped shut and the patient will be asked to breathe into a mouthpiece. A sample of lung tissue taken via a surgical lung biopsy (sometimes called a video-assisted thoracoscopic surgery (VATS) lung biopsy) and studied under a microscope can reveal characteristic changes in the lung that indicate COPA syndrome. During this procedure, a small needle is passed through the skin to the lungs to obtain a small sample of tissue. This sample is viewed under a microscope by a special doctor called a pathologist who studies the specific cells and characteristics of the tissue sample to identify disease. Follicular bronchiolitis can be confirmed through a lung biopsy. A bronchoscopy exam might be needed during the workup to evaluate for alveolar hemorrhaging or other diseases that might be present, such as a lung infection. During a bronchoscopy, a physician inserts a bronchoscope through the mouth and down an affected individual’s throat and obtains a sample of tissue to be analyzed (biopsy). A bronchoscopy exam may also be used to allow doctors to see into the airways and air passages of the lungs. Blood tests can reveal the presence of autoantibodies including anti-neutrophil cytoplasmic antibody and anti-nuclear antibody. Some individuals may be positive for rheumatoid factor. | Diagnosis of COPA Syndrome. A diagnosis of COPA syndrome is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. Molecular genetic testing can confirm a diagnosis. Two findings that are suggestive of COPA syndrome are diffuse alveolar hemorrhaging and follicular bronchiolitis. Follicular bronchiolitis is when there is an overgrowth (hyperplasia) of lymphoid tissue within the small airways (bronchioles) of the lungs causing inflammation of those airways. Lymphoid tissue is the tissue in the body that produces white blood cells and antibodies. Clinical Testing and Workup
Molecular genetic testing can detect variations in the COPA gene known to cause the disorder. Doctors will take a blood sample of individuals suspected of having COPA syndrome and the sample will undergo targeted sequencing of the region of the COPA gene that is known to cause the disease to assess for the presence of variations known to cause the disease. Additional tests may be run before or after molecular genetic testing to determine the extent of the disease or to rule out other conditions. Such tests can include plain chest x-rays (radiographs) or a specialized imaging technique such as computerized tomography (CT) scanning of the lungs. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. Affected individuals have distinctive changes in lung tissue that can be detected on x-rays. For example, a CT scan can show areas of haziness that resembles ground glass (ground glass opacity) or small bumps (nodules) in the lungs. Pulmonary function tests may be administered to determine how effectively or ineffectively the lungs are working. This can include having an individual breathe into a machine called a spirometer to measure how much air they can breathe out or take in, and can reveal reduced airflow and reduced air volume. Doctors may measure a person’s forced vital capacity, which is the amount of air that can be forcibly blown out after taking a deep breath. A similar test called forced expiratory volume may also be recommended. This test measures how much air a person can breathe out during a forced breath. Another test called a plethysmography measures the total among of air people can hold in their lungs, which is called total lung capacity. During this exam, patients will sit or stand in an airtight chamber that is similar to a phone booth. The nostrils will be clipped shut and the patient will be asked to breathe into a mouthpiece. A sample of lung tissue taken via a surgical lung biopsy (sometimes called a video-assisted thoracoscopic surgery (VATS) lung biopsy) and studied under a microscope can reveal characteristic changes in the lung that indicate COPA syndrome. During this procedure, a small needle is passed through the skin to the lungs to obtain a small sample of tissue. This sample is viewed under a microscope by a special doctor called a pathologist who studies the specific cells and characteristics of the tissue sample to identify disease. Follicular bronchiolitis can be confirmed through a lung biopsy. A bronchoscopy exam might be needed during the workup to evaluate for alveolar hemorrhaging or other diseases that might be present, such as a lung infection. During a bronchoscopy, a physician inserts a bronchoscope through the mouth and down an affected individual’s throat and obtains a sample of tissue to be analyzed (biopsy). A bronchoscopy exam may also be used to allow doctors to see into the airways and air passages of the lungs. Blood tests can reveal the presence of autoantibodies including anti-neutrophil cytoplasmic antibody and anti-nuclear antibody. Some individuals may be positive for rheumatoid factor. | 322 | COPA Syndrome |
nord_322_6 | Therapies of COPA Syndrome | Treatment
The treatment of COPA 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, general internists, physicians who specialize in diagnosing and treating lung disorders (pulmonologists), physicians who specialize in diagnosing and treating kidney disorders (nephrologists), physicians who specialize in diagnosing and treating inflammation of the bones and joints (rheumatologists), physical therapists, and other healthcare professionals may need to systematically and comprehensively plan treatment.Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well. Several of the organizations listed in the Resources section provide support and information on COPA syndrome.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 would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with COPA syndrome. There is no cure for COPA syndrome, but affected individuals can be treated with drugs that suppress the immune system (immunosuppressive drugs). COPA syndrome involves abnormal functioning (dysregulation) of the immune system. By suppressing the activity of the immune system, doctors can reduce the damage to the healthy organ systems (e.g. the lungs) affected by the disorder. Some affected individuals may also receive low doses of systemic corticosteroids, which are drugs that reduce inflammation in the body. Individuals will respond to these medications differently. During periods of time when symptoms are worse, called exacerbations, stronger immunosuppressive drugs may be tried. Sometimes, high doses of systemic corticosteroids. Long-term use of high doses of systemic corticosteroids is often associated with significant side effects. Most patients have the drug dosage slowly reduced (tapered) after the exacerbation has passed. Some affected individuals have required supplemental oxygen at a young age. Supplemental oxygen, or oxygen therapy, is required when the lungs cannot take in enough oxygen to deliver oxygen to the bloodstream. Supplemental oxygen can help with symptoms like shortness of breath or fatigue. In severe disease, an endotracheal intubation may be necessary. This involves inserting a thin tube into the mouth or nostrils, down the windpipe (trachea), and into the lungs. This allows air to pass freely to the lungs. Several patients have received or are awaiting a lung transplant for progressive, severe lung disease. At least one patient has received a kidney transplant. | Therapies of COPA Syndrome. Treatment
The treatment of COPA 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, general internists, physicians who specialize in diagnosing and treating lung disorders (pulmonologists), physicians who specialize in diagnosing and treating kidney disorders (nephrologists), physicians who specialize in diagnosing and treating inflammation of the bones and joints (rheumatologists), physical therapists, and other healthcare professionals may need to systematically and comprehensively plan treatment.Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well. Several of the organizations listed in the Resources section provide support and information on COPA syndrome.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 would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with COPA syndrome. There is no cure for COPA syndrome, but affected individuals can be treated with drugs that suppress the immune system (immunosuppressive drugs). COPA syndrome involves abnormal functioning (dysregulation) of the immune system. By suppressing the activity of the immune system, doctors can reduce the damage to the healthy organ systems (e.g. the lungs) affected by the disorder. Some affected individuals may also receive low doses of systemic corticosteroids, which are drugs that reduce inflammation in the body. Individuals will respond to these medications differently. During periods of time when symptoms are worse, called exacerbations, stronger immunosuppressive drugs may be tried. Sometimes, high doses of systemic corticosteroids. Long-term use of high doses of systemic corticosteroids is often associated with significant side effects. Most patients have the drug dosage slowly reduced (tapered) after the exacerbation has passed. Some affected individuals have required supplemental oxygen at a young age. Supplemental oxygen, or oxygen therapy, is required when the lungs cannot take in enough oxygen to deliver oxygen to the bloodstream. Supplemental oxygen can help with symptoms like shortness of breath or fatigue. In severe disease, an endotracheal intubation may be necessary. This involves inserting a thin tube into the mouth or nostrils, down the windpipe (trachea), and into the lungs. This allows air to pass freely to the lungs. Several patients have received or are awaiting a lung transplant for progressive, severe lung disease. At least one patient has received a kidney transplant. | 322 | COPA Syndrome |
nord_323_0 | Overview of Cor Triatriatum | Cor triatriatum is an extremely rare congenital (present at birth) heart defect. Normally, the human heart has four chambers of which two are the atria. These two are separated from each other by a partition (septum) called the atrial septum. The other two chambers, known as ventricles, are also separated by a septum. In cor triatriatum there is a small extra chamber above the left atrium of the heart. The pulmonary veins, returning blood from the lungs, drain into this extra “third atrium.” The passage of blood from the lungs into the heart (left atrium and ventricle) is slowed by this extra chamber. Cor triatriatum may eventually lead to features of congestive heart failure and obstruction over time. | Overview of Cor Triatriatum. Cor triatriatum is an extremely rare congenital (present at birth) heart defect. Normally, the human heart has four chambers of which two are the atria. These two are separated from each other by a partition (septum) called the atrial septum. The other two chambers, known as ventricles, are also separated by a septum. In cor triatriatum there is a small extra chamber above the left atrium of the heart. The pulmonary veins, returning blood from the lungs, drain into this extra “third atrium.” The passage of blood from the lungs into the heart (left atrium and ventricle) is slowed by this extra chamber. Cor triatriatum may eventually lead to features of congestive heart failure and obstruction over time. | 323 | Cor Triatriatum |
nord_323_1 | Symptoms of Cor Triatriatum | The symptoms of cor triatriatum vary greatly, depending on the size of the opening between the extra chamber and the left atrium. If the opening is small, symptoms usually develop early in infancy and probably will include abnormally rapid breathing (tachypnea), wheezing, coughing, and/or abnormal accumulation of fluid in the lungs (pulmonary congestion). Progressive enlargement of the heart (cardiomegaly) occurs and often results in congestive heart failure along with abnormally high pressure within the artery that leads to the heart from the lungs (pulmonary artery). Some newborns with cor triatriatum may also have abnormal heart sounds or heart murmurs.In older people (after childhood), the symptoms of cor triatriatum may include abnormal swelling of areas of the body (generalized edema), pain and discomfort while breathing (dyspnea), an abnormally rapid heartbeat (tachycardia), and the excessive accumulation of fluid in the lungs (pulmonary congestion). Acute inflammation of the lungs (pneumonia) and bronchial tubes (bronchitis) may occur frequently and may lead to congestive heart failure. Individuals with cor triatriatum are also at increased risk for bacterial infection of the delicate membranes surrounding the heart (endocarditis). | Symptoms of Cor Triatriatum. The symptoms of cor triatriatum vary greatly, depending on the size of the opening between the extra chamber and the left atrium. If the opening is small, symptoms usually develop early in infancy and probably will include abnormally rapid breathing (tachypnea), wheezing, coughing, and/or abnormal accumulation of fluid in the lungs (pulmonary congestion). Progressive enlargement of the heart (cardiomegaly) occurs and often results in congestive heart failure along with abnormally high pressure within the artery that leads to the heart from the lungs (pulmonary artery). Some newborns with cor triatriatum may also have abnormal heart sounds or heart murmurs.In older people (after childhood), the symptoms of cor triatriatum may include abnormal swelling of areas of the body (generalized edema), pain and discomfort while breathing (dyspnea), an abnormally rapid heartbeat (tachycardia), and the excessive accumulation of fluid in the lungs (pulmonary congestion). Acute inflammation of the lungs (pneumonia) and bronchial tubes (bronchitis) may occur frequently and may lead to congestive heart failure. Individuals with cor triatriatum are also at increased risk for bacterial infection of the delicate membranes surrounding the heart (endocarditis). | 323 | Cor Triatriatum |
nord_323_2 | Causes of Cor Triatriatum | The exact cause of cor triatriatum is not known. | Causes of Cor Triatriatum. The exact cause of cor triatriatum is not known. | 323 | Cor Triatriatum |
nord_323_3 | Affects of Cor Triatriatum | Cor triatriatum is an extremely rare congenital heart condition that affects males and females in equal numbers. In the USA, this disorder accounts for an extremely small percentage (0.1% to 0.4%) of all infants with congenital heart disease. | Affects of Cor Triatriatum. Cor triatriatum is an extremely rare congenital heart condition that affects males and females in equal numbers. In the USA, this disorder accounts for an extremely small percentage (0.1% to 0.4%) of all infants with congenital heart disease. | 323 | Cor Triatriatum |
nord_323_4 | Related disorders of Cor Triatriatum | Symptoms of the following disorders can be similar to those of cor triatriatum. Comparisons may be useful for a differential diagnosis:Atrial Septal Defects are common congenital heart defects characterized by the presence of a small opening between the two atria of the heart. This defect leads to an increase in the workload on the right side of the heart, and excessive blood flow to the lungs. The symptoms, which may occur during infancy, childhood, or adulthood, can vary greatly and depend on the severity of the defect. The symptoms tend to be mild at first and may include difficulty breathing (dyspnea), increased susceptibility to respiratory infections, abnormal bluish discoloration of the skin and/or mucous membranes (cyanosis). Some people with Atrial Septal Defects may be at increased risk for the formation of blood clots that can travel to the major arteries of the blood system (embolism). (For more information on this disorder, choose “Atrial Septal Defects” as your search term in the Rare Disease Database.)Ventricular Septal Defects (Cor Triloculare Biventricularis) are a group of common congenital heart defects characterized by the absence of one ventricle. Infants with this defect have 2 atria and 1 large ventricle. Symptoms of these defects which are similar to Atrioventricular Septal Defect may include an abnormal rapid rate of breathing (tachypnea), wheezing, a rapid heartbeat (tachycardia), and an abnormally enlarged liver (hepatomegaly). Ventricular Septal Defects can also cause the excessive accumulation of fluid around the heart leading to congestive heart failure. (For more information on this disorder, choose “Ventricular Septal Defects” as your search term in the Rare Disease Database.)Atrioventricular Septal Defect is a rare congenital heart defect characterized by the improper development of the heart's valves and septa. Symptoms may include difficulty breathing (dyspnea), a bluish discoloration of the skin and mucous membranes (cyanosis), excessive accumulation of fluid in the lungs (pulmonary edema), and/or congestive heart failure. Other symptoms may include poor feeding habits, abnormally rapid breathing (tachypnea), excessive sweating (hyperhidrosis), and/or an abnormally rapid heartbeat (tachycardia). (For more information on this disorder, choose “Atrioventricular Septal Defect” as your search term in the Rare Disease Database.)Cor Triloculare Biatriatum is an extremely rare congenital heart defect characterized by the absence of one ventricle. Infants with this defect have two atria and one large ventricle. The symptoms are similar to those of Atrioventricular Septal Defect and include breathing difficulties (dyspnea), excessive accumulation of fluid in the lungs and around the heart (pulmonary edema), and/or a bluish discoloration of the skin and mucous membranes (cyanosis). Other symptoms may include poor feeding habits, abnormally rapid breathing (tachypnea), and/or an abnormally rapid heartbeat (tachycardia).Mitral Valve Stenosis is a rare heart defect that may be present at birth (congenital) or acquired. In the congenital form, the symptoms vary greatly and may include coughing, difficulty breathing, heart palpitations, and/or frequent respiratory infections. In acquired Mitral Valve Stenosis, the symptoms may also include weakness, abdominal discomfort, chest pain (angina), and periodic loss of consciousness. | Related disorders of Cor Triatriatum. Symptoms of the following disorders can be similar to those of cor triatriatum. Comparisons may be useful for a differential diagnosis:Atrial Septal Defects are common congenital heart defects characterized by the presence of a small opening between the two atria of the heart. This defect leads to an increase in the workload on the right side of the heart, and excessive blood flow to the lungs. The symptoms, which may occur during infancy, childhood, or adulthood, can vary greatly and depend on the severity of the defect. The symptoms tend to be mild at first and may include difficulty breathing (dyspnea), increased susceptibility to respiratory infections, abnormal bluish discoloration of the skin and/or mucous membranes (cyanosis). Some people with Atrial Septal Defects may be at increased risk for the formation of blood clots that can travel to the major arteries of the blood system (embolism). (For more information on this disorder, choose “Atrial Septal Defects” as your search term in the Rare Disease Database.)Ventricular Septal Defects (Cor Triloculare Biventricularis) are a group of common congenital heart defects characterized by the absence of one ventricle. Infants with this defect have 2 atria and 1 large ventricle. Symptoms of these defects which are similar to Atrioventricular Septal Defect may include an abnormal rapid rate of breathing (tachypnea), wheezing, a rapid heartbeat (tachycardia), and an abnormally enlarged liver (hepatomegaly). Ventricular Septal Defects can also cause the excessive accumulation of fluid around the heart leading to congestive heart failure. (For more information on this disorder, choose “Ventricular Septal Defects” as your search term in the Rare Disease Database.)Atrioventricular Septal Defect is a rare congenital heart defect characterized by the improper development of the heart's valves and septa. Symptoms may include difficulty breathing (dyspnea), a bluish discoloration of the skin and mucous membranes (cyanosis), excessive accumulation of fluid in the lungs (pulmonary edema), and/or congestive heart failure. Other symptoms may include poor feeding habits, abnormally rapid breathing (tachypnea), excessive sweating (hyperhidrosis), and/or an abnormally rapid heartbeat (tachycardia). (For more information on this disorder, choose “Atrioventricular Septal Defect” as your search term in the Rare Disease Database.)Cor Triloculare Biatriatum is an extremely rare congenital heart defect characterized by the absence of one ventricle. Infants with this defect have two atria and one large ventricle. The symptoms are similar to those of Atrioventricular Septal Defect and include breathing difficulties (dyspnea), excessive accumulation of fluid in the lungs and around the heart (pulmonary edema), and/or a bluish discoloration of the skin and mucous membranes (cyanosis). Other symptoms may include poor feeding habits, abnormally rapid breathing (tachypnea), and/or an abnormally rapid heartbeat (tachycardia).Mitral Valve Stenosis is a rare heart defect that may be present at birth (congenital) or acquired. In the congenital form, the symptoms vary greatly and may include coughing, difficulty breathing, heart palpitations, and/or frequent respiratory infections. In acquired Mitral Valve Stenosis, the symptoms may also include weakness, abdominal discomfort, chest pain (angina), and periodic loss of consciousness. | 323 | Cor Triatriatum |
nord_323_5 | Diagnosis of Cor Triatriatum | The diagnosis of cor triatriatum is usually made by using imaging techniques such as magnetic resonance imaging (MRI) and echocardiography (EC). In another procedure known as a cardiac catheterization, a long fine tube (catheter) is inserted into a large vein and then channeled directly into the heart. This allows the physician to further identify heart defects and to determine the rates of blood flow through the heart. Angiography is also a very useful diagnostic procedure and allows the physician to view an enhanced x-ray of the heart. Children with cor triatriatum also have abnormal EKG patterns. | Diagnosis of Cor Triatriatum. The diagnosis of cor triatriatum is usually made by using imaging techniques such as magnetic resonance imaging (MRI) and echocardiography (EC). In another procedure known as a cardiac catheterization, a long fine tube (catheter) is inserted into a large vein and then channeled directly into the heart. This allows the physician to further identify heart defects and to determine the rates of blood flow through the heart. Angiography is also a very useful diagnostic procedure and allows the physician to view an enhanced x-ray of the heart. Children with cor triatriatum also have abnormal EKG patterns. | 323 | Cor Triatriatum |
