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nord_328_4 | Related disorders of Craniofrontonasal Dysplasia | Symptoms of the following disorders can be similar to those of craniofrontonasal dysplasia. Comparisons may be useful for a differential diagnosis:Aarskog syndrome is an extremely rare genetic disorder marked by stunted growth that may not become obvious until the child is about three years of age, broad facial abnormalities, musculoskeletal and genital anomalies, and mild intellectual disability. Aarskog syndrome is inherited as an X-linked recessive genetic condition. (For more information on this disorder, choose “Aarskog” as your search term in the Rare Disease Database.)Frontofacionasal dysplasia is a very rare inherited disorder characterized by cleft lip and/or palate, an unusually wide space between the eyes, an abnormally large distance between the upper and lower eyelids (telecanthus), a short broad head (brachycephaly), and/or underdevelopment of the middle portion of the face (e.g., forehead, nose, and/or chin). Additional abnormalities may include an abnormal opening in the skull (cranium bifidum occultum), through which part of the brain and the membranes that cover the brain may protrude (encephalocele), and/or a fatty tumor (lipomata) on the frontal lobe of the brain. Frontofacionasal dysplasia is inherited as an autosomal recessive genetic condition. (For more information on this disorder, choose “frontofacionasal dysplasia” as your search term in the Rare Disease Database.)Greig cephalopolysyndactyly syndrome (GCPS) is a rare genetic disorder characterized by physical abnormalities affecting the fingers and toes (digits) and the head and facial (craniofacial) area. Characteristic digital features may include extra (supernumerary) fingers and/or toes (polydactyly), webbing and/or fusion of the fingers and/or toes (cutaneous or osseous syndactyly), and/or additional abnormalities. Craniofacial malformations associated with this disorder may include a large and/or unusually shaped skull; a high, prominent forehead (frontal bossing); an abnormally broad nasal bridge; widely spaced eyes (ocular hypertelorism); and/or other physical abnormalities. The range and severity of symptoms may vary greatly among affected individuals. In most cases, GCPS is inherited as an autosomal dominant trait.. (For more information on this disorder, choose “Greig” as your search term in the Rare Disease Database).Frontonasal dysplasia, also known as median cleft face syndrome, is a rare craniofacial disorder characterized by widely spaced eyes, a broad nose, a vertical groove down the tip of the nose, a nose that may be split in two, and/or an abnormal, covered gap in the skull (cranium bifidum occultum). Other symptoms may include a short, broad head (brachycephaly); cleft lip and/or palate; abnormally small eyeballs (microphthalmia); and/or mild intellectual disability. Frontonasal dysplasia is a heterogeneous disorder. Mutations in the ALX1, ALX3 and ALX4 genes have been reported; most cases tend to occur randomly with no apparent cause (sporadic). However, some cases are thought to run in families. (For more information, choose “frontonasal” as your search term in the Rare Disease Database.)Orocraniodigital syndrome is a rare inherited disorder characterized by cleft lip and/or palate, webbing and malformation of the toes, and/or incomplete development (hypoplasia) of the thumbs. Other symptoms may include intellectual disability, an abnormally small head (microcephaly), and/or low birthweight. Orocraniodigital syndrome is thought to be inherited as an autosomal recessive genetic condition. (For more information on this disorder, choose “orocraniodigital syndrome” as your search terms in the Rare Disease Database.)There are many other rare craniofacial disorders that are characterized by facial abnormalities similar to those of CFND. (For more information on these disorders, choose “craniofacial” as your search term in the Rare Disease Database.)The following disorders may be associated with CFND as secondary characteristics. They are not necessary for a differential diagnosis:Sprengel deformity is a rare birth defect characterized by elevation and/or underdevelopment of the shoulder blade (scapula), limited movement of the arm on the affected side, and development of a lump at the base of the neck due to the scapular elevation. Most affected individuals also have additional abnormalities, such as underdevelopment (hypoplasia) of shoulder muscles, sideways curvature of the spine (scoliosis), fused vertebrae, underdevelopment of one side of vertebrae (hemivertebrae), missing and/or fused ribs, and/or incomplete closure of bones in the spinal column surrounding the spinal cord (spina bifida occulta). In most patients, Sprengel deformity appears to occur randomly with no apparent cause (sporadic). Rarely, the disorder may be inherited as an autosomal dominant genetic condition. (For more information on this disorder, choose “Sprengel deformity” as your search term in the Rare Disease Database.)Cleft lip and palate are malformations of the mouth and/or lip that are noticeable at birth (congenital). A cleft is an incomplete closure of or a groove on the palate or lips, or both. These abnormalities result when the pair of long bones that form the upper jaw (maxillae) do not fuse properly during the development of the embryo. More than 200 syndromes have cleft lip and/or palate as a feature. Clefts may occur on one or both sides of the lip and/or palate. | Related disorders of Craniofrontonasal Dysplasia. Symptoms of the following disorders can be similar to those of craniofrontonasal dysplasia. Comparisons may be useful for a differential diagnosis:Aarskog syndrome is an extremely rare genetic disorder marked by stunted growth that may not become obvious until the child is about three years of age, broad facial abnormalities, musculoskeletal and genital anomalies, and mild intellectual disability. Aarskog syndrome is inherited as an X-linked recessive genetic condition. (For more information on this disorder, choose “Aarskog” as your search term in the Rare Disease Database.)Frontofacionasal dysplasia is a very rare inherited disorder characterized by cleft lip and/or palate, an unusually wide space between the eyes, an abnormally large distance between the upper and lower eyelids (telecanthus), a short broad head (brachycephaly), and/or underdevelopment of the middle portion of the face (e.g., forehead, nose, and/or chin). Additional abnormalities may include an abnormal opening in the skull (cranium bifidum occultum), through which part of the brain and the membranes that cover the brain may protrude (encephalocele), and/or a fatty tumor (lipomata) on the frontal lobe of the brain. Frontofacionasal dysplasia is inherited as an autosomal recessive genetic condition. (For more information on this disorder, choose “frontofacionasal dysplasia” as your search term in the Rare Disease Database.)Greig cephalopolysyndactyly syndrome (GCPS) is a rare genetic disorder characterized by physical abnormalities affecting the fingers and toes (digits) and the head and facial (craniofacial) area. Characteristic digital features may include extra (supernumerary) fingers and/or toes (polydactyly), webbing and/or fusion of the fingers and/or toes (cutaneous or osseous syndactyly), and/or additional abnormalities. Craniofacial malformations associated with this disorder may include a large and/or unusually shaped skull; a high, prominent forehead (frontal bossing); an abnormally broad nasal bridge; widely spaced eyes (ocular hypertelorism); and/or other physical abnormalities. The range and severity of symptoms may vary greatly among affected individuals. In most cases, GCPS is inherited as an autosomal dominant trait.. (For more information on this disorder, choose “Greig” as your search term in the Rare Disease Database).Frontonasal dysplasia, also known as median cleft face syndrome, is a rare craniofacial disorder characterized by widely spaced eyes, a broad nose, a vertical groove down the tip of the nose, a nose that may be split in two, and/or an abnormal, covered gap in the skull (cranium bifidum occultum). Other symptoms may include a short, broad head (brachycephaly); cleft lip and/or palate; abnormally small eyeballs (microphthalmia); and/or mild intellectual disability. Frontonasal dysplasia is a heterogeneous disorder. Mutations in the ALX1, ALX3 and ALX4 genes have been reported; most cases tend to occur randomly with no apparent cause (sporadic). However, some cases are thought to run in families. (For more information, choose “frontonasal” as your search term in the Rare Disease Database.)Orocraniodigital syndrome is a rare inherited disorder characterized by cleft lip and/or palate, webbing and malformation of the toes, and/or incomplete development (hypoplasia) of the thumbs. Other symptoms may include intellectual disability, an abnormally small head (microcephaly), and/or low birthweight. Orocraniodigital syndrome is thought to be inherited as an autosomal recessive genetic condition. (For more information on this disorder, choose “orocraniodigital syndrome” as your search terms in the Rare Disease Database.)There are many other rare craniofacial disorders that are characterized by facial abnormalities similar to those of CFND. (For more information on these disorders, choose “craniofacial” as your search term in the Rare Disease Database.)The following disorders may be associated with CFND as secondary characteristics. They are not necessary for a differential diagnosis:Sprengel deformity is a rare birth defect characterized by elevation and/or underdevelopment of the shoulder blade (scapula), limited movement of the arm on the affected side, and development of a lump at the base of the neck due to the scapular elevation. Most affected individuals also have additional abnormalities, such as underdevelopment (hypoplasia) of shoulder muscles, sideways curvature of the spine (scoliosis), fused vertebrae, underdevelopment of one side of vertebrae (hemivertebrae), missing and/or fused ribs, and/or incomplete closure of bones in the spinal column surrounding the spinal cord (spina bifida occulta). In most patients, Sprengel deformity appears to occur randomly with no apparent cause (sporadic). Rarely, the disorder may be inherited as an autosomal dominant genetic condition. (For more information on this disorder, choose “Sprengel deformity” as your search term in the Rare Disease Database.)Cleft lip and palate are malformations of the mouth and/or lip that are noticeable at birth (congenital). A cleft is an incomplete closure of or a groove on the palate or lips, or both. These abnormalities result when the pair of long bones that form the upper jaw (maxillae) do not fuse properly during the development of the embryo. More than 200 syndromes have cleft lip and/or palate as a feature. Clefts may occur on one or both sides of the lip and/or palate. | 328 | Craniofrontonasal Dysplasia |
nord_328_5 | Diagnosis of Craniofrontonasal Dysplasia | A diagnosis of CFND may be suspected after a thorough clinical evaluation and characteristic physical findings. Molecular genetic testing for mutations in the EFNB1 gene is available to confirm the diagnosis. CFND can sometimes be detected before birth (prenatally) by ultrasound. | Diagnosis of Craniofrontonasal Dysplasia. A diagnosis of CFND may be suspected after a thorough clinical evaluation and characteristic physical findings. Molecular genetic testing for mutations in the EFNB1 gene is available to confirm the diagnosis. CFND can sometimes be detected before birth (prenatally) by ultrasound. | 328 | Craniofrontonasal Dysplasia |
nord_328_6 | Therapies of Craniofrontonasal Dysplasia | TreatmentTreatment of CFND depends upon the specific malformations and their severity in each individual patient, and the timing of diagnosis. Surgery may be performed to correct craniofacial deformities and malformations of the hands and feet. Surgery may also be used to narrow the nose and reduce neck webbing. A team approach for infants and children with this disorder may be of benefit and may include special social support and other medical services. Other treatment is symptomatic and supportive.Genetic counseling is recommended for affected individuals and their families. | Therapies of Craniofrontonasal Dysplasia. TreatmentTreatment of CFND depends upon the specific malformations and their severity in each individual patient, and the timing of diagnosis. Surgery may be performed to correct craniofacial deformities and malformations of the hands and feet. Surgery may also be used to narrow the nose and reduce neck webbing. A team approach for infants and children with this disorder may be of benefit and may include special social support and other medical services. Other treatment is symptomatic and supportive.Genetic counseling is recommended for affected individuals and their families. | 328 | Craniofrontonasal Dysplasia |
nord_329_0 | Overview of Craniometaphyseal Dysplasia | SummaryCraniometaphyseal dysplasia (CMD) is a rare disorder that involves the way the bones in the head, arms, and legs grow. The skull is made up of about 20 bones that grow and get larger as people grow. For persons with CMD, the bones of the skull grow too much and push into each other. When these bones push against each other, the pressure causes the symptoms of CMD. The bones of the head can also be unusually hard (sclerosis). CMD can cause mild changes in the shape of the face and head. MCD can also cause more serious symptoms such as hearing loss and blindness. Because of this, it is important that individuals with CMD see medical professionals that are knowledgeable about CMD and can watch for these symptoms.CMD also causes the long bones in the legs and arms to be shaped differently. Persons with CMD can have unique facial features. Intelligence and quality of life are usually normal. CMD is often first noticed within the first few weeks of life and the symptoms are life-long. CMD is genetic and can be seen in multiple family members. | Overview of Craniometaphyseal Dysplasia. SummaryCraniometaphyseal dysplasia (CMD) is a rare disorder that involves the way the bones in the head, arms, and legs grow. The skull is made up of about 20 bones that grow and get larger as people grow. For persons with CMD, the bones of the skull grow too much and push into each other. When these bones push against each other, the pressure causes the symptoms of CMD. The bones of the head can also be unusually hard (sclerosis). CMD can cause mild changes in the shape of the face and head. MCD can also cause more serious symptoms such as hearing loss and blindness. Because of this, it is important that individuals with CMD see medical professionals that are knowledgeable about CMD and can watch for these symptoms.CMD also causes the long bones in the legs and arms to be shaped differently. Persons with CMD can have unique facial features. Intelligence and quality of life are usually normal. CMD is often first noticed within the first few weeks of life and the symptoms are life-long. CMD is genetic and can be seen in multiple family members. | 329 | Craniometaphyseal Dysplasia |
nord_329_1 | Symptoms of Craniometaphyseal Dysplasia | CMD is often first noticed within the first few weeks of life. The early symptoms of CMD are difficulty eating and breathing. Persons with CMD have unique facial features. These can include widely-spaced eyes (hypertelorism), wide portion of the nose between the eyes (wide nasal bridge), and large lower jaw (mandible). The increased pressure caused by facial bone growth can cause the eyes to stick out further (proptosis). The head can also be unusually long in shape (dolichocephaly). Hardening and increased growth of the bone that holds the teeth can cause teeth to come in late or not at all. CMD can cause the air passages in the nose to be small. This can make it difficult for mucus to pass through, causing swelling in the nose and sinuses. This swelling can cause difficulty breathing. Persons with CMD can develop different-shaped long bones in the arms and legs. These bones can be broad in the middle or “club-shaped” (metaphyseal dysplasia). The different-shaped bones are best seen on an x-ray and may not be noticeable by looking at a person. If the pressure on the face and head is not reduced, some of the more severe symptoms of CMD can develop. The inability to move the muscles of the face can be caused by pressure on the nerves that connect to these muscles (cranial nerves). Hearing loss or deafness can be caused by pressure on the nerves that connect to the ears (sensorineural hearing loss) or pressure on the inside of the ear (conductive hearing loss). Blindness can be caused by pressure on the nerves that connect to the eye. Not all persons with CMD will have these features and they can often be prevented with surgery. Individuals with CMD who do not have major complications can have a normal lifespan and a good quality of life. | Symptoms of Craniometaphyseal Dysplasia. CMD is often first noticed within the first few weeks of life. The early symptoms of CMD are difficulty eating and breathing. Persons with CMD have unique facial features. These can include widely-spaced eyes (hypertelorism), wide portion of the nose between the eyes (wide nasal bridge), and large lower jaw (mandible). The increased pressure caused by facial bone growth can cause the eyes to stick out further (proptosis). The head can also be unusually long in shape (dolichocephaly). Hardening and increased growth of the bone that holds the teeth can cause teeth to come in late or not at all. CMD can cause the air passages in the nose to be small. This can make it difficult for mucus to pass through, causing swelling in the nose and sinuses. This swelling can cause difficulty breathing. Persons with CMD can develop different-shaped long bones in the arms and legs. These bones can be broad in the middle or “club-shaped” (metaphyseal dysplasia). The different-shaped bones are best seen on an x-ray and may not be noticeable by looking at a person. If the pressure on the face and head is not reduced, some of the more severe symptoms of CMD can develop. The inability to move the muscles of the face can be caused by pressure on the nerves that connect to these muscles (cranial nerves). Hearing loss or deafness can be caused by pressure on the nerves that connect to the ears (sensorineural hearing loss) or pressure on the inside of the ear (conductive hearing loss). Blindness can be caused by pressure on the nerves that connect to the eye. Not all persons with CMD will have these features and they can often be prevented with surgery. Individuals with CMD who do not have major complications can have a normal lifespan and a good quality of life. | 329 | Craniometaphyseal Dysplasia |
nord_329_2 | Causes of Craniometaphyseal Dysplasia | CMD is a genetic condition caused by changes (mutations) in the genes ANKH or GJA1. The function of ANKH is to move a chemical called pyrophosphate in the body. The function of GJA1 is to create a passage for chemicals in the body between cells.CMD can follow an autosomal recessive or autosomal dominant pattern of inheritance.Recessive genetic disorders occur when an individual inherits an abnormal gene from each parent. In the recessive form, individuals have two non-working copies of the GJA1 gene. If an individual receives one normal gene and one abnormal gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the abnormal gene and, therefore, have an affected child is 25% with each pregnancy. The risk 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. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. In dominant form, persons have one working copy of ANKH gene and one non-working copy of the ANKH gene. The abnormal gene can be inherited from either parent or can be the result of a changed (mutated) gene in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.The dominant form of CMD is more common and tends to be milder than the recessive form. Persons with the recessive form can have a reduced life expectancy due to complications of pressure on the brain and spine. | Causes of Craniometaphyseal Dysplasia. CMD is a genetic condition caused by changes (mutations) in the genes ANKH or GJA1. The function of ANKH is to move a chemical called pyrophosphate in the body. The function of GJA1 is to create a passage for chemicals in the body between cells.CMD can follow an autosomal recessive or autosomal dominant pattern of inheritance.Recessive genetic disorders occur when an individual inherits an abnormal gene from each parent. In the recessive form, individuals have two non-working copies of the GJA1 gene. If an individual receives one normal gene and one abnormal gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the abnormal gene and, therefore, have an affected child is 25% with each pregnancy. The risk 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. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. In dominant form, persons have one working copy of ANKH gene and one non-working copy of the ANKH gene. The abnormal gene can be inherited from either parent or can be the result of a changed (mutated) gene in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.The dominant form of CMD is more common and tends to be milder than the recessive form. Persons with the recessive form can have a reduced life expectancy due to complications of pressure on the brain and spine. | 329 | Craniometaphyseal Dysplasia |
nord_329_3 | Affects of Craniometaphyseal Dysplasia | CMD is a very rare disorder. Males and females are affected equally. Little is known about how many people have CMD. | Affects of Craniometaphyseal Dysplasia. CMD is a very rare disorder. Males and females are affected equally. Little is known about how many people have CMD. | 329 | Craniometaphyseal Dysplasia |
nord_329_4 | Related disorders of Craniometaphyseal Dysplasia | Pyle’s disease has features similar to CMD. Pyle’s disease is a disorder of the bones. Pyle’s disease and CMD both have widening of the long bones of the arms and legs. Persons with Pyle’s disease have wide collar bones (clavicle), ribs, or bones in the fingers and hands. These bones are usually not wide in persons with CMD. Pyle’s and CMD can have delayed presence of adult teeth. Pyle’s disease can also have misplacement of the teeth, muscle weakness, and pain in the joints. Osteoporosis is most often seen in adults. However, symptoms of osteoporosis in babies and children can appear similar to CMD. Some features of osteoporosis include bones that are fragile and can break easily. Osteoporosis and CMD can have vision and hearing loss. Persons with early onset osteoporosis can have dental cavities (decay) and unusual chest shape. Persons with frontometaphyseal dysplasia and CMD can have similar features. These features include wide nose between the eyes (broad nasal bridge), eyes that are further apart (hypertelorism), extra growth of the bones over the eyes (supraorbital bossing), and small jaw. Persons with CMD can have the same features (broad nasal bridge and eyes further apart). However, supraorbital bossing and small jaw are often not seen in CMD.Osteopathia striata with cranial sclerosis also has features that involve the long bones and face bones; however, people with this condition have different bone findings than CMD. SOST-related bone dysplasia also involves bones that grow too much (overgrowth). In addition, both conditions involve hardening (sclerosis) of bones and pressure on the nerves in the head (cranial nerves). However, the facial features look different than those seen in CMD. | Related disorders of Craniometaphyseal Dysplasia. Pyle’s disease has features similar to CMD. Pyle’s disease is a disorder of the bones. Pyle’s disease and CMD both have widening of the long bones of the arms and legs. Persons with Pyle’s disease have wide collar bones (clavicle), ribs, or bones in the fingers and hands. These bones are usually not wide in persons with CMD. Pyle’s and CMD can have delayed presence of adult teeth. Pyle’s disease can also have misplacement of the teeth, muscle weakness, and pain in the joints. Osteoporosis is most often seen in adults. However, symptoms of osteoporosis in babies and children can appear similar to CMD. Some features of osteoporosis include bones that are fragile and can break easily. Osteoporosis and CMD can have vision and hearing loss. Persons with early onset osteoporosis can have dental cavities (decay) and unusual chest shape. Persons with frontometaphyseal dysplasia and CMD can have similar features. These features include wide nose between the eyes (broad nasal bridge), eyes that are further apart (hypertelorism), extra growth of the bones over the eyes (supraorbital bossing), and small jaw. Persons with CMD can have the same features (broad nasal bridge and eyes further apart). However, supraorbital bossing and small jaw are often not seen in CMD.Osteopathia striata with cranial sclerosis also has features that involve the long bones and face bones; however, people with this condition have different bone findings than CMD. SOST-related bone dysplasia also involves bones that grow too much (overgrowth). In addition, both conditions involve hardening (sclerosis) of bones and pressure on the nerves in the head (cranial nerves). However, the facial features look different than those seen in CMD. | 329 | Craniometaphyseal Dysplasia |
nord_329_5 | Diagnosis of Craniometaphyseal Dysplasia | A diagnosis of CMD can be made by an examination by a doctor familiar with craniofacial disorders. X-rays or other imaging are often required to diagnose and treat CMD. Genetic testing can also help diagnose CMD. | Diagnosis of Craniometaphyseal Dysplasia. A diagnosis of CMD can be made by an examination by a doctor familiar with craniofacial disorders. X-rays or other imaging are often required to diagnose and treat CMD. Genetic testing can also help diagnose CMD. | 329 | Craniometaphyseal Dysplasia |
nord_329_6 | Therapies of Craniometaphyseal Dysplasia | Treatment
The care team of individuals with CMD can include
– clinical genetics (care for genetic disorders)
– otolaryngology (care for the ears, nose, and throat)
– ophthalmology (care for the eye)
– neurology (care for the brain and nerves)
– endocrinology (care for growth of the bones)
– dentistry (care for the teeth)
– audiology (care for hearing)There is no single treatment for CMD. Individual symptoms of CMD are treated as they arise. Early surgical treatment to relieve pressure in the head and change the shape of the face bones may help reduce some of the complications of CMD. Genetic counseling to determine the genetic cause and risk for other relatives may be helpful for persons with CMD and their families. | Therapies of Craniometaphyseal Dysplasia. Treatment
The care team of individuals with CMD can include
– clinical genetics (care for genetic disorders)
– otolaryngology (care for the ears, nose, and throat)
– ophthalmology (care for the eye)
– neurology (care for the brain and nerves)
– endocrinology (care for growth of the bones)
– dentistry (care for the teeth)
– audiology (care for hearing)There is no single treatment for CMD. Individual symptoms of CMD are treated as they arise. Early surgical treatment to relieve pressure in the head and change the shape of the face bones may help reduce some of the complications of CMD. Genetic counseling to determine the genetic cause and risk for other relatives may be helpful for persons with CMD and their families. | 329 | Craniometaphyseal Dysplasia |
nord_330_0 | Overview of Craniopharyngioma | SummaryA craniopharyngioma is a benign tumor (neoplasm) derived from embryonic tissue from the sellar region and its surroundings (parasellar region). The sellar region is located in the center of the cranial base and notably comprises the pituitary gland, the “master gland” of the body, and the sella turcica, a bony depression in the skull (in the sphenoid bone, specifically) where the pituitary gland sits.Craniopharyngiomas develop in around 0.5 to 2 per million individuals each year and has a bimodal distribution, 5 to 14 years of age and 50 to 74 year. Many experts consider craniopharyngiomas to be a chronic disease, as they tend to recur even when they have been completely removed (resected) surgically. The tumor itself is usually not dangerous, as it is benign and only very rarely becomes malignant. However, the tumor’s location is such that it can compress the pituitary gland and lead to hormonal dysfunction. The optic chiasm, where the two optic nerves partially cross, is located above the pituitary gland and can therefore be compressed by a craniopharyngioma, leading to visual defects. The hypothalamus, to which the pituitary gland is connected, can also be damaged, especially after surgery. As the hypothalamus is a regulator of many biological functions, damage to this structure is associated with symptoms such as the development of obesity (hypothalamic obesity) and disruption of sleep cycles. Another anatomical structure that can be compressed by a craniopharyngioma is the foramen of Monro within the ventricles. If this foramen is occluded, the cerebrospinal fluid that normally circulates in the brain and spinal cord will accumulate (a condition known as hydrocephalus), potentially leading to numerous symptoms, including an enlarged head in babies. Headaches and nausea can also occur due to an elevation in intracranial pressure. Treatment of craniopharyngioma includes surgical resection of the tumor and radiation therapy, especially when the tumor is not entirely resectable due to its location. Specific hormonal treatment might also be required, depending on the needs of the patient.IntroductionThere are two types of craniopharyngioma: adamantinomatous and papillary. The first type most commonly occurs in children, while the second is more common in adults. Adamantinomatous craniopharyngiomas arise from cells from an embryologic structure known as the craniopharyngeal duct. They can be solid or form a hollow (cystic) structure filled with dark brown to black (motor oil-like) fluid and are frequently calcified. Papillary craniopharyngiomas are rarer and arise from cells from the anterior part of the pituitary gland. They are usually well circumscribed and can also be solid or cystic, although they are filled with yellow and viscous fluid. They rarely calcify. The clinical manifestations of both types of craniopharyngioma are largely similar. As craniopharyngiomas are rare tumors with atypical and non-specific symptoms, they can be diagnosed years after the appearance of symptoms. An early diagnosis is beneficial, as it can greatly improve the quality of life of affected individuals and reduce the risk of long term complications. | Overview of Craniopharyngioma. SummaryA craniopharyngioma is a benign tumor (neoplasm) derived from embryonic tissue from the sellar region and its surroundings (parasellar region). The sellar region is located in the center of the cranial base and notably comprises the pituitary gland, the “master gland” of the body, and the sella turcica, a bony depression in the skull (in the sphenoid bone, specifically) where the pituitary gland sits.Craniopharyngiomas develop in around 0.5 to 2 per million individuals each year and has a bimodal distribution, 5 to 14 years of age and 50 to 74 year. Many experts consider craniopharyngiomas to be a chronic disease, as they tend to recur even when they have been completely removed (resected) surgically. The tumor itself is usually not dangerous, as it is benign and only very rarely becomes malignant. However, the tumor’s location is such that it can compress the pituitary gland and lead to hormonal dysfunction. The optic chiasm, where the two optic nerves partially cross, is located above the pituitary gland and can therefore be compressed by a craniopharyngioma, leading to visual defects. The hypothalamus, to which the pituitary gland is connected, can also be damaged, especially after surgery. As the hypothalamus is a regulator of many biological functions, damage to this structure is associated with symptoms such as the development of obesity (hypothalamic obesity) and disruption of sleep cycles. Another anatomical structure that can be compressed by a craniopharyngioma is the foramen of Monro within the ventricles. If this foramen is occluded, the cerebrospinal fluid that normally circulates in the brain and spinal cord will accumulate (a condition known as hydrocephalus), potentially leading to numerous symptoms, including an enlarged head in babies. Headaches and nausea can also occur due to an elevation in intracranial pressure. Treatment of craniopharyngioma includes surgical resection of the tumor and radiation therapy, especially when the tumor is not entirely resectable due to its location. Specific hormonal treatment might also be required, depending on the needs of the patient.IntroductionThere are two types of craniopharyngioma: adamantinomatous and papillary. The first type most commonly occurs in children, while the second is more common in adults. Adamantinomatous craniopharyngiomas arise from cells from an embryologic structure known as the craniopharyngeal duct. They can be solid or form a hollow (cystic) structure filled with dark brown to black (motor oil-like) fluid and are frequently calcified. Papillary craniopharyngiomas are rarer and arise from cells from the anterior part of the pituitary gland. They are usually well circumscribed and can also be solid or cystic, although they are filled with yellow and viscous fluid. They rarely calcify. The clinical manifestations of both types of craniopharyngioma are largely similar. As craniopharyngiomas are rare tumors with atypical and non-specific symptoms, they can be diagnosed years after the appearance of symptoms. An early diagnosis is beneficial, as it can greatly improve the quality of life of affected individuals and reduce the risk of long term complications. | 330 | Craniopharyngioma |
nord_330_1 | Symptoms of Craniopharyngioma | They are almost always benign but they can cause symptoms by compressing closely located important anatomical structures such as the pituitary gland, the hypothalamus, and the crossing of the two optic nerves (optic chiasm). Limb weakness (paresis), difficulty walking, seizures, and psychiatric symptoms such as paranoid delusions can also occur from compression of the brain. Another general consequence of tumor compression is a raise in intracranial pressure, which can cause symptoms such as headache and nausea. As craniopharyngiomas are difficult to treat and located in an anatomical location difficult to access and close to many important structures, patients can experience many symptoms that are related to the treatment of the disease rather than the disease itself.Pituitary gland dysfunctionThe pituitary gland is the “master gland” of the body and its integrity is crucial to many hormonal processes throughout the body. Most patients with a craniopharyngioma experience hormonal (endocrine) deficits due to compression of the pituitary gland by the tumor. Deficits can affect every hormonal pathway influenced by the pituitary gland and tend to be more pronounced in patients with adult-onset craniopharyngiomas. GH (growth hormone) deficiency can lead to a decreased growth rate in children (for more information on this disorder, choose “growth hormone deficiency” as your search term in the Rare Disease Database). Delayed puberty and absence of menses in women (amenorrhea) can occur in cases of FSH and LH (gonadotropins) deficiency. Less commonly, craniopharyngiomas can also trigger precocious puberty (for more information on this disorder, choose “precocious puberty” as your search term in the Rare Disease Database). ACTH (adrenocorticotropic hormone) deficiency can cause many symptoms such as weakness and tiredness (for more information on this disorder, choose “ACTH deficiency” as your search term in the Rare Disease Database). TSH (thyroid stimulating hormone) deficiency is also associated with many clinical manifestations, including fatigue, generalized weakness, menstrual irregularity, and forgetfulness. Compression of the pituitary gland can also be the cause of a disorder, known as central diabetes insipidus (which is not related to the more common diabetes mellitus, also known as “sugar diabetes”), that is characterized by excessive thirst (polydipsia) and excessive urination (polyuria) (for more information on this disorder, choose “Insipidus” as your search term in the Rare Disease Database).Hypothalamic dysfunctionThe hypothalamus is connected to the pituitary gland and controls its hormone secretion, in addition to being responsible for the regulation of numerous biological processes. Hypothalamic dysfunction can occur due to compression of the hypothalamus by the tumor, but can also occur as a consequence of surgical removal (resection) of the tumor. One major symptom related to dysfunction of the hypothalamus is hypothalamic obesity, a type of obesity that occurs even with caloric restriction and lifestyle changes. Froelich’s syndrome is a combination of hypothalamic obesity, delayed sexual development, and small testes that is caused by damage to the hypothalamus (for more information on this disorder, choose “Froelich’s syndrome” as your search term in the Rare Disease Database). Other symptoms of hypothalamic dysfunction include changes in behavior and imbalances in body temperature, thirst, heart rate and blood pressure. Hypothalamic dysfunction can also lead to a disorders of sleep cycle such as non-24-hour sleep-wake syndrome. Symptoms of this disorder include night-time insomnia and excessive daytime sleepiness (for more information on this disorder, choose “N24” as your search term in the Rare Disease Database).Optic nerves and optic chiasm compressionThe optic nerves, which carry visual information to the brain, partially cross right above the pituitary gland to form a structure called the optic chiasm. Both the optic nerves and the optic chiasm can be compressed by a craniopharyngioma. This can lead to two main visual symptoms: blurry vision (decreased visual acuity) and loss of vision in certain areas of the visual field (visual field defects). Visual symptoms are common in individuals with a craniopharyngioma.Foramen of Monro occlusionThe brain contains the ventricular system: a system of four cavities (ventricles) where cerebrospinal fluid (CSF), is produced and circulates. A craniopharyngioma might occlude some of the channels that connect ventricles together (foramen of Monro). If the foramen of Monro are occluded, cerebrospinal fluid will not be able to circulate properly and will accumulate (hydrocephalus). Symptoms associated with hydrocephalus are numerous and depend on the age of the affected individual. Babies might feed poorly, be irritable, and have an enlarged head. Children and adults can have symptoms such as neck pain, headaches, vomiting, and blurred vision. Treatment-associated (iatrogenic) complicationsCraniopharyngiomas are difficult to remove surgically, as they are usually located near multiple anatomical structures that can be damaged during surgery. Craniopharyngiomas also tend to recur, even when they seem to have been removed completely. Many patients therefore have to undergo multiple surgeries during their lifetime. Consequences of surgery include damage to close anatomical structures, especially the pituitary gland and the hypothalamus. Cognition, memory, and attention deficits can also be consequences of surgery. Especially in patients where the tumor cannot be entirely removed, radiation therapy usually follows surgical treatment. The internal carotid arteries can be damaged by such therapy (radiation-induced vasculopathies), leading to cerebrovascular complications such as dilatation and weakening of blood vessel wall (aneurysm), and Moyamoya disease, where the internal carotid arteries are narrowed, which can lead to further complications such as headaches, strokes, and seizures (for more information on this disorder, choose “Moyamoya” as your search term in the Rare Disease Database). Exposure to radiation is also a risk factor for the development of brain tumors such as gliomas (for more information on this disorder, choose “glioma” as your search term in the Rare Disease Database).Long term outcomesWhen properly managed, individuals with a craniopharyngioma have an over 90% survival rate over 20 years. Many experts consider craniopharyngiomas to be a chronic disease, as tumor recurrence rates are high, even with apparent complete resection of the tumor. Significant complications that can lead to mortality include strokes, cardiac complications, respiratory complications, chronic hypothalamic insufficiency, hormonal deficiencies, and seizures. In very rare cases, craniopharyngiomas can become malignant (malignant transformation). | Symptoms of Craniopharyngioma. They are almost always benign but they can cause symptoms by compressing closely located important anatomical structures such as the pituitary gland, the hypothalamus, and the crossing of the two optic nerves (optic chiasm). Limb weakness (paresis), difficulty walking, seizures, and psychiatric symptoms such as paranoid delusions can also occur from compression of the brain. Another general consequence of tumor compression is a raise in intracranial pressure, which can cause symptoms such as headache and nausea. As craniopharyngiomas are difficult to treat and located in an anatomical location difficult to access and close to many important structures, patients can experience many symptoms that are related to the treatment of the disease rather than the disease itself.Pituitary gland dysfunctionThe pituitary gland is the “master gland” of the body and its integrity is crucial to many hormonal processes throughout the body. Most patients with a craniopharyngioma experience hormonal (endocrine) deficits due to compression of the pituitary gland by the tumor. Deficits can affect every hormonal pathway influenced by the pituitary gland and tend to be more pronounced in patients with adult-onset craniopharyngiomas. GH (growth hormone) deficiency can lead to a decreased growth rate in children (for more information on this disorder, choose “growth hormone deficiency” as your search term in the Rare Disease Database). Delayed puberty and absence of menses in women (amenorrhea) can occur in cases of FSH and LH (gonadotropins) deficiency. Less commonly, craniopharyngiomas can also trigger precocious puberty (for more information on this disorder, choose “precocious puberty” as your search term in the Rare Disease Database). ACTH (adrenocorticotropic hormone) deficiency can cause many symptoms such as weakness and tiredness (for more information on this disorder, choose “ACTH deficiency” as your search term in the Rare Disease Database). TSH (thyroid stimulating hormone) deficiency is also associated with many clinical manifestations, including fatigue, generalized weakness, menstrual irregularity, and forgetfulness. Compression of the pituitary gland can also be the cause of a disorder, known as central diabetes insipidus (which is not related to the more common diabetes mellitus, also known as “sugar diabetes”), that is characterized by excessive thirst (polydipsia) and excessive urination (polyuria) (for more information on this disorder, choose “Insipidus” as your search term in the Rare Disease Database).Hypothalamic dysfunctionThe hypothalamus is connected to the pituitary gland and controls its hormone secretion, in addition to being responsible for the regulation of numerous biological processes. Hypothalamic dysfunction can occur due to compression of the hypothalamus by the tumor, but can also occur as a consequence of surgical removal (resection) of the tumor. One major symptom related to dysfunction of the hypothalamus is hypothalamic obesity, a type of obesity that occurs even with caloric restriction and lifestyle changes. Froelich’s syndrome is a combination of hypothalamic obesity, delayed sexual development, and small testes that is caused by damage to the hypothalamus (for more information on this disorder, choose “Froelich’s syndrome” as your search term in the Rare Disease Database). Other symptoms of hypothalamic dysfunction include changes in behavior and imbalances in body temperature, thirst, heart rate and blood pressure. Hypothalamic dysfunction can also lead to a disorders of sleep cycle such as non-24-hour sleep-wake syndrome. Symptoms of this disorder include night-time insomnia and excessive daytime sleepiness (for more information on this disorder, choose “N24” as your search term in the Rare Disease Database).Optic nerves and optic chiasm compressionThe optic nerves, which carry visual information to the brain, partially cross right above the pituitary gland to form a structure called the optic chiasm. Both the optic nerves and the optic chiasm can be compressed by a craniopharyngioma. This can lead to two main visual symptoms: blurry vision (decreased visual acuity) and loss of vision in certain areas of the visual field (visual field defects). Visual symptoms are common in individuals with a craniopharyngioma.Foramen of Monro occlusionThe brain contains the ventricular system: a system of four cavities (ventricles) where cerebrospinal fluid (CSF), is produced and circulates. A craniopharyngioma might occlude some of the channels that connect ventricles together (foramen of Monro). If the foramen of Monro are occluded, cerebrospinal fluid will not be able to circulate properly and will accumulate (hydrocephalus). Symptoms associated with hydrocephalus are numerous and depend on the age of the affected individual. Babies might feed poorly, be irritable, and have an enlarged head. Children and adults can have symptoms such as neck pain, headaches, vomiting, and blurred vision. Treatment-associated (iatrogenic) complicationsCraniopharyngiomas are difficult to remove surgically, as they are usually located near multiple anatomical structures that can be damaged during surgery. Craniopharyngiomas also tend to recur, even when they seem to have been removed completely. Many patients therefore have to undergo multiple surgeries during their lifetime. Consequences of surgery include damage to close anatomical structures, especially the pituitary gland and the hypothalamus. Cognition, memory, and attention deficits can also be consequences of surgery. Especially in patients where the tumor cannot be entirely removed, radiation therapy usually follows surgical treatment. The internal carotid arteries can be damaged by such therapy (radiation-induced vasculopathies), leading to cerebrovascular complications such as dilatation and weakening of blood vessel wall (aneurysm), and Moyamoya disease, where the internal carotid arteries are narrowed, which can lead to further complications such as headaches, strokes, and seizures (for more information on this disorder, choose “Moyamoya” as your search term in the Rare Disease Database). Exposure to radiation is also a risk factor for the development of brain tumors such as gliomas (for more information on this disorder, choose “glioma” as your search term in the Rare Disease Database).Long term outcomesWhen properly managed, individuals with a craniopharyngioma have an over 90% survival rate over 20 years. Many experts consider craniopharyngiomas to be a chronic disease, as tumor recurrence rates are high, even with apparent complete resection of the tumor. Significant complications that can lead to mortality include strokes, cardiac complications, respiratory complications, chronic hypothalamic insufficiency, hormonal deficiencies, and seizures. In very rare cases, craniopharyngiomas can become malignant (malignant transformation). | 330 | Craniopharyngioma |
