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nord_414_2 | Causes of Epidermal Nevus Syndromes | Most epidermal nevus syndromes are thought to be caused by a gene mutation that occurs after fertilization of the embryo (postzygotic mutation), at an early stage of embryonic development. Affected individuals have some cells with a normal copy of this gene and some cells with the abnormal gene (mosaic pattern). This may be referred to as having two distinct cell lines in the body. The variability of symptoms associated with ENSs is due in part to the ratio of healthy cells to abnormal cells. When all cells have the abnormal gene, the condition is not compatible with life. Researchers believe that this postzygotic mutation occurs randomly for no apparent reason (sporadically). By contrast, CHILD syndrome is inherited as an X-linked dominant, male-lethal trait which means that the disorder can be transmitted from a mother to 50% of her daughters. Her sons will not be affected because male embryos can only survive when they have inherited the normal (healthy) X-chromosome from the mother.The molecular basis of some types of ENSs is known. CHILD syndrome is caused by mutations of the NSDHL gene. Type 2 segmental Cowden disease is caused by mutations of the PTEN gene. Garcia-Hafner-Happle syndrome is caused by mutations of the FGFR3 gene. Further research into the underlying molecular basis of ENSs should enable researchers to improve the classification system for these disorders | Causes of Epidermal Nevus Syndromes. Most epidermal nevus syndromes are thought to be caused by a gene mutation that occurs after fertilization of the embryo (postzygotic mutation), at an early stage of embryonic development. Affected individuals have some cells with a normal copy of this gene and some cells with the abnormal gene (mosaic pattern). This may be referred to as having two distinct cell lines in the body. The variability of symptoms associated with ENSs is due in part to the ratio of healthy cells to abnormal cells. When all cells have the abnormal gene, the condition is not compatible with life. Researchers believe that this postzygotic mutation occurs randomly for no apparent reason (sporadically). By contrast, CHILD syndrome is inherited as an X-linked dominant, male-lethal trait which means that the disorder can be transmitted from a mother to 50% of her daughters. Her sons will not be affected because male embryos can only survive when they have inherited the normal (healthy) X-chromosome from the mother.The molecular basis of some types of ENSs is known. CHILD syndrome is caused by mutations of the NSDHL gene. Type 2 segmental Cowden disease is caused by mutations of the PTEN gene. Garcia-Hafner-Happle syndrome is caused by mutations of the FGFR3 gene. Further research into the underlying molecular basis of ENSs should enable researchers to improve the classification system for these disorders | 414 | Epidermal Nevus Syndromes |
nord_414_3 | Affects of Epidermal Nevus Syndromes | Epidermal nevi (including as an isolated finding) have been reported to occur in approximately 1 to 3 per 1,000 live births. The percentage of individuals with epidermal nevi who also have extra-cutaneous malformations is much lower but likewise unknown. The prevalence and incidence of individual ENSs is unknown. | Affects of Epidermal Nevus Syndromes. Epidermal nevi (including as an isolated finding) have been reported to occur in approximately 1 to 3 per 1,000 live births. The percentage of individuals with epidermal nevi who also have extra-cutaneous malformations is much lower but likewise unknown. The prevalence and incidence of individual ENSs is unknown. | 414 | Epidermal Nevus Syndromes |
nord_414_4 | Related disorders of Epidermal Nevus Syndromes | Symptoms of the following disorders can be similar to those of ENS. Comparisons may be useful for a differential diagnosis.Inflammatory liner verrucous epidermal nevus (ILVEN) is a rare skin disorder characterized by itchy (pruritic) and reddened (erythematous) papules on the body. These lesions are also dry and scaly (hyperkeratotic). ILVEN usually affects only one side of the body (unilateral). ILVEN is usually present at birth or within the first 6 months of life. Itching can be severe. Some researchers believe that case reports have been published in the literature where ILVEN has been associated with skeletal and central nervous system abnormalities. According to present knowledge, however, there are no confirmed cases of ILVEN associated with extracutaneous abnormalities. Such cases reported in the medical literature were actually cases of CHILD syndrome. Contrasting with CHILD nevus, the molecular cause of ILVEN is unknown. There are several different disorders that are characterized by the association of skin lesions and additional symptoms such as central nervous system abnormalities or skeletal abnormalities. These disorders include tuberous sclerosis, McCune-Albright syndrome, Sturge-Weber syndrome and neurofibromatosis types 1 and 2. (For more information, choose the exact disorder name as your search term in the Rare Disease Database.) | Related disorders of Epidermal Nevus Syndromes. Symptoms of the following disorders can be similar to those of ENS. Comparisons may be useful for a differential diagnosis.Inflammatory liner verrucous epidermal nevus (ILVEN) is a rare skin disorder characterized by itchy (pruritic) and reddened (erythematous) papules on the body. These lesions are also dry and scaly (hyperkeratotic). ILVEN usually affects only one side of the body (unilateral). ILVEN is usually present at birth or within the first 6 months of life. Itching can be severe. Some researchers believe that case reports have been published in the literature where ILVEN has been associated with skeletal and central nervous system abnormalities. According to present knowledge, however, there are no confirmed cases of ILVEN associated with extracutaneous abnormalities. Such cases reported in the medical literature were actually cases of CHILD syndrome. Contrasting with CHILD nevus, the molecular cause of ILVEN is unknown. There are several different disorders that are characterized by the association of skin lesions and additional symptoms such as central nervous system abnormalities or skeletal abnormalities. These disorders include tuberous sclerosis, McCune-Albright syndrome, Sturge-Weber syndrome and neurofibromatosis types 1 and 2. (For more information, choose the exact disorder name as your search term in the Rare Disease Database.) | 414 | Epidermal Nevus Syndromes |
nord_414_5 | Diagnosis of Epidermal Nevus Syndromes | A diagnosis of an epidermal nevus syndrome is made based upon identification of characteristic symptoms, a detailed patient history and a thorough clinical evaluation. In some cases, a small sample of affected skin may be taken for microscopic study (biopsy). Additional tests may be required to detect the presence and extent of associated symptoms. Such tests include a skeletal survey, chest x-rays and specialized imaging techniques to evaluate the brain. Such imaging techniques may include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). Whether a child with an epidermal nevus should undergo such imaging techniques is controversial. Some researchers believe that these tests should be avoided unless there are clinical signs of central nervous involvement. In three of the well-defined ENSs (type 2 segmental Cowden disease, García-Hafner-Happle syndrome, CHILD syndrome), molecular testing is now possible. | Diagnosis of Epidermal Nevus Syndromes. A diagnosis of an epidermal nevus syndrome is made based upon identification of characteristic symptoms, a detailed patient history and a thorough clinical evaluation. In some cases, a small sample of affected skin may be taken for microscopic study (biopsy). Additional tests may be required to detect the presence and extent of associated symptoms. Such tests include a skeletal survey, chest x-rays and specialized imaging techniques to evaluate the brain. Such imaging techniques may include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). Whether a child with an epidermal nevus should undergo such imaging techniques is controversial. Some researchers believe that these tests should be avoided unless there are clinical signs of central nervous involvement. In three of the well-defined ENSs (type 2 segmental Cowden disease, García-Hafner-Happle syndrome, CHILD syndrome), molecular testing is now possible. | 414 | Epidermal Nevus Syndromes |
nord_414_6 | Therapies of Epidermal Nevus Syndromes | TreatmentThe treatment of ENS is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, pediatric neurologists, dermatologists, orthopedists, orthopedic surgeons, ophthalmologists, and other healthcare professionals may need to systematically and comprehensively plan an affected child's treatment.The specific therapeutic procedures and interventions for individuals with an ENS will vary, depending upon numerous factors including the specific symptoms present, the extent of the disorder, an individual's age and overall health, tolerance of certain medications or procedures, personal preference and other factors. Decisions concerning the use of particular therapeutic interventions should be made by physicians and other members of the healthcare team in careful consultation with the patient and/or parents 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.Surgery may be performed to improve cosmetic appearance. However, surgical excision of a lesion may not always be possible due to the specific location of an epidermal nevus.Additional therapies for ENS depend upon the specific abnormalities present and usually follow standard guidelines. For example, epilepsy may be treated by anti-seizure medications and certain skeletal and ocular malformations may also be treated surgically. In the medical literature, several cases have been reported where neurosurgery has been used to treat individuals with an ENS and epilepsy.Additional therapies that may be used to treat individuals with ENSs include remedial education, physical therapy and occupational therapy all of which should be individualized. Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive. | Therapies of Epidermal Nevus Syndromes. TreatmentThe treatment of ENS is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, pediatric neurologists, dermatologists, orthopedists, orthopedic surgeons, ophthalmologists, and other healthcare professionals may need to systematically and comprehensively plan an affected child's treatment.The specific therapeutic procedures and interventions for individuals with an ENS will vary, depending upon numerous factors including the specific symptoms present, the extent of the disorder, an individual's age and overall health, tolerance of certain medications or procedures, personal preference and other factors. Decisions concerning the use of particular therapeutic interventions should be made by physicians and other members of the healthcare team in careful consultation with the patient and/or parents 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.Surgery may be performed to improve cosmetic appearance. However, surgical excision of a lesion may not always be possible due to the specific location of an epidermal nevus.Additional therapies for ENS depend upon the specific abnormalities present and usually follow standard guidelines. For example, epilepsy may be treated by anti-seizure medications and certain skeletal and ocular malformations may also be treated surgically. In the medical literature, several cases have been reported where neurosurgery has been used to treat individuals with an ENS and epilepsy.Additional therapies that may be used to treat individuals with ENSs include remedial education, physical therapy and occupational therapy all of which should be individualized. Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive. | 414 | Epidermal Nevus Syndromes |
nord_415_0 | Overview of Epidermolysis Bullosa | Epidermolysis bullosa (EB) is a genetic skin disorder characterized clinically by blister formation from mechanical trauma. There are four main types with additional sub-types identified. There is a spectrum of severity, and within each type, one may be either mildly or severely affected. EB ranges from being a minor inconvenience requiring modification of some activities, to being completely disabling and, in some cases, fatal.Friction causes blister formation. Blisters can form anywhere on the surface of the skin, within the oral cavity and in more severe forms may also involve the external surface of the eye, as well as the respiratory, gastrointestinal and genitourinary tracts. In some forms of the disease, disfiguring scars and disabling musculoskeletal deformities occur.Currently, there is no cure for EB. Supportive care includes daily wound care, bandaging, and pain management as needed. | Overview of Epidermolysis Bullosa. Epidermolysis bullosa (EB) is a genetic skin disorder characterized clinically by blister formation from mechanical trauma. There are four main types with additional sub-types identified. There is a spectrum of severity, and within each type, one may be either mildly or severely affected. EB ranges from being a minor inconvenience requiring modification of some activities, to being completely disabling and, in some cases, fatal.Friction causes blister formation. Blisters can form anywhere on the surface of the skin, within the oral cavity and in more severe forms may also involve the external surface of the eye, as well as the respiratory, gastrointestinal and genitourinary tracts. In some forms of the disease, disfiguring scars and disabling musculoskeletal deformities occur.Currently, there is no cure for EB. Supportive care includes daily wound care, bandaging, and pain management as needed. | 415 | Epidermolysis Bullosa |
nord_415_1 | Symptoms of Epidermolysis Bullosa | Epidermolysis bullosa is divided into four subdivisions, and each subdivision has subtypes.Epidermolysis bullosa simplex (EBS) is usually dominantly inherited, and involves disorders of the genes for Keratins 5 and 14 and plectin. Recently, several suprabasal types of EBS have been described as well. Blistering occurs within the uppermost layer of the skin, the epidermis. EBS may be localized to the hands and feet or there may be a generalized distribution, with relatively mild internal involvement. Those with EBS may have thickened calluses on the palms and soles, oral blistering during infancy and rough, thickened fingernails/toenails. EBS does not usually scar. There are rare recessive forms. EBS with plectin mutations may be associated with muscular dystrophy.Junctional epidermolysis bullosa (JEB), is recessively inherited, and involves mutations in the genes for several components of the junction between the epidermis and dermis such as Laminin 332 (previously known as Laminin 5), plectin, and a6b4integrin. There are two major subtypes, Herlitz JEB and JEB- other (includes non-Herlitz JEB, and JEB with pyloric atresia and several other subtypes). Junctional Herlitz EB is due to mutations in any of the three Laminin 332 chains and can be a very severe form of EB. Death often occurs during infancy due to overwhelming infection (sepsis), malnutrition, dehydration, electrolyte imbalance or obstructive airway complications. There is a wide spectrum of JEB- O. Oral cavity involvement and irregular pitting of the surfaces of the teeth is common in all subtypes. Infants presenting with pyloric atresia will have trouble with feeding and abdominal distension as neonates and present as surgical emergencies in the newborn period.Dystrophic epidermolysis bullosa (DEB) can be either dominantly or recessively inherited, and involves defects in Type VII collagen. Blisters occur within the lower layer of the skin, the dermis. There are two major subtypes, dominant DEB (DDEB) and recessive DEB (RDEB).Dominant dystrophic EB (DDEB): DDEB is usually mild. Blistering may be localized to the hands, feet, elbows and knees or it may be generalized. Common findings include scarring, milia (tiny white bumps), mucous membrane involvement, and abnormal or absent nails. Some family members may only have nail dystrophy.Recessive dystrophic EB (RDEB): RDEB is typically more generalized and severe than DDEB. In addition to scarring, milia, mucous membrane involvement and nail dystrophy, common manifestations include malnutrition, anemia, esophageal strictures, growth retardation, webbing or fusion of the fingers and toes causing mitten deformity (pseudosyndactyly) with loss of function, development of contractures, malformation of teeth, microstomia and corneal abrasions. Severe generalized RDEB (formerly Hallopeau-Siemens RDEB) tends to be the most severe form.Kindler syndrome is very rare and involves all layers of the skin with extreme fragility. | Symptoms of Epidermolysis Bullosa. Epidermolysis bullosa is divided into four subdivisions, and each subdivision has subtypes.Epidermolysis bullosa simplex (EBS) is usually dominantly inherited, and involves disorders of the genes for Keratins 5 and 14 and plectin. Recently, several suprabasal types of EBS have been described as well. Blistering occurs within the uppermost layer of the skin, the epidermis. EBS may be localized to the hands and feet or there may be a generalized distribution, with relatively mild internal involvement. Those with EBS may have thickened calluses on the palms and soles, oral blistering during infancy and rough, thickened fingernails/toenails. EBS does not usually scar. There are rare recessive forms. EBS with plectin mutations may be associated with muscular dystrophy.Junctional epidermolysis bullosa (JEB), is recessively inherited, and involves mutations in the genes for several components of the junction between the epidermis and dermis such as Laminin 332 (previously known as Laminin 5), plectin, and a6b4integrin. There are two major subtypes, Herlitz JEB and JEB- other (includes non-Herlitz JEB, and JEB with pyloric atresia and several other subtypes). Junctional Herlitz EB is due to mutations in any of the three Laminin 332 chains and can be a very severe form of EB. Death often occurs during infancy due to overwhelming infection (sepsis), malnutrition, dehydration, electrolyte imbalance or obstructive airway complications. There is a wide spectrum of JEB- O. Oral cavity involvement and irregular pitting of the surfaces of the teeth is common in all subtypes. Infants presenting with pyloric atresia will have trouble with feeding and abdominal distension as neonates and present as surgical emergencies in the newborn period.Dystrophic epidermolysis bullosa (DEB) can be either dominantly or recessively inherited, and involves defects in Type VII collagen. Blisters occur within the lower layer of the skin, the dermis. There are two major subtypes, dominant DEB (DDEB) and recessive DEB (RDEB).Dominant dystrophic EB (DDEB): DDEB is usually mild. Blistering may be localized to the hands, feet, elbows and knees or it may be generalized. Common findings include scarring, milia (tiny white bumps), mucous membrane involvement, and abnormal or absent nails. Some family members may only have nail dystrophy.Recessive dystrophic EB (RDEB): RDEB is typically more generalized and severe than DDEB. In addition to scarring, milia, mucous membrane involvement and nail dystrophy, common manifestations include malnutrition, anemia, esophageal strictures, growth retardation, webbing or fusion of the fingers and toes causing mitten deformity (pseudosyndactyly) with loss of function, development of contractures, malformation of teeth, microstomia and corneal abrasions. Severe generalized RDEB (formerly Hallopeau-Siemens RDEB) tends to be the most severe form.Kindler syndrome is very rare and involves all layers of the skin with extreme fragility. | 415 | Epidermolysis Bullosa |
nord_415_2 | Causes of Epidermolysis Bullosa | Inherited epidermolysis bullosa is the focus of this report. The inherited forms follow either autosomal dominant or autosomal recessive inheritance. There is also a rare acquired autoimmune disorder called epidermolysis bullosa aquisita. A mutation in any of at least 18 genes encoding the proteins in the epidermis, basement membrane or dermis causes poor integrity of the skin leading to fragility.Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.All individuals carry at least 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females. | Causes of Epidermolysis Bullosa. Inherited epidermolysis bullosa is the focus of this report. The inherited forms follow either autosomal dominant or autosomal recessive inheritance. There is also a rare acquired autoimmune disorder called epidermolysis bullosa aquisita. A mutation in any of at least 18 genes encoding the proteins in the epidermis, basement membrane or dermis causes poor integrity of the skin leading to fragility.Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.All individuals carry at least 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females. | 415 | Epidermolysis Bullosa |
nord_415_3 | Affects of Epidermolysis Bullosa | Some type of EB occurs in an estimated 1 out of every 50,000 live births. The disorder occurs in every racial and ethnic group throughout the world and affects both sexes equally. | Affects of Epidermolysis Bullosa. Some type of EB occurs in an estimated 1 out of every 50,000 live births. The disorder occurs in every racial and ethnic group throughout the world and affects both sexes equally. | 415 | Epidermolysis Bullosa |
nord_415_4 | Related disorders of Epidermolysis Bullosa | Any blistering disorder in the newborn period may mimic EB. These include herpes simplex virus, epidermolytic ichthyosis, bullous impetigo and incontinentia pigmenti. | Related disorders of Epidermolysis Bullosa. Any blistering disorder in the newborn period may mimic EB. These include herpes simplex virus, epidermolytic ichthyosis, bullous impetigo and incontinentia pigmenti. | 415 | Epidermolysis Bullosa |
nord_415_5 | Diagnosis of Epidermolysis Bullosa | Clinical diagnosis of the type of EB based on presentation in the neonatal period should be avoided as all types of EB may look alike in this age group. When EB is suspected, a skin biopsy should be obtained and sent to an appropriate laboratory to confirm the diagnosis with transmission electron microscopy (TEM) and/or immunofluorescent antibody/antigen mapping. Molecular genetic testing for mutations in most of the genes known to be associated with the various types of EB is clinically available. | Diagnosis of Epidermolysis Bullosa. Clinical diagnosis of the type of EB based on presentation in the neonatal period should be avoided as all types of EB may look alike in this age group. When EB is suspected, a skin biopsy should be obtained and sent to an appropriate laboratory to confirm the diagnosis with transmission electron microscopy (TEM) and/or immunofluorescent antibody/antigen mapping. Molecular genetic testing for mutations in most of the genes known to be associated with the various types of EB is clinically available. | 415 | Epidermolysis Bullosa |
nord_415_6 | Therapies of Epidermolysis Bullosa | By definition, inherited EB is a genetically transmitted disorder characterized by marked fragility of the skin. Any trauma, no matter how minimal it may seem, is likely to cause the skin of an EB child or adult to tear or blister. The following are recommended ways to avoid or minimize this problem:In 2023, Vyjuvek was approved by the U.S. Food and Drug Administration (FDA) as the first topical gene therapy treatment for patients 6 months of age and older with dystrophic epidermolysis bullosa (DEB) who have mutations in the COL7A1 gene. | Therapies of Epidermolysis Bullosa. By definition, inherited EB is a genetically transmitted disorder characterized by marked fragility of the skin. Any trauma, no matter how minimal it may seem, is likely to cause the skin of an EB child or adult to tear or blister. The following are recommended ways to avoid or minimize this problem:In 2023, Vyjuvek was approved by the U.S. Food and Drug Administration (FDA) as the first topical gene therapy treatment for patients 6 months of age and older with dystrophic epidermolysis bullosa (DEB) who have mutations in the COL7A1 gene. | 415 | Epidermolysis Bullosa |
nord_416_0 | Overview of Epidermolytic Ichthyosis | Epidermolytic ichthyosis (EI) is a genetic skin disorder that is characterized by varying degrees of blistering and scaling of the skin. The symptoms of the disease are often noticed at birth or shortly after, and symptoms change as the patient ages. Symptoms may vary from mild blistering upon friction to severe erosions or widespread warty scaling. Hair and nail abnormalities, reduced sweating and the formation of calluses on the palms or soles (palmoplantar keratoderma) of the feet can also occur. Under a microscope, the skin may show mid-epidermal splitting and skin thickening (hyperkeratosis). Current treatments address the specific symptoms and can include topical treatments, medications and antiseptic washes for skin infections. The cosmetic issues and sometimes unpleasant odor associated with EI can lead to stress and psychological distress. | Overview of Epidermolytic Ichthyosis. Epidermolytic ichthyosis (EI) is a genetic skin disorder that is characterized by varying degrees of blistering and scaling of the skin. The symptoms of the disease are often noticed at birth or shortly after, and symptoms change as the patient ages. Symptoms may vary from mild blistering upon friction to severe erosions or widespread warty scaling. Hair and nail abnormalities, reduced sweating and the formation of calluses on the palms or soles (palmoplantar keratoderma) of the feet can also occur. Under a microscope, the skin may show mid-epidermal splitting and skin thickening (hyperkeratosis). Current treatments address the specific symptoms and can include topical treatments, medications and antiseptic washes for skin infections. The cosmetic issues and sometimes unpleasant odor associated with EI can lead to stress and psychological distress. | 416 | Epidermolytic Ichthyosis |
nord_416_1 | Symptoms of Epidermolytic Ichthyosis | The symptoms of EI progress with the patient’s age. Infants more commonly show signs of red, blistering skin and will usually develop thickened skin (cornification) and scaling into adulthood. Infants may also show growths on the inner surface of the eyelid (conjunctival hamartoma). Scales tend to form in parallel rows of spines or ridges. Reddened skin (erythroderma), itchiness (pruritus) and abnormal dryness (xerosis) are common symptoms. Skin ulcers and other damage can lead to bacterial infections. Heat intolerance and sensitivity to sunlight may also occur. A palmoplantar keratoderma may be present and can be so severe as to limit movement and hand function. Milder cases usually show minimal blistering in areas subject to friction or have only a palmoplantar keratoderma. | Symptoms of Epidermolytic Ichthyosis. The symptoms of EI progress with the patient’s age. Infants more commonly show signs of red, blistering skin and will usually develop thickened skin (cornification) and scaling into adulthood. Infants may also show growths on the inner surface of the eyelid (conjunctival hamartoma). Scales tend to form in parallel rows of spines or ridges. Reddened skin (erythroderma), itchiness (pruritus) and abnormal dryness (xerosis) are common symptoms. Skin ulcers and other damage can lead to bacterial infections. Heat intolerance and sensitivity to sunlight may also occur. A palmoplantar keratoderma may be present and can be so severe as to limit movement and hand function. Milder cases usually show minimal blistering in areas subject to friction or have only a palmoplantar keratoderma. | 416 | Epidermolytic Ichthyosis |
nord_416_2 | Causes of Epidermolytic Ichthyosis | EI is caused by harmful changes (variants) in the KRT1 or KRT10 genes. These variants result in improper expression of keratin 1 and keratin 10, which are structural proteins specifically found in epithelial and epidermal cells. The malfunctioning proteins result in barrier abnormalities that can lead to epidermal inflammation, causing the various symptoms seen with the disease. Some patients have some cells with the harmful gene variant and other cells without the harmful gene variant (somatic mosaicism). This can cause blistering and hyperkeratotic lesions specific to certain areas of the skin. The severity of the disease in these patients is directly correlated to the percentage of cells affected. In somatic mosaicism, the gene change is not inherited.EI is an autosomal dominant genetic disorder. Dominant genetic disorders occur when only a single copy of a harmful gene variant is necessary to cause a particular disease. EI can be inherited or sporadic, meaning the gene variant can be the result of a new mutation (gene change) in the affected individual. About 50% of cases are caused by spontaneous changes in the KRT1 or KRT10 genes, and the variant can then be passed down to children. The risk of passing the harmful gene variant from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females. | Causes of Epidermolytic Ichthyosis. EI is caused by harmful changes (variants) in the KRT1 or KRT10 genes. These variants result in improper expression of keratin 1 and keratin 10, which are structural proteins specifically found in epithelial and epidermal cells. The malfunctioning proteins result in barrier abnormalities that can lead to epidermal inflammation, causing the various symptoms seen with the disease. Some patients have some cells with the harmful gene variant and other cells without the harmful gene variant (somatic mosaicism). This can cause blistering and hyperkeratotic lesions specific to certain areas of the skin. The severity of the disease in these patients is directly correlated to the percentage of cells affected. In somatic mosaicism, the gene change is not inherited.EI is an autosomal dominant genetic disorder. Dominant genetic disorders occur when only a single copy of a harmful gene variant is necessary to cause a particular disease. EI can be inherited or sporadic, meaning the gene variant can be the result of a new mutation (gene change) in the affected individual. About 50% of cases are caused by spontaneous changes in the KRT1 or KRT10 genes, and the variant can then be passed down to children. The risk of passing the harmful gene variant from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females. | 416 | Epidermolytic Ichthyosis |
nord_416_3 | Affects of Epidermolytic Ichthyosis | EI occurs in approximately 1 in 200,000 individuals, affecting males and females equally. | Affects of Epidermolytic Ichthyosis. EI occurs in approximately 1 in 200,000 individuals, affecting males and females equally. | 416 | Epidermolytic Ichthyosis |
nord_416_4 | Related disorders of Epidermolytic Ichthyosis | Epidermolytic ichthyosis can resemble different diseases depending on the stage it is in. Early stages of EI can resemble diseases that involve the extreme onset of blisters and lesions in infants. Specific disorders include toxic epidermal necrolysis (TEN), epidermolysis bullosa (EB) and incontinentia pigmenti (IP). Blister presentation associated with TEN is caused by the first-time exposure to drugs during infancy. EB is a group of diseases, each characterized by the fragility and blistering of skin and mucosae. IP is an X-linked dominant skin disease caused by variants in the IKBKG gene. IP is a multisystem disorder, and the skin is most commonly affected in infants. Later stages can resemble other conditions, such as Curth Macklin-type ichthyosis hystrix and superficial EI. KPI’s, or keratinopathic ichthyoses, includes a group of multiple diseases that involve variants in the genes KRT1, KRT2, and KRT10. Curth Macklin-type ichthyosis hystrix is caused by a variant in KRT1 and presents similar skin conditions to EI. However, Curth Macklin-type ichthyosis hystrix also includes nail dystrophy and chronic loss of joint function (flexion contracture). Superficial EI is caused by a variant in KRT2 and is characterized by much milder skin thickening and scaling that remains superficial.Erythrokeratodermia variabilis (EKV) and keratitis-ichthyosis-deafness (KID) like disorders exhibit autosomal dominant inheritance and are caused by variants in genes coding for gap junction proteins. EKV is caused by variants in genes GJB3 and GJB4 while KID is caused by variants in GJB2. These disorders can cause skin thickening and redness, as well as the formation of plaques. EKV can also mimic the cyclic nature of annular epidermolytic ichthyosis. The spine-like scaling (hystrix-like scaling) that can be present with EI must be distinguished from Lelis syndrome. Lelis syndrome is a very rare hyperkeratotic presentation of hypohidrotic ectodermal dysplasia (XHED). XHED is an X-linked recessive condition that can present with sparse hair and abnormal teeth. Lelis syndrome can also present discolored and thickened skin. However, unlike EI, Lelis syndrome is accompanied with a lack of sweating (hypohidrosis).Psoriasis is a common and chronic disorder characterized by dry, well-circumscribed silvery-gray scaling spots (papules) or plaques that usually appear on the scalp, elbows or knees. The cause is not well understood but it is thought to be immune mediated and genetic. Sometimes it can be difficult to distinguish from the palmoplantar keratodermas caused by a KRT1 gene variant. However, psoriasis does not follow autosomal dominant inheritance like EI. | Related disorders of Epidermolytic Ichthyosis. Epidermolytic ichthyosis can resemble different diseases depending on the stage it is in. Early stages of EI can resemble diseases that involve the extreme onset of blisters and lesions in infants. Specific disorders include toxic epidermal necrolysis (TEN), epidermolysis bullosa (EB) and incontinentia pigmenti (IP). Blister presentation associated with TEN is caused by the first-time exposure to drugs during infancy. EB is a group of diseases, each characterized by the fragility and blistering of skin and mucosae. IP is an X-linked dominant skin disease caused by variants in the IKBKG gene. IP is a multisystem disorder, and the skin is most commonly affected in infants. Later stages can resemble other conditions, such as Curth Macklin-type ichthyosis hystrix and superficial EI. KPI’s, or keratinopathic ichthyoses, includes a group of multiple diseases that involve variants in the genes KRT1, KRT2, and KRT10. Curth Macklin-type ichthyosis hystrix is caused by a variant in KRT1 and presents similar skin conditions to EI. However, Curth Macklin-type ichthyosis hystrix also includes nail dystrophy and chronic loss of joint function (flexion contracture). Superficial EI is caused by a variant in KRT2 and is characterized by much milder skin thickening and scaling that remains superficial.Erythrokeratodermia variabilis (EKV) and keratitis-ichthyosis-deafness (KID) like disorders exhibit autosomal dominant inheritance and are caused by variants in genes coding for gap junction proteins. EKV is caused by variants in genes GJB3 and GJB4 while KID is caused by variants in GJB2. These disorders can cause skin thickening and redness, as well as the formation of plaques. EKV can also mimic the cyclic nature of annular epidermolytic ichthyosis. The spine-like scaling (hystrix-like scaling) that can be present with EI must be distinguished from Lelis syndrome. Lelis syndrome is a very rare hyperkeratotic presentation of hypohidrotic ectodermal dysplasia (XHED). XHED is an X-linked recessive condition that can present with sparse hair and abnormal teeth. Lelis syndrome can also present discolored and thickened skin. However, unlike EI, Lelis syndrome is accompanied with a lack of sweating (hypohidrosis).Psoriasis is a common and chronic disorder characterized by dry, well-circumscribed silvery-gray scaling spots (papules) or plaques that usually appear on the scalp, elbows or knees. The cause is not well understood but it is thought to be immune mediated and genetic. Sometimes it can be difficult to distinguish from the palmoplantar keratodermas caused by a KRT1 gene variant. However, psoriasis does not follow autosomal dominant inheritance like EI. | 416 | Epidermolytic Ichthyosis |
nord_416_5 | Diagnosis of Epidermolytic Ichthyosis | EI is diagnosed by clinical signs and symptoms. Histopathology tests and electron microscopy assessments may be used but are not the most definitive. Genetic testing for harmful variants in the KRT1 and KRT10 genes can confirm a diagnosis. | Diagnosis of Epidermolytic Ichthyosis. EI is diagnosed by clinical signs and symptoms. Histopathology tests and electron microscopy assessments may be used but are not the most definitive. Genetic testing for harmful variants in the KRT1 and KRT10 genes can confirm a diagnosis. | 416 | Epidermolytic Ichthyosis |
nord_416_6 | Therapies of Epidermolytic Ichthyosis | The main goal of treating EI is to ease the presenting symptoms. This can be challenging as it may require a combination of treatments and therapies. The medications that help to remove the excess thickened skin (topical keratolytics or oral retinoids) can leave the very fragile epidermis (underlying living cell layers) exposed. Therefore, application of a barrier repair formula containing ceramides or cholesterol, or topical emollients, may be used in conjunction to relieve and protect the vulnerable skin. Since bacterial infections are a cause of concern, it is recommended that patients wash with antiseptic soap 2-3 times per week. Many patients find baths with salt or sodium bicarbonate, as well as bleach, beneficial as it helps to descale and prevent bacterial overgrowth. If symptoms are seen at birth, the newborn is recommended to be transferred to the neonatal ICU for proper monitoring and care. | Therapies of Epidermolytic Ichthyosis. The main goal of treating EI is to ease the presenting symptoms. This can be challenging as it may require a combination of treatments and therapies. The medications that help to remove the excess thickened skin (topical keratolytics or oral retinoids) can leave the very fragile epidermis (underlying living cell layers) exposed. Therefore, application of a barrier repair formula containing ceramides or cholesterol, or topical emollients, may be used in conjunction to relieve and protect the vulnerable skin. Since bacterial infections are a cause of concern, it is recommended that patients wash with antiseptic soap 2-3 times per week. Many patients find baths with salt or sodium bicarbonate, as well as bleach, beneficial as it helps to descale and prevent bacterial overgrowth. If symptoms are seen at birth, the newborn is recommended to be transferred to the neonatal ICU for proper monitoring and care. | 416 | Epidermolytic Ichthyosis |