nord_323_6 | Therapies of Cor Triatriatum | Infants with cor triatriatum should be referred to a hospital that can perform sophisticated diagnostic procedures and cardiovascular surgery. Most patients with cor triatriatum will require surgery at a young age, usually before the age of one year.Prior to surgery, congestive heart failure associated with cor triatriatum may be managed by reducing fluid volume with diuretic drugs and, if necessary, the dietary restriction of fluids and salt. The drug digitalis may also be administered to decrease the heart rate and increase the strength of the heart's contractions. Oxygen therapy may also prove beneficial.Because people with cor triatriatum are susceptible to bacterial infection of the membranes that surround the heart (endocarditis), any respiratory infection should be treated vigorously and early. Affected individuals should also be given antibiotics before invasive dental procedures (i.e., root canal or extractions) or other surgical procedures to help prevent potentially life-threatening infections. | Therapies of Cor Triatriatum. Infants with cor triatriatum should be referred to a hospital that can perform sophisticated diagnostic procedures and cardiovascular surgery. Most patients with cor triatriatum will require surgery at a young age, usually before the age of one year.Prior to surgery, congestive heart failure associated with cor triatriatum may be managed by reducing fluid volume with diuretic drugs and, if necessary, the dietary restriction of fluids and salt. The drug digitalis may also be administered to decrease the heart rate and increase the strength of the heart's contractions. Oxygen therapy may also prove beneficial.Because people with cor triatriatum are susceptible to bacterial infection of the membranes that surround the heart (endocarditis), any respiratory infection should be treated vigorously and early. Affected individuals should also be given antibiotics before invasive dental procedures (i.e., root canal or extractions) or other surgical procedures to help prevent potentially life-threatening infections. | 323 | Cor Triatriatum |
nord_324_0 | Overview of Corneal Dystrophies | Corneal dystrophies are a group of genetic, often progressive, eye disorders in which abnormal material often accumulates in the clear (transparent) outer layer of the eye (cornea). Corneal dystrophies may not cause symptoms (asymptomatic) in some individuals; in others they may cause significant vision impairment. The age of onset and specific symptoms vary among the different forms of corneal dystrophy. The disorders have some similar characteristics – most forms of corneal dystrophy affect both eyes (bilateral), progress slowly, do not affect other areas of the body, and tend to run in families. Most forms are inherited as autosomal dominant traits; a few are inherited as autosomal recessive traits.An international classification of the corneal dystrophies has been developed that takes into account the chromosomal loci of the various corneal dystrophies as well as the responsible genes and their mutations. Traditionally, these disorders have classified based upon their clinical findings and the specific layer of the cornea affected. Advances in molecular genetics (e.g., identification of specific disease genes) have led to a greater understanding of these disorders. | Overview of Corneal Dystrophies. Corneal dystrophies are a group of genetic, often progressive, eye disorders in which abnormal material often accumulates in the clear (transparent) outer layer of the eye (cornea). Corneal dystrophies may not cause symptoms (asymptomatic) in some individuals; in others they may cause significant vision impairment. The age of onset and specific symptoms vary among the different forms of corneal dystrophy. The disorders have some similar characteristics – most forms of corneal dystrophy affect both eyes (bilateral), progress slowly, do not affect other areas of the body, and tend to run in families. Most forms are inherited as autosomal dominant traits; a few are inherited as autosomal recessive traits.An international classification of the corneal dystrophies has been developed that takes into account the chromosomal loci of the various corneal dystrophies as well as the responsible genes and their mutations. Traditionally, these disorders have classified based upon their clinical findings and the specific layer of the cornea affected. Advances in molecular genetics (e.g., identification of specific disease genes) have led to a greater understanding of these disorders. | 324 | Corneal Dystrophies |
nord_324_1 | Symptoms of Corneal Dystrophies | The symptoms of corneal dystrophies result from the accumulation of abnormal material within the cornea, the clear outer layer of the eye. The cornea serves two functions – it protects the rest of the eye from dust, germs and other harmful or irritating material, and it acts as the eye's outermost lens, bending incoming light onto the inner lens, where the light is then directed to the retina (a membranous layer of light-sensing cells in the back of the eye). The retina converts light to images, which are then transmitted to the brain. The cornea must remain clear (transparent) to be able to focus incoming light. The cornea is made up of five distinct layers: the epithelium, the outermost, protective layer of the cornea; the Bowman membrane, this second layer is extreme tough and difficult to penetrate further protecting the eye; the stroma, the thickest layer of the cornea, consisting of water, collagen fibers and other connective tissue components that give the cornea its strength, elasticity and clarity; Descemet membrane, a thin, strong inner layer that also acts as a protective layer; and the endothelium, the innermost layer consisting of specialized cells that pump excess water out of the cornea. Corneal dystrophies are characterized by the accumulation of foreign material in one or more of the five layers of the cornea. Such material may cause the cornea to lose its transparency potentially causing loss of vision or blurred vision. A symptom common to many forms of corneal dystrophy is recurrent corneal erosion, in which the outermost layer of the cornea (epithelium) does not stick (adhere) to the eye properly. Recurrent corneal erosion can cause discomfort or severe pain, an abnormal sensitivity to light (photophobia), the sensation of a foreign body (such as dirt or an eyelash) in the eye, and blurred vision.ANTERIOR CORNEAL DYSTROPHIESThese corneal dystrophies affect the outer layers of the cornea including the epithelium, the epithelial basement membrane (a thin membrane that separates epithelial cells from underlying tissue), and the Bowman membrane. Epithelial Basement Membrane DystrophyThis form of corneal dystrophy is characterized by the development of very tiny dots (microcysts), gray areas that, collectively, resemble the outlines of countries on a map, or fine lines that resemble fingerprints on the epithelial layer of the cornea. Most individuals do not have any symptoms (asymptomatic). In some cases, symptoms may include recurrent erosions and blurred vision, which affect apparently 10 percent of individuals. An abnormal sensitivity to light (photophobia) and the sensation of foreign material within the eye may also occur. Epithelial basement membrane dystrophy is a common form of corneal dystrophy and is also known as map-dot-fingerprint dystrophy and Cogan microcystic dystrophy. Meesmann Corneal DystrophyThis extremely rare form of corneal dystrophy affects the epithelial layer of the cornea. It is characterized by the development of clusters of multiple, small, clear cysts. The cysts are roughly the same size. Affected individuals may experience mild irritation and a slight decrease in clarity of vision (visual acuity). A sensitivity to light (photophobia) and excessive tear formation (lacrimation) can occur in this form of corneal dystrophy. Clouding (opacity) of the cornea rarely occurs, but may develop in some elderly individuals. Meesmann corneal dystrophy is also known as juvenile epithelial dystrophy.Lisch Corneal Dystrophy This rare form of corneal dystrophy is characterized by clusters of multiple, tiny cysts or lesions that may be band-shaped or curved or spiraled (whorled) in appearance. In some cases, affected individuals do not have any symptoms (asymptomatic). Some individuals may have decreased clarity of vision (visual acuity), blurred vision, and double vision affecting only one eye (monocular diplopia). Reis-Buckler Corneal DystrophyThis form affects the Bowman membrane and is characterized by clouding (opacity) and progressive scarring of the membrane. During the first decade of life, affected individuals may initially develop recurrent erosions that cause significant pain. Recurrent erosions may eventually stabilize as affected individuals grow older. Additional symptoms may develop including an abnormal sensitivity to light (photophobia), a feeling or sensation of a foreign body in the eye, and a marked decrease in clarity of vision (visual acuity) often by 20 years of age. Reis-Buckler corneal dystrophy is also known as granular corneal dystrophy type III or corneal dystrophy of Bowman layer type I. Thiel-Behnke Corneal DystrophyThis form of corneal dystrophy affects the Bowman membrane and may be extremely difficult to distinguish from Reis-Buckler corneal dystrophy. The abnormalities affecting the cornea may resemble honeycombs. Recurrent corneal erosions begin during childhood, but visual acuity is not affected until later during life. Pain and an abnormal sensitivity to light (photophobia) may also occur. Thiel-Behnke corneal dystrophy is also known as honeycomb corneal dystrophy or corneal dystrophy of Bowman layer type II. STROMAL CORNEAL DYSTROPHIESThese corneal dystrophies affect the stromal or central layer of the cornea. Some of these disorders can progress to affect other layers of the cornea.Granular Corneal Dystrophy Type IThis form of corneal dystrophy is characterized by the development of small particles (granules) that collectively resemble breadcrumbs, usually during the second or third decade of life. These lesions slowly grow eventually combining (coalescing) to form larger lesions. Individuals may develop recurrent erosions. Although vision is usually unaffected early in the disease, decreased visual acuity may occur by the fourth or fifth decade. Some individuals may have an abnormal sensitivity to light (photophobia). Eye pain may result from recurrent corneal erosions. Granular Corneal Dystrophy Type IIIn granular corneal dystrophy type II, also known as Avellino corneal dystrophy, lesions develop on the stroma usually beginning in the first or second decade of life. The opacities in the cornea sometimes resemble a cross between the granular lesions of granular corneal dystrophy type 1 and lattice lesions of lattice corneal dystrophy (see below). As affected individuals age, the lesions may become larger, more prominent and involved the entire stromal layer. Some older individuals have decreased clarity of vision (visual acuity) due to haze (clouding of the cornea). Recurrent erosions may develop in some cases. Lattice Corneal DystrophyLattice corneal dystrophies are a common form of stromal dystrophy and two main variants have been identified. They are characterized by the development of lesions that form branching lines that resemble cracked glass or the crisscrossed, overlapping pattern of lattice. Lattice dystrophy type I and its variants usually occur by the end of the first decade. Recurrent corneal erosions (which can be painful) often precede these characteristic changes to the stroma. Affected individuals may have decreased clarity of vision (visual acuity) and an abnormal sensitivity to light (photophobia). Lattice dystrophy type II is classified as a corneal dystrophy, but occurs as part of a larger disorder called Merejota syndrome, which is more serious than the corneal disease. Gelatinous droplike corneal dystrophy, also known as familial subepithelial corneal dystrophy, develops in individuals during the first decade of life and is characterized by loss of vision, an abnormal sensitivity to light (photophobia), excessive tearing (lacrimation), and the feeling (sensation) of foreign substances in the eye. Gelatinous masses of amyloid, a type of protein, accumulate beneath the corneal epithelium and make the cornea opaque and progressively impair vision.Macular Corneal DystrophyIndividuals with this form of corneal dystrophy are born with clear corneas, but eventually develop clouding of the stroma, usually between 3-9 years of age. Progression of the lesions results in decreased clarity of vision (visual acuity) and irritation early during life. In some cases, significant vision loss can occur by the second decade. Severe vision loss may develop by the third or fourth decade. Painful recurrent erosions sometimes occur, but are less common than in other corneal dystrophies affecting the stroma. Macular corneal dystrophy is also known as Groenouw dystrophy type II. Schnyder Crystalline Corneal DystrophyThis form of corneal dystrophy usually develops during the second decade of life, but can develop as early as the first year of life. Affected individuals develop opaque corneas due to an accumulation of fat or cholesterol within the stroma that eventually cause clouding, haziness and blurred vision. Crystals commonly accumulate in the cornea. Affected individuals have visual impairment that is worsened by glare. POSTERIOR CORNEAL DYSTROPHIESThese corneal dystrophies affect the innermost layers of the cornea including Descement membrane and the endothelium, which are the layers of the cornea closest to the inner structures of the eye. These disorders can potentially progress to affect all layers of the cornea. Fuchs Endothelial DystrophyThis form of corneal dystrophy usually develops during middle age, although there may be no symptoms initially (asymptomatic). Fuchs dystrophy is characterized by problems with tiny cells called “pumper” cells on the innermost layer of the cornea. Normally, these cells pump water out of the eye. In Fuchs dystrophy these cells deteriorate (“die off”) and the cornea fills with water and swells. The swelling worsens and blurred vision occurs that is worse in the morning, but gradually improves throughout the day. Tiny blisters form on the cornea, eventually rupturing and causing extreme pain. Affected individuals may also have a gritty or sandy feeling within the eye (foreign body sensation), be abnormally sensitive to light and see a glare or halo when looking at lights. As the disease progress, vision no longer improves during the day and significant vision loss may occur, possibly necessitating a corneal transplant. Posterior Polymorphous DystrophyThis uncommon form of corneal dystrophy may present at birth (with clouding of the cornea) or later during life and is characterized by lesions affecting the endothelium. Most individuals do not develop symptoms (asymptomatic). Effects on the cornea may be slowly progressive. Both eyes are usually affected, but one eye may be more severely affected than the other (asymmetric). In severe cases, individuals with posterior polymorphous dystrophy may develop swelling (edema) of the stroma, an abnormal sensitivity to light (photophobia), decreased vision, and the feeling (sensation) of foreign material in the eye. In rare cases, increased pressure with the eye (intraocular pressure) may occur. Congenital Hereditary Corneal DystrophyTwo types of congenital hereditary corneal dystrophy exist, one inherited as an autosomal dominant trait and one as an autosomal recessive trait. The autosomal dominant form (type I) is characterized by swelling (edema) of the cornea, pain, and corneas that are clear at birth, but become cloudy during early infancy. The autosomal recessive form (type II) is characterized by corneal swelling and cloudy corneas at birth. Rapid, jittery eye movements (nystagmus) may occur with this form. The recessive form is more common than the dominant form. | Symptoms of Corneal Dystrophies. The symptoms of corneal dystrophies result from the accumulation of abnormal material within the cornea, the clear outer layer of the eye. The cornea serves two functions – it protects the rest of the eye from dust, germs and other harmful or irritating material, and it acts as the eye's outermost lens, bending incoming light onto the inner lens, where the light is then directed to the retina (a membranous layer of light-sensing cells in the back of the eye). The retina converts light to images, which are then transmitted to the brain. The cornea must remain clear (transparent) to be able to focus incoming light. The cornea is made up of five distinct layers: the epithelium, the outermost, protective layer of the cornea; the Bowman membrane, this second layer is extreme tough and difficult to penetrate further protecting the eye; the stroma, the thickest layer of the cornea, consisting of water, collagen fibers and other connective tissue components that give the cornea its strength, elasticity and clarity; Descemet membrane, a thin, strong inner layer that also acts as a protective layer; and the endothelium, the innermost layer consisting of specialized cells that pump excess water out of the cornea. Corneal dystrophies are characterized by the accumulation of foreign material in one or more of the five layers of the cornea. Such material may cause the cornea to lose its transparency potentially causing loss of vision or blurred vision. A symptom common to many forms of corneal dystrophy is recurrent corneal erosion, in which the outermost layer of the cornea (epithelium) does not stick (adhere) to the eye properly. Recurrent corneal erosion can cause discomfort or severe pain, an abnormal sensitivity to light (photophobia), the sensation of a foreign body (such as dirt or an eyelash) in the eye, and blurred vision.ANTERIOR CORNEAL DYSTROPHIESThese corneal dystrophies affect the outer layers of the cornea including the epithelium, the epithelial basement membrane (a thin membrane that separates epithelial cells from underlying tissue), and the Bowman membrane. Epithelial Basement Membrane DystrophyThis form of corneal dystrophy is characterized by the development of very tiny dots (microcysts), gray areas that, collectively, resemble the outlines of countries on a map, or fine lines that resemble fingerprints on the epithelial layer of the cornea. Most individuals do not have any symptoms (asymptomatic). In some cases, symptoms may include recurrent erosions and blurred vision, which affect apparently 10 percent of individuals. An abnormal sensitivity to light (photophobia) and the sensation of foreign material within the eye may also occur. Epithelial basement membrane dystrophy is a common form of corneal dystrophy and is also known as map-dot-fingerprint dystrophy and Cogan microcystic dystrophy. Meesmann Corneal DystrophyThis extremely rare form of corneal dystrophy affects the epithelial layer of the cornea. It is characterized by the development of clusters of multiple, small, clear cysts. The cysts are roughly the same size. Affected individuals may experience mild irritation and a slight decrease in clarity of vision (visual acuity). A sensitivity to light (photophobia) and excessive tear formation (lacrimation) can occur in this form of corneal dystrophy. Clouding (opacity) of the cornea rarely occurs, but may develop in some elderly individuals. Meesmann corneal dystrophy is also known as juvenile epithelial dystrophy.Lisch Corneal Dystrophy This rare form of corneal dystrophy is characterized by clusters of multiple, tiny cysts or lesions that may be band-shaped or curved or spiraled (whorled) in appearance. In some cases, affected individuals do not have any symptoms (asymptomatic). Some individuals may have decreased clarity of vision (visual acuity), blurred vision, and double vision affecting only one eye (monocular diplopia). Reis-Buckler Corneal DystrophyThis form affects the Bowman membrane and is characterized by clouding (opacity) and progressive scarring of the membrane. During the first decade of life, affected individuals may initially develop recurrent erosions that cause significant pain. Recurrent erosions may eventually stabilize as affected individuals grow older. Additional symptoms may develop including an abnormal sensitivity to light (photophobia), a feeling or sensation of a foreign body in the eye, and a marked decrease in clarity of vision (visual acuity) often by 20 years of age. Reis-Buckler corneal dystrophy is also known as granular corneal dystrophy type III or corneal dystrophy of Bowman layer type I. Thiel-Behnke Corneal DystrophyThis form of corneal dystrophy affects the Bowman membrane and may be extremely difficult to distinguish from Reis-Buckler corneal dystrophy. The abnormalities affecting the cornea may resemble honeycombs. Recurrent corneal erosions begin during childhood, but visual acuity is not affected until later during life. Pain and an abnormal sensitivity to light (photophobia) may also occur. Thiel-Behnke corneal dystrophy is also known as honeycomb corneal dystrophy or corneal dystrophy of Bowman layer type II. STROMAL CORNEAL DYSTROPHIESThese corneal dystrophies affect the stromal or central layer of the cornea. Some of these disorders can progress to affect other layers of the cornea.Granular Corneal Dystrophy Type IThis form of corneal dystrophy is characterized by the development of small particles (granules) that collectively resemble breadcrumbs, usually during the second or third decade of life. These lesions slowly grow eventually combining (coalescing) to form larger lesions. Individuals may develop recurrent erosions. Although vision is usually unaffected early in the disease, decreased visual acuity may occur by the fourth or fifth decade. Some individuals may have an abnormal sensitivity to light (photophobia). Eye pain may result from recurrent corneal erosions. Granular Corneal Dystrophy Type IIIn granular corneal dystrophy type II, also known as Avellino corneal dystrophy, lesions develop on the stroma usually beginning in the first or second decade of life. The opacities in the cornea sometimes resemble a cross between the granular lesions of granular corneal dystrophy type 1 and lattice lesions of lattice corneal dystrophy (see below). As affected