nord_330_2 | Causes of Craniopharyngioma | Craniopharyngiomas are caused by malformations of embryonic tissue in the sellar and parasellar regions. Adamantinomatous craniopharyngioma, which occur mostly in children, and papillary craniopharyngioma, which occur mostly in adults, have different embryological origins.Adamantinomatous craniopharyngiomaAdamantinomatous craniopharyngiomas arise from the transformation into tumor cells (neoplastic transformation) of cells from the craniopharyngeal duct, an embryological structure connected to Rathke’s pouch, which gives rise to part of the pituitary gland. The exact cause of development of adamantinomatous craniopharyngioma is unknown, although mutations in the CTNNB1 or APC genes are present in more than 70% of tumors. These genes produce a protein, known as beta-catenin, that is important in the development of the embryo (embryogenesis). Mutations in these genes might therefore play a role in the development of adamantinomatous craniopharyngiomas.Papillary craniopharyngioma Papillary craniopharyngiomas are caused by a change in cell type (metaplasia) of cells in the anterior pituitary gland. This leads to the formation of nests made from a cell type known as squamous cells. As for adamantinomatous craniopharyngioma, the exact cause of development of papillary craniopharyngioma is unknown. | Causes of Craniopharyngioma. Craniopharyngiomas are caused by malformations of embryonic tissue in the sellar and parasellar regions. Adamantinomatous craniopharyngioma, which occur mostly in children, and papillary craniopharyngioma, which occur mostly in adults, have different embryological origins.Adamantinomatous craniopharyngiomaAdamantinomatous craniopharyngiomas arise from the transformation into tumor cells (neoplastic transformation) of cells from the craniopharyngeal duct, an embryological structure connected to Rathke’s pouch, which gives rise to part of the pituitary gland. The exact cause of development of adamantinomatous craniopharyngioma is unknown, although mutations in the CTNNB1 or APC genes are present in more than 70% of tumors. These genes produce a protein, known as beta-catenin, that is important in the development of the embryo (embryogenesis). Mutations in these genes might therefore play a role in the development of adamantinomatous craniopharyngiomas.Papillary craniopharyngioma Papillary craniopharyngiomas are caused by a change in cell type (metaplasia) of cells in the anterior pituitary gland. This leads to the formation of nests made from a cell type known as squamous cells. As for adamantinomatous craniopharyngioma, the exact cause of development of papillary craniopharyngioma is unknown. | 330 | Craniopharyngioma |
nord_330_3 | Affects of Craniopharyngioma | Craniopharyngiomas occur in around 0.5 to 2 people per million each year and represent around 1.2 to 4% of all intracranial tumors in children. They mostly develop in two age groups (bimodal incidence peaks): children aged 0 to 14 years and adults aged 50 to 74 years. They occur in men and women equally. Adamantinomatous craniopharyngioma are more common, representing 86 to 89% of all craniopharyngiomas. | Affects of Craniopharyngioma. Craniopharyngiomas occur in around 0.5 to 2 people per million each year and represent around 1.2 to 4% of all intracranial tumors in children. They mostly develop in two age groups (bimodal incidence peaks): children aged 0 to 14 years and adults aged 50 to 74 years. They occur in men and women equally. Adamantinomatous craniopharyngioma are more common, representing 86 to 89% of all craniopharyngiomas. | 330 | Craniopharyngioma |
nord_330_4 | Related disorders of Craniopharyngioma | Disorders that can damage or compress structures in proximity to the sellar region, such as the pituitary gland, the hypothalamus, and the optic chiasm, can have clinical manifestations similar to those of a craniopharyngioma. Examples of entities that can lead to compression or damage include tumors, cysts, and blood vessel disruptions. Pituitary adenomas are hormone-secreting tumors from the pituitary gland. They can secrete various pituitary hormones, depending on the type of cell that is affected. This can lead to various clinical manifestations related to the hypersecreted hormone. For instance, a prolactinoma is a pituitary adenoma that secretes prolactin. Symptoms related to excessive prolactin include irregular menstrual periods, infertility, production of milk even if an affected woman is not pregnant, and erectile dysfunction in men. (for more information on this disorder, choose “prolactinoma” as your search term in the Rare Disease Database). As it is the case for craniopharyngiomas, pituitary adenomas can also cause compression of the pituitary gland, leading to pituitary hormone deficiencies, and compression of the optic nerves and optic chiasm, leading to visual defects. Some pituitary adenomas, known as non-functioning adenomas, do not secrete any pituitary hormone, but can still be responsible for compressive symptoms. A glioma is a tumor of the central nervous system that arises from glial cells, a type of cell widely present in the nervous system. Gliomas mostly occur in the brain and, rarely, in the spinal cord. They occur at various ages, depending on the subtype. Developing gliomas can compress areas of the brain where they occur and cause various symptoms including headaches, nausea, vomiting, cognitive impairment, seizures, gait imbalance, language impairment (aphasia), weakness of one side of the body (hemiparesis), visual field defects, and personality changes. Gliomas compressing structures such as the pituitary gland, the hypothalamus, and the optic chiasm can have symptoms similar to those of a craniopharyngioma. (For more information on this disorder, choose “glioma” as your search term in the Rare Disease Database.)As their name indicate, intracranial germ cell tumors are derived from germ cells and are located within the skull. The exact mechanism for the development of intracranial germ cell tumor is not known, but embryological abnormalities play a role. They can clinically mimic craniopharyngiomas by compressing structures such as the pituitary gland, the hypothalamus, and the optic chiasm. Langerhans cells histiocytosis (LCH) is a rare disease involving the proliferation of Langerhans cells, which are derived from the bone marrow. Symptoms related to multiple organ systems can result, including hormonal abnormalities such as diabetes insipidus. If the front part of the pituitary gland is damaged by LCH, the patient may have low levels of pituitary hormones. (For more information on this disorder, choose “Langerhans cells histiocytosis” as your search term in the Rare Disease Database.)An aneurysm is a local weakening and outward bulging of a blood vessel. Cerebral aneurysm can bleed and rupture, leading to a sub-arachnoid hemorrhage (SAH) and symptoms such as headaches, seizures, and loss of consciousness. The outward bulging of the vessel can also compress adjacent anatomical structures. Visual symptoms and hormonal deficiencies can occur if the aneurysm is located near the pituitary gland or an optic nerve. As it is the case for tumors and aneurysms, cysts of multiple origins can lead to compression of anatomical structures close to the sellar region and result in symptoms that resemble those of a craniopharyngioma. This can notably happen in the case of Rathke cleft cysts, arachnoid cysts, and colloidal cysts of the third ventricle. | Related disorders of Craniopharyngioma. Disorders that can damage or compress structures in proximity to the sellar region, such as the pituitary gland, the hypothalamus, and the optic chiasm, can have clinical manifestations similar to those of a craniopharyngioma. Examples of entities that can lead to compression or damage include tumors, cysts, and blood vessel disruptions. Pituitary adenomas are hormone-secreting tumors from the pituitary gland. They can secrete various pituitary hormones, depending on the type of cell that is affected. This can lead to various clinical manifestations related to the hypersecreted hormone. For instance, a prolactinoma is a pituitary adenoma that secretes prolactin. Symptoms related to excessive prolactin include irregular menstrual periods, infertility, production of milk even if an affected woman is not pregnant, and erectile dysfunction in men. (for more information on this disorder, choose “prolactinoma” as your search term in the Rare Disease Database). As it is the case for craniopharyngiomas, pituitary adenomas can also cause compression of the pituitary gland, leading to pituitary hormone deficiencies, and compression of the optic nerves and optic chiasm, leading to visual defects. Some pituitary adenomas, known as non-functioning adenomas, do not secrete any pituitary hormone, but can still be responsible for compressive symptoms. A glioma is a tumor of the central nervous system that arises from glial cells, a type of cell widely present in the nervous system. Gliomas mostly occur in the brain and, rarely, in the spinal cord. They occur at various ages, depending on the subtype. Developing gliomas can compress areas of the brain where they occur and cause various symptoms including headaches, nausea, vomiting, cognitive impairment, seizures, gait imbalance, language impairment (aphasia), weakness of one side of the body (hemiparesis), visual field defects, and personality changes. Gliomas compressing structures such as the pituitary gland, the hypothalamus, and the optic chiasm can have symptoms similar to those of a craniopharyngioma. (For more information on this disorder, choose “glioma” as your search term in the Rare Disease Database.)As their name indicate, intracranial germ cell tumors are derived from germ cells and are located within the skull. The exact mechanism for the development of intracranial germ cell tumor is not known, but embryological abnormalities play a role. They can clinically mimic craniopharyngiomas by compressing structures such as the pituitary gland, the hypothalamus, and the optic chiasm. Langerhans cells histiocytosis (LCH) is a rare disease involving the proliferation of Langerhans cells, which are derived from the bone marrow. Symptoms related to multiple organ systems can result, including hormonal abnormalities such as diabetes insipidus. If the front part of the pituitary gland is damaged by LCH, the patient may have low levels of pituitary hormones. (For more information on this disorder, choose “Langerhans cells histiocytosis” as your search term in the Rare Disease Database.)An aneurysm is a local weakening and outward bulging of a blood vessel. Cerebral aneurysm can bleed and rupture, leading to a sub-arachnoid hemorrhage (SAH) and symptoms such as headaches, seizures, and loss of consciousness. The outward bulging of the vessel can also compress adjacent anatomical structures. Visual symptoms and hormonal deficiencies can occur if the aneurysm is located near the pituitary gland or an optic nerve. As it is the case for tumors and aneurysms, cysts of multiple origins can lead to compression of anatomical structures close to the sellar region and result in symptoms that resemble those of a craniopharyngioma. This can notably happen in the case of Rathke cleft cysts, arachnoid cysts, and colloidal cysts of the third ventricle. | 330 | Craniopharyngioma |
nord_330_5 | Diagnosis of Craniopharyngioma | A diagnosis of craniopharyngioma is based on three main modalities: clinical history and physical exam, laboratory testing, and imaging.Clinical history and physical examA diagnosis of craniopharyngioma requires an extensive clinical history and physical examination. Clinical manifestations that rise a suspicion of craniopharyngioma include a combination of headache, visual impairment, decreased growth rate, increased thirst and urination (polydipsia and polyuria), and other signs of hormonal (endocrine) deficiency.Laboratory testsLaboratory testing will usually be needed to confirm clinical suspicion of endocrine deficiency. Typically tests for craniopharyngioma include evaluation of serum electrolytes, as well as all the hormones that can be affected by pituitary dysfunction: GH, IGF-1, TSH, free thyroxin, cortisol, FSH, LH, testosterone, estradiol, and prolactin.ImagingComputed tomography (CT scan) and magnetic resonance imaging (MRI) are the imaging modalities of choice to diagnose craniopharyngiomas. CT scan is used to detect tumor calcification, while a MRI can be used to detect fluid accumulation inside cystic tumors. | Diagnosis of Craniopharyngioma. A diagnosis of craniopharyngioma is based on three main modalities: clinical history and physical exam, laboratory testing, and imaging.Clinical history and physical examA diagnosis of craniopharyngioma requires an extensive clinical history and physical examination. Clinical manifestations that rise a suspicion of craniopharyngioma include a combination of headache, visual impairment, decreased growth rate, increased thirst and urination (polydipsia and polyuria), and other signs of hormonal (endocrine) deficiency.Laboratory testsLaboratory testing will usually be needed to confirm clinical suspicion of endocrine deficiency. Typically tests for craniopharyngioma include evaluation of serum electrolytes, as well as all the hormones that can be affected by pituitary dysfunction: GH, IGF-1, TSH, free thyroxin, cortisol, FSH, LH, testosterone, estradiol, and prolactin.ImagingComputed tomography (CT scan) and magnetic resonance imaging (MRI) are the imaging modalities of choice to diagnose craniopharyngiomas. CT scan is used to detect tumor calcification, while a MRI can be used to detect fluid accumulation inside cystic tumors. | 330 | Craniopharyngioma |
nord_330_6 | Therapies of Craniopharyngioma | Treatment
Individuals with a craniopharyngioma might initially present with neurological, visual, and hormonal dysfunctions and might need to be evaluated by neurologists, ophthalmologists, and endocrinologists. A radiologist or neuro-radiologist will then be required to interpret medical imaging. The combination of clinical manifestations, laboratory values, and medical imaging will lead to a clinical diagnosis of craniopharyngioma. The diagnosis can be confirmed by a neuropathologist that will analyze the tumor microscopically once it has been removed (resected).Neurosurgical treatment is central to the management of craniopharyngioma. If there is no risk to damage nearby anatomical structures, a neurosurgeon will remove (resect) the entirety of the tumor. If the tumor is in proximity to crucial structures, the surgical team might decide not to remove the entirety of the tumor. Radiation oncologists will then be involved to administer radiotherapy to patients. There is no clear consensus on the balance that should be adopted between attempt at resecting the tumor and radiation therapy. Multiple surgical procedures might be required throughout a patient’s lifetime, as craniopharyngiomas tend to recur even when they seem to have been completely resected. Endocrinologists will often be involved, as hormone replacement therapy is required to treat patients with hypothalamic and pituitary gland dysfunction. Hypothalamic obesity is also an issue that can significantly impact the quality of life of affected individuals. Medication, such as Octreotide, that reduces insulin secretion, and bariatric surgery might be indicated for some patients suffering from morbid obesity. Due to the high rate of recurrence of craniopharyngioma and the numerous effects they can have on the body, affected individuals will usually have to be followed by numerous medical specialists throughout their life. | Therapies of Craniopharyngioma. Treatment
Individuals with a craniopharyngioma might initially present with neurological, visual, and hormonal dysfunctions and might need to be evaluated by neurologists, ophthalmologists, and endocrinologists. A radiologist or neuro-radiologist will then be required to interpret medical imaging. The combination of clinical manifestations, laboratory values, and medical imaging will lead to a clinical diagnosis of craniopharyngioma. The diagnosis can be confirmed by a neuropathologist that will analyze the tumor microscopically once it has been removed (resected).Neurosurgical treatment is central to the management of craniopharyngioma. If there is no risk to damage nearby anatomical structures, a neurosurgeon will remove (resect) the entirety of the tumor. If the tumor is in proximity to crucial structures, the surgical team might decide not to remove the entirety of the tumor. Radiation oncologists will then be involved to administer radiotherapy to patients. There is no clear consensus on the balance that should be adopted between attempt at resecting the tumor and radiation therapy. Multiple surgical procedures might be required throughout a patient’s lifetime, as craniopharyngiomas tend to recur even when they seem to have been completely resected. Endocrinologists will often be involved, as hormone replacement therapy is required to treat patients with hypothalamic and pituitary gland dysfunction. Hypothalamic obesity is also an issue that can significantly impact the quality of life of affected individuals. Medication, such as Octreotide, that reduces insulin secretion, and bariatric surgery might be indicated for some patients suffering from morbid obesity. Due to the high rate of recurrence of craniopharyngioma and the numerous effects they can have on the body, affected individuals will usually have to be followed by numerous medical specialists throughout their life. | 330 | Craniopharyngioma |
nord_331_0 | Overview of Creatine Transporter Deficiency | SummaryCreatine transporter deficiency (CTD) is an inborn error of creatine metabolism. The onset of symptoms occurs during infancy, but the average age of diagnosis ranges from 2 to 66 years of age. Since the disease is now becoming better recognized and testing is available, it is anticipated that diagnosis will primarily occur within the first 3 years of life..IntroductionCTD is one of the three cerebral creatine deficiency syndromes (CCDS). These conditions are inborn errors of creatine metabolism which interrupt the formation or transport of creatine. Creatine is necessary to favor the utilization of adenosine triphosphate (ATP), which provides energy to all cells in the body. Creatine is essential to sustain the high energy levels needed for muscle and brain development. | Overview of Creatine Transporter Deficiency. SummaryCreatine transporter deficiency (CTD) is an inborn error of creatine metabolism. The onset of symptoms occurs during infancy, but the average age of diagnosis ranges from 2 to 66 years of age. Since the disease is now becoming better recognized and testing is available, it is anticipated that diagnosis will primarily occur within the first 3 years of life..IntroductionCTD is one of the three cerebral creatine deficiency syndromes (CCDS). These conditions are inborn errors of creatine metabolism which interrupt the formation or transport of creatine. Creatine is necessary to favor the utilization of adenosine triphosphate (ATP), which provides energy to all cells in the body. Creatine is essential to sustain the high energy levels needed for muscle and brain development. | 331 | Creatine Transporter Deficiency |
nord_331_1 | Symptoms of Creatine Transporter Deficiency | The severity of CTD varies from patient to patient. Global developmental delays affect all children with this disorder and may be the first sign, appearing before other symptoms. Intellectual disability of variable severity is typically present with prominent speech and language delay, autistic behavior and seizures.
Additional symptoms may include, muscle weakness, behavior disorders, hyperactivity and gastrointestinal problems. Children with CTD may experience slow growth (failure to thrive) and delayed development of motor skills such as sitting and walking. Affected individuals tend to tire easily. | Symptoms of Creatine Transporter Deficiency. The severity of CTD varies from patient to patient. Global developmental delays affect all children with this disorder and may be the first sign, appearing before other symptoms. Intellectual disability of variable severity is typically present with prominent speech and language delay, autistic behavior and seizures.
Additional symptoms may include, muscle weakness, behavior disorders, hyperactivity and gastrointestinal problems. Children with CTD may experience slow growth (failure to thrive) and delayed development of motor skills such as sitting and walking. Affected individuals tend to tire easily. | 331 | Creatine Transporter Deficiency |
nord_331_2 | Causes of Creatine Transporter Deficiency | CTD is caused by a change (called a variant or mutation) in the creatine transporter gene, SLC6A8. This mutation results in a block in the transport of creatine to the brain and muscle.The inheritance pattern for CTD is X-linked. X-linked genetic disorders are conditions caused by a non-working gene on the X chromosome and manifest mostly in males. Females that have a non-working gene 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 non-working gene. Rarely female can have symptoms as well. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a non-working gene, he will develop the disease.Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.If a male with an X-linked disorder can reproduce, he will pass the non-working gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. | Causes of Creatine Transporter Deficiency. CTD is caused by a change (called a variant or mutation) in the creatine transporter gene, SLC6A8. This mutation results in a block in the transport of creatine to the brain and muscle.The inheritance pattern for CTD is X-linked. X-linked genetic disorders are conditions caused by a non-working gene on the X chromosome and manifest mostly in males. Females that have a non-working gene 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 non-working gene. Rarely female can have symptoms as well. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a non-working gene, he will develop the disease.Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.If a male with an X-linked disorder can reproduce, he will pass the non-working gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. | 331 | Creatine Transporter Deficiency |
nord_331_3 | Affects of Creatine Transporter Deficiency | CTD is estimated to account for 1-2% of all unexplained X-linked intellectual disabilities. It is the most common of the three cerebral creatine deficiency syndromes. | Affects of Creatine Transporter Deficiency. CTD is estimated to account for 1-2% of all unexplained X-linked intellectual disabilities. It is the most common of the three cerebral creatine deficiency syndromes. | 331 | Creatine Transporter Deficiency |
nord_331_4 | Related disorders of Creatine Transporter Deficiency | Children with CTD often have autism or global developmental delays. | Related disorders of Creatine Transporter Deficiency. Children with CTD often have autism or global developmental delays. | 331 | Creatine Transporter Deficiency |
nord_331_5 | Diagnosis of Creatine Transporter Deficiency | Testing in both urine and plasma is recommended by measuring the concentration of creatine (Cr), guanidinoacetate (GAA) and creatinine (Crn). A positive screen for CTD is based on normal plasma GAA and creatine, with abnormally elevated urine creatine being elevated (maybe normal in females).Follow up genomic testing for mutations in the SLC6A8 gene may be ordered along with brain MRI with spectroscopy to confirm a CTD diagnosis. MRI with spectroscopy is useful for measuring creatine levels in the brain. | Diagnosis of Creatine Transporter Deficiency. Testing in both urine and plasma is recommended by measuring the concentration of creatine (Cr), guanidinoacetate (GAA) and creatinine (Crn). A positive screen for CTD is based on normal plasma GAA and creatine, with abnormally elevated urine creatine being elevated (maybe normal in females).Follow up genomic testing for mutations in the SLC6A8 gene may be ordered along with brain MRI with spectroscopy to confirm a CTD diagnosis. MRI with spectroscopy is useful for measuring creatine levels in the brain. | 331 | Creatine Transporter Deficiency |
nord_331_6 | Therapies of Creatine Transporter Deficiency | Treatment
Individuals diagnosed with CTD may require the coordinated efforts of a team of specialists. A pediatrician or an adult primary care physician, neurologist, geneticist, dietician and a doctor who is familiar with metabolic disorders may need to work together to ensure a comprehensive approach to treatment. Occupational, speech and physical therapists may be necessary to treat developmental disabilities and behavior therapy to address behavior problems.Treatments with oral supplementation are available for individuals with a cerebral creatine deficiency syndrome, but this type of treatment has not shown to improve the outcomes in most people with CTD.However, there may be some clinical benefits to a subset of individuals with a CTD when treated with creatine monohydrate, L-arginine, glycine, and betaine. Additional treatments for CTD are under investigation.For CTD patients being treated with creatine monohydrate, a routine measurement of renal function should be considered to detect possible creatine-associated kidney disease (nephropathy). | Therapies of Creatine Transporter Deficiency. Treatment
Individuals diagnosed with CTD may require the coordinated efforts of a team of specialists. A pediatrician or an adult primary care physician, neurologist, geneticist, dietician and a doctor who is familiar with metabolic disorders may need to work together to ensure a comprehensive approach to treatment. Occupational, speech and physical therapists may be necessary to treat developmental disabilities and behavior therapy to address behavior problems.Treatments with oral supplementation are available for individuals with a cerebral creatine deficiency syndrome, but this type of treatment has not shown to improve the outcomes in most people with CTD.However, there may be some clinical benefits to a subset of individuals with a CTD when treated with creatine monohydrate, L-arginine, glycine, and betaine. Additional treatments for CTD are under investigation.For CTD patients being treated with creatine monohydrate, a routine measurement of renal function should be considered to detect possible creatine-associated kidney disease (nephropathy). | 331 | Creatine Transporter Deficiency |
nord_332_0 | Overview of Creutzfeldt Jakob Disease | SummaryCreutzfeldt-Jakob disease (CJD) is an extremely rare, degenerative brain disorder. It affects about one in every million people per year worldwide. People with CJD typically develop symptoms later in life and may show changes in behavior, memory troubles, lack of coordination and vision problems. As the disease progresses, there may be rapidly progressive deterioration of mental functioning, memory (dementia) and muscle control. CJD is a fatal disease. In most affected individuals, life-threatening complications develop less than a year after they start showing symptoms.There are three major subtypes of CJD. In 85-90 percent of patients, CJD randomly appears even though the person has no known risk factors such as family history or environmental exposure (sporadic CJD). In about 10-15 percent of patients, there may be a family history of CJD (genetic CJD). In less than 1 percent of patients, the disease can be caused by exposure to infected brain or nervous system tissue through medical treatment (iatrogenic) or ingestion (orally) (acquired CJD). A subset of acquired CJD called variant CJD (vCJD) or, commonly, “mad cow disease” first appeared in the United Kingdom and is caused by eating beef infected with bovine spongiform encephalopathy (BSE). This vCJD occurs in younger people (median age of onset is 28 years). All types of CJD are due to the presence of a disease-causing protein called a prion. Disease-causing prions can disrupt the structure of the brain and lead to degeneration. Currently, there are no treatments that can cure or stop the progression of CJD. Treatment is supportive and aimed at making the person as comfortable as possible. Introduction Creutzfeldt-Jakob disease (CJD) was named by two German doctors named Hans Creutzfeldt and Alfons Jakob who studied the disease in the 1920s. Over time, scientists noted the similarities of human CJD to animal diseases (called bovine spongiform encephalopathy or “mad cow disease” in cows and scrapie in sheep) and learned that human and animal forms are caused by a similar mechanism; an abnormal, infectious protein called a prion. The term prion, derived from proteinaceous infectious particle, was coined by Stanley Prusiner. In humans, there are three subtypes of CJD based on how the abnormal prion protein occurred: sporadic (sCJD), genetic (gCJD) and acquired (aCJD). | Overview of Creutzfeldt Jakob Disease. SummaryCreutzfeldt-Jakob disease (CJD) is an extremely rare, degenerative brain disorder. It affects about one in every million people per year worldwide. People with CJD typically develop symptoms later in life and may show changes in behavior, memory troubles, lack of coordination and vision problems. As the disease progresses, there may be rapidly progressive deterioration of mental functioning, memory (dementia) and muscle control. CJD is a fatal disease. In most affected individuals, life-threatening complications develop less than a year after they start showing symptoms.There are three major subtypes of CJD. In 85-90 percent of patients, CJD randomly appears even though the person has no known risk factors such as family history or environmental exposure (sporadic CJD). In about 10-15 percent of patients, there may be a family history of CJD (genetic CJD). In less than 1 percent of patients, the disease can be caused by exposure to infected brain or nervous system tissue through medical treatment (iatrogenic) or ingestion (orally) (acquired CJD). A subset of acquired CJD called variant CJD (vCJD) or, commonly, “mad cow disease” first appeared in the United Kingdom and is caused by eating beef infected with bovine spongiform encephalopathy (BSE). This vCJD occurs in younger people (median age of onset is 28 years). All types of CJD are due to the presence of a disease-causing protein called a prion. Disease-causing prions can disrupt the structure of the brain and lead to degeneration. Currently, there are no treatments that can cure or stop the progression of CJD. Treatment is supportive and aimed at making the person as comfortable as possible. Introduction Creutzfeldt-Jakob disease (CJD) was named by two German doctors named Hans Creutzfeldt and Alfons Jakob who studied the disease in the 1920s. Over time, scientists noted the similarities of human CJD to animal diseases (called bovine spongiform encephalopathy or “mad cow disease” in cows and scrapie in sheep) and learned that human and animal forms are caused by a similar mechanism; an abnormal, infectious protein called a prion. The term prion, derived from proteinaceous infectious particle, was coined by Stanley Prusiner. In humans, there are three subtypes of CJD based on how the abnormal prion protein occurred: sporadic (sCJD), genetic (gCJD) and acquired (aCJD). | 332 | Creutzfeldt Jakob Disease |
nord_332_1 | Symptoms of Creutzfeldt Jakob Disease | All types of Creutzfeldt-Jakob disease (CJD) are extremely rare degenerative brain disorders (i.e., spongiform encephalopathies), characterized by the sudden onset of cognitive impairments and neuromuscular symptoms. Specific signs and symptoms of each type are outlined below.Sporadic CJD and genetic CJDIn sporadic CJD (sCJD) and genetic CJD (gCJD), symptoms typically arise between ages 40-60 years. Initially, these symptoms may look like subtle signs of confusion, depression, forgetfulness, sleeping difficulties (insomnia) and/or behavioral changes. Affected individuals may also experience impaired vision, abnormal physical sensations and/or difficulties with voluntary movement coordination.Individuals may then experience rapidly progressive loss of intellectual abilities, demonstrating impaired memory and judgment and distinct personality changes (dementia). Neuromuscular abnormalities become more apparent at this stage of the disorder and may include muscle weakness and loss of muscle mass (wasting); muscular rigidity; tremors; repeated, involuntary, shock-like muscle spasms (myoclonus) and/or slow, continual, involuntary writhing movements, particularly of the arms and legs (athetosis); increasingly impaired coordination of voluntary movements; and/or difficulty with speech (dysarthria) due to impaired muscular control. Vision may also become increasingly impaired.In individuals with sCJD and gCJD, neurological and neuromuscular impairment continues to progress and later stages of the disorder may be characterized by loss of physical and intellectual functions, coma and increased susceptibility to repeated infections of the respiratory tract (e.g., pneumonia). In many patients, life-threatening complications tend to develop less than a year after the disorder becomes apparent.Acquired CJDAcquired CJD (aCJD) and a specific variant form of Creutzfeldt-Jakob disease (vCJD) occur very rarely (<1 percent of all CJD; less than 500 cases ever known). Symptoms are similar to other forms of CJD, however, there are three key differences. First, acquired forms of CJD typically occur in young adults (i.e., teens and 20s) rather than in the 40s-50s as in sCJD and gCJD. Second, patients tend to have a slightly longer clinical course. Third, acquired forms usually begin with more significant psychiatric symptoms. Delusions are also sometimes reported. Some people with the disorder may have abnormal sensations (dysesthesia) or pain in the face, arms, and legs.
Within a few weeks or months, individuals with aCJD or vCJD experience the onset of progressive neuromuscular symptoms including an impaired ability to coordinate voluntary movement (cerebellar ataxia); severely diminished muscle tone (hypotonia); and slow, halting speech. In some patients, neuromuscular abnormalities may include irregular, rapid, involuntary jerky movements (chorea). As the disease advances, individuals with aCJD or vCJD demonstrate increasing memory impairment that progresses to dementia. During later stages of the disorder, affected individuals may experience repeated, involuntary, shock-like muscle spasms (myoclonus). In individuals with aCJD or vCJD, life-threatening complications tend to develop approximately 13 to 14 months after initial symptoms occur.
| Symptoms of Creutzfeldt Jakob Disease. All types of Creutzfeldt-Jakob disease (CJD) are extremely rare degenerative brain disorders (i.e., spongiform encephalopathies), characterized by the sudden onset of cognitive impairments and neuromuscular symptoms. Specific signs and symptoms of each type are outlined below.Sporadic CJD and genetic CJDIn sporadic CJD (sCJD) and genetic CJD (gCJD), symptoms typically arise between ages 40-60 years. Initially, these symptoms may look like subtle signs of confusion, depression, forgetfulness, sleeping difficulties (insomnia) and/or behavioral changes. Affected individuals may also experience impaired vision, abnormal physical sensations and/or difficulties with voluntary movement coordination.Individuals may then experience rapidly progressive loss of intellectual abilities, demonstrating impaired memory and judgment and distinct personality changes (dementia). Neuromuscular abnormalities become more apparent at this stage of the disorder and may include muscle weakness and loss of muscle mass (wasting); muscular rigidity; tremors; repeated, involuntary, shock-like muscle spasms (myoclonus) and/or slow, continual, involuntary writhing movements, particularly of the arms and legs (athetosis); increasingly impaired coordination of voluntary movements; and/or difficulty with speech (dysarthria) due to impaired muscular control. Vision may also become increasingly impaired.In individuals with sCJD and gCJD, neurological and neuromuscular impairment continues to progress and later stages of the disorder may be characterized by loss of physical and intellectual functions, coma and increased susceptibility to repeated infections of the respiratory tract (e.g., pneumonia). In many patients, life-threatening complications tend to develop less than a year after the disorder becomes apparent.Acquired CJDAcquired CJD (aCJD) and a specific variant form of Creutzfeldt-Jakob disease (vCJD) occur very rarely (<1 percent of all CJD; less than 500 cases ever known). Symptoms are similar to other forms of CJD, however, there are three key differences. First, acquired forms of CJD typically occur in young adults (i.e., teens and 20s) rather than in the 40s-50s as in sCJD and gCJD. Second, patients tend to have a slightly longer clinical course. Third, acquired forms usually begin with more significant psychiatric symptoms. Delusions are also sometimes reported. Some people with the disorder may have abnormal sensations (dysesthesia) or pain in the face, arms, and legs.
Within a few weeks or months, individuals with aCJD or vCJD experience the onset of progressive neuromuscular symptoms including an impaired ability to coordinate voluntary movement (cerebellar ataxia); severely diminished muscle tone (hypotonia); and slow, halting speech. In some patients, neuromuscular abnormalities may include irregular, rapid, involuntary jerky movements (chorea). As the disease advances, individuals with aCJD or vCJD demonstrate increasing memory impairment that progresses to dementia. During later stages of the disorder, affected individuals may experience repeated, involuntary, shock-like muscle spasms (myoclonus). In individuals with aCJD or vCJD, life-threatening complications tend to develop approximately 13 to 14 months after initial symptoms occur.