nord_417_0 | Overview of Epilepsy with Eyelid Myoclonia | Epilepsy with eyelid myoclonia (EEM) is a genetic generalized epilepsy syndrome with an average age of onset between 6-8 years. Patients typically present in childhood with prominent eyelid myoclonia, which is a jerking or flickering up of the eyelids associated with the eyes rolling up. This typically happens many times a day. Patients may be misdiagnosed, as eyelid myoclonia may be mistaken as a tic or a behavioral reaction and these children are often referred to a psychologist or psychiatrist. Eyelid myoclonia may be associated with absence seizures and eye closure sensitivity, and other seizure types may also be present. Intellectual ability and development are typically normal, but school difficulties and attention problems may occur. The underlying cause is thought to be genetic, and studies suggest that many different genes may be involved. Seizures typically persist for life and drug-resistant epilepsy is common. Sunflower syndrome was classified as a subgroup of EEM termed “EEM with prominent photic induction” in the 2022 classifications by the International League Against Epilepsy. These patients display sun-seeking behavior with hand waving in front of the eyes, which may trigger seizures. | Overview of Epilepsy with Eyelid Myoclonia. Epilepsy with eyelid myoclonia (EEM) is a genetic generalized epilepsy syndrome with an average age of onset between 6-8 years. Patients typically present in childhood with prominent eyelid myoclonia, which is a jerking or flickering up of the eyelids associated with the eyes rolling up. This typically happens many times a day. Patients may be misdiagnosed, as eyelid myoclonia may be mistaken as a tic or a behavioral reaction and these children are often referred to a psychologist or psychiatrist. Eyelid myoclonia may be associated with absence seizures and eye closure sensitivity, and other seizure types may also be present. Intellectual ability and development are typically normal, but school difficulties and attention problems may occur. The underlying cause is thought to be genetic, and studies suggest that many different genes may be involved. Seizures typically persist for life and drug-resistant epilepsy is common. Sunflower syndrome was classified as a subgroup of EEM termed “EEM with prominent photic induction” in the 2022 classifications by the International League Against Epilepsy. These patients display sun-seeking behavior with hand waving in front of the eyes, which may trigger seizures. | 417 | Epilepsy with Eyelid Myoclonia |
nord_417_1 | Symptoms of Epilepsy with Eyelid Myoclonia | EEM consists of the following three characteristics: 1) eyelid myoclonia with or without absence seizures, 2) eye closure induced seizures or EEG paroxysms and 3) sensitivity to light (photosensitivity). Eyelid myoclonia is required for the diagnosis, which is defined as a jerking, flickering or fluttering of the eyelids usually associated with upward deviation of the orbit and can be associated with a tendency for the head to go backwards (retropulsion of the head). Eyelid myoclonia is typically prominent and the most difficult to control seizure type. Eyelid myoclonia can be induced by eye closure, especially in sunlight or other bright lights and may be associated with loss of awareness, known as absence seizures.Other seizure types may be present including myoclonic seizures, where there are brief jerks of the extremities. Generalized tonic-clonic seizures are seen in most patients but are usually infrequent. With these seizures, patients lose control and have jerking movements of all their extremities. Intellectual ability is typically normal, but eyelid myoclonia may interfere with schoolwork and attention problems may be present. Patients may also have anxiety and depression, as these are common conditions seen in patients with epilepsy. Patients with Sunflower syndrome often have developmental delays. | Symptoms of Epilepsy with Eyelid Myoclonia. EEM consists of the following three characteristics: 1) eyelid myoclonia with or without absence seizures, 2) eye closure induced seizures or EEG paroxysms and 3) sensitivity to light (photosensitivity). Eyelid myoclonia is required for the diagnosis, which is defined as a jerking, flickering or fluttering of the eyelids usually associated with upward deviation of the orbit and can be associated with a tendency for the head to go backwards (retropulsion of the head). Eyelid myoclonia is typically prominent and the most difficult to control seizure type. Eyelid myoclonia can be induced by eye closure, especially in sunlight or other bright lights and may be associated with loss of awareness, known as absence seizures.Other seizure types may be present including myoclonic seizures, where there are brief jerks of the extremities. Generalized tonic-clonic seizures are seen in most patients but are usually infrequent. With these seizures, patients lose control and have jerking movements of all their extremities. Intellectual ability is typically normal, but eyelid myoclonia may interfere with schoolwork and attention problems may be present. Patients may also have anxiety and depression, as these are common conditions seen in patients with epilepsy. Patients with Sunflower syndrome often have developmental delays. | 417 | Epilepsy with Eyelid Myoclonia |
nord_417_2 | Causes of Epilepsy with Eyelid Myoclonia | The underlying cause of EEM is thought to be genetic, which is supported by a positive family history of epilepsy in many patients and cases in twins. Many different genes may be involved and in recent years, changes (variants) in specific genes have been recognized in a minority of patients, including the genes RORB, SYNGAP1, KCNB1, NAA10, COL6A3, NEXMIF and CHD2. An underlying gene variant may influence the severity and prognosis. In many patients, a specific gene variant may not be identified at this time. Further research is needed to clarify the role of genetics in this disorder. | Causes of Epilepsy with Eyelid Myoclonia. The underlying cause of EEM is thought to be genetic, which is supported by a positive family history of epilepsy in many patients and cases in twins. Many different genes may be involved and in recent years, changes (variants) in specific genes have been recognized in a minority of patients, including the genes RORB, SYNGAP1, KCNB1, NAA10, COL6A3, NEXMIF and CHD2. An underlying gene variant may influence the severity and prognosis. In many patients, a specific gene variant may not be identified at this time. Further research is needed to clarify the role of genetics in this disorder. | 417 | Epilepsy with Eyelid Myoclonia |
nord_417_3 | Affects of Epilepsy with Eyelid Myoclonia | EEM affects about twice as many females than males. Onset is between the ages of 1-15 years with a peak from 6-8 years of age. EEM accounts for only about 1.2-2.7% of patients with epilepsy. | Affects of Epilepsy with Eyelid Myoclonia. EEM affects about twice as many females than males. Onset is between the ages of 1-15 years with a peak from 6-8 years of age. EEM accounts for only about 1.2-2.7% of patients with epilepsy. | 417 | Epilepsy with Eyelid Myoclonia |
nord_417_4 | Related disorders of Epilepsy with Eyelid Myoclonia | EEM shares similarities with other generalized epilepsy syndromes, which should be considered in the differential diagnosis. The features of EEM, including the eye-closure induced EEG paroxysms, photosensitivity and even the eyelid myoclonia may be seen in other epilepsy syndromes. Childhood absence epilepsy (CAE) is an idiopathic generalized epilepsy with onset around the same age as EEM. Patients typically have multiple absence seizures a day, which can be associated with eye fluttering that is not as pronounced as the eyelid myoclonia seen in EEM. CAE resolves in childhood for most patients, unlike EEM. Rarely, it has been reported that patients with CAE can develop EEM.There can also be overlap between EEM and juvenile myoclonic epilepsy (JME). The age of onset for JME is typically older, between 10-24 years. Myoclonic jerks, typically of the extremities, are a prominent seizure type in addition to generalized tonic-clonic seizures in JME. Absence seizures may be present. Depending on clinical features, other epilepsy syndromes may be considered in the differential diagnosis including photosensitive occipital lobe epilepsy, epilepsy with myoclonic absences, Dravet syndrome and Lennox-Gastaut syndrome. | Related disorders of Epilepsy with Eyelid Myoclonia. EEM shares similarities with other generalized epilepsy syndromes, which should be considered in the differential diagnosis. The features of EEM, including the eye-closure induced EEG paroxysms, photosensitivity and even the eyelid myoclonia may be seen in other epilepsy syndromes. Childhood absence epilepsy (CAE) is an idiopathic generalized epilepsy with onset around the same age as EEM. Patients typically have multiple absence seizures a day, which can be associated with eye fluttering that is not as pronounced as the eyelid myoclonia seen in EEM. CAE resolves in childhood for most patients, unlike EEM. Rarely, it has been reported that patients with CAE can develop EEM.There can also be overlap between EEM and juvenile myoclonic epilepsy (JME). The age of onset for JME is typically older, between 10-24 years. Myoclonic jerks, typically of the extremities, are a prominent seizure type in addition to generalized tonic-clonic seizures in JME. Absence seizures may be present. Depending on clinical features, other epilepsy syndromes may be considered in the differential diagnosis including photosensitive occipital lobe epilepsy, epilepsy with myoclonic absences, Dravet syndrome and Lennox-Gastaut syndrome. | 417 | Epilepsy with Eyelid Myoclonia |
nord_417_5 | Diagnosis of Epilepsy with Eyelid Myoclonia | EEM is diagnosed based on the presence of three features that include eyelid myoclonia with or without absence seizures, eye closure-induced seizures or EEG paroxysms and photosensitivity. Making the diagnosis requires a thorough clinical history, neurological examination and an EEG. An EEG capturing eyelid myoclonia or other seizures is not required to make the diagnosis if eyelid myoclonia is witnessed on exam by a healthcare provider and other features of the diagnosis are seen on EEG. An MRI of the brain is not required for the diagnosis, but when done is typically normal or shows nonspecific changes unrelated to epilepsy. | Diagnosis of Epilepsy with Eyelid Myoclonia. EEM is diagnosed based on the presence of three features that include eyelid myoclonia with or without absence seizures, eye closure-induced seizures or EEG paroxysms and photosensitivity. Making the diagnosis requires a thorough clinical history, neurological examination and an EEG. An EEG capturing eyelid myoclonia or other seizures is not required to make the diagnosis if eyelid myoclonia is witnessed on exam by a healthcare provider and other features of the diagnosis are seen on EEG. An MRI of the brain is not required for the diagnosis, but when done is typically normal or shows nonspecific changes unrelated to epilepsy. | 417 | Epilepsy with Eyelid Myoclonia |
nord_417_6 | Therapies of Epilepsy with Eyelid Myoclonia | Treatment for EEM consists of broad-spectrum antiseizure medications, including valproic acid, levetiracetam, lamotrigine and clobazam. Modern antiseizure medications like lacosamide, brivaracetam and perampanel are also options, but more experience and research are needed to determine the best treatment. The response to different antiseizure medications can vary between patients, and trials of multiple medications may be necessary. In addition, all antiseizure medications have possible side effects that may limit their use and patients should discuss this with their doctors. For patients with significant photosensitivity, sometimes lens therapy can be effective at reducing seizures. Special lenses have been studied but are not readily available worldwide. In addition, these lenses significantly reduce brightness (luminance), and therefore, may not be well tolerated.Additional therapies may include dietary therapy such as the ketogenic diet, modified Atkins diet and low glycemic index diet. These diets are high in fat and low in carbohydrates and require a significant amount of commitment. Patients typically work closely with their doctor and a nutritionist for dietary therapies. Monitoring may be required, and side effects can be seen. Less is known about the use of more advanced treatments for epilepsy, such as a vagus nerve stimulator and responsive neurostimulation, for EEM specifically. | Therapies of Epilepsy with Eyelid Myoclonia. Treatment for EEM consists of broad-spectrum antiseizure medications, including valproic acid, levetiracetam, lamotrigine and clobazam. Modern antiseizure medications like lacosamide, brivaracetam and perampanel are also options, but more experience and research are needed to determine the best treatment. The response to different antiseizure medications can vary between patients, and trials of multiple medications may be necessary. In addition, all antiseizure medications have possible side effects that may limit their use and patients should discuss this with their doctors. For patients with significant photosensitivity, sometimes lens therapy can be effective at reducing seizures. Special lenses have been studied but are not readily available worldwide. In addition, these lenses significantly reduce brightness (luminance), and therefore, may not be well tolerated.Additional therapies may include dietary therapy such as the ketogenic diet, modified Atkins diet and low glycemic index diet. These diets are high in fat and low in carbohydrates and require a significant amount of commitment. Patients typically work closely with their doctor and a nutritionist for dietary therapies. Monitoring may be required, and side effects can be seen. Less is known about the use of more advanced treatments for epilepsy, such as a vagus nerve stimulator and responsive neurostimulation, for EEM specifically. | 417 | Epilepsy with Eyelid Myoclonia |
nord_418_0 | Overview of Epithelioid Hemangioendothelioma | Epithelioid hemangioendothelioma (EHE) is an ultra-rare vascular sarcoma that has a prevalence of less than one in a million people and affects all age groups, with incidence peaking in the fourth and fifth decade of life and is very rare in children. EHE can arise anywhere in the body and most commonly occurs in the liver, lung and bones with more than 50% of patients presenting with metastatic disease. | Overview of Epithelioid Hemangioendothelioma. Epithelioid hemangioendothelioma (EHE) is an ultra-rare vascular sarcoma that has a prevalence of less than one in a million people and affects all age groups, with incidence peaking in the fourth and fifth decade of life and is very rare in children. EHE can arise anywhere in the body and most commonly occurs in the liver, lung and bones with more than 50% of patients presenting with metastatic disease. | 418 | Epithelioid Hemangioendothelioma |
nord_418_1 | Symptoms of Epithelioid Hemangioendothelioma | Symptoms of Epithelioid Hemangioendothelioma. | 418 | Epithelioid Hemangioendothelioma |
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nord_418_2 | Causes of Epithelioid Hemangioendothelioma | Causes of Epithelioid Hemangioendothelioma. | 418 | Epithelioid Hemangioendothelioma |
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nord_418_3 | Affects of Epithelioid Hemangioendothelioma | Affects of Epithelioid Hemangioendothelioma. | 418 | Epithelioid Hemangioendothelioma |
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nord_418_4 | Related disorders of Epithelioid Hemangioendothelioma | Related disorders of Epithelioid Hemangioendothelioma. | 418 | Epithelioid Hemangioendothelioma |
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nord_418_5 | Diagnosis of Epithelioid Hemangioendothelioma | Diagnosis of Epithelioid Hemangioendothelioma. | 418 | Epithelioid Hemangioendothelioma |
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nord_418_6 | Therapies of Epithelioid Hemangioendothelioma | Therapies of Epithelioid Hemangioendothelioma. | 418 | Epithelioid Hemangioendothelioma |
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nord_419_0 | Overview of Epitheliopathy, Acute Posterior Multifocal Placoid Pigment | Acute posterior multifocal placoid pigment epitheliopathy (APMPPE) is a rare eye disorder of unknown (idiopathic) cause. The disorder is characterized by the impairment of central vision in one eye (unilateral) but, within a few days, the second eye may also become affected (bilateral). In most cases, the disorder resolves within a few weeks without loss of clearness of vision (acuity). However, in some cases, visual acuity does not improve. This disorder occurs predominantly in young adults, with a mean age of onset of 27 years. It is reported that, in approximately one-third of the cases, an influenza-like illness preceded the development of the disorder. | Overview of Epitheliopathy, Acute Posterior Multifocal Placoid Pigment. Acute posterior multifocal placoid pigment epitheliopathy (APMPPE) is a rare eye disorder of unknown (idiopathic) cause. The disorder is characterized by the impairment of central vision in one eye (unilateral) but, within a few days, the second eye may also become affected (bilateral). In most cases, the disorder resolves within a few weeks without loss of clearness of vision (acuity). However, in some cases, visual acuity does not improve. This disorder occurs predominantly in young adults, with a mean age of onset of 27 years. It is reported that, in approximately one-third of the cases, an influenza-like illness preceded the development of the disorder. | 419 | Epitheliopathy, Acute Posterior Multifocal Placoid Pigment |
nord_419_1 | Symptoms of Epitheliopathy, Acute Posterior Multifocal Placoid Pigment | Prior to the onset of disease, about 33% of patients present with flu-like or viral symptoms such as fever, swollen lymph glands, nausea, vomiting, joint pain and/or tenderness. Moderate to severe headaches may also be present and, much more rarely, there may be neurological signs such as temporary loss of speech (aphasia) and/or weakness of the arms and legs. In the early stages of APMPPE, patients notice areas of visual blotchiness within the field of clear vision (blotchy scotomata), flashes of light (photopsia) caused by irritation of the retina, distortion of the shapes of objects (metamorphopsia), increased sensitivity to light (photophobia) and conjunctivitis.During the late stages of the disorder, patients usually notice mild decreases in vision. Rarely, the impaired vision may be severe. Examination of the eye usually shows multiple flat, yellow-white lesions of the posterior pole of the nerve-rich membrane lining the eyes (retina). Frequently the veins of the retina are inflamed (vasculitis), but the inflammation often subsides without treatment. In some cases, pigment changes in the retina may be permanent and the resulting visual impairment may also be permanent. However, in most cases the disorder is characterized by a temporary impairment of vision. | Symptoms of Epitheliopathy, Acute Posterior Multifocal Placoid Pigment. Prior to the onset of disease, about 33% of patients present with flu-like or viral symptoms such as fever, swollen lymph glands, nausea, vomiting, joint pain and/or tenderness. Moderate to severe headaches may also be present and, much more rarely, there may be neurological signs such as temporary loss of speech (aphasia) and/or weakness of the arms and legs. In the early stages of APMPPE, patients notice areas of visual blotchiness within the field of clear vision (blotchy scotomata), flashes of light (photopsia) caused by irritation of the retina, distortion of the shapes of objects (metamorphopsia), increased sensitivity to light (photophobia) and conjunctivitis.During the late stages of the disorder, patients usually notice mild decreases in vision. Rarely, the impaired vision may be severe. Examination of the eye usually shows multiple flat, yellow-white lesions of the posterior pole of the nerve-rich membrane lining the eyes (retina). Frequently the veins of the retina are inflamed (vasculitis), but the inflammation often subsides without treatment. In some cases, pigment changes in the retina may be permanent and the resulting visual impairment may also be permanent. However, in most cases the disorder is characterized by a temporary impairment of vision. | 419 | Epitheliopathy, Acute Posterior Multifocal Placoid Pigment |
nord_419_2 | Causes of Epitheliopathy, Acute Posterior Multifocal Placoid Pigment | The exact cause of acute posterior multifocal placoid pigment epitheliopathy is not known. Researchers suspect that it may be caused by a virus. It can subside without treatment or it may recur at any time. The viruses may stay dormant in humans for extended periods of time, then for reasons yet unknown may unexplainably become reactivated. | Causes of Epitheliopathy, Acute Posterior Multifocal Placoid Pigment. The exact cause of acute posterior multifocal placoid pigment epitheliopathy is not known. Researchers suspect that it may be caused by a virus. It can subside without treatment or it may recur at any time. The viruses may stay dormant in humans for extended periods of time, then for reasons yet unknown may unexplainably become reactivated. | 419 | Epitheliopathy, Acute Posterior Multifocal Placoid Pigment |
nord_419_3 | Affects of Epitheliopathy, Acute Posterior Multifocal Placoid Pigment | Acute posterior multifocal placoid pigment epitheliopathy is a rare visual disorder that affects males and females in equal numbers. | Affects of Epitheliopathy, Acute Posterior Multifocal Placoid Pigment. Acute posterior multifocal placoid pigment epitheliopathy is a rare visual disorder that affects males and females in equal numbers. | 419 | Epitheliopathy, Acute Posterior Multifocal Placoid Pigment |
nord_419_4 | Related disorders of Epitheliopathy, Acute Posterior Multifocal Placoid Pigment | Symptoms of the following disorders can be similar to those of acute posterior multifocal placoid pigment epitheliopathy. Comparison may be useful for a differential diagnosis:Diffuse unilateral subacute neuroretinitis (DUSN) is a progressive parasitic disease affecting the outer retina and retinal pigment epithelium (RPE). This syndrome is primarily unilateral, although bilateral cases have occurred. Examination of the eye shows visual loss, vitreous cells, optic disc inflammation and leakage, and transient, but recurrent, crops of gray-white outer retinal lesions.Stationary or migrating parasitic worms (nematodes) have been identified deep in the retina or in the subretinal space. Later in the course of the disease, slowly progressive RPE changes and optic atrophy may be observed, as well as narrowing of the retinal vessels.Multifocal choroidopathy syndromes are a group of rare disorders involving a major pathological change at or near the level of the retinal pigment epithelium (RPE) with or without inflammation of the blood vessels in the choroid layer of the eye. The cause is unclear but is thought to be either an obstruction of the blood vessels feeding the choroid layer or, possibly, an immunologic response directed at the RPE itself. Many clinical features of these individual entities overlap, causing much confusion. Whether these conditions represent distinct entities or whether some may be parts of a spectrum of the same basic disease is still unknown.Retinitis pigmentosa (RP) is one of a group of inherited diseases causing degeneration of the retina. When the retina degenerates, as in retinitis pigmentosa, the vision decreases and may occasionally be lost. One of the earliest symptoms is difficulty seeing at night or in dimly lit places. This is slowly followed by tunnel vision. The rate and extent of progression is extremely variable, but RP does not occur with the sudden onset of APMPPE. (For more information on this disorder, choose “Retinitis Pigmentosa” as your search term in the Rare Disease Database.)Serpiginous choroiditis, also called geographic helicoid peripapillary choroidopathy, is a rare, inflammatory disease of unknown cause (idiopathic) affecting the inner choroid and retinal pigment epithelium. Typically serpiginous choroiditis occurs bilaterally and is almost always progressive. Though longstanding remissions can be achieved through aggressive immunosuppressive therapy, patients not receiving such therapy often suffer through multiple flare-ups and are often left with macular scarring and significant visual loss.The white dot syndromes are a group of idiopathic multifocal inflammatory conditions involving the retina and the choroid. They are characterized by the appearance of white dots in the fundus. The diseases that constitute the white dot syndromes include acute posterior multifocal placoid pigment epitheliopathy (APMPPE), serpiginous choroiditis, multiple evanescent white dot syndrome (MEWDS), multifocal choroiditis and panuveitis (MCP), punctate inner choroidopathy (PIC), and diffuse subretinal fibrosis (DSF). Presumed ocular histoplasmosis syndrome (POHS) and birdshot retinochoroidopathy are additional white dot syndromes. | Related disorders of Epitheliopathy, Acute Posterior Multifocal Placoid Pigment. Symptoms of the following disorders can be similar to those of acute posterior multifocal placoid pigment epitheliopathy. Comparison may be useful for a differential diagnosis:Diffuse unilateral subacute neuroretinitis (DUSN) is a progressive parasitic disease affecting the outer retina and retinal pigment epithelium (RPE). This syndrome is primarily unilateral, although bilateral cases have occurred. Examination of the eye shows visual loss, vitreous cells, optic disc inflammation and leakage, and transient, but recurrent, crops of gray-white outer retinal lesions.Stationary or migrating parasitic worms (nematodes) have been identified deep in the retina or in the subretinal space. Later in the course of the disease, slowly progressive RPE changes and optic atrophy may be observed, as well as narrowing of the retinal vessels.Multifocal choroidopathy syndromes are a group of rare disorders involving a major pathological change at or near the level of the retinal pigment epithelium (RPE) with or without inflammation of the blood vessels in the choroid layer of the eye. The cause is unclear but is thought to be either an obstruction of the blood vessels feeding the choroid layer or, possibly, an immunologic response directed at the RPE itself. Many clinical features of these individual entities overlap, causing much confusion. Whether these conditions represent distinct entities or whether some may be parts of a spectrum of the same basic disease is still unknown.Retinitis pigmentosa (RP) is one of a group of inherited diseases causing degeneration of the retina. When the retina degenerates, as in retinitis pigmentosa, the vision decreases and may occasionally be lost. One of the earliest symptoms is difficulty seeing at night or in dimly lit places. This is slowly followed by tunnel vision. The rate and extent of progression is extremely variable, but RP does not occur with the sudden onset of APMPPE. (For more information on this disorder, choose “Retinitis Pigmentosa” as your search term in the Rare Disease Database.)Serpiginous choroiditis, also called geographic helicoid peripapillary choroidopathy, is a rare, inflammatory disease of unknown cause (idiopathic) affecting the inner choroid and retinal pigment epithelium. Typically serpiginous choroiditis occurs bilaterally and is almost always progressive. Though longstanding remissions can be achieved through aggressive immunosuppressive therapy, patients not receiving such therapy often suffer through multiple flare-ups and are often left with macular scarring and significant visual loss.The white dot syndromes are a group of idiopathic multifocal inflammatory conditions involving the retina and the choroid. They are characterized by the appearance of white dots in the fundus. The diseases that constitute the white dot syndromes include acute posterior multifocal placoid pigment epitheliopathy (APMPPE), serpiginous choroiditis, multiple evanescent white dot syndrome (MEWDS), multifocal choroiditis and panuveitis (MCP), punctate inner choroidopathy (PIC), and diffuse subretinal fibrosis (DSF). Presumed ocular histoplasmosis syndrome (POHS) and birdshot retinochoroidopathy are additional white dot syndromes. | 419 | Epitheliopathy, Acute Posterior Multifocal Placoid Pigment |
nord_419_5 | Diagnosis of Epitheliopathy, Acute Posterior Multifocal Placoid Pigment | Diagnosis of Epitheliopathy, Acute Posterior Multifocal Placoid Pigment. | 419 | Epitheliopathy, Acute Posterior Multifocal Placoid Pigment |
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nord_419_6 | Therapies of Epitheliopathy, Acute Posterior Multifocal Placoid Pigment | Treatment of acute posterior multifocal placoid pigment epitheliopathy is symptomatic and supportive. Very often vision returns without specific treatment. | Therapies of Epitheliopathy, Acute Posterior Multifocal Placoid Pigment. Treatment of acute posterior multifocal placoid pigment epitheliopathy is symptomatic and supportive. Very often vision returns without specific treatment. | 419 | Epitheliopathy, Acute Posterior Multifocal Placoid Pigment |
nord_420_0 | Overview of Erdheim Chester Disease | Erdheim-Chester disease (ECD) is a rare multisystem disorder of adulthood. It is characterized by excessive production and accumulation of histiocytes within multiple tissues and organs. Histiocytes are large phagocytic cells (macrophages) that normally play a role in responding to infection and injury. (A phagocytic cell is any “scavenger cell” that engulfs and destroys invading microorganisms or cellular debris.) In people with ECD, sites of involvement may include the long bones, skin, tissues behind the eyeballs, lungs, brain, pituitary gland and/or additional tissues and organs. Associated symptoms and findings and disease course depend on the specific location and extent of such involvement. The underlying cause of ECD is thought to be a malignancy of the myeloid progenitor cells. | Overview of Erdheim Chester Disease. Erdheim-Chester disease (ECD) is a rare multisystem disorder of adulthood. It is characterized by excessive production and accumulation of histiocytes within multiple tissues and organs. Histiocytes are large phagocytic cells (macrophages) that normally play a role in responding to infection and injury. (A phagocytic cell is any “scavenger cell” that engulfs and destroys invading microorganisms or cellular debris.) In people with ECD, sites of involvement may include the long bones, skin, tissues behind the eyeballs, lungs, brain, pituitary gland and/or additional tissues and organs. Associated symptoms and findings and disease course depend on the specific location and extent of such involvement. The underlying cause of ECD is thought to be a malignancy of the myeloid progenitor cells. | 420 | Erdheim Chester Disease |
nord_420_1 | Symptoms of Erdheim Chester Disease | ECD characteristically affects certain regions of the long bones of the legs, including the shafts (diaphyses) and the areas (i.e., metaphyses) where the shafts converge with the ends (epiphyses). The ends of the long bones are usually spared or may have mild changes. Infiltration by histiocytes typically leads to widespread or patchy increases in bone density as well as hardening (osteosclerosis) and thickening of bone. In some rare cases, there may also be involvement of other bones, such as the lower jawbone (mandible) or certain bones of the spinal column (vertebrae). In many affected individuals, the initial symptom of the disorder is associated bone pain, usually affecting the knees and legs, that is similar on both sides of the body (symmetrical). In some cases, more generalized symptoms may also develop, including weight loss, fever, muscle and joint aches; and a general feeling of discomfort, weakness, and fatigue (malaise).ECD may also be characterized by involvement of the skin, tissues behind the eyeballs (retrobulbar region); the lungs; the brain; the pituitary gland, the region containing organs at the back of the abdominal cavity (retroperitoneum) and/or other sites. Associated symptoms and disease course may vary from case to case, depending on the site and degree of involvement.Some individuals with ECD may develop soft, yellowish, fatty plaques or nodules on the eyelids (xanthelasma) or skin (cutaneous xanthomas). In addition, involvement of the retrobulbar region may lead to marked protrusion of the eyeballs (exophthalmos) and other symptoms and findings.In those with lung (pulmonary) involvement, progressive scarring and thickening of lung tissue (pulmonary fibrosis) may lead to a dry cough, increasingly labored breathing (dyspnea) with exertion, insufficient oxygenation of the blood, impaired ability of the heart to pump enough blood to the lungs and the rest of the body (heart failure), and potentially life-threatening complications.In some affected individuals, there may also be infiltration of the pituitary gland, leading to diabetes insipidus. This is a metabolic condition in which insufficient secretion of antidiuretic hormone (ADH) by the pituitary gland leads to the passing of large amounts of dilute urine (polyuria) and excessive thirst (polydipsia). (ADH normally reduces the amount of water lost in urine. The pituitary gland produces several hormones, including ADH; it is controlled by and connected to a region of the brain called the hypothalamus.)In some rare cases, ECD may also be characterized by involvement of other brain regions, such as part of the lowest region of the brain (brainstem) and the cerebellum, which is involved in coordinating voluntary movement, balance and posture. Associated neurologic symptoms may be variable from person to person. However, such abnormalities often include impaired muscular coordination (ataxia); an abnormal staggering manner of walking (gait); slurred speech (dysarthria) and/or involuntary, rhythmic, rapid eye movements (nystagmus).ECD may also be characterized by infiltration and associated scarring of tissues within the retroperitoneal region (retroperitoneal fibrosis). In some cases, such changes may result in obstruction of the tubes (i.e., ureters) that carry urine from the kidneys into the bladder, causing abnormal swelling of the kidneys with urine (hydronephrosis), impaired kidney (renal) function, and possible renal failure. A few cases have also been described in which retroperitoneal fibrosis has involved the major artery of the body (aorta) and its branching blood vessels (periaortic fibrosis).As noted above, the course of the disease is variable, depending on the extent of involvement occurring outside of bone (extraosseous involvement) and affecting internal organs (visceral involvement). In some cases, disease progression and associated organ system dysfunction may lead to potentially life-threatening complications, such as due to pulmonary fibrosis, heart failure, and/or renal failure. | Symptoms of Erdheim Chester Disease. ECD characteristically affects certain regions of the long bones of the legs, including the shafts (diaphyses) and the areas (i.e., metaphyses) where the shafts converge with the ends (epiphyses). The ends of the long bones are usually spared or may have mild changes. Infiltration by histiocytes typically leads to widespread or patchy increases in bone density as well as hardening (osteosclerosis) and thickening of bone. In some rare cases, there may also be involvement of other bones, such as the lower jawbone (mandible) or certain bones of the spinal column (vertebrae). In many affected individuals, the initial symptom of the disorder is associated bone pain, usually affecting the knees and legs, that is similar on both sides of the body (symmetrical). In some cases, more generalized symptoms may also develop, including weight loss, fever, muscle and joint aches; and a general feeling of discomfort, weakness, and fatigue (malaise).ECD may also be characterized by involvement of the skin, tissues behind the eyeballs (retrobulbar region); the lungs; the brain; the pituitary gland, the region containing organs at the back of the abdominal cavity (retroperitoneum) and/or other sites. Associated symptoms and disease course may vary from case to case, depending on the site and degree of involvement.Some individuals with ECD may develop soft, yellowish, fatty plaques or nodules on the eyelids (xanthelasma) or skin (cutaneous xanthomas). In addition, involvement of the retrobulbar region may lead to marked protrusion of the eyeballs (exophthalmos) and other symptoms and findings.In those with lung (pulmonary) involvement, progressive scarring and thickening of lung tissue (pulmonary fibrosis) may lead to a dry cough, increasingly labored breathing (dyspnea) with exertion, insufficient oxygenation of the blood, impaired ability of the heart to pump enough blood to the lungs and the rest of the body (heart failure), and potentially life-threatening complications.In some affected individuals, there may also be infiltration of the pituitary gland, leading to diabetes insipidus. This is a metabolic condition in which insufficient secretion of antidiuretic hormone (ADH) by the pituitary gland leads to the passing of large amounts of dilute urine (polyuria) and excessive thirst (polydipsia). (ADH normally reduces the amount of water lost in urine. The pituitary gland produces several hormones, including ADH; it is controlled by and connected to a region of the brain called the hypothalamus.)In some rare cases, ECD may also be characterized by involvement of other brain regions, such as part of the lowest region of the brain (brainstem) and the cerebellum, which is involved in coordinating voluntary movement, balance and posture. Associated neurologic symptoms may be variable from person to person. However, such abnormalities often include impaired muscular coordination (ataxia); an abnormal staggering manner of walking (gait); slurred speech (dysarthria) and/or involuntary, rhythmic, rapid eye movements (nystagmus).ECD may also be characterized by infiltration and associated scarring of tissues within the retroperitoneal region (retroperitoneal fibrosis). In some cases, such changes may result in obstruction of the tubes (i.e., ureters) that carry urine from the kidneys into the bladder, causing abnormal swelling of the kidneys with urine (hydronephrosis), impaired kidney (renal) function, and possible renal failure. A few cases have also been described in which retroperitoneal fibrosis has involved the major artery of the body (aorta) and its branching blood vessels (periaortic fibrosis).As noted above, the course of the disease is variable, depending on the extent of involvement occurring outside of bone (extraosseous involvement) and affecting internal organs (visceral involvement). In some cases, disease progression and associated organ system dysfunction may lead to potentially life-threatening complications, such as due to pulmonary fibrosis, heart failure, and/or renal failure. | 420 | Erdheim Chester Disease |