individuals age, the lesions may become larger, more prominent and involved the entire stromal layer. Some older individuals have decreased clarity of vision (visual acuity) due to haze (clouding of the cornea). Recurrent erosions may develop in some cases. Lattice Corneal DystrophyLattice corneal dystrophies are a common form of stromal dystrophy and two main variants have been identified. They are characterized by the development of lesions that form branching lines that resemble cracked glass or the crisscrossed, overlapping pattern of lattice. Lattice dystrophy type I and its variants usually occur by the end of the first decade. Recurrent corneal erosions (which can be painful) often precede these characteristic changes to the stroma. Affected individuals may have decreased clarity of vision (visual acuity) and an abnormal sensitivity to light (photophobia). Lattice dystrophy type II is classified as a corneal dystrophy, but occurs as part of a larger disorder called Merejota syndrome, which is more serious than the corneal disease. Gelatinous droplike corneal dystrophy, also known as familial subepithelial corneal dystrophy, develops in individuals during the first decade of life and is characterized by loss of vision, an abnormal sensitivity to light (photophobia), excessive tearing (lacrimation), and the feeling (sensation) of foreign substances in the eye. Gelatinous masses of amyloid, a type of protein, accumulate beneath the corneal epithelium and make the cornea opaque and progressively impair vision.Macular Corneal DystrophyIndividuals with this form of corneal dystrophy are born with clear corneas, but eventually develop clouding of the stroma, usually between 3-9 years of age. Progression of the lesions results in decreased clarity of vision (visual acuity) and irritation early during life. In some cases, significant vision loss can occur by the second decade. Severe vision loss may develop by the third or fourth decade. Painful recurrent erosions sometimes occur, but are less common than in other corneal dystrophies affecting the stroma. Macular corneal dystrophy is also known as Groenouw dystrophy type II. Schnyder Crystalline Corneal DystrophyThis form of corneal dystrophy usually develops during the second decade of life, but can develop as early as the first year of life. Affected individuals develop opaque corneas due to an accumulation of fat or cholesterol within the stroma that eventually cause clouding, haziness and blurred vision. Crystals commonly accumulate in the cornea. Affected individuals have visual impairment that is worsened by glare. POSTERIOR CORNEAL DYSTROPHIESThese corneal dystrophies affect the innermost layers of the cornea including Descement membrane and the endothelium, which are the layers of the cornea closest to the inner structures of the eye. These disorders can potentially progress to affect all layers of the cornea. Fuchs Endothelial DystrophyThis form of corneal dystrophy usually develops during middle age, although there may be no symptoms initially (asymptomatic). Fuchs dystrophy is characterized by problems with tiny cells called “pumper” cells on the innermost layer of the cornea. Normally, these cells pump water out of the eye. In Fuchs dystrophy these cells deteriorate (“die off”) and the cornea fills with water and swells. The swelling worsens and blurred vision occurs that is worse in the morning, but gradually improves throughout the day. Tiny blisters form on the cornea, eventually rupturing and causing extreme pain. Affected individuals may also have a gritty or sandy feeling within the eye (foreign body sensation), be abnormally sensitive to light and see a glare or halo when looking at lights. As the disease progress, vision no longer improves during the day and significant vision loss may occur, possibly necessitating a corneal transplant. Posterior Polymorphous DystrophyThis uncommon form of corneal dystrophy may present at birth (with clouding of the cornea) or later during life and is characterized by lesions affecting the endothelium. Most individuals do not develop symptoms (asymptomatic). Effects on the cornea may be slowly progressive. Both eyes are usually affected, but one eye may be more severely affected than the other (asymmetric). In severe cases, individuals with posterior polymorphous dystrophy may develop swelling (edema) of the stroma, an abnormal sensitivity to light (photophobia), decreased vision, and the feeling (sensation) of foreign material in the eye. In rare cases, increased pressure with the eye (intraocular pressure) may occur. Congenital Hereditary Corneal DystrophyTwo types of congenital hereditary corneal dystrophy exist, one inherited as an autosomal dominant trait and one as an autosomal recessive trait. The autosomal dominant form (type I) is characterized by swelling (edema) of the cornea, pain, and corneas that are clear at birth, but become cloudy during early infancy. The autosomal recessive form (type II) is characterized by corneal swelling and cloudy corneas at birth. Rapid, jittery eye movements (nystagmus) may occur with this form. The recessive form is more common than the dominant form. | 324 | Corneal Dystrophies |
nord_324_2 | Causes of Corneal Dystrophies | Most cases of corneal dystrophy are inherited as an autosomal dominant trait with variable expressivity. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.Variable expressivity means that some individuals who inherit the same gene for a dominant disorder may not develop (express) the same symptoms.The epithelial basement membrane, Reis-Buckler, Thiel-Behnke, Meesmann, Schnyder, lattice type I, lattice type II, granular type I, granular type II (Avellino), congenital hereditary corneal dystrophy type I, and posterior polymorphous forms of corneal dystrophy have autosomal dominance inheritance. Fuchs dystrophy may have autosomal dominant inheritance in some cases; in others it may occur spontaneously for no apparent reason (sporadic). Macular corneal dystrophy and congenital hereditary corneal dystrophy type II forms of corneal dystrophy have autosomal recessive inheritance. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25 percent. The risk is the same for males and females. Investigators have determined that several corneal dystrophies occur due to disruptions or changes (mutations) of the transforming growth factor beta-induced (TGFB1) gene located on the long arm (q) of chromosome 5 (5q31). 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 5q31” refers to band 31 on the long arm of chromosome 5. The numbered bands specify the location of the thousands of genes that are present on each chromosome.A variety of epithelial basement, Reis-Buckler, Thiel-Behnke, granular types I and II, and lattice types I corneal dystrophies have all been linked to the transforming growth factor beta induced (TGFB1) gene. These forms of corneal dystrophy develop due to different mutations of this gene, which was formerly known as the beta-induced gene human cell clone number 3 (BIGH3) gene. The TGFB1 gene contains instructions for creating (encoding) a protein known as transforming growth factor beta induced protein (keratoepithelin), which aids the corneal layers to remain stuck (adhered) together. An accumulation of this protein due to a mutated gene causes the symptoms of the corneal dystrophies associated with this gene. Meesmann corneal dystrophy has been linked to mutations to two separate genes, one (KTR3) on the long arm of chromosome 17 (17q12) and one (KTR12) on the long arm of chromosome 12 (12q13). These genes contain instructions for creating (encoding) certain proteins called keratins essential for the proper formation of the cornea. Some cases of Thiel-Behnke corneal dystrophy have been linked to mutations of a gene located on the long arm of chromosome 10 (10q23-q24). Macular corneal dystrophy has been linked to mutations of the carbohydrate sulfotransferase-6 (CHST6) gene on the long arm of chromosome 16 (16q22). This gene encodes for keratan sulfate, a complex sulfated carbohydrate that is essential for the proper development of cartilage and the cornea. There is no creation (synthesis) of normal keratan sulfate. Schnyder corneal dystrophy has been linked to mutations of the UBIAD1 gene located on the short arm of chromosome 1 (1p34-q36). Posterior polymorphous dystrophy has been linked to three different chromosomes. One is on the long arm of chromosome 20 (20p11.2), another is on chromosome 1 (1p34.3-p32.3) involving the COL8A2 gene, and a third is due to a mutation in the TCF8 gene on chromosome 10 (10p11-q11). The autosomal recessive form of congenital hereditary endothelial corneal dystrophy is due to mutations in the SLC4A11 gene on chromosome 20(20p13). The gene for autosomal dominant congenital hereditary endothelial corneal dystrophy has not been identified, but it is located on the short arm of chromosome 20 (20p11.2-q11.20). Lisch corneal dystrophy has been linked to a gene on the short arm of the X chromosome (Xp23). It is believed that this form of corneal dystrophy is inherited as an X-linked dominant trait. X-linked dominant disorders are caused by an abnormal gene on the X chromosome. Males with an abnormal gene are more severely affected than females. | Causes of Corneal Dystrophies. Most cases of corneal dystrophy are inherited as an autosomal dominant trait with variable expressivity. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.Variable expressivity means that some individuals who inherit the same gene for a dominant disorder may not develop (express) the same symptoms.The epithelial basement membrane, Reis-Buckler, Thiel-Behnke, Meesmann, Schnyder, lattice type I, lattice type II, granular type I, granular type II (Avellino), congenital hereditary corneal dystrophy type I, and posterior polymorphous forms of corneal dystrophy have autosomal dominance inheritance. Fuchs dystrophy may have autosomal dominant inheritance in some cases; in others it may occur spontaneously for no apparent reason (sporadic). Macular corneal dystrophy and congenital hereditary corneal dystrophy type II forms of corneal dystrophy have autosomal recessive inheritance. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25 percent. The risk is the same for males and females. Investigators have determined that several corneal dystrophies occur due to disruptions or changes (mutations) of the transforming growth factor beta-induced (TGFB1) gene located on the long arm (q) of chromosome 5 (5q31). 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 5q31” refers to band 31 on the long arm of chromosome 5. The numbered bands specify the location of the thousands of genes that are present on each chromosome.A variety of epithelial basement, Reis-Buckler, Thiel-Behnke, granular types I and II, and lattice types I corneal dystrophies have all been linked to the transforming growth factor beta induced (TGFB1) gene. These forms of corneal dystrophy develop due to different mutations of this gene, which was formerly known as the beta-induced gene human cell clone number 3 (BIGH3) gene. The TGFB1 gene contains instructions for creating (encoding) a protein known as transforming growth factor beta induced protein (keratoepithelin), which aids the corneal layers to remain stuck (adhered) together. An accumulation of this protein due to a mutated gene causes the symptoms of the corneal dystrophies associated with this gene. Meesmann corneal dystrophy has been linked to mutations to two separate genes, one (KTR3) on the long arm of chromosome 17 (17q12) and one (KTR12) on the long arm of chromosome 12 (12q13). These genes contain instructions for creating (encoding) certain proteins called keratins essential for the proper formation of the cornea. Some cases of Thiel-Behnke corneal dystrophy have been linked to mutations of a gene located on the long arm of chromosome 10 (10q23-q24). Macular corneal dystrophy has been linked to mutations of the carbohydrate sulfotransferase-6 (CHST6) gene on the long arm of chromosome 16 (16q22). This gene encodes for keratan sulfate, a complex sulfated carbohydrate that is essential for the proper development of cartilage and the cornea. There is no creation (synthesis) of normal keratan sulfate. Schnyder corneal dystrophy has been linked to mutations of the UBIAD1 gene located on the short arm of chromosome 1 (1p34-q36). Posterior polymorphous dystrophy has been linked to three different chromosomes. One is on the long arm of chromosome 20 (20p11.2), another is on chromosome 1 (1p34.3-p32.3) involving the COL8A2 gene, and a third is due to a mutation in the TCF8 gene on chromosome 10 (10p11-q11). The autosomal recessive form of congenital hereditary endothelial corneal dystrophy is due to mutations in the SLC4A11 gene on chromosome 20(20p13). The gene for autosomal dominant congenital hereditary endothelial corneal dystrophy has not been identified, but it is located on the short arm of chromosome 20 (20p11.2-q11.20). Lisch corneal dystrophy has been linked to a gene on the short arm of the X chromosome (Xp23). It is believed that this form of corneal dystrophy is inherited as an X-linked dominant trait. X-linked dominant disorders are caused by an abnormal gene on the X chromosome. Males with an abnormal gene are more severely affected than females. | 324 | Corneal Dystrophies |
nord_324_3 | Affects of Corneal Dystrophies | Corneal dystrophies affect women and men in equal numbers, except for Fuchs corneal dystrophy which affects women about four times as often as men. The corneal dystrophies can affect individuals of any age. The incidence of corneal dystrophies is unknown. Because some individuals do not have symptoms (asymptomatic), determining the true frequency of these disorders in the general population is difficult. | Affects of Corneal Dystrophies. Corneal dystrophies affect women and men in equal numbers, except for Fuchs corneal dystrophy which affects women about four times as often as men. The corneal dystrophies can affect individuals of any age. The incidence of corneal dystrophies is unknown. Because some individuals do not have symptoms (asymptomatic), determining the true frequency of these disorders in the general population is difficult. | 324 | Corneal Dystrophies |
nord_324_4 | Related disorders of Corneal Dystrophies | Symptoms of the following disorders can be similar to those of corneal dystrophy. Comparisons may be useful for a differential diagnosis.Keratoconus is a noninflammatory eye (ocular) condition characterized by progressive changes of the shape of the cornea. The cornea is the thin-walled, “dome-shaped” transparent layer forming the front of the eyeball; it serves as a protective covering and helps to focus or bend (refract) light waves onto the retina at the back of the eye. In individuals with keratoconus, slowly progressive thinning of the cornea causes it to bulge or protrude forward in an irregular, cone-like (conical shape) leading to blurry vision, an increased sensitivity to light, and other vision problems. Keratoconus often begins at puberty. Although the specific underlying cause of the condition is unknown, investigators indicate that genetic factors may play some role. In addition, in some cases, keratoconus may occur in association with a variety of other disorders. (For more information on this disorder, choose “keratoconus” as your search term in the Rare Disease Database.)Bullous keratopathy is an eye condition characterized by swelling (edema) of the cornea due to abnormal water retention by the cornea. Bullous keratopathy can result in pain and loss of vision. Small blisters (bullae) can form on the surface of the eye, which can potentially rupture causing severe pain and infection. Bullous keratopathy can be caused by surgery to the eye, trauma to the eye, and inflammatory eye disorders. | Related disorders of Corneal Dystrophies. Symptoms of the following disorders can be similar to those of corneal dystrophy. Comparisons may be useful for a differential diagnosis.Keratoconus is a noninflammatory eye (ocular) condition characterized by progressive changes of the shape of the cornea. The cornea is the thin-walled, “dome-shaped” transparent layer forming the front of the eyeball; it serves as a protective covering and helps to focus or bend (refract) light waves onto the retina at the back of the eye. In individuals with keratoconus, slowly progressive thinning of the cornea causes it to bulge or protrude forward in an irregular, cone-like (conical shape) leading to blurry vision, an increased sensitivity to light, and other vision problems. Keratoconus often begins at puberty. Although the specific underlying cause of the condition is unknown, investigators indicate that genetic factors may play some role. In addition, in some cases, keratoconus may occur in association with a variety of other disorders. (For more information on this disorder, choose “keratoconus” as your search term in the Rare Disease Database.)Bullous keratopathy is an eye condition characterized by swelling (edema) of the cornea due to abnormal water retention by the cornea. Bullous keratopathy can result in pain and loss of vision. Small blisters (bullae) can form on the surface of the eye, which can potentially rupture causing severe pain and infection. Bullous keratopathy can be caused by surgery to the eye, trauma to the eye, and inflammatory eye disorders. | 324 | Corneal Dystrophies |
nord_324_5 | Diagnosis of Corneal Dystrophies | The presence of a corneal dystrophy may be found incidentally during a routine eye examination. A diagnosis may be confirmed by a thorough clinical evaluation, a detailed patient history and a variety of tests, such as a slit lamp examination, in which a special microscope (slit lamp) allows a physician to view the eye through high magnification. Some specific corneal dystrophies can be diagnosed with molecular genetic tests even before symptoms develop. | Diagnosis of Corneal Dystrophies. The presence of a corneal dystrophy may be found incidentally during a routine eye examination. A diagnosis may be confirmed by a thorough clinical evaluation, a detailed patient history and a variety of tests, such as a slit lamp examination, in which a special microscope (slit lamp) allows a physician to view the eye through high magnification. Some specific corneal dystrophies can be diagnosed with molecular genetic tests even before symptoms develop. | 324 | Corneal Dystrophies |
nord_324_6 | Therapies of Corneal Dystrophies | TreatmentThe treatment of corneal dystrophies varies. Individuals who do not have symptoms (asymptomatic) or only have mild symptoms may not require treatment and may instead be regularly observed to detect potential progression of the disease.Specific treatments for corneal dystrophies may include eye drops, ointments, lasers and corneal transplant. Recurrent corneal erosions (a common finding in most corneal dystrophies) may be treated with lubricating eye drops, ointments, antibiotics or specialized (bandage soft) contact lenses. If recurrent erosions persist, additional measures such as corneal scraping or the use of excimer laser therapy, which can remove abnormalities from the surface of the cornea (phototherapeutic keratectomy).In individuals with significant associated symptoms a corneal transplant, known as a keratoplasty, may be necessary. Corneal transplants have been highly successful in treating individuals with advanced symptoms of corneal dystrophies. There is a risk, however, that the lesions will eventually develop in the graft (donated) cornea.Several factors determine what therapies may be used to treat individuals with corneal dystrophies including the specific type of corneal dystrophy present, the severity of associated symptoms, the rate of progression of the disease, and a patient's overall health and quality of life.Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive. | Therapies of Corneal Dystrophies. TreatmentThe treatment of corneal dystrophies varies. Individuals who do not have symptoms (asymptomatic) or only have mild symptoms may not require treatment and may instead be regularly observed to detect potential progression of the disease.Specific treatments for corneal dystrophies may include eye drops, ointments, lasers and corneal transplant. Recurrent corneal erosions (a common finding in most corneal dystrophies) may be treated with lubricating eye drops, ointments, antibiotics or specialized (bandage soft) contact lenses. If recurrent erosions persist, additional measures such as corneal scraping or the use of excimer laser therapy, which can remove abnormalities from the surface of the cornea (phototherapeutic keratectomy).In individuals with significant associated symptoms a corneal transplant, known as a keratoplasty, may be necessary. Corneal transplants have been highly successful in treating individuals with advanced symptoms of corneal dystrophies. There is a risk, however, that the lesions will eventually develop in the graft (donated) cornea.Several factors determine what therapies may be used to treat individuals with corneal dystrophies including the specific type of corneal dystrophy present, the severity of associated symptoms, the rate of progression of the disease, and a patient's overall health and quality of life.Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive. | 324 | Corneal Dystrophies |