| 332 | Creutzfeldt Jakob Disease |
nord_332_2 | Causes of Creutzfeldt Jakob Disease | All types of CJD are caused by the presence of abnormal prion proteins in the brain. Abnormal changes in the prion protein are thought to play some role in causing deterioration in certain areas of the brain, appearing as sponge-like holes and gaps (thus, the term spongiform encephalopathy). Such spongiform deterioration in turn results in the progressive neurological and neuromuscular symptoms associated with CJD.How the abnormal prion protein arises is distinct in the different subtypes of CJD. Sporadic CJDsCJD accounts for 85% of CJD and is thought to result from random (sporadic) changes in prion protein structure. Some researchers suggest that the normal cellular prion protein (PrPc) plays an essential role in preventing the degeneration and loss of brain cells. During one laboratory study, researchers removed the normal prion protein from nerve cells (i.e., cultured neurons) and the cells did not survive. However, when researchers restored normal PrPc to cells without the protein, affected neurons returned to health. This suggests the normal prion protein is important for the health of neurons. Further research is necessary to determine the implications of such findings and the specific role of PRPc.The modified or “misfolded” form of PrPc that causes disease is known as PrPsc (for scrapie prion protein). PrPsc can cause normal PrPc to change shape into the disease-causing form. The misfolded shape of PrPsc is thought to prevent it from being appropriately broken down by the body. As a result, more and more normal PrPc change into PrPsc, which gradually accumulate, forming fixed deposits (plaques) in the brain. Genetic CJDgCJD results from changes (mutations) in the PRNP gene which regulates (encodes for) the production of the human prion protein. Genetic forms of CJD are rare (10-15 percent of cases) and follow an autosomal dominant inheritance 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 changed (mutated) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females. In the case of gCJD, the non-working gene is PNRP. (aCJD)Acquired forms of CJD account for 1 percent of all CJD (less than 500 cases ever reported in the world). Direct contamination (transmission) with PrPsc causes the acquired form. This transmission has been reported to occur through medical treatments (iatrogenic), most notably, growth hormone and dura mater grafts made from PrPsc infected human tissue, or from consumption of PrPsc -contaminated meat. In March of 1996, the British government announced that consumption of beef from cows with the infectious brain disorder bovine spongiform encephalopathy (BSE) caused a variant form of Creutzfeldt-Jakob disease (vCJD) in several young people in the United Kingdom. Cows with BSE or “mad cow disease,” experience rapidly progressive neurological and neuromuscular symptoms similar to those associated with CJD in humans. As with CJD, abnormal changes in prion proteins are also thought to play a role in the brain degeneration associated with BSE.BSE was first recognized in the UK in 1986 and was linked to contaminated cow feed composed of sheep meat and bone meal. The sheep may have been infected with scrapie, the sheep form of prion disease. In the late 1980s, Britain banned the use of such feeds in animals raised for human consumption. | Causes of Creutzfeldt Jakob Disease. All types of CJD are caused by the presence of abnormal prion proteins in the brain. Abnormal changes in the prion protein are thought to play some role in causing deterioration in certain areas of the brain, appearing as sponge-like holes and gaps (thus, the term spongiform encephalopathy). Such spongiform deterioration in turn results in the progressive neurological and neuromuscular symptoms associated with CJD.How the abnormal prion protein arises is distinct in the different subtypes of CJD. Sporadic CJDsCJD accounts for 85% of CJD and is thought to result from random (sporadic) changes in prion protein structure. Some researchers suggest that the normal cellular prion protein (PrPc) plays an essential role in preventing the degeneration and loss of brain cells. During one laboratory study, researchers removed the normal prion protein from nerve cells (i.e., cultured neurons) and the cells did not survive. However, when researchers restored normal PrPc to cells without the protein, affected neurons returned to health. This suggests the normal prion protein is important for the health of neurons. Further research is necessary to determine the implications of such findings and the specific role of PRPc.The modified or “misfolded” form of PrPc that causes disease is known as PrPsc (for scrapie prion protein). PrPsc can cause normal PrPc to change shape into the disease-causing form. The misfolded shape of PrPsc is thought to prevent it from being appropriately broken down by the body. As a result, more and more normal PrPc change into PrPsc, which gradually accumulate, forming fixed deposits (plaques) in the brain. Genetic CJDgCJD results from changes (mutations) in the PRNP gene which regulates (encodes for) the production of the human prion protein. Genetic forms of CJD are rare (10-15 percent of cases) and follow an autosomal dominant inheritance 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 changed (mutated) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females. In the case of gCJD, the non-working gene is PNRP. (aCJD)Acquired forms of CJD account for 1 percent of all CJD (less than 500 cases ever reported in the world). Direct contamination (transmission) with PrPsc causes the acquired form. This transmission has been reported to occur through medical treatments (iatrogenic), most notably, growth hormone and dura mater grafts made from PrPsc infected human tissue, or from consumption of PrPsc -contaminated meat. In March of 1996, the British government announced that consumption of beef from cows with the infectious brain disorder bovine spongiform encephalopathy (BSE) caused a variant form of Creutzfeldt-Jakob disease (vCJD) in several young people in the United Kingdom. Cows with BSE or “mad cow disease,” experience rapidly progressive neurological and neuromuscular symptoms similar to those associated with CJD in humans. As with CJD, abnormal changes in prion proteins are also thought to play a role in the brain degeneration associated with BSE.BSE was first recognized in the UK in 1986 and was linked to contaminated cow feed composed of sheep meat and bone meal. The sheep may have been infected with scrapie, the sheep form of prion disease. In the late 1980s, Britain banned the use of such feeds in animals raised for human consumption. | 332 | Creutzfeldt Jakob Disease |
nord_332_3 | Affects of Creutzfeldt Jakob Disease | CJD affects males and females in equal numbers. It is rare, arising in approximately one to two individuals per million people each year.In individuals with aCJD, symptoms appear to occur approximately 10 years after initial infection (incubation period) although, in some patients, incubation periods have extended up to 30 years. No direct cases of surgically acquired CJD have been identified since 2005. Since it was first identified in 1996, a total of 231 cases of vCJD have been reported worldwide. The majority (178/231) of the cases were in the United Kingdom. The annual number of confirmed cases of vCJD has declined globally in the past 15 years. | Affects of Creutzfeldt Jakob Disease. CJD affects males and females in equal numbers. It is rare, arising in approximately one to two individuals per million people each year.In individuals with aCJD, symptoms appear to occur approximately 10 years after initial infection (incubation period) although, in some patients, incubation periods have extended up to 30 years. No direct cases of surgically acquired CJD have been identified since 2005. Since it was first identified in 1996, a total of 231 cases of vCJD have been reported worldwide. The majority (178/231) of the cases were in the United Kingdom. The annual number of confirmed cases of vCJD has declined globally in the past 15 years. | 332 | Creutzfeldt Jakob Disease |
nord_332_4 | Related disorders of Creutzfeldt Jakob Disease | Symptoms of the following disorders may be similar to those of Creutzfeldt-Jakob disease (CJD). Comparison may be useful for a differential diagnosis:Prion diseasesThere are additional rare degenerative brain disorders that are human prion diseases. These include Gerstmann-Straussler-Scheinker disease, fatal familial insomnia and kuru.Gerstmann-Straussler-Scheinker (GSS) disease is a rare degenerative brain disease that follows an autosomal dominant inheritance pattern. The disorder is typically characterized by increasingly impaired coordination of voluntary movements (cerebellar ataxia), with associated unsteadiness, clumsiness, imbalance and an abnormal manner of walking (gait disturbances). With disease progression, affected individuals may develop involuntary, rhythmic, rapid eye movements (nystagmus) and abnormally slow, slurred speech (dysarthria). Additional findings may include stiffness (rigidity), unusually slow movement (bradykinesia) and, in some patients, dementia. GSS disease is caused by certain specific changes (mutations) in the PRNP gene that regulates production of the human prion protein. Classic GSS disease is typically distinguished from CJD by an earlier age at symptom onset, a longer duration of disease progression, slowly evolving dementia, more prominent signs of cerebellar ataxia and differences in degenerative changes of the brain (e.g., plaque deposits, “spongiform” changes). However, a form of GSS disease has been described in a Hungarian family with three affected sisters in whom associated symptoms were indistinguishable from those associated with sporadic CJD. According to researchers, the implications of such findings are currently unknown.Fatal familial insomnia (FFI) is a rare, rapidly progressive, degenerative brain disorder that follows an autosomal dominant inheritance pattern. The disorder typically becomes apparent during middle age or later life and is characterized by an inability to sleep or abnormal wakefulness that is resistant to treatment (intractable insomnia) and impaired functioning of the portion of the nervous system (i.e., autonomic nervous system) that regulates certain involuntary functions (dysautonomia). Dysautonomia may be characterized by fever (pyrexia), profuse sweating (diaphoresis), abnormal contraction of the pupils (miosis) and other associated findings. Individuals with FFI may also develop slurred, slowed speech (dysarthria); memory impairment and attention disturbances; complex hallucinations that may be described as “dream-like” states; and neuromuscular abnormalities. These may include increased reflex responses (hyperreflexia); impaired coordination of voluntary movements (ataxia); tremors; and involuntary, shock-like contractions of certain muscles (myoclonus). Neurodegenerative changes associated with FFI may be limited to certain regions of the brain (e.g., thalamic nuclei). Fatal familial insomnia is caused by a specific mutation of the PRNP gene.Kuru is a rare progressive degenerative brain disorder that occurs exclusively in members of the Fore linguistic tribal group of the New Guinea highlands. Associated symptoms include progressively impaired coordination of voluntary movements (ataxia) of the trunk, arms, and legs; slurred speech (dysarthria); a “shivering-like” tremor; visual disturbances; and paralysis. Neurodegenerative changes include generalized loss of nerve cells, particularly in the outer region of the brain (cerebral cortex) and the development of characteristic plaques (i.e., “kuru plaques”). Transmission of the disease is thought to result from ritualistic handling and ingestion (cannibalism) of brain tissue of deceased relatives. The incidence of kuru has dramatically declined with the cessation of such practices.Non-Prion diseasesAlzheimer’s disease is a common, progressive, degenerative brain disorder affecting memory, thought and language. Neurodegenerative changes lead to the formation of plaques or patches within the brain and the loss of cholinergic neurotransmitter function. The early behavioral changes may be subtle; however, as the disease progresses, memory losses increase and there are personality, mood, and behavioral changes. There may also be disturbances of judgment, concentration, and speech along with confusion and restlessness. There are several additional progressive conditions of the brain (e.g., FTD/ALS, cerebral hematomas, etc.) that may be characterized by behavioral abnormalities, memory loss, dementia, neuromuscular symptoms and/or other features similar to those associated with Creutzfeldt-Jakob disease. | Related disorders of Creutzfeldt Jakob Disease. Symptoms of the following disorders may be similar to those of Creutzfeldt-Jakob disease (CJD). Comparison may be useful for a differential diagnosis:Prion diseasesThere are additional rare degenerative brain disorders that are human prion diseases. These include Gerstmann-Straussler-Scheinker disease, fatal familial insomnia and kuru.Gerstmann-Straussler-Scheinker (GSS) disease is a rare degenerative brain disease that follows an autosomal dominant inheritance pattern. The disorder is typically characterized by increasingly impaired coordination of voluntary movements (cerebellar ataxia), with associated unsteadiness, clumsiness, imbalance and an abnormal manner of walking (gait disturbances). With disease progression, affected individuals may develop involuntary, rhythmic, rapid eye movements (nystagmus) and abnormally slow, slurred speech (dysarthria). Additional findings may include stiffness (rigidity), unusually slow movement (bradykinesia) and, in some patients, dementia. GSS disease is caused by certain specific changes (mutations) in the PRNP gene that regulates production of the human prion protein. Classic GSS disease is typically distinguished from CJD by an earlier age at symptom onset, a longer duration of disease progression, slowly evolving dementia, more prominent signs of cerebellar ataxia and differences in degenerative changes of the brain (e.g., plaque deposits, “spongiform” changes). However, a form of GSS disease has been described in a Hungarian family with three affected sisters in whom associated symptoms were indistinguishable from those associated with sporadic CJD. According to researchers, the implications of such findings are currently unknown.Fatal familial insomnia (FFI) is a rare, rapidly progressive, degenerative brain disorder that follows an autosomal dominant inheritance pattern. The disorder typically becomes apparent during middle age or later life and is characterized by an inability to sleep or abnormal wakefulness that is resistant to treatment (intractable insomnia) and impaired functioning of the portion of the nervous system (i.e., autonomic nervous system) that regulates certain involuntary functions (dysautonomia). Dysautonomia may be characterized by fever (pyrexia), profuse sweating (diaphoresis), abnormal contraction of the pupils (miosis) and other associated findings. Individuals with FFI may also develop slurred, slowed speech (dysarthria); memory impairment and attention disturbances; complex hallucinations that may be described as “dream-like” states; and neuromuscular abnormalities. These may include increased reflex responses (hyperreflexia); impaired coordination of voluntary movements (ataxia); tremors; and involuntary, shock-like contractions of certain muscles (myoclonus). Neurodegenerative changes associated with FFI may be limited to certain regions of the brain (e.g., thalamic nuclei). Fatal familial insomnia is caused by a specific mutation of the PRNP gene.Kuru is a rare progressive degenerative brain disorder that occurs exclusively in members of the Fore linguistic tribal group of the New Guinea highlands. Associated symptoms include progressively impaired coordination of voluntary movements (ataxia) of the trunk, arms, and legs; slurred speech (dysarthria); a “shivering-like” tremor; visual disturbances; and paralysis. Neurodegenerative changes include generalized loss of nerve cells, particularly in the outer region of the brain (cerebral cortex) and the development of characteristic plaques (i.e., “kuru plaques”). Transmission of the disease is thought to result from ritualistic handling and ingestion (cannibalism) of brain tissue of deceased relatives. The incidence of kuru has dramatically declined with the cessation of such practices.Non-Prion diseasesAlzheimer’s disease is a common, progressive, degenerative brain disorder affecting memory, thought and language. Neurodegenerative changes lead to the formation of plaques or patches within the brain and the loss of cholinergic neurotransmitter function. The early behavioral changes may be subtle; however, as the disease progresses, memory losses increase and there are personality, mood, and behavioral changes. There may also be disturbances of judgment, concentration, and speech along with confusion and restlessness. There are several additional progressive conditions of the brain (e.g., FTD/ALS, cerebral hematomas, etc.) that may be characterized by behavioral abnormalities, memory loss, dementia, neuromuscular symptoms and/or other features similar to those associated with Creutzfeldt-Jakob disease. | 332 | Creutzfeldt Jakob Disease |
nord_332_5 | Diagnosis of Creutzfeldt Jakob Disease | Genetic forms of the disease can be diagnosed through clinical symptoms, family history and genetic testing for variants in the PRNP gene. Genetic counseling is recommended for individuals with suspected genetic CJD. Confirming or ruling out a diagnosis of sCJD in a living patient can be difficult. In 2018, the Centers for Disease Control and Prevention (CDC) updated the diagnostic criteria for sCJD stating a definite diagnosis of CJD can only be determined through positive brain tissue testing. This would include standard neuropathological techniques (i.e., histology and immunohistochemistry); and/or western blot confirmed protease-resistant PrP. This testing is usually performed at the time of autopsy.Along with clinical symptoms, there are tests which can be useful to determine a probable diagnosis of CJD in a living patient. The first is called real-time quaking-induced conversion (RT-QuIC). This method looks for abnormal prion protein through formation of prion aggregates in fluid from the spinal cord. The second is brain imaging with magnetic resonance imaging (MRI), which allows specialist to look for distinct patterns of neurodegeneration. Using results from RT-QuIC, MRI, and clinical symptoms, specialists can determine if an individual meets the criteria for a probable CJD diagnosis. Other possible tests that could be considered include electroencephalogram (EEG), which records the brains electrical impulses. | Diagnosis of Creutzfeldt Jakob Disease. Genetic forms of the disease can be diagnosed through clinical symptoms, family history and genetic testing for variants in the PRNP gene. Genetic counseling is recommended for individuals with suspected genetic CJD. Confirming or ruling out a diagnosis of sCJD in a living patient can be difficult. In 2018, the Centers for Disease Control and Prevention (CDC) updated the diagnostic criteria for sCJD stating a definite diagnosis of CJD can only be determined through positive brain tissue testing. This would include standard neuropathological techniques (i.e., histology and immunohistochemistry); and/or western blot confirmed protease-resistant PrP. This testing is usually performed at the time of autopsy.Along with clinical symptoms, there are tests which can be useful to determine a probable diagnosis of CJD in a living patient. The first is called real-time quaking-induced conversion (RT-QuIC). This method looks for abnormal prion protein through formation of prion aggregates in fluid from the spinal cord. The second is brain imaging with magnetic resonance imaging (MRI), which allows specialist to look for distinct patterns of neurodegeneration. Using results from RT-QuIC, MRI, and clinical symptoms, specialists can determine if an individual meets the criteria for a probable CJD diagnosis. Other possible tests that could be considered include electroencephalogram (EEG), which records the brains electrical impulses. | 332 | Creutzfeldt Jakob Disease |
nord_332_6 | Therapies of Creutzfeldt Jakob Disease | TreatmentThe treatment of Creutzfeldt-Jakob disease is symptomatic and supportive. | Therapies of Creutzfeldt Jakob Disease. TreatmentThe treatment of Creutzfeldt-Jakob disease is symptomatic and supportive. | 332 | Creutzfeldt Jakob Disease |
nord_333_0 | Overview of Cri du Chat Syndrome | SummaryCri du chat syndrome (CdCS or 5p-) is a rare genetic disorder in which a variable portion of the short arm of chromosome 5 is missing or deleted (monosomic). Symptoms vary greatly from case to case depending upon the exact size and location of the deleted genetic material. Common symptoms include a distinctive cry that resembles the mewing of a cat, characteristic facial features, slow growth, and microcephaly, a condition that indicates that head circumference is smaller than would be expected for an infant's age and sex. Affected children also exhibit delays in the acquisition of skills requiring the coordination of muscular and mental activities (psychomotor disability) and moderate to severe intellectual disability. Additional symptoms affecting different organ systems of the body can also occur. Most cases are thought arise from spontaneous (de novo) genetic errors very early in embryonic development.IntroductionThe disorder was first described in the medical literature in 1963 by doctor Lejeune who named the disorder after the distinctive cat-like cry. In French, Cri du chat translates into “cry of the cat”. | Overview of Cri du Chat Syndrome. SummaryCri du chat syndrome (CdCS or 5p-) is a rare genetic disorder in which a variable portion of the short arm of chromosome 5 is missing or deleted (monosomic). Symptoms vary greatly from case to case depending upon the exact size and location of the deleted genetic material. Common symptoms include a distinctive cry that resembles the mewing of a cat, characteristic facial features, slow growth, and microcephaly, a condition that indicates that head circumference is smaller than would be expected for an infant's age and sex. Affected children also exhibit delays in the acquisition of skills requiring the coordination of muscular and mental activities (psychomotor disability) and moderate to severe intellectual disability. Additional symptoms affecting different organ systems of the body can also occur. Most cases are thought arise from spontaneous (de novo) genetic errors very early in embryonic development.IntroductionThe disorder was first described in the medical literature in 1963 by doctor Lejeune who named the disorder after the distinctive cat-like cry. In French, Cri du chat translates into “cry of the cat”. | 333 | Cri du Chat Syndrome |
nord_333_1 | Symptoms of Cri du Chat Syndrome | The symptoms of cri du chat syndrome vary from case to case. The characteristic high-pitched, shrill cry associated with cri du chat syndrome is present during the first few weeks of life. The cry, which resembles the mewing of a cat, becomes less pronounced as affected infants grow older.Affected infants may also display low birth weight, growth deficiencies, diminished muscle tone (hypotonia), and microcephaly, a condition that indicates that head circumference is smaller than would be expected for an infant’s age and sex.Distinctive facial features may include an abnormally round or plump (moon) face, a broad nasal bridge, widely spaced eyes (hypertelorism), crossed eyes (strabismus), downwardly slanting eyelid folds (palpebral fissures), vertical skin folds that may cover the eyes’ inner corners (epicanthal folds), low-set ears, and an abnormally small jaw (micrognathia). Improper alignment of the upper and lower teeth (malocclusion) may also occur.Additional facial features include an abnormally small distance from the upper lip to the nose (short philtrum), incomplete closure of the roof of the mouth (cleft palate), an abnormal groove or gap in the upper lip (cleft lip), and abnormal fullness of the lower lip. In addition, the fleshy mass (uvula) that hangs in the back of the throat may be spilt (bifid uvula). As affected infants age the face may lose its plumpness and become abnormally long and narrow.Most affected infants also display some degree of psychomotor and intellectual disability. Psychomotor disability is a delay in the acquisition of skills requiring mental and muscular activities such head control, sitting up, and walking. About half of children with cri du chat syndrome were able to dress themselves by age 5 years. Moderate to severe intellectual disability is present in most cases. Speech development is especially delayed in children with cri du chat syndrome. Affected children usually understand speech better than they can communicate. Some children may display hyperactivity or self-abusive behaviors. While children with cri du chat syndrome are born hypotonic (low muscle tone), they tend to become hypertonic (high muscle tone) as they grow older.Affected infants may have feeding difficulties due to low muscle tone, poor suck, and gastroesophageal reflux disease. Some are also at risk for aspiration which can lead to pneumonias. In one study, only 50% of children with cri du chat syndrome were able to feed themselves with a spoon by 3.5 years of age.A variety of additional findings may occur in association with cri du chat syndrome. Abnormal side-to-side curvature of the spine (scoliosis) is a frequent complication. Affected children also have a higher risk of ear infections and hearing loss. Approximately 15-20 percent of affected infants have congenital heart defects. The most common heart defect is patent ductus arteriosus, a condition in which the passage (ductus) between the blood vessel that leads to the lungs (pulmonary artery) and the major artery of the body (aorta) fails to close after birth.Less common findings associated with cri du chat syndrome include the development of a tear in the supportive tissue of the lower abdomen (inguinal hernia) allowing a portion of the intestines to protrude out; the passage or flowing back (reflux) of the contents of the stomach or small intestines (duodenum) into the esophagus (gastroesophageal reflux); abnormalities of the kidney and urinary tract; respiratory difficulties; webbing of the fingers and toes (syndactyly); abnormal bending or curving of the pinkies inward toward the fourth finger (clinodactyly); clubfeet; and structural anomalies of the voice box (larynx). In some cases, nearsightedness (myopia) and cataracts may develop. Prematurely graying of the hair has also been reported. Some individuals may develop repeated respiratory and intestinal infections. In affected male infants, the testes may fail to descend into the scrotum (cryptorchidism) and the urinary opening may be located on the underside of the penis (hypospadias). There has also been an association with cri du chat and Hirschsprung’s disease. | Symptoms of Cri du Chat Syndrome. The symptoms of cri du chat syndrome vary from case to case. The characteristic high-pitched, shrill cry associated with cri du chat syndrome is present during the first few weeks of life. The cry, which resembles the mewing of a cat, becomes less pronounced as affected infants grow older.Affected infants may also display low birth weight, growth deficiencies, diminished muscle tone (hypotonia), and microcephaly, a condition that indicates that head circumference is smaller than would be expected for an infant’s age and sex.Distinctive facial features may include an abnormally round or plump (moon) face, a broad nasal bridge, widely spaced eyes (hypertelorism), crossed eyes (strabismus), downwardly slanting eyelid folds (palpebral fissures), vertical skin folds that may cover the eyes’ inner corners (epicanthal folds), low-set ears, and an abnormally small jaw (micrognathia). Improper alignment of the upper and lower teeth (malocclusion) may also occur.Additional facial features include an abnormally small distance from the upper lip to the nose (short philtrum), incomplete closure of the roof of the mouth (cleft palate), an abnormal groove or gap in the upper lip (cleft lip), and abnormal fullness of the lower lip. In addition, the fleshy mass (uvula) that hangs in the back of the throat may be spilt (bifid uvula). As affected infants age the face may lose its plumpness and become abnormally long and narrow.Most affected infants also display some degree of psychomotor and intellectual disability. Psychomotor disability is a delay in the acquisition of skills requiring mental and muscular activities such head control, sitting up, and walking. About half of children with cri du chat syndrome were able to dress themselves by age 5 years. Moderate to severe intellectual disability is present in most cases. Speech development is especially delayed in children with cri du chat syndrome. Affected children usually understand speech better than they can communicate. Some children may display hyperactivity or self-abusive behaviors. While children with cri du chat syndrome are born hypotonic (low muscle tone), they tend to become hypertonic (high muscle tone) as they grow older.Affected infants may have feeding difficulties due to low muscle tone, poor suck, and gastroesophageal reflux disease. Some are also at risk for aspiration which can lead to pneumonias. In one study, only 50% of children with cri du chat syndrome were able to feed themselves with a spoon by 3.5 years of age.A variety of additional findings may occur in association with cri du chat syndrome. Abnormal side-to-side curvature of the spine (scoliosis) is a frequent complication. Affected children also have a higher risk of ear infections and hearing loss. Approximately 15-20 percent of affected infants have congenital heart defects. The most common heart defect is patent ductus arteriosus, a condition in which the passage (ductus) between the blood vessel that leads to the lungs (pulmonary artery) and the major artery of the body (aorta) fails to close after birth.Less common findings associated with cri du chat syndrome include the development of a tear in the supportive tissue of the lower abdomen (inguinal hernia) allowing a portion of the intestines to protrude out; the passage or flowing back (reflux) of the contents of the stomach or small intestines (duodenum) into the esophagus (gastroesophageal reflux); abnormalities of the kidney and urinary tract; respiratory difficulties; webbing of the fingers and toes (syndactyly); abnormal bending or curving of the pinkies inward toward the fourth finger (clinodactyly); clubfeet; and structural anomalies of the voice box (larynx). In some cases, nearsightedness (myopia) and cataracts may develop. Prematurely graying of the hair has also been reported. Some individuals may develop repeated respiratory and intestinal infections. In affected male infants, the testes may fail to descend into the scrotum (cryptorchidism) and the urinary opening may be located on the underside of the penis (hypospadias). There has also been an association with cri du chat and Hirschsprung’s disease. | 333 | Cri du Chat Syndrome |
nord_333_2 | Causes of Cri du Chat Syndrome | Cri du chat syndrome is a chromosomal disorder caused by a partial deletion (monosomy) of a varying length of the short arm (p) of chromosome 5. Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Pairs of human chromosomes are numbered from 1 through 22, and an additional 23rd pair of sex chromosomes which include one X and one Y chromosome in males and two X chromosomes in females. 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 5p15.3” refers to band 15 on the short arm of chromosome 5. The numbered bands specify the location of the thousands of genes that are present on each chromosome. In individuals with cri du chat syndrome, the range and severity of associated symptoms and findings can vary, depending upon the exact length or location of the deleted portion of chromosome 5p. Researchers have determined that certain symptoms may be associated with specific regions on the short arm of chromosome 5. Researchers have identified several genes that are believed to play a role in the development of cri du chat syndrome. The telomerase reverse transcriptase gene that is located on the short arm of chromosome 5 at band 13.33 (5p13.33) and semaphorin F gene at 5p15.2 could contribute to the wide variety in features. The deletion of the d-catenin gene, also at 5p15.2, is linked to more severe intellectual disability as this protein is expressed in early neuronal development. If researchers can link specific sets of symptoms and findings (phenotypes) to specific deletion of chromosome 5p, it may greatly aid in diagnosis and prognosis.Most cases of cri du chat syndrome appear to occur spontaneously (de novo) for unknown reasons very early in embryonic development. Most deletions (80-90%) are paternal in origin meaning they likely occur as part of sperm formation. The parents of a child with a “de novo” deletion usually have normal chromosomes and a relatively low risk of having another child with the chromosomal abnormality. In approximately 10-15 percent of cases, cri du chat syndrome may result from a balanced translocation involving chromosome 5p and another chromosome or chromosomes. Translocations occur when regions of certain chromosomes break off and are rearranged, resulting in shifting of genetic material and an altered set of chromosomes. Such translocations may occur spontaneously for unknown reasons (de novo) or be transmitted by a parent who is a carrier of such a balanced translocation. A balanced translocation consists of an altered but balanced set of chromosomes and is usually harmless to the carrier. However, such a chromosomal rearrangement may be associated with an increased risk of abnormal chromosomal development in the carrier’s offspring. Chromosomal analysis may determine whether a parent has a balanced translocation. | Causes of Cri du Chat Syndrome. Cri du chat syndrome is a chromosomal disorder caused by a partial deletion (monosomy) of a varying length of the short arm (p) of chromosome 5. Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Pairs of human chromosomes are numbered from 1 through 22, and an additional 23rd pair of sex chromosomes which include one X and one Y chromosome in males and two X chromosomes in females. 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 5p15.3” refers to band 15 on the short arm of chromosome 5. The numbered bands specify the location of the thousands of genes that are present on each chromosome. In individuals with cri du chat syndrome, the range and severity of associated symptoms and findings can vary, depending upon the exact length or location of the deleted portion of chromosome 5p. Researchers have determined that certain symptoms may be associated with specific regions on the short arm of chromosome 5. Researchers have identified several genes that are believed to play a role in the development of cri du chat syndrome. The telomerase reverse transcriptase gene that is located on the short arm of chromosome 5 at band 13.33 (5p13.33) and semaphorin F gene at 5p15.2 could contribute to the wide variety in features. The deletion of the d-catenin gene, also at 5p15.2, is linked to more severe intellectual disability as this protein is expressed in early neuronal development. If researchers can link specific sets of symptoms and findings (phenotypes) to specific deletion of chromosome 5p, it may greatly aid in diagnosis and prognosis.Most cases of cri du chat syndrome appear to occur spontaneously (de novo) for unknown reasons very early in embryonic development. Most deletions (80-90%) are paternal in origin meaning they likely occur as part of sperm formation. The parents of a child with a “de novo” deletion usually have normal chromosomes and a relatively low risk of having another child with the chromosomal abnormality. In approximately 10-15 percent of cases, cri du chat syndrome may result from a balanced translocation involving chromosome 5p and another chromosome or chromosomes. Translocations occur when regions of certain chromosomes break off and are rearranged, resulting in shifting of genetic material and an altered set of chromosomes. Such translocations may occur spontaneously for unknown reasons (de novo) or be transmitted by a parent who is a carrier of such a balanced translocation. A balanced translocation consists of an altered but balanced set of chromosomes and is usually harmless to the carrier. However, such a chromosomal rearrangement may be associated with an increased risk of abnormal chromosomal development in the carrier’s offspring. Chromosomal analysis may determine whether a parent has a balanced translocation. | 333 | Cri du Chat Syndrome |
nord_333_3 | Affects of Cri du Chat Syndrome | Cri du chat syndrome affects females more often than males. The incidence ranges from 1-15,000 to 50,000 live births. Some cases of cri du chat syndrome may go undiagnosed making it difficult to determine the true frequency of this disorder in the general population. | Affects of Cri du Chat Syndrome. Cri du chat syndrome affects females more often than males. The incidence ranges from 1-15,000 to 50,000 live births. Some cases of cri du chat syndrome may go undiagnosed making it difficult to determine the true frequency of this disorder in the general population. | 333 | Cri du Chat Syndrome |
nord_333_4 | Related disorders of Cri du Chat Syndrome | Symptoms of the following disorders can be similar to those of cri du chat syndrome. Comparisons may be useful for a differential diagnosis.Wolf-Hirschhorn syndrome, also known as Wolf syndrome, is a rare chromosomal disorder in which there is partial deletion (monosomy) of the short arm (p) of chromosome 4 (4p). Although the size and location of the 4p deletion vary from case to case, it is believed that deletion of band 4p16.3 is the critical region leading to characteristic features of the disorder. Associated abnormalities typically include a low birth weight, growth retardation, poor muscle tone (hypotonia), and delays in the acquisition of skills requiring the coordination of physical and mental activities (psychomotor retardation). Most affected infants and children also have distinctive malformations of the skull and facial (craniofacial) region. These may include a small head (microcephaly) and high forehead; highly arched eyebrows; widely spaced eyes (ocular hypertelorism); vertical skin folds that cover the eyes’ inner corners (epicanthal folds); a “beaked” nose with an abnormally wide nasal bridge; a downturned mouth; an unusually short vertical groove in the middle of the upper lip (philtrum); and/or large, malformed ears. Due to these and/or additional craniofacial malformations, the face may appear relatively dissimilar from one side to the other (craniofacial asymmetry). Additional physical abnormalities may also be present. Such features may include abnormal deviation of one eye in relation to the other (strabismus); partial absence of tissue from the colored region of the eye (iris coloboma); incomplete closure of the roof of the mouth (cleft palate); undescended testes (cryptorchidism) and abnormal placement of the urinary opening on the underside of the penis (hypospadias) in affected males; structural malformations of the heart; sudden episodes of uncontrolled electrical activity in the brain (seizures); skeletal abnormalities; and/or other findings. Wolf-Hirschhorn syndrome usually appears to occur spontaneously (de novo) for unknown reasons very early in embryonic development. Less commonly, it may appear to result from a balanced translocation in one of the parents.Additional chromosomal disorders may have features similar to those associated with cri du chat syndrome. Chromosomal testing is necessary to confirm the specific chromosomal abnormality present. (For further information on such disorders, choose the name of the specific chromosomal disorder in question or use “chromosome” as your search term in the Rare Disease Database.) | Related disorders of Cri du Chat Syndrome. Symptoms of the following disorders can be similar to those of cri du chat syndrome. Comparisons may be useful for a differential diagnosis.Wolf-Hirschhorn syndrome, also known as Wolf syndrome, is a rare chromosomal disorder in which there is partial deletion (monosomy) of the short arm (p) of chromosome 4 (4p). Although the size and location of the 4p deletion vary from case to case, it is believed that deletion of band 4p16.3 is the critical region leading to characteristic features of the disorder. Associated abnormalities typically include a low birth weight, growth retardation, poor muscle tone (hypotonia), and delays in the acquisition of skills requiring the coordination of physical and mental activities (psychomotor retardation). Most affected infants and children also have distinctive malformations of the skull and facial (craniofacial) region. These may include a small head (microcephaly) and high forehead; highly arched eyebrows; widely spaced eyes (ocular hypertelorism); vertical skin folds that cover the eyes’ inner corners (epicanthal folds); a “beaked” nose with an abnormally wide nasal bridge; a downturned mouth; an unusually short vertical groove in the middle of the upper lip (philtrum); and/or large, malformed ears. Due to these and/or additional craniofacial malformations, the face may appear relatively dissimilar from one side to the other (craniofacial asymmetry). Additional physical abnormalities may also be present. Such features may include abnormal deviation of one eye in relation to the other (strabismus); partial absence of tissue from the colored region of the eye (iris coloboma); incomplete closure of the roof of the mouth (cleft palate); undescended testes (cryptorchidism) and abnormal placement of the urinary opening on the underside of the penis (hypospadias) in affected males; structural malformations of the heart; sudden episodes of uncontrolled electrical activity in the brain (seizures); skeletal abnormalities; and/or other findings. Wolf-Hirschhorn syndrome usually appears to occur spontaneously (de novo) for unknown reasons very early in embryonic development. Less commonly, it may appear to result from a balanced translocation in one of the parents.Additional chromosomal disorders may have features similar to those associated with cri du chat syndrome. Chromosomal testing is necessary to confirm the specific chromosomal abnormality present. (For further information on such disorders, choose the name of the specific chromosomal disorder in question or use “chromosome” as your search term in the Rare Disease Database.) | 333 | Cri du Chat Syndrome |
nord_333_5 | Diagnosis of Cri du Chat Syndrome | In newborns, the diagnosis of cri du chat syndrome is confirmed by a thorough clinical evaluation, identification of characteristic findings (e.g., cat-like cry) and chromosomal studies (karyotyping) that reveal a deletion on the short arm of chromosome 5. A specific test known as fluorescence in situ hybridization (FISH) may be used to confirm a diagnosis of cri du chat syndrome.Chromosomal studies may also be performed to determine whether a balanced translocation is present in one parent. Additional diagnostic tests may be used to determine the extent of the disorder such as x-rays to reveal skeletal abnormalities such as scoliosis.Scientific techniques in determining chromosomal abnormalities are becoming more and more refined. This means diagnostic techniques have improved and in certain instances prenatal diagnosis of cri du chat syndrome is possible. | Diagnosis of Cri du Chat Syndrome. In newborns, the diagnosis of cri du chat syndrome is confirmed by a thorough clinical evaluation, identification of characteristic findings (e.g., cat-like cry) and chromosomal studies (karyotyping) that reveal a deletion on the short arm of chromosome 5. A specific test known as fluorescence in situ hybridization (FISH) may be used to confirm a diagnosis of cri du chat syndrome.Chromosomal studies may also be performed to determine whether a balanced translocation is present in one parent. Additional diagnostic tests may be used to determine the extent of the disorder such as x-rays to reveal skeletal abnormalities such as scoliosis.Scientific techniques in determining chromosomal abnormalities are becoming more and more refined. This means diagnostic techniques have improved and in certain instances prenatal diagnosis of cri du chat syndrome is possible. | 333 | Cri du Chat Syndrome |
nord_333_6 | Therapies of Cri du Chat Syndrome | Treatment
The treatment of cri du chat 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, orthopedists, surgeons, cardiologists, speech pathologists, neurologist, dentist, physical and occupational therapists, and other health care professionals may need to systematically and comprehensively plan an affected child's treatment. As some children with cri du chat can have sensory-neural deafness, auditory testing should be performed.Early intervention is important in ensuring that children with cri du chat syndrome reach their highest potential. Services that may be beneficial may include special remedial education, physical therapy, speech therapy, special services, and other medical, social, and/or vocational services. Most children are enrolled in therapy before one year of age.Surgery may be performed to treat a variety of symptoms potentially associated with cri du chat syndrome including congenital heart defects, strabismus, scoliosis, clubfoot, cleft palate and cleft lip.
The survival for children with cri du chat is generally good. Most syndrome related deaths occur within the first year of life. Several children have lived to be over 50 years of age.Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive. | Therapies of Cri du Chat Syndrome. Treatment
The treatment of cri du chat 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, orthopedists, surgeons, cardiologists, speech pathologists, neurologist, dentist, physical and occupational therapists, and other health care professionals may need to systematically and comprehensively plan an affected child's treatment. As some children with cri du chat can have sensory-neural deafness, auditory testing should be performed.Early intervention is important in ensuring that children with cri du chat syndrome reach their highest potential. Services that may be beneficial may include special remedial education, physical therapy, speech therapy, special services, and other medical, social, and/or vocational services. Most children are enrolled in therapy before one year of age.Surgery may be performed to treat a variety of symptoms potentially associated with cri du chat syndrome including congenital heart defects, strabismus, scoliosis, clubfoot, cleft palate and cleft lip.