nord_420_2 | Causes of Erdheim Chester Disease | ECD is thought to represent an abnormal inflammatory process characterized by excessive proliferation and accumulation of certain cells, with associated scarring or overgrowth of fibrous connective tissue (fibrosis). Somatic mutations in the BRAF-V600 gene and other mutations in the mitogen-activated protein kinase (MAPK) signaling and phosphatidylinositol 3-kinase (PI3K)-ART pathways have established ECD as a malignancy of myeloid progenitor cells. A BRAF V600 gene mutation has been found in about half of patients with ECD. There may be widespread infiltration of affected tissues by histiocytic cells that contain large amounts of fatty (lipid) material (xanthomatous histiocytes); certain lymphocytes; and distinctive, large cells with multiple nuclei (Touton giant cells). (Lymphocytes are an immune system cell type that originates in the bone marrow.) In those with ECD, these fatty, nodular (xanthogranulomatous) cell deposits may infiltrate multiple tissues and organs, leading to impaired organ functioning. | Causes of Erdheim Chester Disease. ECD is thought to represent an abnormal inflammatory process characterized by excessive proliferation and accumulation of certain cells, with associated scarring or overgrowth of fibrous connective tissue (fibrosis). Somatic mutations in the BRAF-V600 gene and other mutations in the mitogen-activated protein kinase (MAPK) signaling and phosphatidylinositol 3-kinase (PI3K)-ART pathways have established ECD as a malignancy of myeloid progenitor cells. A BRAF V600 gene mutation has been found in about half of patients with ECD. There may be widespread infiltration of affected tissues by histiocytic cells that contain large amounts of fatty (lipid) material (xanthomatous histiocytes); certain lymphocytes; and distinctive, large cells with multiple nuclei (Touton giant cells). (Lymphocytes are an immune system cell type that originates in the bone marrow.) In those with ECD, these fatty, nodular (xanthogranulomatous) cell deposits may infiltrate multiple tissues and organs, leading to impaired organ functioning. | 420 | Erdheim Chester Disease |
nord_420_3 | Affects of Erdheim Chester Disease | ECD is a rare disorder of adulthood that most frequently becomes apparent in middle age, with an average age of onset in the mid-50s. More than 100 cases have been reported in the medical literature with a slight male preponderance. ECD is named for the two investigators who originally described the disease. | Affects of Erdheim Chester Disease. ECD is a rare disorder of adulthood that most frequently becomes apparent in middle age, with an average age of onset in the mid-50s. More than 100 cases have been reported in the medical literature with a slight male preponderance. ECD is named for the two investigators who originally described the disease. | 420 | Erdheim Chester Disease |
nord_420_4 | Related disorders of Erdheim Chester Disease | Symptoms of the following disorders may be similar to those of Erdheim-Chester disease. Comparisons may be useful for a differential diagnosis:Histiocytosis X, also known as Langerhans cell histiocytosis (LCH), is a group of diseases characterized by excessive production and accumulation of histiocytes in various tissues and organs. The lesions may include certain distinctive granule-containing cells (known as Langerhans’ cells) involved in certain immune responses as well as lymphocytes and other immune system cell types (e.g., monocytes, eosinophils). Associated symptoms and findings may vary from case to case, depending on the specific tissues and organs affected and the extent of involvement. Most affected individuals have single or multiple bone lesions characterized by degenerative changes and loss of the calcium of bone (osteolysis). Although the skull is most commonly affected, there may also be involvement of other bones, such as those of the spine (vertebrae) and long bones. Affected individuals may have no apparent symptoms (asymptomatic), experience associated pain and swelling, and/or develop certain complications, such as fractures or secondary compression of the spinal cord. In some cases, other tissues and organs may also be affected, including the skin, lungs, or other regions. In some individuals, LCH may be associated with involvement of the pituitary gland, leading to diabetes insipidus; this form of LCH is known as Hand-Schuller-Christian disease. Certain cellular tissue changes, symptoms, and findings seen in LCH may resemble those associated with ECD, causing some to suggest that the latter may represent a form of LCH. However, evidence suggests that it is a distinct disease entity that differs from LCH regarding age of onset, characteristic bone changes, and other features. LCH most commonly becomes apparent during childhood, while ECD primarily affects middle-aged adults. In addition, the bone changes in LCH are typically characterized by osteolysis and involve the axial skeleton (e.g., the skull and vertebrae); in contrast, as noted earlier, ECD is associated with symmetric hardening (osteosclerosis) and thickening of certain regions of the long bones. (For more information on LCH, choose “histiocytosis” as your search term in the Rare Disease Database.)Cerebrotendinous xanthomatosis (CTX) is an extremely rare, inherited lipid storage disease that is present at birth. It is characterized by the accumulation of large amounts of cholesterol (xanthomatosis) in many tissues of the body. Excessive cholesterol cannot be eliminated from the body. When cholesterol accumulates in the brain, affected children may have difficulty walking, developmental delays, and/or intellectual disability. During young adulthood, some people with cerebrotendinous xanthomatosis may have severe heart problems due to the buildup of cholesterol in the major arteries that surround the heart. Symptoms develop due to a deficiency of an enzyme sterol 26-hydroxycholesterol. (For more information on LCH, choose “cerebrotendinous xanthomatosis” as your search term in the Rare Disease Database.)There are several other disorders and conditions that may be characterized by certain symptoms and findings similar to those potentially associated with ECD. (For further information, choose the exact disease name in question as your search term in the Rare Disease Database.) | Related disorders of Erdheim Chester Disease. Symptoms of the following disorders may be similar to those of Erdheim-Chester disease. Comparisons may be useful for a differential diagnosis:Histiocytosis X, also known as Langerhans cell histiocytosis (LCH), is a group of diseases characterized by excessive production and accumulation of histiocytes in various tissues and organs. The lesions may include certain distinctive granule-containing cells (known as Langerhans’ cells) involved in certain immune responses as well as lymphocytes and other immune system cell types (e.g., monocytes, eosinophils). Associated symptoms and findings may vary from case to case, depending on the specific tissues and organs affected and the extent of involvement. Most affected individuals have single or multiple bone lesions characterized by degenerative changes and loss of the calcium of bone (osteolysis). Although the skull is most commonly affected, there may also be involvement of other bones, such as those of the spine (vertebrae) and long bones. Affected individuals may have no apparent symptoms (asymptomatic), experience associated pain and swelling, and/or develop certain complications, such as fractures or secondary compression of the spinal cord. In some cases, other tissues and organs may also be affected, including the skin, lungs, or other regions. In some individuals, LCH may be associated with involvement of the pituitary gland, leading to diabetes insipidus; this form of LCH is known as Hand-Schuller-Christian disease. Certain cellular tissue changes, symptoms, and findings seen in LCH may resemble those associated with ECD, causing some to suggest that the latter may represent a form of LCH. However, evidence suggests that it is a distinct disease entity that differs from LCH regarding age of onset, characteristic bone changes, and other features. LCH most commonly becomes apparent during childhood, while ECD primarily affects middle-aged adults. In addition, the bone changes in LCH are typically characterized by osteolysis and involve the axial skeleton (e.g., the skull and vertebrae); in contrast, as noted earlier, ECD is associated with symmetric hardening (osteosclerosis) and thickening of certain regions of the long bones. (For more information on LCH, choose “histiocytosis” as your search term in the Rare Disease Database.)Cerebrotendinous xanthomatosis (CTX) is an extremely rare, inherited lipid storage disease that is present at birth. It is characterized by the accumulation of large amounts of cholesterol (xanthomatosis) in many tissues of the body. Excessive cholesterol cannot be eliminated from the body. When cholesterol accumulates in the brain, affected children may have difficulty walking, developmental delays, and/or intellectual disability. During young adulthood, some people with cerebrotendinous xanthomatosis may have severe heart problems due to the buildup of cholesterol in the major arteries that surround the heart. Symptoms develop due to a deficiency of an enzyme sterol 26-hydroxycholesterol. (For more information on LCH, choose “cerebrotendinous xanthomatosis” as your search term in the Rare Disease Database.)There are several other disorders and conditions that may be characterized by certain symptoms and findings similar to those potentially associated with ECD. (For further information, choose the exact disease name in question as your search term in the Rare Disease Database.) | 420 | Erdheim Chester Disease |
nord_420_5 | Diagnosis of Erdheim Chester Disease | A diagnosis of ECD is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic symptoms, and a variety of specialized tests. Such studies may include plain x-rays; advanced imaging techniques, including computed tomography (CT) scanning, magnetic resonance imaging (MRI), FDG-PET-CT and/or a bone scan (bone scintigraphy); and/or other tests. Plain x-rays of involved bones typically reveal symmetrical increased hardening and thickening, mainly in the metaphyses and diaphyses with sparing of the epiphyses, a finding that is considered distinctive of ECD. In addition, the diagnosis may be confirmed by removal (biopsy) and microscopic evaluation of tissue samples that demonstrate infiltration by fatty (lipid)-laden, foamy histiocytes with certain non-Langerhans cellular features and distinctive, large cells with multiple nuclei (Touton giant cells). Molecular testing of biopsy specimens can identify specific somatic mutations that can direct specific treatments. (For more on Langerhans cell histiocytosis, please see the “Related Disorders” section above.) | Diagnosis of Erdheim Chester Disease. A diagnosis of ECD is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic symptoms, and a variety of specialized tests. Such studies may include plain x-rays; advanced imaging techniques, including computed tomography (CT) scanning, magnetic resonance imaging (MRI), FDG-PET-CT and/or a bone scan (bone scintigraphy); and/or other tests. Plain x-rays of involved bones typically reveal symmetrical increased hardening and thickening, mainly in the metaphyses and diaphyses with sparing of the epiphyses, a finding that is considered distinctive of ECD. In addition, the diagnosis may be confirmed by removal (biopsy) and microscopic evaluation of tissue samples that demonstrate infiltration by fatty (lipid)-laden, foamy histiocytes with certain non-Langerhans cellular features and distinctive, large cells with multiple nuclei (Touton giant cells). Molecular testing of biopsy specimens can identify specific somatic mutations that can direct specific treatments. (For more on Langerhans cell histiocytosis, please see the “Related Disorders” section above.) | 420 | Erdheim Chester Disease |
nord_420_6 | Therapies of Erdheim Chester Disease | Treatment
There is no cure for ECD. Asymptomatic patients will generally be followed until they develop specific symptoms. Treatment of symptomatic patients will be guided by the type of somatic mutations and by organ specific involvement such as the CNS. Reports indicate that various treatments have been used with variable success. Zelboraf (vemurafenib) is the only therapy approved by the U.S. Food and Drug Administration (FDA) to treat certain adult patients with ECD who have the BRAF V6000 gene mutation. Targeted therapies are being tried including BRAF-inhibitors, MEK-inhibitors, interferon alfa, glucocorticoids, mTOR inhibitors or systemic therapies such as cytotoxic chemotherapy or cytokine-directed therapy. Radiation therapy is not used since ECD is not radiosensitive. Surgery has a limited role due to extensive disease.Patients are encouraged to enroll in clinical trials for ECD as several trials are underway. Further research is needed to determine optimal treatments for this disorder. Additional treatment for individuals with ECD is symptomatic and supportive. | Therapies of Erdheim Chester Disease. Treatment
There is no cure for ECD. Asymptomatic patients will generally be followed until they develop specific symptoms. Treatment of symptomatic patients will be guided by the type of somatic mutations and by organ specific involvement such as the CNS. Reports indicate that various treatments have been used with variable success. Zelboraf (vemurafenib) is the only therapy approved by the U.S. Food and Drug Administration (FDA) to treat certain adult patients with ECD who have the BRAF V6000 gene mutation. Targeted therapies are being tried including BRAF-inhibitors, MEK-inhibitors, interferon alfa, glucocorticoids, mTOR inhibitors or systemic therapies such as cytotoxic chemotherapy or cytokine-directed therapy. Radiation therapy is not used since ECD is not radiosensitive. Surgery has a limited role due to extensive disease.Patients are encouraged to enroll in clinical trials for ECD as several trials are underway. Further research is needed to determine optimal treatments for this disorder. Additional treatment for individuals with ECD is symptomatic and supportive. | 420 | Erdheim Chester Disease |
nord_421_0 | Overview of Erythema Multiforme | Erythema multiforme (EM) is the name applied to a group of hypersensitivity disorders, affecting mostly children and young adults, and characterized by symmetric red, patchy lesions, primarily on the arms and legs. The cause is unknown, but EM frequently occurs in association with herpes simplex virus, suggesting an immunologic process initiated by the virus. In half of the cases, the triggering agents appear to be medications, including anticonvulsants, sulfonamides, nonsteroidal anti-inflammatory drugs, and other antibiotics. In addition, some cases appear to be associated with infectious organisms such as Mycoplasma pneumoniae and many viral agents.Erythema multiforme is the mildest of three skin disorders that are often discussed in relation to each other. It is generally the mildest of the three. More severe is Stevens-Johnson syndrome. The most severe of the three is toxic epidermal necrolysis (TEN). | Overview of Erythema Multiforme. Erythema multiforme (EM) is the name applied to a group of hypersensitivity disorders, affecting mostly children and young adults, and characterized by symmetric red, patchy lesions, primarily on the arms and legs. The cause is unknown, but EM frequently occurs in association with herpes simplex virus, suggesting an immunologic process initiated by the virus. In half of the cases, the triggering agents appear to be medications, including anticonvulsants, sulfonamides, nonsteroidal anti-inflammatory drugs, and other antibiotics. In addition, some cases appear to be associated with infectious organisms such as Mycoplasma pneumoniae and many viral agents.Erythema multiforme is the mildest of three skin disorders that are often discussed in relation to each other. It is generally the mildest of the three. More severe is Stevens-Johnson syndrome. The most severe of the three is toxic epidermal necrolysis (TEN). | 421 | Erythema Multiforme |
nord_421_1 | Symptoms of Erythema Multiforme | Onset of erythema multiforme is usually sudden in an otherwise healthy individual. Red spots (macules or papules), or ridges (wheals), and sometimes blisters appear on the tops of the hands and forearms. Other areas of involvement may include the face, neck, palms, soles of feet, legs, and trunk. The lesions continue to erupt for two or three days. Some spots, especially on the hands and forearms, may evolve into concentric circles that resemble a target, with a grayish discoloration in the center. A crust may develop over the center. In about half of the cases, lesions may develop on the lips and the mucous membranes in the mouth. The skin lesions are usually distributed on both sides of the body. Itching can also occur.Systemic symptoms vary, but malaise, pain in the joints (arthralgia), muscular stiffness and fever are frequent. Additional symptoms may include vision abnormalities; dry or bloodshot eyes; and eye pain, itching, or burning.Attacks usually last two to four weeks, and may recur. Classic EM tends to recur two or three times a year for several years after its first appearance. | Symptoms of Erythema Multiforme. Onset of erythema multiforme is usually sudden in an otherwise healthy individual. Red spots (macules or papules), or ridges (wheals), and sometimes blisters appear on the tops of the hands and forearms. Other areas of involvement may include the face, neck, palms, soles of feet, legs, and trunk. The lesions continue to erupt for two or three days. Some spots, especially on the hands and forearms, may evolve into concentric circles that resemble a target, with a grayish discoloration in the center. A crust may develop over the center. In about half of the cases, lesions may develop on the lips and the mucous membranes in the mouth. The skin lesions are usually distributed on both sides of the body. Itching can also occur.Systemic symptoms vary, but malaise, pain in the joints (arthralgia), muscular stiffness and fever are frequent. Additional symptoms may include vision abnormalities; dry or bloodshot eyes; and eye pain, itching, or burning.Attacks usually last two to four weeks, and may recur. Classic EM tends to recur two or three times a year for several years after its first appearance. | 421 | Erythema Multiforme |
nord_421_2 | Causes of Erythema Multiforme | The cause of erythema multiforme is unknown, but it appears to be an allergic reaction that occurs in response to medications, infections, or illness. As noted above, it often appears in association with herpes simplex virus or with infectious organisms such as Mycoplasma pneumoniae. In approximately half of the cases, it appears that the triggering agent is a medication. Drugs that have been associated with erythema multiforme include anticonvulsants, sulfonamides, nonsteroidal anti-inflammatory drugs, and other antibiotics. | Causes of Erythema Multiforme. The cause of erythema multiforme is unknown, but it appears to be an allergic reaction that occurs in response to medications, infections, or illness. As noted above, it often appears in association with herpes simplex virus or with infectious organisms such as Mycoplasma pneumoniae. In approximately half of the cases, it appears that the triggering agent is a medication. Drugs that have been associated with erythema multiforme include anticonvulsants, sulfonamides, nonsteroidal anti-inflammatory drugs, and other antibiotics. | 421 | Erythema Multiforme |
nord_421_3 | Affects of Erythema Multiforme | Erythema multiforme is a rare disorder that affects slightly more males than females. It may begin at any age, but is most common in children and young adults. | Affects of Erythema Multiforme. Erythema multiforme is a rare disorder that affects slightly more males than females. It may begin at any age, but is most common in children and young adults. | 421 | Erythema Multiforme |
nord_421_4 | Related disorders of Erythema Multiforme | Symptoms of the following disorders can be similar to those of Erythema Multiforme. Comparisons may be useful for a differential diagnosis:Urticaria (hives) is easily recognized by the typical well-defined edematous ridges (wheals). This type of skin disorder does not include blisters. (For more information on this disorder, choose “Urticaria” as your search term in the Rare Disease Database.)Erythema Nodosum is an inflammatory disease of the skin and subcutaneous tissue characterized by tender red nodules, predominantly appearing on the shins but occasionally involving the arms or other areas. (For more information on this disorder, choose “Erythema Nodosum” as your search term in the Rare Disease Database.)Bullous Pemphigoid is a chronic benign blistery (bullous) skin eruption seen chiefly in the elderly. (For more information on this disorder, choose “Bullous Pemphigoid” as your search term in the Rare Disease Database.)Dermatitis Herpetiformis (Duhring Disease) is a chronic skin eruption characterized by clusters of intensely itchy blisters, elevated spots (papules) and urticaria-like lesions. (For more information on this disorder, choose “Duhring” as your search term in the Rare Disease Database.)Pemphigus is an uncommon serious hereditary skin disorder characterized by blisters (bullae) in the top layer (epidermis) of apparently healthy skin and mucous membranes. (For more information on this disorder, “Pemphigus” as your search term in the Rare Disease Database.) | Related disorders of Erythema Multiforme. Symptoms of the following disorders can be similar to those of Erythema Multiforme. Comparisons may be useful for a differential diagnosis:Urticaria (hives) is easily recognized by the typical well-defined edematous ridges (wheals). This type of skin disorder does not include blisters. (For more information on this disorder, choose “Urticaria” as your search term in the Rare Disease Database.)Erythema Nodosum is an inflammatory disease of the skin and subcutaneous tissue characterized by tender red nodules, predominantly appearing on the shins but occasionally involving the arms or other areas. (For more information on this disorder, choose “Erythema Nodosum” as your search term in the Rare Disease Database.)Bullous Pemphigoid is a chronic benign blistery (bullous) skin eruption seen chiefly in the elderly. (For more information on this disorder, choose “Bullous Pemphigoid” as your search term in the Rare Disease Database.)Dermatitis Herpetiformis (Duhring Disease) is a chronic skin eruption characterized by clusters of intensely itchy blisters, elevated spots (papules) and urticaria-like lesions. (For more information on this disorder, choose “Duhring” as your search term in the Rare Disease Database.)Pemphigus is an uncommon serious hereditary skin disorder characterized by blisters (bullae) in the top layer (epidermis) of apparently healthy skin and mucous membranes. (For more information on this disorder, “Pemphigus” as your search term in the Rare Disease Database.) | 421 | Erythema Multiforme |
nord_421_5 | Diagnosis of Erythema Multiforme | Usually, the diagnosis can be made on the basis of the size, shape, color and distribution of the target lesions. | Diagnosis of Erythema Multiforme. Usually, the diagnosis can be made on the basis of the size, shape, color and distribution of the target lesions. | 421 | Erythema Multiforme |
nord_421_6 | Therapies of Erythema Multiforme | TreatmentWhen a cause for erythema multiforme can be found, it should be treated, eliminated, or avoided (e.g. drugs or other substances to which the patient is allergic). Local treatment depends on the type of lesion.Most people with classic erythema multiforme can be treated as outpatients with therapy, such as antihistamines, addressing their symptoms. Sometimes, no treatment is required.For blisters and erosive lesions, intermittent moist compresses may be helpful. Over-the-counter antihistamines usually take care of whatever itching may be present. Infections of the lips and mouth usually can be managed with topical anesthetics but may, in some cases, require special care. | Therapies of Erythema Multiforme. TreatmentWhen a cause for erythema multiforme can be found, it should be treated, eliminated, or avoided (e.g. drugs or other substances to which the patient is allergic). Local treatment depends on the type of lesion.Most people with classic erythema multiforme can be treated as outpatients with therapy, such as antihistamines, addressing their symptoms. Sometimes, no treatment is required.For blisters and erosive lesions, intermittent moist compresses may be helpful. Over-the-counter antihistamines usually take care of whatever itching may be present. Infections of the lips and mouth usually can be managed with topical anesthetics but may, in some cases, require special care. | 421 | Erythema Multiforme |
nord_422_0 | Overview of Erythrokeratoderma | SummaryErythrokeratoderma is an umbrella term for a group of rare genetic skin disorders characterized by well-demarcated plaques of reddened, dry and thickened skin. Typically, these lesions are distributed symmetrically on the body and tend to slowly expand and progress over time. The severity and progression of the disorder can vary greatly from one person to another, even among members of the same family. Progressive symmetric erythrokeratoderma (PSEK) and erythokeratodermia variabilis et progressiva (EKVP) are the most common forms of erythrokeratoderma. | Overview of Erythrokeratoderma. SummaryErythrokeratoderma is an umbrella term for a group of rare genetic skin disorders characterized by well-demarcated plaques of reddened, dry and thickened skin. Typically, these lesions are distributed symmetrically on the body and tend to slowly expand and progress over time. The severity and progression of the disorder can vary greatly from one person to another, even among members of the same family. Progressive symmetric erythrokeratoderma (PSEK) and erythokeratodermia variabilis et progressiva (EKVP) are the most common forms of erythrokeratoderma. | 422 | Erythrokeratoderma |
nord_422_1 | Symptoms of Erythrokeratoderma | The symptoms of PSEK usually develop shortly after birth or during the first year of life. Infants develop reddened plaques of thickened, rough and/or scaly skin, especially on the face, buttocks, arms and legs. Over time, these lesions can cover large areas of the body. The distribution of these lesions is almost perfectly symmetrical, meaning the size, shape and location of the lesions are extremely similar on both sides of the body. These plaques are slowly progressive increasing in number and size throughout early childhood before either stabilizing, regressing or disappearing sometime later during life. Rarely, waxing and waning may occur. In some patients, the chest and abdomen may become involved. Abnormally thickened or calloused skin on the palms and soles (palmoplantar keratoderma; PPK) is not uncommon and can be disabling.The majority of individuals with features of erythrokeratoderma belong to the clinical spectrum of erythrokeratodermia variabilis (EKV) or PSEK, hence a unifying name of ‘erythrokeratodermia variabilis et progressiva’ (EKVP) has been coined. The hallmark of classic EKV is the occurrence of figurate-outlined red patches, which seem to come and go quickly (so-called ‘fleeting erythema’), sometimes provoked by sudden temperature changes or other triggers. These red patches are more common in childhood and seem to disappear in adulthood. Features of both EKV and PSEK may be present within a single family, caused by a sequence change in a connexin gene. Extremely rarely, the sharply demarcated, thickened and red skin plaques may be distributed in a linear or whorl-like pattern due to mosaicism for a connexin gene mutation in a subset of epidermal skin cells.Nevertheless, there are many other different forms and causes of erythrokeratoderma, reflecting the clinical and genetic heterogeneity of this condition, which is delineated in the section below. | Symptoms of Erythrokeratoderma. The symptoms of PSEK usually develop shortly after birth or during the first year of life. Infants develop reddened plaques of thickened, rough and/or scaly skin, especially on the face, buttocks, arms and legs. Over time, these lesions can cover large areas of the body. The distribution of these lesions is almost perfectly symmetrical, meaning the size, shape and location of the lesions are extremely similar on both sides of the body. These plaques are slowly progressive increasing in number and size throughout early childhood before either stabilizing, regressing or disappearing sometime later during life. Rarely, waxing and waning may occur. In some patients, the chest and abdomen may become involved. Abnormally thickened or calloused skin on the palms and soles (palmoplantar keratoderma; PPK) is not uncommon and can be disabling.The majority of individuals with features of erythrokeratoderma belong to the clinical spectrum of erythrokeratodermia variabilis (EKV) or PSEK, hence a unifying name of ‘erythrokeratodermia variabilis et progressiva’ (EKVP) has been coined. The hallmark of classic EKV is the occurrence of figurate-outlined red patches, which seem to come and go quickly (so-called ‘fleeting erythema’), sometimes provoked by sudden temperature changes or other triggers. These red patches are more common in childhood and seem to disappear in adulthood. Features of both EKV and PSEK may be present within a single family, caused by a sequence change in a connexin gene. Extremely rarely, the sharply demarcated, thickened and red skin plaques may be distributed in a linear or whorl-like pattern due to mosaicism for a connexin gene mutation in a subset of epidermal skin cells.Nevertheless, there are many other different forms and causes of erythrokeratoderma, reflecting the clinical and genetic heterogeneity of this condition, which is delineated in the section below. | 422 | Erythrokeratoderma |
nord_422_2 | Causes of Erythrokeratoderma | Erythrokeratoderma is typically caused by pathogenic variants (mutations) in any of the known genes or an as of yet unidentified gene. These conditions may occur at random (i.e., spontaneous new mutation) or be inherited in an autosomal dominant or autosomal recessive pattern.Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.Recent research has shown that erythrokeratoderma may have several different causes and may be a feature of a variety of genetic skin disorders. Types of erythrokeratoderma have been classified as follows based on genetic causes.Autosomal dominant erythrokeratodermaAutosomal recessive erythrokeratodermaInformation about the specific causal genes:Connexin genesErythrokeratodermia variabilis et progressiva: GJB3, GJB4, GJA1The underlying cause of autosomal dominant inherited EKVP is sequence variants (mutations) in one of several connexin genes (GJB3, GJB4, GJA1), which produce components of gap junction channels. Gap junction channels of neighboring cells are assembled from hemichannels accumulating at the cellular membranes at points of cell-cell contact, and connect with another to allow the rapid exchange of ions and small molecules. Gap junction channels and hemichannels play an important role for control of cell volume, for a synchronized response of cells to stimuli and during growth and development. Disease-causing sequence variants on one copy of a connexin gene either have a toxic gain-of-function effect, leading to necrotic cell death due to augmented hemichannel function as shown for GJB3, and/or negatively interfere with the function of other connexins found in the top layers of the skin (epidermis). Very rarely, missense variants in both copies of the GJB3 gene are observed.Loricrin geneLoricrin keratoderma: LORPSEK-like features are part of the clinical spectrum of loricrin keratoderma caused by a sequence variant (mutation) in the loricrin (LOR) gene. Individuals with loricrin keratoderma have generalized palmoplantar keratoderma with a honeycomb-like surface pattern and may develop circular constriction bands on their digits (so-called ‘mutilating palmoplantar keratoderma’). Individuals in two such families also had typical features of PSEK with well-demarcated red and thickened plaques on the extremities. A few other individuals with loricrin keratoderma were born with a collodion membrane and had generalized redness and scaling resembling congenital ichthyosis. Loricrin keratoderma is inherited in an autosomal dominant manner and caused by small nucleotide deletions/insertions on one copy of the LOR gene, which shift the reading frame and create a protein with significantly altered structural and biochemical characteristics, leading to its accumulation in the nucleus of keratinocytes.Ceramide synthesis pathway gene KDSRAutosomal recessive erythrokeratoderma with or without thrombocytopenia; PERIOPTER (periorificial and ptychotropic erythrokeratoderma) syndrome: KDSRKDSR-related erythrokeratoderma has a broad spectrum of skin features of variable severity, with or without impaired platelet function (thrombocytopenia). Most reported individuals presented at birth with generalized redness, thickened, tight skin (collodion membrane) or severe features of Harlequin ichthyosis. Others had only localized involvement with red, thickened and scaly plaques in the diaper area, or developed thickened skin on palms and soles between 1-2 years of age. Hallmark of this form of erythrokeratoderma are sharply demarcated, red, thickened, verrucous (wart-like) or scaly plaques or linear streaks on the cheeks, chin, nose, around eyes, mouth, and genital and anal regions, as well as palmoplantar keratoderma. Rarely, more extensive skin involvement on arms, legs and torso has been observed. At least half of the reported individuals developed already during infancy a reduced platelet count (thrombocytopenia), which is persistent and sometimes progressive, resulting in easy bruising or bleedings. This disorder is inherited in an autosomal recessive manner, and is caused by sequence variants on both copies of the KDSR gene. KDSR encodes an enzyme involved in the synthesis of complex lipids (ceramides) in skin and bone marrow. Disease-causing gene variants impair enzyme activity and lead to defective acylceramid biosynthesis, thus causing skin features and reduced platelet number and function.Transient receptor potential channel gene TRPM4Autosomal dominant PSEK: TRPM4In three unrelated Chinese families, classic presentation of PSEK with palmoplantar keratoderma transgressing to the back of feet, ankles and lower legs, and fixed, sharp defined plaques around mouth, eyes, and genital areas has been reported in association with disease-causing variants in the TRPM4 gene. This gene encodes a transient receptor potential (TRP) channel that responds to various chemical and physical stimuli by mediating the influx of cations, such as potassium and sodium ions, in skin cells. They have been shown to be regulators of keratinocyte proliferation and differentiation. The reported sequence variants have a gain-of-function effect and increase baseline activity and membrane potential of cation channels, which in turn promotes cell proliferation. The disorder is inherited in an autosomal dominant pattern with a trend for spontaneous remission after puberty.Very long chain fatty acid elongation gene ELOVL4Spinocerebellar ataxia-erythrokeratoderma (SCA34): ELOVL4Spinocerebellar ataxia and erythrokeratoderma (type Giroux-Barbeau; OMIM 133190) is a very rare form of ataxia originally described in a large French-Canadian family. Affected individuals manifested during childhood with symmetrical, well-demarcated, fleeting erythematous patches and scaling or hyperkeratotic plaques on dorsum of hands and feet and on limbs. While the skin lesions disappear in the 3rd decade of life, progressive gait ataxia due to cerebellar atrophy manifests in the fourth and fifth decade. Exome sequencing uncovered a pathogenic missense variant (p. L168F) in the ELOVL4 gene that completely co-segregates with the disorder and appears to have a dominant-negative effect. Other missense variants were reported in additional families, some with ataxia but without skin findings. Loss-of-function variants on one copy of the ELOVL4 gene cause isolated macular degeneration of the eyes, while complete loss of this enzyme due to variants on both copies of ELOVL4 have been associated with ichthyosis, intellectual disability, and spastic quadriplegia, resembling the autosomal recessive neuro-ichthyosis Sjoegren-Larsson syndrome. ELOVL4 encodes an enzyme of the elongase family responsible for the elongation of very long-chain fatty acids, which are crucial for formation of complex lipids in the skin, retina and CNS.Desmosomal gene PERPAutosomal dominant or recessive (erythro) keratoderma: PERPOne individual with generalized redness and thickening (hyperkeratosis) of the skin, severe palmoplantar keratoderma with thick plaques over pressure points, and wooly hair was shown to have a loss-of-function variant on both copies of the PERP gene (autosomal recessive inheritance). More frequently, protein truncating variants were observed on one copy of this gene, causing a different clinical presentation consistent with Olmsted syndrome. Affected individuals developed cheilitis, red, thick and scaly plaques around the mouth and outer ears, on buttocks, groin and abdomen, and palmoplantar keratoderma that extends to the dorsum of hands, feet, wrists and ankles (transgredient PPK). In addition, nails were thickened and hair was wooly or curly and yellow. The PERP gene codes for a transcription factor and apoptosis mediator that is also a protein component of desmosomes and other cell junctions. Disease-causing variants likely result in immature desmosomes, reduced cell-cell adhesion in response to mechanical stress and hyperproliferation of the epidermis.Desmoplakin geneErythrokeratodermia-cardiomyopathy (EKC) syndrome- DSPErythrokeratodermia associated with cardiomyopathy manifests initially at or after birth as generalized erythrokeratoderma with thickened, peeling and cracking of skin on palms and soles and occasionally hyperkeratotic papules. The disorder involves also other ectodermal tissues, as evidenced by sparse or absent hair, nail dystrophy, enamel defects with widespread caries, hoarse voice and photophobia with corneal opacities leading to vision impairment. Skin lesions are very itchy (pruritus) and unresponsive to oral steroids and antihistamine treatment. There is failure to thrive, and in early childhood affected children develop progressive, left-ventricular dilated cardiomyopathy which can be fatal. This disorder is caused by specific, sporadic occurring missense variants in the DSP gene, which each introduce a proline residue in the spectrin repeat 6 (SR6) of desmoplakin. Desmoplakin is an abundant desmosomal protein in skin and heart responsible for proper cell-cell adhesion, and many other sequence variants have been shown to cause autosomal dominant or autosomal recessive disorders involving the skin, heart, or both, such as wooly hair, palmoplantar keratoderma and cardiomyopathy (Carvajal syndrome), lethal acantholytic epidermolysis bullosa, striate palmoplantar keratoderma, or arrhythmogenic cardiomyopathy (ARVC).Other, not yet identified genesNot all individuals with features of erythrokeratoderma have causative sequence changes in the epidermal gene discussed above, and more research is necessary to identify and confirm the specific genetic mutation(s) that cause erythrokeratoderma and to determine the exact underlying mechanisms involved in the development of the disorder. | Causes of Erythrokeratoderma. Erythrokeratoderma is typically caused by pathogenic variants (mutations) in any of the known genes or an as of yet unidentified gene. These conditions may occur at random (i.e., spontaneous new mutation) or be inherited in an autosomal dominant or autosomal recessive pattern.Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.Recent research has shown that erythrokeratoderma may have several different causes and may be a feature of a variety of genetic skin disorders. Types of erythrokeratoderma have been classified as follows based on genetic causes.Autosomal dominant erythrokeratodermaAutosomal recessive erythrokeratodermaInformation about the specific causal genes:Connexin genesErythrokeratodermia variabilis et progressiva: GJB3, GJB4, GJA1The underlying cause of autosomal dominant inherited EKVP is sequence variants (mutations) in one of several connexin genes (GJB3, GJB4, GJA1), which produce components of gap junction channels. Gap junction channels of neighboring cells are assembled from hemichannels accumulating at the cellular membranes at points of cell-cell contact, and connect with another to allow the rapid exchange of ions and small molecules. Gap junction channels and hemichannels play an important role for control of cell volume, for a synchronized response of cells to stimuli and during growth and development. Disease-causing sequence variants on one copy of a connexin gene either have a toxic gain-of-function effect, leading to necrotic cell death due to augmented hemichannel function as shown for GJB3, and/or negatively interfere with the function of other connexins found in the top layers of the skin (epidermis). Very rarely, missense variants in both copies of the GJB3 gene are observed.Loricrin geneLoricrin keratoderma: LORPSEK-like features are part of the clinical spectrum of loricrin keratoderma caused by a sequence variant (mutation) in the loricrin (LOR) gene. Individuals with loricrin keratoderma have generalized palmoplantar keratoderma with a honeycomb-like surface pattern and may develop circular constriction bands on their digits (so-called ‘mutilating palmoplantar keratoderma’). Individuals in two such families also had typical features of PSEK with well-demarcated red and thickened plaques on the extremities. A few other individuals with loricrin keratoderma were born with a collodion membrane and had generalized redness and scaling resembling congenital ichthyosis. Loricrin keratoderma is inherited in an autosomal dominant manner and caused by small nucleotide deletions/insertions on one copy of the LOR gene, which shift the reading frame and create a protein with significantly altered structural and biochemical characteristics, leading to its accumulation in the nucleus of keratinocytes.Ceramide synthesis pathway gene KDSRAutosomal recessive erythrokeratoderma with or without thrombocytopenia; PERIOPTER (periorificial and ptychotropic erythrokeratoderma) syndrome: KDSRKDSR-related erythrokeratoderma has a broad spectrum of skin features of variable severity, with or without impaired platelet function (thrombocytopenia). Most reported individuals presented at birth with generalized redness, thickened, tight skin (collodion membrane) or severe features of Harlequin ichthyosis. Others had only localized involvement with red, thickened and scaly plaques in the diaper area, or developed thickened skin on palms and soles between 1-2 years of age. Hallmark of this form of erythrokeratoderma are sharply demarcated, red, thickened, verrucous (wart-like) or scaly plaques or linear streaks on the cheeks, chin, nose, around eyes, mouth, and genital and anal regions, as well as palmoplantar keratoderma. Rarely, more extensive skin involvement on arms, legs and torso has been observed. At least half of the reported individuals developed already during infancy a reduced platelet count (thrombocytopenia), which is persistent and sometimes progressive, resulting in easy bruising or bleedings. This disorder is inherited in an autosomal recessive manner, and is caused by sequence variants on both copies of the KDSR gene. KDSR encodes an enzyme involved in the synthesis of complex lipids (ceramides) in skin and bone marrow. Disease-causing gene variants impair enzyme activity and lead to defective acylceramid biosynthesis, thus causing skin features and reduced platelet number and function.Transient receptor potential channel gene TRPM4Autosomal dominant PSEK: TRPM4In three unrelated Chinese families, classic presentation of PSEK with palmoplantar keratoderma transgressing to the back of feet, ankles and lower legs, and fixed, sharp defined plaques around mouth, eyes, and genital areas has been reported in association with disease-causing variants in the TRPM4 gene. This gene encodes a transient receptor potential (TRP) channel that responds to various chemical and physical stimuli by mediating the influx of cations, such as potassium and sodium ions, in skin cells. They have been shown to be regulators of keratinocyte proliferation and differentiation. The reported sequence variants have a gain-of-function effect and increase baseline activity and membrane potential of cation channels, which in turn promotes cell proliferation. The disorder is inherited in an autosomal dominant pattern with a trend for spontaneous remission after puberty.Very long chain fatty acid elongation gene ELOVL4Spinocerebellar ataxia-erythrokeratoderma (SCA34): ELOVL4Spinocerebellar ataxia and erythrokeratoderma (type Giroux-Barbeau; OMIM 133190) is a very rare form of ataxia originally described in a large French-Canadian family. Affected individuals manifested during childhood with symmetrical, well-demarcated, fleeting erythematous patches and scaling or hyperkeratotic plaques on dorsum of hands and feet and on limbs. While the skin lesions disappear in the 3rd decade of life, progressive gait ataxia due to cerebellar atrophy manifests in the fourth and fifth decade. Exome sequencing uncovered a pathogenic missense variant (p. L168F) in the ELOVL4 gene that completely co-segregates with the disorder and appears to have a dominant-negative effect. Other missense variants were reported in additional families, some with ataxia but without skin findings. Loss-of-function variants on one copy of the ELOVL4 gene cause isolated macular degeneration of the eyes, while complete loss of this enzyme due to variants on both copies of ELOVL4 have been associated with ichthyosis, intellectual disability, and spastic quadriplegia, resembling the autosomal recessive neuro-ichthyosis Sjoegren-Larsson syndrome. ELOVL4 encodes an enzyme of the elongase family responsible for the elongation of very long-chain fatty acids, which are crucial for formation of complex lipids in the skin, retina and CNS.Desmosomal gene PERPAutosomal dominant or recessive (erythro) keratoderma: PERPOne individual with generalized redness and thickening (hyperkeratosis) of the skin, severe palmoplantar keratoderma with thick plaques over pressure points, and wooly hair was shown to have a loss-of-function variant on both copies of the PERP gene (autosomal recessive inheritance). More frequently, protein truncating variants were observed on one copy of this gene, causing a different clinical presentation consistent with Olmsted syndrome. Affected individuals developed cheilitis, red, thick and scaly plaques around the mouth and outer ears, on buttocks, groin and abdomen, and palmoplantar keratoderma that extends to the dorsum of hands, feet, wrists and ankles (transgredient PPK). In addition, nails were thickened and hair was wooly or curly and yellow. The PERP gene codes for a transcription factor and apoptosis mediator that is also a protein component of desmosomes and other cell junctions. Disease-causing variants likely result in immature desmosomes, reduced cell-cell adhesion in response to mechanical stress and hyperproliferation of the epidermis.Desmoplakin geneErythrokeratodermia-cardiomyopathy (EKC) syndrome- DSPErythrokeratodermia associated with cardiomyopathy manifests initially at or after birth as generalized erythrokeratoderma with thickened, peeling and cracking of skin on palms and soles and occasionally hyperkeratotic papules. The disorder involves also other ectodermal tissues, as evidenced by sparse or absent hair, nail dystrophy, enamel defects with widespread caries, hoarse voice and photophobia with corneal opacities leading to vision impairment. Skin lesions are very itchy (pruritus) and unresponsive to oral steroids and antihistamine treatment. There is failure to thrive, and in early childhood affected children develop progressive, left-ventricular dilated cardiomyopathy which can be fatal. This disorder is caused by specific, sporadic occurring missense variants in the DSP gene, which each introduce a proline residue in the spectrin repeat 6 (SR6) of desmoplakin. Desmoplakin is an abundant desmosomal protein in skin and heart responsible for proper cell-cell adhesion, and many other sequence variants have been shown to cause autosomal dominant or autosomal recessive disorders involving the skin, heart, or both, such as wooly hair, palmoplantar keratoderma and cardiomyopathy (Carvajal syndrome), lethal acantholytic epidermolysis bullosa, striate palmoplantar keratoderma, or arrhythmogenic cardiomyopathy (ARVC).Other, not yet identified genesNot all individuals with features of erythrokeratoderma have causative sequence changes in the epidermal gene discussed above, and more research is necessary to identify and confirm the specific genetic mutation(s) that cause erythrokeratoderma and to determine the exact underlying mechanisms involved in the development of the disorder. | 422 | Erythrokeratoderma |
nord_422_3 | Affects of Erythrokeratoderma | Erythrokeratoderma affects males and females in equal numbers. The prevalence of the disorder in the general population is unknown. The disorder was first described by Darier in 1911. Since then, more than 100 cases have been described in the medical literature. Autosomal recessive inherited forms of erythrokeratoderma have been reported more commonly in Middle Eastern populations with a higher degree of marriage among blood relatives (consanguinity). | Affects of Erythrokeratoderma. Erythrokeratoderma affects males and females in equal numbers. The prevalence of the disorder in the general population is unknown. The disorder was first described by Darier in 1911. Since then, more than 100 cases have been described in the medical literature. Autosomal recessive inherited forms of erythrokeratoderma have been reported more commonly in Middle Eastern populations with a higher degree of marriage among blood relatives (consanguinity). | 422 | Erythrokeratoderma |
nord_422_4 | Related disorders of Erythrokeratoderma | Symptoms of the following disorders can be similar to those of erythrokeratoderma. Comparisons may be useful for a differential diagnosis.Ichthyosis in general terms describes a group of generalized scaly skin disorders with or without redness (erythema), which may have variable hair, nail, eye, hearing involvement and additional abnormalities. Several forms of autosomal recessive congenital ichthyosis (ie., due to mutations in the PNPLA1, ALDH3A2 genes) or neutral lipid storage disease with ichthyosis (ABHD5 gene) may present occasionally with localized, symmetrically distributed, well-demarcated plaques, annular or figurate-outlined lesions closely overlapping with PSEK. Some individuals with unusual presentations of annular, circinate or symmetric forms of epidermolytic ichthyosis or transgredient palmoplantar keratoderma (Greither type) caused by missense variants in the keratin genes KRT1 or KRT10 may show striking clinical resemblance with EKVP/PSEK. These disorders are autosomal dominant inherited. (For more information on these disorders, choose ‘Ichthyosis’ as your search term in the Rare Disease Database.)Psoriasis is a chronic, inflammatory skin disease characterized by dry, reddish (erythematous), thickened patches of skin that are covered with silvery-gray scales. These patches may be referred to as papules or plaques and most often affect the scalp, elbows, knees, hands, feet and/or lower back. The plaques may be intensely itchy (pruritis) or sore. Some individuals with psoriasis may experience abnormalities affecting the fingernails, toenails, and the soft tissues inside the mouth. The severity of psoriasis varies from person to person. Psoriasis may be classified as mild, moderate or severe depending upon the amount of skin involved and the effect on an individual’s quality of life. In approximately one-third of cases a family history of psoriasis is present.Olmsted syndrome is a very rare disorder with prominent and transgredient palmoplantar keratoderma and sharply demarcated, red, hyperkeratotic plaques around the mouth, nose, eyes, and in the genitoanal region. More extensive skin involvement with symmetric thickened plaques (erythrokeratoderma) may occur. Conventional topical and systemic therapy often shows only limited effect. This severe and disabling disorder is either due to disease-causing variants on one copy of the PERP channel gene (see above) or due to gain-of-function variants in the TRPV3 gene that cause constitutive opening of TRPV3 channels and calcium ion overload in skin keratinocytes. | Related disorders of Erythrokeratoderma. Symptoms of the following disorders can be similar to those of erythrokeratoderma. Comparisons may be useful for a differential diagnosis.Ichthyosis in general terms describes a group of generalized scaly skin disorders with or without redness (erythema), which may have variable hair, nail, eye, hearing involvement and additional abnormalities. Several forms of autosomal recessive congenital ichthyosis (ie., due to mutations in the PNPLA1, ALDH3A2 genes) or neutral lipid storage disease with ichthyosis (ABHD5 gene) may present occasionally with localized, symmetrically distributed, well-demarcated plaques, annular or figurate-outlined lesions closely overlapping with PSEK. Some individuals with unusual presentations of annular, circinate or symmetric forms of epidermolytic ichthyosis or transgredient palmoplantar keratoderma (Greither type) caused by missense variants in the keratin genes KRT1 or KRT10 may show striking clinical resemblance with EKVP/PSEK. These disorders are autosomal dominant inherited. (For more information on these disorders, choose ‘Ichthyosis’ as your search term in the Rare Disease Database.)Psoriasis is a chronic, inflammatory skin disease characterized by dry, reddish (erythematous), thickened patches of skin that are covered with silvery-gray scales. These patches may be referred to as papules or plaques and most often affect the scalp, elbows, knees, hands, feet and/or lower back. The plaques may be intensely itchy (pruritis) or sore. Some individuals with psoriasis may experience abnormalities affecting the fingernails, toenails, and the soft tissues inside the mouth. The severity of psoriasis varies from person to person. Psoriasis may be classified as mild, moderate or severe depending upon the amount of skin involved and the effect on an individual’s quality of life. In approximately one-third of cases a family history of psoriasis is present.Olmsted syndrome is a very rare disorder with prominent and transgredient palmoplantar keratoderma and sharply demarcated, red, hyperkeratotic plaques around the mouth, nose, eyes, and in the genitoanal region. More extensive skin involvement with symmetric thickened plaques (erythrokeratoderma) may occur. Conventional topical and systemic therapy often shows only limited effect. This severe and disabling disorder is either due to disease-causing variants on one copy of the PERP channel gene (see above) or due to gain-of-function variants in the TRPV3 gene that cause constitutive opening of TRPV3 channels and calcium ion overload in skin keratinocytes. | 422 | Erythrokeratoderma |
nord_422_5 | Diagnosis of Erythrokeratoderma | A diagnosis of erythrokeratoderma is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and specialized tests including genetic testing or surgical removal (biopsy) and microscopic evaluation of affected tissue. | Diagnosis of Erythrokeratoderma. A diagnosis of erythrokeratoderma is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and specialized tests including genetic testing or surgical removal (biopsy) and microscopic evaluation of affected tissue. | 422 | Erythrokeratoderma |
nord_422_6 | Therapies of Erythrokeratoderma | Treatment
The treatment of erythrokeratoderma is directed toward the specific symptoms that are apparent in each individual such as reducing the thickening and cracking of the skin. Affected individuals may also benefit from treatment with skin softening ointments (emollients) such as petroleum jelly. Some but not all individuals with erythrokeratoderma may also benefit from treatment with keratolytics. Keratolytics are drugs that cause the hardened outer layer of skin to come off (slough). Salicyclic acid is an example of a keratolytic agent that has been used to treat individuals with erythrokeratoderma. Other keratolytics include lotions that contain alpha-hydroxy acids, propylene glycol, lactic acid, vitamin D analogs (calcipotriol), or urea. Some individuals with severe erythrokeratoderma may respond to therapy with narrow-band UV-B light or systemic retinoids. Retinoids are synthetic versions of vitamin A that are used to treat many different skin conditions, and may be highly effective for EKVP and KDSR-related erythrokeratoderma, but also may have serious side effects or adverse reactions and require rigorous monitoring. Other treatment is symptomatic and supportive.To discuss the potential causes of erythrokeratoderma, the risk of having children with this disorder and the possibility of genetic testing, genetic counseling is recommended for affected individuals and their families. | Therapies of Erythrokeratoderma. Treatment
The treatment of erythrokeratoderma is directed toward the specific symptoms that are apparent in each individual such as reducing the thickening and cracking of the skin. Affected individuals may also benefit from treatment with skin softening ointments (emollients) such as petroleum jelly. Some but not all individuals with erythrokeratoderma may also benefit from treatment with keratolytics. Keratolytics are drugs that cause the hardened outer layer of skin to come off (slough). Salicyclic acid is an example of a keratolytic agent that has been used to treat individuals with erythrokeratoderma. Other keratolytics include lotions that contain alpha-hydroxy acids, propylene glycol, lactic acid, vitamin D analogs (calcipotriol), or urea. Some individuals with severe erythrokeratoderma may respond to therapy with narrow-band UV-B light or systemic retinoids. Retinoids are synthetic versions of vitamin A that are used to treat many different skin conditions, and may be highly effective for EKVP and KDSR-related erythrokeratoderma, but also may have serious side effects or adverse reactions and require rigorous monitoring. Other treatment is symptomatic and supportive.To discuss the potential causes of erythrokeratoderma, the risk of having children with this disorder and the possibility of genetic testing, genetic counseling is recommended for affected individuals and their families. | 422 | Erythrokeratoderma |
nord_423_0 | Overview of Erythromelalgia | Erythromelalgia is a rare condition that primarily affects the feet and, less commonly, the hands (extremities). It is characterized by intense, burning pain of affected extremities, severe redness (erythema) and increased skin temperature that may be episodic or almost continuous in nature. (The prefix “erythro-” denotes redness, “mel-” is a combining form meaning limb or limbs and the suffix “-algia” indicates pain.) Although erythromelalgia typically affects both sides of the body (bilateral), it may sometimes involve only one side (unilateral). The disease course may be extremely variable from person to person.In most individuals, it is episodic/intermittent, with episodes of painful red-hot feet and/or hands intermittently. Symptom onset may be gradual (insidious), with the condition potentially remaining relatively mild for years. However, in others, it may have a sudden (acute) onset, and becoming severe over weeks or months.The specific underlying cause of erythromelalgia remains unknown. Erythromelalgia is thought to result from vasomotor abnormalities or dysfunction in the normal narrowing (constriction) and widening (dilation) of the diameter (caliber) of certain blood vessels, leading to abnormalities of blood flow to the extremities. Erythromelalgia may be an isolated, primary condition or occur secondary to various underlying disorders. Primary erythromelalgia may appear to occur randomly for unknown reasons (sporadically) or may be familial, suggesting autosomal dominant inheritance. | Overview of Erythromelalgia. Erythromelalgia is a rare condition that primarily affects the feet and, less commonly, the hands (extremities). It is characterized by intense, burning pain of affected extremities, severe redness (erythema) and increased skin temperature that may be episodic or almost continuous in nature. (The prefix “erythro-” denotes redness, “mel-” is a combining form meaning limb or limbs and the suffix “-algia” indicates pain.) Although erythromelalgia typically affects both sides of the body (bilateral), it may sometimes involve only one side (unilateral). The disease course may be extremely variable from person to person.In most individuals, it is episodic/intermittent, with episodes of painful red-hot feet and/or hands intermittently. Symptom onset may be gradual (insidious), with the condition potentially remaining relatively mild for years. However, in others, it may have a sudden (acute) onset, and becoming severe over weeks or months.The specific underlying cause of erythromelalgia remains unknown. Erythromelalgia is thought to result from vasomotor abnormalities or dysfunction in the normal narrowing (constriction) and widening (dilation) of the diameter (caliber) of certain blood vessels, leading to abnormalities of blood flow to the extremities. Erythromelalgia may be an isolated, primary condition or occur secondary to various underlying disorders. Primary erythromelalgia may appear to occur randomly for unknown reasons (sporadically) or may be familial, suggesting autosomal dominant inheritance. | 423 | Erythromelalgia |
nord_423_1 | Symptoms of Erythromelalgia | Erythromelalgia is characterized by predominantly intermittent episodes of severe, burning pain associated with red hot extremities: during episodes there is marked redness (erythema) of the skin and increased skin temperature, particularly of the feet. In some affected individuals, the hands may be the primary sites of involvement. Although both sides of the body are usually affected (bilateral), involvement may sometimes be limited to one side (unilateral).Erythromelalgia often starts with occasional episodes of red, of feet occurring for example once a week or once a month. The episodes may increase in frequency with time; the progression may sometimes occur gradually and subtly or remaining relatively mild and unchanged in nature or degree over years or decades. However, in others with the condition, symptoms may begin suddenly (acutely) and, in some people, may rapidly spread, increase in severity, and possibly become disabling over months. Reports suggest that in many affected individuals, the disorder has a chronic course that may gradually increase in severity over time. Rarely, involvement may spread (usually bilaterally), such as from the feet up the legs (lower limbs), from the hands up the arms (upper limbs), from the upper to the lower limbs, from the lower to the upper limbs and occasionally involve the ears or face.Associated symptoms may occur intermittently or on an almost continuous basis. Episodes or intensification of symptoms are sometimes described as “flaring”, during which there is sudden (acute) redness, pain, sensation of heat and swelling. During a flare, some affected individuals may also experience tingling pain or other symptoms similar to those associated with peripheral neuropathy. (For further information on this condition, please see the “Related Disorders” section of this report below.) Many patients report that flares occur late in the day and may occur at night in bed, thus potentially interfering with sleep.“Hallmarks” or characteristics of erythromelalgia include triggering or worsening of symptoms with exposure to heat (heat intolerance) or exercise and relief with cooling. These symptoms are characteristic of erythromelalgia but may occur with other disorders. They are not unique to erythromelalgia. The temperature at which symptoms may be triggered or exacerbated varies from person to person. (Please see the “Standard Therapies” section below for further information). | Symptoms of Erythromelalgia. Erythromelalgia is characterized by predominantly intermittent episodes of severe, burning pain associated with red hot extremities: during episodes there is marked redness (erythema) of the skin and increased skin temperature, particularly of the feet. In some affected individuals, the hands may be the primary sites of involvement. Although both sides of the body are usually affected (bilateral), involvement may sometimes be limited to one side (unilateral).Erythromelalgia often starts with occasional episodes of red, of feet occurring for example once a week or once a month. The episodes may increase in frequency with time; the progression may sometimes occur gradually and subtly or remaining relatively mild and unchanged in nature or degree over years or decades. However, in others with the condition, symptoms may begin suddenly (acutely) and, in some people, may rapidly spread, increase in severity, and possibly become disabling over months. Reports suggest that in many affected individuals, the disorder has a chronic course that may gradually increase in severity over time. Rarely, involvement may spread (usually bilaterally), such as from the feet up the legs (lower limbs), from the hands up the arms (upper limbs), from the upper to the lower limbs, from the lower to the upper limbs and occasionally involve the ears or face.Associated symptoms may occur intermittently or on an almost continuous basis. Episodes or intensification of symptoms are sometimes described as “flaring”, during which there is sudden (acute) redness, pain, sensation of heat and swelling. During a flare, some affected individuals may also experience tingling pain or other symptoms similar to those associated with peripheral neuropathy. (For further information on this condition, please see the “Related Disorders” section of this report below.) Many patients report that flares occur late in the day and may occur at night in bed, thus potentially interfering with sleep.“Hallmarks” or characteristics of erythromelalgia include triggering or worsening of symptoms with exposure to heat (heat intolerance) or exercise and relief with cooling. These symptoms are characteristic of erythromelalgia but may occur with other disorders. They are not unique to erythromelalgia. The temperature at which symptoms may be triggered or exacerbated varies from person to person. (Please see the “Standard Therapies” section below for further information). | 423 | Erythromelalgia |
nord_423_2 | Causes of Erythromelalgia | In most cases, erythromelalgia is an apparently isolated, primary condition. Primary erythromelalgia may appear to occur randomly for unknown reasons (sporadically) or rarely (in approximately 5% of cases) may be familial.Several families (kindreds) have been reported in which individuals in several generations have been affected. Reported familial cases appear to suggest autosomal dominant inheritance. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Dominant genetic disorders occur when only a single copy of an altered gene is necessary to cause a particular disease. The altered 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 altered gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.In some individuals, the disorder is due to a spontaneous (de novo) genetic mutation that occurs in the egg or sperm cell. In such situations, the disorder is not inherited from the parents.Studies of families with autosomal dominant erythermalgia have demonstrated pathogenic variants (mutations) in the gene for sodium channel Na(v)1.7, which is selectively expressed within nociceptive dorsal root ganglion and sympathetic ganglion neurons. Shifts in activation and deactivation, and enhanced responses to small stimuli in mutant channels, decrease the threshold for single impulses and high-frequency trains of impulses in pain-sensing neurons. This is termed a ‘gain of function’ mutation and results in disproportionate pain in the affected red, hot areas (most often the feet)In others with erythromelalgia, the condition may occur secondary to various underlying disorders, particularly certain bone marrow disorders characterized by abnormally increased production of particular blood cells (myeloproliferative disorders). Many additional disorders have also been reported in association with erythromelalgia. (For more information, please see the “Related Disorders” section of this report below.) There is increasing evidence that neuropathies (large or small fiber) are strongly associated with erythromelalgia- whether this is a cause or effect of erythromelalgia is unclear. Indeed, many medical experts think that erythromelalgia is a neurologic disorder. The exact underlying cause of erythromelalgia is not known. However, evidence suggests that it results from abnormalities in the normal narrowing (vasoconstriction) and widening (vasodilation) of the diameter (caliber) of certain blood vessels, leading to abnormalities in blood flow to the extremities.In erythromelalgia, additional evidence indicates that ring-shaped muscle regions (sphincters) of certain blood vessels that control blood flow from small arteries (arterioles) to capillaries (i.e., precapillary sphincters) may be abnormally narrowed while “arteriovenous shunts” are open. (According to researchers, blood flow through skin capillaries primarily provides necessary oxygen and nutrients to cells. Arteriovenous shunts, which are blood vessels that directly connect certain arteries and veins and thus bypass the capillary network, are thought to play a role in regulating temperature.) Constriction of some precapillary sphincters while arteriovenous shunts are open may lead to increased total blood flow but decreased transport of oxygen and nutrients to cells. This results in a simultaneous insufficient oxygen supply (hypoxia) and excess of blood (hyperemia) in affected skin. The presence of hypoxia may in turn trigger increased, localized blood flow to skin regions, thus exacerbating pain, heat sensation, and redness.In addition, some researchers indicate that there may be three different subtypes of erythromelalgia, with most individuals affected by vasoconstriction followed by reactive hyperemia (as described above); some with primarily vasodilation abnormalities; and others with erythromelalgia secondary to conditions characterized by increased numbers of certain cells in the blood, such as platelets (thrombocythemia) and associated, excessive viscosity of the blood (hyperviscosity). (For more information, please see the “Related Disorders” section below.) | Causes of Erythromelalgia. In most cases, erythromelalgia is an apparently isolated, primary condition. Primary erythromelalgia may appear to occur randomly for unknown reasons (sporadically) or rarely (in approximately 5% of cases) may be familial.Several families (kindreds) have been reported in which individuals in several generations have been affected. Reported familial cases appear to suggest autosomal dominant inheritance. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Dominant genetic disorders occur when only a single copy of an altered gene is necessary to cause a particular disease. The altered 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 altered gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.In some individuals, the disorder is due to a spontaneous (de novo) genetic mutation that occurs in the egg or sperm cell. In such situations, the disorder is not inherited from the parents.Studies of families with autosomal dominant erythermalgia have demonstrated pathogenic variants (mutations) in the gene for sodium channel Na(v)1.7, which is selectively expressed within nociceptive dorsal root ganglion and sympathetic ganglion neurons. Shifts in activation and deactivation, and enhanced responses to small stimuli in mutant channels, decrease the threshold for single impulses and high-frequency trains of impulses in pain-sensing neurons. This is termed a ‘gain of function’ mutation and results in disproportionate pain in the affected red, hot areas (most often the feet)In others with erythromelalgia, the condition may occur secondary to various underlying disorders, particularly certain bone marrow disorders characterized by abnormally increased production of particular blood cells (myeloproliferative disorders). Many additional disorders have also been reported in association with erythromelalgia. (For more information, please see the “Related Disorders” section of this report below.) There is increasing evidence that neuropathies (large or small fiber) are strongly associated with erythromelalgia- whether this is a cause or effect of erythromelalgia is unclear. Indeed, many medical experts think that erythromelalgia is a neurologic disorder. The exact underlying cause of erythromelalgia is not known. However, evidence suggests that it results from abnormalities in the normal narrowing (vasoconstriction) and widening (vasodilation) of the diameter (caliber) of certain blood vessels, leading to abnormalities in blood flow to the extremities.In erythromelalgia, additional evidence indicates that ring-shaped muscle regions (sphincters) of certain blood vessels that control blood flow from small arteries (arterioles) to capillaries (i.e., precapillary sphincters) may be abnormally narrowed while “arteriovenous shunts” are open. (According to researchers, blood flow through skin capillaries primarily provides necessary oxygen and nutrients to cells. Arteriovenous shunts, which are blood vessels that directly connect certain arteries and veins and thus bypass the capillary network, are thought to play a role in regulating temperature.) Constriction of some precapillary sphincters while arteriovenous shunts are open may lead to increased total blood flow but decreased transport of oxygen and nutrients to cells. This results in a simultaneous insufficient oxygen supply (hypoxia) and excess of blood (hyperemia) in affected skin. The presence of hypoxia may in turn trigger increased, localized blood flow to skin regions, thus exacerbating pain, heat sensation, and redness.In addition, some researchers indicate that there may be three different subtypes of erythromelalgia, with most individuals affected by vasoconstriction followed by reactive hyperemia (as described above); some with primarily vasodilation abnormalities; and others with erythromelalgia secondary to conditions characterized by increased numbers of certain cells in the blood, such as platelets (thrombocythemia) and associated, excessive viscosity of the blood (hyperviscosity). (For more information, please see the “Related Disorders” section below.) | 423 | Erythromelalgia |
nord_423_3 | Affects of Erythromelalgia | Erythromelalgia is a rare disorder that was originally described in 1878. The overall age- and sex-adjusted incidence rate per 100,000 people per year in a population-based study in the US was 1.3. Researchers in Norway have estimated an incidence of 0.25 per 100,000 and a prevalence of 2 per 100,000 in Norway. (Incidence refers to the number of new cases of a particular condition during a specific period, while prevalence indicates the total of new and old cases of a condition at any one time.)Females are more often affected than males. Although disorder onset occurs most commonly in middle age, associated symptoms may develop at any age. For example, researchers have reported an extended family (kindred) in which affected members typically developed symptoms beginning between ages two to eight years. | Affects of Erythromelalgia. Erythromelalgia is a rare disorder that was originally described in 1878. The overall age- and sex-adjusted incidence rate per 100,000 people per year in a population-based study in the US was 1.3. Researchers in Norway have estimated an incidence of 0.25 per 100,000 and a prevalence of 2 per 100,000 in Norway. (Incidence refers to the number of new cases of a particular condition during a specific period, while prevalence indicates the total of new and old cases of a condition at any one time.)Females are more often affected than males. Although disorder onset occurs most commonly in middle age, associated symptoms may develop at any age. For example, researchers have reported an extended family (kindred) in which affected members typically developed symptoms beginning between ages two to eight years. | 423 | Erythromelalgia |