nord_325_0 | Overview of Cornelia de Lange Syndrome | Cornelia de Lange syndrome (CdLS) is a rare genetic disorder that is generally apparent at birth (congenital). Associated symptoms and findings typically include delays in physical development before and after birth (prenatal and postnatal growth delay); characteristic appearance of the head and facial (craniofacial) area, resulting in a distinctive facial appearance; malformations of the hands and arms (upper limbs); and mild to severe intellectual disability. Many infants and children with the disorder have an unusually small, short head (microbrachycephaly); a prominent vertical groove between the upper lip and nose (philtrum); a depressed nasal bridge; upturned nostrils (anteverted nares); and a small chin (micrognathia). Additional characteristic facial features may include thin, downturned lips; low-set ears; arched, well-defined eyebrows that grow together across the base of the nose (synophrys); an unusually low hairline on the forehead and the back of the neck; and curly, unusually long eyelashes. Affected individuals may also have distinctive malformations of the limbs, such as unusually small hands and feet, inward deviation (clinodactyly) of the fifth fingers, and webbing (syndactyly) of certain toes. Less commonly, there may be absence of the forearms, hands, and fingers. Infants with CdLS may also have feeding and breathing difficulties; an increased susceptibility to respiratory infections; a low-pitched “growling” cry and low voice; heart defects; delayed skeletal maturation; hearing loss; or other physical differences. The range and severity of associated symptoms and findings may be extremely variable from person to person.CdLS can be inherited as an autosomal dominant condition or an X-linked condition. Seven genes have been found to be associated with CdLS including the NIPBL gene on chromosome 5, the SMC1A gene on the X chromosome, the SMC3 gene on chromosome 10, the Rad21 gene on chromosome 8, the HDAC8 gene on the X chromosome, the ANKRD11 on chromosome 16 and the BRD4 gene on chromosome 19. Most affected individuals have an abnormal gene as a result of a new gene mutation and do not have an affected parent. Other genes may be found to be associated with CdLS in the future. It is now referred to as Cornelia de Lange syndrome spectrum because of the broad nature of the presentations. | Overview of Cornelia de Lange Syndrome. Cornelia de Lange syndrome (CdLS) is a rare genetic disorder that is generally apparent at birth (congenital). Associated symptoms and findings typically include delays in physical development before and after birth (prenatal and postnatal growth delay); characteristic appearance of the head and facial (craniofacial) area, resulting in a distinctive facial appearance; malformations of the hands and arms (upper limbs); and mild to severe intellectual disability. Many infants and children with the disorder have an unusually small, short head (microbrachycephaly); a prominent vertical groove between the upper lip and nose (philtrum); a depressed nasal bridge; upturned nostrils (anteverted nares); and a small chin (micrognathia). Additional characteristic facial features may include thin, downturned lips; low-set ears; arched, well-defined eyebrows that grow together across the base of the nose (synophrys); an unusually low hairline on the forehead and the back of the neck; and curly, unusually long eyelashes. Affected individuals may also have distinctive malformations of the limbs, such as unusually small hands and feet, inward deviation (clinodactyly) of the fifth fingers, and webbing (syndactyly) of certain toes. Less commonly, there may be absence of the forearms, hands, and fingers. Infants with CdLS may also have feeding and breathing difficulties; an increased susceptibility to respiratory infections; a low-pitched “growling” cry and low voice; heart defects; delayed skeletal maturation; hearing loss; or other physical differences. The range and severity of associated symptoms and findings may be extremely variable from person to person.CdLS can be inherited as an autosomal dominant condition or an X-linked condition. Seven genes have been found to be associated with CdLS including the NIPBL gene on chromosome 5, the SMC1A gene on the X chromosome, the SMC3 gene on chromosome 10, the Rad21 gene on chromosome 8, the HDAC8 gene on the X chromosome, the ANKRD11 on chromosome 16 and the BRD4 gene on chromosome 19. Most affected individuals have an abnormal gene as a result of a new gene mutation and do not have an affected parent. Other genes may be found to be associated with CdLS in the future. It is now referred to as Cornelia de Lange syndrome spectrum because of the broad nature of the presentations. | 325 | Cornelia de Lange Syndrome |
nord_325_1 | Symptoms of Cornelia de Lange Syndrome | CdLS is a very rare disorder characterized by growth delays; distinctive facial features; malformations of the hands, feet, arms, and/or legs (limb anomalies); other physical differences; intellectual disability and/or developmental delays. The range and severity of symptoms and physical characteristics may vary greatly from person to person.Individuals with CdLS exhibit abnormal growth delays that affect both weight and linear growth before and after birth (prenatal and postnatal growth delay). Most affected infants may have a low birth weight and may fail to gain weight or grow at the expected rate (failure to thrive). CdLS growth charts are available to compare growth to other affected individuals. Individuals may experience feeding, chewing, and swallowing difficulties during the first several months/years of life.Many affected infants may frequently “spit up” food that has already been swallowed (regurgitation) and may experience episodes of severe, forceful vomiting (projectile vomiting). Infants with CdLS may also demonstrate abnormally increased muscle tone (hypertonicity) and have an unusual, low-pitched, growling cry.Individuals with CdLS also have distinctive features of the head and facial (craniofacial) area including a small head (microcephaly) that may also be unusually short (brachycephaly); a short, thick neck; low hairline; small, broad, upturned nose with nostrils that tip upwards (anteverted nares); neat, arched eyebrows that grow together (synophrys); long, curly eyelashes and/or excessive hair growth on various areas of the body (hypertrichosis). Additional features may include thin, downturned lips; a long vertical gap between the upper lip (philtrum) and the nose; a small, underdeveloped jaw (micrognathia); late-erupting, widely-spaced, small teeth; and low-set ears. Some affected infants may also have an incomplete closure of the roof of the mouth (cleft palate), a hidden incomplete closure (submucous cleft palate) and/or a highly arched palate.Most infants with CdLS have hands and feet that are small for their size. In addition, affected individuals may have short fingers that become smaller and thinner toward the ends (tapered fingers), fifth fingers that are permanently curved toward the ring finger (clinodactyly) and/or absence of one or more fingers (oligodactyly). The thumbs may be abnormally positioned (i.e., proximally placed) and the arms may be permanently bent or flexed at the elbows due to bone fusions. Many affected individuals have underdevelopment (hypoplasia) of some of the bones of the fingers and toes, and the second and third toes are often fused or webbed (syndactyly). Some affected infants may also have, in rare cases, missing fingers, hands and forearms. Upper limb differences may involve one side (unilateral) or both sides (bilateral) of the body. If bilateral limb malformations are present, those on one side of the body may be completely different from those on the other side (asymmetrical). Although the feet are small, only in extremely rare cases are there absent bones in the feet or lower legs.Individuals with CdLS also have delayed bone age. In addition, affected individuals may remain low in weight and have short stature (prenatal and postnatal growth delay), failure to thrive during infancy, delayed bone age and/or other differences. Many individuals with CdLS also exhibit additional skeletal abnormalities. These may include a deformity of the hip (coxa valga), a short breastbone (sternum) and/or abnormally thin ribs.Many infants and children with CdLS may have delays in the acquisition of skills requiring the coordination of mental and muscular activity (psychomotor delay), mild to severe intellectual disability and/or demonstrate behavioral problems (e.g., episodes of biting, screaming, hitting themselves, etc.). In addition, although affected children may have decreased facial expression based on emotion, they appear to respond positively to certain stimuli (e.g., fast movements). A CdLS developmental chart is available to compare milestones.Many children with CdLS also have hearing impairment as well as delayed speech development. Middle ear infections (otitis media), which sometimes occur chronically with an accumulation of sticky fluid (otitis media with effusion or glue ear) are common. Younger children may have difficulty speaking (dysphonia and/or apraxia), while older children may have abnormally hoarse speech.Many individuals with CdLS also exhibit additional physical differences. The skin may appear “marbled” (cutis marmorata) and the skin above the eyes, mouth, and nose may have an unusual bluish tone. Many affected individuals have irregularities in the skin ridge patterns on the palms of the hands (dermatoglyphics). As mentioned earlier, most affected individuals may have excessive hair growth (hypertrichosis) on various areas of the body including the ears. Hair may also tend to appear on the lower back, limbs and/or other areas of the body.Many individuals with CdLS also have various abnormalities of the gastrointestinal system including gastroesophageal reflux, a condition in which the acidic contents of the stomach flow upward into the lower esophagus; inflammation of the lining of the esophagus (esophagitis) and/or narrowing of the esophagus (esophageal stenosis). In addition, affected individuals are at risk for twisting (malrotation) of the intestines, potentially causing intestinal obstruction (volvulus). In some children, the bands of muscle fibers (pyloric sphincter) at the junction between the stomach and small intestine (pyloric stenosis) may become narrowed (stenosis) in infancy, resulting in obstruction of the normal flow of stomach contents into the small intestine. In addition, some individuals with CdLS may also have protrusion of portions of the large intestine through an opening in musculature lining the abdominal cavity in the area of the groin (inguinal hernia) and/or part of the stomach through an opening where the esophagus passes through the diaphragm (hiatal hernia). Some babies with CdLS are born with diaphragmatic hernia, in which some of the contents of the abdomen have not been separated from the lungs as a fetus; this needs to be repaired for survival. In some individuals with CdLS, certain gastrointestinal abnormalities may lead to intestinal obstruction, potentially causing serious or life-threatening complications if left untreated.Some individuals with CdLS may also have malformations of the genitourinary tract. In affected males, such abnormalities may include underdevelopment (hypoplasia) of the genitals, failure of one or both of the testes to descend into the scrotum (cryptorchidism) and/or abnormal placement of the urinary opening (urinary meatus) on the underside of the penis (hypospadias). Affected females may have abnormal development of the uterus (e.g., bicornate or septate uterus) and menstruation may be irregular.Many children with CdLS have additional physical differences including various heart (cardiac) abnormalities. Some affected individuals may also have an increased susceptibility to repeated respiratory infections, eye abnormalities such as nearsightedness (myopia), rapid, involuntary eye movements (nystagmus) and/or abnormal drooping of the upper eyelid(s) (ptosis). Some infants and children with CdLS may also experience episodes of uncontrolled electrical disturbances in the brain (seizures). | Symptoms of Cornelia de Lange Syndrome. CdLS is a very rare disorder characterized by growth delays; distinctive facial features; malformations of the hands, feet, arms, and/or legs (limb anomalies); other physical differences; intellectual disability and/or developmental delays. The range and severity of symptoms and physical characteristics may vary greatly from person to person.Individuals with CdLS exhibit abnormal growth delays that affect both weight and linear growth before and after birth (prenatal and postnatal growth delay). Most affected infants may have a low birth weight and may fail to gain weight or grow at the expected rate (failure to thrive). CdLS growth charts are available to compare growth to other affected individuals. Individuals may experience feeding, chewing, and swallowing difficulties during the first several months/years of life.Many affected infants may frequently “spit up” food that has already been swallowed (regurgitation) and may experience episodes of severe, forceful vomiting (projectile vomiting). Infants with CdLS may also demonstrate abnormally increased muscle tone (hypertonicity) and have an unusual, low-pitched, growling cry.Individuals with CdLS also have distinctive features of the head and facial (craniofacial) area including a small head (microcephaly) that may also be unusually short (brachycephaly); a short, thick neck; low hairline; small, broad, upturned nose with nostrils that tip upwards (anteverted nares); neat, arched eyebrows that grow together (synophrys); long, curly eyelashes and/or excessive hair growth on various areas of the body (hypertrichosis). Additional features may include thin, downturned lips; a long vertical gap between the upper lip (philtrum) and the nose; a small, underdeveloped jaw (micrognathia); late-erupting, widely-spaced, small teeth; and low-set ears. Some affected infants may also have an incomplete closure of the roof of the mouth (cleft palate), a hidden incomplete closure (submucous cleft palate) and/or a highly arched palate.Most infants with CdLS have hands and feet that are small for their size. In addition, affected individuals may have short fingers that become smaller and thinner toward the ends (tapered fingers), fifth fingers that are permanently curved toward the ring finger (clinodactyly) and/or absence of one or more fingers (oligodactyly). The thumbs may be abnormally positioned (i.e., proximally placed) and the arms may be permanently bent or flexed at the elbows due to bone fusions. Many affected individuals have underdevelopment (hypoplasia) of some of the bones of the fingers and toes, and the second and third toes are often fused or webbed (syndactyly). Some affected infants may also have, in rare cases, missing fingers, hands and forearms. Upper limb differences may involve one side (unilateral) or both sides (bilateral) of the body. If bilateral limb malformations are present, those on one side of the body may be completely different from those on the other side (asymmetrical). Although the feet are small, only in extremely rare cases are there absent bones in the feet or lower legs.Individuals with CdLS also have delayed bone age. In addition, affected individuals may remain low in weight and have short stature (prenatal and postnatal growth delay), failure to thrive during infancy, delayed bone age and/or other differences. Many individuals with CdLS also exhibit additional skeletal abnormalities. These may include a deformity of the hip (coxa valga), a short breastbone (sternum) and/or abnormally thin ribs.Many infants and children with CdLS may have delays in the acquisition of skills requiring the coordination of mental and muscular activity (psychomotor delay), mild to severe intellectual disability and/or demonstrate behavioral problems (e.g., episodes of biting, screaming, hitting themselves, etc.). In addition, although affected children may have decreased facial expression based on emotion, they appear to respond positively to certain stimuli (e.g., fast movements). A CdLS developmental chart is available to compare milestones.Many children with CdLS also have hearing impairment as well as delayed speech development. Middle ear infections (otitis media), which sometimes occur chronically with an accumulation of sticky fluid (otitis media with effusion or glue ear) are common. Younger children may have difficulty speaking (dysphonia and/or apraxia), while older children may have abnormally hoarse speech.Many individuals with CdLS also exhibit additional physical differences. The skin may appear “marbled” (cutis marmorata) and the skin above the eyes, mouth, and nose may have an unusual bluish tone. Many affected individuals have irregularities in the skin ridge patterns on the palms of the hands (dermatoglyphics). As mentioned earlier, most affected individuals may have excessive hair growth (hypertrichosis) on various areas of the body including the ears. Hair may also tend to appear on the lower back, limbs and/or other areas of the body.Many individuals with CdLS also have various abnormalities of the gastrointestinal system including gastroesophageal reflux, a condition in which the acidic contents of the stomach flow upward into the lower esophagus; inflammation of the lining of the esophagus (esophagitis) and/or narrowing of the esophagus (esophageal stenosis). In addition, affected individuals are at risk for twisting (malrotation) of the intestines, potentially causing intestinal obstruction (volvulus). In some children, the bands of muscle fibers (pyloric sphincter) at the junction between the stomach and small intestine (pyloric stenosis) may become narrowed (stenosis) in infancy, resulting in obstruction of the normal flow of stomach contents into the small intestine. In addition, some individuals with CdLS may also have protrusion of portions of the large intestine through an opening in musculature lining the abdominal cavity in the area of the groin (inguinal hernia) and/or part of the stomach through an opening where the esophagus passes through the diaphragm (hiatal hernia). Some babies with CdLS are born with diaphragmatic hernia, in which some of the contents of the abdomen have not been separated from the lungs as a fetus; this needs to be repaired for survival. In some individuals with CdLS, certain gastrointestinal abnormalities may lead to intestinal obstruction, potentially causing serious or life-threatening complications if left untreated.Some individuals with CdLS may also have malformations of the genitourinary tract. In affected males, such abnormalities may include underdevelopment (hypoplasia) of the genitals, failure of one or both of the testes to descend into the scrotum (cryptorchidism) and/or abnormal placement of the urinary opening (urinary meatus) on the underside of the penis (hypospadias). Affected females may have abnormal development of the uterus (e.g., bicornate or septate uterus) and menstruation may be irregular.Many children with CdLS have additional physical differences including various heart (cardiac) abnormalities. Some affected individuals may also have an increased susceptibility to repeated respiratory infections, eye abnormalities such as nearsightedness (myopia), rapid, involuntary eye movements (nystagmus) and/or abnormal drooping of the upper eyelid(s) (ptosis). Some infants and children with CdLS may also experience episodes of uncontrolled electrical disturbances in the brain (seizures). | 325 | Cornelia de Lange Syndrome |
nord_325_2 | Causes of Cornelia de Lange Syndrome | CdLS can be inherited as an autosomal dominant condition or an X-linked condition. Most affected individuals have an abnormal gene as a result of a new gene mutation. Seven genes have been found to be associated with CdLS including the NIPBL gene on chromosome 5, the SMC1A gene on the X chromosome, the SMC3 gene on chromosome 10, the Rad21 gene on chromosome 8, the HDAC8 gene on the X chromosome, the ANKRD11 on chromosome 16 and the BRD4 gene on chromosome 19. Approximately 60% of those affected have a NIPBL gene mutation and a small percentage (about 10%) have mutations in the other genes. Other genes may be found to be associated with CdLS in the future. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and occur mostly in males. Females that have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and one is inactivated so that the genes on that chromosome are nonfunctioning. It is often the X chromosome with the abnormal gene that is inactivated. However, in CdLS, because the gene change is likely dominant over the corresponding gene on the X chromosomes, females also often show similar findings as males.Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a disease 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. Males with X-linked disorders pass the disease gene to all of their daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. | Causes of Cornelia de Lange Syndrome. CdLS can be inherited as an autosomal dominant condition or an X-linked condition. Most affected individuals have an abnormal gene as a result of a new gene mutation. Seven genes have been found to be associated with CdLS including the NIPBL gene on chromosome 5, the SMC1A gene on the X chromosome, the SMC3 gene on chromosome 10, the Rad21 gene on chromosome 8, the HDAC8 gene on the X chromosome, the ANKRD11 on chromosome 16 and the BRD4 gene on chromosome 19. Approximately 60% of those affected have a NIPBL gene mutation and a small percentage (about 10%) have mutations in the other genes. Other genes may be found to be associated with CdLS in the future. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and occur mostly in males. Females that have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and one is inactivated so that the genes on that chromosome are nonfunctioning. It is often the X chromosome with the abnormal gene that is inactivated. However, in CdLS, because the gene change is likely dominant over the corresponding gene on the X chromosomes, females also often show similar findings as males.Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a disease 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. Males with X-linked disorders pass the disease gene to all of their daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. | 325 | Cornelia de Lange Syndrome |
nord_325_3 | Affects of Cornelia de Lange Syndrome | CdLS is a very rare disorder that is apparent at birth (congenital). Males and females appear to be affected in equal numbers. It has been estimated that CdLS occurs in approximately one in every 10,000 live births in the United States. More than 400 cases have been reported in the medical literature, including affected individuals within several families (kindreds). Multiple affected siblings have been reported in some families. It is estimated that there is a 1-2 % rate of recurrence within affected families. | Affects of Cornelia de Lange Syndrome. CdLS is a very rare disorder that is apparent at birth (congenital). Males and females appear to be affected in equal numbers. It has been estimated that CdLS occurs in approximately one in every 10,000 live births in the United States. More than 400 cases have been reported in the medical literature, including affected individuals within several families (kindreds). Multiple affected siblings have been reported in some families. It is estimated that there is a 1-2 % rate of recurrence within affected families. | 325 | Cornelia de Lange Syndrome |