The survival for children with cri du chat is generally good. Most syndrome related deaths occur within the first year of life. Several children have lived to be over 50 years of age.Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive. | 333 | Cri du Chat Syndrome |
nord_334_0 | Overview of Crigler Najjar Syndrome | SummaryCrigler-Najjar syndrome is a rare genetic disorder characterized by an inability to properly convert and clear bilirubin from the body. Bilirubin is an orange-yellow bile pigment that is mainly a byproduct of the natural breakdown (degeneration) of old or worn out red blood cells (hemolysis). Normally, bilirubin created in this process is converted from an unconjugated form to a form that can be dissolved in water and excreted from the body (called conjugated bilirubin). Affected individuals cannot convert unconjugated bilirubin to the conjugated form because they lack a specific liver enzyme required to break down (metabolize) bilirubin. Since they cannot convert bilirubin, they develop abnormally high levels of unconjugated bilirubin in the blood (hyperbilirubinemia).The hallmark finding of Crigler-Najjar syndrome is a persistent yellowing of the skin, mucous membranes and whites of the eyes (jaundice). There are two forms of this disorder: Crigler-Najjar syndrome type I, characterized by a nearly complete lack of enzyme activity and severe, even life-threatening symptoms; and Crigler-Najjar syndrome type II, characterized by partial enzyme activity and milder symptoms. Both forms are inherited as autosomal recessive traits and are caused by errors or disruptions (mutations) of the UGT1A1 gene.IntroductionCrigler-Najjar syndrome was first recognized in six infants of three couples who were blood relatives (consanguineous). These cases were reported in the medical literature in 1952 by Drs. Crigler and Najjar. In 1962, Dr. Arias reported a milder version of this disorder, which is now termed Crigler-Najjar syndrome type II. | Overview of Crigler Najjar Syndrome. SummaryCrigler-Najjar syndrome is a rare genetic disorder characterized by an inability to properly convert and clear bilirubin from the body. Bilirubin is an orange-yellow bile pigment that is mainly a byproduct of the natural breakdown (degeneration) of old or worn out red blood cells (hemolysis). Normally, bilirubin created in this process is converted from an unconjugated form to a form that can be dissolved in water and excreted from the body (called conjugated bilirubin). Affected individuals cannot convert unconjugated bilirubin to the conjugated form because they lack a specific liver enzyme required to break down (metabolize) bilirubin. Since they cannot convert bilirubin, they develop abnormally high levels of unconjugated bilirubin in the blood (hyperbilirubinemia).The hallmark finding of Crigler-Najjar syndrome is a persistent yellowing of the skin, mucous membranes and whites of the eyes (jaundice). There are two forms of this disorder: Crigler-Najjar syndrome type I, characterized by a nearly complete lack of enzyme activity and severe, even life-threatening symptoms; and Crigler-Najjar syndrome type II, characterized by partial enzyme activity and milder symptoms. Both forms are inherited as autosomal recessive traits and are caused by errors or disruptions (mutations) of the UGT1A1 gene.IntroductionCrigler-Najjar syndrome was first recognized in six infants of three couples who were blood relatives (consanguineous). These cases were reported in the medical literature in 1952 by Drs. Crigler and Najjar. In 1962, Dr. Arias reported a milder version of this disorder, which is now termed Crigler-Najjar syndrome type II. | 334 | Crigler Najjar Syndrome |
nord_334_1 | Symptoms of Crigler Najjar Syndrome | The symptoms of Crigler-Najjar syndrome type I become apparent shortly after birth. Affected infants develop severe, persistent yellowing of the skin, mucous membranes and whites of the eyes (jaundice). These symptoms persist after the first three weeks of life. Infants are at risk for developing kernicterus, also known as bilirubin encephalopathy, within the first month of life. Kernicterus is a potentially life-threatening neurological condition in which toxic levels of bilirubin accumulate in the brain, causing damage to the central nervous system. Early signs of kernicterus may include lack of energy (lethargy), vomiting, fever, and/or unsatisfactory feedings. Other symptoms that may follow include absence of certain reflexes (Moro reflex); mild to severe muscle spasms, including spasms in which the head and heels are bent or arched backward and the body bows forward (opisthotonus); and/or uncontrolled involuntary muscle movements (spasticity). In addition, affected infants may suck or nurse weakly, develop a high-pitched cry, and/or exhibit diminished muscle tone (hypotonia), resulting in abnormal “floppiness.” Kernicterus can result in milder symptoms such as clumsiness, difficulty with fine motor skills and underdevelopment of the enamel of teeth, or it can result in severe complications such as hearing loss, problems with sensory perception, convulsions, and slow, continuous, involuntary, writhing movements (athetosis) of the arms and legs or the entire body. An episode of kernicterus can ultimately result in life-threatening brain damage. Although kernicterus usually develops early during infancy, in some cases, individuals with Crigler-Najjar syndrome type I may not develop kernicterus until later during childhood or in early adulthood. Patients in whom the blood bilirubin concentration is maintained at safe levels by exposure to light (see below under treatment) can develop kernicterus at any age if the light treatment is interrupted or the patient is affected by other illnesses.Crigler-Najjar syndrome type II is a milder disorder than type I. Affected infants develop jaundice, which increases during times when an infant is sick (concurrent illness), has not eaten for an extended period of time (prolonged fasting) or is under general anesthesia. Some people have not been diagnosed until they are adults. Kernicterus is rare in Crigler-Najjar syndrome type II, but can occur especially when an affected individual is sick, not eating or under anesthesia. | Symptoms of Crigler Najjar Syndrome. The symptoms of Crigler-Najjar syndrome type I become apparent shortly after birth. Affected infants develop severe, persistent yellowing of the skin, mucous membranes and whites of the eyes (jaundice). These symptoms persist after the first three weeks of life. Infants are at risk for developing kernicterus, also known as bilirubin encephalopathy, within the first month of life. Kernicterus is a potentially life-threatening neurological condition in which toxic levels of bilirubin accumulate in the brain, causing damage to the central nervous system. Early signs of kernicterus may include lack of energy (lethargy), vomiting, fever, and/or unsatisfactory feedings. Other symptoms that may follow include absence of certain reflexes (Moro reflex); mild to severe muscle spasms, including spasms in which the head and heels are bent or arched backward and the body bows forward (opisthotonus); and/or uncontrolled involuntary muscle movements (spasticity). In addition, affected infants may suck or nurse weakly, develop a high-pitched cry, and/or exhibit diminished muscle tone (hypotonia), resulting in abnormal “floppiness.” Kernicterus can result in milder symptoms such as clumsiness, difficulty with fine motor skills and underdevelopment of the enamel of teeth, or it can result in severe complications such as hearing loss, problems with sensory perception, convulsions, and slow, continuous, involuntary, writhing movements (athetosis) of the arms and legs or the entire body. An episode of kernicterus can ultimately result in life-threatening brain damage. Although kernicterus usually develops early during infancy, in some cases, individuals with Crigler-Najjar syndrome type I may not develop kernicterus until later during childhood or in early adulthood. Patients in whom the blood bilirubin concentration is maintained at safe levels by exposure to light (see below under treatment) can develop kernicterus at any age if the light treatment is interrupted or the patient is affected by other illnesses.Crigler-Najjar syndrome type II is a milder disorder than type I. Affected infants develop jaundice, which increases during times when an infant is sick (concurrent illness), has not eaten for an extended period of time (prolonged fasting) or is under general anesthesia. Some people have not been diagnosed until they are adults. Kernicterus is rare in Crigler-Najjar syndrome type II, but can occur especially when an affected individual is sick, not eating or under anesthesia. | 334 | Crigler Najjar Syndrome |
nord_334_2 | Causes of Crigler Najjar Syndrome | Crigler-Najjar syndrome is caused by an alteration (mutation) in the UGT1A1 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, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.The UGT1A1 gene contains instructions for creating (encoding) a liver enzyme known as uridine disphosphate-glucuronosyltransferase-1 (UGT1A1). This enzyme is required for the conversion (conjugation) and subsequent excretion of bilirubin from the body. Symptoms are caused by a complete or partial absence of this enzyme, which results in the accumulation of unconjugated bilirubin in the body. Bilirubin circulates in the liquid portion of the blood (plasma) in conjunction with a protein called albumin; this is called unconjugated bilirubin, which does not dissolve in water (water-insoluble). Normally, this unconjugated bilirubin is taken up by the liver cells and, with the help of the UGT1A1 enzyme, converted to form water-soluble bilirubin glucuronides (conjugated bilirubin), which are then excreted in the bile. The bile is stored in the gall bladder and, when called upon, passes into the common bile duct and then into the upper portion of the small intestine (duodenum) and aids in digestion. Most bilirubin is eliminated from the body in the feces. When bilirubin levels increase high enough, it can eventually cross the blood-brain barrier, infiltrating brain tissue and causing the neurological symptoms sometimes associated with Crigler-Najjar syndrome. Parents of children with Crigler-Najjar syndrome type I may exhibit some defects in bilirubin metabolism; however, they do not display any physical findings of this disorder because they are have only one copy (heterozygous) of the altered UGT1A1 gene).Crigler-Najjar syndrome is inherited in an autosomal recessive manner. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits 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 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. | Causes of Crigler Najjar Syndrome. Crigler-Najjar syndrome is caused by an alteration (mutation) in the UGT1A1 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, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.The UGT1A1 gene contains instructions for creating (encoding) a liver enzyme known as uridine disphosphate-glucuronosyltransferase-1 (UGT1A1). This enzyme is required for the conversion (conjugation) and subsequent excretion of bilirubin from the body. Symptoms are caused by a complete or partial absence of this enzyme, which results in the accumulation of unconjugated bilirubin in the body. Bilirubin circulates in the liquid portion of the blood (plasma) in conjunction with a protein called albumin; this is called unconjugated bilirubin, which does not dissolve in water (water-insoluble). Normally, this unconjugated bilirubin is taken up by the liver cells and, with the help of the UGT1A1 enzyme, converted to form water-soluble bilirubin glucuronides (conjugated bilirubin), which are then excreted in the bile. The bile is stored in the gall bladder and, when called upon, passes into the common bile duct and then into the upper portion of the small intestine (duodenum) and aids in digestion. Most bilirubin is eliminated from the body in the feces. When bilirubin levels increase high enough, it can eventually cross the blood-brain barrier, infiltrating brain tissue and causing the neurological symptoms sometimes associated with Crigler-Najjar syndrome. Parents of children with Crigler-Najjar syndrome type I may exhibit some defects in bilirubin metabolism; however, they do not display any physical findings of this disorder because they are have only one copy (heterozygous) of the altered UGT1A1 gene).Crigler-Najjar syndrome is inherited in an autosomal recessive manner. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits 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 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. | 334 | Crigler Najjar Syndrome |
nord_334_3 | Affects of Crigler Najjar Syndrome | Crigler-Najjar syndrome affects males and females in equal numbers. The incidence is estimated to be 1 in 750,000-1,000,000 people in the general population. Many researchers believe that the disorder often goes undiagnosed or misdiagnosed making it difficult to determine its true frequency in the general population. It is likely more common than estimated. | Affects of Crigler Najjar Syndrome. Crigler-Najjar syndrome affects males and females in equal numbers. The incidence is estimated to be 1 in 750,000-1,000,000 people in the general population. Many researchers believe that the disorder often goes undiagnosed or misdiagnosed making it difficult to determine its true frequency in the general population. It is likely more common than estimated. | 334 | Crigler Najjar Syndrome |
nord_334_4 | Related disorders of Crigler Najjar Syndrome | Symptoms of the following disorders can be similar to those of Crigler-Najjar syndrome. Comparisons may be useful for a differential diagnosis.Gilbert syndrome is an inherited metabolic disorder characterized by a defect in the clearance of unconjugated bilirubin from the liquid portion of the blood (plasma) by the liver. Symptoms of this disorder (if any) may result from reduced activity of the liver UGT1A1 enzyme. Gilbert syndrome is caused by mutations of the same gene that causes Crigler-Najjar syndrome, but affected individuals maintain about one third of the normal activity of the UGT1A1 enzyme. Most affected individuals have no symptoms (asymptomatic) or may only exhibit mild yellowing of the skin, mucous membranes, and whites of the eyes (jaundice), which may be intermittent. Jaundice may not be apparent until adolescence. Some affected individuals may exhibit a general feeling of discomfort (malaise), sluggishness, and/or abdominal discomfort. Bilirubin levels may increase following stress, exertion, alcohol consumption, fasting, and/or infection. Gilbert syndrome is inherited as an autosomal recessive trait. This disorder is also usually responsive to phenobarbital treatment. (For more information on this disorder, choose “Gilbert” as your search term in the Rare Disease Database.) Rotor syndrome is an extremely rare inherited metabolic disorder characterized by the presence of excessive bilirubin in the blood (hyperbilirubinemia). While most of the conjugated bilirubin produced in the liver cells is excreted in bile, a small fraction goes back to the blood plasma. The conjugated bilirubin is taken up by other liver cells (re-uptake). Rotor syndrome is now thought to be caused by an inherited abnormality simultaneously affecting two genes, SLCO1B1 and SLCO1B3. In most instances, affected individuals exhibit no symptoms of this disorder (asymptomatic). Sometimes persistent yellowing of the skin, mucous membranes, and whites of the eyes (jaundice) is present. Unlike Crigler-Najjar syndrome, affected individuals have high levels of conjugated bilirubin. Rotor syndrome is thought to be inherited as an autosomal recessive trait. Dubin-Johnson syndrome is a rare genetic liver disorder characterized by elevated levels of bilirubin in blood (hyperbilirubinemia). Persistent yellowing of the skin, mucous membranes, and whites of the eyes (jaundice) is usually the only symptom and, in most cases, does not appear before puberty. In rare cases, enlargement of the liver or spleen may occur (hepatomegaly). Like Rotor syndrome, and unlike Crigler-Najjar syndrome, high levels of conjugated bilirubin characterize this disorder. Dubin-Johnson syndrome is inherited as an autosomal recessive disorder, resulting from mutations of the ABCC2 gene. (For more information, choose “Dubin Johnson” as your search term in the Rare Disease Database.)Rh disease (isoimmunization) is a rare disorder in which red blood cells from the fetus are not compatible with those of the mother. In Rh disease, red blood cells from the fetus may cross the placenta and enter into the mother’s bloodstream during pregnancy. This stimulates maternal antibody formation against these “foreign” blood cells. These antibodies eventually reach the fetus via the placenta and cause destruction of fetal red blood cells (hemolysis), resulting in low levels of circulating red blood cells (anemia) in the fetus. In response, the fetal bone marrow releases immature red blood cells (erythroblasts) into the fetal bloodstream. The hemoglobin from the destroyed red blood cells is broken down into bilirubin, a yellow-orange bile pigment. Bilirubin is cleared from the fetal bloodstream by crossing the placenta into the mother’s bloodstream. However, after birth abnormally high levels of bilirubin (hyperbilirubinemia) may accumulate in the newborn’s bloodstream and other areas of the body, potentially causing jaundice and kernicterus. This disease is now almost non-existent due to the availability of anti-Rh globulin, which prevents isoimmunization. (For more information on this disorder, choose “Rh disease” as your search term in the Rare Disease Database.) | Related disorders of Crigler Najjar Syndrome. Symptoms of the following disorders can be similar to those of Crigler-Najjar syndrome. Comparisons may be useful for a differential diagnosis.Gilbert syndrome is an inherited metabolic disorder characterized by a defect in the clearance of unconjugated bilirubin from the liquid portion of the blood (plasma) by the liver. Symptoms of this disorder (if any) may result from reduced activity of the liver UGT1A1 enzyme. Gilbert syndrome is caused by mutations of the same gene that causes Crigler-Najjar syndrome, but affected individuals maintain about one third of the normal activity of the UGT1A1 enzyme. Most affected individuals have no symptoms (asymptomatic) or may only exhibit mild yellowing of the skin, mucous membranes, and whites of the eyes (jaundice), which may be intermittent. Jaundice may not be apparent until adolescence. Some affected individuals may exhibit a general feeling of discomfort (malaise), sluggishness, and/or abdominal discomfort. Bilirubin levels may increase following stress, exertion, alcohol consumption, fasting, and/or infection. Gilbert syndrome is inherited as an autosomal recessive trait. This disorder is also usually responsive to phenobarbital treatment. (For more information on this disorder, choose “Gilbert” as your search term in the Rare Disease Database.) Rotor syndrome is an extremely rare inherited metabolic disorder characterized by the presence of excessive bilirubin in the blood (hyperbilirubinemia). While most of the conjugated bilirubin produced in the liver cells is excreted in bile, a small fraction goes back to the blood plasma. The conjugated bilirubin is taken up by other liver cells (re-uptake). Rotor syndrome is now thought to be caused by an inherited abnormality simultaneously affecting two genes, SLCO1B1 and SLCO1B3. In most instances, affected individuals exhibit no symptoms of this disorder (asymptomatic). Sometimes persistent yellowing of the skin, mucous membranes, and whites of the eyes (jaundice) is present. Unlike Crigler-Najjar syndrome, affected individuals have high levels of conjugated bilirubin. Rotor syndrome is thought to be inherited as an autosomal recessive trait. Dubin-Johnson syndrome is a rare genetic liver disorder characterized by elevated levels of bilirubin in blood (hyperbilirubinemia). Persistent yellowing of the skin, mucous membranes, and whites of the eyes (jaundice) is usually the only symptom and, in most cases, does not appear before puberty. In rare cases, enlargement of the liver or spleen may occur (hepatomegaly). Like Rotor syndrome, and unlike Crigler-Najjar syndrome, high levels of conjugated bilirubin characterize this disorder. Dubin-Johnson syndrome is inherited as an autosomal recessive disorder, resulting from mutations of the ABCC2 gene. (For more information, choose “Dubin Johnson” as your search term in the Rare Disease Database.)Rh disease (isoimmunization) is a rare disorder in which red blood cells from the fetus are not compatible with those of the mother. In Rh disease, red blood cells from the fetus may cross the placenta and enter into the mother’s bloodstream during pregnancy. This stimulates maternal antibody formation against these “foreign” blood cells. These antibodies eventually reach the fetus via the placenta and cause destruction of fetal red blood cells (hemolysis), resulting in low levels of circulating red blood cells (anemia) in the fetus. In response, the fetal bone marrow releases immature red blood cells (erythroblasts) into the fetal bloodstream. The hemoglobin from the destroyed red blood cells is broken down into bilirubin, a yellow-orange bile pigment. Bilirubin is cleared from the fetal bloodstream by crossing the placenta into the mother’s bloodstream. However, after birth abnormally high levels of bilirubin (hyperbilirubinemia) may accumulate in the newborn’s bloodstream and other areas of the body, potentially causing jaundice and kernicterus. This disease is now almost non-existent due to the availability of anti-Rh globulin, which prevents isoimmunization. (For more information on this disorder, choose “Rh disease” as your search term in the Rare Disease Database.) | 334 | Crigler Najjar Syndrome |
nord_334_5 | Diagnosis of Crigler Najjar Syndrome | A diagnosis may be suspected within the first few days of life in infants with persistent jaundice. A diagnosis may be confirmed by a thorough clinical evaluation, characteristic findings, detailed patient history, and specialized testing. For example, in infants with this disorder, blood tests reveal abnormally high levels of unconjugated bilirubin in the absence of increased levels of red blood cell degeneration (hemolysis), as in Rh disease (isoimmunization). In addition, bile analysis reveals no detectable bilirubin glucuronides and urine analysis may demonstrate a lack of bilirubin.Molecular genetic testing can confirm a diagnosis of Crigler-Najjar syndrome. Molecular genetic testing can detect mutations in the UGT1A1 gene that are known to cause the disorder, but is available only as a diagnostic service at specialized laboratories.It is important to distinguish Crigler-Najjar syndrome type I and type II. The administration of phenobarbital, a barbiturate, reduces blood bilirubin levels individuals affected with Crigler-Najjar syndrome type II and Gilbert syndrome, but is ineffective for those with Crigler-Najjar syndrome type I. Therefore, failure to respond to this medication is an important indication for differential diagnostic purposes. | Diagnosis of Crigler Najjar Syndrome. A diagnosis may be suspected within the first few days of life in infants with persistent jaundice. A diagnosis may be confirmed by a thorough clinical evaluation, characteristic findings, detailed patient history, and specialized testing. For example, in infants with this disorder, blood tests reveal abnormally high levels of unconjugated bilirubin in the absence of increased levels of red blood cell degeneration (hemolysis), as in Rh disease (isoimmunization). In addition, bile analysis reveals no detectable bilirubin glucuronides and urine analysis may demonstrate a lack of bilirubin.Molecular genetic testing can confirm a diagnosis of Crigler-Najjar syndrome. Molecular genetic testing can detect mutations in the UGT1A1 gene that are known to cause the disorder, but is available only as a diagnostic service at specialized laboratories.It is important to distinguish Crigler-Najjar syndrome type I and type II. The administration of phenobarbital, a barbiturate, reduces blood bilirubin levels individuals affected with Crigler-Najjar syndrome type II and Gilbert syndrome, but is ineffective for those with Crigler-Najjar syndrome type I. Therefore, failure to respond to this medication is an important indication for differential diagnostic purposes. | 334 | Crigler Najjar Syndrome |
nord_334_6 | Therapies of Crigler Najjar Syndrome | Treatment is directed toward lowering the level of unconjugated bilirubin in the blood. Early treatment is imperative in Crigler-Najjar syndrome type I to prevent the development of kernicterus during the first few months of life. Because Crigler-Najjar syndrome type II is milder and responds to phenobarbital, treatment is different.The mainstay of treatment for Crigler-Najjar syndrome type I is aggressive phototherapy. During this procedure, the bare skin is exposed to intense light, while the eyes are shielded. This helps to change the bilirubin molecules in the skin, so that it can be excreted in bile without conjugation. As affected individuals age, the body mass increases and the skin thickens, making phototherapy less effective for preventing kernicterus. For years, fluorescent light has been used, but has drawbacks including exposing patients to ultraviolet radiation. Some doctors recommend using light-emitting diodes (LEDs) technology, which uses blue light. This technology can be adjusted to the specific treatment level needed in an individual and does not expose people to ultraviolet radiation. However, it is not widely available. Exposure of skin to sun light is very effective in reducing blood bilirubin levels.Infections, episodes of fevers, and other types of illnesses should be treated immediately to reduce the risk of an affected individual developing kernicterus.Plasmapherersis has been used to rapidly lower bilirubin levels in the blood. Plasmapheresis is a method for removing unwanted substances (toxins, metabolic substances and plasma components) from the blood. During plasmapheresis, blood is removed from the affected individual and blood cells are separated from plasma. The plasma is then replaced with other human plasma and the blood is transfused back into the affected individual.Liver transplantation is the only definitive treatment for individuals with Crigler-Najjar syndrome type I. Liver transplantation has drawbacks such as cost, limited availability of a donor, need for prolonged use of immunosuppressive drugs and the potential of rejection. Some physicians recommend a liver transplant if infants or children with severely elevated levels of unconjugated bilirubin do not respond to other therapy (refractory hyperbilirubinemia) or if there is a progression of neurological symptoms. Other physicians believe that liver transplantation should be performed before adolescence as preventive therapy, before brain damage can result from early onset kernicterus.Crigler-Najjar syndrome type II responds to treatment with phenobarbital. In some instances, during an episode of severe hyperbilirubinemia, individuals with Crigler-Najjar syndrome type II may need phototherapy. Some affected individuals may not require any treatment, but should be monitored routinely.Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well. Other treatment is symptomatic and supportive. | Therapies of Crigler Najjar Syndrome. Treatment is directed toward lowering the level of unconjugated bilirubin in the blood. Early treatment is imperative in Crigler-Najjar syndrome type I to prevent the development of kernicterus during the first few months of life. Because Crigler-Najjar syndrome type II is milder and responds to phenobarbital, treatment is different.The mainstay of treatment for Crigler-Najjar syndrome type I is aggressive phototherapy. During this procedure, the bare skin is exposed to intense light, while the eyes are shielded. This helps to change the bilirubin molecules in the skin, so that it can be excreted in bile without conjugation. As affected individuals age, the body mass increases and the skin thickens, making phototherapy less effective for preventing kernicterus. For years, fluorescent light has been used, but has drawbacks including exposing patients to ultraviolet radiation. Some doctors recommend using light-emitting diodes (LEDs) technology, which uses blue light. This technology can be adjusted to the specific treatment level needed in an individual and does not expose people to ultraviolet radiation. However, it is not widely available. Exposure of skin to sun light is very effective in reducing blood bilirubin levels.Infections, episodes of fevers, and other types of illnesses should be treated immediately to reduce the risk of an affected individual developing kernicterus.Plasmapherersis has been used to rapidly lower bilirubin levels in the blood. Plasmapheresis is a method for removing unwanted substances (toxins, metabolic substances and plasma components) from the blood. During plasmapheresis, blood is removed from the affected individual and blood cells are separated from plasma. The plasma is then replaced with other human plasma and the blood is transfused back into the affected individual.Liver transplantation is the only definitive treatment for individuals with Crigler-Najjar syndrome type I. Liver transplantation has drawbacks such as cost, limited availability of a donor, need for prolonged use of immunosuppressive drugs and the potential of rejection. Some physicians recommend a liver transplant if infants or children with severely elevated levels of unconjugated bilirubin do not respond to other therapy (refractory hyperbilirubinemia) or if there is a progression of neurological symptoms. Other physicians believe that liver transplantation should be performed before adolescence as preventive therapy, before brain damage can result from early onset kernicterus.Crigler-Najjar syndrome type II responds to treatment with phenobarbital. In some instances, during an episode of severe hyperbilirubinemia, individuals with Crigler-Najjar syndrome type II may need phototherapy. Some affected individuals may not require any treatment, but should be monitored routinely.Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well. Other treatment is symptomatic and supportive. | 334 | Crigler Najjar Syndrome |
nord_335_0 | Overview of Cronkhite-Canada Syndrome | Cronkhite-Canada syndrome (CCS) is an extremely rare disease characterized by various intestinal polyps, loss of taste, hair loss, and nail growth problems. It is difficult to treat because of malabsorption that accompanies the polyps. CCS occurs primarily in the older population (average age 59) and predominantly occurs in males. It is considered to be an acquired, not hereditary, disease. | Overview of Cronkhite-Canada Syndrome. Cronkhite-Canada syndrome (CCS) is an extremely rare disease characterized by various intestinal polyps, loss of taste, hair loss, and nail growth problems. It is difficult to treat because of malabsorption that accompanies the polyps. CCS occurs primarily in the older population (average age 59) and predominantly occurs in males. It is considered to be an acquired, not hereditary, disease. | 335 | Cronkhite-Canada Syndrome |
nord_335_1 | Symptoms of Cronkhite-Canada Syndrome | The symptoms of Cronkhite-Canada syndrome occur because of multiple polyps occurring in the stomach, small intestine, colon and, less frequently, the esophagus. These include chronic or recurring watery diarrhea, cramps, and abdominal discomfort. These people may also have abnormally low levels of protein in the blood (protein-losing enteropathy), causing a feeling of general ill health (cachexia), malnutrition, nausea and vomiting. The earliest symptoms reported are changes in taste and loss of smell. Patients can even experience a profound loss of appetite, sometimes to the point of malnutrition, weight-loss and/or excess fluid accumulation in the arms and legs (peripheral edema). An imbalance of certain essential minerals (electrolytes) may occur because of chronic diarrhea. Some people with CCS may also have large skin bruises (ecchymotic plaques) and/or impaired lung function. Other symptoms may include loss of hair (alopecia), large areas of dark spots on the skin (hyperpigmentation) and degenerative changes and, eventually, loss of the fingernails (onychodystrophy).Patients with CCS can also have coexisting autoimmune disorders, where the body develops antibodies against an organ, thereby attacking itself, e.g. hypothyroidism, rheumatoid arthritis, scleroderma, systemic lupus erythematous, etc. | Symptoms of Cronkhite-Canada Syndrome. The symptoms of Cronkhite-Canada syndrome occur because of multiple polyps occurring in the stomach, small intestine, colon and, less frequently, the esophagus. These include chronic or recurring watery diarrhea, cramps, and abdominal discomfort. These people may also have abnormally low levels of protein in the blood (protein-losing enteropathy), causing a feeling of general ill health (cachexia), malnutrition, nausea and vomiting. The earliest symptoms reported are changes in taste and loss of smell. Patients can even experience a profound loss of appetite, sometimes to the point of malnutrition, weight-loss and/or excess fluid accumulation in the arms and legs (peripheral edema). An imbalance of certain essential minerals (electrolytes) may occur because of chronic diarrhea. Some people with CCS may also have large skin bruises (ecchymotic plaques) and/or impaired lung function. Other symptoms may include loss of hair (alopecia), large areas of dark spots on the skin (hyperpigmentation) and degenerative changes and, eventually, loss of the fingernails (onychodystrophy).Patients with CCS can also have coexisting autoimmune disorders, where the body develops antibodies against an organ, thereby attacking itself, e.g. hypothyroidism, rheumatoid arthritis, scleroderma, systemic lupus erythematous, etc. | 335 | Cronkhite-Canada Syndrome |
nord_335_2 | Causes of Cronkhite-Canada Syndrome | The exact cause of Cronkhite-Canada syndrome is unknown. It seems to occur for no known reason (sporadically) and is not thought to be hereditary. | Causes of Cronkhite-Canada Syndrome. The exact cause of Cronkhite-Canada syndrome is unknown. It seems to occur for no known reason (sporadically) and is not thought to be hereditary. | 335 | Cronkhite-Canada Syndrome |
nord_335_3 | Affects of Cronkhite-Canada Syndrome | Cronkhite-Canada syndrome is an extremely rare disorder that affects males predominantly. (The ratio seems to be approximately 3 males to 2 females.) Typically, the age of onset is during the middle years or old age. The average is about 59 years with a range of 31 to 86 years. Worldwide, over 500 cases have been reported in the past 50 years, primarily in Japan but also in the United States and other countries. | Affects of Cronkhite-Canada Syndrome. Cronkhite-Canada syndrome is an extremely rare disorder that affects males predominantly. (The ratio seems to be approximately 3 males to 2 females.) Typically, the age of onset is during the middle years or old age. The average is about 59 years with a range of 31 to 86 years. Worldwide, over 500 cases have been reported in the past 50 years, primarily in Japan but also in the United States and other countries. | 335 | Cronkhite-Canada Syndrome |
nord_335_4 | Related disorders of Cronkhite-Canada Syndrome | Symptoms of the following disorders can be similar to those of Cronkhite-Canada syndrome. Comparisons may be useful for a differential diagnosis:Familial adenomatous polyposis (FAP) is a rare inherited cancer predisposition syndrome characterized by hundreds to thousands of precancerous colorectal polyps (adenomatous polyps) appearing on average at age 16 years. If left untreated, affected individuals inevitably develop cancer of the colon and/or rectum at a relatively young age. FAP is inherited in an autosomal dominant manner and caused by abnormalities (mutations) in the APC gene. (For more information on this disorder, choose “FAP” as your search term in the Rare Disease Database.)Peutz-Jeghers syndrome (PJS) is a rare inherited gastrointestinal disorder characterized by the development of polyps on the mucous lining of the intestine and dark discolorations on the skin and mucous membranes. Symptoms include nausea, vomiting, and abdominal pain that occur because of a form of intestinal obstruction. Other symptoms include bleeding from the rectum and dark skin discolorations around the lips, inside the cheeks, and on the arms. Severe rectal bleeding can cause anemia and episodes of recurring, severe abdominal pain. PJS is inherited in an autosomal dominant manner and caused by mutations in the STK11 gene. (For more information on this disorder, choose “Peutz Jeghers” as your search term in the Rare Disease Database.) | Related disorders of Cronkhite-Canada Syndrome. Symptoms of the following disorders can be similar to those of Cronkhite-Canada syndrome. Comparisons may be useful for a differential diagnosis:Familial adenomatous polyposis (FAP) is a rare inherited cancer predisposition syndrome characterized by hundreds to thousands of precancerous colorectal polyps (adenomatous polyps) appearing on average at age 16 years. If left untreated, affected individuals inevitably develop cancer of the colon and/or rectum at a relatively young age. FAP is inherited in an autosomal dominant manner and caused by abnormalities (mutations) in the APC gene. (For more information on this disorder, choose “FAP” as your search term in the Rare Disease Database.)Peutz-Jeghers syndrome (PJS) is a rare inherited gastrointestinal disorder characterized by the development of polyps on the mucous lining of the intestine and dark discolorations on the skin and mucous membranes. Symptoms include nausea, vomiting, and abdominal pain that occur because of a form of intestinal obstruction. Other symptoms include bleeding from the rectum and dark skin discolorations around the lips, inside the cheeks, and on the arms. Severe rectal bleeding can cause anemia and episodes of recurring, severe abdominal pain. PJS is inherited in an autosomal dominant manner and caused by mutations in the STK11 gene. (For more information on this disorder, choose “Peutz Jeghers” as your search term in the Rare Disease Database.) | 335 | Cronkhite-Canada Syndrome |
nord_335_5 | Diagnosis of Cronkhite-Canada Syndrome | The diagnostic criteria for Cronkhite Canada Syndrome is based on symptoms and particular features; however, there is no specific diagnostic test for this syndrome. The mean age of onset is 60, ranging from 31 to 86 years old. There are usually large numbers of polyps in the digestive tract, most often sparing the esophagus. The polyps have hamartomatous features, meaning they contain mucus and are inflamed within an intact surface. Besides the GI tract, findings in the skin are also diagnostic for this disease. Patients experience alopecia (loss of hair), dark spots on the skin of the arms, legs and face (hyperpigmented macules) and have a loss of finger nails (onychodystrophy). One test that can be positive with this syndrome is IgG4 plasma cells but a negative test does not rule out the syndrome. The most important aspects for a diagnosis of Cronkhite Canada Syndrome are the aforementioned physical presentations as there is no particular test to provide a definitive diagnosis of the syndrome. | Diagnosis of Cronkhite-Canada Syndrome. The diagnostic criteria for Cronkhite Canada Syndrome is based on symptoms and particular features; however, there is no specific diagnostic test for this syndrome. The mean age of onset is 60, ranging from 31 to 86 years old. There are usually large numbers of polyps in the digestive tract, most often sparing the esophagus. The polyps have hamartomatous features, meaning they contain mucus and are inflamed within an intact surface. Besides the GI tract, findings in the skin are also diagnostic for this disease. Patients experience alopecia (loss of hair), dark spots on the skin of the arms, legs and face (hyperpigmented macules) and have a loss of finger nails (onychodystrophy). One test that can be positive with this syndrome is IgG4 plasma cells but a negative test does not rule out the syndrome. The most important aspects for a diagnosis of Cronkhite Canada Syndrome are the aforementioned physical presentations as there is no particular test to provide a definitive diagnosis of the syndrome. | 335 | Cronkhite-Canada Syndrome |
nord_335_6 | Therapies of Cronkhite-Canada Syndrome | Treatment
Treatment is based on controlling symptoms and providing support. The primary goal of treatment is to correct fluid, electrolyte and protein loss by nutritional supplementation or a nutritionally balanced liquid diet. Corticosteroids (i.e., prednisone) may be given occasionally to help reduce intestinal inflammation. Bacterial overgrowth in the intestines, which can cause malabsorption, may be treated with antibiotics. In rare cases, symptoms have resolved for no apparent reason (spontaneous remission).
Surgical removal of polyps may help to relieve some of the symptoms of Cronkhite-Canada syndrome. However, they may recur or be too numerous to remove individually. If necessary, severely affected portions of the colon may be removed. Case reports have suggested the use of immunosuppressive treatment, including aziathioprin and ciclosporin, if other treatments are not effective. | Therapies of Cronkhite-Canada Syndrome. Treatment
Treatment is based on controlling symptoms and providing support. The primary goal of treatment is to correct fluid, electrolyte and protein loss by nutritional supplementation or a nutritionally balanced liquid diet. Corticosteroids (i.e., prednisone) may be given occasionally to help reduce intestinal inflammation. Bacterial overgrowth in the intestines, which can cause malabsorption, may be treated with antibiotics. In rare cases, symptoms have resolved for no apparent reason (spontaneous remission).
Surgical removal of polyps may help to relieve some of the symptoms of Cronkhite-Canada syndrome. However, they may recur or be too numerous to remove individually. If necessary, severely affected portions of the colon may be removed. Case reports have suggested the use of immunosuppressive treatment, including aziathioprin and ciclosporin, if other treatments are not effective. | 335 | Cronkhite-Canada Syndrome |
nord_336_0 | Overview of Crouzon Syndrome | SummaryCrouzon syndrome is a rare genetic disorder. It is a form of craniosynostosis, a condition in which there is premature fusion of the fibrous joints (sutures) between certain bones of the skull. The sutures allow an infant’s head to grow and expand. Eventually, these bones fuse together to form the skull. In Crouzon syndrome, the sutures fuse prematurely affecting the proper growth of the skull and head and potentially altering the shape and development of the skull. Certain bones in the face may be affected as well. The severity of craniosynostosis can be different in one infant when compared to another. Symptoms primarily include differences of the face and head. Intelligence is usually not affected. Crouzon syndrome is caused by changes (pathogenic variants or mutations) in one of the FGFR genes, usually FGFR2, and is inherited in an autosomal dominant pattern. | Overview of Crouzon Syndrome. SummaryCrouzon syndrome is a rare genetic disorder. It is a form of craniosynostosis, a condition in which there is premature fusion of the fibrous joints (sutures) between certain bones of the skull. The sutures allow an infant’s head to grow and expand. Eventually, these bones fuse together to form the skull. In Crouzon syndrome, the sutures fuse prematurely affecting the proper growth of the skull and head and potentially altering the shape and development of the skull. Certain bones in the face may be affected as well. The severity of craniosynostosis can be different in one infant when compared to another. Symptoms primarily include differences of the face and head. Intelligence is usually not affected. Crouzon syndrome is caused by changes (pathogenic variants or mutations) in one of the FGFR genes, usually FGFR2, and is inherited in an autosomal dominant pattern. | 336 | Crouzon Syndrome |
nord_336_1 | Symptoms of Crouzon Syndrome | Crouzon syndrome, also known as craniofacial dysostosis, is primarily characterized by premature closure of the fibrous joints (cranial sutures) between certain bones in the skull (craniosynostosis) and distinctive facial features. Cranial and facial malformations may vary, ranging from mild to potentially severe, including among members of the same family (kindred). For example, the degree of cranial malformation is variable and depends on the specific cranial sutures involved as well as the order and rate of progression. In most affected individuals, there is premature fusion of the sutures (i.e., coronal and sagittal sutures) between bones forming the forehead (frontal bone) and the upper sides of the skull (parietal bones). In addition, the suture between the back and the sides of the skull (i.e., lambdoidal suture) or other sutures may be involved in some people. In most individuals with Crouzon syndrome, early sutural fusion causes the head to appear unusually short and broad (brachycephaly). In other patients, the head may appear long and narrow (scaphocephaly) or triangular (trigonocephaly). Rarely, premature closure of multiple sutures (known as Kleeblattschadel type craniosynostosis) causes the skull to be divided into three lobes (cloverleaf skull deformity). In children with Crouzon syndrome, craniosynostosis typically begins during the first year of life and progresses until approximately age two to three. However, craniosynostosis may sometimes be apparent at birth or, more rarely, may not be noted during early childhood.
In most individuals, there is unusual shallowness of the orbits or the bony cavities of the skull that accommodate the eyeballs. As a result, the eyeballs appear to protrude or bulge forward (proptosis). Affected individuals are unusually susceptible to developing inflammation of the front, transparent regions of the eyes (i.e., exposure keratitis) as well as the membranes that line the inner surfaces of the eyelids and cover the whites of the eyes (exposure conjunctivitis). This effect is most apparent before 2 years of life. Crouzon syndrome is also often associated with additional eye characteristics including eyes that are spaced apart wider than usual (hypertelorism) and eyes that are crossed or do not point in the same direction (strabismus), which could be due to the shape of the orbit, or abnormalities in the muscles attached to the eye (anomalous extraocular muscles). There is also a higher incidence of refractive errors than in the general population. In over 1/3 of individuals, the various eye abnormalities can lead to a loss in vision. Crouzon syndrome is associated with additional craniofacial characteristics. Affected individuals often have a prominent forehead (frontal bossing); a curved nose; unusually flat or underdeveloped mid-facial regions (midface hypoplasia); and a short upper lip. In addition, a small, underdeveloped upper jaw (hypoplastic maxilla) with protrusion of the lower jaw (relative mandibular prognathism) may also occur. Clefting of the lip and/or palate (incomplete closure of the palate or an abnormal groove in the upper lip) can occur rarely. Typical dental problems include a highly arched narrow palate with crowded teeth, and upper and lower teeth that don’t meet when biting (malocclusion).
Approximately 30% of individuals with Crouzon syndrome develop hydrocephalus, a condition which is characterized by impaired flow or absorption of the fluid (i.e., cerebrospinal fluid [CSF]) that circulates through cavities (ventricles) of the brain and the spinal canal, potentially leading to increasing fluid pressure within the skull (intracranial pressure) and the brain and other associated findings.Some affected individuals have hearing impairment due to an inability to transmit sound impulses to the brain (sensorineural hearing loss). In some infants, breathing problems may occur during the first few years due to a greatly reduced cross-sectional area of the airway. In severe instances, this can lead to life-threatening breathing complications, requiring creation of a surgical airway (tracheostomy). While extracranial manifestations in Crouzon syndrome are not as common as with other craniosynostosis syndromes, up to 1/3 of individuals can have C2-C3 vertebral fusion. | Symptoms of Crouzon Syndrome. Crouzon syndrome, also known as craniofacial dysostosis, is primarily characterized by premature closure of the fibrous joints (cranial sutures) between certain bones in the skull (craniosynostosis) and distinctive facial features. Cranial and facial malformations may vary, ranging from mild to potentially severe, including among members of the same family (kindred). For example, the degree of cranial malformation is variable and depends on the specific cranial sutures involved as well as the order and rate of progression. In most affected individuals, there is premature fusion of the sutures (i.e., coronal and sagittal sutures) between bones forming the forehead (frontal bone) and the upper sides of the skull (parietal bones). In addition, the suture between the back and the sides of the skull (i.e., lambdoidal suture) or other sutures may be involved in some people. In most individuals with Crouzon syndrome, early sutural fusion causes the head to appear unusually short and broad (brachycephaly). In other patients, the head may appear long and narrow (scaphocephaly) or triangular (trigonocephaly). Rarely, premature closure of multiple sutures (known as Kleeblattschadel type craniosynostosis) causes the skull to be divided into three lobes (cloverleaf skull deformity). In children with Crouzon syndrome, craniosynostosis typically begins during the first year of life and progresses until approximately age two to three. However, craniosynostosis may sometimes be apparent at birth or, more rarely, may not be noted during early childhood.
In most individuals, there is unusual shallowness of the orbits or the bony cavities of the skull that accommodate the eyeballs. As a result, the eyeballs appear to protrude or bulge forward (proptosis). Affected individuals are unusually susceptible to developing inflammation of the front, transparent regions of the eyes (i.e., exposure keratitis) as well as the membranes that line the inner surfaces of the eyelids and cover the whites of the eyes (exposure conjunctivitis). This effect is most apparent before 2 years of life. Crouzon syndrome is also often associated with additional eye characteristics including eyes that are spaced apart wider than usual (hypertelorism) and eyes that are crossed or do not point in the same direction (strabismus), which could be due to the shape of the orbit, or abnormalities in the muscles attached to the eye (anomalous extraocular muscles). There is also a higher incidence of refractive errors than in the general population. In over 1/3 of individuals, the various eye abnormalities can lead to a loss in vision. Crouzon syndrome is associated with additional craniofacial characteristics. Affected individuals often have a prominent forehead (frontal bossing); a curved nose; unusually flat or underdeveloped mid-facial regions (midface hypoplasia); and a short upper lip. In addition, a small, underdeveloped upper jaw (hypoplastic maxilla) with protrusion of the lower jaw (relative mandibular prognathism) may also occur. Clefting of the lip and/or palate (incomplete closure of the palate or an abnormal groove in the upper lip) can occur rarely. Typical dental problems include a highly arched narrow palate with crowded teeth, and upper and lower teeth that don’t meet when biting (malocclusion).