nord_423_4 | Related disorders of Erythromelalgia | Symptoms of the following disorders may be similar to those of erythromelalgia. Comparisons may be useful for a differential diagnosis:Fabry disease is a rare genetic disorder of lipid metabolism that is one of the more than 40 lysosomal storage diseases. Its early symptoms include severe burning pain in the hands and feet and sometimes in the arms and legs; however, the extremities do not change color. These episodes may last only a few minutes or days and are sometimes associated with exercise, fatigue and/or fever. The disorder leads to kidney dysfunction in males and heart disease in females. An enzyme replacement therapy for Fabry disease became available in 2003, so it is important to rule out Fabry disease in suspected cases of erythromelalgia (for further information, choose “Fabry Disease” as your search term in the Rare Disease Database).Raynaud’s disease and Raynaud’s phenomenon are blood vessel (vascular) conditions characterized by sudden contraction (vasoconstriction) of small arteries (arterioles) supplying the fingers and toes (digits) and less commonly, the nose or ears, causing a temporarily decreased blood supply. Episodes are typically triggered by exposure to the cold, while warming relieves symptoms. Due to such responses to heat and cold, these conditions were often considered “opposite” to that of erythromelalgia. However, according to researchers, evidence currently suggests that the conditions may share more similarities than differences. In fact, it has been observed that some patients with erythromelalgia (red, hot extremities with exercise or increased ambient heat) also experience Raynaud’s phenomenon (cold, white extremities associated with exposure to cold)Episodes of Raynaud’s are typically characterized by whitening of affected regions followed by bluish (cyanotic) discoloration and are often accompanied by tingling and numbness. Subsequent restoration of blood supply is associated with widening of the diameter of blood vessels (vasodilation) and temporarily excessive blood flow to affected regions (reactive hyperemia). Symptoms that may occur in association with this “hyperemia phase” include reddening of affected regions, intense heat and throbbing or burning pain, findings that are similar to those associated with erythromelalgia. Some researchers suggest that Raynaud’s and erythromelalgia may result from similar vasomotor abnormalities, with the vasoconstriction phase more prominent in Raynaud’s and the hyperemia phase more apparent in erythromelalgia. (For further information, please see the “Causes” section above.)The term Raynaud’s disease is used when such episodes appear to occur as an isolated, primary condition. However, the term Raynaud’s phenomenon indicates that the condition occurs secondary to another underlying disorder or condition, such as certain autoimmune connective tissue disorders, nerve diseases, injury, adverse reactions to certain drugs or other abnormalities. There have also been some reports in which Raynaud’s phenomenon has occurred in some individuals with erythromelalgia.Complex regional pain syndrome (CRPS) is a disorder in which pain, occurring spontaneously or from a sensory stimulus, is disproportionately far more painful than it should be. An example of this would be light touching of the skin, which normally is not painful, yet it causes extreme pain perception in CRPS patients. The disproportionate pain is also reflected in normally painful stimuli, such as a pinprick, hurting more than it should (hyperalgesia). CRPS usually affects one limb after a limb injury or surgery. CRPS is subdivided into 2 categories: type I and type II CRPS. In CRPS type I, there are no nerve injuries or lesions identified. CRPS type I is also known as “reflex sympathetic dystrophy,” and it comprises about 90 percent of all cases of CRPS. CRPS type II (causalgia), on the other hand, is diagnosed when there is evidence of nerve damage. (For more information on this disorder, choose “CPRS” as your search term in the Rare Disease Database.)As noted above, erythromelalgia may sometimes occur secondary to certain disorders, including the following. They may be useful in identifying an underlying cause in some cases:Essential thrombocythemia (thrombocytosis) is considered a myeloproliferative disorder, meaning that it is characterized by abnormalities of certain bone marrow (i.e., precursor) cells that produce particular blood cells. In essential thrombocythemia, there is abnormally increased production of platelets (thrombocytes), which are essential in blood clotting. Associated findings may include the abnormal, spontaneous development of blood clots (thrombi) within intact blood vessels, blocking proper blood flow; bleeding episodes that may be characterized by nose bleeds, easy bruising, and/or bleeding into the gastrointestinal tract; abnormal enlargement of the liver and spleen (hepatosplenomegaly) and/or other symptoms and findings. (For more information on this disorder, choose “essential thrombocythemia” as your search term in the Rare Disease Database.)Polycythemia vera is a myeloproliferative disorder characterized by abnormally increased production of red cells by the bone marrow, resulting in high numbers of circulating red blood cells (erythrocytes) and a rise in the concentration of the oxygen-carrying component (hemoglobin) of the blood. Associated symptoms and findings may include fatigue, weakness, headaches, shortness of breath and/or blurred vision. Affected individuals may also develop abnormal redness (erythema) of the skin and severe, widespread itching (pruritus), particularly after hot baths. Additional findings may include platelet abnormalities, leading to the development of blood clots and bleeding episodes; abnormal enlargement of the liver and spleen (hepatosplenomegaly) and/or other complications. (For more information on this disorder, choose “polycythemia vera” as your search term in the Rare Disease Database.)Peripheral neuropathy is a general term used to describe a group of neurological conditions that affect nerves known as peripheral nerves, which extend from the brain or spinal cord (central nervous system) to muscles, glands, skin, sensory organs and internal organs. Peripheral nerves include motor nerves; sensory nerves and nerves of the autonomic nervous system, which are involved in involuntary functions, including regulating blood pressure, temperature and heart rate. In individuals with peripheral neuropathy, a single nerve (mononeuropathy) or many nerves (polyneuropathy) may be affected. Depending upon the nerve(s) involved and other factors, peripheral neuropathy may produce symptoms that relate to motor, sensory and/or autonomic malfunction. Damage to motor nerve fibers may lead to muscle weakness and wasting (atrophy). Symptoms associated with sensory nerve involvement may include pain or abnormal sensations, such as numbness, burning, sensations of cold or tingling. Involvement of autonomic nerves may lead to various symptoms and findings, such as high or low blood pressure, impaired sweating, inability to control urination or defecation (incontinence), impotence and/or other abnormalities. Peripheral neuropathy may result from many underlying causes, including injury, exposure to certain toxic agents, nutritional deficiencies, alcohol abuse, viral infections, autoimmune diseases, diabetes mellitus or other underlying disorders or conditions.Systemic lupus erythematosus (SLE) is a chronic, inflammatory disease of connective tissue that may affect multiple organ systems and tissues, such as the skin, joints, membranes lining the walls of certain body cavities, the kidneys and/or the nervous system. The disorder is thought to result from an abnormal immune response against the body’s own cells and tissues (autoimmune disease), leading to inflammation and malfunction of various organ systems. The range and severity of associated symptoms and findings may vary from person to person. However, many affected individuals may initially develop generalized symptoms, such as excessive fatigue, fever, a general feeling of ill health (malaise), loss of appetite (anorexia), weight loss, and joint swelling, inflammation and pain. The disorder may also be associated with skin abnormalities, such as a scaling, reddish rash in a “butterfly” pattern across the cheeks and the nasal bridge; increased sensitivity to light (photosensitivity); reddish swelling around the nails; tender, reddish-purplish skin swellings or other findings. Additional abnormalities may include muscle inflammation (myositis); Raynaud’s phenomenon (see above); inflammation of the filtering units of the kidneys; neurologic symptoms, such as headaches and seizures; and/or inflammatory changes of the membranes lining the chest cavity and lungs, lining the abdominal wall and organs and/or surrounding the heart. Disease progression may also affect other tissues, leading to additional symptoms and findings.As mentioned above, erythromelalgia has also been reported in association with a number of other underlying conditions and disorders. These have included other myeloproliferative and blood (hematologic), connective tissue, and neurologic disorders as well as certain disorders of the heart and blood vessels (cardiovascular disorders), musculoskeletal disorders, infectious diseases, underlying benign tumors or malignancies and/or other disorders and conditions. | Related disorders of Erythromelalgia. Symptoms of the following disorders may be similar to those of erythromelalgia. Comparisons may be useful for a differential diagnosis:Fabry disease is a rare genetic disorder of lipid metabolism that is one of the more than 40 lysosomal storage diseases. Its early symptoms include severe burning pain in the hands and feet and sometimes in the arms and legs; however, the extremities do not change color. These episodes may last only a few minutes or days and are sometimes associated with exercise, fatigue and/or fever. The disorder leads to kidney dysfunction in males and heart disease in females. An enzyme replacement therapy for Fabry disease became available in 2003, so it is important to rule out Fabry disease in suspected cases of erythromelalgia (for further information, choose “Fabry Disease” as your search term in the Rare Disease Database).Raynaud’s disease and Raynaud’s phenomenon are blood vessel (vascular) conditions characterized by sudden contraction (vasoconstriction) of small arteries (arterioles) supplying the fingers and toes (digits) and less commonly, the nose or ears, causing a temporarily decreased blood supply. Episodes are typically triggered by exposure to the cold, while warming relieves symptoms. Due to such responses to heat and cold, these conditions were often considered “opposite” to that of erythromelalgia. However, according to researchers, evidence currently suggests that the conditions may share more similarities than differences. In fact, it has been observed that some patients with erythromelalgia (red, hot extremities with exercise or increased ambient heat) also experience Raynaud’s phenomenon (cold, white extremities associated with exposure to cold)Episodes of Raynaud’s are typically characterized by whitening of affected regions followed by bluish (cyanotic) discoloration and are often accompanied by tingling and numbness. Subsequent restoration of blood supply is associated with widening of the diameter of blood vessels (vasodilation) and temporarily excessive blood flow to affected regions (reactive hyperemia). Symptoms that may occur in association with this “hyperemia phase” include reddening of affected regions, intense heat and throbbing or burning pain, findings that are similar to those associated with erythromelalgia. Some researchers suggest that Raynaud’s and erythromelalgia may result from similar vasomotor abnormalities, with the vasoconstriction phase more prominent in Raynaud’s and the hyperemia phase more apparent in erythromelalgia. (For further information, please see the “Causes” section above.)The term Raynaud’s disease is used when such episodes appear to occur as an isolated, primary condition. However, the term Raynaud’s phenomenon indicates that the condition occurs secondary to another underlying disorder or condition, such as certain autoimmune connective tissue disorders, nerve diseases, injury, adverse reactions to certain drugs or other abnormalities. There have also been some reports in which Raynaud’s phenomenon has occurred in some individuals with erythromelalgia.Complex regional pain syndrome (CRPS) is a disorder in which pain, occurring spontaneously or from a sensory stimulus, is disproportionately far more painful than it should be. An example of this would be light touching of the skin, which normally is not painful, yet it causes extreme pain perception in CRPS patients. The disproportionate pain is also reflected in normally painful stimuli, such as a pinprick, hurting more than it should (hyperalgesia). CRPS usually affects one limb after a limb injury or surgery. CRPS is subdivided into 2 categories: type I and type II CRPS. In CRPS type I, there are no nerve injuries or lesions identified. CRPS type I is also known as “reflex sympathetic dystrophy,” and it comprises about 90 percent of all cases of CRPS. CRPS type II (causalgia), on the other hand, is diagnosed when there is evidence of nerve damage. (For more information on this disorder, choose “CPRS” as your search term in the Rare Disease Database.)As noted above, erythromelalgia may sometimes occur secondary to certain disorders, including the following. They may be useful in identifying an underlying cause in some cases:Essential thrombocythemia (thrombocytosis) is considered a myeloproliferative disorder, meaning that it is characterized by abnormalities of certain bone marrow (i.e., precursor) cells that produce particular blood cells. In essential thrombocythemia, there is abnormally increased production of platelets (thrombocytes), which are essential in blood clotting. Associated findings may include the abnormal, spontaneous development of blood clots (thrombi) within intact blood vessels, blocking proper blood flow; bleeding episodes that may be characterized by nose bleeds, easy bruising, and/or bleeding into the gastrointestinal tract; abnormal enlargement of the liver and spleen (hepatosplenomegaly) and/or other symptoms and findings. (For more information on this disorder, choose “essential thrombocythemia” as your search term in the Rare Disease Database.)Polycythemia vera is a myeloproliferative disorder characterized by abnormally increased production of red cells by the bone marrow, resulting in high numbers of circulating red blood cells (erythrocytes) and a rise in the concentration of the oxygen-carrying component (hemoglobin) of the blood. Associated symptoms and findings may include fatigue, weakness, headaches, shortness of breath and/or blurred vision. Affected individuals may also develop abnormal redness (erythema) of the skin and severe, widespread itching (pruritus), particularly after hot baths. Additional findings may include platelet abnormalities, leading to the development of blood clots and bleeding episodes; abnormal enlargement of the liver and spleen (hepatosplenomegaly) and/or other complications. (For more information on this disorder, choose “polycythemia vera” as your search term in the Rare Disease Database.)Peripheral neuropathy is a general term used to describe a group of neurological conditions that affect nerves known as peripheral nerves, which extend from the brain or spinal cord (central nervous system) to muscles, glands, skin, sensory organs and internal organs. Peripheral nerves include motor nerves; sensory nerves and nerves of the autonomic nervous system, which are involved in involuntary functions, including regulating blood pressure, temperature and heart rate. In individuals with peripheral neuropathy, a single nerve (mononeuropathy) or many nerves (polyneuropathy) may be affected. Depending upon the nerve(s) involved and other factors, peripheral neuropathy may produce symptoms that relate to motor, sensory and/or autonomic malfunction. Damage to motor nerve fibers may lead to muscle weakness and wasting (atrophy). Symptoms associated with sensory nerve involvement may include pain or abnormal sensations, such as numbness, burning, sensations of cold or tingling. Involvement of autonomic nerves may lead to various symptoms and findings, such as high or low blood pressure, impaired sweating, inability to control urination or defecation (incontinence), impotence and/or other abnormalities. Peripheral neuropathy may result from many underlying causes, including injury, exposure to certain toxic agents, nutritional deficiencies, alcohol abuse, viral infections, autoimmune diseases, diabetes mellitus or other underlying disorders or conditions.Systemic lupus erythematosus (SLE) is a chronic, inflammatory disease of connective tissue that may affect multiple organ systems and tissues, such as the skin, joints, membranes lining the walls of certain body cavities, the kidneys and/or the nervous system. The disorder is thought to result from an abnormal immune response against the body’s own cells and tissues (autoimmune disease), leading to inflammation and malfunction of various organ systems. The range and severity of associated symptoms and findings may vary from person to person. However, many affected individuals may initially develop generalized symptoms, such as excessive fatigue, fever, a general feeling of ill health (malaise), loss of appetite (anorexia), weight loss, and joint swelling, inflammation and pain. The disorder may also be associated with skin abnormalities, such as a scaling, reddish rash in a “butterfly” pattern across the cheeks and the nasal bridge; increased sensitivity to light (photosensitivity); reddish swelling around the nails; tender, reddish-purplish skin swellings or other findings. Additional abnormalities may include muscle inflammation (myositis); Raynaud’s phenomenon (see above); inflammation of the filtering units of the kidneys; neurologic symptoms, such as headaches and seizures; and/or inflammatory changes of the membranes lining the chest cavity and lungs, lining the abdominal wall and organs and/or surrounding the heart. Disease progression may also affect other tissues, leading to additional symptoms and findings.As mentioned above, erythromelalgia has also been reported in association with a number of other underlying conditions and disorders. These have included other myeloproliferative and blood (hematologic), connective tissue, and neurologic disorders as well as certain disorders of the heart and blood vessels (cardiovascular disorders), musculoskeletal disorders, infectious diseases, underlying benign tumors or malignancies and/or other disorders and conditions. | 423 | Erythromelalgia |
nord_423_5 | Diagnosis of Erythromelalgia | The diagnosis of erythromelalgia is established by a thorough evaluation of the characteristic symptoms and signs of the disease. Photographs of the affected areas during symptoms are extremely helpful (for example, photos of red feet or hands during symptoms – the redness is almost unique to erythromelalgia when associated with the history). Patient and family history can be helpful and specialized tests may help to exclude certain disorders with similar symptoms. It is also helpful to confirm or rule out underlying diseases or conditions that may occur in association with erythromelalgia (i.e., to help differentiate primary and secondary erythromelalgia). For example, because erythromelalgia may be an early sign of certain conditions (e.g., thrombocythemia, polycythemia vera), certain laboratory tests, such as yearly blood cell counts and other specialized tests may be periodically conducted to help ensure prompt diagnosis and treatment of such underlying disorders.Experts indicate that the intermittent nature of erythromelalgia in some people may potentially lead to difficulties or delays in its diagnosis. Therefore, because symptoms may be reduced or absent until late in the day, for example, physicians may recommend that affected individuals take photographs of the involved regions during flaring and/or schedule clinical examinations late in the day if possible. | Diagnosis of Erythromelalgia. The diagnosis of erythromelalgia is established by a thorough evaluation of the characteristic symptoms and signs of the disease. Photographs of the affected areas during symptoms are extremely helpful (for example, photos of red feet or hands during symptoms – the redness is almost unique to erythromelalgia when associated with the history). Patient and family history can be helpful and specialized tests may help to exclude certain disorders with similar symptoms. It is also helpful to confirm or rule out underlying diseases or conditions that may occur in association with erythromelalgia (i.e., to help differentiate primary and secondary erythromelalgia). For example, because erythromelalgia may be an early sign of certain conditions (e.g., thrombocythemia, polycythemia vera), certain laboratory tests, such as yearly blood cell counts and other specialized tests may be periodically conducted to help ensure prompt diagnosis and treatment of such underlying disorders.Experts indicate that the intermittent nature of erythromelalgia in some people may potentially lead to difficulties or delays in its diagnosis. Therefore, because symptoms may be reduced or absent until late in the day, for example, physicians may recommend that affected individuals take photographs of the involved regions during flaring and/or schedule clinical examinations late in the day if possible. | 423 | Erythromelalgia |
nord_423_6 | Therapies of Erythromelalgia | TreatmentAs mentioned above (see “Symptoms”), in individuals with erythromelalgia, associated symptoms are typically relieved with cooling. More specifically, in almost all cases, affected individuals may experience pain relief by immersing the affected regions in ice water. However, according to experts, it is essential to note that the repeated immersion sometimes performed by those with severe erythromelalgia may lead to skin injury and potentially serious complications. Such complications may include infection; nonhealing skin sores (ulcerations); softening and breaking down of skin due to abnormally prolonged exposure to moisture (maceration) and/or localized tissue loss (necrosis).Many people with the disorder also experience symptom relief by exposing affected areas to cold air, such as through the use of air conditioners or fans, although excessive blowing air on the skin can cause its own cycle of problems (the equivalent of ‘windburn’). In addition, even those with mild disease may find themselves avoiding warm or hot temperatures to help minimize symptoms.Many affected individuals find that symptoms worsen with a dependent (or “hanging down”) position. Accordingly, episodes may potentially be avoided or reduced by elevating involved regions.Unfortunately, in some cases, the use of such measures as described above–such as avoidance of warm temperatures, ongoing elevation required by some with severe erythromelalgia, etc.–may significantly affect daily functioning.For many patients, medications are available that can help to reduce symptoms.Topical medications may go a long way towards helping with symptoms. The use of lidocaine topically such as in a lidocaine patch, and topical preparations designed to block the opening of sodium channels in nerve (amitriptyline combined with ketamine for example) have been described to be helpful in many patients, either alone or in combination with oral treatments.Oral medications include, selective serotonin reuptake inhibitors, tricyclic antidepressants, gabapentin, pregabalin, or carbamazepine, antihistamines, misoprostol, magnesium and others. No single medication works for all EM patients, and some trial and error may be necessary. Some individuals with EM require lower doses of these drugs, and when started at higher doses, side effects can occur. Sometimes a combination of medications is more effective than one drug alone. Experts indicate that through such measures and careful ongoing monitoring, many affected individuals may obtain significant benefit.Some patients with erythromelalgia develop the equivalent of a chronic pain syndrome, and this aspect should be intensively managed. In patients whose lives are severely impacted by the erythromelalgia, consideration should be given to engagement in a multidisciplinary pain rehabilitation program, so that patients can learn techniques to live a more normal life despite the chronic pain of the erythromelalgia.Genetic counseling may be helpful for people with erythromelalgia and their families. Other treatment for the condition is symptomatic and supportive. | Therapies of Erythromelalgia. TreatmentAs mentioned above (see “Symptoms”), in individuals with erythromelalgia, associated symptoms are typically relieved with cooling. More specifically, in almost all cases, affected individuals may experience pain relief by immersing the affected regions in ice water. However, according to experts, it is essential to note that the repeated immersion sometimes performed by those with severe erythromelalgia may lead to skin injury and potentially serious complications. Such complications may include infection; nonhealing skin sores (ulcerations); softening and breaking down of skin due to abnormally prolonged exposure to moisture (maceration) and/or localized tissue loss (necrosis).Many people with the disorder also experience symptom relief by exposing affected areas to cold air, such as through the use of air conditioners or fans, although excessive blowing air on the skin can cause its own cycle of problems (the equivalent of ‘windburn’). In addition, even those with mild disease may find themselves avoiding warm or hot temperatures to help minimize symptoms.Many affected individuals find that symptoms worsen with a dependent (or “hanging down”) position. Accordingly, episodes may potentially be avoided or reduced by elevating involved regions.Unfortunately, in some cases, the use of such measures as described above–such as avoidance of warm temperatures, ongoing elevation required by some with severe erythromelalgia, etc.–may significantly affect daily functioning.For many patients, medications are available that can help to reduce symptoms.Topical medications may go a long way towards helping with symptoms. The use of lidocaine topically such as in a lidocaine patch, and topical preparations designed to block the opening of sodium channels in nerve (amitriptyline combined with ketamine for example) have been described to be helpful in many patients, either alone or in combination with oral treatments.Oral medications include, selective serotonin reuptake inhibitors, tricyclic antidepressants, gabapentin, pregabalin, or carbamazepine, antihistamines, misoprostol, magnesium and others. No single medication works for all EM patients, and some trial and error may be necessary. Some individuals with EM require lower doses of these drugs, and when started at higher doses, side effects can occur. Sometimes a combination of medications is more effective than one drug alone. Experts indicate that through such measures and careful ongoing monitoring, many affected individuals may obtain significant benefit.Some patients with erythromelalgia develop the equivalent of a chronic pain syndrome, and this aspect should be intensively managed. In patients whose lives are severely impacted by the erythromelalgia, consideration should be given to engagement in a multidisciplinary pain rehabilitation program, so that patients can learn techniques to live a more normal life despite the chronic pain of the erythromelalgia.Genetic counseling may be helpful for people with erythromelalgia and their families. Other treatment for the condition is symptomatic and supportive. | 423 | Erythromelalgia |
nord_424_0 | Overview of Erythropoietic Protoporphyria and X-Linked Protoporphyria | SummaryErythropoietic protoporphyria (EPP) is a rare inherited metabolic disorder caused by a deficiency of the enzyme ferrochelatase (FECH), which results from changes (mutations) in the FECH gene. Due to abnormally low levels of this enzyme, excessive amounts of protoporphyrin accumulate in the bone marrow, blood plasma, and red blood cells. Some patients with symptoms of EPP have a genetic change in a different gene called ALAS2. When a patient has a genetic change in this gene, the condition is referred to as X-linked protoporphyria (XLP). The major symptoms of these disorders is severe pain on exposure to sunlight and some types of artificial light, such as fluorescent lights (phototoxicity). On sun exposure, patients may first experience tingling, itching, burning of the skin. After continued exposure to light, the skin may become red and swollen. The hands, arms, and face are the most commonly affected areas. Some people with EPP/XLP may also have complications related to liver and gallbladder function.IntroductionErythropoietic protoporphyria is one of a group of disorders known as the porphyrias. The porphyrias are all characterized by abnormally high levels of particular chemicals (porphyrins) in the body due to deficiencies of certain enzymes essential to the synthesis of hemoglobin. There are at least eight types of porphyria. The symptoms associated with the various types of porphyria differ, depending upon the specific enzyme that is deficient. It is important to note that people who have one type of porphyria do not develop any of the other types. | Overview of Erythropoietic Protoporphyria and X-Linked Protoporphyria. SummaryErythropoietic protoporphyria (EPP) is a rare inherited metabolic disorder caused by a deficiency of the enzyme ferrochelatase (FECH), which results from changes (mutations) in the FECH gene. Due to abnormally low levels of this enzyme, excessive amounts of protoporphyrin accumulate in the bone marrow, blood plasma, and red blood cells. Some patients with symptoms of EPP have a genetic change in a different gene called ALAS2. When a patient has a genetic change in this gene, the condition is referred to as X-linked protoporphyria (XLP). The major symptoms of these disorders is severe pain on exposure to sunlight and some types of artificial light, such as fluorescent lights (phototoxicity). On sun exposure, patients may first experience tingling, itching, burning of the skin. After continued exposure to light, the skin may become red and swollen. The hands, arms, and face are the most commonly affected areas. Some people with EPP/XLP may also have complications related to liver and gallbladder function.IntroductionErythropoietic protoporphyria is one of a group of disorders known as the porphyrias. The porphyrias are all characterized by abnormally high levels of particular chemicals (porphyrins) in the body due to deficiencies of certain enzymes essential to the synthesis of hemoglobin. There are at least eight types of porphyria. The symptoms associated with the various types of porphyria differ, depending upon the specific enzyme that is deficient. It is important to note that people who have one type of porphyria do not develop any of the other types. | 424 | Erythropoietic Protoporphyria and X-Linked Protoporphyria |
nord_424_1 | Symptoms of Erythropoietic Protoporphyria and X-Linked Protoporphyria | The most common symptom of erythropoietic protoporphyria and X-linked protoporphyria is severe pain on sun exposure. Some patients may also be sensitive to some types of artificial light. When the skin is exposed to sun, patients first develop tingling, itching, and/or burning of the skin. These symptoms serve as warning signs as longer exposure can result in severe pain. Affected individuals may also have an abnormal accumulation of body fluid under affected areas (edema) and/or persistent redness or inflammation of the skin (erythema). In rare cases, affected areas of the skin may develop sac-like lesions (blisters) and scar if exposure to sunlight is prolonged. However, scarring and/or discoloring of the skin is uncommon and rarely severe. These affected areas of skin may become abnormally thick. The severity and degree of symptoms is different from case to case. Some patients may only be able to tolerate a few minutes of sun exposure while others may be able to tolerate longer sun exposure without symptoms. The amount of sun tolerated may also be different based on weather conditions. Symptoms are often seen during infancy; however, in some cases, it may not occur until adolescence or rarely in adulthood.In some affected individuals, the flow of bile through the gallbladder and bile ducts (biliary system) may be interrupted (cholestasis) causing gallstones (cholelithiasis) to form. In turn, such stones can cause obstruction and/or inflammation of the gallbladder (cholecystitis). Rarely, affected individuals may also develop liver damage that, in very severe cases, may lead to liver failure requiring transplantation. As liver transplantation does not cure EPP or XLP, a bone marrow transplant following liver transplant may be necessary in some cases.Symptoms usually start in childhood but diagnosis is often delayed since blistering is not common and, because the porphyrins are insoluble, they cannot be detected on urinanalysis. The diagnosis is made upon finding increased levels of the protoporphyrin in the plasma or red blood cells in both EPP and XLP. Genetic testing is useful to confirm the diagnosis. Patients with EPP and XLP may also have mild anemia (low blood counts). In many cases, this may be due to low iron stores. They may also have high levels of liver enzymes on blood tests. | Symptoms of Erythropoietic Protoporphyria and X-Linked Protoporphyria. The most common symptom of erythropoietic protoporphyria and X-linked protoporphyria is severe pain on sun exposure. Some patients may also be sensitive to some types of artificial light. When the skin is exposed to sun, patients first develop tingling, itching, and/or burning of the skin. These symptoms serve as warning signs as longer exposure can result in severe pain. Affected individuals may also have an abnormal accumulation of body fluid under affected areas (edema) and/or persistent redness or inflammation of the skin (erythema). In rare cases, affected areas of the skin may develop sac-like lesions (blisters) and scar if exposure to sunlight is prolonged. However, scarring and/or discoloring of the skin is uncommon and rarely severe. These affected areas of skin may become abnormally thick. The severity and degree of symptoms is different from case to case. Some patients may only be able to tolerate a few minutes of sun exposure while others may be able to tolerate longer sun exposure without symptoms. The amount of sun tolerated may also be different based on weather conditions. Symptoms are often seen during infancy; however, in some cases, it may not occur until adolescence or rarely in adulthood.In some affected individuals, the flow of bile through the gallbladder and bile ducts (biliary system) may be interrupted (cholestasis) causing gallstones (cholelithiasis) to form. In turn, such stones can cause obstruction and/or inflammation of the gallbladder (cholecystitis). Rarely, affected individuals may also develop liver damage that, in very severe cases, may lead to liver failure requiring transplantation. As liver transplantation does not cure EPP or XLP, a bone marrow transplant following liver transplant may be necessary in some cases.Symptoms usually start in childhood but diagnosis is often delayed since blistering is not common and, because the porphyrins are insoluble, they cannot be detected on urinanalysis. The diagnosis is made upon finding increased levels of the protoporphyrin in the plasma or red blood cells in both EPP and XLP. Genetic testing is useful to confirm the diagnosis. Patients with EPP and XLP may also have mild anemia (low blood counts). In many cases, this may be due to low iron stores. They may also have high levels of liver enzymes on blood tests. | 424 | Erythropoietic Protoporphyria and X-Linked Protoporphyria |
nord_424_2 | Causes of Erythropoietic Protoporphyria and X-Linked Protoporphyria | EPP is a rare genetic disorder caused by genetic changes in the FECH gene. The FECH gene is responsible for providing instructions for the body to create an enzyme called ferrochelatase. This enzyme is involved in a long process to make heme, a chemical that functions to transport oxygen around the body. Without enough of the enzyme, ferrochelatase, the body is not able to finish converting a heme precursor called protoporphyrin into heme, causing buildup of protoporphyrins in certain tissues in the body (i.e., the plasma, red blood cells, and the liver). These protoporphyrins also build up in the superficial blood vessels under the skin. These protoporphyrins are highly sensitive to sunlight. When they absorb sunlight, it results in a reaction which causes severe pain and inflammation resulting in symptoms of EPP. EPP is inherited, or passed down through the generations, in an autosomal recessive manner. Everyone has two copies of the FECH gene, one inherited from the mother and one from the father. Most individuals with EPP have a different gene change on each copy of the FECH genes. On one copy, the change, called a mutation, has stopped this copy of the gene from working properly. On the other copy, there is a small change called a “low-expression allele” or a polymorphism. This alteration still affects the way the FECH gene works; it produces less ferrochelatase enzyme than normal. This small change is common in the general population, with up to 10% of Caucasians with one copy of this change. This alteration will not cause EPP by itself, and people who have the alteration on each copy of the FECH gene will NOT develop EPP. But when someone inherits the small alteration from one parent and a mutation from the other, they will develop EPP, because there will not be enough enzyme made. Most patients with EPP have the low-expression alteration on one copy of the FECH gene and a mutation on the other copy. The risk for patients with EPP to have a child who also has the condition depends on the genetic changes in their partner. Some patients with symptoms of EPP have a genetic change in a different gene called ALAS2, a gene located on the X chromosome. When a patient has a genetic change in this gene, the condition is referred to as X-linked protoporphyria (XLP). XLP is passed down through families in an X-linked manner. Males have one X chromosome and one Y chromosome, while females have two X chromosomes.This means that males have only one copy of the ALAS2 gene and females have two copies of the ALAS2 gene. When a male has a mutation is his single copy of ALAS2, he is expected to have symptoms of XLP. In a woman with a mutation in one of her ALAS2 genes, the second functioning copy of the gene can help compensate and may lead to less severe symptoms or no symptoms at all. It is not possible to predict or control the severity of disease in females. Men with XLP pass on their X chromosome to their daughters and their Y chromosome to their sons. Therefore, a man with XLP with pass on his genetic change to all his daughters, and none of his sons. For a female with XLP, she will pass on the X chromosome with the genetic change 50% of the time. Thus, in each pregnancy, there is a 50% chance of having a child with a mutation in ALAS2. Genetic counseling is recommended for affected individuals and their families. | Causes of Erythropoietic Protoporphyria and X-Linked Protoporphyria. EPP is a rare genetic disorder caused by genetic changes in the FECH gene. The FECH gene is responsible for providing instructions for the body to create an enzyme called ferrochelatase. This enzyme is involved in a long process to make heme, a chemical that functions to transport oxygen around the body. Without enough of the enzyme, ferrochelatase, the body is not able to finish converting a heme precursor called protoporphyrin into heme, causing buildup of protoporphyrins in certain tissues in the body (i.e., the plasma, red blood cells, and the liver). These protoporphyrins also build up in the superficial blood vessels under the skin. These protoporphyrins are highly sensitive to sunlight. When they absorb sunlight, it results in a reaction which causes severe pain and inflammation resulting in symptoms of EPP. EPP is inherited, or passed down through the generations, in an autosomal recessive manner. Everyone has two copies of the FECH gene, one inherited from the mother and one from the father. Most individuals with EPP have a different gene change on each copy of the FECH genes. On one copy, the change, called a mutation, has stopped this copy of the gene from working properly. On the other copy, there is a small change called a “low-expression allele” or a polymorphism. This alteration still affects the way the FECH gene works; it produces less ferrochelatase enzyme than normal. This small change is common in the general population, with up to 10% of Caucasians with one copy of this change. This alteration will not cause EPP by itself, and people who have the alteration on each copy of the FECH gene will NOT develop EPP. But when someone inherits the small alteration from one parent and a mutation from the other, they will develop EPP, because there will not be enough enzyme made. Most patients with EPP have the low-expression alteration on one copy of the FECH gene and a mutation on the other copy. The risk for patients with EPP to have a child who also has the condition depends on the genetic changes in their partner. Some patients with symptoms of EPP have a genetic change in a different gene called ALAS2, a gene located on the X chromosome. When a patient has a genetic change in this gene, the condition is referred to as X-linked protoporphyria (XLP). XLP is passed down through families in an X-linked manner. Males have one X chromosome and one Y chromosome, while females have two X chromosomes.This means that males have only one copy of the ALAS2 gene and females have two copies of the ALAS2 gene. When a male has a mutation is his single copy of ALAS2, he is expected to have symptoms of XLP. In a woman with a mutation in one of her ALAS2 genes, the second functioning copy of the gene can help compensate and may lead to less severe symptoms or no symptoms at all. It is not possible to predict or control the severity of disease in females. Men with XLP pass on their X chromosome to their daughters and their Y chromosome to their sons. Therefore, a man with XLP with pass on his genetic change to all his daughters, and none of his sons. For a female with XLP, she will pass on the X chromosome with the genetic change 50% of the time. Thus, in each pregnancy, there is a 50% chance of having a child with a mutation in ALAS2. Genetic counseling is recommended for affected individuals and their families. | 424 | Erythropoietic Protoporphyria and X-Linked Protoporphyria |