nord_325_4 | Related disorders of Cornelia de Lange Syndrome | Symptoms of the following disorders can be similar to those of Cornelia de Lange syndrome. Comparisons may be useful for a differential diagnosis:Coffin-Siris syndrome is an extremely rare genetic disorder that is present at birth (congenital). Infants with this disorder typically have underdeveloped (hypoplastic) or missing fifth fingers on both hands. The toenails may be underdeveloped or absent. Affected individuals may also exhibit characteristic abnormalities of the head and facial (craniofacial) area including a small head (microcephaly), broad nose, wide mouth with thick lips, low nasal bridge, widely-spaced eyes (ocular hypertelorism), droopy upper eyelids (ptosis), thick eyelashes, dental abnormalities and/or sparse scalp hair. During infancy, many affected individuals have feeding difficulties, vomiting, slow growth and/or frequent respiratory infections. During the first two years of life, developmental delays, unusually short stature, and varying degrees of intellectual disability may become apparent. Some children with Coffin-Siris syndrome may also have additional physical differences including abnormally loose joints (laxity) that may result in frequent dislocations, particularly of the elbows; mild to severe muscle weakness (hypotonia); motor delays; sideways curvature of the spine (scoliosis) and/or other skeletal, gastrointestinal, genitourinary and/or cardiac malformations. In some cases, Coffin-Siris syndrome may occur randomly, for no apparent reason (sporadically); in other cases, the disorder may be inherited as an autosomal recessive genetic trait. (For more information on this disorder, choose “Coffin Siris” as your search term in the Rare Disease Database.)Rubinstein-Taybi syndrome is a rare genetic disorder associated with multiple abnormalities that include characteristic facial features, such as a prominent end to the nose, narrows eyes and short fingers with wide thumbs and great toes. Affected individuals are usually shorter than average and can have excessive hair on the body (hypertrichosis). Vision and hearing problems along with intellectual disability may also occur. (For more information on this disorder, choose “Rubinstein-Taybi” as your search term in the Rare Disease Database.)Fetal alcohol spectrum disorder (FASD) is a syndrome of altered fetal growth resulting in certain birth defects due to maternal consumption of alcohol during pregnancy. When a pregnant woman drinks alcoholic beverages, a pattern of abnormalities in the fetus may occur at different stages of pregnancy. Affected infants are unusually small at birth, have an abnormally small head (microcephaly) and may fail to gain weight and grow at the expected rate (failure to thrive). Affected infants and children may have delays in intellectual development as well as in the acquisition of fine and gross motor skills. In addition, affected individuals may have characteristic craniofacial differences including a protruding forehead, an abnormally short opening between the upper and lower eyelids (palpebral fissures), the presence of vertical skin folds on the inner corners of the eyes (epicanthal folds), a long flat area between nose and mouth (philtrum), an incompletely developed, abnormally small upper jaw (maxillary hypoplasia) and/or incomplete closure of the roof of the mouth (cleft palate). Affected infants may also have other physical differences including joint abnormalities, heart (cardiac) defects, and/or genital malformations. Infants with FASD often experience alcohol addiction withdrawal symptoms within 24 hours after birth. These may include tremors and/or convulsions, irritability, increased muscle tone, muscle and/or whole body spasms, increased respiratory rate, abdominal swelling (distention) and/or vomiting. (For more information on this disorder, choose “Fetal Alcohol” as your search term in the Rare Disease Database.)Ruvalcaba syndrome is a very rare disorder thought to be inherited as an autosomal dominant genetic trait. The symptoms vary greatly among individuals with the disorder. Characteristic facial features are among the most distinguishable symptoms of this disorder. Affected individuals may have an abnormally small head (microcephaly) with an oval face; downslanting eyelid folds; abnormalities of the nose; a small, downturned mouth; a narrow, pointed jaw; and/or low-set ears. Additional features may include short stature; a narrow chest; protruding breastbone (pectus carinatum); abnormal sideways and/or front-to-back curvature of the spine (scoliosis and/or kyphosis); short fingers, toes, arms and/or legs; abnormally small hands and feet; and/or abnormal bending of the fingers (clinodactyly). Affected individuals may also have certain skin abnormalities, underdevelopment (hypoplasia) of the reproductive organs, delayed puberty, and/or other physical differences. Many individuals with Ruvalcaba syndrome may also have varying degrees of intellectual disability. (For more information on this disorder, choose “Ruvalcaba” as your search term in the Rare Disease Database.)Scott craniodigital syndrome with intellectual disability is an extremely rare disorder that is thought to be inherited as an X-linked recessive genetic trait. This disorder is characterized by intellectual disability and various physical differences affecting the head and facial (craniofacial) area and the fingers and/or toes (digits). Characteristic craniofacial features may include a short, wide head (brachycephaly); a small, narrow nose; widely-spaced eyes (ocular hypertelorism); and/or a small lower jaw (mandible). In addition, some children may have a “startled” expression to their faces. Other characteristic features may include webbing of some of the fingers and toes (syndactyly); uncommon skin ridge patterns (dermatoglyphic patterns) on the palms of the hands; and/or abnormal inward turning of the heel of the foot (talipes varus). In addition, individuals with this disorder may have scalp hair that is very thick with hair growing down onto the temples and in front of the ears; long, dark eyelashes; abnormally thick eyebrows; and/or excessive hair growth (hirsutism) on other areas of the body. (For more information on this disorder, choose “Scott Craniodigital” as your search term in the Rare Disease Database.)Duplication on the long arm of chromosome 3, or partial trisomy 3q2, is an extremely rare chromosomal disorder in which the end (distal) portion of the long arm (q) of chromosome 3 (3q) is present three times (trisomy) rather than twice in cells of the body. This disorder is characterized by differences of the head and facial (craniofacial) area, other physical malformations, moderate to severe developmental delays and/or intellectual disability. Many of the craniofacial differences and/or other physical malformations associated with partial trisomy 3q2 are very similar to those often associated with CdLS. For example, many infants and children with partial trisomy 3q2 may have a small head (microcephaly) that also appears unusually short and wide (brachycephaly); a low hairline; a small, broad nose; thick, well-defined, bushy eyebrows that grow together (synophyrys); long eyelashes and/or thin, downturned lips. Affected infants and children may also have excessive hair growth (hypertrichosis) on various areas of the body; abnormalities of the hands, feet, arms, and/or legs; hearing loss and speech impairment and/or eye (ocular) abnormalities including crossing of the eyes (strabismus), rapid, involuntary eye movements (nystagmus), clouding of the lenses of the eyes (cataracts), and/or other ocular abnormalities. Individuals with partial trisomy 3q2 may also have seizure episodes and/or genital, heart (cardiac), gastrointestinal, and/or kidney (renal) malformations. In most children, partial trisomy 3q2 is due to a balanced translocation in one of the parents. (For more information on this disorder, choose “Trisomy 3q2” as your search term in the Rare Disease Database.)There may be other chromosomal disorders that are characterized by symptoms similar to those of CdLS. The only way to determine which chromosomal disorder an individual has is through chromosomal testing. Most individuals with CdLS have normal chromosomes. (For more information on such disorders, choose the exact disease name in question or “Chromosome” as your search term in the Rare Disease Database.) | Related disorders of Cornelia de Lange Syndrome. Symptoms of the following disorders can be similar to those of Cornelia de Lange syndrome. Comparisons may be useful for a differential diagnosis:Coffin-Siris syndrome is an extremely rare genetic disorder that is present at birth (congenital). Infants with this disorder typically have underdeveloped (hypoplastic) or missing fifth fingers on both hands. The toenails may be underdeveloped or absent. Affected individuals may also exhibit characteristic abnormalities of the head and facial (craniofacial) area including a small head (microcephaly), broad nose, wide mouth with thick lips, low nasal bridge, widely-spaced eyes (ocular hypertelorism), droopy upper eyelids (ptosis), thick eyelashes, dental abnormalities and/or sparse scalp hair. During infancy, many affected individuals have feeding difficulties, vomiting, slow growth and/or frequent respiratory infections. During the first two years of life, developmental delays, unusually short stature, and varying degrees of intellectual disability may become apparent. Some children with Coffin-Siris syndrome may also have additional physical differences including abnormally loose joints (laxity) that may result in frequent dislocations, particularly of the elbows; mild to severe muscle weakness (hypotonia); motor delays; sideways curvature of the spine (scoliosis) and/or other skeletal, gastrointestinal, genitourinary and/or cardiac malformations. In some cases, Coffin-Siris syndrome may occur randomly, for no apparent reason (sporadically); in other cases, the disorder may be inherited as an autosomal recessive genetic trait. (For more information on this disorder, choose “Coffin Siris” as your search term in the Rare Disease Database.)Rubinstein-Taybi syndrome is a rare genetic disorder associated with multiple abnormalities that include characteristic facial features, such as a prominent end to the nose, narrows eyes and short fingers with wide thumbs and great toes. Affected individuals are usually shorter than average and can have excessive hair on the body (hypertrichosis). Vision and hearing problems along with intellectual disability may also occur. (For more information on this disorder, choose “Rubinstein-Taybi” as your search term in the Rare Disease Database.)Fetal alcohol spectrum disorder (FASD) is a syndrome of altered fetal growth resulting in certain birth defects due to maternal consumption of alcohol during pregnancy. When a pregnant woman drinks alcoholic beverages, a pattern of abnormalities in the fetus may occur at different stages of pregnancy. Affected infants are unusually small at birth, have an abnormally small head (microcephaly) and may fail to gain weight and grow at the expected rate (failure to thrive). Affected infants and children may have delays in intellectual development as well as in the acquisition of fine and gross motor skills. In addition, affected individuals may have characteristic craniofacial differences including a protruding forehead, an abnormally short opening between the upper and lower eyelids (palpebral fissures), the presence of vertical skin folds on the inner corners of the eyes (epicanthal folds), a long flat area between nose and mouth (philtrum), an incompletely developed, abnormally small upper jaw (maxillary hypoplasia) and/or incomplete closure of the roof of the mouth (cleft palate). Affected infants may also have other physical differences including joint abnormalities, heart (cardiac) defects, and/or genital malformations. Infants with FASD often experience alcohol addiction withdrawal symptoms within 24 hours after birth. These may include tremors and/or convulsions, irritability, increased muscle tone, muscle and/or whole body spasms, increased respiratory rate, abdominal swelling (distention) and/or vomiting. (For more information on this disorder, choose “Fetal Alcohol” as your search term in the Rare Disease Database.)Ruvalcaba syndrome is a very rare disorder thought to be inherited as an autosomal dominant genetic trait. The symptoms vary greatly among individuals with the disorder. Characteristic facial features are among the most distinguishable symptoms of this disorder. Affected individuals may have an abnormally small head (microcephaly) with an oval face; downslanting eyelid folds; abnormalities of the nose; a small, downturned mouth; a narrow, pointed jaw; and/or low-set ears. Additional features may include short stature; a narrow chest; protruding breastbone (pectus carinatum); abnormal sideways and/or front-to-back curvature of the spine (scoliosis and/or kyphosis); short fingers, toes, arms and/or legs; abnormally small hands and feet; and/or abnormal bending of the fingers (clinodactyly). Affected individuals may also have certain skin abnormalities, underdevelopment (hypoplasia) of the reproductive organs, delayed puberty, and/or other physical differences. Many individuals with Ruvalcaba syndrome may also have varying degrees of intellectual disability. (For more information on this disorder, choose “Ruvalcaba” as your search term in the Rare Disease Database.)Scott craniodigital syndrome with intellectual disability is an extremely rare disorder that is thought to be inherited as an X-linked recessive genetic trait. This disorder is characterized by intellectual disability and various physical differences affecting the head and facial (craniofacial) area and the fingers and/or toes (digits). Characteristic craniofacial features may include a short, wide head (brachycephaly); a small, narrow nose; widely-spaced eyes (ocular hypertelorism); and/or a small lower jaw (mandible). In addition, some children may have a “startled” expression to their faces. Other characteristic features may include webbing of some of the fingers and toes (syndactyly); uncommon skin ridge patterns (dermatoglyphic patterns) on the palms of the hands; and/or abnormal inward turning of the heel of the foot (talipes varus). In addition, individuals with this disorder may have scalp hair that is very thick with hair growing down onto the temples and in front of the ears; long, dark eyelashes; abnormally thick eyebrows; and/or excessive hair growth (hirsutism) on other areas of the body. (For more information on this disorder, choose “Scott Craniodigital” as your search term in the Rare Disease Database.)Duplication on the long arm of chromosome 3, or partial trisomy 3q2, is an extremely rare chromosomal disorder in which the end (distal) portion of the long arm (q) of chromosome 3 (3q) is present three times (trisomy) rather than twice in cells of the body. This disorder is characterized by differences of the head and facial (craniofacial) area, other physical malformations, moderate to severe developmental delays and/or intellectual disability. Many of the craniofacial differences and/or other physical malformations associated with partial trisomy 3q2 are very similar to those often associated with CdLS. For example, many infants and children with partial trisomy 3q2 may have a small head (microcephaly) that also appears unusually short and wide (brachycephaly); a low hairline; a small, broad nose; thick, well-defined, bushy eyebrows that grow together (synophyrys); long eyelashes and/or thin, downturned lips. Affected infants and children may also have excessive hair growth (hypertrichosis) on various areas of the body; abnormalities of the hands, feet, arms, and/or legs; hearing loss and speech impairment and/or eye (ocular) abnormalities including crossing of the eyes (strabismus), rapid, involuntary eye movements (nystagmus), clouding of the lenses of the eyes (cataracts), and/or other ocular abnormalities. Individuals with partial trisomy 3q2 may also have seizure episodes and/or genital, heart (cardiac), gastrointestinal, and/or kidney (renal) malformations. In most children, partial trisomy 3q2 is due to a balanced translocation in one of the parents. (For more information on this disorder, choose “Trisomy 3q2” as your search term in the Rare Disease Database.)There may be other chromosomal disorders that are characterized by symptoms similar to those of CdLS. The only way to determine which chromosomal disorder an individual has is through chromosomal testing. Most individuals with CdLS have normal chromosomes. (For more information on such disorders, choose the exact disease name in question or “Chromosome” as your search term in the Rare Disease Database.) | 325 | Cornelia de Lange Syndrome |
nord_325_5 | Diagnosis of Cornelia de Lange Syndrome | Most children with CdLS are diagnosed clinically after birth or in childhood based upon a thorough clinical evaluation and identification of characteristic physical findings. A diagnosis of CdLS should be considered in children who exhibit certain distinctive facial features in association with limb anomalies, prenatal and postnatal growth delay and intellectual disability. Diagnosis may be more difficult if symptoms and physical characteristics associated with the disorder are very mild. Molecular genetic testing for mutations in the five genes associated with CdLS is available to confirm the diagnosis and may be particularly helpful when the physical features are mild or unusual. Prenatal diagnosis is available if a specific NIPBL, SMC1A, SMC3, Rad21, HDAC8, ANKRD11 or BRD4 gene mutation has been identified.Sometimes a diagnosis of CdLS may be suspected before birth (prenatally) through the use of ultrasound imaging. During such testing, reflected sound waves create an image of the fetus that may reveal certain characteristics of CdLS such as delayed growth, limb abnormalities, facial anomalies and/or organ malformations. | Diagnosis of Cornelia de Lange Syndrome. Most children with CdLS are diagnosed clinically after birth or in childhood based upon a thorough clinical evaluation and identification of characteristic physical findings. A diagnosis of CdLS should be considered in children who exhibit certain distinctive facial features in association with limb anomalies, prenatal and postnatal growth delay and intellectual disability. Diagnosis may be more difficult if symptoms and physical characteristics associated with the disorder are very mild. Molecular genetic testing for mutations in the five genes associated with CdLS is available to confirm the diagnosis and may be particularly helpful when the physical features are mild or unusual. Prenatal diagnosis is available if a specific NIPBL, SMC1A, SMC3, Rad21, HDAC8, ANKRD11 or BRD4 gene mutation has been identified.Sometimes a diagnosis of CdLS may be suspected before birth (prenatally) through the use of ultrasound imaging. During such testing, reflected sound waves create an image of the fetus that may reveal certain characteristics of CdLS such as delayed growth, limb abnormalities, facial anomalies and/or organ malformations. | 325 | Cornelia de Lange Syndrome |
nord_325_6 | Therapies of Cornelia de Lange Syndrome | Treatment
The treatment of CdLS is directed toward the specific symptoms that are apparent in each individual. Treatment may require the efforts of a team of specialists working together to systematically and comprehensively plan an affected child’s treatment. Such specialists may include pediatricians; geneticists; surgeons; specialists who diagnose and treat skeletal disorders (orthopedists); plastic surgeons; orthopedic surgeons; specialists who diagnose and treat abnormalities of the digestive system (gastroenterologists), feeding specialists, disorders of the urinary tract (urologists), and abnormalities of the ears, nose, and throat (otolaryngologists); pediatric heart specialists (cardiologists); dental specialists; speech pathologists; specialists who assess and treat hearing problems (audiologists); eye specialists; physical and occupational therapists and/or other health care professionals.Affected infants and children may be closely monitored for certain abnormalities potentially associated with CdLS (e.g., potential intestinal obstruction due to gastrointestinal abnormalities, cardiac defects, gastroesophageal reflux, glue ear and/or susceptibility to respiratory infections) to ensure early detection and prompt treatment.Specific therapies for the treatment of CdLS are symptomatic and supportive. In some children, surgery may be performed to help correct cleft palate, cardiac defects and/or diaphragmatic hernias. Plastic surgery may be helpful in reducing excessive hair. Some gastrointestinal, genitourinary and/or cardiac malformations may be treated with certain medications, surgical intervention and/or other techniques. The surgical procedures performed will depend upon the location and severity of the anatomical differences and their associated symptoms. Respiratory infections may be treated with antibiotic drug therapy and/or other medications that may help fight infection.Various orthopedic techniques may be used to help treat limb differences. Hearing aids may be beneficial in some children. Treatment with anticonvulsant medications may help prevent, reduce or control seizures in some affected children.Early intervention is important in ensuring that children with CdLS reach their highest potential. Services that may be beneficial include special remedial education, vocational training, speech therapy and/or other medical and/or social services.Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive. | Therapies of Cornelia de Lange Syndrome. Treatment