Approximately 30% of individuals with Crouzon syndrome develop hydrocephalus, a condition which is characterized by impaired flow or absorption of the fluid (i.e., cerebrospinal fluid [CSF]) that circulates through cavities (ventricles) of the brain and the spinal canal, potentially leading to increasing fluid pressure within the skull (intracranial pressure) and the brain and other associated findings.Some affected individuals have hearing impairment due to an inability to transmit sound impulses to the brain (sensorineural hearing loss). In some infants, breathing problems may occur during the first few years due to a greatly reduced cross-sectional area of the airway. In severe instances, this can lead to life-threatening breathing complications, requiring creation of a surgical airway (tracheostomy). While extracranial manifestations in Crouzon syndrome are not as common as with other craniosynostosis syndromes, up to 1/3 of individuals can have C2-C3 vertebral fusion. | 336 | Crouzon Syndrome |
nord_336_2 | Causes of Crouzon Syndrome | Crouzon syndrome is caused by changes (pathogenic variants or mutations) in one of the FGFR genes, most commonly FGFR2. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a variant in a gene occurs, the protein product may be faulty, inefficient or absent. Depending upon the functions of the protein, this can affect many organ systems of the body. The variants in the FGFR gene that cause Crouzon syndrome are inherited in an autosomal dominant manner. Dominant genetic disorders occur when only a single copy of a mutated gene is necessary to cause the disease. The mutated gene can be inherited from either parent or can be the result of a changed gene in the affected individual. The risk of passing the mutated gene from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females. . In most individuals, the disorder occurs because of spontaneous (de novo) genetic mutations that occur in the egg or sperm cell. In such situations, the disorder is not inherited from the parents. The FGFR2 gene regulates the production of a protein known as a fibroblast growth factor receptor (FGFR). Variants that disrupt the functioning of such proteins may result in abnormalities of bone growth and development, ultimately leading to certain malformations of the craniofacial area. Evidence indicates that different variants in the FGFR2 gene may cause several other related disorders, including Apert syndrome, isolated coronal synostosis, Beare-Stevenson syndrome, Pfeiffer syndrome and Jackson-Weiss syndrome. In addition, according to some reports, certain FGFR2 variants may result in Crouzon syndrome in some families, whereas the same variants cause Pfeiffer syndrome in other families. The implications of such findings are not completely understood. (For further information on these disorders, please see the “Related Disorders” section of this report below.) | Causes of Crouzon Syndrome. Crouzon syndrome is caused by changes (pathogenic variants or mutations) in one of the FGFR genes, most commonly FGFR2. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a variant in a gene occurs, the protein product may be faulty, inefficient or absent. Depending upon the functions of the protein, this can affect many organ systems of the body. The variants in the FGFR gene that cause Crouzon syndrome are inherited in an autosomal dominant manner. Dominant genetic disorders occur when only a single copy of a mutated gene is necessary to cause the disease. The mutated gene can be inherited from either parent or can be the result of a changed gene in the affected individual. The risk of passing the mutated gene from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females. . In most individuals, the disorder occurs because of spontaneous (de novo) genetic mutations that occur in the egg or sperm cell. In such situations, the disorder is not inherited from the parents. The FGFR2 gene regulates the production of a protein known as a fibroblast growth factor receptor (FGFR). Variants that disrupt the functioning of such proteins may result in abnormalities of bone growth and development, ultimately leading to certain malformations of the craniofacial area. Evidence indicates that different variants in the FGFR2 gene may cause several other related disorders, including Apert syndrome, isolated coronal synostosis, Beare-Stevenson syndrome, Pfeiffer syndrome and Jackson-Weiss syndrome. In addition, according to some reports, certain FGFR2 variants may result in Crouzon syndrome in some families, whereas the same variants cause Pfeiffer syndrome in other families. The implications of such findings are not completely understood. (For further information on these disorders, please see the “Related Disorders” section of this report below.) | 336 | Crouzon Syndrome |
nord_336_3 | Affects of Crouzon Syndrome | Crouzon syndrome affects males and females. Some articles in the medical literature report that males are affected more often than females. Crouzon syndrome is estimated to affect about 1.6 in 100,000 people in the general population. All forms of craniosynostosis are estimated to affect about 1 in 2,000-2,5000 live births. | Affects of Crouzon Syndrome. Crouzon syndrome affects males and females. Some articles in the medical literature report that males are affected more often than females. Crouzon syndrome is estimated to affect about 1.6 in 100,000 people in the general population. All forms of craniosynostosis are estimated to affect about 1 in 2,000-2,5000 live births. | 336 | Crouzon Syndrome |
nord_336_4 | Related disorders of Crouzon Syndrome | Symptoms of the following disorders can be similar to those of Crouzon syndrome. Comparisons may be useful for a differential diagnosis. There are other disorders that are caused by variants in the same or different FGFR genes. When different disorders are caused by different variants in the same gene, they are called allelic disorders. These disorders often share similar characteristics and symptoms. Disorders associated with variants of the FGFR2 gene include Apert syndrome, isolated coronal synostosis, Beare-Stevenson syndrome, Pfeiffer syndrome and Jackson-Weiss syndrome. These disorders are inherited in an autosomal dominant manner. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) Crouzon syndrome with acanthosis nigricans (CAN) is a rare genetic disorder in which the classic symptoms of Crouzon syndrome occur in association with a skin disease (i.e., acanthosis nigricans) that is characterized by “velvety” thickening and increased coloration (hyperpigmentation) of the skin. Such skin abnormalities are apparent by puberty and typically affect skin of the neck, abdomen, chest, breasts, eyelids, and nostrils; under the arms (axillae) and around the mouth. Reports suggest that individuals affected by Crouzon syndrome with acanthosis nigricans often have progressive hydrocephalus and narrowing or blockage of the back of nasal passage (choanal atresia), both of which are unusual in those with Crouzon syndrome alone. Crouzon syndrome with acanthosis nigricans is caused by a specific variant of the FGFR3 gene and is inherited in an autosomal dominant manner. Saethre-Chotzen syndrome, also known as acrocephalosyndactyly type III, is a rare genetic disorder characterized by premature closure of certain cranial sutures (craniosynostosis). In some patients, the cranial sutures may fuse unevenly, causing the head and face to appear dissimilar from one side to the other (craniofacial asymmetry). Additional craniofacial characteristics may include underdevelopment of midfacial regions (midface hypoplasia); widely spaced eyes with unusually shallow orbits; deviation of one eye in relation to the other (strabismus); a thin, pointed nose; and incomplete closure of the roof of the mouth (cleft palate). Affected individuals may also have additional physical characteristics, such as partial fusion of soft tissues (cutaneous syndactyly) of certain digits, particularly the second and third fingers; “finger-like” thumbs; limited extension of the elbows; and/or, in some people, heart (cardiac) defects, kidney (renal) malformations or other findings. Although intelligence is usually normal, mild to moderate intellectual disability has been reported. Saethre-Chotzen syndrome is inherited in an autosomal dominant pattern. (For more information on this disorder, choose “Saethre Chotzen” as your search term in the Rare Disease Database.)Additional congenital disorders may be characterized by various forms of craniosynostosis, additional craniofacial abnormalities, and other symptoms and findings similar to those potentially associated with Crouzon syndrome. These disorders include isolated craniosynostosis, Antley-Bixler syndrome, Baller-Gerold syndrome, Carpenter syndrome and other acrocephalopolysyndactyly disorders. (For more information on these disorders, choose the exact disease name in question as your search term in the Rare Disease Database.) | Related disorders of Crouzon Syndrome. Symptoms of the following disorders can be similar to those of Crouzon syndrome. Comparisons may be useful for a differential diagnosis. There are other disorders that are caused by variants in the same or different FGFR genes. When different disorders are caused by different variants in the same gene, they are called allelic disorders. These disorders often share similar characteristics and symptoms. Disorders associated with variants of the FGFR2 gene include Apert syndrome, isolated coronal synostosis, Beare-Stevenson syndrome, Pfeiffer syndrome and Jackson-Weiss syndrome. These disorders are inherited in an autosomal dominant manner. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) Crouzon syndrome with acanthosis nigricans (CAN) is a rare genetic disorder in which the classic symptoms of Crouzon syndrome occur in association with a skin disease (i.e., acanthosis nigricans) that is characterized by “velvety” thickening and increased coloration (hyperpigmentation) of the skin. Such skin abnormalities are apparent by puberty and typically affect skin of the neck, abdomen, chest, breasts, eyelids, and nostrils; under the arms (axillae) and around the mouth. Reports suggest that individuals affected by Crouzon syndrome with acanthosis nigricans often have progressive hydrocephalus and narrowing or blockage of the back of nasal passage (choanal atresia), both of which are unusual in those with Crouzon syndrome alone. Crouzon syndrome with acanthosis nigricans is caused by a specific variant of the FGFR3 gene and is inherited in an autosomal dominant manner. Saethre-Chotzen syndrome, also known as acrocephalosyndactyly type III, is a rare genetic disorder characterized by premature closure of certain cranial sutures (craniosynostosis). In some patients, the cranial sutures may fuse unevenly, causing the head and face to appear dissimilar from one side to the other (craniofacial asymmetry). Additional craniofacial characteristics may include underdevelopment of midfacial regions (midface hypoplasia); widely spaced eyes with unusually shallow orbits; deviation of one eye in relation to the other (strabismus); a thin, pointed nose; and incomplete closure of the roof of the mouth (cleft palate). Affected individuals may also have additional physical characteristics, such as partial fusion of soft tissues (cutaneous syndactyly) of certain digits, particularly the second and third fingers; “finger-like” thumbs; limited extension of the elbows; and/or, in some people, heart (cardiac) defects, kidney (renal) malformations or other findings. Although intelligence is usually normal, mild to moderate intellectual disability has been reported. Saethre-Chotzen syndrome is inherited in an autosomal dominant pattern. (For more information on this disorder, choose “Saethre Chotzen” as your search term in the Rare Disease Database.)Additional congenital disorders may be characterized by various forms of craniosynostosis, additional craniofacial abnormalities, and other symptoms and findings similar to those potentially associated with Crouzon syndrome. These disorders include isolated craniosynostosis, Antley-Bixler syndrome, Baller-Gerold syndrome, Carpenter syndrome and other acrocephalopolysyndactyly disorders. (For more information on these disorders, choose the exact disease name in question as your search term in the Rare Disease Database.) | 336 | Crouzon Syndrome |
nord_336_5 | Diagnosis of Crouzon Syndrome | Crouzon syndrome is usually diagnosed at birth or during infancy based upon a thorough clinical evaluation, identification of characteristic physical findings and a variety of specialized tests. Such testing may include advanced imaging techniques, such as computerized tomography (CT) scanning or magnetic resonance imaging (MRI) or other imaging studies. Clinical Testing and Workup
CT scanning and MRIs are used to help detect or characterize certain abnormalities that may be associated with the disorder (e.g., craniosynostosis, other skeletal abnormalities, etc.). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of internal structures. During MRI, a magnetic field and radio waves create detailed cross-sectional images of certain organs and tissues. Molecular genetic testing can confirm a diagnosis of Crouzon syndrome in some people. Molecular genetic testing can detect variants in the FGFR2 gene known to cause the disorder but is available only as a diagnostic service at specialized laboratories. | Diagnosis of Crouzon Syndrome. Crouzon syndrome is usually diagnosed at birth or during infancy based upon a thorough clinical evaluation, identification of characteristic physical findings and a variety of specialized tests. Such testing may include advanced imaging techniques, such as computerized tomography (CT) scanning or magnetic resonance imaging (MRI) or other imaging studies. Clinical Testing and Workup
CT scanning and MRIs are used to help detect or characterize certain abnormalities that may be associated with the disorder (e.g., craniosynostosis, other skeletal abnormalities, etc.). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of internal structures. During MRI, a magnetic field and radio waves create detailed cross-sectional images of certain organs and tissues. Molecular genetic testing can confirm a diagnosis of Crouzon syndrome in some people. Molecular genetic testing can detect variants in the FGFR2 gene known to cause the disorder but is available only as a diagnostic service at specialized laboratories. | 336 | Crouzon Syndrome |
nord_336_6 | Therapies of Crouzon Syndrome | Treatment
The treatment of Crouzon syndrome is directed toward the specific symptoms that are apparent in each individual. Surgery is the main form of therapy for affected children, but not all children will require surgery. Surgery is performed to create and ensure that there is enough room within the skull for the developing brain to grow; to relieve intracranial pressure (if present); and to improve the appearance of an affected child’s head. If determined necessary, these surgeries may begin during infancy, with the last of them taking place during teenage years. Affected children should be seen at craniofacial clinics, which are often affiliated with major pediatric hospitals or medical centers. These clinics have a team of physicians and other healthcare providers who are experienced in treating craniofacial disorders. A team of specialists will work together to plan and carry out a child’s treatments. Such specialists include pediatricians, neurosurgeons, plastic surgeons, otolaryngologists, medical geneticists, audiologists, ophthalmologists, dental specialists, social workers and other healthcare professionals. Genetic evaluation is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well. | Therapies of Crouzon Syndrome. Treatment
The treatment of Crouzon syndrome is directed toward the specific symptoms that are apparent in each individual. Surgery is the main form of therapy for affected children, but not all children will require surgery. Surgery is performed to create and ensure that there is enough room within the skull for the developing brain to grow; to relieve intracranial pressure (if present); and to improve the appearance of an affected child’s head. If determined necessary, these surgeries may begin during infancy, with the last of them taking place during teenage years. Affected children should be seen at craniofacial clinics, which are often affiliated with major pediatric hospitals or medical centers. These clinics have a team of physicians and other healthcare providers who are experienced in treating craniofacial disorders. A team of specialists will work together to plan and carry out a child’s treatments. Such specialists include pediatricians, neurosurgeons, plastic surgeons, otolaryngologists, medical geneticists, audiologists, ophthalmologists, dental specialists, social workers and other healthcare professionals. Genetic evaluation is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well. | 336 | Crouzon Syndrome |
nord_337_0 | Overview of Cryptococcosis | Cryptococcosis is caused by a fungus known as Cryptococcosis neoformans. The infection may be spread to humans through contact with pigeon droppings or unwashed raw fruit. Contact with an infected individual may also spread the infection. Individuals with disorders characterized by lowered immunity (for instance, HIV infection) are at high risk for contracting these infections.Cryptococcosis may appear in various forms depending on how the infection is acquired. In most cases, the infection begins in the lungs (pulmonary form) and may then spread to the brain, urinary tract, skin, and/or bones (disseminated form). When the infection is limited to the lungs, symptoms may be minimal or not apparent at all. Respiratory symptoms may include coughing and chest pain. When the infection spreads, it tends to seek out the central nervous system, especially the brain. In some affected individuals, inflammation of the membranes surrounding the brain and spinal cord (meningitis) may occur as a serious complication. Symptoms associated with meningitis may include dizziness, blurred vision, severe headache, and/or stiffness of the neck. In such cases, immediate treatment is essential to help prevent potentially life-threatening complications. | Overview of Cryptococcosis. Cryptococcosis is caused by a fungus known as Cryptococcosis neoformans. The infection may be spread to humans through contact with pigeon droppings or unwashed raw fruit. Contact with an infected individual may also spread the infection. Individuals with disorders characterized by lowered immunity (for instance, HIV infection) are at high risk for contracting these infections.Cryptococcosis may appear in various forms depending on how the infection is acquired. In most cases, the infection begins in the lungs (pulmonary form) and may then spread to the brain, urinary tract, skin, and/or bones (disseminated form). When the infection is limited to the lungs, symptoms may be minimal or not apparent at all. Respiratory symptoms may include coughing and chest pain. When the infection spreads, it tends to seek out the central nervous system, especially the brain. In some affected individuals, inflammation of the membranes surrounding the brain and spinal cord (meningitis) may occur as a serious complication. Symptoms associated with meningitis may include dizziness, blurred vision, severe headache, and/or stiffness of the neck. In such cases, immediate treatment is essential to help prevent potentially life-threatening complications. | 337 | Cryptococcosis |
nord_337_1 | Symptoms of Cryptococcosis | The pulmonary forms of this disease include acute infections and chronic pulmonary infections. The disseminated forms include central nervous system (brain) infections, cutaneous (skin) infections, and infections involving other organs or systems.Pulmonary forms.Acute infections are only rarely diagnosed except in patients with weakened immune systems. In people with normal immune systems, cryptoccosis may not result in any symptoms at all (asymptomatic). Chronic pulmonary infections may generate rather large masses in the lobes of the lungs, as well as segmental pneumonia (involving parts of lungs), fluid in the lungs (pleural effusions), and swollen lymph nodes.Disseminated formsCentral nervous system infections, especially of the brain, may present as only modestly severe rather than acute. Complications may include an abnormally large head (hydrocephalus) and failing sight, among others.Cutaneous or skin infections may present as fluid-filled bumps (papules), hardened plate-like patches (plaques), and ulcerous sores.Infections of other organs or systems may involve sight (chorioretinitis), ears (otitis), the heart (myocarditis, endocarditis), the digestive system (gastroduodenitis, hepatitis), and the kidneys.In general, symptoms of various forms of cryptococcosis may include: chest pain, dry cough, headache, nausea, confusion, blurred or double vision, fatigue, fever, unusual and excessive sweating at night, swollen glands without the appearance of infection in nearby areas, skin rash, pinpoint red spots (petechiae), bleeding into the skin, bruises, unintentional weight loss, appetite loss, abdominal bloating, abdominal pain, abdominal swelling, weakness, bone pain, and numbness and/or tingling. | Symptoms of Cryptococcosis. The pulmonary forms of this disease include acute infections and chronic pulmonary infections. The disseminated forms include central nervous system (brain) infections, cutaneous (skin) infections, and infections involving other organs or systems.Pulmonary forms.Acute infections are only rarely diagnosed except in patients with weakened immune systems. In people with normal immune systems, cryptoccosis may not result in any symptoms at all (asymptomatic). Chronic pulmonary infections may generate rather large masses in the lobes of the lungs, as well as segmental pneumonia (involving parts of lungs), fluid in the lungs (pleural effusions), and swollen lymph nodes.Disseminated formsCentral nervous system infections, especially of the brain, may present as only modestly severe rather than acute. Complications may include an abnormally large head (hydrocephalus) and failing sight, among others.Cutaneous or skin infections may present as fluid-filled bumps (papules), hardened plate-like patches (plaques), and ulcerous sores.Infections of other organs or systems may involve sight (chorioretinitis), ears (otitis), the heart (myocarditis, endocarditis), the digestive system (gastroduodenitis, hepatitis), and the kidneys.In general, symptoms of various forms of cryptococcosis may include: chest pain, dry cough, headache, nausea, confusion, blurred or double vision, fatigue, fever, unusual and excessive sweating at night, swollen glands without the appearance of infection in nearby areas, skin rash, pinpoint red spots (petechiae), bleeding into the skin, bruises, unintentional weight loss, appetite loss, abdominal bloating, abdominal pain, abdominal swelling, weakness, bone pain, and numbness and/or tingling. | 337 | Cryptococcosis |
nord_337_2 | Causes of Cryptococcosis | Cryptococcosis is caused by the fungus Cyptococcus neoformans. It is spread by contact with pigeon droppings, unwashed raw fruit or by infected individuals. People with immune deficiencies or lowered immunity (such as people undergoing cancer chemotherapy or organ transplants or those infected with HIV-AIDS) are at high risk for contracting this fungal infection. | Causes of Cryptococcosis. Cryptococcosis is caused by the fungus Cyptococcus neoformans. It is spread by contact with pigeon droppings, unwashed raw fruit or by infected individuals. People with immune deficiencies or lowered immunity (such as people undergoing cancer chemotherapy or organ transplants or those infected with HIV-AIDS) are at high risk for contracting this fungal infection. | 337 | Cryptococcosis |
nord_337_3 | Affects of Cryptococcosis | Cryptococcosis occurs worldwide. In the United States it occurs predominately in the Southeastern states and usually in adults aged forty to sixty years of age. It tends to occur more often in males than females. Individuals with disorders involving reduced or impaired immunity to infection are particularly at risk. | Affects of Cryptococcosis. Cryptococcosis occurs worldwide. In the United States it occurs predominately in the Southeastern states and usually in adults aged forty to sixty years of age. It tends to occur more often in males than females. Individuals with disorders involving reduced or impaired immunity to infection are particularly at risk. | 337 | Cryptococcosis |
nord_337_4 | Related disorders of Cryptococcosis | Meningitis is a possible complication of cryptococcosis. Meningitis is an inflammation of the membranes surrounding the brain and spinal cord. There are many types of Meningitis, caused by many different infectious agents with the severity of infection ranging from mild to severe.Toxoplasmosis is an infectious disease that can be caused by contact with a microscopic parasitic organism called Toxoplasma gondii. This parasitic infection, found worldwide, can be either acquired or present at birth. The congenital type is a result of a maternal infection during pregnancy which is transmitted to the fetus, and involves lesions of the central nervous system. These lesions may lead to blindness and brain dysfunction. The disorder may be most severe when it is transmitted to the fetus during the second through the sixth month of pregnancy. Only 20% to 80% of those affected will show the presence of toxoplasmosis antibodies when tested. (For more information on this disorder, choose “Toxoplasmosis” as your search term in the Rare Disease Database.) | Related disorders of Cryptococcosis. Meningitis is a possible complication of cryptococcosis. Meningitis is an inflammation of the membranes surrounding the brain and spinal cord. There are many types of Meningitis, caused by many different infectious agents with the severity of infection ranging from mild to severe.Toxoplasmosis is an infectious disease that can be caused by contact with a microscopic parasitic organism called Toxoplasma gondii. This parasitic infection, found worldwide, can be either acquired or present at birth. The congenital type is a result of a maternal infection during pregnancy which is transmitted to the fetus, and involves lesions of the central nervous system. These lesions may lead to blindness and brain dysfunction. The disorder may be most severe when it is transmitted to the fetus during the second through the sixth month of pregnancy. Only 20% to 80% of those affected will show the presence of toxoplasmosis antibodies when tested. (For more information on this disorder, choose “Toxoplasmosis” as your search term in the Rare Disease Database.) | 337 | Cryptococcosis |
nord_337_5 | Diagnosis of Cryptococcosis | The diagnosis depends on proof of the presence of Cyptococcus neoformans in either a bodily fluid or body tissue. The presence of the fungus may be seen under a light microscope in some circumstances; other circumstances require growing the organism from samples of fluid taken from a patient. An immunological test designed to detect the substance that would be mobilized in the body to fight this fungus if it were present (antigen) is available in commercial kits. | Diagnosis of Cryptococcosis. The diagnosis depends on proof of the presence of Cyptococcus neoformans in either a bodily fluid or body tissue. The presence of the fungus may be seen under a light microscope in some circumstances; other circumstances require growing the organism from samples of fluid taken from a patient. An immunological test designed to detect the substance that would be mobilized in the body to fight this fungus if it were present (antigen) is available in commercial kits. | 337 | Cryptococcosis |
nord_337_6 | Therapies of Cryptococcosis | TreatmentAmong the antibiotics used to treat cryptococcosis are the anti-fungal agents Amphotericin B, Flucytosine, and Fluconazole. These drugs may have serious side effects, so it is important for their use to be monitored carefully. Individuals with compromised immune systems, or under immune suppressive therapy, should be given prolonged drug treatment to prevent relapses. | Therapies of Cryptococcosis. TreatmentAmong the antibiotics used to treat cryptococcosis are the anti-fungal agents Amphotericin B, Flucytosine, and Fluconazole. These drugs may have serious side effects, so it is important for their use to be monitored carefully. Individuals with compromised immune systems, or under immune suppressive therapy, should be given prolonged drug treatment to prevent relapses. | 337 | Cryptococcosis |
nord_338_0 | Overview of CTNNB1 Syndrome | SummaryCTNNB1 syndrome is an extremely rare genetic neurodevelopmental disorder caused by changes (pathogenic variants or mutations) in the CTNNB1 gene. Neurodevelopmental disorders are ones that impair or alter the growth and development of the brain and the central nervous system. Common signs and symptoms include varying degrees of intellectual disability (cognitive impairment), delays in reaching developmental milestones (developmental delays), speech delays, abnormal muscle tone, vision impairments, distinct facial features and behavioral problems. Less common features include feeding difficulties, abnormalities of body structure or function and growth abnormalities. | Overview of CTNNB1 Syndrome. SummaryCTNNB1 syndrome is an extremely rare genetic neurodevelopmental disorder caused by changes (pathogenic variants or mutations) in the CTNNB1 gene. Neurodevelopmental disorders are ones that impair or alter the growth and development of the brain and the central nervous system. Common signs and symptoms include varying degrees of intellectual disability (cognitive impairment), delays in reaching developmental milestones (developmental delays), speech delays, abnormal muscle tone, vision impairments, distinct facial features and behavioral problems. Less common features include feeding difficulties, abnormalities of body structure or function and growth abnormalities. | 338 | CTNNB1 Syndrome |
nord_338_1 | Symptoms of CTNNB1 Syndrome | CTNNB1 syndrome is a collection of signs and symptoms that can vary between affected individuals. It is important to note that every individual is unique and how the disorder affects one person can be different from how it affects another.Neurologic features are present in most individuals affected by CTNNB1 syndrome. A child's progression through predictable developmental phases like sitting up and crawling may be delayed (developmental delays). Global developmental delays can affect intellectual development ranging from mild to severe and motor functions including muscle coordination to complete tasks like writing and walking. Speech delays and language disorders are common, but the degree of difficulty can range from speaking in simple sentences to communicating through signs, vocalization or manipulating objects.Many individuals affected by CTNNB1 syndrome have altered muscle tone. Most babies have low muscle tone (hypotonia) in the torso which can affect motor developmental milestones and feeding ability. Later in childhood, most children experience abnormally high muscle tone (hypertonia) in the arms and legs, which causes prolonged muscle contractions and muscle tightness (spasticity) and can lead to difficulties with speech and movement like walking and stability. Many individuals experience involuntary contractions of the muscles (dystonia) that can cause abnormal body positions and repetitive or twisting movements.Most people with CTNNB1 syndrome have vision difficulties. Some individuals have a problem seeing clearly (refractive errors) which can cause blurriness of objects that are up-close (farsighted) or at a distance (nearsighted). Focusing difficulties may occur from misalignment of the eyes where one eye aligns inward toward the nose or outward away from the nose while the other eye remains focused (strabismus). The back of the eye contains a nerve and blood vessel-rich lining (retina) which transmits visual images to the brain and makes it possible to see. Some individuals affected by CTNNB1 syndrome have a rare eye condition characterized by abnormal growth and development of the blood vessels in the retina (exudative vitreoretinopathy) which can lead to vision loss and more rarely, blindness. Rarely, the retina can detach from the back of the eye which can lead to blindness.A variety of facial abnormalities are common in individuals affected by CTNNB1 syndrome including a bulbous nose, a longer than usual vertical indentation that extends from the upper lip to the nose (philtrum) and a thin upper lip. Some individuals have sparse and thin hair and eyebrows and long eyelashes. Less common facial features include low set ears and eyes that are spaced closer than usual and a high roof of the mouth (palate).Some individuals affected by CTNNB1 syndrome experience behavioral or psychiatric issues that can include anxiety, aggressive behavior, sleep difficulties, temper tantrums, attention problems and features suggestive of autism spectrum disorder.Some individuals, especially babies, have feeding and gastrointestinal difficulties. Feeding challenges can include difficulty coordinating motor functions to breastfeed, chew food or swallow (dysphagia). Additionally, abnormal gastrointestinal motor functions can lead to frequent constipation, diarrhea and backflow of the contents of the stomach into the esophagus (gastroesophageal reflux).Structural and growth abnormalities can occur in individuals affected by CTNNB1 syndrome. Infants may be born with a birth weight that is lower than expected based on sex (intrauterine growth restriction) and some children will continue to have difficulties gaining weight and growing in height. Infants may also be born with a head circumference that is smaller than expected based on age and sex (microcephaly) and may continue to have a smaller head compared to peers of the same age and sex as they grow. Occasionally, brain anomalies that can further contribute to developmental delays may occur including underdevelopment of the area of brain which connects the two cerebral hemispheres (hypoplasia of the corpus callosum) and an abnormal fluid space in the brain (ventriculomegaly). Rarely, as some children grow up, spinal anomalies that further affect motor functions can occur including abnormal restrictions on spinal cord movements (tethered spinal cord), abnormal growth of a fluid-filled pockets (cysts) in the spinal cord (syringomyelia) and an abnormal curvature of the spinal cord. A minority of children may be born with heart anomalies but may not experience any symptoms. | Symptoms of CTNNB1 Syndrome. CTNNB1 syndrome is a collection of signs and symptoms that can vary between affected individuals. It is important to note that every individual is unique and how the disorder affects one person can be different from how it affects another.Neurologic features are present in most individuals affected by CTNNB1 syndrome. A child's progression through predictable developmental phases like sitting up and crawling may be delayed (developmental delays). Global developmental delays can affect intellectual development ranging from mild to severe and motor functions including muscle coordination to complete tasks like writing and walking. Speech delays and language disorders are common, but the degree of difficulty can range from speaking in simple sentences to communicating through signs, vocalization or manipulating objects.Many individuals affected by CTNNB1 syndrome have altered muscle tone. Most babies have low muscle tone (hypotonia) in the torso which can affect motor developmental milestones and feeding ability. Later in childhood, most children experience abnormally high muscle tone (hypertonia) in the arms and legs, which causes prolonged muscle contractions and muscle tightness (spasticity) and can lead to difficulties with speech and movement like walking and stability. Many individuals experience involuntary contractions of the muscles (dystonia) that can cause abnormal body positions and repetitive or twisting movements.Most people with CTNNB1 syndrome have vision difficulties. Some individuals have a problem seeing clearly (refractive errors) which can cause blurriness of objects that are up-close (farsighted) or at a distance (nearsighted). Focusing difficulties may occur from misalignment of the eyes where one eye aligns inward toward the nose or outward away from the nose while the other eye remains focused (strabismus). The back of the eye contains a nerve and blood vessel-rich lining (retina) which transmits visual images to the brain and makes it possible to see. Some individuals affected by CTNNB1 syndrome have a rare eye condition characterized by abnormal growth and development of the blood vessels in the retina (exudative vitreoretinopathy) which can lead to vision loss and more rarely, blindness. Rarely, the retina can detach from the back of the eye which can lead to blindness.A variety of facial abnormalities are common in individuals affected by CTNNB1 syndrome including a bulbous nose, a longer than usual vertical indentation that extends from the upper lip to the nose (philtrum) and a thin upper lip. Some individuals have sparse and thin hair and eyebrows and long eyelashes. Less common facial features include low set ears and eyes that are spaced closer than usual and a high roof of the mouth (palate).Some individuals affected by CTNNB1 syndrome experience behavioral or psychiatric issues that can include anxiety, aggressive behavior, sleep difficulties, temper tantrums, attention problems and features suggestive of autism spectrum disorder.Some individuals, especially babies, have feeding and gastrointestinal difficulties. Feeding challenges can include difficulty coordinating motor functions to breastfeed, chew food or swallow (dysphagia). Additionally, abnormal gastrointestinal motor functions can lead to frequent constipation, diarrhea and backflow of the contents of the stomach into the esophagus (gastroesophageal reflux).Structural and growth abnormalities can occur in individuals affected by CTNNB1 syndrome. Infants may be born with a birth weight that is lower than expected based on sex (intrauterine growth restriction) and some children will continue to have difficulties gaining weight and growing in height. Infants may also be born with a head circumference that is smaller than expected based on age and sex (microcephaly) and may continue to have a smaller head compared to peers of the same age and sex as they grow. Occasionally, brain anomalies that can further contribute to developmental delays may occur including underdevelopment of the area of brain which connects the two cerebral hemispheres (hypoplasia of the corpus callosum) and an abnormal fluid space in the brain (ventriculomegaly). Rarely, as some children grow up, spinal anomalies that further affect motor functions can occur including abnormal restrictions on spinal cord movements (tethered spinal cord), abnormal growth of a fluid-filled pockets (cysts) in the spinal cord (syringomyelia) and an abnormal curvature of the spinal cord. A minority of children may be born with heart anomalies but may not experience any symptoms. | 338 | CTNNB1 Syndrome |
nord_338_2 | Causes of CTNNB1 Syndrome | CTNNB1 syndrome is caused by changes (pathogenic variants or mutations) in the CTNNB1 gene. Genes provide instructions for creating (encoding) proteins that play a critical role in many functions of the body. When a variation in a gene occurs, the protein that is created may be faulty, inefficient, absent or overproduced. Depending upon the functions of the protein, this can affect many parts of the body.Researchers are trying to understand if specific types of variants in the CTNNB1 gene may affect the specific clinical features that an individual experiences. This is called genotype-phenotype correlation and is currently being studied.The CTNNB1 gene contains instructions for creating a protein called beta-catenin (β-catenin). Beta-catenin is found in cells throughout the body and plays an essential role in growth and development, especially in the brain. It helps strengthen connections between nerve cells (neurons) which allows for proper brain function, and it helps coordinate when other genes are read (expressed) which ensures the right proteins are produced at the right time for the body to develop properly. Individuals with CTNNB1 syndrome have a variant of the CTNNB1 gene which prevents the normal beta-catenin protein from being produced and consequently, can lead to a range of neurodevelopmental and health issues.Variants in the CTNNB1 gene almost always occur as new (sporadic or de novo) mutations, which means they occurred randomly in that child without either parent having the gene variant. Since the disorder is usually not inherited from a parent, it's estimated there is only a 1% risk of the gene variant reoccurring in another child from the same parents. When it does recur, it’s because one of the parents has some cells in their body (egg or sperm cells) that have the gene variant although the variant was not detected in the genetic test on blood or saliva.If a person with a CTNNB1 syndrome were to have a child, they have a 50% chance to pass the CTNNB1 gene variant to each of their children, since the gene is inherited in an autosomal dominant pattern. Dominant genetic disorders occur when only a single copy of a mutated gene is necessary to cause the disease. | Causes of CTNNB1 Syndrome. CTNNB1 syndrome is caused by changes (pathogenic variants or mutations) in the CTNNB1 gene. Genes provide instructions for creating (encoding) proteins that play a critical role in many functions of the body. When a variation in a gene occurs, the protein that is created may be faulty, inefficient, absent or overproduced. Depending upon the functions of the protein, this can affect many parts of the body.Researchers are trying to understand if specific types of variants in the CTNNB1 gene may affect the specific clinical features that an individual experiences. This is called genotype-phenotype correlation and is currently being studied.The CTNNB1 gene contains instructions for creating a protein called beta-catenin (β-catenin). Beta-catenin is found in cells throughout the body and plays an essential role in growth and development, especially in the brain. It helps strengthen connections between nerve cells (neurons) which allows for proper brain function, and it helps coordinate when other genes are read (expressed) which ensures the right proteins are produced at the right time for the body to develop properly. Individuals with CTNNB1 syndrome have a variant of the CTNNB1 gene which prevents the normal beta-catenin protein from being produced and consequently, can lead to a range of neurodevelopmental and health issues.Variants in the CTNNB1 gene almost always occur as new (sporadic or de novo) mutations, which means they occurred randomly in that child without either parent having the gene variant. Since the disorder is usually not inherited from a parent, it's estimated there is only a 1% risk of the gene variant reoccurring in another child from the same parents. When it does recur, it’s because one of the parents has some cells in their body (egg or sperm cells) that have the gene variant although the variant was not detected in the genetic test on blood or saliva.If a person with a CTNNB1 syndrome were to have a child, they have a 50% chance to pass the CTNNB1 gene variant to each of their children, since the gene is inherited in an autosomal dominant pattern. Dominant genetic disorders occur when only a single copy of a mutated gene is necessary to cause the disease. | 338 | CTNNB1 Syndrome |
nord_338_3 | Affects of CTNNB1 Syndrome | CTNNB1 syndrome is believed to affect females and males in equal numbers. The exact number of people who have this disorder is unknown. According to CTNNB1 Connect & Cure, as of March 2023, there are 300 individuals around the world known to have CTNNB1 syndrome. Rare disorders like CTNNB1 syndrome often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. As molecular genetic testing becomes more widely used, it is estimated that approximately 3 individuals in every 100,000 births may be affected by CTNNB1 syndrome. | Affects of CTNNB1 Syndrome. CTNNB1 syndrome is believed to affect females and males in equal numbers. The exact number of people who have this disorder is unknown. According to CTNNB1 Connect & Cure, as of March 2023, there are 300 individuals around the world known to have CTNNB1 syndrome. Rare disorders like CTNNB1 syndrome often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. As molecular genetic testing becomes more widely used, it is estimated that approximately 3 individuals in every 100,000 births may be affected by CTNNB1 syndrome. | 338 | CTNNB1 Syndrome |
nord_338_4 | Related disorders of CTNNB1 Syndrome | Clinical features of the following disorders can be similar to those of CTNNB1 syndrome. Comparisons may be useful for a differential diagnosis.Hereditary spastic paraplegias (HSP) are a large group of inherited neurologic disorders that share motor and movement clinical features, like difficulty walking due to muscle tightness (spasticity) in the legs. There are more than 80 different genetic types of HSP that can have large overlaps in clinical features with CTNNB1 syndrome and a differential diagnosis may not always be possible. In some patients, a detailed family history, molecular genetic testing or extensive clinical testing may help differentiate these disorders from CTNNB1 syndrome. (For more information on this disorder, choose “Hereditary Spastic Paraplegia” as your search term in the Rare Disease Database.)Several intellectual disability disorders can have large overlaps in clinical features with CTNNB1 syndrome. In some patients, a detailed family history, molecular genetic testing or extensive clinical testing may help differentiate these disorders from CTNNB1 syndrome.KIF1A-related disorders are a group of neurological disorders with a wide spectrum of clinical features ranging from mild to life threatening. Features they can share with CTNNB1 syndrome include intellectual disability, developmental delay, hypotonia and hypertonia. In some patients, a detailed family history, molecular genetic testing or extensive clinical testing may help differentiate these disorders from CTNNB1 syndrome. (For more information on this disorder, choose “KIF1A-Related Disorders” as your search term in the Rare Disease Database.)Cerebral palsy is a group of conditions commonly associated with a lack of oxygen to the brain during labor or delivery. Features that some patients can share with CTNNB1 syndrome include low muscle tone (hypotonia) in the torso, abnormally high muscle tone (hyptertonia) in the arms and legs and prolonged muscle contractions and muscle tightness (spasticity) which can lead to difficulties with speech and movement like walking. In some people, clinical features are nearly indistinguishable from CTNNB1 syndrome and molecular genetic testing is required to differentiate between the disorders. | Related disorders of CTNNB1 Syndrome. Clinical features of the following disorders can be similar to those of CTNNB1 syndrome. Comparisons may be useful for a differential diagnosis.Hereditary spastic paraplegias (HSP) are a large group of inherited neurologic disorders that share motor and movement clinical features, like difficulty walking due to muscle tightness (spasticity) in the legs. There are more than 80 different genetic types of HSP that can have large overlaps in clinical features with CTNNB1 syndrome and a differential diagnosis may not always be possible. In some patients, a detailed family history, molecular genetic testing or extensive clinical testing may help differentiate these disorders from CTNNB1 syndrome. (For more information on this disorder, choose “Hereditary Spastic Paraplegia” as your search term in the Rare Disease Database.)Several intellectual disability disorders can have large overlaps in clinical features with CTNNB1 syndrome. In some patients, a detailed family history, molecular genetic testing or extensive clinical testing may help differentiate these disorders from CTNNB1 syndrome.KIF1A-related disorders are a group of neurological disorders with a wide spectrum of clinical features ranging from mild to life threatening. Features they can share with CTNNB1 syndrome include intellectual disability, developmental delay, hypotonia and hypertonia. In some patients, a detailed family history, molecular genetic testing or extensive clinical testing may help differentiate these disorders from CTNNB1 syndrome. (For more information on this disorder, choose “KIF1A-Related Disorders” as your search term in the Rare Disease Database.)Cerebral palsy is a group of conditions commonly associated with a lack of oxygen to the brain during labor or delivery. Features that some patients can share with CTNNB1 syndrome include low muscle tone (hypotonia) in the torso, abnormally high muscle tone (hyptertonia) in the arms and legs and prolonged muscle contractions and muscle tightness (spasticity) which can lead to difficulties with speech and movement like walking. In some people, clinical features are nearly indistinguishable from CTNNB1 syndrome and molecular genetic testing is required to differentiate between the disorders. | 338 | CTNNB1 Syndrome |