nord_424_3 | Affects of Erythropoietic Protoporphyria and X-Linked Protoporphyria | EPP is a very rare inherited disorder that affects males and females in equal numbers. It is estimated that the disorder occurs in about 1 in about 75,000 to 1 in 200,000 individuals in Europe. The number of patients affected by these disorders in the US is unknown. XLP accounts for about 10% of cases in the United States. It is more likely to present in males. Females with XLP may or may not have symptoms. The onset of symptoms affecting the skin usually occurs in infancy, with an average of diagnosis at age 4; however, in some cases, onset may not occur until adolescence or rarely even adulthood. | Affects of Erythropoietic Protoporphyria and X-Linked Protoporphyria. EPP is a very rare inherited disorder that affects males and females in equal numbers. It is estimated that the disorder occurs in about 1 in about 75,000 to 1 in 200,000 individuals in Europe. The number of patients affected by these disorders in the US is unknown. XLP accounts for about 10% of cases in the United States. It is more likely to present in males. Females with XLP may or may not have symptoms. The onset of symptoms affecting the skin usually occurs in infancy, with an average of diagnosis at age 4; however, in some cases, onset may not occur until adolescence or rarely even adulthood. | 424 | Erythropoietic Protoporphyria and X-Linked Protoporphyria |
nord_424_4 | Related disorders of Erythropoietic Protoporphyria and X-Linked Protoporphyria | Symptoms of the following disorders can be similar to those of EPP and XLP. Comparisons may be useful for a differential diagnosis:There are several other types of porphyrias, all of which involve deficiencies of specific enzymes. Most of the symptoms of these porphyrias are not similar to the symptoms found in erythropoietic protoporphyria. Individuals with porphyria cutanea tarda and congenital erythropoietic porphyria may develop skin lesions; however, these lesions do not resemble the skin lesions found in EPP. It is important to note that individuals with one type of porphyria do not develop any of the other types. In addition, there are skin disorders characterized by hypersensitivity to artificial light and sunlight besides EPP, such as xeroderma pigmentosum and epidermolysis bullosa. The skin lesions in these disorders do not resemble the skin lesions in EPP. (For more information on these disorders, choose “porphyria, xeroderma pigmentosum or epidermolysis bullosa” as your search terms in the Rare Disease Database.).Other skin disorders which may cause photosensitivity include polymorphous light eruption, solar urticaria and drug-induced photosensitivity. | Related disorders of Erythropoietic Protoporphyria and X-Linked Protoporphyria. Symptoms of the following disorders can be similar to those of EPP and XLP. Comparisons may be useful for a differential diagnosis:There are several other types of porphyrias, all of which involve deficiencies of specific enzymes. Most of the symptoms of these porphyrias are not similar to the symptoms found in erythropoietic protoporphyria. Individuals with porphyria cutanea tarda and congenital erythropoietic porphyria may develop skin lesions; however, these lesions do not resemble the skin lesions found in EPP. It is important to note that individuals with one type of porphyria do not develop any of the other types. In addition, there are skin disorders characterized by hypersensitivity to artificial light and sunlight besides EPP, such as xeroderma pigmentosum and epidermolysis bullosa. The skin lesions in these disorders do not resemble the skin lesions in EPP. (For more information on these disorders, choose “porphyria, xeroderma pigmentosum or epidermolysis bullosa” as your search terms in the Rare Disease Database.).Other skin disorders which may cause photosensitivity include polymorphous light eruption, solar urticaria and drug-induced photosensitivity. | 424 | Erythropoietic Protoporphyria and X-Linked Protoporphyria |
nord_424_5 | Diagnosis of Erythropoietic Protoporphyria and X-Linked Protoporphyria | The diagnosis of EPP and XLP may be made by a thorough clinical evaluation, and specialized laboratory tests. EPP and XLP are usually diagnosed during infancy or early childhood, due to characteristic symptoms, and by testing the red blood cells (erythrocytes) for increased levels of protoporphyrin. Genetic testing is useful to confirm the diagnosis and identify if it is EPP or XLP. This information is useful for genetic counseling and testing family members as both are inherited in a different manner. | Diagnosis of Erythropoietic Protoporphyria and X-Linked Protoporphyria. The diagnosis of EPP and XLP may be made by a thorough clinical evaluation, and specialized laboratory tests. EPP and XLP are usually diagnosed during infancy or early childhood, due to characteristic symptoms, and by testing the red blood cells (erythrocytes) for increased levels of protoporphyrin. Genetic testing is useful to confirm the diagnosis and identify if it is EPP or XLP. This information is useful for genetic counseling and testing family members as both are inherited in a different manner. | 424 | Erythropoietic Protoporphyria and X-Linked Protoporphyria |
nord_424_6 | Therapies of Erythropoietic Protoporphyria and X-Linked Protoporphyria | TreatmentAvoidance of sunlight will be of benefit to individuals with EPP. The use of sun protective clothing such as long sleeves, hats, and sunglasses will also benefit patients. Tanning creams which increase skin pigmentation or sunscreens which contain physical reflecting agents may be beneficial to some patients. Individuals with EPP and XLP may also benefit from window tinting or using films to cover the windows in their car or house. Before tinting or shading car windows, affected individuals should check with their local Registry of Motor Vehicles to ensure that such measures do not violate any local codes. In EPP, a high potency form of Lumitene (oral beta-carotene) has been used to improve an affected individual's tolerance of sunlight. While some patients report improvement, recent studies show that there is no data to support the benefit of this treatment. In 2019, the Food and Drug Administration (FDA) approved Scenesse (afamelanotide) for the treatment of adult patients with EPP. Scenesse is an injectable implant and works by increasing skin pigmentation which provides protection and improves sun tolerance. Scenesse was available in Europe for a period of time before its approval in the United States. When iron deficiency is present, iron supplements may be given. A drug called Prevalite (cholestyramine) or activated charcoal maybe prescribed to interrupt the circulation of protoporphyrin through the liver and intestines in patients with liver disease. In addition, individuals with high levels of protoporphyrin in the plasma and red blood cells should be observed closely by a physician for possible liver malfunction that could eventually lead to liver failure. Liver transplantation has been performed as a life-saving measure in patients with EPP and XLP related liver failure. Bone marrow transplant can also be performed after liver transplant to prevent further damage to the liver. EPP and XLP patients should take vitamin D supplements as they are likely to have low vitamin D levels since they avoid sunlight. They should also receive vaccination against hepatitis A and B to prevent other causes of liver damage. Patients should be seen at least yearly to monitor protoporphyrin levels, anemia, liver enzymes, iron and vitamin D levels. Other treatment is symptomatic and supportive. | Therapies of Erythropoietic Protoporphyria and X-Linked Protoporphyria. TreatmentAvoidance of sunlight will be of benefit to individuals with EPP. The use of sun protective clothing such as long sleeves, hats, and sunglasses will also benefit patients. Tanning creams which increase skin pigmentation or sunscreens which contain physical reflecting agents may be beneficial to some patients. Individuals with EPP and XLP may also benefit from window tinting or using films to cover the windows in their car or house. Before tinting or shading car windows, affected individuals should check with their local Registry of Motor Vehicles to ensure that such measures do not violate any local codes. In EPP, a high potency form of Lumitene (oral beta-carotene) has been used to improve an affected individual's tolerance of sunlight. While some patients report improvement, recent studies show that there is no data to support the benefit of this treatment. In 2019, the Food and Drug Administration (FDA) approved Scenesse (afamelanotide) for the treatment of adult patients with EPP. Scenesse is an injectable implant and works by increasing skin pigmentation which provides protection and improves sun tolerance. Scenesse was available in Europe for a period of time before its approval in the United States. When iron deficiency is present, iron supplements may be given. A drug called Prevalite (cholestyramine) or activated charcoal maybe prescribed to interrupt the circulation of protoporphyrin through the liver and intestines in patients with liver disease. In addition, individuals with high levels of protoporphyrin in the plasma and red blood cells should be observed closely by a physician for possible liver malfunction that could eventually lead to liver failure. Liver transplantation has been performed as a life-saving measure in patients with EPP and XLP related liver failure. Bone marrow transplant can also be performed after liver transplant to prevent further damage to the liver. EPP and XLP patients should take vitamin D supplements as they are likely to have low vitamin D levels since they avoid sunlight. They should also receive vaccination against hepatitis A and B to prevent other causes of liver damage. Patients should be seen at least yearly to monitor protoporphyrin levels, anemia, liver enzymes, iron and vitamin D levels. Other treatment is symptomatic and supportive. | 424 | Erythropoietic Protoporphyria and X-Linked Protoporphyria |
nord_425_0 | Overview of ESCO2 Spectrum Disorder | Summary ESCO2 spectrum disorder includes conditions caused by changes (variants or mutations) in the ESCO2 gene that range from Roberts syndrome at the severe end to SC phocomelia at the milder end. Roberts syndrome is the best known and most widely studied condition in this group. These conditions are inherited in an autosomal recessive pattern.Roberts syndrome is a rare genetic disorder characterized by growth delays before and after birth, malformations of the arms and legs, and distinctive abnormalities of the skull and facial (craniofacial) region. Intellectual disability occurs in about half of affected children. In infants with Roberts syndrome, the arms and legs may be incompletely developed (limb reduction abnormalities), however, such limb defects are usually symmetrical which are distinct from the asymmetrical limb defects in Cornelia de Lange syndrome (CdLS). Such abnormalities may range from absence of all four limbs (tetraphocomelia) to less severe degrees of limb reduction, such as underdevelopment and/or absence of certain bones of the upper arms (humeri), forearms (radii and/or ulnae), thighs (femurs), shins (tibiae), and/or on the outside of the lower legs (fibulae). Characteristic craniofacial abnormalities may include an unusually small, broad head (microbrachycephaly); abnormal grooves on either side of the upper lip (bilateral cleft lip); incomplete development of the roof of the mouth (cleft palate); thin, small wings of the nose (hypoplastic nasal alae) and/or low-set, malformed (dysplastic) ears. Additional abnormalities are often present. IntroductionInitially, researchers believed that Roberts syndrome and SC phocomelia syndrome were separate disorders. However, researchers now believe that the two disorders are different expressions of one distinct disorder because different changes in the same gene are the underlying cause for both conditions. Juberg-Hayward syndrome is a malformation syndrome characterized by cleft lip/palate, microcephaly, drooping upper eye lids (ptosis), short stature, hypoplasia or aplasia of thumbs, and dislocation of radial head and fusion of humerus and radius leading to elbow restriction. | Overview of ESCO2 Spectrum Disorder. Summary ESCO2 spectrum disorder includes conditions caused by changes (variants or mutations) in the ESCO2 gene that range from Roberts syndrome at the severe end to SC phocomelia at the milder end. Roberts syndrome is the best known and most widely studied condition in this group. These conditions are inherited in an autosomal recessive pattern.Roberts syndrome is a rare genetic disorder characterized by growth delays before and after birth, malformations of the arms and legs, and distinctive abnormalities of the skull and facial (craniofacial) region. Intellectual disability occurs in about half of affected children. In infants with Roberts syndrome, the arms and legs may be incompletely developed (limb reduction abnormalities), however, such limb defects are usually symmetrical which are distinct from the asymmetrical limb defects in Cornelia de Lange syndrome (CdLS). Such abnormalities may range from absence of all four limbs (tetraphocomelia) to less severe degrees of limb reduction, such as underdevelopment and/or absence of certain bones of the upper arms (humeri), forearms (radii and/or ulnae), thighs (femurs), shins (tibiae), and/or on the outside of the lower legs (fibulae). Characteristic craniofacial abnormalities may include an unusually small, broad head (microbrachycephaly); abnormal grooves on either side of the upper lip (bilateral cleft lip); incomplete development of the roof of the mouth (cleft palate); thin, small wings of the nose (hypoplastic nasal alae) and/or low-set, malformed (dysplastic) ears. Additional abnormalities are often present. IntroductionInitially, researchers believed that Roberts syndrome and SC phocomelia syndrome were separate disorders. However, researchers now believe that the two disorders are different expressions of one distinct disorder because different changes in the same gene are the underlying cause for both conditions. Juberg-Hayward syndrome is a malformation syndrome characterized by cleft lip/palate, microcephaly, drooping upper eye lids (ptosis), short stature, hypoplasia or aplasia of thumbs, and dislocation of radial head and fusion of humerus and radius leading to elbow restriction. | 425 | ESCO2 Spectrum Disorder |
nord_425_1 | Symptoms of ESCO2 Spectrum Disorder | The symptoms associated with Roberts syndrome vary widely from person to person even among members of the same family. Most infants experience growth deficiencies and have abnormalities of the limbs and craniofacial region. Infants with Roberts syndrome often experience life-threatening complications early in infancy.Affected infants may experience growth deficiencies before and after birth. Intellectual disability is a variable finding that occurs in approximately 50 percent of affected children.Limb abnormalities are common in infants with Roberts syndrome and may range from underdeveloped bones in the arms and legs (hypomelia) to complete absence of all four limbs (tetraphocomelia). The arms are usually more severely affected than the legs.Additional abnormalities may affect the arms and legs including permanent fixation (contracture) of various joints, especially the knees and elbows. The number of fingers and/or toes may be reduced, and the fifth fingers may be in a fixed laterally deviated position (clinodactyly). Webbing of the finger and toes (syndactyly) may also be present. Infants with Roberts syndrome may also have a form of club foot where the heel of the foot may be elevated and turned outward away from the body (talipes equinovalgus).Infants with Roberts syndrome also have a variety of craniofacial abnormalities including a small, broad head (microbrachycephaly); an abnormal groove in the upper lip (cleft lip) with or without incomplete closure of the roof of the mouth (cleft palate); a flattened nose with small wings; an abnormally small jaw (micrognathia); sparse, silvery hair; and malformed, low-set ears that often lack lobes. Some infants may experience premature fusion of the fibrous joints (cranial sutures) between certain bones in the skull (craniosynostosis). Affected infants may have eye (ocular) abnormalities including widely spaced eyes (hypertelorism); unusually small eyes (microphthalmia); cloudy corneas; and bulging or prominent eyes (proptosis) due to shallow eye cavities (orbits). In some children, the whites of the eyes may be blue (blue sclera) and increased pressure within the eyeball (glaucoma) may also be present.Some infants with Roberts syndrome may have one or more pink or dark red irregularly shaped patches of skin (hemangiomas) on the face caused by dense collections of small blood vessels (capillaries).Infants with Roberts syndrome often have abnormalities affecting the genitourinary system. Males may have the urinary opening located on the underside of the penis (hypospadias) and the testicles may fail to descend into the scrotum (cryptorchidism). Females may have a malformed uterus with horn-like branches (bicornuate uterus).Less common symptoms associated with Roberts syndrome include malformed kidneys, an abnormal increase in cerebrospinal fluid resulting in enlargement of the skull (hydrocephalus), paralysis of cranial nerves, seizures, heart defects and a decreased number of blood platelets (thrombocytopenia). | Symptoms of ESCO2 Spectrum Disorder. The symptoms associated with Roberts syndrome vary widely from person to person even among members of the same family. Most infants experience growth deficiencies and have abnormalities of the limbs and craniofacial region. Infants with Roberts syndrome often experience life-threatening complications early in infancy.Affected infants may experience growth deficiencies before and after birth. Intellectual disability is a variable finding that occurs in approximately 50 percent of affected children.Limb abnormalities are common in infants with Roberts syndrome and may range from underdeveloped bones in the arms and legs (hypomelia) to complete absence of all four limbs (tetraphocomelia). The arms are usually more severely affected than the legs.Additional abnormalities may affect the arms and legs including permanent fixation (contracture) of various joints, especially the knees and elbows. The number of fingers and/or toes may be reduced, and the fifth fingers may be in a fixed laterally deviated position (clinodactyly). Webbing of the finger and toes (syndactyly) may also be present. Infants with Roberts syndrome may also have a form of club foot where the heel of the foot may be elevated and turned outward away from the body (talipes equinovalgus).Infants with Roberts syndrome also have a variety of craniofacial abnormalities including a small, broad head (microbrachycephaly); an abnormal groove in the upper lip (cleft lip) with or without incomplete closure of the roof of the mouth (cleft palate); a flattened nose with small wings; an abnormally small jaw (micrognathia); sparse, silvery hair; and malformed, low-set ears that often lack lobes. Some infants may experience premature fusion of the fibrous joints (cranial sutures) between certain bones in the skull (craniosynostosis). Affected infants may have eye (ocular) abnormalities including widely spaced eyes (hypertelorism); unusually small eyes (microphthalmia); cloudy corneas; and bulging or prominent eyes (proptosis) due to shallow eye cavities (orbits). In some children, the whites of the eyes may be blue (blue sclera) and increased pressure within the eyeball (glaucoma) may also be present.Some infants with Roberts syndrome may have one or more pink or dark red irregularly shaped patches of skin (hemangiomas) on the face caused by dense collections of small blood vessels (capillaries).Infants with Roberts syndrome often have abnormalities affecting the genitourinary system. Males may have the urinary opening located on the underside of the penis (hypospadias) and the testicles may fail to descend into the scrotum (cryptorchidism). Females may have a malformed uterus with horn-like branches (bicornuate uterus).Less common symptoms associated with Roberts syndrome include malformed kidneys, an abnormal increase in cerebrospinal fluid resulting in enlargement of the skull (hydrocephalus), paralysis of cranial nerves, seizures, heart defects and a decreased number of blood platelets (thrombocytopenia). | 425 | ESCO2 Spectrum Disorder |
nord_425_2 | Causes of ESCO2 Spectrum Disorder | The ESCO2 spectrum disorders, including Roberts syndrome, are caused by changes (variants or mutations) in the ESCO2 gene.Chromosomes, which are present in the nucleus of human cells, carry genetic information for each individual. There are certain complex chromosomal abnormalities which are distinguishing features of ESCO2 spectrum disorders. Cells from affected individuals show premature centromere separation of various chromosomes, especially chromosomes 1, 9, and 16, a phenomenon often referred to as “puffing.” The centromere is the center of a chromosome located between the long and short arms of a chromosome. The characteristic “puffing” abnormality is apparent in mitosis, the process in which a cell divides ultimately forming two cells identical to the original.ESCO2 spectrum disorders, including Roberts syndrome, are inherited in an autosomal recessive pattern. Genetic diseases of this type are determined by two abnormal genes, one received from the father and one from the mother.Recessive genetic disorders occur when an individual inherits a mutated gene from each parent. If an individual receives one normal gene and one mutated gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the mutated gene and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.It is also possible that a new mutation in an autosomal dominant gene could be the cause of Roberts syndrome in some families. 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. | Causes of ESCO2 Spectrum Disorder. The ESCO2 spectrum disorders, including Roberts syndrome, are caused by changes (variants or mutations) in the ESCO2 gene.Chromosomes, which are present in the nucleus of human cells, carry genetic information for each individual. There are certain complex chromosomal abnormalities which are distinguishing features of ESCO2 spectrum disorders. Cells from affected individuals show premature centromere separation of various chromosomes, especially chromosomes 1, 9, and 16, a phenomenon often referred to as “puffing.” The centromere is the center of a chromosome located between the long and short arms of a chromosome. The characteristic “puffing” abnormality is apparent in mitosis, the process in which a cell divides ultimately forming two cells identical to the original.ESCO2 spectrum disorders, including Roberts syndrome, are inherited in an autosomal recessive pattern. Genetic diseases of this type are determined by two abnormal genes, one received from the father and one from the mother.Recessive genetic disorders occur when an individual inherits a mutated gene from each parent. If an individual receives one normal gene and one mutated gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the mutated gene and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.It is also possible that a new mutation in an autosomal dominant gene could be the cause of Roberts syndrome in some families. 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. | 425 | ESCO2 Spectrum Disorder |
nord_425_3 | Affects of ESCO2 Spectrum Disorder | ESCO2 spectrum disorders affect males and females in equal numbers. Affected children often have parents who are blood relatives. Patients have been reported from all over the world. The two families with Juberg-Hayward syndrome were identified in a tribe in Thailand with the identical ESCO gene mutation. | Affects of ESCO2 Spectrum Disorder. ESCO2 spectrum disorders affect males and females in equal numbers. Affected children often have parents who are blood relatives. Patients have been reported from all over the world. The two families with Juberg-Hayward syndrome were identified in a tribe in Thailand with the identical ESCO gene mutation. | 425 | ESCO2 Spectrum Disorder |
nord_425_4 | Related disorders of ESCO2 Spectrum Disorder | Symptoms of the following disorders can be similar to those of Roberts syndrome. Comparisons may be useful for a differential diagnosis:Cornelia de Lange syndrome (CdLS) is a dominantly inherited, multi-system developmental disorder. The asymmetrical upper limb defects are similar but different from those in Roberts syndrome, which is ranging from small hands with single palmar creases and subtle changes in the bones of fingers (phalanges) and the palm (metacarpal bones) to severe forms of lack of fingers (oligodactyly) and truncation of the forearm primarily involving the structures on “pinky” side (ulnar). The characteristic facial features seen in individuals with CdLS are easy to identify and may be one of the most useful diagnostic signs, which includes one fused heavy eyebrow (synophrys), long eyelashes, depressed nasal bridge, long philtrum, thin upper lip, small widely spaced teeth, disproportionate small and short head (brachycephaly), and low-set ears. Other common clinical presentations are excessive bodily or facial hair (hirsutism), various eye (ophthalmologic) problems, stomach and esophagus (gastroesophageal) dysfunction, heart defects, growth delay, and neurodevelopmental delay. The intellectual disability seen in CdLS is severe; autism and self-destructive tendencies are also seen in many patients. Mildly affected patients may go undiagnosed.About 50% of CdLS patients have a mutation in the NIPBL gene and a small portion of patients have mutations in the SMC1A or SMC3 gene, while the rest have no reported gene mutations. SMC1A and SMC3 proteins are structural subunits of the cohesin complex. Both ESCO2 (the disease-causing gene of RBS) and NIPBL regulate cohesin complex, although through different mechanisms. (For more information on this disorder, choose “CdLS” as your search term in the Rare Disease Database.)Thrombocytopenia-absent radius (TAR) syndrome is a rare genetic disorder that is apparent at birth (congenital). The disorder is characterized by low levels of platelets in the blood (thrombocytopenia), resulting in potentially severe bleeding episodes (hemorrhages) primarily during infancy. Other characteristic findings include absence (aplasia) of the bones on the thumb side of the forearms (radii) and underdevelopment (hypoplasia) or absence of the bones on the “pinky” side of the forearms (ulnae). Other abnormalities may also be present, such as structural malformations of the heart (congenital heart defects), kidney (renal) defects, and/or intellectual disability that may be secondary to bleeding episodes in the skull (intracranial hemorrhages) during infancy. TAR syndrome is inherited in an autosomal recessive pattern. (For more information on this disorder, choose “TAR syndrome” as your search term in the Rare Disease Database.)Baller-Gerold syndrome is a rare genetic disorder that is apparent at birth (congenital). The disorder is characterized by distinctive malformations of the skull and facial (craniofacial) area and bones of the forearms and hands. In infants with Baller-Gerold syndrome, there is premature fusion of the fibrous joints (cranial sutures) between certain bones in the skull (craniosynostosis). As a result, the head may appear unusually short and wide and/or pointed at the top (turribrachycephaly) or relatively triangular (trigonocephaly). Affected infants may also have a prominent forehead; down slanting eyelid folds (palpebral fissures); small, malformed (dysplastic), low-set ears; and/or other craniofacial abnormalities. Baller-Gerold syndrome is also characterized by underdevelopment (hypoplasia) or absence (aplasia) of the bone on the thumb side of the forearms (radii). In addition, the bone on the “pinky” side of the forearms (ulnae) is unusually short and curved and the thumbs may be underdeveloped or absent. In some patients, additional physical abnormalities and/or intellectual disability may also be present. Baller-Gerold syndrome is thought to be inherited in an autosomal recessive pattern and caused by mutations in the RECQL4 gene (For more information on this disorder, choose “Baller Gerold” as your search term in the Rare Disease Database.)Holt-Oram syndrome (HOS), also known as cardiac-limb syndrome, is a rare genetic disorder characterized by malformations of bones of the forearms and hands (upper limbs) and/or heart abnormalities. The thumbs may be absent (aplastic) or underdeveloped (hypoplastic) or have an extra bone (triphalangy). Additional upper limb malformations may include defects of certain bones of the wrists (carpals), the middle portion of the hands (metacarpals), the thumb side of the forearms (radii), and/or the pinky side of the forearms (ulnae). Some affected individuals also have additional musculoskeletal abnormalities, such as malformations of the bones of the upper arms (humeri), shoulder blades (scapulae), and collarbones (clavicles); other skeletal defects; and restricted range of movements at the shoulders and elbows. Characteristic heart abnormalities may include structural cardiac defects, such as an abnormal opening in the fibrous partition (septum) between the upper and/or lower chambers of the heart (atrial and/or ventricular septal defects), or abnormal transmission of electrical impulses that coordinate the heart’s muscular contractions (electrocardiographic conduction defects). In some instances, other abnormalities are also present. Holt-Oram syndrome may be inherited in an autosomal dominant pattern or appear to occur spontaneously due to new genetic mutations. Mutations in the TBX5 gene have been associated with HOS (For further information, choose “Holt Oram” as your search term in the Rare Disease Database.) | Related disorders of ESCO2 Spectrum Disorder. Symptoms of the following disorders can be similar to those of Roberts syndrome. Comparisons may be useful for a differential diagnosis:Cornelia de Lange syndrome (CdLS) is a dominantly inherited, multi-system developmental disorder. The asymmetrical upper limb defects are similar but different from those in Roberts syndrome, which is ranging from small hands with single palmar creases and subtle changes in the bones of fingers (phalanges) and the palm (metacarpal bones) to severe forms of lack of fingers (oligodactyly) and truncation of the forearm primarily involving the structures on “pinky” side (ulnar). The characteristic facial features seen in individuals with CdLS are easy to identify and may be one of the most useful diagnostic signs, which includes one fused heavy eyebrow (synophrys), long eyelashes, depressed nasal bridge, long philtrum, thin upper lip, small widely spaced teeth, disproportionate small and short head (brachycephaly), and low-set ears. Other common clinical presentations are excessive bodily or facial hair (hirsutism), various eye (ophthalmologic) problems, stomach and esophagus (gastroesophageal) dysfunction, heart defects, growth delay, and neurodevelopmental delay. The intellectual disability seen in CdLS is severe; autism and self-destructive tendencies are also seen in many patients. Mildly affected patients may go undiagnosed.About 50% of CdLS patients have a mutation in the NIPBL gene and a small portion of patients have mutations in the SMC1A or SMC3 gene, while the rest have no reported gene mutations. SMC1A and SMC3 proteins are structural subunits of the cohesin complex. Both ESCO2 (the disease-causing gene of RBS) and NIPBL regulate cohesin complex, although through different mechanisms. (For more information on this disorder, choose “CdLS” as your search term in the Rare Disease Database.)Thrombocytopenia-absent radius (TAR) syndrome is a rare genetic disorder that is apparent at birth (congenital). The disorder is characterized by low levels of platelets in the blood (thrombocytopenia), resulting in potentially severe bleeding episodes (hemorrhages) primarily during infancy. Other characteristic findings include absence (aplasia) of the bones on the thumb side of the forearms (radii) and underdevelopment (hypoplasia) or absence of the bones on the “pinky” side of the forearms (ulnae). Other abnormalities may also be present, such as structural malformations of the heart (congenital heart defects), kidney (renal) defects, and/or intellectual disability that may be secondary to bleeding episodes in the skull (intracranial hemorrhages) during infancy. TAR syndrome is inherited in an autosomal recessive pattern. (For more information on this disorder, choose “TAR syndrome” as your search term in the Rare Disease Database.)Baller-Gerold syndrome is a rare genetic disorder that is apparent at birth (congenital). The disorder is characterized by distinctive malformations of the skull and facial (craniofacial) area and bones of the forearms and hands. In infants with Baller-Gerold syndrome, there is premature fusion of the fibrous joints (cranial sutures) between certain bones in the skull (craniosynostosis). As a result, the head may appear unusually short and wide and/or pointed at the top (turribrachycephaly) or relatively triangular (trigonocephaly). Affected infants may also have a prominent forehead; down slanting eyelid folds (palpebral fissures); small, malformed (dysplastic), low-set ears; and/or other craniofacial abnormalities. Baller-Gerold syndrome is also characterized by underdevelopment (hypoplasia) or absence (aplasia) of the bone on the thumb side of the forearms (radii). In addition, the bone on the “pinky” side of the forearms (ulnae) is unusually short and curved and the thumbs may be underdeveloped or absent. In some patients, additional physical abnormalities and/or intellectual disability may also be present. Baller-Gerold syndrome is thought to be inherited in an autosomal recessive pattern and caused by mutations in the RECQL4 gene (For more information on this disorder, choose “Baller Gerold” as your search term in the Rare Disease Database.)Holt-Oram syndrome (HOS), also known as cardiac-limb syndrome, is a rare genetic disorder characterized by malformations of bones of the forearms and hands (upper limbs) and/or heart abnormalities. The thumbs may be absent (aplastic) or underdeveloped (hypoplastic) or have an extra bone (triphalangy). Additional upper limb malformations may include defects of certain bones of the wrists (carpals), the middle portion of the hands (metacarpals), the thumb side of the forearms (radii), and/or the pinky side of the forearms (ulnae). Some affected individuals also have additional musculoskeletal abnormalities, such as malformations of the bones of the upper arms (humeri), shoulder blades (scapulae), and collarbones (clavicles); other skeletal defects; and restricted range of movements at the shoulders and elbows. Characteristic heart abnormalities may include structural cardiac defects, such as an abnormal opening in the fibrous partition (septum) between the upper and/or lower chambers of the heart (atrial and/or ventricular septal defects), or abnormal transmission of electrical impulses that coordinate the heart’s muscular contractions (electrocardiographic conduction defects). In some instances, other abnormalities are also present. Holt-Oram syndrome may be inherited in an autosomal dominant pattern or appear to occur spontaneously due to new genetic mutations. Mutations in the TBX5 gene have been associated with HOS (For further information, choose “Holt Oram” as your search term in the Rare Disease Database.) | 425 | ESCO2 Spectrum Disorder |
nord_425_5 | Diagnosis of ESCO2 Spectrum Disorder | A diagnosis of ESCO2 spectrum disorders, including Roberts syndrome, is suspected based upon a thorough clinical evaluation, detailed patient history and identification of characteristic abnormalities. A diagnosis may be supported by chromosomal analysis that detects characteristic premature centromere separation (puffing) on various chromosomes. The diagnosis is confirmed by molecular testing for ESCO2 gene mutations. The presence of mutations in this gene is strictly correlated with the centromere puffing phenomenon.In some children, it is possible that a diagnosis of ESCO spectrum disorder may be suspected before birth (prenatally) based upon specialized tests, such as amniocentesis, chorionic villus sampling (CVS) or ultrasonography. During amniocentesis, a sample of fluid that surrounds the developing fetus is removed and analyzed, while CVS involves the removal of tissue samples from a portion of the placenta. In families with high risk where both parents are carriers, DNA sequencing of fetal samples can detect an ESCO2 mutation. During fetal ultrasonography, reflected sound waves create an image of the developing fetus, potentially revealing certain developmental abnormalities suggestive of the diagnosis (e.g., cleft lip/palate, limb abnormalities). | Diagnosis of ESCO2 Spectrum Disorder. A diagnosis of ESCO2 spectrum disorders, including Roberts syndrome, is suspected based upon a thorough clinical evaluation, detailed patient history and identification of characteristic abnormalities. A diagnosis may be supported by chromosomal analysis that detects characteristic premature centromere separation (puffing) on various chromosomes. The diagnosis is confirmed by molecular testing for ESCO2 gene mutations. The presence of mutations in this gene is strictly correlated with the centromere puffing phenomenon.In some children, it is possible that a diagnosis of ESCO spectrum disorder may be suspected before birth (prenatally) based upon specialized tests, such as amniocentesis, chorionic villus sampling (CVS) or ultrasonography. During amniocentesis, a sample of fluid that surrounds the developing fetus is removed and analyzed, while CVS involves the removal of tissue samples from a portion of the placenta. In families with high risk where both parents are carriers, DNA sequencing of fetal samples can detect an ESCO2 mutation. During fetal ultrasonography, reflected sound waves create an image of the developing fetus, potentially revealing certain developmental abnormalities suggestive of the diagnosis (e.g., cleft lip/palate, limb abnormalities). | 425 | ESCO2 Spectrum Disorder |
nord_425_6 | Therapies of ESCO2 Spectrum Disorder | Treatment
The treatment of ESCO spectrum disorder is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, cardiologists, neurologists, eye specialists, and other health care professionals may need to plan an affected child’s treatment systematically and comprehensively.Patients may benefit from surgery for facial and limb defects. Prosthetic devices can also reduce problems associated with missing limbs.
Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive. | Therapies of ESCO2 Spectrum Disorder. Treatment
The treatment of ESCO spectrum disorder is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, cardiologists, neurologists, eye specialists, and other health care professionals may need to plan an affected child’s treatment systematically and comprehensively.Patients may benefit from surgery for facial and limb defects. Prosthetic devices can also reduce problems associated with missing limbs.
Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive. | 425 | ESCO2 Spectrum Disorder |
nord_426_0 | Overview of Esophageal Atresia and/or Tracheoesophageal Fistula | Esophageal atresia (EA) is a rare birth defect in which the esophagus (the tube that connects the throat with the stomach) does not develop normally. In infants with EA, the esophagus is usually separated into two parts, an upper and lower segment. These two segments do not connect. One or both segments (usually the upper) end in a blind pouch. Consequently, the normal passage between the mouth and stomach does not exist. EA often occurs in association with a tracheoesophageal fistula (TEF), which is an abnormal passage or connection (fistula) between the esophagus (usually the lower) and the trachea (windpipe). The trachea is the tube that runs from the voice box in the throat to the lungs (bronchi), and carries air to and from the lungs. EA/TEF is a life-threatening condition, however, the majority of affected infants will recover fully if the defect is detected early and treated appropriately. The exact underlying causes of EA/TEF are not fully understood. EA/TEF can occur as isolated findings (nonsyndromic), associated with other birth defects (non-isolated), or as part of a larger syndrome. | Overview of Esophageal Atresia and/or Tracheoesophageal Fistula. Esophageal atresia (EA) is a rare birth defect in which the esophagus (the tube that connects the throat with the stomach) does not develop normally. In infants with EA, the esophagus is usually separated into two parts, an upper and lower segment. These two segments do not connect. One or both segments (usually the upper) end in a blind pouch. Consequently, the normal passage between the mouth and stomach does not exist. EA often occurs in association with a tracheoesophageal fistula (TEF), which is an abnormal passage or connection (fistula) between the esophagus (usually the lower) and the trachea (windpipe). The trachea is the tube that runs from the voice box in the throat to the lungs (bronchi), and carries air to and from the lungs. EA/TEF is a life-threatening condition, however, the majority of affected infants will recover fully if the defect is detected early and treated appropriately. The exact underlying causes of EA/TEF are not fully understood. EA/TEF can occur as isolated findings (nonsyndromic), associated with other birth defects (non-isolated), or as part of a larger syndrome. | 426 | Esophageal Atresia and/or Tracheoesophageal Fistula |
nord_426_1 | Symptoms of Esophageal Atresia and/or Tracheoesophageal Fistula | Infants with EA/TEF are unable to swallow normally and can have trouble breathing (respiratory distress). After birth, infants will exhibit excessive amounts of drool, mucus and other oral secretions because they are unable to swallow. These secretions may appear as frothy white bubbles in an infant’s mouth and recur even after being suctioned out.If a TEF is present, affected infants are also at risk of secretions, such as gastric juices and saliva/mucus, being inhaled into the lungs (aspiration). Consequently, these infants can develop significant respiratory distress and/or pneumonia.Affected infants may experience episodes of coughing, gagging or choking. They can also experience repeated episodes of low levels of oxygen in the blood (hypoxia/cyanosis). Cyanosis is characterized by shortness of breath, coughing, flaring of the nostrils when breathing and bluish discoloration of the skin. Some of these infants have abnormal softening and weakening of the cartilage of the trachea (tracheomalacia) so that the walls of the trachea are floppy instead of rigid. This is often mild, but can be severe, leading to collapse of the air passage. Tracheomalacia can contribute to breathing difficulties and may precipitate respiratory arrest (near death episodes).Approximately 50 percent of infants with an EA/TEF have another birth defect. Heart (cardiac) abnormalities are the most frequent additional birth defect associated with EA/TEF. Such abnormalities can include ventricular septal defects or more complex abnormalities such as Tetralogy of Fallot. Abnormalities of the gastrointestinal system and urogenital tract are the next most common birth defects that occur along with EA/TEF. These include imperforate anus, a condition in which the anal opening fails to develop properly. Less common are abnormalities of the neurological and musculoskeletal systems. Many abnormalities occur in combination – the VACTERL association (Vertebral, Anorectal, Cardiac, TracheoEsophageal, Renal and Limb defects)A classification system has been devised that breaks EA/TEF into different subtypes. Although this classification system is commonly used, it is not universal. Type C is the most common form. The other types affect less than 15 percent of individuals with EA/TEF. Under the classification, the subtypes include,TYPE A
Only EA is present (there is no TEF). The esophagus is separated in two with both the upper and lower portions ending in blind pouches. This is sometimes referred to as pure esophageal atresia and accounts for approximately 8 percent of cases.TYPE B
The lower segment of the esophagus ends in a blind pouch and the upper segment is connected to the trachea via a TEF. This form is rare, accounting for approximately 2 percent of cases.TYPE C
The upper segment of the esophagus ends in a blind pouch and the lower segment is connected to the trachea via a TEF. This is the most common type of EA/TEF occurring in approximately 85 percent of individuals.TYPE D
A TEF is present connecting both the upper and lower segments of the esophagus to the trachea. This is the rarest form of EA/TEF affecting less than 1 percent of cases.TYPE E
In this form, the esophagus is intact and connects normally to the stomach. However, a TEF is present connecting the esophagus and the trachea. This is also known as H-type fistula. (4 percent). | Symptoms of Esophageal Atresia and/or Tracheoesophageal Fistula. Infants with EA/TEF are unable to swallow normally and can have trouble breathing (respiratory distress). After birth, infants will exhibit excessive amounts of drool, mucus and other oral secretions because they are unable to swallow. These secretions may appear as frothy white bubbles in an infant’s mouth and recur even after being suctioned out.If a TEF is present, affected infants are also at risk of secretions, such as gastric juices and saliva/mucus, being inhaled into the lungs (aspiration). Consequently, these infants can develop significant respiratory distress and/or pneumonia.Affected infants may experience episodes of coughing, gagging or choking. They can also experience repeated episodes of low levels of oxygen in the blood (hypoxia/cyanosis). Cyanosis is characterized by shortness of breath, coughing, flaring of the nostrils when breathing and bluish discoloration of the skin. Some of these infants have abnormal softening and weakening of the cartilage of the trachea (tracheomalacia) so that the walls of the trachea are floppy instead of rigid. This is often mild, but can be severe, leading to collapse of the air passage. Tracheomalacia can contribute to breathing difficulties and may precipitate respiratory arrest (near death episodes).Approximately 50 percent of infants with an EA/TEF have another birth defect. Heart (cardiac) abnormalities are the most frequent additional birth defect associated with EA/TEF. Such abnormalities can include ventricular septal defects or more complex abnormalities such as Tetralogy of Fallot. Abnormalities of the gastrointestinal system and urogenital tract are the next most common birth defects that occur along with EA/TEF. These include imperforate anus, a condition in which the anal opening fails to develop properly. Less common are abnormalities of the neurological and musculoskeletal systems. Many abnormalities occur in combination – the VACTERL association (Vertebral, Anorectal, Cardiac, TracheoEsophageal, Renal and Limb defects)A classification system has been devised that breaks EA/TEF into different subtypes. Although this classification system is commonly used, it is not universal. Type C is the most common form. The other types affect less than 15 percent of individuals with EA/TEF. Under the classification, the subtypes include,TYPE A
Only EA is present (there is no TEF). The esophagus is separated in two with both the upper and lower portions ending in blind pouches. This is sometimes referred to as pure esophageal atresia and accounts for approximately 8 percent of cases.TYPE B
The lower segment of the esophagus ends in a blind pouch and the upper segment is connected to the trachea via a TEF. This form is rare, accounting for approximately 2 percent of cases.TYPE C
The upper segment of the esophagus ends in a blind pouch and the lower segment is connected to the trachea via a TEF. This is the most common type of EA/TEF occurring in approximately 85 percent of individuals.TYPE D
A TEF is present connecting both the upper and lower segments of the esophagus to the trachea. This is the rarest form of EA/TEF affecting less than 1 percent of cases.TYPE E
In this form, the esophagus is intact and connects normally to the stomach. However, a TEF is present connecting the esophagus and the trachea. This is also known as H-type fistula. (4 percent). | 426 | Esophageal Atresia and/or Tracheoesophageal Fistula |
nord_426_2 | Causes of Esophageal Atresia and/or Tracheoesophageal Fistula | EA/TEF occurs as a result of a developmental failure during early fetal (embryonic) growth. The reason this failure occurs is not fully understood. Isolated (nonsyndromic) EA/TEF is believed to occur due to the combination of multiple different factors (multifactorial inheritance). Such factors can potentially include genetic, environmental, and immunological ones. However, no specific contributing factors have been identified. Most cases of isolated EA/TEF occur sporadically and the risk of recurrence in subsequent pregnancies is less than 1 percent.EA/TEF can also occur as part of a larger genetic syndrome such as CHARGE syndrome, Feingold syndrome, anophthalmia-esophageal-genital (AEC) syndrome, Pallister-Hall syndrome, Fanconi anemia, chromosome 22q deletion syndrome, or chromosomal disorders such as trisomy 18, trisomy 13, or Down syndrome (trisomy 21). These disorders are due to specific genetic mutations or chromosomal abnormalities.Non-isolated EA/TEF refers to cases of EA/TEF that occur along with other congenital defects, but without a known genetic defect. Heart defects are the most common associated congenital defect. Some individuals with non-isolated EA/TEF have VACTERL/VATER association. This disorder is a non-random association of birth defects, most likely due to, as yet unidentified, genetic factors. The term VACTERL/VATER is an acronym; the “TE” stands for (t)racheoesophageal fistula and (e)sophageal atresia. | Causes of Esophageal Atresia and/or Tracheoesophageal Fistula. EA/TEF occurs as a result of a developmental failure during early fetal (embryonic) growth. The reason this failure occurs is not fully understood. Isolated (nonsyndromic) EA/TEF is believed to occur due to the combination of multiple different factors (multifactorial inheritance). Such factors can potentially include genetic, environmental, and immunological ones. However, no specific contributing factors have been identified. Most cases of isolated EA/TEF occur sporadically and the risk of recurrence in subsequent pregnancies is less than 1 percent.EA/TEF can also occur as part of a larger genetic syndrome such as CHARGE syndrome, Feingold syndrome, anophthalmia-esophageal-genital (AEC) syndrome, Pallister-Hall syndrome, Fanconi anemia, chromosome 22q deletion syndrome, or chromosomal disorders such as trisomy 18, trisomy 13, or Down syndrome (trisomy 21). These disorders are due to specific genetic mutations or chromosomal abnormalities.Non-isolated EA/TEF refers to cases of EA/TEF that occur along with other congenital defects, but without a known genetic defect. Heart defects are the most common associated congenital defect. Some individuals with non-isolated EA/TEF have VACTERL/VATER association. This disorder is a non-random association of birth defects, most likely due to, as yet unidentified, genetic factors. The term VACTERL/VATER is an acronym; the “TE” stands for (t)racheoesophageal fistula and (e)sophageal atresia. | 426 | Esophageal Atresia and/or Tracheoesophageal Fistula |
nord_426_3 | Affects of Esophageal Atresia and/or Tracheoesophageal Fistula | EA and TEF affect males and females in equal numbers. The incidence is estimated to be approximately 1 in 4,000 live births in the United States. The majority of cases are sporadic/non-syndromic. Familial (syndromic) cases account for less than 1 percent of all cases. EA/TEF is present at birth (congenital). | Affects of Esophageal Atresia and/or Tracheoesophageal Fistula. EA and TEF affect males and females in equal numbers. The incidence is estimated to be approximately 1 in 4,000 live births in the United States. The majority of cases are sporadic/non-syndromic. Familial (syndromic) cases account for less than 1 percent of all cases. EA/TEF is present at birth (congenital). | 426 | Esophageal Atresia and/or Tracheoesophageal Fistula |
nord_426_4 | Related disorders of Esophageal Atresia and/or Tracheoesophageal Fistula | Related disorders of Esophageal Atresia and/or Tracheoesophageal Fistula. | 426 | Esophageal Atresia and/or Tracheoesophageal Fistula |
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nord_426_5 | Diagnosis of Esophageal Atresia and/or Tracheoesophageal Fistula | The diagnosis of EA may be suspected before birth because of the presence of a small or absent stomach bubble on a routine ultrasound examination performed after the 18th week of pregnancy. The presence on an ultrasound of excessive amounts of amniotic fluid (polyhydramnios) raises further suspicion of EA. However, polyhydramnios alone is a poor indicator of EA because polyhydramnios has numerous, varied causes. In cases where EA/TEF is not suspected or detected before birth, it may be suspected within a few hours of birth when an affected newborn is unable to swallow, has excessive mucous, or has breathing difficulties.Clinical Testing and Work-Up
The diagnosis of EA/TEF is confirmed by attempting to pass a nasogastric tube (a tube that runs from the nose to the stomach via the esophagus) down the throat of infants who have require excessive suction of mucus, or are born to mothers with polyhydramnios, or, if earlier signs are missed have difficulty feeding. In infants with EA, the tube will proceed no farther than 10-12cm from the mouth. Because a nasogastric tube may coil at the bottom of the obstructed esophagus, a plain x-ray of the chest and abdomen will confirm a diagnosis of EA by determining the position of the nasogastric tube. A plain abdomen x-ray can also demonstrate gas in the stomach and intestines, which is indicative of a TEF. Lack of gas in the abdomen is suggestive of isolated esophageal atresia (Type A).Because 50 percent of infants with EA/TEF also have other birth defects, additional tests should be performed to rule out or identify associated birth defects. For example, infants with EA/TEF should receive an echocardiogram to rule out any heart defects that are potentially associated with these disorders. An echocardiogram ideally should be conducted before surgery to repair an EA because the presence of certain heart defects, such as a right sided aortic arch, can influence how best to perform the surgery. During an echocardiogram, sound waves are directed toward the heart, enabling physicians to study cardiac structure, function and motion. | Diagnosis of Esophageal Atresia and/or Tracheoesophageal Fistula. The diagnosis of EA may be suspected before birth because of the presence of a small or absent stomach bubble on a routine ultrasound examination performed after the 18th week of pregnancy. The presence on an ultrasound of excessive amounts of amniotic fluid (polyhydramnios) raises further suspicion of EA. However, polyhydramnios alone is a poor indicator of EA because polyhydramnios has numerous, varied causes. In cases where EA/TEF is not suspected or detected before birth, it may be suspected within a few hours of birth when an affected newborn is unable to swallow, has excessive mucous, or has breathing difficulties.Clinical Testing and Work-Up
The diagnosis of EA/TEF is confirmed by attempting to pass a nasogastric tube (a tube that runs from the nose to the stomach via the esophagus) down the throat of infants who have require excessive suction of mucus, or are born to mothers with polyhydramnios, or, if earlier signs are missed have difficulty feeding. In infants with EA, the tube will proceed no farther than 10-12cm from the mouth. Because a nasogastric tube may coil at the bottom of the obstructed esophagus, a plain x-ray of the chest and abdomen will confirm a diagnosis of EA by determining the position of the nasogastric tube. A plain abdomen x-ray can also demonstrate gas in the stomach and intestines, which is indicative of a TEF. Lack of gas in the abdomen is suggestive of isolated esophageal atresia (Type A).Because 50 percent of infants with EA/TEF also have other birth defects, additional tests should be performed to rule out or identify associated birth defects. For example, infants with EA/TEF should receive an echocardiogram to rule out any heart defects that are potentially associated with these disorders. An echocardiogram ideally should be conducted before surgery to repair an EA because the presence of certain heart defects, such as a right sided aortic arch, can influence how best to perform the surgery. During an echocardiogram, sound waves are directed toward the heart, enabling physicians to study cardiac structure, function and motion. | 426 | Esophageal Atresia and/or Tracheoesophageal Fistula |
nord_426_6 | Therapies of Esophageal Atresia and/or Tracheoesophageal Fistula | TreatmentTreatment may require the coordinated efforts of a team of specialists. Pediatric surgeon, pediatrician, cardiologists, speech therapist, intensive care specialists and nurses, and other healthcare professionals may need to systematically and comprehensively plan a program for the child’s treatment and ongoing care. Treatment is best performed at tertiary referral hospitals that are well versed in treating these conditions.EA/TEF requires surgical correction. Before surgery, affected infants should receive a thorough clinical evaluation for any potentially associated congenital defects, especially heart defects. In most cases, surgery is performed shortly after birth. However, surgery may be delayed in infants with certain additional congenital defects, pneumonia or in cases of isolated atresia where the gap between the two ends of the esophagus is too large for primary repair.While awaiting surgery, supportive care to prevent aspiration is necessary. A suction catheter is placed in the pouch at the end of the upper portion of the esophagus. A catheter is a hollow flexible tube. The suction catheter continually sucks out secretions that accumulate in the pouch to prevent aspiration. Broad spectrum antibiotics may be given to the infant if sepsis or pulmonary infection is present or suspected. In infants with respiratory failure, additional measures such as assisted ventilation may be required but should be used with extreme caution.A few risk classification systems have been developed to help assess EA/TEF. The prognosis regarding these conditions has continually and significantly improved for many years. One such system is the Spitz classification:Group 1 – birth weight greater than 1,500 grams (approximately 3.3 pounds) and no major heart defect
Group 2 – birth weight less than 1,500 grams or major heart defect
Group 3 – birth weight less than 1,500 grams and a major heart defectThe survival rate for a full-term infant with EA/TEF and no associated cardiovascular abnormalities (Group 1) is near 100%. Group 2 is approximately 82% and group 3 is approximately 50%.In the majority of cases, surgery to reconnect the two segments of the esophagus and close the TEF is performed within the first 24-48 hours of birth. Surgery for EA/TEF requires the chest to be opened to allow disconnection of the fistula and closure of the resulting hole in the trachea. The esophagus is repaired through a procedure called anastomosis, in which the two separate segments of the esophagus are surgically reconnected. The procedure is increasingly performed by “key-hole surgery” by specially trained and experienced pediatric surgeons.In some cases, the gap between the upper and lower segments of the esophagus is too large to permit the two segments to be reconnected. This is referred to as long-gap esophageal atresia. Surgery is delayed to allow the continued growth of the esophagus which may take up to 3 months. In the interim, a gastrostomy (a tube inserted directly into the stomach through the abdominal wall) is used for feeding and the upper pouch is sucked out to prevent aspiration. Treatment for long gap esophageal atresia is complex. Several different surgical procedures have been created to treat long-gap esophageal atresia. Most researchers advocate procedures that use the child’s own esophagus (if possible) such as delayed primary anastomosis rather than procedures that require substitute tissue obtained from elsewhere in the body.The Foker technique, which is controversial, involves stimulating the two ends of the esophagus to grow until they are close enough to allow surgical reconnection. This procedure requires at least two operations. The first involves attaching traction sutures to appropriate ends of the two segments of the esophagus. Over the course of several weeks, the tension of these sutures is increased (to encourage the ends of the two segments to grow). A second operation will be performed, when the gap has sufficiently narrowed, to remove the sutures and surgically join the two segments of the esophagus together.Additional techniques used to treat long gap EA are the gastric pull-up and colonic or jejunum interposition. With gastric pull-up the stomach is repositioned and “pulled-up” and attached directly to the esophagus in the neck. With colonic interposition, a section of the colon is detached with its blood supply and used to bridge the gap between the upper and lower segments of the esophagus, creating one “esophageal tube” running from the mouth to the stomach. In jejunum interposition, a section of the jejunum (the middle portion of the small intestine) is used instead of a piece of the colon.Additional treatment is symptomatic and supportive. For example, treatment for conditions potentially associated with EA/TEF such as tracheomalacia, cardiac defects or gastroesophageal reflux follow standard treatment guidelines.Early complications
Several side effects are associated with surgery to correct EA/TEF including those that occur within days or weeks of surgery such as a leak at the site of anastomosis, abnormal narrowing (stricture) near the site of anastomosis, and recurrence of the TEF.Late effects
As the treatment of EA/TEF has improved over the years, more individuals are reaching adulthood and researchers are seeking to identify potential long-term complications associated with therapy for EA/TEF during infancy. Some degree of esophageal dysmotility, a condition where the smooth muscle of the esophagus contracts in an uncoordinated fashion, is invariably present. This affects the normal mechanism that propels food down the esophagus and to the stomach (motility) and results in swallowing difficulties. Esophageal dysmotility can contribute to the development of gastroesophageal reflux disease (GERD), a common finding in individuals who have undergone esophageal repair. Gastroesophageal reflux is a condition in which the stomach contents flow backward into the esophagus. GERD can cause swallowing problems, recurrent chest infections, heartburn and other symptoms and may lead to inflammation of the esophagus (esophagitis), Barrett’s esophagus, and respiratory complications such as asthma. Affected children often experience recurrent chest infections particularly in the first few years after the repair.In 2017, the U.S. Food and Drug Administration (FDA) authorized the Flourish pediatric esophageal atresia device under the Humanitarian Device Exemption (HDE) for the treatment of pediatric esophageal atresia. This device is a non-surgical tool for repair of the esophagus in infants under one year of age with esophageal atresia without a TEF or for whom a TEF has been closed with a prior procedure. The device consists of two tubes with magnets; one tube is inserted through the mouth and the other through the stomach. The magnetic ends of the tubes attract one another and pull the ends of the esophagus together. Over several days, the gap between the upper and lower esophagus is closed and the surrounding tissue grows together. This device is manufactured by Cook Medical. | Therapies of Esophageal Atresia and/or Tracheoesophageal Fistula. TreatmentTreatment may require the coordinated efforts of a team of specialists. Pediatric surgeon, pediatrician, cardiologists, speech therapist, intensive care specialists and nurses, and other healthcare professionals may need to systematically and comprehensively plan a program for the child’s treatment and ongoing care. Treatment is best performed at tertiary referral hospitals that are well versed in treating these conditions.EA/TEF requires surgical correction. Before surgery, affected infants should receive a thorough clinical evaluation for any potentially associated congenital defects, especially heart defects. In most cases, surgery is performed shortly after birth. However, surgery may be delayed in infants with certain additional congenital defects, pneumonia or in cases of isolated atresia where the gap between the two ends of the esophagus is too large for primary repair.While awaiting surgery, supportive care to prevent aspiration is necessary. A suction catheter is placed in the pouch at the end of the upper portion of the esophagus. A catheter is a hollow flexible tube. The suction catheter continually sucks out secretions that accumulate in the pouch to prevent aspiration. Broad spectrum antibiotics may be given to the infant if sepsis or pulmonary infection is present or suspected. In infants with respiratory failure, additional measures such as assisted ventilation may be required but should be used with extreme caution.A few risk classification systems have been developed to help assess EA/TEF. The prognosis regarding these conditions has continually and significantly improved for many years. One such system is the Spitz classification:Group 1 – birth weight greater than 1,500 grams (approximately 3.3 pounds) and no major heart defect
Group 2 – birth weight less than 1,500 grams or major heart defect
Group 3 – birth weight less than 1,500 grams and a major heart defectThe survival rate for a full-term infant with EA/TEF and no associated cardiovascular abnormalities (Group 1) is near 100%. Group 2 is approximately 82% and group 3 is approximately 50%.In the majority of cases, surgery to reconnect the two segments of the esophagus and close the TEF is performed within the first 24-48 hours of birth. Surgery for EA/TEF requires the chest to be opened to allow disconnection of the fistula and closure of the resulting hole in the trachea. The esophagus is repaired through a procedure called anastomosis, in which the two separate segments of the esophagus are surgically reconnected. The procedure is increasingly performed by “key-hole surgery” by specially trained and experienced pediatric surgeons.In some cases, the gap between the upper and lower segments of the esophagus is too large to permit the two segments to be reconnected. This is referred to as long-gap esophageal atresia. Surgery is delayed to allow the continued growth of the esophagus which may take up to 3 months. In the interim, a gastrostomy (a tube inserted directly into the stomach through the abdominal wall) is used for feeding and the upper pouch is sucked out to prevent aspiration. Treatment for long gap esophageal atresia is complex. Several different surgical procedures have been created to treat long-gap esophageal atresia. Most researchers advocate procedures that use the child’s own esophagus (if possible) such as delayed primary anastomosis rather than procedures that require substitute tissue obtained from elsewhere in the body.The Foker technique, which is controversial, involves stimulating the two ends of the esophagus to grow until they are close enough to allow surgical reconnection. This procedure requires at least two operations. The first involves attaching traction sutures to appropriate ends of the two segments of the esophagus. Over the course of several weeks, the tension of these sutures is increased (to encourage the ends of the two segments to grow). A second operation will be performed, when the gap has sufficiently narrowed, to remove the sutures and surgically join the two segments of the esophagus together.Additional techniques used to treat long gap EA are the gastric pull-up and colonic or jejunum interposition. With gastric pull-up the stomach is repositioned and “pulled-up” and attached directly to the esophagus in the neck. With colonic interposition, a section of the colon is detached with its blood supply and used to bridge the gap between the upper and lower segments of the esophagus, creating one “esophageal tube” running from the mouth to the stomach. In jejunum interposition, a section of the jejunum (the middle portion of the small intestine) is used instead of a piece of the colon.Additional treatment is symptomatic and supportive. For example, treatment for conditions potentially associated with EA/TEF such as tracheomalacia, cardiac defects or gastroesophageal reflux follow standard treatment guidelines.Early complications
Several side effects are associated with surgery to correct EA/TEF including those that occur within days or weeks of surgery such as a leak at the site of anastomosis, abnormal narrowing (stricture) near the site of anastomosis, and recurrence of the TEF.Late effects
As the treatment of EA/TEF has improved over the years, more individuals are reaching adulthood and researchers are seeking to identify potential long-term complications associated with therapy for EA/TEF during infancy. Some degree of esophageal dysmotility, a condition where the smooth muscle of the esophagus contracts in an uncoordinated fashion, is invariably present. This affects the normal mechanism that propels food down the esophagus and to the stomach (motility) and results in swallowing difficulties. Esophageal dysmotility can contribute to the development of gastroesophageal reflux disease (GERD), a common finding in individuals who have undergone esophageal repair. Gastroesophageal reflux is a condition in which the stomach contents flow backward into the esophagus. GERD can cause swallowing problems, recurrent chest infections, heartburn and other symptoms and may lead to inflammation of the esophagus (esophagitis), Barrett’s esophagus, and respiratory complications such as asthma. Affected children often experience recurrent chest infections particularly in the first few years after the repair.In 2017, the U.S. Food and Drug Administration (FDA) authorized the Flourish pediatric esophageal atresia device under the Humanitarian Device Exemption (HDE) for the treatment of pediatric esophageal atresia. This device is a non-surgical tool for repair of the esophagus in infants under one year of age with esophageal atresia without a TEF or for whom a TEF has been closed with a prior procedure. The device consists of two tubes with magnets; one tube is inserted through the mouth and the other through the stomach. The magnetic ends of the tubes attract one another and pull the ends of the esophagus together. Over several days, the gap between the upper and lower esophagus is closed and the surrounding tissue grows together. This device is manufactured by Cook Medical. | 426 | Esophageal Atresia and/or Tracheoesophageal Fistula |
nord_427_0 | Overview of Esophageal Cancer | SummaryEsophageal cancer is an uncommon form of cancer (malignancy) that arises in the esophagus. Esophageal cancer is characterized by abnormal, uncontrolled cellular growth that forms in tissues and cells of the esophagus. This cancer can invade surrounding tissues and may spread (metastasize) to distant bodily tissues or organs via the bloodstream, the lymphatic system, or other means. The esophagus is the muscular tube that runs from the back of the throat to the stomach. The esophagus is lined with a mucous membrane, which is a type of tissue that secretes mucus. Mucus provides lubrication and protection. In most people, the esophagus is about 9 inches long (or about 23 centimeters for women and 25 centimeters for men). Esophageal cancer usually begins in the cells that line the wall of the esophagus, eventually forming a tumor. The cancer can then grow to partially block the esophageal tube, making it difficult for food to reach the stomach. More than 95% of people with esophageal cancer have one of two main types – squamous cell carcinoma or adenocarcinoma. The remaining forms are extremely rare instances of lymphoma, melanoma, carcinoid tumors, leiomyosarcoma, or sarcoma occurring in the esophagus. In extremely rare instances, cancer that arises in another areas of the body can spread to the esophagus. | Overview of Esophageal Cancer. SummaryEsophageal cancer is an uncommon form of cancer (malignancy) that arises in the esophagus. Esophageal cancer is characterized by abnormal, uncontrolled cellular growth that forms in tissues and cells of the esophagus. This cancer can invade surrounding tissues and may spread (metastasize) to distant bodily tissues or organs via the bloodstream, the lymphatic system, or other means. The esophagus is the muscular tube that runs from the back of the throat to the stomach. The esophagus is lined with a mucous membrane, which is a type of tissue that secretes mucus. Mucus provides lubrication and protection. In most people, the esophagus is about 9 inches long (or about 23 centimeters for women and 25 centimeters for men). Esophageal cancer usually begins in the cells that line the wall of the esophagus, eventually forming a tumor. The cancer can then grow to partially block the esophageal tube, making it difficult for food to reach the stomach. More than 95% of people with esophageal cancer have one of two main types – squamous cell carcinoma or adenocarcinoma. The remaining forms are extremely rare instances of lymphoma, melanoma, carcinoid tumors, leiomyosarcoma, or sarcoma occurring in the esophagus. In extremely rare instances, cancer that arises in another areas of the body can spread to the esophagus. | 427 | Esophageal Cancer |