The treatment of CdLS is directed toward the specific symptoms that are apparent in each individual. Treatment may require the efforts of a team of specialists working together to systematically and comprehensively plan an affected child’s treatment. Such specialists may include pediatricians; geneticists; surgeons; specialists who diagnose and treat skeletal disorders (orthopedists); plastic surgeons; orthopedic surgeons; specialists who diagnose and treat abnormalities of the digestive system (gastroenterologists), feeding specialists, disorders of the urinary tract (urologists), and abnormalities of the ears, nose, and throat (otolaryngologists); pediatric heart specialists (cardiologists); dental specialists; speech pathologists; specialists who assess and treat hearing problems (audiologists); eye specialists; physical and occupational therapists and/or other health care professionals.Affected infants and children may be closely monitored for certain abnormalities potentially associated with CdLS (e.g., potential intestinal obstruction due to gastrointestinal abnormalities, cardiac defects, gastroesophageal reflux, glue ear and/or susceptibility to respiratory infections) to ensure early detection and prompt treatment.Specific therapies for the treatment of CdLS are symptomatic and supportive. In some children, surgery may be performed to help correct cleft palate, cardiac defects and/or diaphragmatic hernias. Plastic surgery may be helpful in reducing excessive hair. Some gastrointestinal, genitourinary and/or cardiac malformations may be treated with certain medications, surgical intervention and/or other techniques. The surgical procedures performed will depend upon the location and severity of the anatomical differences and their associated symptoms. Respiratory infections may be treated with antibiotic drug therapy and/or other medications that may help fight infection.Various orthopedic techniques may be used to help treat limb differences. Hearing aids may be beneficial in some children. Treatment with anticonvulsant medications may help prevent, reduce or control seizures in some affected children.Early intervention is important in ensuring that children with CdLS reach their highest potential. Services that may be beneficial include special remedial education, vocational training, speech therapy and/or other medical and/or social services.Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive. | 325 | Cornelia de Lange Syndrome |
nord_326_0 | Overview of Corticobasal Degeneration | SummaryCorticobasal degeneration (CBD) is a rare progressive neurological disorder characterized by cell loss and deterioration of specific areas of the brain. Affected individuals often experience movement disorders initially in one limb that might spread to both the arms and legs. Symptoms include muscle rigidity and the inability to perform purposeful or voluntary movements (apraxia). Affected individuals may have sufficient muscle power for manual tasks but struggle to direct their movements appropriately. Although CBD was historically described as a motor disease, it is now recognized that cognitive and behavioral symptoms are also associated with CBD and often come before the motor symptoms. Initial signs typically appear in people ages 60-70, and may include language difficulties, poor coordination and issues with memory. The exact cause of CBD is unknown; however, it may be linked to the accumulation of the tau protein in the brain. | Overview of Corticobasal Degeneration. SummaryCorticobasal degeneration (CBD) is a rare progressive neurological disorder characterized by cell loss and deterioration of specific areas of the brain. Affected individuals often experience movement disorders initially in one limb that might spread to both the arms and legs. Symptoms include muscle rigidity and the inability to perform purposeful or voluntary movements (apraxia). Affected individuals may have sufficient muscle power for manual tasks but struggle to direct their movements appropriately. Although CBD was historically described as a motor disease, it is now recognized that cognitive and behavioral symptoms are also associated with CBD and often come before the motor symptoms. Initial signs typically appear in people ages 60-70, and may include language difficulties, poor coordination and issues with memory. The exact cause of CBD is unknown; however, it may be linked to the accumulation of the tau protein in the brain. | 326 | Corticobasal Degeneration |
nord_326_1 | Symptoms of Corticobasal Degeneration | Because signs and symptoms associated with CBD are frequently caused by other neurodegenerative disorders, researchers use the term “corticobasal syndrome” to indicate the clinical diagnosis. “Corticobasal degeneration” is diagnosed after a patient dies and an autopsy reveals the necessary criteria of brain pathway abnormalities specific to CBD. This is an important distinction because less than half (35-50%) of patients presenting with symptoms of of corticobasal syndrome during life have CBD at autopsy.The symptoms, progression, severity and presentation of CBD can vary greatly from one person to another. It is important to note that affected individuals may not have all of the symptoms discussed below. Patients should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.In many patients, the first sign of CBD is trouble with movement of the limbs. The muscles of affected individuals may stiffen or shake, primarily in the limbs (progressive extrapyramidal muscle rigidity). Individuals are often unable to make voluntary, purposeful movements with the affected limb (apraxia). Affected individuals have sufficient muscle power for manual tasks but have difficulty directing their movements appropriately. Difficulties with the affected limb can worsen over time. People with CBD may first become aware of the disorder when they have difficulty coordinating movements in the performance of manual tasks such as buttoning a shirt, combing their hair or gesturing with their hands. Affected individuals often describe their actions as stiff, clumsy or uncoordinated. Some patients may be unaware of the movement or unable to control the movement of a limb (alien limb syndrome). Some individuals may experience a loss of discriminative sensation in one or two areas of the body. Symptoms typically begin on one side of the body (unilateral) but usually progress over time to affect both sides and all four limbs. Arms are usually affected before the legs, but in rare cases, legs may show symptoms first. Additional symptoms of CBD may include shaking while in particular positions (postural tremor) or while performing a task (action tremor) and/or exaggerated slowness of movements (bradykinesia) or lack of movement (akinesia). The combination of movement abnormalities including limb rigidity, rest tremor and bradykinesia/akinesia. is known as parkinsonism. Sudden, brief involuntary muscle spasms causing jerky movements (myoclonus) may also occur. In some patients, involuntary muscle contractions can force certain part(s) of the body into abnormal, sometimes painful movements and positions (dystonia). Affected individuals often experience focal dystonia, where only one area such as the leg, neck or arm, has involuntary muscle spasms. Affected individuals may also develop contractures, a condition in which a joint becomes permanently fixed in a bent (flexed) or straightened (extended) position, completely or partially restricting the movement of the affected joint. Oftentimes balance is affected as well (postural instability). For example, affected individuals may have trouble resuming walking when slightly unstabilized. CBD may also cause speech and language abnormalities including difficulties understanding or expressing language (aphasia), difficulty saying what they want to say despite knowing the right words (apraxia of speech) and speech difficulties due to problems with the muscles that enable speech (dysarthria). Additional symptoms that may occur include difficulty swallowing (dysphagia), an inability to control eyelid blinking and/or an uncoordinated walk (ataxic gait). Eventually, affected individuals may be unable to walk without assistance. Individuals with CBD can develop a more global loss of intellectual abilities (dementia), usually later in the course of the disease. Affected individuals may also exhibit memory loss, impulsiveness, disinhibition, apathy, irritability, reduced attention span and obsessive-compulsive behaviors. In some patients, the signs and symptoms of dementia may even precede the development of motor symptoms. Initial cognitive symptoms include a non-fluent, progressive aphasia and impairments in executive function.For many years, CBD was thought to be a neurological condition primarily associated with movement disorders. In recent years, researchers have noted that cognitive and behavioral abnormalities occur more frequently than initially believed. As CBD progresses, affected individuals may become unable to communicate effectively. Eventually, affected individuals may become bedridden and susceptible to life-threatening complications such as pneumonia, bacterial infections, blood infection (sepsis) or blockage of one or more of the main arteries of the lungs, usually due to blood clots (pulmonary embolism). | Symptoms of Corticobasal Degeneration. Because signs and symptoms associated with CBD are frequently caused by other neurodegenerative disorders, researchers use the term “corticobasal syndrome” to indicate the clinical diagnosis. “Corticobasal degeneration” is diagnosed after a patient dies and an autopsy reveals the necessary criteria of brain pathway abnormalities specific to CBD. This is an important distinction because less than half (35-50%) of patients presenting with symptoms of of corticobasal syndrome during life have CBD at autopsy.The symptoms, progression, severity and presentation of CBD can vary greatly from one person to another. It is important to note that affected individuals may not have all of the symptoms discussed below. Patients should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.In many patients, the first sign of CBD is trouble with movement of the limbs. The muscles of affected individuals may stiffen or shake, primarily in the limbs (progressive extrapyramidal muscle rigidity). Individuals are often unable to make voluntary, purposeful movements with the affected limb (apraxia). Affected individuals have sufficient muscle power for manual tasks but have difficulty directing their movements appropriately. Difficulties with the affected limb can worsen over time. People with CBD may first become aware of the disorder when they have difficulty coordinating movements in the performance of manual tasks such as buttoning a shirt, combing their hair or gesturing with their hands. Affected individuals often describe their actions as stiff, clumsy or uncoordinated. Some patients may be unaware of the movement or unable to control the movement of a limb (alien limb syndrome). Some individuals may experience a loss of discriminative sensation in one or two areas of the body. Symptoms typically begin on one side of the body (unilateral) but usually progress over time to affect both sides and all four limbs. Arms are usually affected before the legs, but in rare cases, legs may show symptoms first. Additional symptoms of CBD may include shaking while in particular positions (postural tremor) or while performing a task (action tremor) and/or exaggerated slowness of movements (bradykinesia) or lack of movement (akinesia). The combination of movement abnormalities including limb rigidity, rest tremor and bradykinesia/akinesia. is known as parkinsonism. Sudden, brief involuntary muscle spasms causing jerky movements (myoclonus) may also occur. In some patients, involuntary muscle contractions can force certain part(s) of the body into abnormal, sometimes painful movements and positions (dystonia). Affected individuals often experience focal dystonia, where only one area such as the leg, neck or arm, has involuntary muscle spasms. Affected individuals may also develop contractures, a condition in which a joint becomes permanently fixed in a bent (flexed) or straightened (extended) position, completely or partially restricting the movement of the affected joint. Oftentimes balance is affected as well (postural instability). For example, affected individuals may have trouble resuming walking when slightly unstabilized. CBD may also cause speech and language abnormalities including difficulties understanding or expressing language (aphasia), difficulty saying what they want to say despite knowing the right words (apraxia of speech) and speech difficulties due to problems with the muscles that enable speech (dysarthria). Additional symptoms that may occur include difficulty swallowing (dysphagia), an inability to control eyelid blinking and/or an uncoordinated walk (ataxic gait). Eventually, affected individuals may be unable to walk without assistance. Individuals with CBD can develop a more global loss of intellectual abilities (dementia), usually later in the course of the disease. Affected individuals may also exhibit memory loss, impulsiveness, disinhibition, apathy, irritability, reduced attention span and obsessive-compulsive behaviors. In some patients, the signs and symptoms of dementia may even precede the development of motor symptoms. Initial cognitive symptoms include a non-fluent, progressive aphasia and impairments in executive function.For many years, CBD was thought to be a neurological condition primarily associated with movement disorders. In recent years, researchers have noted that cognitive and behavioral abnormalities occur more frequently than initially believed. As CBD progresses, affected individuals may become unable to communicate effectively. Eventually, affected individuals may become bedridden and susceptible to life-threatening complications such as pneumonia, bacterial infections, blood infection (sepsis) or blockage of one or more of the main arteries of the lungs, usually due to blood clots (pulmonary embolism). | 326 | Corticobasal Degeneration |
nord_326_2 | Causes of Corticobasal Degeneration | The exact, underlying cause of CBD is unknown. Researchers believe that multiple different factors contribute to the development of the disorder, such as environmental changes and aging. The symptoms of CBD develop due to the progressive deterioration of brain tissue. Nerve cell loss occurs in specific areas, leading to atrophy or shrinkage in specific lobes of the brain. The severity and type of symptoms depend on the area of the brain affected by the disease. The cerebral cortex and basal ganglia are the two areas most typically affected, although other parts of the brain may become involved. The cerebral cortex is the outer layer of nerve tissue surrounding the brain (cerebral hemispheres) called the grey matter. The cerebral cortex is involved with higher brain functions including voluntary movement, memory, learning and coordination of sensory information. The basal ganglia is a cluster of nerve cells involved with motor and learning functions. Researchers have determined that a protein called tau plays a role in the development of CBD. Tau is a specific type of protein normally found in brain cells. The function of tau within nerve cells is complex and not fully understood, although it is believed to be associated with healthy brain function as it contributes to transportation of nutrients (microtubule stability). In CBD, abnormal levels of tau accumulate in certain brain cells, eventually causing their deterioration. These tau proteins are also hyperphosphorylated, meaning that extra phosphate groups are attached to the protein, which destabilizes nutrient transportation. The exact role that tau plays in the development of CBD is not fully understood, and abnormalities involving tau are also seen in other neurodegenerative brain disorders including Alzheimer’s disease, progressive supranuclear palsy, Niemann-Pick disease type C and frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). These disorders collectively are referred to as “tauopathies.”Because CBD occurs randomly, it is considered to be a non-inherited illness. However, a genetic basis may exist given that there are rare familial cases. Some research has found links between CBD and a tau gene variant. Researchers have discovered that the H1 haplotype of MAPT, a tau gene, is present in people with CBD at a higher frequency than in controls. However, not all CBD patients have the tau gene variant, and not all people with the gene variant develop CBD. | Causes of Corticobasal Degeneration. The exact, underlying cause of CBD is unknown. Researchers believe that multiple different factors contribute to the development of the disorder, such as environmental changes and aging. The symptoms of CBD develop due to the progressive deterioration of brain tissue. Nerve cell loss occurs in specific areas, leading to atrophy or shrinkage in specific lobes of the brain. The severity and type of symptoms depend on the area of the brain affected by the disease. The cerebral cortex and basal ganglia are the two areas most typically affected, although other parts of the brain may become involved. The cerebral cortex is the outer layer of nerve tissue surrounding the brain (cerebral hemispheres) called the grey matter. The cerebral cortex is involved with higher brain functions including voluntary movement, memory, learning and coordination of sensory information. The basal ganglia is a cluster of nerve cells involved with motor and learning functions. Researchers have determined that a protein called tau plays a role in the development of CBD. Tau is a specific type of protein normally found in brain cells. The function of tau within nerve cells is complex and not fully understood, although it is believed to be associated with healthy brain function as it contributes to transportation of nutrients (microtubule stability). In CBD, abnormal levels of tau accumulate in certain brain cells, eventually causing their deterioration. These tau proteins are also hyperphosphorylated, meaning that extra phosphate groups are attached to the protein, which destabilizes nutrient transportation. The exact role that tau plays in the development of CBD is not fully understood, and abnormalities involving tau are also seen in other neurodegenerative brain disorders including Alzheimer’s disease, progressive supranuclear palsy, Niemann-Pick disease type C and frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). These disorders collectively are referred to as “tauopathies.”Because CBD occurs randomly, it is considered to be a non-inherited illness. However, a genetic basis may exist given that there are rare familial cases. Some research has found links between CBD and a tau gene variant. Researchers have discovered that the H1 haplotype of MAPT, a tau gene, is present in people with CBD at a higher frequency than in controls. However, not all CBD patients have the tau gene variant, and not all people with the gene variant develop CBD. | 326 | Corticobasal Degeneration |
nord_326_3 | Affects of Corticobasal Degeneration | CBD typically occurs in older populations. No confirmed cases of CBD have been reported in individuals under 40. People between the ages of 50-70 are susceptible, with the average age of CBD onset being 64. Some studies have suggested the disease is slightly more prevalent among women. The disorder is estimated to affect 5 people per 100,000 in the general population, with approximately 1 new case per year per 100,000 people. CBD also represents 4–6% of patients with parkinsonism. However, cases may go undiagnosed or misdiagnosed making it difficult to determine the true frequency of CBD in the general population. | Affects of Corticobasal Degeneration. CBD typically occurs in older populations. No confirmed cases of CBD have been reported in individuals under 40. People between the ages of 50-70 are susceptible, with the average age of CBD onset being 64. Some studies have suggested the disease is slightly more prevalent among women. The disorder is estimated to affect 5 people per 100,000 in the general population, with approximately 1 new case per year per 100,000 people. CBD also represents 4–6% of patients with parkinsonism. However, cases may go undiagnosed or misdiagnosed making it difficult to determine the true frequency of CBD in the general population. | 326 | Corticobasal Degeneration |