nord_338_5 | Diagnosis of CTNNB1 Syndrome | A diagnosis of CTNNB1 syndrome is based on characteristic clinical features, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. No formal clinical diagnostic criteria have been established for CTNNB1 syndrome. A diagnosis can only be made through molecular genetic testing.Clinical Testing and WorkupMolecular genetic testing can detect variants in the CTNNB1 gene but is available only as a diagnostic service at specialized laboratories. Doctors will take a blood or saliva sample of individuals suspected of having CTNNB1 syndrome for a molecular genetic test called whole exome sequencing (WES). WES examines the parts of genes that provide instructions to create proteins called exons and evaluates all of the exons (exome) at the same time. WES can detect variants in the CTNNB1 gene or in other genes that may have overlapping clinical features. More recently, the CTNNB1 gene has been added to a molecular genetic test known as the intellectual disability next generation sequencing panel. This test only examines genes throughout the genome that have known associations with intellectual disabilities. This more targeted approach means the test can be less expensive.Affected individuals may undergo additional tests to assess the extent of clinical features. Developmental examinations can help assess any developmental delays including motor function and speech or language delays. Neuropsychological assessments can help evaluate brain function and its impact on cognition and behaviors, particularly in individuals older than 12 months. An advanced imaging test called magnetic resonance imaging (MRI) may be recommended. An MRI uses a magnetic field and radio waves to produce cross-sectional images of organs and body tissues. An MRI of the brain and spine can help detect abnormalities. Swallow tests are frequently needed to assess any feeding issues and eye exams can evaluate eye and vision function. | Diagnosis of CTNNB1 Syndrome. A diagnosis of CTNNB1 syndrome is based on characteristic clinical features, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. No formal clinical diagnostic criteria have been established for CTNNB1 syndrome. A diagnosis can only be made through molecular genetic testing.Clinical Testing and WorkupMolecular genetic testing can detect variants in the CTNNB1 gene but is available only as a diagnostic service at specialized laboratories. Doctors will take a blood or saliva sample of individuals suspected of having CTNNB1 syndrome for a molecular genetic test called whole exome sequencing (WES). WES examines the parts of genes that provide instructions to create proteins called exons and evaluates all of the exons (exome) at the same time. WES can detect variants in the CTNNB1 gene or in other genes that may have overlapping clinical features. More recently, the CTNNB1 gene has been added to a molecular genetic test known as the intellectual disability next generation sequencing panel. This test only examines genes throughout the genome that have known associations with intellectual disabilities. This more targeted approach means the test can be less expensive.Affected individuals may undergo additional tests to assess the extent of clinical features. Developmental examinations can help assess any developmental delays including motor function and speech or language delays. Neuropsychological assessments can help evaluate brain function and its impact on cognition and behaviors, particularly in individuals older than 12 months. An advanced imaging test called magnetic resonance imaging (MRI) may be recommended. An MRI uses a magnetic field and radio waves to produce cross-sectional images of organs and body tissues. An MRI of the brain and spine can help detect abnormalities. Swallow tests are frequently needed to assess any feeding issues and eye exams can evaluate eye and vision function. | 338 | CTNNB1 Syndrome |
nord_338_6 | Therapies of CTNNB1 Syndrome | TreatmentThe treatment of CTNNB syndrome is directed toward the specific clinical features that are present. There are no standardized treatment protocols or guidelines, but the coordinated efforts of a team of specialists can help tailor treatments to the affected individual. Body systems that are or may be affected should be routinely evaluated. Regular monitoring by healthcare professionals can track symptoms as they change or develop over time and treatments can be appropriately adjusted to best support current needs.Healthcare professionals that may be part of the care team can include pediatricians and physicians who specialize in diagnosing and treating developmental neurological disorders (neurologists), disorders of the eyes (ophthalmologists), digestive system (gastroenterologists), musculoskeletal system (orthopedist) and heart (cardiologists). Additionally, rehabilitation therapists (physical, occupational and speech therapists), psychiatrists and other healthcare professionals may be needed to plan treatments and administer therapies.Feeding and swallowing issues should be evaluated regularly at clinic visits and appropriately addressed by rehabilitation therapists. Feeding therapy may help resolve motor function and coordination difficulties or provide helpful feeding techniques like chilling or thickening food. In some patients, a nasogastric tube (NG-tube) or gastrostomy tube (G-tube) to deliver food directly to the stomach may be appropriate. Close monitoring for constipation and diarrhea may be needed.A developmental assessment should be performed, and appropriate rehabilitation therapies may be instituted. Mobility and motor functions can be addressed by physical and occupational therapy. In some children, orthopedic devices for proper positioning or durable medical devices for mobility assistance may be required. Increased muscle tone abnormalities may benefit from muscle relaxant therapies. Behavioral concerns may be addressed through applied behavior analysis (ABA) or by a developmental pediatrician. Eye abnormalities and vision changes should be evaluated regularly. Individuals with abnormal growth and development of blood vessels in the retina (exudative vitreoretinopathy) may require laser therapy, while eye misalignment or blurred vision should be addressed to prevent further vision complications.Speech therapy may be required, and some affected individuals may benefit from the use of sign language and various communication devices or modalities. Additional medical, social or vocational services including specialized learning programs may be necessary, including an individualized learning plan (IEP) and 504 plan that are updated regularly.Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is also often recommended. | Therapies of CTNNB1 Syndrome. TreatmentThe treatment of CTNNB syndrome is directed toward the specific clinical features that are present. There are no standardized treatment protocols or guidelines, but the coordinated efforts of a team of specialists can help tailor treatments to the affected individual. Body systems that are or may be affected should be routinely evaluated. Regular monitoring by healthcare professionals can track symptoms as they change or develop over time and treatments can be appropriately adjusted to best support current needs.Healthcare professionals that may be part of the care team can include pediatricians and physicians who specialize in diagnosing and treating developmental neurological disorders (neurologists), disorders of the eyes (ophthalmologists), digestive system (gastroenterologists), musculoskeletal system (orthopedist) and heart (cardiologists). Additionally, rehabilitation therapists (physical, occupational and speech therapists), psychiatrists and other healthcare professionals may be needed to plan treatments and administer therapies.Feeding and swallowing issues should be evaluated regularly at clinic visits and appropriately addressed by rehabilitation therapists. Feeding therapy may help resolve motor function and coordination difficulties or provide helpful feeding techniques like chilling or thickening food. In some patients, a nasogastric tube (NG-tube) or gastrostomy tube (G-tube) to deliver food directly to the stomach may be appropriate. Close monitoring for constipation and diarrhea may be needed.A developmental assessment should be performed, and appropriate rehabilitation therapies may be instituted. Mobility and motor functions can be addressed by physical and occupational therapy. In some children, orthopedic devices for proper positioning or durable medical devices for mobility assistance may be required. Increased muscle tone abnormalities may benefit from muscle relaxant therapies. Behavioral concerns may be addressed through applied behavior analysis (ABA) or by a developmental pediatrician. Eye abnormalities and vision changes should be evaluated regularly. Individuals with abnormal growth and development of blood vessels in the retina (exudative vitreoretinopathy) may require laser therapy, while eye misalignment or blurred vision should be addressed to prevent further vision complications.Speech therapy may be required, and some affected individuals may benefit from the use of sign language and various communication devices or modalities. Additional medical, social or vocational services including specialized learning programs may be necessary, including an individualized learning plan (IEP) and 504 plan that are updated regularly.Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is also often recommended. | 338 | CTNNB1 Syndrome |
nord_339_0 | Overview of Cushing Syndrome | SummaryCushing syndrome is a rare endocrine disorder, characterized by a variety of symptoms and physical abnormalities that occur as a result of excessive amounts of the hormone cortisol, a vital glucocorticoid. Glucocorticoids are a class of steroid hormones that are important in the regulation of the metabolism of glucose, and also modulate the response to stress. Although it may occur in children, Cushing syndrome most commonly affects adults between the ages of 25 to 40. It can be caused by prolonged exposure to elevated levels of glucocorticoids produced within the body (endogenous) or introduced from outside the body (exogenous). Symptoms can include weight gain, obesity, a rounded face, thin purple streaks (purple striae) which occur on the skin, increased fat around the neck and slender arms and legs. Children with Cushing syndrome are typically obese and have delay in growth.IntroductionIn 1912, Harvey Cushing described a patient who had typical features of hypercortisolemia, but assumed it to be a “polyglandular” disorder. The cause was disputed for almost 40 years. Cushing disease, which is pituitary adrenocorticotropin hormone (ACTH) dependent Cushing syndrome produced by a benign pituitary tumor, was first definitively described by Dr. Cushing in 1932. Although pituitary surgery was introduced in the early 20th century, it was not until 1933 that pituitary neurosurgery began to be performed on patients with Cushing disease. | Overview of Cushing Syndrome. SummaryCushing syndrome is a rare endocrine disorder, characterized by a variety of symptoms and physical abnormalities that occur as a result of excessive amounts of the hormone cortisol, a vital glucocorticoid. Glucocorticoids are a class of steroid hormones that are important in the regulation of the metabolism of glucose, and also modulate the response to stress. Although it may occur in children, Cushing syndrome most commonly affects adults between the ages of 25 to 40. It can be caused by prolonged exposure to elevated levels of glucocorticoids produced within the body (endogenous) or introduced from outside the body (exogenous). Symptoms can include weight gain, obesity, a rounded face, thin purple streaks (purple striae) which occur on the skin, increased fat around the neck and slender arms and legs. Children with Cushing syndrome are typically obese and have delay in growth.IntroductionIn 1912, Harvey Cushing described a patient who had typical features of hypercortisolemia, but assumed it to be a “polyglandular” disorder. The cause was disputed for almost 40 years. Cushing disease, which is pituitary adrenocorticotropin hormone (ACTH) dependent Cushing syndrome produced by a benign pituitary tumor, was first definitively described by Dr. Cushing in 1932. Although pituitary surgery was introduced in the early 20th century, it was not until 1933 that pituitary neurosurgery began to be performed on patients with Cushing disease. | 339 | Cushing Syndrome |
nord_339_1 | Symptoms of Cushing Syndrome | People with Cushing syndrome gain an excessive amount of weight. Obesity extends to include fat deposits around the face causing a “moon-shaped” or rounded appearance. Fat also accumulates around the neck (supraclavicular) and upper back (dorsal cervical) areas. Obesity also occurs in the trunk of the body (“centripetal obesity”), but the arms and legs remain slender. People with Cushing syndrome may have skin that is reddened, thin, fragile and slow to heal. The connective tissue may also become weak, resulting in the appearance of reddish-blue stretch marks on the arms, breasts, underarms (axillae), abdomen, buttocks and/or thighs.Women with Cushing syndrome may have excessive body hair (hirsutism) on the face, neck, chest, abdomen and/or thighs. Acne affecting the face, chest and back may also develop. Some people have thinning and loss of the hair on the head, and some women may develop menstrual irregularities (oligoamenorrhea, amenorrhea). Men and women with this disorder may experience a decrease in fertility and a diminished or absent sex drive (loss of libido).Children and adolescents with Cushing syndrome may experience delayed growth with or without weight gain and/or hypertension. Growth does not always stop entirely; it may be slower than before or only partially affected; however, Cushing syndrome in growing children always affects growth in one way or another.Abnormally high blood pressure (hypertension) occurs in approximately 85 percent of people with Cushing syndrome. Bones may become brittle and break easily. This occurs as a result of progressive bone thinning (osteoporosis). Other features often include abnormally high blood sugar (diabetes mellitus, hyperglycemia), increased thirst and urination, impaired immune function leading to frequent bacterial and fungal infections, severe weakness, fatigue, easy bruising and muscle wasting (lower limbs muscle atrophy). Mild to severe psychic disturbances, including anxiety, depression and irritability, occur in many patients. Headache may also be present. Sleep disorders and sleep apnea are frequent in advanced cases. Some patients note cognitive difficulties and troubles with work performance and interpersonal relationships. | Symptoms of Cushing Syndrome. People with Cushing syndrome gain an excessive amount of weight. Obesity extends to include fat deposits around the face causing a “moon-shaped” or rounded appearance. Fat also accumulates around the neck (supraclavicular) and upper back (dorsal cervical) areas. Obesity also occurs in the trunk of the body (“centripetal obesity”), but the arms and legs remain slender. People with Cushing syndrome may have skin that is reddened, thin, fragile and slow to heal. The connective tissue may also become weak, resulting in the appearance of reddish-blue stretch marks on the arms, breasts, underarms (axillae), abdomen, buttocks and/or thighs.Women with Cushing syndrome may have excessive body hair (hirsutism) on the face, neck, chest, abdomen and/or thighs. Acne affecting the face, chest and back may also develop. Some people have thinning and loss of the hair on the head, and some women may develop menstrual irregularities (oligoamenorrhea, amenorrhea). Men and women with this disorder may experience a decrease in fertility and a diminished or absent sex drive (loss of libido).Children and adolescents with Cushing syndrome may experience delayed growth with or without weight gain and/or hypertension. Growth does not always stop entirely; it may be slower than before or only partially affected; however, Cushing syndrome in growing children always affects growth in one way or another.Abnormally high blood pressure (hypertension) occurs in approximately 85 percent of people with Cushing syndrome. Bones may become brittle and break easily. This occurs as a result of progressive bone thinning (osteoporosis). Other features often include abnormally high blood sugar (diabetes mellitus, hyperglycemia), increased thirst and urination, impaired immune function leading to frequent bacterial and fungal infections, severe weakness, fatigue, easy bruising and muscle wasting (lower limbs muscle atrophy). Mild to severe psychic disturbances, including anxiety, depression and irritability, occur in many patients. Headache may also be present. Sleep disorders and sleep apnea are frequent in advanced cases. Some patients note cognitive difficulties and troubles with work performance and interpersonal relationships. | 339 | Cushing Syndrome |
nord_339_2 | Causes of Cushing Syndrome | Cushing syndrome is a rare endocrine disorder caused by abnormally excessive amounts of the hormone cortisol.Many people develop Cushing syndrome as a result of exogenous, long-term administration of a cortisol-like drug therapy to treat another medical condition such as arthritis, lupus and other inflammatory diseases (oral medication or injection into a joint or muscle), asthma, chronic obstructive lung disease, malignant tumors or leukemia. Steroid treatment is effective for these conditions, but can cause symptoms and signs of Cushing syndrome as a side effect of such treatment.Cushing syndrome can also be due to endogenous causes; approximately 70% of Cushing syndrome is the result of Cushing disease. Cushing disease occurs when excess adrenocorticotropin hormone (ACTH) production from a benign pituitary tumor (adenoma) causes the adrenal glands to produce excessive amounts of cortisol. Approximately 10 to 15 percent of cases of endogenous Cushing syndrome are caused by non-pituitary tumors that secrete excessive ACTH. The causes of this “ectopic ACTH syndrome” include benign or malignant tumors, most commonly in the chest cavity or abdomen. Other types of ACTH-producing tumors include medullary carcinomas of the thyroid, pheochromocytomas and pancreatic islet cell tumors. Another 10 – 15% of patients have benign or malignant tumors of the adrenal glands (adenomas) that secrete excessive cortisol. Insulin resistance can be an important factor in the evolution of Cushing syndrome.Although most cases of Cushing syndrome are not inherited, in rare instances it results from an inherited tendency to develop tumors in one or more hormone-secreting glands. Children or young adults with primary pigmented nodular adrenocortical disease (PPNAD) develop small cortisol-producing tumors in the adrenal glands. Cushing syndrome may develop along with the genetic disorder multiple endocrine neoplasia type 1 (MEN1) that is associated with hormone-secreting tumors of the lung, pancreas, parathyroids or pituitary gland. | Causes of Cushing Syndrome. Cushing syndrome is a rare endocrine disorder caused by abnormally excessive amounts of the hormone cortisol.Many people develop Cushing syndrome as a result of exogenous, long-term administration of a cortisol-like drug therapy to treat another medical condition such as arthritis, lupus and other inflammatory diseases (oral medication or injection into a joint or muscle), asthma, chronic obstructive lung disease, malignant tumors or leukemia. Steroid treatment is effective for these conditions, but can cause symptoms and signs of Cushing syndrome as a side effect of such treatment.Cushing syndrome can also be due to endogenous causes; approximately 70% of Cushing syndrome is the result of Cushing disease. Cushing disease occurs when excess adrenocorticotropin hormone (ACTH) production from a benign pituitary tumor (adenoma) causes the adrenal glands to produce excessive amounts of cortisol. Approximately 10 to 15 percent of cases of endogenous Cushing syndrome are caused by non-pituitary tumors that secrete excessive ACTH. The causes of this “ectopic ACTH syndrome” include benign or malignant tumors, most commonly in the chest cavity or abdomen. Other types of ACTH-producing tumors include medullary carcinomas of the thyroid, pheochromocytomas and pancreatic islet cell tumors. Another 10 – 15% of patients have benign or malignant tumors of the adrenal glands (adenomas) that secrete excessive cortisol. Insulin resistance can be an important factor in the evolution of Cushing syndrome.Although most cases of Cushing syndrome are not inherited, in rare instances it results from an inherited tendency to develop tumors in one or more hormone-secreting glands. Children or young adults with primary pigmented nodular adrenocortical disease (PPNAD) develop small cortisol-producing tumors in the adrenal glands. Cushing syndrome may develop along with the genetic disorder multiple endocrine neoplasia type 1 (MEN1) that is associated with hormone-secreting tumors of the lung, pancreas, parathyroids or pituitary gland. | 339 | Cushing Syndrome |
nord_339_3 | Affects of Cushing Syndrome | Many cases of Cushing syndrome are due to exogenous corticosteroid medication. It is reported that the incidence of endogenous Cushing syndrome is approximately 13 per million people annually.Cushing syndrome caused by either an adrenal or pituitary tumor affects women five times more frequently than men. Symptoms commonly begin between 25 to 40 years of age. Men are affected 3 times more often than women by ectopic ACTH production that is caused by lung cancer, which occurs later in life. The ACTH secreting pituitary adenomas that occur in children tend to be larger, and somewhat more rapidly growing than those in adults. | Affects of Cushing Syndrome. Many cases of Cushing syndrome are due to exogenous corticosteroid medication. It is reported that the incidence of endogenous Cushing syndrome is approximately 13 per million people annually.Cushing syndrome caused by either an adrenal or pituitary tumor affects women five times more frequently than men. Symptoms commonly begin between 25 to 40 years of age. Men are affected 3 times more often than women by ectopic ACTH production that is caused by lung cancer, which occurs later in life. The ACTH secreting pituitary adenomas that occur in children tend to be larger, and somewhat more rapidly growing than those in adults. | 339 | Cushing Syndrome |
nord_339_4 | Related disorders of Cushing Syndrome | The following disorders can have symptoms similar to those of Cushing syndrome, even though people with these disorders do not have abnormally elevated cortisol levels. Comparisons may be useful for a differential diagnosis:Polycystic ovary syndrome (PCOS) is characterized by absent or irregular menstruation, excessive hair on the face and/or body (hirsutism), weight gain, acne, male pattern balding and impaired insulin action and diabetes mellitus. The metabolic syndrome is a combination of medical conditions related to obesity that includes excess weight around the waist, high blood pressure, high blood sugar level and abnormal levels of cholesterol and triglycerides in the blood. This cluster of problems increases the risk of heart disease, stroke and diabetes.Pseudo-Cushing syndrome presents with some symptoms and mildly abnormal hormone levels that overlap with those seen in Cushing syndrome. These patients, however, do not have the tumors that are associated with Cushing syndrome. Pseudo-Cushing syndrome has been identified in patients with alcoholism, depression, obesity or poorly controlled diabetes. The mechanism that causes it is unclear (idiopathic).Cyclical Cushing disease is a somewhat controversial and rare, in which symptoms and signs can occur and regress over periods of time. Accordingly, repeated testing becomes necessary and the cause usually is uncertain. | Related disorders of Cushing Syndrome. The following disorders can have symptoms similar to those of Cushing syndrome, even though people with these disorders do not have abnormally elevated cortisol levels. Comparisons may be useful for a differential diagnosis:Polycystic ovary syndrome (PCOS) is characterized by absent or irregular menstruation, excessive hair on the face and/or body (hirsutism), weight gain, acne, male pattern balding and impaired insulin action and diabetes mellitus. The metabolic syndrome is a combination of medical conditions related to obesity that includes excess weight around the waist, high blood pressure, high blood sugar level and abnormal levels of cholesterol and triglycerides in the blood. This cluster of problems increases the risk of heart disease, stroke and diabetes.Pseudo-Cushing syndrome presents with some symptoms and mildly abnormal hormone levels that overlap with those seen in Cushing syndrome. These patients, however, do not have the tumors that are associated with Cushing syndrome. Pseudo-Cushing syndrome has been identified in patients with alcoholism, depression, obesity or poorly controlled diabetes. The mechanism that causes it is unclear (idiopathic).Cyclical Cushing disease is a somewhat controversial and rare, in which symptoms and signs can occur and regress over periods of time. Accordingly, repeated testing becomes necessary and the cause usually is uncertain. | 339 | Cushing Syndrome |
nord_339_5 | Diagnosis of Cushing Syndrome | The diagnosis is based upon a detailed medical history to assess for any use of exogenous glucocorticoids (oral, topical, injection, inhaled), other symptoms or signs and a thorough physical examination and a series of laboratory tests.Usually several laboratory tests are used to confirm the diagnosis of Cushing syndrome. Tests used include: 24-hour urine test for cortisol; measurement of late-night cortisol levels in the blood and saliva; and the low dose dexamethasone suppression test (LDDST) which evaluates the cortisol response to a low dose of a synthetic glucocorticoid (dexamethasone).The dexamethasone-corticotropin-releasing hormone (CRH) test helps to distinguish Cushing syndrome from other causes of excess cortisol, such as pseudo-Cushing syndrome. This test combines the LDDST and a CRH stimulation test. In the CRH stimulation test, an injection of CRH causes the pituitary to secrete ACTH. People with pseudo-Cushing respond to the pretreatment with dexamethasone, which prevents CRH from causing an increase in ACTH and hence cortisol. Elevated cortisol levels from this test generally indicate Cushing syndrome.Clinical Testing and Work-up
Once Cushing syndrome has been diagnosed, the cause of excess cortisol production needs to be determined.The first test is measurement of blood (plasma) ACTH levels. A low or undetectable level of ACTH in the blood combined with simultaneously elevated blood (serum) cortisol levels indicates that the cause of Cushing syndrome is likely due to a primary cortisol-producing adrenal adenoma or carcinoma, assuming that use of corticosteroid medication as the cause has been ruled out.Patients with ACTH-producing tumors have measurable (normal) or high ACTH levels, and a tumor that is in the pituitary gland (Cushing disease) or elsewhere (ectopic ACTH syndrome). Radiologic imaging helps to identify these tumors. Because pituitary disease is most common, and identification of such a tumor influences the need for other testing, magnetic resonance imaging (MRI) of the pituitary is usually the next test. However, pituitary tumors are often very small (microadenomas, (10mm or less in diameter), and may not be detected with radiologic imaging in almost half of people who ultimately require surgery.A CRH stimulation test conducted without pretreatment with dexamethasone helps to distinguish between pituitary and non-pituitary tumors. The high-dose dexamethasone suppression test (HDDST) may also be helpful. HDDST testing follows the same format as LDDST, but uses higher doses of dexamethasone.Inferior petrosal sinus sampling (IPSS) is an effective way to confirm a pituitary etiology for Cushing syndrome, in which levels of ACTH are measured in the blood from veins that drain the pituitary (inferior petrosal sinuses). If this study indicates ectopic ACTH secretion, other imaging tests are done to find the tumor, possibly including computerized tomography (CT and MRI scans of chest and abdomen) and other nuclear medicine studies such as Octreoscan or PET studies. | Diagnosis of Cushing Syndrome. The diagnosis is based upon a detailed medical history to assess for any use of exogenous glucocorticoids (oral, topical, injection, inhaled), other symptoms or signs and a thorough physical examination and a series of laboratory tests.Usually several laboratory tests are used to confirm the diagnosis of Cushing syndrome. Tests used include: 24-hour urine test for cortisol; measurement of late-night cortisol levels in the blood and saliva; and the low dose dexamethasone suppression test (LDDST) which evaluates the cortisol response to a low dose of a synthetic glucocorticoid (dexamethasone).The dexamethasone-corticotropin-releasing hormone (CRH) test helps to distinguish Cushing syndrome from other causes of excess cortisol, such as pseudo-Cushing syndrome. This test combines the LDDST and a CRH stimulation test. In the CRH stimulation test, an injection of CRH causes the pituitary to secrete ACTH. People with pseudo-Cushing respond to the pretreatment with dexamethasone, which prevents CRH from causing an increase in ACTH and hence cortisol. Elevated cortisol levels from this test generally indicate Cushing syndrome.Clinical Testing and Work-up
Once Cushing syndrome has been diagnosed, the cause of excess cortisol production needs to be determined.The first test is measurement of blood (plasma) ACTH levels. A low or undetectable level of ACTH in the blood combined with simultaneously elevated blood (serum) cortisol levels indicates that the cause of Cushing syndrome is likely due to a primary cortisol-producing adrenal adenoma or carcinoma, assuming that use of corticosteroid medication as the cause has been ruled out.Patients with ACTH-producing tumors have measurable (normal) or high ACTH levels, and a tumor that is in the pituitary gland (Cushing disease) or elsewhere (ectopic ACTH syndrome). Radiologic imaging helps to identify these tumors. Because pituitary disease is most common, and identification of such a tumor influences the need for other testing, magnetic resonance imaging (MRI) of the pituitary is usually the next test. However, pituitary tumors are often very small (microadenomas, (10mm or less in diameter), and may not be detected with radiologic imaging in almost half of people who ultimately require surgery.A CRH stimulation test conducted without pretreatment with dexamethasone helps to distinguish between pituitary and non-pituitary tumors. The high-dose dexamethasone suppression test (HDDST) may also be helpful. HDDST testing follows the same format as LDDST, but uses higher doses of dexamethasone.Inferior petrosal sinus sampling (IPSS) is an effective way to confirm a pituitary etiology for Cushing syndrome, in which levels of ACTH are measured in the blood from veins that drain the pituitary (inferior petrosal sinuses). If this study indicates ectopic ACTH secretion, other imaging tests are done to find the tumor, possibly including computerized tomography (CT and MRI scans of chest and abdomen) and other nuclear medicine studies such as Octreoscan or PET studies. | 339 | Cushing Syndrome |
nord_339_6 | Therapies of Cushing Syndrome | TreatmentThe treatment of Cushing syndrome is directly related to the cause of the cortisol overproduction.If the cause of the elevated level of cortisol is the result of the long-term use of hormones such as prednisone for the treatment of another disorder, the dosage should gradually be reduced under medical supervision until symptoms are under control.Pituitary tumors may be surgically removed during an operation known as a trans-nasal or sub-labial transsphenoidal adenomectomy. Specific surgical procedures and long-term results can vary greatly depending on the type and location of the tumor and the expertise of the surgeon. The success rate of this surgery is approximately 80 percent. The complication rate is generally low, and similar to that for gall bladder surgery. If surgery only produces a temporary cure, or recurrence of disease, surgery can be repeated. After successful surgery, there is an expected drop in the production of adrenocorticotrophic hormone and cortisol. Therefore, patients may require temporary administration of synthetic replacement hormone (hydrocortisone or prednisone). This drug therapy typically lasts for less than one year, while the normal glands are recovering.Some people with Cushing disease are not good candidates for surgery and some others may have had surgery that was unsuccessful. For these affected individuals, conventional radiation therapy directed at the pituitary gland may be administered for a minimum of six weeks. Alternatively, at certain centers, a one-time, focused radiation treatment can be used (stereotactic radiosurgery, gamma knife, and Cyber knife or proton beam radiation). Improvement of symptoms over time occurs in up to 85 percent of patients.The drug ketoconazole may be given alone or in combination with radiation therapy to help inhibit cortisol production and to speed recovery. Other drugs used to reduce adrenal gland production of cortisol include metyrapone and mitotane. Another drug, cabergoline, has occasionally shown to reduce cortisol production in about 20% of patients by acting on the pituitary tumor.The removal or destruction of ACTH-secreting tumors is essential to reverse ectopic ACTH syndrome. Surgical removal is effective treatment of benign and some malignant tumors. Other treatments of cancers producing Cushing syndrome depend on the type of cancer and the extent to which it has spread. Such treatments may include surgery, radiation, chemotherapy and/or immunotherapy. In addition, the administration of a cortisol-inhibiting drug such as ketoconazole or mitotane can be an important part of this treatment.Korlym (mifepristone) was approved by the FDA in 2012 as a treatment to control hyperglycemia in adults with endogenous Cushing syndrome who have type 2 diabetes or glucose intolerance and are not candidates for surgery, or who have not successfully responded to surgery. Korlym works by blocking the binding of cortisol to its receptor, thus reducing the effects of excess cortisol. Another form of suppressive medical therapy is the drug Signifor (pasireotide) which may be effective but has elevated glucose levels as a side effect.In 2020, the FDA approved Isturisa (osilodrostat) for adults with Cushing’s disease who either cannot undergo pituitary gland surgery or have undergone the surgery but still have the disease. This drug directly addresses cortisol overproduction by blocking the enzyme known as 11-beta-hydroxylase, thus preventing cortisol synthesis.Because cortisol hypersecretion comes from the adrenal glands, in selected cases (usually in very ill patients who have not responded to other therapies), surgical removal of the adrenal glands can be considered. This surgery risks the development of another problem called Nelson syndrome, which can result in the activation of the underlying pituitary tumor due to a loss of inhibition from adrenal secretions. | Therapies of Cushing Syndrome. TreatmentThe treatment of Cushing syndrome is directly related to the cause of the cortisol overproduction.If the cause of the elevated level of cortisol is the result of the long-term use of hormones such as prednisone for the treatment of another disorder, the dosage should gradually be reduced under medical supervision until symptoms are under control.Pituitary tumors may be surgically removed during an operation known as a trans-nasal or sub-labial transsphenoidal adenomectomy. Specific surgical procedures and long-term results can vary greatly depending on the type and location of the tumor and the expertise of the surgeon. The success rate of this surgery is approximately 80 percent. The complication rate is generally low, and similar to that for gall bladder surgery. If surgery only produces a temporary cure, or recurrence of disease, surgery can be repeated. After successful surgery, there is an expected drop in the production of adrenocorticotrophic hormone and cortisol. Therefore, patients may require temporary administration of synthetic replacement hormone (hydrocortisone or prednisone). This drug therapy typically lasts for less than one year, while the normal glands are recovering.Some people with Cushing disease are not good candidates for surgery and some others may have had surgery that was unsuccessful. For these affected individuals, conventional radiation therapy directed at the pituitary gland may be administered for a minimum of six weeks. Alternatively, at certain centers, a one-time, focused radiation treatment can be used (stereotactic radiosurgery, gamma knife, and Cyber knife or proton beam radiation). Improvement of symptoms over time occurs in up to 85 percent of patients.The drug ketoconazole may be given alone or in combination with radiation therapy to help inhibit cortisol production and to speed recovery. Other drugs used to reduce adrenal gland production of cortisol include metyrapone and mitotane. Another drug, cabergoline, has occasionally shown to reduce cortisol production in about 20% of patients by acting on the pituitary tumor.The removal or destruction of ACTH-secreting tumors is essential to reverse ectopic ACTH syndrome. Surgical removal is effective treatment of benign and some malignant tumors. Other treatments of cancers producing Cushing syndrome depend on the type of cancer and the extent to which it has spread. Such treatments may include surgery, radiation, chemotherapy and/or immunotherapy. In addition, the administration of a cortisol-inhibiting drug such as ketoconazole or mitotane can be an important part of this treatment.Korlym (mifepristone) was approved by the FDA in 2012 as a treatment to control hyperglycemia in adults with endogenous Cushing syndrome who have type 2 diabetes or glucose intolerance and are not candidates for surgery, or who have not successfully responded to surgery. Korlym works by blocking the binding of cortisol to its receptor, thus reducing the effects of excess cortisol. Another form of suppressive medical therapy is the drug Signifor (pasireotide) which may be effective but has elevated glucose levels as a side effect.In 2020, the FDA approved Isturisa (osilodrostat) for adults with Cushing’s disease who either cannot undergo pituitary gland surgery or have undergone the surgery but still have the disease. This drug directly addresses cortisol overproduction by blocking the enzyme known as 11-beta-hydroxylase, thus preventing cortisol synthesis.Because cortisol hypersecretion comes from the adrenal glands, in selected cases (usually in very ill patients who have not responded to other therapies), surgical removal of the adrenal glands can be considered. This surgery risks the development of another problem called Nelson syndrome, which can result in the activation of the underlying pituitary tumor due to a loss of inhibition from adrenal secretions. | 339 | Cushing Syndrome |
nord_340_0 | Overview of Cutaneous T-Cell Lymphomas | General DiscussionCutaneous T-cell lymphomas (CTCLs) are a group of disorders characterized by abnormal accumulation of malignant T-cells in the skin potentially resulting in the development of rashes, plaques and tumors. CTCLs belong to a larger group of disorders known as non-Hodgkin's lymphomas (NHLs), which are related malignancies (cancers) that affect the lymphatic system (lymphomas).Functioning as part of the immune system, the lymphatic system helps to protect the body against infection and disease. It consists of a network of tubular channels (lymph vessels) that drain a thin watery fluid known as lymph from different areas of the body into the bloodstream. Lymph accumulates in the tiny spaces between tissue cells and contains proteins, fats, and certain white blood cells known as lymphocytes.There are two main types of lymphocytes: B-lymphocytes, which may produce specific antibodies to “neutralize” certain invading microorganisms, and T-lymphocytes, which may directly destroy microorganisms or assist in the activities of other lymphocytes. CTCLs result from errors in the production of T-lymphocytes or transformation of T-lymphocytes into malignant cells. In CTCLs, abnormal, uncontrolled growth and multiplication (proliferation) of malignant T-lymphocytes result in accumulation of these lymphocytes in the skin. In some cases, malignant lymphocytes may spread to affect the lymph nodes and eventually to other bodily tissues and organs, potentially resulting in life-threatening complications. The specific symptoms and physical findings may vary from case to case, depending upon the extent and region(s) of involvement, the specific type of CTCL present, and various additional factors.Non-Hodgkin's lymphomas, such as CTCLs, may also be categorized based upon certain characteristics of the cancer cells as seen under a microscope and how quickly they may tend to grow and spread. For example, CTCLs may be characterized as “low-grade” (or indolent) lymphomas, which tend to grow slowly and result in few associated symptoms, or “intermediate-grade” or “high-grade” (aggressive) lymphomas, which typically grow rapidly, requiring prompt treatment. Most cases of CTCL, especially the classic form (mycosis fungoides), are slow-growing (indolent) lymphomas. | Overview of Cutaneous T-Cell Lymphomas. General DiscussionCutaneous T-cell lymphomas (CTCLs) are a group of disorders characterized by abnormal accumulation of malignant T-cells in the skin potentially resulting in the development of rashes, plaques and tumors. CTCLs belong to a larger group of disorders known as non-Hodgkin's lymphomas (NHLs), which are related malignancies (cancers) that affect the lymphatic system (lymphomas).Functioning as part of the immune system, the lymphatic system helps to protect the body against infection and disease. It consists of a network of tubular channels (lymph vessels) that drain a thin watery fluid known as lymph from different areas of the body into the bloodstream. Lymph accumulates in the tiny spaces between tissue cells and contains proteins, fats, and certain white blood cells known as lymphocytes.There are two main types of lymphocytes: B-lymphocytes, which may produce specific antibodies to “neutralize” certain invading microorganisms, and T-lymphocytes, which may directly destroy microorganisms or assist in the activities of other lymphocytes. CTCLs result from errors in the production of T-lymphocytes or transformation of T-lymphocytes into malignant cells. In CTCLs, abnormal, uncontrolled growth and multiplication (proliferation) of malignant T-lymphocytes result in accumulation of these lymphocytes in the skin. In some cases, malignant lymphocytes may spread to affect the lymph nodes and eventually to other bodily tissues and organs, potentially resulting in life-threatening complications. The specific symptoms and physical findings may vary from case to case, depending upon the extent and region(s) of involvement, the specific type of CTCL present, and various additional factors.Non-Hodgkin's lymphomas, such as CTCLs, may also be categorized based upon certain characteristics of the cancer cells as seen under a microscope and how quickly they may tend to grow and spread. For example, CTCLs may be characterized as “low-grade” (or indolent) lymphomas, which tend to grow slowly and result in few associated symptoms, or “intermediate-grade” or “high-grade” (aggressive) lymphomas, which typically grow rapidly, requiring prompt treatment. Most cases of CTCL, especially the classic form (mycosis fungoides), are slow-growing (indolent) lymphomas. | 340 | Cutaneous T-Cell Lymphomas |
nord_340_1 | Symptoms of Cutaneous T-Cell Lymphomas | The signs and symptoms associated with cutaneous T-cell lymphomas vary greatly from case to case, depending upon the specific type of lymphoma present and how far the disease has progressed (i.e., staging). (For further information on stages, please see the section entitled “Standard Therapies: Diagnosis” [Staging] below.)The most common type and classic presentation of CTCL is known as mycosis fungoides and usually progresses slowly over many years. The associated skin symptoms of mycosis fungoides progress through three separate phases. Affected individuals may first develop a red rash or dry, red, scaly patches of skin that most often affect the buttocks and trunk (premyotic phase). These patches may remain unchanged, spontaneously go away, or slowly grow larger. The skin lesions associated with the initial phase of mycosis fungoides are termed “nonspecific” because they cannot be differentiated from skin lesions associated with other, more common, skin disorders such as psoriasis. This initial phase of mycosis fungoides may persist for months, years, or decades.In the second phase of mycosis fungoides, slightly-elevated, reddish-brown, scaly bumps (plaques) develop on the skin (mycotic stage). These plaques may develop from existing patches or spontaneously in unaffected areas. Eventually, these plaques may expand and grow together (coalesce) forming larger plaques. Any area of the body may be affected.The skin lesions associated with the first two phases of mycosis fungoides may not be associated with other symptoms (asymptomatic) or may occur along with itchiness (pruritis) and pain. In rare cases, affected individuals may experience difficulty sleeping due to severe itchiness.The third phase of mycosis fungoides is characterized by the development of mushroom-shaped tumors. In some cases, the tumors may become ulcerated and infected. Some individuals may not progress beyond the plaque phase of mycosis fungoides and do not develop tumors. Other individuals may develop tumors without first developing the patches or plaques associated with the early stages of mycosis fungoides (tumeur d' emblee variant).In approximately 10 percent of individuals with the classic mycosis fungoides presentation of CTCL, malignant lymphocytes may spread beyond the skin to affect the lymph nodes and major organs of the body including the liver, spleen and gastrointestinal system. Depending upon specific sites and extent of involvement, disease management, and additional factors, disease progression may eventually lead to life-threatening complications. (For more information on this disorder, choose “mycosis fungoides” as your search term in the Rare Disease Database.)In rare cases, affected individuals may develop Sezary syndrome, a form of CTCL that is considered the leukemic variant of mycosis fungoides. It is characterized by a widespread red rash that may cover most of the body (generalized erythroderma), the presence of specific malignant lymphocytes (Sezary cells) in the blood, and abnormally enlarged lymph nodes (lymphadenopathy). Individuals with Sezary syndrome may experience intense itchiness (pruritis) and thickening, scaling, and peeling (exfoliation) of the skin. Additional symptoms associated with Sezary syndrome include outward turning of the eyelids (ectropion); abnormally thick, rough skin on the palms of the hands and the soles of the feet (palmoplantar keratoderma); malformation of the nails (onychodystrophy); and abnormal enlargement of the liver and/or spleen (hepatosplenomegaly). General symptoms associated with Sezary syndrome include fevers, weight loss, bald patches on the scalp (alopecia), and a general feeling of ill health (malaise).Granulomatous slack skin is a rare form of CTCL characterized by areas (folds) of lax, reddened skin. The underarms, groin, and stomach are most often affected. Granulomatous slack skin is usually a benign, slow-growing (indolent) form of CTCL. In some cases, affected individuals may develop a more serious form of CTCL, such as mycosis fungoides, later during life.Primary cutaneous anaplastic large cell lymphomas represent a subgroup of CTCL characterized by positive expression of the CD30 (Ki-1) antigen. Affected individuals develop tumors on the skin. The tumors may become ulcerated or infected. In some cases, the lesions or tumors go away without treatment (spontaneous regression). However, lesions often return (relapse). In rare cases, other organ systems of the body may become involved.Lymphomatoid papulosis is a rare skin disorder that some researchers believe is an early from of CD30+ lymphoma. The disorder is characterized by groups of slightly-elevated, reddish-brown bumps (nodules or papules) that most often affect the trunk, face, and arms and legs. These lesions often become crusted or ulcerated, sometimes leaving a scar. Approximately 5-20 percent of individuals with lymphomatoid papulosis develop CTCL. Other researchers believe that lymphomatoid papulosis is a similar, yet distinct, “premalignant” condition and not a form of CTCL.Subcutaneous pannulitic T-cell lymphoma is a rare variant of CTCL. Affected individuals may have multiple, tender, bumps (nodules) just under the surface of the skin of various areas of the body especially the arms and legs (extremities). These nodules may lead to inflammation of the subcutaneous layer of fat (panniculitis). Affected individuals may also experience weight loss, fevers, and joint pain (arthralgia). Unlike mycosis fungoides, this form of CTCL is often aggressive may lead to the involvement of other organ systems and, potentially, life-threatening complications.Pagetoid reticulosis (PR), also known as Woringer-Kolopp disease, is a rare skin condition characterized by a solitary lesion that usually affects the arms or legs and may grow slowly. The lesion is similar in appearance to the lesions associated with mycosis fungoides. In addition, there are also microscopic similarities between the skin lesions in mycosis fungoides and pagetoid reticulosis. Consequently, most researchers believe that PR is a slow-growing variant of CTCL.According to the medical literature, cases have been reported in which individuals developed more than one form of CTCL at the same time. | Symptoms of Cutaneous T-Cell Lymphomas. The signs and symptoms associated with cutaneous T-cell lymphomas vary greatly from case to case, depending upon the specific type of lymphoma present and how far the disease has progressed (i.e., staging). (For further information on stages, please see the section entitled “Standard Therapies: Diagnosis” [Staging] below.)The most common type and classic presentation of CTCL is known as mycosis fungoides and usually progresses slowly over many years. The associated skin symptoms of mycosis fungoides progress through three separate phases. Affected individuals may first develop a red rash or dry, red, scaly patches of skin that most often affect the buttocks and trunk (premyotic phase). These patches may remain unchanged, spontaneously go away, or slowly grow larger. The skin lesions associated with the initial phase of mycosis fungoides are termed “nonspecific” because they cannot be differentiated from skin lesions associated with other, more common, skin disorders such as psoriasis. This initial phase of mycosis fungoides may persist for months, years, or decades.In the second phase of mycosis fungoides, slightly-elevated, reddish-brown, scaly bumps (plaques) develop on the skin (mycotic stage). These plaques may develop from existing patches or spontaneously in unaffected areas. Eventually, these plaques may expand and grow together (coalesce) forming larger plaques. Any area of the body may be affected.The skin lesions associated with the first two phases of mycosis fungoides may not be associated with other symptoms (asymptomatic) or may occur along with itchiness (pruritis) and pain. In rare cases, affected individuals may experience difficulty sleeping due to severe itchiness.The third phase of mycosis fungoides is characterized by the development of mushroom-shaped tumors. In some cases, the tumors may become ulcerated and infected. Some individuals may not progress beyond the plaque phase of mycosis fungoides and do not develop tumors. Other individuals may develop tumors without first developing the patches or plaques associated with the early stages of mycosis fungoides (tumeur d' emblee variant).In approximately 10 percent of individuals with the classic mycosis fungoides presentation of CTCL, malignant lymphocytes may spread beyond the skin to affect the lymph nodes and major organs of the body including the liver, spleen and gastrointestinal system. Depending upon specific sites and extent of involvement, disease management, and additional factors, disease progression may eventually lead to life-threatening complications. (For more information on this disorder, choose “mycosis fungoides” as your search term in the Rare Disease Database.)In rare cases, affected individuals may develop Sezary syndrome, a form of CTCL that is considered the leukemic variant of mycosis fungoides. It is characterized by a widespread red rash that may cover most of the body (generalized erythroderma), the presence of specific malignant lymphocytes (Sezary cells) in the blood, and abnormally enlarged lymph nodes (lymphadenopathy). Individuals with Sezary syndrome may experience intense itchiness (pruritis) and thickening, scaling, and peeling (exfoliation) of the skin. Additional symptoms associated with Sezary syndrome include outward turning of the eyelids (ectropion); abnormally thick, rough skin on the palms of the hands and the soles of the feet (palmoplantar keratoderma); malformation of the nails (onychodystrophy); and abnormal enlargement of the liver and/or spleen (hepatosplenomegaly). General symptoms associated with Sezary syndrome include fevers, weight loss, bald patches on the scalp (alopecia), and a general feeling of ill health (malaise).Granulomatous slack skin is a rare form of CTCL characterized by areas (folds) of lax, reddened skin. The underarms, groin, and stomach are most often affected. Granulomatous slack skin is usually a benign, slow-growing (indolent) form of CTCL. In some cases, affected individuals may develop a more serious form of CTCL, such as mycosis fungoides, later during life.Primary cutaneous anaplastic large cell lymphomas represent a subgroup of CTCL characterized by positive expression of the CD30 (Ki-1) antigen. Affected individuals develop tumors on the skin. The tumors may become ulcerated or infected. In some cases, the lesions or tumors go away without treatment (spontaneous regression). However, lesions often return (relapse). In rare cases, other organ systems of the body may become involved.Lymphomatoid papulosis is a rare skin disorder that some researchers believe is an early from of CD30+ lymphoma. The disorder is characterized by groups of slightly-elevated, reddish-brown bumps (nodules or papules) that most often affect the trunk, face, and arms and legs. These lesions often become crusted or ulcerated, sometimes leaving a scar. Approximately 5-20 percent of individuals with lymphomatoid papulosis develop CTCL. Other researchers believe that lymphomatoid papulosis is a similar, yet distinct, “premalignant” condition and not a form of CTCL.Subcutaneous pannulitic T-cell lymphoma is a rare variant of CTCL. Affected individuals may have multiple, tender, bumps (nodules) just under the surface of the skin of various areas of the body especially the arms and legs (extremities). These nodules may lead to inflammation of the subcutaneous layer of fat (panniculitis). Affected individuals may also experience weight loss, fevers, and joint pain (arthralgia). Unlike mycosis fungoides, this form of CTCL is often aggressive may lead to the involvement of other organ systems and, potentially, life-threatening complications.Pagetoid reticulosis (PR), also known as Woringer-Kolopp disease, is a rare skin condition characterized by a solitary lesion that usually affects the arms or legs and may grow slowly. The lesion is similar in appearance to the lesions associated with mycosis fungoides. In addition, there are also microscopic similarities between the skin lesions in mycosis fungoides and pagetoid reticulosis. Consequently, most researchers believe that PR is a slow-growing variant of CTCL.According to the medical literature, cases have been reported in which individuals developed more than one form of CTCL at the same time. | 340 | Cutaneous T-Cell Lymphomas |
nord_340_2 | Causes of Cutaneous T-Cell Lymphomas | The exact underlying cause of cutaneous T-cell lymphomas is unknown. Researchers speculate that genetic and immunologic abnormalities, environmental factors (e.g., exposure to ultraviolet rays, certain chemicals, ionizing radiation [carcinogens]; certain viral infections; bacterial skin infections, etc.), diet, stress, and/or additional factors may play varying contributing roles in causing specific types of cancer. Investigators at the National Institutes of Health (NIH)/National Cancer Institute, across the United States, and around the world are conducting ongoing basic research to learn more about the many factors that may result in cancer. (The National Cancer Institute is listed in the “Resources” section of this report below.)In individuals with cancer, including CTCLs, malignancies may develop due to abnormal changes in the structure and orientation of certain cells (e.g., T-lymphocytes). As mentioned above, the specific cause of such changes is unknown. However, current research suggests that abnormalities of DNA (deoxyribonucleic acid), which is the carrier of the body's genetic code, are the underlying basis of cellular malignant transformation. Depending upon the form of cancer present and several other factors, these abnormal genetic changes may occur spontaneously for unknown reasons (sporadically), such as due to exposure to certain environmental factors, or, more rarely, may be inherited.The symptoms of CTCLs result from abnormal, uncontrolled growth and multiplication (proliferation) of malignant T-lymphocytes, which results in accumulation of these lymphocytes in the skin and, in some cases, other organ systems of the body. There are two types of T-lymphocytes known as CD4 and CD8. CD4s (helper cells) help regulate functions of the immune system. CD8s (killer cells) breakdown or rid the body of foreign substances. In most cases of CTCL, CD4s are the cells that become malignant. | Causes of Cutaneous T-Cell Lymphomas. The exact underlying cause of cutaneous T-cell lymphomas is unknown. Researchers speculate that genetic and immunologic abnormalities, environmental factors (e.g., exposure to ultraviolet rays, certain chemicals, ionizing radiation [carcinogens]; certain viral infections; bacterial skin infections, etc.), diet, stress, and/or additional factors may play varying contributing roles in causing specific types of cancer. Investigators at the National Institutes of Health (NIH)/National Cancer Institute, across the United States, and around the world are conducting ongoing basic research to learn more about the many factors that may result in cancer. (The National Cancer Institute is listed in the “Resources” section of this report below.)In individuals with cancer, including CTCLs, malignancies may develop due to abnormal changes in the structure and orientation of certain cells (e.g., T-lymphocytes). As mentioned above, the specific cause of such changes is unknown. However, current research suggests that abnormalities of DNA (deoxyribonucleic acid), which is the carrier of the body's genetic code, are the underlying basis of cellular malignant transformation. Depending upon the form of cancer present and several other factors, these abnormal genetic changes may occur spontaneously for unknown reasons (sporadically), such as due to exposure to certain environmental factors, or, more rarely, may be inherited.The symptoms of CTCLs result from abnormal, uncontrolled growth and multiplication (proliferation) of malignant T-lymphocytes, which results in accumulation of these lymphocytes in the skin and, in some cases, other organ systems of the body. There are two types of T-lymphocytes known as CD4 and CD8. CD4s (helper cells) help regulate functions of the immune system. CD8s (killer cells) breakdown or rid the body of foreign substances. In most cases of CTCL, CD4s are the cells that become malignant. | 340 | Cutaneous T-Cell Lymphomas |
nord_340_3 | Affects of Cutaneous T-Cell Lymphomas | According to the medical literature, CTCL affects males twice as often as females. In the majority of cases, diagnosis is made between 40 and 60 years of age. One study estimated that from .5 to 5 percent of all CTCLs occur in children. CTCLs occur twice as often in individuals of African-American descent as in individuals of European or Asian descent.There are approximately 1,000 new cases of skin lymphoma each year in the United States. Approximately 16,000-20,000 Americans have the classic presentation of CTCL known as mycosis fungoides. One estimate placed the incidence of mycosis fungoides at one case per 1,000,000 people in the United States. | Affects of Cutaneous T-Cell Lymphomas. According to the medical literature, CTCL affects males twice as often as females. In the majority of cases, diagnosis is made between 40 and 60 years of age. One study estimated that from .5 to 5 percent of all CTCLs occur in children. CTCLs occur twice as often in individuals of African-American descent as in individuals of European or Asian descent.There are approximately 1,000 new cases of skin lymphoma each year in the United States. Approximately 16,000-20,000 Americans have the classic presentation of CTCL known as mycosis fungoides. One estimate placed the incidence of mycosis fungoides at one case per 1,000,000 people in the United States. | 340 | Cutaneous T-Cell Lymphomas |
nord_340_4 | Related disorders of Cutaneous T-Cell Lymphomas | Symptoms of the following disorders can be similar to those of CTCL. Comparisons may be useful for a differential diagnosis:A variety of disorders are associated with CTCL, including small plaque parapsoriasis, large plaque parapsoriasis (poikiloderma atrophicans vasculare) and follicular (alopecia) mucinosa. Significant debate exists in the medical literature as to whether these disorders are distinct “premalignant conditions” or early forms of CTCL. Individuals with these disorders have a greater chance than the general population of developing CTCL later during life. Approximately 10-30 percent of cases of large plaque parapsoriasis progress to CTCL.A variety of general skin conditions including psoriasis, contact dermatitis, certain drug reactions, or fungal infections may resemble the early stages of CTCLs. Thorough diagnostic evaluation is necessary to help differentiate CTCLs from such disorders, including the surgical removal (biopsy) and microscopic examination of tissue from skin lesions that are suspected of being cancerous. | Related disorders of Cutaneous T-Cell Lymphomas. Symptoms of the following disorders can be similar to those of CTCL. Comparisons may be useful for a differential diagnosis:A variety of disorders are associated with CTCL, including small plaque parapsoriasis, large plaque parapsoriasis (poikiloderma atrophicans vasculare) and follicular (alopecia) mucinosa. Significant debate exists in the medical literature as to whether these disorders are distinct “premalignant conditions” or early forms of CTCL. Individuals with these disorders have a greater chance than the general population of developing CTCL later during life. Approximately 10-30 percent of cases of large plaque parapsoriasis progress to CTCL.A variety of general skin conditions including psoriasis, contact dermatitis, certain drug reactions, or fungal infections may resemble the early stages of CTCLs. Thorough diagnostic evaluation is necessary to help differentiate CTCLs from such disorders, including the surgical removal (biopsy) and microscopic examination of tissue from skin lesions that are suspected of being cancerous. | 340 | Cutaneous T-Cell Lymphomas |
nord_340_5 | Diagnosis of Cutaneous T-Cell Lymphomas | The diagnosis of cutaneous T-cell lymphomas is based upon a thorough clinical evaluation, detection of certain symptoms and physical findings, a detailed patient history, and a variety of specialized tests. Such testing is necessary to confirm the specific type (and subtype) of CTCL, to assess the nature and extent of the disease, and to determine the most appropriate treatments.For those with suspected lymphoma as suggested by thorough patient history and clinical examination, various diagnostic tests may be recommended. These may include biopsies, blood tests, specialized imaging tests, and/or additional tests.Biopsies typically involve surgical removal and microscopic examination (i.e., histologic) of small samples of tissue cells gathered from CTCL skin lesions. A biopsy may confirm a diagnosis of CTCL. However, the skin lesions associated with the early stages of CTCL are difficult to distinguish from other skin conditions such as psoriasis. Consequently, several biopsies performed over an extended period of time may be necessary to detect characteristic microscopic changes associated with CTCL. A separate test that is often used to help diagnose early stage CTCL is T-cell receptor gene rearrangement analysis (TCRGR). This test can help identify specific rearrangements of particular T-cell gene segments that are characteristic of most individuals with CTCL. The presence of identical twin T-cells may support the diagnosis of CTCL.Blood tests may include studies to evaluate the number and appearance of white blood cells, red blood cells, and platelets; liver enzyme studies; tests to measure levels of the enzyme lactate dehydrogenase (LDH); and/or other studies. (High elevations of LDH may suggest that the lymphoma may have rapid progression, potentially requiring more intensive therapies.) Blood tests may also be performed to detect the presence of characteristic cells (Sezary cells) in individuals with suspected Sezary syndrome.To determine the extent of the disease, various specialized imaging procedures may also be recommended, such as standard x-ray imaging and computed tomography (CT) scanning. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of internal structures. For those with suspected or diagnosed CTCL, CT scans may be taken of the neck, chest, abdominal, and/or pelvic regions to help detect enlargement of certain lymph nodes or spread of the malignancy to certain organs.A procedure known as a bone marrow biopsy may also be recommended to help determine whether the malignancy involves the bone marrow. During this procedure, a sample of bone marrow is obtained, usually from the hipbone (iliac crest). Skin and tissue over the bone is first numbed with local anesthetic, and a needle is inserted into the bone through which a bone marrow sample is withdrawn. The sample is then examined under a microscope by a pathologist. Because a bone marrow biopsy may be painful, a mild, calming (sedative) medication may be offered before the procedure is conducted.In some cases, physicians may recommend other testing procedures to help assess the extent of disease and to follow treatment. In addition, tests may be required to help evaluate the health and functioning of certain organs that may potentially be adversely affected due to certain treatments (e.g., particular anticancer [chemotherapeutic] drugs]). For example, such tests may include certain procedures to evaluate functioning of the heart and lungs.StagingWhen an individual is diagnosed with a CTCL, assessment is also required to determine the extent or “stage” of the disease. Staging is important to help determine how far the disease has spread, characterize the potential disease course, and determine appropriate treatment approaches. Some of the same diagnostic tests described above may be used in staging a CTCL (e.g., blood tests, CT scanning, gallium scanning, bone marrow biopsy). In addition, in some cases, additional biopsies may be obtained to assist in lymphoma staging.Different staging systems have been proposed for CTCLs. The most accepted and widely used system is the tumor-node-metastasis (TNM) system. It includes the following stages:Stage I indicates the presence of red, scaly patches or plaques of skin on the body. There is no involvement of the lymph nodes, blood, or additional organ systems.Stage II indicates either of the following: IIA: the presence of red, scaly patches of skin, but no tumors. The lymph nodes are enlarged, but without the presence of cancer cells; or IIB: tumors are present. Lymph nodes may be enlarged, but without the presence of cancer cells.Stage III indicates that nearly all of the skin is red and scaly. Lymph nodes may be enlarged, but without the presence of cancer cells.Stage IV indicates that individuals have red, scaly skin and involvement of lymph nodes or additional organ systems (e.g., liver, lungs, spleen). | Diagnosis of Cutaneous T-Cell Lymphomas. The diagnosis of cutaneous T-cell lymphomas is based upon a thorough clinical evaluation, detection of certain symptoms and physical findings, a detailed patient history, and a variety of specialized tests. Such testing is necessary to confirm the specific type (and subtype) of CTCL, to assess the nature and extent of the disease, and to determine the most appropriate treatments.For those with suspected lymphoma as suggested by thorough patient history and clinical examination, various diagnostic tests may be recommended. These may include biopsies, blood tests, specialized imaging tests, and/or additional tests.Biopsies typically involve surgical removal and microscopic examination (i.e., histologic) of small samples of tissue cells gathered from CTCL skin lesions. A biopsy may confirm a diagnosis of CTCL. However, the skin lesions associated with the early stages of CTCL are difficult to distinguish from other skin conditions such as psoriasis. Consequently, several biopsies performed over an extended period of time may be necessary to detect characteristic microscopic changes associated with CTCL. A separate test that is often used to help diagnose early stage CTCL is T-cell receptor gene rearrangement analysis (TCRGR). This test can help identify specific rearrangements of particular T-cell gene segments that are characteristic of most individuals with CTCL. The presence of identical twin T-cells may support the diagnosis of CTCL.Blood tests may include studies to evaluate the number and appearance of white blood cells, red blood cells, and platelets; liver enzyme studies; tests to measure levels of the enzyme lactate dehydrogenase (LDH); and/or other studies. (High elevations of LDH may suggest that the lymphoma may have rapid progression, potentially requiring more intensive therapies.) Blood tests may also be performed to detect the presence of characteristic cells (Sezary cells) in individuals with suspected Sezary syndrome.To determine the extent of the disease, various specialized imaging procedures may also be recommended, such as standard x-ray imaging and computed tomography (CT) scanning. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of internal structures. For those with suspected or diagnosed CTCL, CT scans may be taken of the neck, chest, abdominal, and/or pelvic regions to help detect enlargement of certain lymph nodes or spread of the malignancy to certain organs.A procedure known as a bone marrow biopsy may also be recommended to help determine whether the malignancy involves the bone marrow. During this procedure, a sample of bone marrow is obtained, usually from the hipbone (iliac crest). Skin and tissue over the bone is first numbed with local anesthetic, and a needle is inserted into the bone through which a bone marrow sample is withdrawn. The sample is then examined under a microscope by a pathologist. Because a bone marrow biopsy may be painful, a mild, calming (sedative) medication may be offered before the procedure is conducted.In some cases, physicians may recommend other testing procedures to help assess the extent of disease and to follow treatment. In addition, tests may be required to help evaluate the health and functioning of certain organs that may potentially be adversely affected due to certain treatments (e.g., particular anticancer [chemotherapeutic] drugs]). For example, such tests may include certain procedures to evaluate functioning of the heart and lungs.StagingWhen an individual is diagnosed with a CTCL, assessment is also required to determine the extent or “stage” of the disease. Staging is important to help determine how far the disease has spread, characterize the potential disease course, and determine appropriate treatment approaches. Some of the same diagnostic tests described above may be used in staging a CTCL (e.g., blood tests, CT scanning, gallium scanning, bone marrow biopsy). In addition, in some cases, additional biopsies may be obtained to assist in lymphoma staging.Different staging systems have been proposed for CTCLs. The most accepted and widely used system is the tumor-node-metastasis (TNM) system. It includes the following stages:Stage I indicates the presence of red, scaly patches or plaques of skin on the body. There is no involvement of the lymph nodes, blood, or additional organ systems.Stage II indicates either of the following: IIA: the presence of red, scaly patches of skin, but no tumors. The lymph nodes are enlarged, but without the presence of cancer cells; or IIB: tumors are present. Lymph nodes may be enlarged, but without the presence of cancer cells.Stage III indicates that nearly all of the skin is red and scaly. Lymph nodes may be enlarged, but without the presence of cancer cells.Stage IV indicates that individuals have red, scaly skin and involvement of lymph nodes or additional organ systems (e.g., liver, lungs, spleen). | 340 | Cutaneous T-Cell Lymphomas |
nord_340_6 | Therapies of Cutaneous T-Cell Lymphomas | TreatmentIn 2006, the U.S. Food and Drug Administration (FDA) approved vorinostat (Zolinza) for the treatment of cutaneous T-cell lymphoma. Zolinza is to be used when the disease persists or returns after treatment by other medicines. For information, contact the sponsor, Merck & Co., or go to http://www.merck.com/product/usa/pi_circulars/z/zolinza/zolinza_ppi.pdf .In 2018, Poteligeo (mogamulizumab-kpkc) injection was approved for the treatment of adult patients with Sezary Syndrome (SS) after at least one prior systemic therapy. This approval is the first FDA approval of a drug specifically for SS. Poteligeo is manufactured by Kyowa Kirin, Inc.The diagnosis and therapeutic management of cutaneous T-cell lymphomas may require the coordinated efforts of a team of medical professionals, such as specialists who diagnose and treat skin disorders (dermatologists); physicians who specialize in the diagnosis and treatment of cancer (medical oncologists), disorders of the blood and blood-forming tissues (hematologists), or the use of radiation to treat cancers (radiation oncologists); oncology nurses; surgeons; dietitians; and/or other healthcare professionals.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease stage; tumor size; specific subtype of CTCL; the presence or absence of certain symptoms; individual's age and general health; and/or additional elements. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.A wide variety of treatment options exist for individuals with CTCL including topical chemotherapy, radiation therapy, photochemotherapy, vitamin A derivatives (retinoids), and chemotherapy. These treatments may be used alone or in varied combination.During the early stages of CTCLs, conservative topical treatment may be recommended. Early-stage disease confined to the skin often responds extremely well to skin-directed therapies. Such therapies include topical chemotherapy, radiation therapy, and a procedure known as phototherapy. Chemotherapy is treatment with certain anticancer drugs. Specific topical chemotherapies used to treat individuals with early-stage CTCL include mechlorethamine (nitrogen mustard) or carmustine (BCNU). These drugs may be administered as an ointment or watery solution.In 2013, the FDA approved mechlorethamine gel for the topical treatment of stage IA-IB mycosis fungoides-type cutaneous T-cell lymphoma (CTCL). The mechlorethamine gel is applied once per day on the affected skin.Radiation therapy is a treatment method that uses radiation to destroy cancer cells. Radiation therapy may be used to treat specific lesions on the skin. During the early stages of CTCL, electron beam radiation therapy (EBRT), which uses energy rays containing electrons to destroy cancer cells, may be used to treat specific skin lesions. The procedure can treat the entire surface of the skin (total electron beam radiation therapy) without affecting internal organs. Another form of radiation treatment uses conventional x-rays to treat individuals with CTCLs. The x-rays are directed at specific skin lesions. Radiation therapy is effective in treating individuals with early stage and tumor stage CTCL.A procedure known as psoralen plus ultraviolet A phototherapy (PUVA) may also be used to treat individuals with early state CTCL. During this procedure, affected individuals take the drug psoralen, which binds to the DNA in cancer cells making the cells extra sensitive to light. Affected individuals are then exposed to ultraviolet A light, which activates the drug, damages the DNA and ultimately destroys the cancer cells. PUVA therapy has been effective in treating individuals with early stage CTCL and in sustaining remission with long-term maintenance therapy. Another form of phototherapy using ultraviolet B light is effective in treating early patch stage disease.In some cases, a procedure known as extracorporeal photochemotherapy or photopheresis is used to treat individuals with CTCL. In this procedure, the drug psoralen is added to a concentrated blood sample, removed from the body, run under ultraviolet light and, ultimately, returned to the body. This procedure is often used for individuals with the Sezary syndrome variant of CTCL.In some case, individuals with CTCL may be treated with topical and oral retinoids. The FDA has approved bexarotene (Targretin), in both capsule and gel form, for the treatment of individuals with CTCL who have not responded to at least one other systemic treatment.The FDA has also approved a fusion toxin protein, denileukin diftitox (Ontak), for the treatment of individuals with persistent or recurrent CTCL whose malignant cells express the CD25 component of the IL-2 receptor.In individuals with advanced CTCL that has spread to other organ systems of the body or resists standard treatments, a regimen of high-doses of single or multiple anticancer drugs (e.g., methotrexate) may be administered (systemic chemotherapy).Because certain therapies directed against destroying cancer cells may also damage healthy cells, many of these therapies may be associated with various side effects. Therefore, affected individuals should ask their physicians about the specific effects that may be associated with certain treatments. In addition, physicians and other members of the health care team may be able to take certain steps during and following treatment and may advise affected individuals to take particular precautions during therapy that may help to alleviate or prevent certain side effects.Response to standard treatments varies widely; some individuals will respond favorably to certain treatments while other will not. Some individuals with CTCL may have insufficient response to standard therapies or may experience relapses. In some cases, the disease may become resistant (refractory) to standard treatments, potentially leading to life-threatening complications. Therefore, researchers are exploring the potential effectiveness of differing combinations of various chemotherapeutic drugs, high-dose chemotherapy regimens followed by stem cell/bone marrow transplantation, and/or other investigational therapies that may be warranted for selected individuals, possibly at the time of diagnosis, following certain standard therapies, and/or for those with refractory disease or relapse. They are also investigating appropriate ways in which to combine various therapies and to reduce potential side effects. (For further information, please see the “Investigational Therapies” section below.)Other standard therapies for individuals with CTCL include symptomatic and supportive measures (e.g., antibiotics for infection or antihistamines for severe itching). | Therapies of Cutaneous T-Cell Lymphomas. TreatmentIn 2006, the U.S. Food and Drug Administration (FDA) approved vorinostat (Zolinza) for the treatment of cutaneous T-cell lymphoma. Zolinza is to be used when the disease persists or returns after treatment by other medicines. For information, contact the sponsor, Merck & Co., or go to http://www.merck.com/product/usa/pi_circulars/z/zolinza/zolinza_ppi.pdf .In 2018, Poteligeo (mogamulizumab-kpkc) injection was approved for the treatment of adult patients with Sezary Syndrome (SS) after at least one prior systemic therapy. This approval is the first FDA approval of a drug specifically for SS. Poteligeo is manufactured by Kyowa Kirin, Inc.The diagnosis and therapeutic management of cutaneous T-cell lymphomas may require the coordinated efforts of a team of medical professionals, such as specialists who diagnose and treat skin disorders (dermatologists); physicians who specialize in the diagnosis and treatment of cancer (medical oncologists), disorders of the blood and blood-forming tissues (hematologists), or the use of radiation to treat cancers (radiation oncologists); oncology nurses; surgeons; dietitians; and/or other healthcare professionals.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease stage; tumor size; specific subtype of CTCL; the presence or absence of certain symptoms; individual's age and general health; and/or additional elements. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.A wide variety of treatment options exist for individuals with CTCL including topical chemotherapy, radiation therapy, photochemotherapy, vitamin A derivatives (retinoids), and chemotherapy. These treatments may be used alone or in varied combination.During the early stages of CTCLs, conservative topical treatment may be recommended. Early-stage disease confined to the skin often responds extremely well to skin-directed therapies. Such therapies include topical chemotherapy, radiation therapy, and a procedure known as phototherapy. Chemotherapy is treatment with certain anticancer drugs. Specific topical chemotherapies used to treat individuals with early-stage CTCL include mechlorethamine (nitrogen mustard) or carmustine (BCNU). These drugs may be administered as an ointment or watery solution.In 2013, the FDA approved mechlorethamine gel for the topical treatment of stage IA-IB mycosis fungoides-type cutaneous T-cell lymphoma (CTCL). The mechlorethamine gel is applied once per day on the affected skin.Radiation therapy is a treatment method that uses radiation to destroy cancer cells. Radiation therapy may be used to treat specific lesions on the skin. During the early stages of CTCL, electron beam radiation therapy (EBRT), which uses energy rays containing electrons to destroy cancer cells, may be used to treat specific skin lesions. The procedure can treat the entire surface of the skin (total electron beam radiation therapy) without affecting internal organs. Another form of radiation treatment uses conventional x-rays to treat individuals with CTCLs. The x-rays are directed at specific skin lesions. Radiation therapy is effective in treating individuals with early stage and tumor stage CTCL.A procedure known as psoralen plus ultraviolet A phototherapy (PUVA) may also be used to treat individuals with early state CTCL. During this procedure, affected individuals take the drug psoralen, which binds to the DNA in cancer cells making the cells extra sensitive to light. Affected individuals are then exposed to ultraviolet A light, which activates the drug, damages the DNA and ultimately destroys the cancer cells. PUVA therapy has been effective in treating individuals with early stage CTCL and in sustaining remission with long-term maintenance therapy. Another form of phototherapy using ultraviolet B light is effective in treating early patch stage disease.In some cases, a procedure known as extracorporeal photochemotherapy or photopheresis is used to treat individuals with CTCL. In this procedure, the drug psoralen is added to a concentrated blood sample, removed from the body, run under ultraviolet light and, ultimately, returned to the body. This procedure is often used for individuals with the Sezary syndrome variant of CTCL.In some case, individuals with CTCL may be treated with topical and oral retinoids. The FDA has approved bexarotene (Targretin), in both capsule and gel form, for the treatment of individuals with CTCL who have not responded to at least one other systemic treatment.The FDA has also approved a fusion toxin protein, denileukin diftitox (Ontak), for the treatment of individuals with persistent or recurrent CTCL whose malignant cells express the CD25 component of the IL-2 receptor.In individuals with advanced CTCL that has spread to other organ systems of the body or resists standard treatments, a regimen of high-doses of single or multiple anticancer drugs (e.g., methotrexate) may be administered (systemic chemotherapy).Because certain therapies directed against destroying cancer cells may also damage healthy cells, many of these therapies may be associated with various side effects. Therefore, affected individuals should ask their physicians about the specific effects that may be associated with certain treatments. In addition, physicians and other members of the health care team may be able to take certain steps during and following treatment and may advise affected individuals to take particular precautions during therapy that may help to alleviate or prevent certain side effects.Response to standard treatments varies widely; some individuals will respond favorably to certain treatments while other will not. Some individuals with CTCL may have insufficient response to standard therapies or may experience relapses. In some cases, the disease may become resistant (refractory) to standard treatments, potentially leading to life-threatening complications. Therefore, researchers are exploring the potential effectiveness of differing combinations of various chemotherapeutic drugs, high-dose chemotherapy regimens followed by stem cell/bone marrow transplantation, and/or other investigational therapies that may be warranted for selected individuals, possibly at the time of diagnosis, following certain standard therapies, and/or for those with refractory disease or relapse. They are also investigating appropriate ways in which to combine various therapies and to reduce potential side effects. (For further information, please see the “Investigational Therapies” section below.)Other standard therapies for individuals with CTCL include symptomatic and supportive measures (e.g., antibiotics for infection or antihistamines for severe itching). | 340 | Cutaneous T-Cell Lymphomas |
nord_341_0 | Overview of Cutaneous Vasculitis | Cutaneous necrotizing vasculitis (CNV) is characterized by inflammation and tissue damage (necrosis) of blood vessel walls (lumen) and associated skin (cutaneous) lesions. CNV may be a primary disease process or occur as a result of, or in association with, a number of different underlying disorders (e.g., certain infections, certain autoimmune disorders) or other factors (e.g., allergic reaction or hypersensitivity to certain medications, toxins, or inhaled environmental irritants). It is important to determine whether there is an underlying disorder that leads to the CNV before treatment is started.CNV is one of a larger group of disorders involving inflammation and blood vessels known as the vasculitides or the vasculitic syndromes. These syndromes range from modest disorders limited to the skin to more serious ones that may involve various organ systems. | Overview of Cutaneous Vasculitis. Cutaneous necrotizing vasculitis (CNV) is characterized by inflammation and tissue damage (necrosis) of blood vessel walls (lumen) and associated skin (cutaneous) lesions. CNV may be a primary disease process or occur as a result of, or in association with, a number of different underlying disorders (e.g., certain infections, certain autoimmune disorders) or other factors (e.g., allergic reaction or hypersensitivity to certain medications, toxins, or inhaled environmental irritants). It is important to determine whether there is an underlying disorder that leads to the CNV before treatment is started.CNV is one of a larger group of disorders involving inflammation and blood vessels known as the vasculitides or the vasculitic syndromes. These syndromes range from modest disorders limited to the skin to more serious ones that may involve various organ systems. | 341 | Cutaneous Vasculitis |
nord_341_1 | Symptoms of Cutaneous Vasculitis | Cutaneous necrotizing vasculitis is a not uncommon disorder characterized by an inflammation of the blood vessel walls and skin lesions. These skin lesions may be flat and red (macules), nodules or more substantial hemorrhages under the skin (purpura). They may occur on many areas of the body but are seen most often on the back, hands, buttocks, the inside areas of the forearm and the lower extremities. These skin symptoms may occur only once or at regular intervals. They will usually last for several weeks and may leave darkened spots and scarring. In some cases there may be wheel-like lesions that cause intense itching (urticaria), or ring-shaped lesions and ulcers. Blister-like lesions (vesicles, bullae) may develop in severe cases. There may also be fever, generalized discomfort (malaise), muscle or joint pain. | Symptoms of Cutaneous Vasculitis. Cutaneous necrotizing vasculitis is a not uncommon disorder characterized by an inflammation of the blood vessel walls and skin lesions. These skin lesions may be flat and red (macules), nodules or more substantial hemorrhages under the skin (purpura). They may occur on many areas of the body but are seen most often on the back, hands, buttocks, the inside areas of the forearm and the lower extremities. These skin symptoms may occur only once or at regular intervals. They will usually last for several weeks and may leave darkened spots and scarring. In some cases there may be wheel-like lesions that cause intense itching (urticaria), or ring-shaped lesions and ulcers. Blister-like lesions (vesicles, bullae) may develop in severe cases. There may also be fever, generalized discomfort (malaise), muscle or joint pain. | 341 | Cutaneous Vasculitis |
nord_341_2 | Causes of Cutaneous Vasculitis | The exact cause of cutaneous necrotizing vasculitis is unknown. One review suggests that 45-55% of cases are of unknown origin (idiopathic), 15-20% of cases are a response to infection, another 15-20% are the result of connective tissue diseases, 10-15% are the result of reactions to drugs and/or medications, and about 5% are responses to the presence of cancer cells.Some lesions may be caused by an allergic reaction or hypersensitivity to certain medications such as sulfa or penicillin, other drugs, toxins, and inhaled environmental irritants. Skin manifestations may also occur because of a fungal infection, parasites or viral infections, while in some instances the cause may be due to an autoimmune disorder. Autoimmune disorders are caused when the body's natural defenses against “foreign” or invading organisms (e.g., antibodies) begin to attack healthy tissue for unknown reasons. | Causes of Cutaneous Vasculitis. The exact cause of cutaneous necrotizing vasculitis is unknown. One review suggests that 45-55% of cases are of unknown origin (idiopathic), 15-20% of cases are a response to infection, another 15-20% are the result of connective tissue diseases, 10-15% are the result of reactions to drugs and/or medications, and about 5% are responses to the presence of cancer cells.Some lesions may be caused by an allergic reaction or hypersensitivity to certain medications such as sulfa or penicillin, other drugs, toxins, and inhaled environmental irritants. Skin manifestations may also occur because of a fungal infection, parasites or viral infections, while in some instances the cause may be due to an autoimmune disorder. Autoimmune disorders are caused when the body's natural defenses against “foreign” or invading organisms (e.g., antibodies) begin to attack healthy tissue for unknown reasons. | 341 | Cutaneous Vasculitis |
nord_341_3 | Affects of Cutaneous Vasculitis | Cutaneous necrotizing vasculitis affects males and females in equal numbers. It affects children as well as adults. CNV is more common than the other inflammatory vascular disorders. | Affects of Cutaneous Vasculitis. Cutaneous necrotizing vasculitis affects males and females in equal numbers. It affects children as well as adults. CNV is more common than the other inflammatory vascular disorders. | 341 | Cutaneous Vasculitis |
nord_341_4 | Related disorders of Cutaneous Vasculitis | The following diseases can have similarities to cutaneous necrotizing vasculitis:Polyarteritis nodosa is a group of systemic necrotizing vasculitis including the original classic polyarteritis nodosa, allergic granulomatosis, and those disorders that have the characteristics of both (an overlap syndrome). (For more information on this disorder, choose “Polyarteritis” as your search term in the Rare Disease Database.)Wegener's granulomatosis is a rare collagen vascular disorder that begins as a localized inflammation of the upper and lower respiratory tract mucosa, and usually progresses into generalized inflammation of the blood vessels (vasculitis) and kidneys (glomulonephritis). (For more information on this disorder, choose “Wegener” as your search term in the Rare Disease Database.)Churg-Strauss syndrome is a rare disorder that may affect multiple organ systems, particularly the lungs. The disorder is characterized by the formation and accumulation of an unusually large number of antibodies, abnormal clustering of certain white blood cells (eosinophilia), inflammation of blood vessels (vasculitis), and the development of inflammatory nodular lesions (granulomatosis).Many individuals with Churg-Strauss syndrome have a history of allergy. In addition, asthma and other associated lung (pulmonary) abnormalities often precede the development of the generalized symptoms and findings seen in Churg-Strauss syndrome. Asthma, a chronic respiratory disorder, is characterized by inflammation and narrowing of the lungs' airways, causing difficulties breathing (dyspnea), coughing, the production of a high-pitched whistling sound while breathing (wheezing), and/or other symptoms and findings.Henoch-Shonlein purpura is one of a group of disorders characterized by discolored purplish or brownish-red skin. These spots may be large or small. Internal bleeding may occur in various areas of the body. This blood vessel disorder may affect the skin, joints, gastrointestinal system, kidneys, and in a very few cases the central nervous system. Little is known about the cause of this form of purpura although it may be an allergic reaction which more often occurs in children than adults. (For more information on this disorder, choose “Henoch-Shonlein” as your search term in the Rare Disease Database.) | Related disorders of Cutaneous Vasculitis. The following diseases can have similarities to cutaneous necrotizing vasculitis:Polyarteritis nodosa is a group of systemic necrotizing vasculitis including the original classic polyarteritis nodosa, allergic granulomatosis, and those disorders that have the characteristics of both (an overlap syndrome). (For more information on this disorder, choose “Polyarteritis” as your search term in the Rare Disease Database.)Wegener's granulomatosis is a rare collagen vascular disorder that begins as a localized inflammation of the upper and lower respiratory tract mucosa, and usually progresses into generalized inflammation of the blood vessels (vasculitis) and kidneys (glomulonephritis). (For more information on this disorder, choose “Wegener” as your search term in the Rare Disease Database.)Churg-Strauss syndrome is a rare disorder that may affect multiple organ systems, particularly the lungs. The disorder is characterized by the formation and accumulation of an unusually large number of antibodies, abnormal clustering of certain white blood cells (eosinophilia), inflammation of blood vessels (vasculitis), and the development of inflammatory nodular lesions (granulomatosis).Many individuals with Churg-Strauss syndrome have a history of allergy. In addition, asthma and other associated lung (pulmonary) abnormalities often precede the development of the generalized symptoms and findings seen in Churg-Strauss syndrome. Asthma, a chronic respiratory disorder, is characterized by inflammation and narrowing of the lungs' airways, causing difficulties breathing (dyspnea), coughing, the production of a high-pitched whistling sound while breathing (wheezing), and/or other symptoms and findings.Henoch-Shonlein purpura is one of a group of disorders characterized by discolored purplish or brownish-red skin. These spots may be large or small. Internal bleeding may occur in various areas of the body. This blood vessel disorder may affect the skin, joints, gastrointestinal system, kidneys, and in a very few cases the central nervous system. Little is known about the cause of this form of purpura although it may be an allergic reaction which more often occurs in children than adults. (For more information on this disorder, choose “Henoch-Shonlein” as your search term in the Rare Disease Database.) | 341 | Cutaneous Vasculitis |
nord_341_5 | Diagnosis of Cutaneous Vasculitis | The results of a skin biopsy demonstrate the presence or absence of CNV. Since a number of the more severe vasculitides involve the skin as well as other organ systems, additional tests of other organs must be prescribed in order to be sure that CNV is limited to the skin. | Diagnosis of Cutaneous Vasculitis. The results of a skin biopsy demonstrate the presence or absence of CNV. Since a number of the more severe vasculitides involve the skin as well as other organ systems, additional tests of other organs must be prescribed in order to be sure that CNV is limited to the skin. | 341 | Cutaneous Vasculitis |
nord_341_6 | Therapies of Cutaneous Vasculitis | TreatmentTreatment of cutaneous necrotizing bvasculitis depends on the cause and symptoms. Removing the irritating agent (e.g., drug) and treating the underlying infection will usually eliminate the symptoms of this disorder. The drugs prednisone, cyclophosphamide, pentoxifylline and azathioprine have proven to be successful in treating the autoimmune form of Vasculitis. Other treatment is symptomatic and supportive. | Therapies of Cutaneous Vasculitis. TreatmentTreatment of cutaneous necrotizing bvasculitis depends on the cause and symptoms. Removing the irritating agent (e.g., drug) and treating the underlying infection will usually eliminate the symptoms of this disorder. The drugs prednisone, cyclophosphamide, pentoxifylline and azathioprine have proven to be successful in treating the autoimmune form of Vasculitis. Other treatment is symptomatic and supportive. | 341 | Cutaneous Vasculitis |
nord_342_0 | Overview of Cutis Laxa | Cutis laxa is a general term for a group of rare disorders that may occur in several inherited (congenital) forms or acquired at some point during life (acquired cutis laxa). This group of disorders involves a wide spectrum of symptoms and signs that result from defects in connective tissue, the material between cells of the body that gives the tissue form and strength. Connective tissue is found throughout the body in muscles, joints, skin and other organs. Cutis laxa is characterized by skin that is loose (lax), wrinkled, sagging, redundant, and lacking elasticity (inelastic). When stretched, inelastic skin returns to place abnormally slowly. The skin around the face, arms, legs and trunk is most commonly affected. Abnormal skin may give affected individuals and children a prematurely-aged appearance and they can look much older than their true age. Unlike similar skin disorders, easy bruising and scarring are generally not associated with cutis laxa. The joints are often abnormally loose (hypermobility) because of lax ligaments and tendons. Several inherited forms of the disorder have been identified. Most cases are inherited as either an autosomal dominant or recessive disorder. An X-linked form of cutis laxa, known as occipital horn syndrome, is now considered a mild form of disorders of copper metabolism caused by a mutation in the ATP7A gene and is not discussed in this report. | Overview of Cutis Laxa. Cutis laxa is a general term for a group of rare disorders that may occur in several inherited (congenital) forms or acquired at some point during life (acquired cutis laxa). This group of disorders involves a wide spectrum of symptoms and signs that result from defects in connective tissue, the material between cells of the body that gives the tissue form and strength. Connective tissue is found throughout the body in muscles, joints, skin and other organs. Cutis laxa is characterized by skin that is loose (lax), wrinkled, sagging, redundant, and lacking elasticity (inelastic). When stretched, inelastic skin returns to place abnormally slowly. The skin around the face, arms, legs and trunk is most commonly affected. Abnormal skin may give affected individuals and children a prematurely-aged appearance and they can look much older than their true age. Unlike similar skin disorders, easy bruising and scarring are generally not associated with cutis laxa. The joints are often abnormally loose (hypermobility) because of lax ligaments and tendons. Several inherited forms of the disorder have been identified. Most cases are inherited as either an autosomal dominant or recessive disorder. An X-linked form of cutis laxa, known as occipital horn syndrome, is now considered a mild form of disorders of copper metabolism caused by a mutation in the ATP7A gene and is not discussed in this report. | 342 | Cutis Laxa |