nord_326_4 | Related disorders of Corticobasal Degeneration | Symptoms of the following disorders can be similar to those of corticobasal degeneration. Comparisons may be useful for a differential diagnosis. Tauopathies is a general term for a group of neurodegenerative disorders characterized by the abnormal accumulation of the tau protein in certain nerve cells. Abnormal accumulation and function of tau is believed to be a significant factor in the development of all these disorders, although the exact role of tau is not fully understood. Tauopathies often cause movement abnormalities or progressive memory loss (dementia). Examples include Alzheimer’s disease, progressive supranuclear palsy (PSP), and frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)Alzheimer’s disease is progressive disorder that affects memory, thinking, and behavior. It is the most common form of memory loss, accounting for 60-80% of dementia cases. Most Alzheimer patients are over the age of 65, but there are many reported cases of early-onset Alzheimer’s in individuals under 65. There is no cure for Alzheimer’s disease, and current treatments aim to slow the symptoms of dementia. The cause of Alzheimer’s disease is not fully understood, but two abnormal structures (plaque buildup of beta-amyloid and tangles of tau protein) are major indicators. Progressive supranuclear palsy (PSP) is a rare degenerative neurological disorder that affects balance, walking, coordination, eye movement, speech (dysarthria), swallowing (dysphagia) and thinking. Affected individuals frequently experience personality changes, cognitive impairment, forgetfulness and memory loss. Symptoms typically begin in the 60s but can start as early as the 40s and can progressively worsen over time. The exact cause of PSP is unknown. PSP is often misdiagnosed as Parkinson’s disease, Alzheimer’s disease or other neurodegenerative disorders. The results of autopsy differentiate CBD and PSP based on the location and arrangement of the tau protein masses. However, even pathological examination cannot always differentiate PSP from CBD. Tau accumulation in astrocytes, a type of glial cell that supports neurons, can be important in differentiating CBD and PSP. For CBD, the tau protein cluster is referred to as an astrocytic plaque. In PSP, the astrocytes appear as star-like tufts of tau-positive abnormal fibers. The location of tau accumulation also differs. CBD astrocytic plaques are more abundant in the outer layer of the brain, whereas PSP tufted astrocytes are more common in the lower part of the brainstem. (For more information on this disorder, choose “progressive supranuclear palsy” as your search term in the Rare Disease Database.)Parkinson’s disease is also characterized by nerve cell deterioration leading to a decrease in a chemical messenger called dopamine. The disorder is also associated with the accumulation of an abnormal protein called alpha-synuclein. This disease is linked to a post-translational modification (hyperphosphorylation) of the tau protein in the brain. In CBD, both the cortex, the outermost brain layer and the basal ganglia are impacted. Parkinson's disease is most prominent in just the basal ganglia. Parkinsonian symptoms can include involuntary, resting tremor, muscular stiffness or lack of flexibility (rigidity), slowness of movement (bradykinesia) and difficulty controlling voluntary movements. Parkinsonian symptoms not due to Parkinson’s disease may also occur because of head trauma, inflammation of the brain (encephalitis), obstructions (infarcts) or tumors deep within the cerebral hemispheres (cerebrum) and base of the brain (i.e., basal ganglia), or exposure to certain drugs and toxins. Multiple system atrophy (MSA) is a rare progressive neurological disorder that affects the body’s involuntary (autonomic) functions. The impairment can impact blood pressure, heart rate, breathing, bladder control and sweating. Patients may experience symptoms like those found in Parkinson’s disease (parkinsonism), such as muscle rigidity; and uncoordinated muscle movement (cerebellar ataxia). The exact cause of multiple system atrophy is unknown. (For more information on this disorder, choose “multiple system atrophy” as your search term in the Rare Disease Database.) Conditions such as a stroke or a brain tumor can mimic the movement abnormalities and cognitive dysfunction present in CBD. Neuroimaging is used to exclude these conditions. | Related disorders of Corticobasal Degeneration. Symptoms of the following disorders can be similar to those of corticobasal degeneration. Comparisons may be useful for a differential diagnosis. Tauopathies is a general term for a group of neurodegenerative disorders characterized by the abnormal accumulation of the tau protein in certain nerve cells. Abnormal accumulation and function of tau is believed to be a significant factor in the development of all these disorders, although the exact role of tau is not fully understood. Tauopathies often cause movement abnormalities or progressive memory loss (dementia). Examples include Alzheimer’s disease, progressive supranuclear palsy (PSP), and frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)Alzheimer’s disease is progressive disorder that affects memory, thinking, and behavior. It is the most common form of memory loss, accounting for 60-80% of dementia cases. Most Alzheimer patients are over the age of 65, but there are many reported cases of early-onset Alzheimer’s in individuals under 65. There is no cure for Alzheimer’s disease, and current treatments aim to slow the symptoms of dementia. The cause of Alzheimer’s disease is not fully understood, but two abnormal structures (plaque buildup of beta-amyloid and tangles of tau protein) are major indicators. Progressive supranuclear palsy (PSP) is a rare degenerative neurological disorder that affects balance, walking, coordination, eye movement, speech (dysarthria), swallowing (dysphagia) and thinking. Affected individuals frequently experience personality changes, cognitive impairment, forgetfulness and memory loss. Symptoms typically begin in the 60s but can start as early as the 40s and can progressively worsen over time. The exact cause of PSP is unknown. PSP is often misdiagnosed as Parkinson’s disease, Alzheimer’s disease or other neurodegenerative disorders. The results of autopsy differentiate CBD and PSP based on the location and arrangement of the tau protein masses. However, even pathological examination cannot always differentiate PSP from CBD. Tau accumulation in astrocytes, a type of glial cell that supports neurons, can be important in differentiating CBD and PSP. For CBD, the tau protein cluster is referred to as an astrocytic plaque. In PSP, the astrocytes appear as star-like tufts of tau-positive abnormal fibers. The location of tau accumulation also differs. CBD astrocytic plaques are more abundant in the outer layer of the brain, whereas PSP tufted astrocytes are more common in the lower part of the brainstem. (For more information on this disorder, choose “progressive supranuclear palsy” as your search term in the Rare Disease Database.)Parkinson’s disease is also characterized by nerve cell deterioration leading to a decrease in a chemical messenger called dopamine. The disorder is also associated with the accumulation of an abnormal protein called alpha-synuclein. This disease is linked to a post-translational modification (hyperphosphorylation) of the tau protein in the brain. In CBD, both the cortex, the outermost brain layer and the basal ganglia are impacted. Parkinson's disease is most prominent in just the basal ganglia. Parkinsonian symptoms can include involuntary, resting tremor, muscular stiffness or lack of flexibility (rigidity), slowness of movement (bradykinesia) and difficulty controlling voluntary movements. Parkinsonian symptoms not due to Parkinson’s disease may also occur because of head trauma, inflammation of the brain (encephalitis), obstructions (infarcts) or tumors deep within the cerebral hemispheres (cerebrum) and base of the brain (i.e., basal ganglia), or exposure to certain drugs and toxins. Multiple system atrophy (MSA) is a rare progressive neurological disorder that affects the body’s involuntary (autonomic) functions. The impairment can impact blood pressure, heart rate, breathing, bladder control and sweating. Patients may experience symptoms like those found in Parkinson’s disease (parkinsonism), such as muscle rigidity; and uncoordinated muscle movement (cerebellar ataxia). The exact cause of multiple system atrophy is unknown. (For more information on this disorder, choose “multiple system atrophy” as your search term in the Rare Disease Database.) Conditions such as a stroke or a brain tumor can mimic the movement abnormalities and cognitive dysfunction present in CBD. Neuroimaging is used to exclude these conditions. | 326 | Corticobasal Degeneration |
nord_326_5 | Diagnosis of Corticobasal Degeneration | The definitive diagnosis for CBD can only be confirmed after a patient’s death during autopsy. However, CBD is suspected if characteristic neurologic symptoms occur in a slowly progressive course in the absence of a stroke, tumor or other structural lesion. Distinguishing CBD from other, similar neurodegenerative disorders is difficult, so patients with similar signs and symptoms are diagnosed with “corticobasal syndrome” (as opposed to the definitive diagnosis of “corticobasal degeneration”) during clinical care. One of the most common misdiagnoses of CBD is progressive supranuclear palsy (PSP). During autopsy, PSP and CBD can be differentiated by the location of accumulated tau proteins. In general, CBD mostly affects in the white matter and cortical regions while PSP shows more effects in the deep grey matter regions. There are no specific tests for a diagnosis of CBD, but researchers are currently looking to see if positron emission photography (PET scans) or single-photon emission computerized tomography (SPECT scans) can uncover changes related to the disorder. A clinical diagnosis is made based upon a thorough neurological exam involving a variety of specialized tests.Clinical Testing and Work-UpImaging techniques such as computerized tomography (CT) scanning and magnetic resonance imaging (MRI) may be used to rule out other conditions or reveal brain tissue degeneration within the cerebral cortex and basal ganglia. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures including the brain. An MRI uses magnetic field pulses to produce cross-sectional images of organs and bodily tissues such as the brain. | Diagnosis of Corticobasal Degeneration. The definitive diagnosis for CBD can only be confirmed after a patient’s death during autopsy. However, CBD is suspected if characteristic neurologic symptoms occur in a slowly progressive course in the absence of a stroke, tumor or other structural lesion. Distinguishing CBD from other, similar neurodegenerative disorders is difficult, so patients with similar signs and symptoms are diagnosed with “corticobasal syndrome” (as opposed to the definitive diagnosis of “corticobasal degeneration”) during clinical care. One of the most common misdiagnoses of CBD is progressive supranuclear palsy (PSP). During autopsy, PSP and CBD can be differentiated by the location of accumulated tau proteins. In general, CBD mostly affects in the white matter and cortical regions while PSP shows more effects in the deep grey matter regions. There are no specific tests for a diagnosis of CBD, but researchers are currently looking to see if positron emission photography (PET scans) or single-photon emission computerized tomography (SPECT scans) can uncover changes related to the disorder. A clinical diagnosis is made based upon a thorough neurological exam involving a variety of specialized tests.Clinical Testing and Work-UpImaging techniques such as computerized tomography (CT) scanning and magnetic resonance imaging (MRI) may be used to rule out other conditions or reveal brain tissue degeneration within the cerebral cortex and basal ganglia. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures including the brain. An MRI uses magnetic field pulses to produce cross-sectional images of organs and bodily tissues such as the brain. | 326 | Corticobasal Degeneration |
nord_326_6 | Therapies of Corticobasal Degeneration | TreatmentWhile there is no specific treatment for slowing the progression of CBD, there are treatments available for managing symptoms. Specific symptoms are dependent on the individual, but most cases prove resistant to such therapy. Affected individuals may be treated with certain drugs for movement symptoms such as levodopa and similar medications that are normally used to treat Parkinson's disease. These drugs are generally ineffective but may help with the slowness or stiffness some individuals experience. Muscle spasms (myoclonus) may be controlled with medications such as clonazepam, however, benzodiazepines should be used sparingly as they may have undesired side effects in these patients. Botulinum toxin (Botox) has been used to treat contractures and pain but does not restore the ability to control movements. Baclofen is another drug that may be used to treat muscle rigidity. Medications called cholinesterase inhibitors may be prescribed to manage memory problems and other symptoms. These include medications such as donepezil, rivastigmine and galantamine.Physical therapy may be beneficial in maintaining the mobility and range of motion of stiffened, rigid joints and prevent muscle tightening (contractures). Occupational therapy is beneficial in assessing the safety of an affected individual's home and in determining what adaptive medical equipment may increase a person's independence. Speech therapy may be beneficial in treating individuals whose speech and language abnormalities are associated with CBD. Affected individuals may need devices such as a cane or walker to assist in walking. | Therapies of Corticobasal Degeneration. TreatmentWhile there is no specific treatment for slowing the progression of CBD, there are treatments available for managing symptoms. Specific symptoms are dependent on the individual, but most cases prove resistant to such therapy. Affected individuals may be treated with certain drugs for movement symptoms such as levodopa and similar medications that are normally used to treat Parkinson's disease. These drugs are generally ineffective but may help with the slowness or stiffness some individuals experience. Muscle spasms (myoclonus) may be controlled with medications such as clonazepam, however, benzodiazepines should be used sparingly as they may have undesired side effects in these patients. Botulinum toxin (Botox) has been used to treat contractures and pain but does not restore the ability to control movements. Baclofen is another drug that may be used to treat muscle rigidity. Medications called cholinesterase inhibitors may be prescribed to manage memory problems and other symptoms. These include medications such as donepezil, rivastigmine and galantamine.Physical therapy may be beneficial in maintaining the mobility and range of motion of stiffened, rigid joints and prevent muscle tightening (contractures). Occupational therapy is beneficial in assessing the safety of an affected individual's home and in determining what adaptive medical equipment may increase a person's independence. Speech therapy may be beneficial in treating individuals whose speech and language abnormalities are associated with CBD. Affected individuals may need devices such as a cane or walker to assist in walking. | 326 | Corticobasal Degeneration |
nord_327_0 | Overview of Costello Syndrome | Costello syndrome is an extremely rare disorder that affects multiple organ systems of the body. This condition is characterized by growth delays after birth; short stature; extra loose skin on the neck, palms of the hands, fingers, and soles of the feet; noncancerous tumors (papillomata) around the face and anus; developmental delay and intellectual disability; and a characteristic facial appearance. Other physical features may include the development of dry hardened skin on the palms of the hands and the soles of the feet (palmoplantar hyperkeratosis), abnormally deep creases on the palms and soles, and/or abnormally flexible joints of the fingers (hyperextensible). There is an increased incidence of congenital abnormalities of the heart and thickening of the heart muscle called a cardiomyopathy. Characteristic craniofacial features may include an abnormally large head (macrocephaly); coarse facial features; unusually thick lips; and/or abnormally wide nostrils (nares). Affected individuals have an increased lifetime risk to develop specific malignant tumors. Costello syndrome is an autosomal dominant genetic condition caused by mutations in the HRAS gene. | Overview of Costello Syndrome. Costello syndrome is an extremely rare disorder that affects multiple organ systems of the body. This condition is characterized by growth delays after birth; short stature; extra loose skin on the neck, palms of the hands, fingers, and soles of the feet; noncancerous tumors (papillomata) around the face and anus; developmental delay and intellectual disability; and a characteristic facial appearance. Other physical features may include the development of dry hardened skin on the palms of the hands and the soles of the feet (palmoplantar hyperkeratosis), abnormally deep creases on the palms and soles, and/or abnormally flexible joints of the fingers (hyperextensible). There is an increased incidence of congenital abnormalities of the heart and thickening of the heart muscle called a cardiomyopathy. Characteristic craniofacial features may include an abnormally large head (macrocephaly); coarse facial features; unusually thick lips; and/or abnormally wide nostrils (nares). Affected individuals have an increased lifetime risk to develop specific malignant tumors. Costello syndrome is an autosomal dominant genetic condition caused by mutations in the HRAS gene. | 327 | Costello Syndrome |
nord_327_1 | Symptoms of Costello Syndrome | Infants with Costello syndrome typically have a normal or high birth weight, but show poor sucking ability, have swallowing difficulties, and fail to grow and gain weight at the expected rate (failure to thrive). Growth delay after birth typically results in short stature during childhood and adulthood. Affected children may have developmental delay or mild to moderate intellectual disability. In some individuals, speech development and/or the ability to walk is significantly delayed. Children with Costello syndrome generally have warm, sociable personalities.Individuals with Costello syndrome typically have loose skin (cutis laxa) on the neck, palms, fingers, and soles. The skin in these areas may lack elasticity and hang loosely; in addition, the skin may appear wrinkled and thickened. In some cases, certain areas of the skin may become unusually dark (hyperpigmentation). In addition, most patients with this disorder develop dry hardened patches of skin (hyperkeratosis) with unusually deep creases on the palms and soles. Some affected individuals may also have skeletal abnormalities such as dislocated hips, abnormally flexible (hyperextensible) joints of the fingers, wrists bent toward the little finger (ulnar deviation) and/or unusual tightening of the fibrous cords on the back of the heels (Achilles tendon). Additional skeletal abnormalities include side-to-side curvature of the spine (scoliosis), front-to-back curvature of the spine (kyphosis), and reduced range of motion in the shoulder and elbows.Children with Costello syndrome usually devlelop papillomata around the mouth and nostrils. Papillomata may develop as early as two years of age or at older ages. In some cases, these wart-like (verrucal) lesions may be found near the anus. Papillomata usually become more apparent with age. Other benign tumors have also been reported.Children with Costello syndrome have a distinctive facial appearance. Characteristic facial features may include an abnormally large head (macrocephaly); low-set ears with large, thick lobes; unusually thick lips; a large, depressed nasal bridge; abnormally wide nostrils (nares); and a coarse facial appearance. In addition, affected children may have unusually curly hair and/or sparse, thin hair on the front (anterior) of the head. Some children have folds of skin over the inner corners of the eyes (epicanthal folds).In early childhood relative overgrowth of the hindbrain compared to the space available in the posterior fossa of skull cavity can result in crowding and neurologic problems. Because severe crowding requires surgical intervention, screening with brain and cervical spine MRI has been suggested.Eye and vision changes are common and include nystagmus (rapid eye movements) in younger individuals, strabismus and rarely in older individuals keratoconus (abnormal thickening of the cornea).Children with Costello syndrome often have certain heart abnormalities. These may include structural malformations of the heart that are present at birth (congenital heart defects); abnormal thickening of the muscular walls of the left lower chamber of the heart (hypertrophic cardiomyopathy); leakage of the valve between the left upper (atrial) and lower (ventricular) heart chambers (mitral valve prolapse); and/or other cardiac defects. Associated symptoms and findings may include abnormal heart sounds (heart murmurs) that may be detected by a physician through use of a stethoscope; shortness of breath, particularly upon exertion; faintness; chest pain; abnormal heart rhythms (arrhythmias); and/or other findings that may potentially lead to life-threatening complications without appropriate treatment.Affected individuals have an approximately 15% lifetime risk to develop malignant tumors such as a cancer of the muscle tissue (rhabdomyosarcoma), a cancer of the nerve cells (neuroblastoma), and transitional cell carcinoma of the bladder.In some cases, the symptoms and findings of Costello syndrome overlap with two similar disorders known as Noonan syndrome and cardiofaciocutaneous syndrome which are caused by mutations in different genes. (For more information on Noonan and cardiofaciocutaneous syndromes, see the Related Disorders section below.) | Symptoms of Costello Syndrome. Infants with Costello syndrome typically have a normal or high birth weight, but show poor sucking ability, have swallowing difficulties, and fail to grow and gain weight at the expected rate (failure to thrive). Growth delay after birth typically results in short stature during childhood and adulthood. Affected children may have developmental delay or mild to moderate intellectual disability. In some individuals, speech development and/or the ability to walk is significantly delayed. Children with Costello syndrome generally have warm, sociable personalities.Individuals with Costello syndrome typically have loose skin (cutis laxa) on the neck, palms, fingers, and soles. The skin in these areas may lack elasticity and hang loosely; in addition, the skin may appear wrinkled and thickened. In some cases, certain areas of the skin may become unusually dark (hyperpigmentation). In addition, most patients with this disorder develop dry hardened patches of skin (hyperkeratosis) with unusually deep creases on the palms and soles. Some affected individuals may also have skeletal abnormalities such as dislocated hips, abnormally flexible (hyperextensible) joints of the fingers, wrists bent toward the little finger (ulnar deviation) and/or unusual tightening of the fibrous cords on the back of the heels (Achilles tendon). Additional skeletal abnormalities include side-to-side curvature of the spine (scoliosis), front-to-back curvature of the spine (kyphosis), and reduced range of motion in the shoulder and elbows.Children with Costello syndrome usually devlelop papillomata around the mouth and nostrils. Papillomata may develop as early as two years of age or at older ages. In some cases, these wart-like (verrucal) lesions may be found near the anus. Papillomata usually become more apparent with age. Other benign tumors have also been reported.Children with Costello syndrome have a distinctive facial appearance. Characteristic facial features may include an abnormally large head (macrocephaly); low-set ears with large, thick lobes; unusually thick lips; a large, depressed nasal bridge; abnormally wide nostrils (nares); and a coarse facial appearance. In addition, affected children may have unusually curly hair and/or sparse, thin hair on the front (anterior) of the head. Some children have folds of skin over the inner corners of the eyes (epicanthal folds).In early childhood relative overgrowth of the hindbrain compared to the space available in the posterior fossa of skull cavity can result in crowding and neurologic problems. Because severe crowding requires surgical intervention, screening with brain and cervical spine MRI has been suggested.Eye and vision changes are common and include nystagmus (rapid eye movements) in younger individuals, strabismus and rarely in older individuals keratoconus (abnormal thickening of the cornea).Children with Costello syndrome often have certain heart abnormalities. These may include structural malformations of the heart that are present at birth (congenital heart defects); abnormal thickening of the muscular walls of the left lower chamber of the heart (hypertrophic cardiomyopathy); leakage of the valve between the left upper (atrial) and lower (ventricular) heart chambers (mitral valve prolapse); and/or other cardiac defects. Associated symptoms and findings may include abnormal heart sounds (heart murmurs) that may be detected by a physician through use of a stethoscope; shortness of breath, particularly upon exertion; faintness; chest pain; abnormal heart rhythms (arrhythmias); and/or other findings that may potentially lead to life-threatening complications without appropriate treatment.Affected individuals have an approximately 15% lifetime risk to develop malignant tumors such as a cancer of the muscle tissue (rhabdomyosarcoma), a cancer of the nerve cells (neuroblastoma), and transitional cell carcinoma of the bladder.In some cases, the symptoms and findings of Costello syndrome overlap with two similar disorders known as Noonan syndrome and cardiofaciocutaneous syndrome which are caused by mutations in different genes. (For more information on Noonan and cardiofaciocutaneous syndromes, see the Related Disorders section below.) | 327 | Costello Syndrome |