nord_342_1 | Symptoms of Cutis Laxa | Cutis laxa encompasses a wide variety of disorders. The specific symptoms present, severity and prognosis can vary greatly depending upon the specific type of cutis laxa and the presence and extent of associated symptoms. The specific symptoms and severity can vary even among individuals with the same subtype and even among members of the same family. In addition, some subtypes of cutis laxa have only been reported in a handful of individuals, which prevents 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. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis. Despite the wide variety in presentation, most affected individuals develop the characteristic skin abnormalities and joints problems described above.In the past, cutis laxa subtypes were defined by clinical symptoms. However, cutis laxa is now separated based upon the molecular basis of the disorders (i.e. mutated gene). The information below is broken down by specific subtype.EFEMP2-RELATED CUTIS LAXAThis disorder is also known as FBLN4-related cutis laxa or autosomal recessive cutis laxa type 1B (ARCL1B). It is a highly variable disorder that range from severe, life-threatening complications early in life (i.e. heart or lung [cardiopulmonary] failure) to cases that are limited to vascular disease and abnormalities of the head and face (craniofacial abnormalities).Individuals with EFEMP2-related cutis laxa develop the skin symptoms of cutis laxa as well as systemic involvement, particularly the cardiovascular and skeletal systems. The skin symptoms may be mild. Affected infants may have distinctive facial features including eyes that are farther apart than normal (ocular hypertelorism), low-set, malformed (dysplastic) ears, highly arched palate, and a small, receding jaw (retrognathia). Joint laxity and arachnodactyly, a condition in which the fingers and toes are abnormally long, thin and curved, are common findings.Affected individuals may develop abnormalities affecting various blood vessels including twisting or distortion of arteries (arterial tortuosity), a stretched or bulging section of the wall of the main artery of the heart (aortic aneurysm), and underdevelopment of the arteries of the lungs (pulmonary arterial hypoplasia). In some cases, affected individuals may also develop abnormal enlargement of the heart (cardiac hypertrophy) and a slower than normal heart rate (bradycardia). In severe cases, the various vascular and cardiac abnormalities can progress to cause heart failure.Some individuals with EFEMP2-related cutis laxa develop pulmonary emphysema, a chronic lung disease in which the tiny air sacs in the lungs (alveoli) are damaged or do not function properly, resulting in shortness of breath and a chronic cough. Pulmonary emphysema can progress to cause lung failure.Additional symptoms can develop in some cases of EFEMP2-related cutis laxa including diminished muscle tone (hypotonia), a sunken chest (pectus excavatum), and fragile bones that are prone to fracture. Diaphragmatic hernia, a condition in which part of the stomach and/or the small intestines can protrude into the chest cavity, can also occur.FBLN5-RELATED CUTIS LAXAThis disorder is also known as autosomal recessive cutis laxa type 1A (ARCL1A). The symptoms and age of onset are highly variable. Affected individuals develop the skin and joint symptoms of cutis laxa. Growth deficiencies and delayed motor development have been reported in some cases.There is usually childhood onset of serious complications such as narrowing (stenosis) of the pulmonary artery, hernias, and the formation of diverticula within the intestines and bladder. In some cases, stenosis of the aorta just above the valve that connects the aorta to the heart may occur (supravalvular aortic stenosis). In severe cases, the disorder can progress to cause life-threatening complications such as pulmonary or cardiac insufficiency or failure during childhood. In affected individuals who survive early childhood, additional serious complications such as failure of the right side of the heart (cor pulmonale) and severe pulmonary emphysema may develop.LTBP4-RELATED CUTIS LAXAThis disorder is also known as Urban-Rifkin-Davis syndrome or autosomal recessive cutis laxa type 1C (ARCL1C). In addition to the skin symptoms of cutis laxa, affected individuals can develop joint laxity, diminished muscle tone, growth delays, and severe complications affecting the pulmonary, gastrointestinal, and urinary systems. Cardiovascular involvement is relatively mild.Affected individuals may develop severe breathing difficulties (respiratory distress) associated with cystic changes in the lungs as well as collapse of part of the lung (atelectasis). In some cases, pulmonary issues can be worsened by narrowing of the pulmonary artery and by the occurrence of diaphragmatic hernia and/or softening or weakening of the cartilage of the trachea (tracheomalacia), which can potentially result in the collapse of the air passage. Severe emphysema can develop. Eventually, affected individuals may experience respiratory failure.Gastrointestinal abnormalities include the formation of diverticula and narrowing, twisting or enlargement of segments of the intestinal tract. Urinary tract abnormalities can include abnormal accumulation of urine in the kidneys (hydronephrosis) and the formation of sac-like protrusions or pouches in the intestines (diverticulosis).Individuals with LTBP4-related cutis laxa may have distinctive facial features including an abnormally small jaw (micrognathia), receding forehead, widened soft spots near the back of the head (wide anterior fontanels), widely spaced eyes (hypertelorism), and, in some cases, prominent ears. The middle of the face may appear flattened. Growth deficiencies during infancy have also been reported.ATP6V0A2-RELATED CUTIS LAXAThis disorder is also known autosomal recessive cutis laxa 2A (ARCL2A) and represents a spectrum of disease ranging from wrinkly skin syndrome on the mild end to Debre-type cutis laxa on the severe end. Generally, individuals with the Debre-type have more severe neurological and developmental abnormalities, but less severe skin symptoms. Individuals with wrinkled skin syndrome have only mild developmental delays and subsequent neurodegeneration.Affected individuals may have wrinkled or furrowed skin over the entire body. The skin may be redundant, saggy and inelastic as well. Skin symptoms often improve with age, but degenerative scars may remain in some cases.Infants may experience diminished muscle tone (hypotonia), abnormal fat distribution, feeding difficulties, growth deficiency, and failure to thrive. In addition, affected infants may have an enlarged soft spot (fontanel) that closes later than normal and distinctive facial features that are present at birth and become more distinctive as they grow older. Such features include downward slanting of the opening between the eyelids (down slanting palpebral fissures), a broad, flat bridge of the nose, abnormally large nostrils that are tipped upward (anteverted nares), large ears, and a small mouth.Affected infants may also exhibit nearsightedness (myopia), eyes that do not line up in the same direction such as crossed-eyes (strabismus), dislocation of the hip that is present at birth, joint laxity, and microcephaly, a condition in which head circumference is smaller than would normally be expected based upon age and gender. Some infants may have protrusion of abdominal tissue or part of the small intestines through a bulge in the abdominal muscles near the groin (inguinal hernia).Most affected children have malformations of certain areas of the brain (cortical and cerebellar malformations) that result in delays in reaching developmental milestones (developmental delays) and intellectual disability. Progressive neurological decline (regressions) may begin near the end of the first decade of life. Some children may experience generalized or partial seizures usually between the ages of 8-12.Neurological regression can be associated with a variety of symptoms including slurred speech, an inability to coordinate voluntary movements (ataxia), and increased muscle tone and stiffness (spasticity). Some affected children may eventually require a wheelchair.Cardiovascular and pulmonary complications common in other forms of cutis laxa are rare in ATP6V0A2-related cutis laxa.This disorder is also classified as a congenital disorder of glycosylation, which is an umbrella term for an expanding group of rare metabolic disorders that share similar but not identical genetic changes (mutations) and biochemical activity. These disorders involve a normal, but complex, chemical process known as glycosylation. (For more information, choose “congenital disorders of glycosylation” as your search term in the Rare Disease Database.)PYCR1-RELATED CUTIS LAXAThis disorder is also known as autosomal recessive cutis laxa 2B (ARCL2B). The skin symptoms of cutis laxa are more pronounced in the arms and legs. Affected individuals may experience growth delays, developmental delays, failure to thrive, intellectual disability, joint laxity and skeletal malformations. Underdevelopment (hypoplasia) of the thick band of nerve fibers that separates the cerebellum into right and left hemispheres (corpus callosum) is common. Affected individuals may also have distinctive facial features including an abnormally large forehead, large ears, a rounded (bulbous) nose, a protruding jaw (prognathism), bluish discoloration of the whites of the eyes (blue sclera), and a triangular-shaped face with a prematurely-aged appearance. The circumference of the head may be smaller than expected based upon an infant’s age and gender (microcephaly).Skeletal malformations may include sideways curvature of the spine (scoliosis), bowing of the long bones of the arms and legs, clasped thumbs, abnormally long fingers and toes, reduced bone density (osteopenia), fragile bones that are prone to fracture (osteoporosis), and congenital dislocation of the hip.The specific symptoms and severity of PYCR1-related cutis laxa can vary greatly. Individuals originally diagnosed with gerodermia osteodysplastica, wrinkled skin syndrome and De Barsy syndrome have been found to carry a PYCR1 gene mutation.ALDH18A1-RELATED CUTIS LAXAThis disorder is also known as autosomal recessive cutis laxa type 3 (ARCL3). Affected individuals develop the characteristic skin symptoms of cutis laxa along with growth deficiencies, moderate to severe intellectual disability, loose joints, cataracts and corneal abnormalities. Additional symptoms may eventually develop including dystonia, a group of movement disorders that vary in their symptoms, causes, progression, and treatments. This group of neurological conditions is generally characterized by involuntary muscle contractions that force the body in abnormal, sometimes painful, movements and positions (postures). Individuals with this form of cutis laxa usually do not have cardiovascular or pulmonary complications. Many individuals with de Barsy syndrome were found to have a mutation in the ALDH18A1 gene. NORD has an individual report on de Barsy syndrome. For more information, choose “De Barsy” as your search term in the Rare Disease Database.AUTOSOMAL DOMINANT CUTIS LAXAMost cases of autosomal dominant cutis laxa are caused by mutations in the elastin (ELN) gene and are also known as ELN-related cutis laxa or autosomal dominant cutis laxa type 1 (ADCL1). One case, classified as autosomal dominant cutis laxa type 2 (ADCL2), was caused by a mutation in the fibulin-5 (FBLN5) gene; this gene also causes autosomal recessive cutis laxa 1A.The symptoms of ELN-related cutis laxa can appear at any point between birth and young adulthood. Generally, onset is later than seen in autosomal recessive forms of the disorder. Affected individuals may have distinctive facial features, which can include a beaked nose, an abnormally long groove that runs from the base of the nose to the upper lip (philtrum), a high forehead, and large ears. In some cases, individuals will only develop the characteristic skin symptoms of cutis laxa, although the affected skin may worsen with age. The cutis laxa skin symptoms in the autosomal forms are generally milder than the skin symptoms in the recessive forms. Less often, affected individuals will also develop more serious complications including cardiovascular and pulmonary abnormalities such as aortic aneurysms, pulmonary artery disease, or emphysema. Inguinal hernia has also been reported. Gastrointestinal abnormalities are uncommon with this form of cutis laxa.Autosomal recessive ELN-related cutis laxa has been reportedGERODERMA OSTEODYSPLASTICUMThis rare disorder is also known as gerodermia osteodysplastica or Walt Disney dwarfism and is sometimes classified as a subtype of autosomal recessive cutis laxa type 2. Geroderma osteodysplasticum primarily occurs in infants or young children and is characterized by loose skin, particularly affecting the hands, feet, face and stomach. Affected individuals may have distinctive facial features including underdevelopment of the cheeks (malar hypoplasia), a protruding jaw (prognathism), and a prematurely aged appearance. Joint laxity, hernias, frequent hip dislocations, and varying degrees of growth deficiency and short stature can also occur. Osteoporosis may also present, resulting in fragile bones that are prone to fracture. More severe complications such as cardiovascular or pulmonary symptoms rarely develop.RIN2-RELATED CUTIS LAXAThis extremely rare disorder, also known as (M)acrocephaly, (A)lopecia, (C)utis laxa (S)coliosis or MACS syndrome, has only been reported in several individuals from four families (kindreds) from different ethnic origins. Symptoms include an abnormally large head (macrocephaly), partial or complete hair loss (alopecia) and the skin symptoms of cutis laxa. Cutis laxa is mild with redundant skin on the face the most common manifestation. However, because the disorder has been reported in so few individuals, the complete clinical picture and the symptoms that most often associated with the disorder are unknown. Additional symptoms that were reported in the affected families include joint laxity, moderate to severe scoliosis, and characteristic facial features including abnormal enlargement of the gums (gingival hyperplasia), a lower lip that is turned or rolled outward (everted), a receded jaw (retrognathia), puffy eyelids, and abnormal positioning of the teeth. Some infants may have dry, scaly, thickened skin. Widening (dilation) of the aorta and generalized osteoporosis have also been reported. Mild intellectual disability was seen in some, but not all, affected individuals.ACQUIRED CUTIS LAXAThis form of cutis laxa is generally seen in adults. Affected individuals develop the characteristic skin symptoms associated with cutis laxa. Acquired cutis laxa may begin in the face and progresses downward. Systemic involvement including emphysema, vascular abnormalities, intestinal diverticula, and hernias has also been reported in some cases. The disorder has developed in some individuals following exposure to specific environmental factors such as certain medications, infections or autoimmune diseases.Acquired cutis laxa is sometimes broken down into type 1 and type 2. Type 1 may be associated with cutis laxa that is widespread through the body or localized to a specific area and can occur at any age, although most cases begin in adulthood. Localized forms frequently affect the face or the hands and feet. Systemic involvement may occur in some cases. Type 2 usually develops following acute inflammatory skin lesions, in which the areas affected by the skin lesions develop cutis laxa skin symptoms. | Symptoms of Cutis Laxa. Cutis laxa encompasses a wide variety of disorders. The specific symptoms present, severity and prognosis can vary greatly depending upon the specific type of cutis laxa and the presence and extent of associated symptoms. The specific symptoms and severity can vary even among individuals with the same subtype and even among members of the same family. In addition, some subtypes of cutis laxa have only been reported in a handful of individuals, which prevents 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. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis. Despite the wide variety in presentation, most affected individuals develop the characteristic skin abnormalities and joints problems described above.In the past, cutis laxa subtypes were defined by clinical symptoms. However, cutis laxa is now separated based upon the molecular basis of the disorders (i.e. mutated gene). The information below is broken down by specific subtype.EFEMP2-RELATED CUTIS LAXAThis disorder is also known as FBLN4-related cutis laxa or autosomal recessive cutis laxa type 1B (ARCL1B). It is a highly variable disorder that range from severe, life-threatening complications early in life (i.e. heart or lung [cardiopulmonary] failure) to cases that are limited to vascular disease and abnormalities of the head and face (craniofacial abnormalities).Individuals with EFEMP2-related cutis laxa develop the skin symptoms of cutis laxa as well as systemic involvement, particularly the cardiovascular and skeletal systems. The skin symptoms may be mild. Affected infants may have distinctive facial features including eyes that are farther apart than normal (ocular hypertelorism), low-set, malformed (dysplastic) ears, highly arched palate, and a small, receding jaw (retrognathia). Joint laxity and arachnodactyly, a condition in which the fingers and toes are abnormally long, thin and curved, are common findings.Affected individuals may develop abnormalities affecting various blood vessels including twisting or distortion of arteries (arterial tortuosity), a stretched or bulging section of the wall of the main artery of the heart (aortic aneurysm), and underdevelopment of the arteries of the lungs (pulmonary arterial hypoplasia). In some cases, affected individuals may also develop abnormal enlargement of the heart (cardiac hypertrophy) and a slower than normal heart rate (bradycardia). In severe cases, the various vascular and cardiac abnormalities can progress to cause heart failure.Some individuals with EFEMP2-related cutis laxa develop pulmonary emphysema, a chronic lung disease in which the tiny air sacs in the lungs (alveoli) are damaged or do not function properly, resulting in shortness of breath and a chronic cough. Pulmonary emphysema can progress to cause lung failure.Additional symptoms can develop in some cases of EFEMP2-related cutis laxa including diminished muscle tone (hypotonia), a sunken chest (pectus excavatum), and fragile bones that are prone to fracture. Diaphragmatic hernia, a condition in which part of the stomach and/or the small intestines can protrude into the chest cavity, can also occur.FBLN5-RELATED CUTIS LAXAThis disorder is also known as autosomal recessive cutis laxa type 1A (ARCL1A). The symptoms and age of onset are highly variable. Affected individuals develop the skin and joint symptoms of cutis laxa. Growth deficiencies and delayed motor development have been reported in some cases.There is usually childhood onset of serious complications such as narrowing (stenosis) of the pulmonary artery, hernias, and the formation of diverticula within the intestines and bladder. In some cases, stenosis of the aorta just above the valve that connects the aorta to the heart may occur (supravalvular aortic stenosis). In severe cases, the disorder can progress to cause life-threatening complications such as pulmonary or cardiac insufficiency or failure during childhood. In affected individuals who survive early childhood, additional serious complications such as failure of the right side of the heart (cor pulmonale) and severe pulmonary emphysema may develop.LTBP4-RELATED CUTIS LAXAThis disorder is also known as Urban-Rifkin-Davis syndrome or autosomal recessive cutis laxa type 1C (ARCL1C). In addition to the skin symptoms of cutis laxa, affected individuals can develop joint laxity, diminished muscle tone, growth delays, and severe complications affecting the pulmonary, gastrointestinal, and urinary systems. Cardiovascular involvement is relatively mild.Affected individuals may develop severe breathing difficulties (respiratory distress) associated with cystic changes in the lungs as well as collapse of part of the lung (atelectasis). In some cases, pulmonary issues can be worsened by narrowing of the pulmonary artery and by the occurrence of diaphragmatic hernia and/or softening or weakening of the cartilage of the trachea (tracheomalacia), which can potentially result in the collapse of the air passage. Severe emphysema can develop. Eventually, affected individuals may experience respiratory failure.Gastrointestinal abnormalities include the formation of diverticula and narrowing, twisting or enlargement of segments of the intestinal tract. Urinary tract abnormalities can include abnormal accumulation of urine in the kidneys (hydronephrosis) and the formation of sac-like protrusions or pouches in the intestines (diverticulosis).Individuals with LTBP4-related cutis laxa may have distinctive facial features including an abnormally small jaw (micrognathia), receding forehead, widened soft spots near the back of the head (wide anterior fontanels), widely spaced eyes (hypertelorism), and, in some cases, prominent ears. The middle of the face may appear flattened. Growth deficiencies during infancy have also been reported.ATP6V0A2-RELATED CUTIS LAXAThis disorder is also known autosomal recessive cutis laxa 2A (ARCL2A) and represents a spectrum of disease ranging from wrinkly skin syndrome on the mild end to Debre-type cutis laxa on the severe end. Generally, individuals with the Debre-type have more severe neurological and developmental abnormalities, but less severe skin symptoms. Individuals with wrinkled skin syndrome have only mild developmental delays and subsequent neurodegeneration.Affected individuals may have wrinkled or furrowed skin over the entire body. The skin may be redundant, saggy and inelastic as well. Skin symptoms often improve with age, but degenerative scars may remain in some cases.Infants may experience diminished muscle tone (hypotonia), abnormal fat distribution, feeding difficulties, growth deficiency, and failure to thrive. In addition, affected infants may have an enlarged soft spot (fontanel) that closes later than normal and distinctive facial features that are present at birth and become more distinctive as they grow older. Such features include downward slanting of the opening between the eyelids (down slanting palpebral fissures), a broad, flat bridge of the nose, abnormally large nostrils that are tipped upward (anteverted nares), large ears, and a small mouth.Affected infants may also exhibit nearsightedness (myopia), eyes that do not line up in the same direction such as crossed-eyes (strabismus), dislocation of the hip that is present at birth, joint laxity, and microcephaly, a condition in which head circumference is smaller than would normally be expected based upon age and gender. Some infants may have protrusion of abdominal tissue or part of the small intestines through a bulge in the abdominal muscles near the groin (inguinal hernia).Most affected children have malformations of certain areas of the brain (cortical and cerebellar malformations) that result in delays in reaching developmental milestones (developmental delays) and intellectual disability. Progressive neurological decline (regressions) may begin near the end of the first decade of life. Some children may experience generalized or partial seizures usually between the ages of 8-12.Neurological regression can be associated with a variety of symptoms including slurred speech, an inability to coordinate voluntary movements (ataxia), and increased muscle tone and stiffness (spasticity). Some affected children may eventually require a wheelchair.Cardiovascular and pulmonary complications common in other forms of cutis laxa are rare in ATP6V0A2-related cutis laxa.This disorder is also classified as a congenital disorder of glycosylation, which is an umbrella term for an expanding group of rare metabolic disorders that share similar but not identical genetic changes (mutations) and biochemical activity. These disorders involve a normal, but complex, chemical process known as glycosylation. (For more information, choose “congenital disorders of glycosylation” as your search term in the Rare Disease Database.)PYCR1-RELATED CUTIS LAXAThis disorder is also known as autosomal recessive cutis laxa 2B (ARCL2B). The skin symptoms of cutis laxa are more pronounced in the arms and legs. Affected individuals may experience growth delays, developmental delays, failure to thrive, intellectual disability, joint laxity and skeletal malformations. Underdevelopment (hypoplasia) of the thick band of nerve fibers that separates the cerebellum into right and left hemispheres (corpus callosum) is common. Affected individuals may also have distinctive facial features including an abnormally large forehead, large ears, a rounded (bulbous) nose, a protruding jaw (prognathism), bluish discoloration of the whites of the eyes (blue sclera), and a triangular-shaped face with a prematurely-aged appearance. The circumference of the head may be smaller than expected based upon an infant’s age and gender (microcephaly).Skeletal malformations may include sideways curvature of the spine (scoliosis), bowing of the long bones of the arms and legs, clasped thumbs, abnormally long fingers and toes, reduced bone density (osteopenia), fragile bones that are prone to fracture (osteoporosis), and congenital dislocation of the hip.The specific symptoms and severity of PYCR1-related cutis laxa can vary greatly. Individuals originally diagnosed with gerodermia osteodysplastica, wrinkled skin syndrome and De Barsy syndrome have been found to carry a PYCR1 gene mutation.ALDH18A1-RELATED CUTIS LAXAThis disorder is also known as autosomal recessive cutis laxa type 3 (ARCL3). Affected individuals develop the characteristic skin symptoms of cutis laxa along with growth deficiencies, moderate to severe intellectual disability, loose joints, cataracts and corneal abnormalities. Additional symptoms may eventually develop including dystonia, a group of movement disorders that vary in their symptoms, causes, progression, and treatments. This group of neurological conditions is generally characterized by involuntary muscle contractions that force the body in abnormal, sometimes painful, movements and positions (postures). Individuals with this form of cutis laxa usually do not have cardiovascular or pulmonary complications. Many individuals with de Barsy syndrome were found to have a mutation in the ALDH18A1 gene. NORD has an individual report on de Barsy syndrome. For more information, choose “De Barsy” as your search term in the Rare Disease Database.AUTOSOMAL DOMINANT CUTIS LAXAMost cases of autosomal dominant cutis laxa are caused by mutations in the elastin (ELN) gene and are also known as ELN-related cutis laxa or autosomal dominant cutis laxa type 1 (ADCL1). One case, classified as autosomal dominant cutis laxa type 2 (ADCL2), was caused by a mutation in the fibulin-5 (FBLN5) gene; this gene also causes autosomal recessive cutis laxa 1A.The symptoms of ELN-related cutis laxa can appear at any point between birth and young adulthood. Generally, onset is later than seen in autosomal recessive forms of the disorder. Affected individuals may have distinctive facial features, which can include a beaked nose, an abnormally long groove that runs from the base of the nose to the upper lip (philtrum), a high forehead, and large ears. In some cases, individuals will only develop the characteristic skin symptoms of cutis laxa, although the affected skin may worsen with age. The cutis laxa skin symptoms in the autosomal forms are generally milder than the skin symptoms in the recessive forms. Less often, affected individuals will also develop more serious complications including cardiovascular and pulmonary abnormalities such as aortic aneurysms, pulmonary artery disease, or emphysema. Inguinal hernia has also been reported. Gastrointestinal abnormalities are uncommon with this form of cutis laxa.Autosomal recessive ELN-related cutis laxa has been reportedGERODERMA OSTEODYSPLASTICUMThis rare disorder is also known as gerodermia osteodysplastica or Walt Disney dwarfism and is sometimes classified as a subtype of autosomal recessive cutis laxa type 2. Geroderma osteodysplasticum primarily occurs in infants or young children and is characterized by loose skin, particularly affecting the hands, feet, face and stomach. Affected individuals may have distinctive facial features including underdevelopment of the cheeks (malar hypoplasia), a protruding jaw (prognathism), and a prematurely aged appearance. Joint laxity, hernias, frequent hip dislocations, and varying degrees of growth deficiency and short stature can also occur. Osteoporosis may also present, resulting in fragile bones that are prone to fracture. More severe complications such as cardiovascular or pulmonary symptoms rarely develop.RIN2-RELATED CUTIS LAXAThis extremely rare disorder, also known as (M)acrocephaly, (A)lopecia, (C)utis laxa (S)coliosis or MACS syndrome, has only been reported in several individuals from four families (kindreds) from different ethnic origins. Symptoms include an abnormally large head (macrocephaly), partial or complete hair loss (alopecia) and the skin symptoms of cutis laxa. Cutis laxa is mild with redundant skin on the face the most common manifestation. However, because the disorder has been reported in so few individuals, the complete clinical picture and the symptoms that most often associated with the disorder are unknown. Additional symptoms that were reported in the affected families include joint laxity, moderate to severe scoliosis, and characteristic facial features including abnormal enlargement of the gums (gingival hyperplasia), a lower lip that is turned or rolled outward (everted), a receded jaw (retrognathia), puffy eyelids, and abnormal positioning of the teeth. Some infants may have dry, scaly, thickened skin. Widening (dilation) of the aorta and generalized osteoporosis have also been reported. Mild intellectual disability was seen in some, but not all, affected individuals.ACQUIRED CUTIS LAXAThis form of cutis laxa is generally seen in adults. Affected individuals develop the characteristic skin symptoms associated with cutis laxa. Acquired cutis laxa may begin in the face and progresses downward. Systemic involvement including emphysema, vascular abnormalities, intestinal diverticula, and hernias has also been reported in some cases. The disorder has developed in some individuals following exposure to specific environmental factors such as certain medications, infections or autoimmune diseases.Acquired cutis laxa is sometimes broken down into type 1 and type 2. Type 1 may be associated with cutis laxa that is widespread through the body or localized to a specific area and can occur at any age, although most cases begin in adulthood. Localized forms frequently affect the face or the hands and feet. Systemic involvement may occur in some cases. Type 2 usually develops following acute inflammatory skin lesions, in which the areas affected by the skin lesions develop cutis laxa skin symptoms. | 342 | Cutis Laxa |
nord_342_2 | Causes of Cutis Laxa | Cutis laxa is caused by mutations in specific genes. 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, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body. For disorders classified as cutis laxa, these mutations can be inherited in an autosomal recessive or autosomal dominant trait.Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child. In some cases, an autosomal dominant mutation results from a spontaneous (de novo) mutation that occurs randomly and is not inherited.A significant number of individuals diagnosed with cutis laxa do not have a mutation in one of the genes known to cause a subtype of cutis laxa. Most likely, additional, as-yet-unidentified genes cause cutis laxa in these cases.EFEMP2-related cutis laxa is caused by mutations in the EFEMP2 gene, which is located on the long arm (q) on chromosome 11 (11q13.1). EFEMP2-related cutis laxa is inherited as an autosomal recessive disorder.FBLN5-related cutis laxa is caused by mutations in the FBLN5 gene, which is located on the long arm of chromosome 14 (14q32.12). FBLN5-related cutis laxa is inherited as an autosomal recessive disorder. In one case, a mutation in this gene has been inherited in an autosomal dominant manner.LTBP4-related cutis laxa is caused by mutations in the LTBP4 gene, which is located on the long arm of chromosome 19 (19q13.2). LTBP4-related cutis laxa is inherited as an autosomal recessive disorder.ATP6V0A2-related cutis laxa is caused by mutations in the ATP6V0A2 gene, which is located on the long arm of chromosome 12 (12q24.31). ATP6V0A2-related cutis laxa is inherited as an autosomal recessive disorder.PYCR1-related cutis laxa is caused by mutations in the PYCR1 gene, which is located on the long arm of chromosome 17 (17q25.3). PYCR1-related cutis laxa is inherited as an autosomal recessive disorder.RIN2-related cutis laxa is caused by mutations in the RIN2 gene, which is located on the short arm of chromosome 20 (20p11.23). RIN2-related cutis laxa is inherited as an autosomal recessive disorder.The exact cause of De Barsy syndrome is not fully understood. Individuals with a diagnosis of De Barsy syndrome have been found to have mutations in the PYCR1 or ALDH18A1 genes. The ALDH18A1 gene is located on the long arm of chromosome 10 (10q24.1). De Barsy syndrome is believed to be inherited as an autosomal recessive disorder.Geroderma osteodysplasticum is caused by mutations in the GORAB or SCYL1BP1 gene, which is located on the long arm of chromosome 1 (1q24.2). Gerodermia osteodysplastica is inherited as an autosomal recessive disorder.ELN-related cutis laxa is caused by mutations in the ELN gene, which is located on the long arm of chromosome 7 (7q11.23). ELN-related cutis laxa is generally inherited as an autosomal dominant disorder, but autosomal recessive inheritance of ELN-related cutis laxa has been observed in two related families to date.Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered.The genes that are involved in the cutis laxa syndromes create (encode) specific proteins that are necessary for the proper health, development, transport, and/or function of elastic fibers. Elastic fibers are protein bundles found in various connective tissues of the body including within the skin, lungs and arterial blood vessels such as the aorta. Elastic fibers provide elasticity and resilience to skin and other tissues. Mutations in specific cutis laxa genes result in deficient levels of functional versions of proteins necessary for the proper development, health and function of elastic fibers. Consequently, elastic fibers may develop improperly or insufficiently. The specific manner in which these defective proteins ultimately result in the signs and symptoms of cutis laxa is not fully understood for all subtypes of cutis laxa.The cause of acquired cutis laxa is unknown. The disorder often develops following specific environmental exposures including certain medications such as isoniazid or penicillin, various infections, certain cancers such as multiple myeloma or lymphoma, inflammatory diseases such as Celiac disease or Sweet syndrome, autoimmune diseases including systemic lupus erythematosus and rheumatoid arthritis, and additional disorders including nephrotic syndrome, alpha-1 antitrypsin deficiency, mastocytosis and amyloidosis. Some researchers suspect that certain affected individuals are genetically predisposed to developing cutis laxa following such exposures. A person who is genetically predisposed to a disorder carries a gene (or genes) for the disease, but it may not be expressed unless it is triggered or “activated” under certain circumstances, such as due to particular environmental or immunologic factors. | Causes of Cutis Laxa. Cutis laxa is caused by mutations in specific genes. 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, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body. For disorders classified as cutis laxa, these mutations can be inherited in an autosomal recessive or autosomal dominant trait.Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child. In some cases, an autosomal dominant mutation results from a spontaneous (de novo) mutation that occurs randomly and is not inherited.A significant number of individuals diagnosed with cutis laxa do not have a mutation in one of the genes known to cause a subtype of cutis laxa. Most likely, additional, as-yet-unidentified genes cause cutis laxa in these cases.EFEMP2-related cutis laxa is caused by mutations in the EFEMP2 gene, which is located on the long arm (q) on chromosome 11 (11q13.1). EFEMP2-related cutis laxa is inherited as an autosomal recessive disorder.FBLN5-related cutis laxa is caused by mutations in the FBLN5 gene, which is located on the long arm of chromosome 14 (14q32.12). FBLN5-related cutis laxa is inherited as an autosomal recessive disorder. In one case, a mutation in this gene has been inherited in an autosomal dominant manner.LTBP4-related cutis laxa is caused by mutations in the LTBP4 gene, which is located on the long arm of chromosome 19 (19q13.2). LTBP4-related cutis laxa is inherited as an autosomal recessive disorder.ATP6V0A2-related cutis laxa is caused by mutations in the ATP6V0A2 gene, which is located on the long arm of chromosome 12 (12q24.31). ATP6V0A2-related cutis laxa is inherited as an autosomal recessive disorder.PYCR1-related cutis laxa is caused by mutations in the PYCR1 gene, which is located on the long arm of chromosome 17 (17q25.3). PYCR1-related cutis laxa is inherited as an autosomal recessive disorder.RIN2-related cutis laxa is caused by mutations in the RIN2 gene, which is located on the short arm of chromosome 20 (20p11.23). RIN2-related cutis laxa is inherited as an autosomal recessive disorder.The exact cause of De Barsy syndrome is not fully understood. Individuals with a diagnosis of De Barsy syndrome have been found to have mutations in the PYCR1 or ALDH18A1 genes. The ALDH18A1 gene is located on the long arm of chromosome 10 (10q24.1). De Barsy syndrome is believed to be inherited as an autosomal recessive disorder.Geroderma osteodysplasticum is caused by mutations in the GORAB or SCYL1BP1 gene, which is located on the long arm of chromosome 1 (1q24.2). Gerodermia osteodysplastica is inherited as an autosomal recessive disorder.ELN-related cutis laxa is caused by mutations in the ELN gene, which is located on the long arm of chromosome 7 (7q11.23). ELN-related cutis laxa is generally inherited as an autosomal dominant disorder, but autosomal recessive inheritance of ELN-related cutis laxa has been observed in two related families to date.Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered.The genes that are involved in the cutis laxa syndromes create (encode) specific proteins that are necessary for the proper health, development, transport, and/or function of elastic fibers. Elastic fibers are protein bundles found in various connective tissues of the body including within the skin, lungs and arterial blood vessels such as the aorta. Elastic fibers provide elasticity and resilience to skin and other tissues. Mutations in specific cutis laxa genes result in deficient levels of functional versions of proteins necessary for the proper development, health and function of elastic fibers. Consequently, elastic fibers may develop improperly or insufficiently. The specific manner in which these defective proteins ultimately result in the signs and symptoms of cutis laxa is not fully understood for all subtypes of cutis laxa.The cause of acquired cutis laxa is unknown. The disorder often develops following specific environmental exposures including certain medications such as isoniazid or penicillin, various infections, certain cancers such as multiple myeloma or lymphoma, inflammatory diseases such as Celiac disease or Sweet syndrome, autoimmune diseases including systemic lupus erythematosus and rheumatoid arthritis, and additional disorders including nephrotic syndrome, alpha-1 antitrypsin deficiency, mastocytosis and amyloidosis. Some researchers suspect that certain affected individuals are genetically predisposed to developing cutis laxa following such exposures. A person who is genetically predisposed to a disorder carries a gene (or genes) for the disease, but it may not be expressed unless it is triggered or “activated” under certain circumstances, such as due to particular environmental or immunologic factors. | 342 | Cutis Laxa |
nord_342_3 | Affects of Cutis Laxa | Cutis laxa is a rare disorder that affects males and females in equal numbers. The disorder has been reported in approximately 400 families worldwide. Cutis laxa is estimated to affect 1 in 1,000,000 individuals in the general population. However, because cases may go misdiagnosed or undiagnosed determining the true frequency of cutis laxa in the general population is difficult. Cutis laxa affects individuals of all races and every ethnic group. | Affects of Cutis Laxa. Cutis laxa is a rare disorder that affects males and females in equal numbers. The disorder has been reported in approximately 400 families worldwide. Cutis laxa is estimated to affect 1 in 1,000,000 individuals in the general population. However, because cases may go misdiagnosed or undiagnosed determining the true frequency of cutis laxa in the general population is difficult. Cutis laxa affects individuals of all races and every ethnic group. | 342 | Cutis Laxa |
nord_342_4 | Related disorders of Cutis Laxa | Symptoms of the following disorders can be similar to those of cutis laxa. Comparisons may be useful for a differential diagnosis.Occipital horn syndrome is also known as X-linked cutis laxa. The disorder is often characterized by generalized cutis laxa. The degree of cutis laxa can vary from one person to another and may worsen with age. Affected infants often have distinctive facial features including a thin face, an abnormally long groove that runs from the base of the nose to the upper lip (long philtrum), brittle hair, a high forehead, and an abnormally large soft spot on the skull (large fontanel). Skeletal abnormalities including loose joints, a narrow chest, and abnormal curvature of the spine (scoliosis or kyphosis) are also common. Severe complications affecting the cardiovascular, pulmonary, gastrointestinal and genitourinary systems can occur. Intelligence may range from normal/low to mild intellectual disability. Neurological abnormalities may also develop including failure of the autonomic nervous system (dysautonomia). The autonomic nervous system regulates the body’s various involuntary actions such as digestion, breathing, blood flow and heartbeat. Occipital horn syndrome is caused by mutations in the ATP7A gene. This gene is involved in copper metabolism and also causes Menkes disease. Researchers believe that mutations in this gene result in a spectrum of disease with occipital horn syndrome on the milder end and Menkes disease on the severe end. Individuals with this disorder develop excess bone growth on the occipital bone of the skull, which is located at the back of the head just above the neck. These bony growths, called ‘occipital horns’, can be seen on an x-ray. (For more information on this disorder, choose “Menkes” as your search term in the Rare Disease Database.)Ehlers-Danlos syndrome (EDS) is a group of hereditary connective tissue disorders characterized by defects of the major structural protein in the body (collagen). Collagen, a tough, fibrous protein, plays an essential role in holding together and strengthening the tissues of the body. Due to defects of collagen, primary EDS symptoms and findings include abnormally flexible, loose joints (articular hypermobility) that may easily become dislocated; unusually loose, thin, stretchy (elastic) skin; and excessive fragility of the skin, small blood vessels, and other bodily tissues and membranes. The different types of EDS were originally categorized in a classification system that used Roman numerals (e.g., EDS I to EDS XI), based upon each form's associated symptoms and findings (clinical evidence) and underlying cause. A revised, simplified classification system has since been described in the medical literature that categorizes EDS into six major subtypes, based upon clinical evidence, underlying biochemical defects, and mode of inheritance. Each subtype of EDS is a distinct hereditary disorder that may affect individuals within certain families (kindreds). Depending upon the specific subtype present, EDS is usually transmitted as an autosomal dominant or autosomal recessive trait. Only certain rare types of EDS include a predisposition for severe cardiovascular issues (such as vascular EDS); other types predominantly alter the skin and joints (e.g. hypermobile EDS). (For more information on this disorder, choose “Ehlers Danlos” as your search term in the Rare Disease Database.)Pseudoxanthoma elasticum, PXE, is an inherited disorder caused by mutations in the ABCC6 transporter gene that affects connective tissue in some parts of the body. Elastic tissue in the body becomes mineralized; that is, calcium and other minerals are deposited in the tissue. This can result in changes in the skin, eyes, cardiovascular system, and gastrointestinal system. Individuals with PXE can have excess, wrinkled skin. Unlike individuals with cutis laxa, affected skin in PXE tends to be hyperelastic. Loose joints are also common. Onset can range from early childhood to adulthood. PXE is inherited as an autosomal recessive disorder. (For more information on this disorder, choose “pseudoxanthoma elasticum” as your search term in the Rare Disease Database.)There are many additional disorders in which cutis laxa or similar skin symptoms occur. Such disorders include arterial tortuosity syndrome, Cantu syndrome, SCARF syndrome, Lenz-Majewski hyperostotic dwarfism, Barber-Say syndrome, Hutchinson-Gilford progeria syndrome, Cockayne syndrome, Wiedemann-Rautenstrauch syndrome, Kabuki syndrome, Williams syndrome, Patterson pseudoleprechaunism syndrome, Costello syndrome, Noonan syndrome, cardiofaciocutaneous syndrome, LEOPARD syndrome, and ablepharon-macrostomia syndrome. NORD has individual reports on many of these disorders. (For more information, choose the specific disorder name as your search term in the Rare Disease Database.) | Related disorders of Cutis Laxa. Symptoms of the following disorders can be similar to those of cutis laxa. Comparisons may be useful for a differential diagnosis.Occipital horn syndrome is also known as X-linked cutis laxa. The disorder is often characterized by generalized cutis laxa. The degree of cutis laxa can vary from one person to another and may worsen with age. Affected infants often have distinctive facial features including a thin face, an abnormally long groove that runs from the base of the nose to the upper lip (long philtrum), brittle hair, a high forehead, and an abnormally large soft spot on the skull (large fontanel). Skeletal abnormalities including loose joints, a narrow chest, and abnormal curvature of the spine (scoliosis or kyphosis) are also common. Severe complications affecting the cardiovascular, pulmonary, gastrointestinal and genitourinary systems can occur. Intelligence may range from normal/low to mild intellectual disability. Neurological abnormalities may also develop including failure of the autonomic nervous system (dysautonomia). The autonomic nervous system regulates the body’s various involuntary actions such as digestion, breathing, blood flow and heartbeat. Occipital horn syndrome is caused by mutations in the ATP7A gene. This gene is involved in copper metabolism and also causes Menkes disease. Researchers believe that mutations in this gene result in a spectrum of disease with occipital horn syndrome on the milder end and Menkes disease on the severe end. Individuals with this disorder develop excess bone growth on the occipital bone of the skull, which is located at the back of the head just above the neck. These bony growths, called ‘occipital horns’, can be seen on an x-ray. (For more information on this disorder, choose “Menkes” as your search term in the Rare Disease Database.)Ehlers-Danlos syndrome (EDS) is a group of hereditary connective tissue disorders characterized by defects of the major structural protein in the body (collagen). Collagen, a tough, fibrous protein, plays an essential role in holding together and strengthening the tissues of the body. Due to defects of collagen, primary EDS symptoms and findings include abnormally flexible, loose joints (articular hypermobility) that may easily become dislocated; unusually loose, thin, stretchy (elastic) skin; and excessive fragility of the skin, small blood vessels, and other bodily tissues and membranes. The different types of EDS were originally categorized in a classification system that used Roman numerals (e.g., EDS I to EDS XI), based upon each form's associated symptoms and findings (clinical evidence) and underlying cause. A revised, simplified classification system has since been described in the medical literature that categorizes EDS into six major subtypes, based upon clinical evidence, underlying biochemical defects, and mode of inheritance. Each subtype of EDS is a distinct hereditary disorder that may affect individuals within certain families (kindreds). Depending upon the specific subtype present, EDS is usually transmitted as an autosomal dominant or autosomal recessive trait. Only certain rare types of EDS include a predisposition for severe cardiovascular issues (such as vascular EDS); other types predominantly alter the skin and joints (e.g. hypermobile EDS). (For more information on this disorder, choose “Ehlers Danlos” as your search term in the Rare Disease Database.)Pseudoxanthoma elasticum, PXE, is an inherited disorder caused by mutations in the ABCC6 transporter gene that affects connective tissue in some parts of the body. Elastic tissue in the body becomes mineralized; that is, calcium and other minerals are deposited in the tissue. This can result in changes in the skin, eyes, cardiovascular system, and gastrointestinal system. Individuals with PXE can have excess, wrinkled skin. Unlike individuals with cutis laxa, affected skin in PXE tends to be hyperelastic. Loose joints are also common. Onset can range from early childhood to adulthood. PXE is inherited as an autosomal recessive disorder. (For more information on this disorder, choose “pseudoxanthoma elasticum” as your search term in the Rare Disease Database.)There are many additional disorders in which cutis laxa or similar skin symptoms occur. Such disorders include arterial tortuosity syndrome, Cantu syndrome, SCARF syndrome, Lenz-Majewski hyperostotic dwarfism, Barber-Say syndrome, Hutchinson-Gilford progeria syndrome, Cockayne syndrome, Wiedemann-Rautenstrauch syndrome, Kabuki syndrome, Williams syndrome, Patterson pseudoleprechaunism syndrome, Costello syndrome, Noonan syndrome, cardiofaciocutaneous syndrome, LEOPARD syndrome, and ablepharon-macrostomia syndrome. NORD has individual reports on many of these disorders. (For more information, choose the specific disorder name as your search term in the Rare Disease Database.) | 342 | Cutis Laxa |
nord_342_5 | Diagnosis of Cutis Laxa | A diagnosis of cutis laxa is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Surgical removal and microscopic examination (biopsy) of affected skin can reveal characteristic changes in elastic fibers. Distinguishing between the specific genetic forms of cutis laxa can be difficult. Molecular genetic testing can confirm a diagnosis of an inherited form cutis laxa and establish the specific, underlying subtype in some cases. Molecular genetic testing can detect mutations in specific genes known to cause cutis laxa, but is available only as a diagnostic service at specialized laboratories. | Diagnosis of Cutis Laxa. A diagnosis of cutis laxa is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Surgical removal and microscopic examination (biopsy) of affected skin can reveal characteristic changes in elastic fibers. Distinguishing between the specific genetic forms of cutis laxa can be difficult. Molecular genetic testing can confirm a diagnosis of an inherited form cutis laxa and establish the specific, underlying subtype in some cases. Molecular genetic testing can detect mutations in specific genes known to cause cutis laxa, but is available only as a diagnostic service at specialized laboratories. | 342 | Cutis Laxa |
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