nord_327_2 | Causes of Costello Syndrome | Costello syndrome is inherited as an autosomal dominant genetic condition and is caused my mutations in the HRAS gene. Mutations in this gene result in production of an abnormal H-Ras protein that leads to continuous cell growth and division.Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. Most individuals with Costello syndrome have the disorder as the result of a new mutation. 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.There have been a few reports of more than one sibling with Costello syndrome in a family. This is most likely due to germ cell mosaicism in which some of the parent’s reproductive cells (germ cells) carry the HRAS gene mutation whereas others contain a normal gene. As a result, one or more of the parent’s children may inherit the gene mutation, leading to manifestation of the autosomal dominant disorder, but the parent may have no apparent symptoms. | Causes of Costello Syndrome. Costello syndrome is inherited as an autosomal dominant genetic condition and is caused my mutations in the HRAS gene. Mutations in this gene result in production of an abnormal H-Ras protein that leads to continuous cell growth and division.Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. Most individuals with Costello syndrome have the disorder as the result of a new mutation. 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.There have been a few reports of more than one sibling with Costello syndrome in a family. This is most likely due to germ cell mosaicism in which some of the parent’s reproductive cells (germ cells) carry the HRAS gene mutation whereas others contain a normal gene. As a result, one or more of the parent’s children may inherit the gene mutation, leading to manifestation of the autosomal dominant disorder, but the parent may have no apparent symptoms. | 327 | Costello Syndrome |
nord_327_3 | Affects of Costello Syndrome | Costello syndrome is a very rare disorder that affects males and females in relatively equal numbers. Approximately 350 affected individuals have been reported worldwide. | Affects of Costello Syndrome. Costello syndrome is a very rare disorder that affects males and females in relatively equal numbers. Approximately 350 affected individuals have been reported worldwide. | 327 | Costello Syndrome |
nord_327_4 | Related disorders of Costello Syndrome | Symptoms of the following disorders can be similar to those of Costello syndrome. Comparisons may be useful for a differential diagnosis:Cardiofaciocutaneous (CFC) syndrome is an extremely rare inherited disorder characterized by multiple defects that affect various parts of the body. The major features of this disorder include growth failure; characteristic facial appearance; sparse hair; variable skin disease; heart defects; and/or mild to moderate intellectual disability. Characteristic facial features may include an abnormally large head (macrocephaly) with a prominent forehead (frontal bossing), widely-spaced eyes (ocular hypertelorism), a short upturned nose, and/or unusually shallow eye socket ridges (hypoplastic orbital ridges). CFC syndrome is a dominant genetic disorder caused by a gene abnormality (mutation) in one of three genes named BRAF, MEK1 and MEK2. Some affected individuals do not have a mutation in one of these genes, suggesting that other genes are also associated with CFC. (For more information on this disorder, choose cardiofaciocutaneous as your search term in the Rare Disease Database.)Noonan syndrome is an autosomal dominant genetic disorder caused by abnormalities (mutations) in different genes: PTPN11, KRAS, SOS1, RIT1, SHOC2, RAF1 and others. Noonan syndrome is a genetic disorder that is typically evident at birth and is characterized by a wide spectrum of symptoms and physical features that vary greatly in range and severity. In many affected individuals, associated abnormalities include a distinctive facial appearance; a broad or webbed neck; a low hairline in the back of the head; and short stature. Characteristic abnormalities of the head and facial (craniofacial) area may include widely set eyes (ocular hypertelorism); vertical skin folds that may cover the eyes’ inner corners (epicanthal folds); drooping of the upper eyelids (ptosis); a small jaw (micrognathia); a low nasal bridge; and low-set, prominent, abnormally rotated ears (pinnae). Distinctive skeletal malformations are also typically present, such as abnormalities of the breastbone (sternum), curvature of the spine (kyphosis and/or scoliosis), and outward deviation of the elbows (cubitus valgus). Many infants with Noonan syndrome also have heart (cardiac) defects, such as obstruction of proper blood flow from the lower right chamber of the heart to the lungs (pulmonary valvular stenosis). Additional abnormalities may include malformations of blood and lymph vessels, blood clotting and platelet deficiencies, mild intellectual disability, failure of the testes to descend into the scrotum (cryptorchidism) by the first year of life in affected males, and/or other symptoms and findings. (For more information on this disorder, choose “Noonan” as your search term in the Rare Disease Database.) | Related disorders of Costello Syndrome. Symptoms of the following disorders can be similar to those of Costello syndrome. Comparisons may be useful for a differential diagnosis:Cardiofaciocutaneous (CFC) syndrome is an extremely rare inherited disorder characterized by multiple defects that affect various parts of the body. The major features of this disorder include growth failure; characteristic facial appearance; sparse hair; variable skin disease; heart defects; and/or mild to moderate intellectual disability. Characteristic facial features may include an abnormally large head (macrocephaly) with a prominent forehead (frontal bossing), widely-spaced eyes (ocular hypertelorism), a short upturned nose, and/or unusually shallow eye socket ridges (hypoplastic orbital ridges). CFC syndrome is a dominant genetic disorder caused by a gene abnormality (mutation) in one of three genes named BRAF, MEK1 and MEK2. Some affected individuals do not have a mutation in one of these genes, suggesting that other genes are also associated with CFC. (For more information on this disorder, choose cardiofaciocutaneous as your search term in the Rare Disease Database.)Noonan syndrome is an autosomal dominant genetic disorder caused by abnormalities (mutations) in different genes: PTPN11, KRAS, SOS1, RIT1, SHOC2, RAF1 and others. Noonan syndrome is a genetic disorder that is typically evident at birth and is characterized by a wide spectrum of symptoms and physical features that vary greatly in range and severity. In many affected individuals, associated abnormalities include a distinctive facial appearance; a broad or webbed neck; a low hairline in the back of the head; and short stature. Characteristic abnormalities of the head and facial (craniofacial) area may include widely set eyes (ocular hypertelorism); vertical skin folds that may cover the eyes’ inner corners (epicanthal folds); drooping of the upper eyelids (ptosis); a small jaw (micrognathia); a low nasal bridge; and low-set, prominent, abnormally rotated ears (pinnae). Distinctive skeletal malformations are also typically present, such as abnormalities of the breastbone (sternum), curvature of the spine (kyphosis and/or scoliosis), and outward deviation of the elbows (cubitus valgus). Many infants with Noonan syndrome also have heart (cardiac) defects, such as obstruction of proper blood flow from the lower right chamber of the heart to the lungs (pulmonary valvular stenosis). Additional abnormalities may include malformations of blood and lymph vessels, blood clotting and platelet deficiencies, mild intellectual disability, failure of the testes to descend into the scrotum (cryptorchidism) by the first year of life in affected males, and/or other symptoms and findings. (For more information on this disorder, choose “Noonan” as your search term in the Rare Disease Database.) | 327 | Costello Syndrome |
nord_327_5 | Diagnosis of Costello Syndrome | Costello syndrome is diagnosed by clinical examination and specific diagnostic criteria have been developed. Molecular genetic testing for mutations in the HRAS gene is available to confirm the diagnosis. Most clinically affected individuals have an identifiable HRAS mutation. Experts in the field suggested that individuals without an identifiable HRAS mutation should not be diagnosed with Costello syndrome, as they most likely have a related condition such as Noonan or cardiofaciocutaneous syndrome. The specific mutation in the HRAS gene, often referred to by the resulting amino acid change, is important to identify. While most individuals with Costello syndrome share a mutation that results in a change of the amino acid glycine in position 12 to serine, a number of changes have been seen. The prognosis for a patient is affected by the specific mutation, as some present with more severe medical problems than others. | Diagnosis of Costello Syndrome. Costello syndrome is diagnosed by clinical examination and specific diagnostic criteria have been developed. Molecular genetic testing for mutations in the HRAS gene is available to confirm the diagnosis. Most clinically affected individuals have an identifiable HRAS mutation. Experts in the field suggested that individuals without an identifiable HRAS mutation should not be diagnosed with Costello syndrome, as they most likely have a related condition such as Noonan or cardiofaciocutaneous syndrome. The specific mutation in the HRAS gene, often referred to by the resulting amino acid change, is important to identify. While most individuals with Costello syndrome share a mutation that results in a change of the amino acid glycine in position 12 to serine, a number of changes have been seen. The prognosis for a patient is affected by the specific mutation, as some present with more severe medical problems than others. | 327 | Costello Syndrome |
nord_327_6 | Therapies of Costello Syndrome | TreatmentThe treatment of Costello 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, physicians who diagnose and treat abnormalities of the heart (cardiologists), physicians who diagnose and treat skeletal abnormalities (orthopedists), orthopedic surgeons, specialists who diagnose and treat abnormalities of the skin (dermatologists), speech pathologists, dietitians, and other health care professionals may need to systematically and comprehensively plan an affected child's treatment.Individuals with cardiac abnormalities, such as hypertrophic cardiomyopathy, may be treated with certain medications (e.g., beta-blockers or calcium channel blockers, antiarrhythmic medications), surgical intervention, and/or other measures may be necessary. The specific surgical procedures performed will depend upon the severity and location of the anatomical abnormalities, their associated symptoms, and other factors.Bracing, occupational and physical therapy may be used to treat ulnar deviation of the wrists. Surgery may be used to lengthen Achilles tendons. Facial papillomata can be removed with dry ice.Early intervention is important to ensure that children with Costello syndrome reach their potential. Services that may be beneficial include special remedial education, speech therapy, special social support, and other medical, social, and/or vocational services.Genetic counseling is recommended for affected individuals and their families. Other treatment for this disorder is symptomatic and supportive. | Therapies of Costello Syndrome. TreatmentThe treatment of Costello 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, physicians who diagnose and treat abnormalities of the heart (cardiologists), physicians who diagnose and treat skeletal abnormalities (orthopedists), orthopedic surgeons, specialists who diagnose and treat abnormalities of the skin (dermatologists), speech pathologists, dietitians, and other health care professionals may need to systematically and comprehensively plan an affected child's treatment.Individuals with cardiac abnormalities, such as hypertrophic cardiomyopathy, may be treated with certain medications (e.g., beta-blockers or calcium channel blockers, antiarrhythmic medications), surgical intervention, and/or other measures may be necessary. The specific surgical procedures performed will depend upon the severity and location of the anatomical abnormalities, their associated symptoms, and other factors.Bracing, occupational and physical therapy may be used to treat ulnar deviation of the wrists. Surgery may be used to lengthen Achilles tendons. Facial papillomata can be removed with dry ice.Early intervention is important to ensure that children with Costello syndrome reach their potential. Services that may be beneficial include special remedial education, speech therapy, special social support, and other medical, social, and/or vocational services.Genetic counseling is recommended for affected individuals and their families. Other treatment for this disorder is symptomatic and supportive. | 327 | Costello Syndrome |
nord_328_0 | Overview of Craniofrontonasal Dysplasia | Craniofrontonasal dysplasia (CFND) is a very rare inherited disorder characterized by body – especially facial – asymmetry, midline defects, skeletal abnormalities, and dermatological abnormalities. Major symptoms of this disorder may include widely spaced eyes (ocular hypertelorism), a groove (cleft) on the tip of the nose, an unusually wide mouth, malformations of the fingers and toes, and/or underdevelopment of portions of the face (midface hypoplasia), such as the forehead, nose, and chin. In addition, the head may have an unusual shape due to premature closure of the fibrous joints (sutures) between certain bones in the skull (coronal synostosis). CFND is an X-linked genetic disorder that occurs mostly in females and is caused by a mutation in the EFNB1 gene. | Overview of Craniofrontonasal Dysplasia. Craniofrontonasal dysplasia (CFND) is a very rare inherited disorder characterized by body – especially facial – asymmetry, midline defects, skeletal abnormalities, and dermatological abnormalities. Major symptoms of this disorder may include widely spaced eyes (ocular hypertelorism), a groove (cleft) on the tip of the nose, an unusually wide mouth, malformations of the fingers and toes, and/or underdevelopment of portions of the face (midface hypoplasia), such as the forehead, nose, and chin. In addition, the head may have an unusual shape due to premature closure of the fibrous joints (sutures) between certain bones in the skull (coronal synostosis). CFND is an X-linked genetic disorder that occurs mostly in females and is caused by a mutation in the EFNB1 gene. | 328 | Craniofrontonasal Dysplasia |
nord_328_1 | Symptoms of Craniofrontonasal Dysplasia | The symptoms of CFND vary greatly in number and severity among affected individuals. The most common symptoms of this disorder include widely spaced eyes (ocular hypertelorism), a vertical groove (cleft) on the tip of the nose, shoulder and limb abnormalities and/or underdevelopment of the middle portion of the face (e.g., forehead, nose, and/or chin). The head typically has an unusual shape due to premature closure of the fibrous joints (sutures) between certain bones in the skull (coronal synostosis) resulting in facial asymmetry.Some affected individuals may have additional abnormalities of the head and facial (craniofacial) area. These may include a broad nose and face; a broad and high forehead; cleft lip and palate; low-set ears and a webbed neck. Females usually have thick, wiry and curly hair that appears at 2-3 months of age.Affected individuals may also have webbing of the fingers and toes (syndactyly); a curved fifth finger (clinodactyly); unusually broad fingers and/or toes, especially the first “big” toe; and/or nails that are grooved, split, concave, and/or brittle.Other physical characteristics sometimes associated with CFND may include narrow sloping shoulders. Several skeletal abnormalities may be present such as malformation of a long, flat, vertical bone in the center of the chest (sternum); malformation of the collarbone (clavicle); backward curvature of the spine (lordosis); and/or sideways curvature of the spine (scoliosis). One limb may be shorter than the other. Underdevelopment of one breast is sometimes seen in females. In addition, one shoulder may be unusually high due to the failure of the major bone of the shoulder (scapula) to move into the appropriate position during fetal development (Sprengel deformity). (For more information on Sprengel deformity, see the Related Disorders section of this report.) Females may have a uterus anomaly that may cause an increased incidence of miscarriages. Some individuals affected by CFND may also have diminished muscle tone (hypotonia), developmental delays, hearing impairment (sensorineural deafness), a sunken chest (pectus excavatum), and/or protrusion of part of the stomach and/or small intestines into the chest cavity (diaphragmatic hernia). Several reports have linked CFND to Poland syndrome which is a condition in which there is an absence of chest wall muscles on one side of the body and abnormally short, webbed fingers on the hand on the same side. Some patients have a complete or partial absence of the corpus callosum, the band of nerves that connect the two hemispheres of the brain.Some affected males may have an abnormal fold of skin extending around the base of the penis (shawl scrotum) and/or improper development of the tube leading from the bladder that discharges urine (urethra). In addition, the urinary opening may be misplaced, such as on the underside of the penis (hypospadias). It is possible that a male may show no symptoms but be a carrier of the gene mutation for CFND. | Symptoms of Craniofrontonasal Dysplasia. The symptoms of CFND vary greatly in number and severity among affected individuals. The most common symptoms of this disorder include widely spaced eyes (ocular hypertelorism), a vertical groove (cleft) on the tip of the nose, shoulder and limb abnormalities and/or underdevelopment of the middle portion of the face (e.g., forehead, nose, and/or chin). The head typically has an unusual shape due to premature closure of the fibrous joints (sutures) between certain bones in the skull (coronal synostosis) resulting in facial asymmetry.Some affected individuals may have additional abnormalities of the head and facial (craniofacial) area. These may include a broad nose and face; a broad and high forehead; cleft lip and palate; low-set ears and a webbed neck. Females usually have thick, wiry and curly hair that appears at 2-3 months of age.Affected individuals may also have webbing of the fingers and toes (syndactyly); a curved fifth finger (clinodactyly); unusually broad fingers and/or toes, especially the first “big” toe; and/or nails that are grooved, split, concave, and/or brittle.Other physical characteristics sometimes associated with CFND may include narrow sloping shoulders. Several skeletal abnormalities may be present such as malformation of a long, flat, vertical bone in the center of the chest (sternum); malformation of the collarbone (clavicle); backward curvature of the spine (lordosis); and/or sideways curvature of the spine (scoliosis). One limb may be shorter than the other. Underdevelopment of one breast is sometimes seen in females. In addition, one shoulder may be unusually high due to the failure of the major bone of the shoulder (scapula) to move into the appropriate position during fetal development (Sprengel deformity). (For more information on Sprengel deformity, see the Related Disorders section of this report.) Females may have a uterus anomaly that may cause an increased incidence of miscarriages. Some individuals affected by CFND may also have diminished muscle tone (hypotonia), developmental delays, hearing impairment (sensorineural deafness), a sunken chest (pectus excavatum), and/or protrusion of part of the stomach and/or small intestines into the chest cavity (diaphragmatic hernia). Several reports have linked CFND to Poland syndrome which is a condition in which there is an absence of chest wall muscles on one side of the body and abnormally short, webbed fingers on the hand on the same side. Some patients have a complete or partial absence of the corpus callosum, the band of nerves that connect the two hemispheres of the brain.Some affected males may have an abnormal fold of skin extending around the base of the penis (shawl scrotum) and/or improper development of the tube leading from the bladder that discharges urine (urethra). In addition, the urinary opening may be misplaced, such as on the underside of the penis (hypospadias). It is possible that a male may show no symptoms but be a carrier of the gene mutation for CFND. | 328 | Craniofrontonasal Dysplasia |
nord_328_2 | Causes of Craniofrontonasal Dysplasia | CFND is an X-linked disorder caused by a mutation in the EFNB1 gene. There have been at least 33 different mutations of the EFNB1 gene identified. All daughters of affected males are affected, consistent with X-linked inheritance. | Causes of Craniofrontonasal Dysplasia. CFND is an X-linked disorder caused by a mutation in the EFNB1 gene. There have been at least 33 different mutations of the EFNB1 gene identified. All daughters of affected males are affected, consistent with X-linked inheritance. | 328 | Craniofrontonasal Dysplasia |
nord_328_3 | Affects of Craniofrontonasal Dysplasia | CFND is a very rare genetic disorder that affects females more often than males. Females have a more severe form of the disorder. | Affects of Craniofrontonasal Dysplasia. CFND is a very rare genetic disorder that affects females more often than males. Females have a more severe form of the disorder. | 328 | Craniofrontonasal Dysplasia |
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