nord_427_1 | Symptoms of Esophageal Cancer | In the early stages esophageal cancer may not be associated with any symptoms (asymptomatic). As the cancer grows, affected individuals may have difficulty swallowing solid foods (dysphagia). This occurs because the tumor has grown enough to partially block the esophageal tube. Initially, this may affect certain foods such as meat, apples or bread, which can “stick” in the throat. Eventually, affected individuals may have difficulty swallowing liquids. Many individuals may experience pain when attempting to swallow (odynophagia). This most often occurs with dry foods, and can often differentiate cancer from more benign causes of swallowing difficulty. Additional symptoms that can develop include unintended weight loss, indigestion (dyspepsia), chest pain, and heartburn that is unresponsive to medication. The most common symptoms are the combination of difficulty swallowing and unintended weight loss. Affected individuals may also experience chronic blood loss because of esophageal cancer. This can lead to iron deficiency anemia. Anemia is a condition in which there is a low level of circulating red blood cells. Red blood cells deliver oxygen throughout the body. Anemia is associated with fatigue, pale skin color (pallor), lightheadedness, and other symptoms. Anemia may occur because of unrecognized gastrointestinal bleeding, which if severe can appear as black sticky stools. Uncommon symptoms that can potentially occur include enlargement of the lymph nodes of the neck (cervical lymphadenopathy), vomiting up blood (hematemesis), coughing up of blood (hemoptysis), and hoarseness. Hoarseness usually occurs because the tumor pushes against (compresses) the nerves of the vocal cords. Compression of other nearby nerves can cause persistent hiccups or spinal pain. If the tumor has grown large enough, pain may affect the back, the area behind the breastbone (retrosternal area), or the upper right area of the abdomen. Rarely, individuals may develop a fistula, which is an abnormal passageway that connects the esophagus to windpipe (trachea). The windpipe is the tube (airway) that connects the throat to the lungs. It runs from the voice box (larynx) in the throat to the lungs. When there is an abnormal connection between the esophagus and the trachea, it is called a tracheoesophageal fistula (TEF). A TEF may allow food or other foreign particles to reach the lungs (aspiration) and can cause breathing (respiratory) problems and pneumonia. Esophageal cancer can spread (metastasize) to other areas of the body including in order of frequency: the liver, lungs, bone, and brain. The specific symptoms that develop will depend upon the exact location and extent of the cancer. Esophageal cancer often spreads to the liver and can cause fever and abnormal enlargement of the liver (hepatomegaly). Spread to the lungs can cause a chronic cough, shortness of breath or a collection of fluid within the membrane (pleura) surrounding the lungs (pleural effusion). Spread to the bones can cause bone pain. Headaches, confusion and seizures can be caused by spread to the brain. | Symptoms of Esophageal Cancer. In the early stages esophageal cancer may not be associated with any symptoms (asymptomatic). As the cancer grows, affected individuals may have difficulty swallowing solid foods (dysphagia). This occurs because the tumor has grown enough to partially block the esophageal tube. Initially, this may affect certain foods such as meat, apples or bread, which can “stick” in the throat. Eventually, affected individuals may have difficulty swallowing liquids. Many individuals may experience pain when attempting to swallow (odynophagia). This most often occurs with dry foods, and can often differentiate cancer from more benign causes of swallowing difficulty. Additional symptoms that can develop include unintended weight loss, indigestion (dyspepsia), chest pain, and heartburn that is unresponsive to medication. The most common symptoms are the combination of difficulty swallowing and unintended weight loss. Affected individuals may also experience chronic blood loss because of esophageal cancer. This can lead to iron deficiency anemia. Anemia is a condition in which there is a low level of circulating red blood cells. Red blood cells deliver oxygen throughout the body. Anemia is associated with fatigue, pale skin color (pallor), lightheadedness, and other symptoms. Anemia may occur because of unrecognized gastrointestinal bleeding, which if severe can appear as black sticky stools. Uncommon symptoms that can potentially occur include enlargement of the lymph nodes of the neck (cervical lymphadenopathy), vomiting up blood (hematemesis), coughing up of blood (hemoptysis), and hoarseness. Hoarseness usually occurs because the tumor pushes against (compresses) the nerves of the vocal cords. Compression of other nearby nerves can cause persistent hiccups or spinal pain. If the tumor has grown large enough, pain may affect the back, the area behind the breastbone (retrosternal area), or the upper right area of the abdomen. Rarely, individuals may develop a fistula, which is an abnormal passageway that connects the esophagus to windpipe (trachea). The windpipe is the tube (airway) that connects the throat to the lungs. It runs from the voice box (larynx) in the throat to the lungs. When there is an abnormal connection between the esophagus and the trachea, it is called a tracheoesophageal fistula (TEF). A TEF may allow food or other foreign particles to reach the lungs (aspiration) and can cause breathing (respiratory) problems and pneumonia. Esophageal cancer can spread (metastasize) to other areas of the body including in order of frequency: the liver, lungs, bone, and brain. The specific symptoms that develop will depend upon the exact location and extent of the cancer. Esophageal cancer often spreads to the liver and can cause fever and abnormal enlargement of the liver (hepatomegaly). Spread to the lungs can cause a chronic cough, shortness of breath or a collection of fluid within the membrane (pleura) surrounding the lungs (pleural effusion). Spread to the bones can cause bone pain. Headaches, confusion and seizures can be caused by spread to the brain. | 427 | Esophageal Cancer |
nord_427_2 | Causes of Esophageal Cancer | The exact underlying cause of esophageal cancer is not fully understood. Many cancers are caused by damage to the DNA (deoxyribonucleic acid; genes) in cells which leads to cancer. However, the exact reason normal cells become cancerous is not known. Most likely, multiple factors including genetic and environmental ones play a role in the development of esophageal cancer in certain people. Current research suggests that abnormalities of DNA which is the carrier of the body’s genetic code, are the underlying basis of cellular malignant transformation.Esophageal cancer has run in some families in specific geographic areas, but researchers do not know whether this represents a common environmental factor or an inherited predisposition. Familial esophageal cancer is extremely rare. An inherited (or genetic) predisposition to a disorder is when a person has a gene or genes associated with a particular disorder, but who will not develop the disorder unless other factors such as environmental or immunological ones are also present. In esophageal cancer, genetic changes can affect oncogenes or tumor suppressor genes. These gene changes are acquired during life; they are not inherited. They are acquired because of exposure to environmental factors like smoking or they occur randomly for no known reason (spontaneously). These gene changes are altered or incomplete versions of ordinary genes that normally regulate cell growth and division. An altered oncogene promotes out-of-control growth (cancer). Tumor suppressor genes normally limit or stop the growth of cells. When the tumor suppressor genes are altered (mutated), cells can multiply (proliferate) wildly, causing cancer. When the normal gene is present, they appear to prevent cancer from developing. Certain genes have been identified as being altered (mutated) in people with esophageal cancer than in people without this cancer. This includes the TP53 and the CDKN2A genes in both squamous cell carcinoma and adenocarcinoma. In adenocarcinoma, an additional gene called ERBB2 (also known as the HER2/neu gene) is altered in approximately one in five patients. Several other genes have been noted to be altered in a small percentage of affected individuals with either squamous cell carcinoma or adenocarcinoma of the esophagus. Determining the genetic drivers of each subtype of esophageal cancer can lead to targeted therapies (see Treatment sections below). There are several risk factors associated with esophageal cancer. A risk factor is anything that increases a person’s risk of developing a condition. Having a risk factor does not mean a person will definitely develop that condition, and people who do not have any risk factors can still develop a condition. The main risk factor for esophageal cancer is smoking, particularly cigar and pipe smoking. Alcohol is also a risk factor for squamous cell carcinoma, but not adenocarcinoma, and that risk is greater in people who smoke and drink. Smoking is predominantly associated with squamous cell carcinoma of the esophagus. Chronic or long-standing gastroesophageal reflux is associated with an increased risk of developing an adenocarcinoma of the esophagus. Gastroesophageal reflux is when stomach acids and bile flow backward from the stomach into the esophagus. The majority of people who have gastroesophageal reflux will not develop esophageal cancer. Chronic gastroesophageal reflux can cause Barrett esophagus in approximately one of ten people. Barrett esophagus is a disorder in which chronic backflow of stomach acids and bile into the esophagus damages the tissue of the lower portion of esophagus. The tissue lining the lower portion of the esophagus breaks down because of damage caused by stomach acids and bile. Because of this chronic damage, the affected tissue is slowly replaced by tissue that resembles the lining of the inside of the stomach. The exact reason that esophageal tissue changes into tissue normally found in the stomach is unknown. People with Barrett esophagus have a higher risk of developing adenocarcinoma of the esophagus than the general population. However, only a small percentage of people with Barrett esophagus will eventually develop esophageal cancer. People who are overweight or obese are at a greater risk of developing adenocarcinoma of the esophagus. Diet is also potentially associated with a decreased or increased risk of esophageal cancer. Some studies have suggested that processed meat is associated with an increased risk, but this remains unproven. A high starch diet, low in fruits and vegetables may increase the risk of squamous cell carcinoma of the esophagus. Studies have also shown that a diet high in fruits and vegetables is associated with a decreased risk. Some studies have shown repeatedly drinking extremely hot liquids may cause chronic damage to the esophagus and increase the risk of squamous cell carcinoma. Extremely hot is defined as 149 degrees Fahrenheit, or 65 degrees Celsius, which is considerably hotter than an average cup of coffee. Certain disorders are characterized with a higher risk of developing squamous cell carcinoma of the esophagus including achalasia and tylosis. Achalasia is a rare disorder of the esophagus characterized by the impaired ability to push food down toward the stomach (peristalsis), failure of the ring-shaped muscle at the bottom of the esophagus, the lower esophageal sphincter (LES), to relax. It is the contraction and relaxation of the sphincter that moves food through the tube. Tylosis is an extremely rare, genetic disorder that has been identified in two families. The disorder causes overgrowth and hardening of tissue on the soles of the feet and the palms of the hands. People with tylosis also develop small, wart-like growths (papillomas) on the walls of the esophagus. Another rare disorder that is associated with esophageal cancer is Plummer-Vinson syndrome, or esophageal webs. People with this disorder develop thin strands of membrane that extend out from the walls of the esophagus. These webs may not cause any problems, or can cause narrowing of the esophageal tube. About 1 in 10 people with this disorder eventually develop squamous cell carcinoma in the lower portion of the esophagus. People who have undergone radiation treatment to the chest or upper abdomen (often for a different form of cancer, typically lymphoma or breast cancer) are at an increased risk of developing esophageal cancer. The human papillomavirus (HPV), a virus that only infects humans and has more than 150 related types, is also associated with an increased risk of squamous cell carcinoma of the esophagus in East Asia; an association with the West is uncertain. How HPV infection increases the risk of esophageal cancer is not fully understood. HPV usually causes warts to develop in the late teens, but can be seen in early childhood in some instances. Warts may be widespread affecting the hands, feet, face, and trunk and are often highly resistant to treatment (recalcitrant). Mucosal and genital warts may also develop. Some studies have not demonstrated that HPV is not a significant risk factor for esophageal cancer and some researchers state that any association between HPV and esophageal cancer is “inconclusive.” | Causes of Esophageal Cancer. The exact underlying cause of esophageal cancer is not fully understood. Many cancers are caused by damage to the DNA (deoxyribonucleic acid; genes) in cells which leads to cancer. However, the exact reason normal cells become cancerous is not known. Most likely, multiple factors including genetic and environmental ones play a role in the development of esophageal cancer in certain people. Current research suggests that abnormalities of DNA which is the carrier of the body’s genetic code, are the underlying basis of cellular malignant transformation.Esophageal cancer has run in some families in specific geographic areas, but researchers do not know whether this represents a common environmental factor or an inherited predisposition. Familial esophageal cancer is extremely rare. An inherited (or genetic) predisposition to a disorder is when a person has a gene or genes associated with a particular disorder, but who will not develop the disorder unless other factors such as environmental or immunological ones are also present. In esophageal cancer, genetic changes can affect oncogenes or tumor suppressor genes. These gene changes are acquired during life; they are not inherited. They are acquired because of exposure to environmental factors like smoking or they occur randomly for no known reason (spontaneously). These gene changes are altered or incomplete versions of ordinary genes that normally regulate cell growth and division. An altered oncogene promotes out-of-control growth (cancer). Tumor suppressor genes normally limit or stop the growth of cells. When the tumor suppressor genes are altered (mutated), cells can multiply (proliferate) wildly, causing cancer. When the normal gene is present, they appear to prevent cancer from developing. Certain genes have been identified as being altered (mutated) in people with esophageal cancer than in people without this cancer. This includes the TP53 and the CDKN2A genes in both squamous cell carcinoma and adenocarcinoma. In adenocarcinoma, an additional gene called ERBB2 (also known as the HER2/neu gene) is altered in approximately one in five patients. Several other genes have been noted to be altered in a small percentage of affected individuals with either squamous cell carcinoma or adenocarcinoma of the esophagus. Determining the genetic drivers of each subtype of esophageal cancer can lead to targeted therapies (see Treatment sections below). There are several risk factors associated with esophageal cancer. A risk factor is anything that increases a person’s risk of developing a condition. Having a risk factor does not mean a person will definitely develop that condition, and people who do not have any risk factors can still develop a condition. The main risk factor for esophageal cancer is smoking, particularly cigar and pipe smoking. Alcohol is also a risk factor for squamous cell carcinoma, but not adenocarcinoma, and that risk is greater in people who smoke and drink. Smoking is predominantly associated with squamous cell carcinoma of the esophagus. Chronic or long-standing gastroesophageal reflux is associated with an increased risk of developing an adenocarcinoma of the esophagus. Gastroesophageal reflux is when stomach acids and bile flow backward from the stomach into the esophagus. The majority of people who have gastroesophageal reflux will not develop esophageal cancer. Chronic gastroesophageal reflux can cause Barrett esophagus in approximately one of ten people. Barrett esophagus is a disorder in which chronic backflow of stomach acids and bile into the esophagus damages the tissue of the lower portion of esophagus. The tissue lining the lower portion of the esophagus breaks down because of damage caused by stomach acids and bile. Because of this chronic damage, the affected tissue is slowly replaced by tissue that resembles the lining of the inside of the stomach. The exact reason that esophageal tissue changes into tissue normally found in the stomach is unknown. People with Barrett esophagus have a higher risk of developing adenocarcinoma of the esophagus than the general population. However, only a small percentage of people with Barrett esophagus will eventually develop esophageal cancer. People who are overweight or obese are at a greater risk of developing adenocarcinoma of the esophagus. Diet is also potentially associated with a decreased or increased risk of esophageal cancer. Some studies have suggested that processed meat is associated with an increased risk, but this remains unproven. A high starch diet, low in fruits and vegetables may increase the risk of squamous cell carcinoma of the esophagus. Studies have also shown that a diet high in fruits and vegetables is associated with a decreased risk. Some studies have shown repeatedly drinking extremely hot liquids may cause chronic damage to the esophagus and increase the risk of squamous cell carcinoma. Extremely hot is defined as 149 degrees Fahrenheit, or 65 degrees Celsius, which is considerably hotter than an average cup of coffee. Certain disorders are characterized with a higher risk of developing squamous cell carcinoma of the esophagus including achalasia and tylosis. Achalasia is a rare disorder of the esophagus characterized by the impaired ability to push food down toward the stomach (peristalsis), failure of the ring-shaped muscle at the bottom of the esophagus, the lower esophageal sphincter (LES), to relax. It is the contraction and relaxation of the sphincter that moves food through the tube. Tylosis is an extremely rare, genetic disorder that has been identified in two families. The disorder causes overgrowth and hardening of tissue on the soles of the feet and the palms of the hands. People with tylosis also develop small, wart-like growths (papillomas) on the walls of the esophagus. Another rare disorder that is associated with esophageal cancer is Plummer-Vinson syndrome, or esophageal webs. People with this disorder develop thin strands of membrane that extend out from the walls of the esophagus. These webs may not cause any problems, or can cause narrowing of the esophageal tube. About 1 in 10 people with this disorder eventually develop squamous cell carcinoma in the lower portion of the esophagus. People who have undergone radiation treatment to the chest or upper abdomen (often for a different form of cancer, typically lymphoma or breast cancer) are at an increased risk of developing esophageal cancer. The human papillomavirus (HPV), a virus that only infects humans and has more than 150 related types, is also associated with an increased risk of squamous cell carcinoma of the esophagus in East Asia; an association with the West is uncertain. How HPV infection increases the risk of esophageal cancer is not fully understood. HPV usually causes warts to develop in the late teens, but can be seen in early childhood in some instances. Warts may be widespread affecting the hands, feet, face, and trunk and are often highly resistant to treatment (recalcitrant). Mucosal and genital warts may also develop. Some studies have not demonstrated that HPV is not a significant risk factor for esophageal cancer and some researchers state that any association between HPV and esophageal cancer is “inconclusive.” | 427 | Esophageal Cancer |
nord_427_3 | Affects of Esophageal Cancer | Approximately 17,000 people are diagnosed with esophageal cancer in the United States each year. Squamous cell carcinoma and adenocarcinoma account for about 95% of people with esophageal cancer. The number of people with squamous cell carcinoma is decreasing in the U.S., but the number of people with adenocarcinoma is increasing. The number of people with esophageal cancer varies greatly throughout the world. It is the seventh most common cancer worldwide. Squamous cell carcinoma of the esophagus is more common in East Asia and the Middle East. Adenocarcinoma is more common in Western Europe, North America, and Australia. Adenocarcinoma occurs more often in the lower portion of the esophagus. Esophageal cancer affects males more often than females by a ratio of about 3 to 1. Caucasian men develop adenocarcinoma of the esophagus more often than men of other racial backgrounds. Men of African-American descent are more likely to develop squamous cell carcinoma of the esophagus. Most people who develop esophageal cancer are over the age of 55, although the number of younger adults developing esophageal cancer is increasing in the United States. | Affects of Esophageal Cancer. Approximately 17,000 people are diagnosed with esophageal cancer in the United States each year. Squamous cell carcinoma and adenocarcinoma account for about 95% of people with esophageal cancer. The number of people with squamous cell carcinoma is decreasing in the U.S., but the number of people with adenocarcinoma is increasing. The number of people with esophageal cancer varies greatly throughout the world. It is the seventh most common cancer worldwide. Squamous cell carcinoma of the esophagus is more common in East Asia and the Middle East. Adenocarcinoma is more common in Western Europe, North America, and Australia. Adenocarcinoma occurs more often in the lower portion of the esophagus. Esophageal cancer affects males more often than females by a ratio of about 3 to 1. Caucasian men develop adenocarcinoma of the esophagus more often than men of other racial backgrounds. Men of African-American descent are more likely to develop squamous cell carcinoma of the esophagus. Most people who develop esophageal cancer are over the age of 55, although the number of younger adults developing esophageal cancer is increasing in the United States. | 427 | Esophageal Cancer |
nord_427_4 | Related disorders of Esophageal Cancer | Symptoms of the following disorders can be similar to those of esophageal cancer. Comparisons may be useful for a differential diagnosis.There are many different conditions and disorders that may need to be differentiated from esophageal cancer. This can include non-cancerous narrowing of the esophagus (nonmalignant strictures), benign (noncancerous) tumors like leiomyoma, inflammation of the esophagus (esophagitis), and esophageal webs and rings. Achalasia is a rare disorder of the esophagus, the tube that carries food from the throat to the stomach. It is characterized by impaired ability to push food down toward the stomach (peristalsis), failure of the ring-shaped muscle at the bottom of the esophagus, the lower esophageal sphincter (LES), to relax. It is the contraction and relaxation of the sphincter that moves food through the tube. Achalasia can be clinically indistinguishable from esophageal cancer. (For more information on this disorder, choose “achalasia” as your search term in the Rare Disease Database.) | Related disorders of Esophageal Cancer. Symptoms of the following disorders can be similar to those of esophageal cancer. Comparisons may be useful for a differential diagnosis.There are many different conditions and disorders that may need to be differentiated from esophageal cancer. This can include non-cancerous narrowing of the esophagus (nonmalignant strictures), benign (noncancerous) tumors like leiomyoma, inflammation of the esophagus (esophagitis), and esophageal webs and rings. Achalasia is a rare disorder of the esophagus, the tube that carries food from the throat to the stomach. It is characterized by impaired ability to push food down toward the stomach (peristalsis), failure of the ring-shaped muscle at the bottom of the esophagus, the lower esophageal sphincter (LES), to relax. It is the contraction and relaxation of the sphincter that moves food through the tube. Achalasia can be clinically indistinguishable from esophageal cancer. (For more information on this disorder, choose “achalasia” as your search term in the Rare Disease Database.) | 427 | Esophageal Cancer |
nord_427_5 | Diagnosis of Esophageal Cancer | A diagnosis of esophageal cancer is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. A diagnosis is usually confirmed by a biopsy, in which a small piece of tissue is taken and studied under a microscope to identify cancerous cells. The tissue sample is studied by a doctor who specializes in examining tissue and cells and determining what disease is present (pathologist). Clinical Testing and WorkupDoctors may order an upper endoscopy examination. This examination allows doctors to view the upper portion of the digestive tract including the esophagus and the area where the esophagus connects to the stomach (gastroesophageal junction). During this examination, doctors will run a thin, flexible tube (endoscope) down a person’s throat. This tube has a tiny camera attached to it that allows doctors to visually inspect these areas. This examination can reveal abnormal tissue growths, which can include broad, hardened areas of tissue (plaques), small swellings (nodules), or open sores (ulcerations). More advanced disease may appear as a narrowing of the esophageal tube (stricture), ulcerated masses, or large ulcerations. An endoscopy examination also allows doctors to remove a small sample of tissue to be studied by a pathologist to confirm a diagnosis of esophageal cancer, and to determine what subtype of cancer is present. An endoscopic ultrasonography is performed to provide detailed images of tumors or masses in the esophagus, and their relationship to the layers of tissue that make up the walls of the esophagus. Ultrasounds use high-frequency radio waves to create a picture or image (sonogram) of specific structures like internal organs. The radio waves bounce off of (echo) internal structures within the body and the echoes are recorded to create a sonogram. Endoscopic ultrasonography can be used to determine how far into the esophagus a tumor has grown and whether it has spread to nearby lymph nodes and structures. Routine x-rays (radiographs) and specialized imaging techniques may be performed to determine the extent of cancer and whether it has spread to other areas of the body. X-rays of the esophagus may be recommended and may involve a barium swallow. Affected individuals swallow barium, which is a chalky, white, metallic element. X-rays cannot pass through barium so the x-ray film will be able to outline structures or tissues in these areas such as within the esophagus. A barium study may be done in individuals who cannot undergo an endoscopy. This is often the first test used because a primary care physician can order this test more quickly than ordering an endoscopic examination.A specialized imaging technique called computerized tomography (CT) scanning is a specialized imaging technique that is mandatory to stage the cancer. CT scanning uses a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. Before the test, patients may be required to drink an oral contrast. An oral contrast is a liquid that helps to produce detailed images of internal structures including within the chest, abdomen, and pelvis. CT scans of the chest and abdomen may be done to determine whether the cancer has spread. Another advanced imaging technique known as positron emission tomography or PET/CT scan may also be used. This scan gathers information about how much metabolic activity (glucose uptake, measured by PET) a cancer has at the same time as mapping the adjacent body structures (CT). During a PET scan, a radioactive sugar is injected into the body. This sugar will collect in areas of the body where there is a higher demand for energy. Tumors require a lot of energy to keep growing and spreading, and will soak up the radioactive sugar. When the x-ray (scan) is taken, areas that take up the radioactive sugar including esophageal cancer may show up as bright spots on the film. A PET scan is often used to help show whether esophageal cancer has spread to other areas of the body or how well it is responding to treatment. A PET scan can determine whether cancer has spread to the bones. In the past, this required a bone scan, but when a PET scan is used, a bone scan is no longer necessary, but is mandatory if surgery is being considered. Staging
When an individual is diagnosed with esophageal cancer, 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. The common staging system used for esophageal cancer is called the Tumor Node Metastasis (TNM) Staging System, which is a universal staging system for cancer developed by the American Joint Committee on Cancer/Union for International Cancer Control. This system is based on the extent of the tumor (T), whether and to what extent cancer has spread to the lymph nodes (N), and whether cancer has spread (metastasized) to other areas of the body (M). It is a complex staging system. For more information on this staging system for esophageal cancer, visit the American Cancer Society: https://www.cancer.org/cancer/esophagus-cancer/detection-diagnosis-staging/staging.html | Diagnosis of Esophageal Cancer. A diagnosis of esophageal cancer is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. A diagnosis is usually confirmed by a biopsy, in which a small piece of tissue is taken and studied under a microscope to identify cancerous cells. The tissue sample is studied by a doctor who specializes in examining tissue and cells and determining what disease is present (pathologist). Clinical Testing and WorkupDoctors may order an upper endoscopy examination. This examination allows doctors to view the upper portion of the digestive tract including the esophagus and the area where the esophagus connects to the stomach (gastroesophageal junction). During this examination, doctors will run a thin, flexible tube (endoscope) down a person’s throat. This tube has a tiny camera attached to it that allows doctors to visually inspect these areas. This examination can reveal abnormal tissue growths, which can include broad, hardened areas of tissue (plaques), small swellings (nodules), or open sores (ulcerations). More advanced disease may appear as a narrowing of the esophageal tube (stricture), ulcerated masses, or large ulcerations. An endoscopy examination also allows doctors to remove a small sample of tissue to be studied by a pathologist to confirm a diagnosis of esophageal cancer, and to determine what subtype of cancer is present. An endoscopic ultrasonography is performed to provide detailed images of tumors or masses in the esophagus, and their relationship to the layers of tissue that make up the walls of the esophagus. Ultrasounds use high-frequency radio waves to create a picture or image (sonogram) of specific structures like internal organs. The radio waves bounce off of (echo) internal structures within the body and the echoes are recorded to create a sonogram. Endoscopic ultrasonography can be used to determine how far into the esophagus a tumor has grown and whether it has spread to nearby lymph nodes and structures. Routine x-rays (radiographs) and specialized imaging techniques may be performed to determine the extent of cancer and whether it has spread to other areas of the body. X-rays of the esophagus may be recommended and may involve a barium swallow. Affected individuals swallow barium, which is a chalky, white, metallic element. X-rays cannot pass through barium so the x-ray film will be able to outline structures or tissues in these areas such as within the esophagus. A barium study may be done in individuals who cannot undergo an endoscopy. This is often the first test used because a primary care physician can order this test more quickly than ordering an endoscopic examination.A specialized imaging technique called computerized tomography (CT) scanning is a specialized imaging technique that is mandatory to stage the cancer. CT scanning uses a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. Before the test, patients may be required to drink an oral contrast. An oral contrast is a liquid that helps to produce detailed images of internal structures including within the chest, abdomen, and pelvis. CT scans of the chest and abdomen may be done to determine whether the cancer has spread. Another advanced imaging technique known as positron emission tomography or PET/CT scan may also be used. This scan gathers information about how much metabolic activity (glucose uptake, measured by PET) a cancer has at the same time as mapping the adjacent body structures (CT). During a PET scan, a radioactive sugar is injected into the body. This sugar will collect in areas of the body where there is a higher demand for energy. Tumors require a lot of energy to keep growing and spreading, and will soak up the radioactive sugar. When the x-ray (scan) is taken, areas that take up the radioactive sugar including esophageal cancer may show up as bright spots on the film. A PET scan is often used to help show whether esophageal cancer has spread to other areas of the body or how well it is responding to treatment. A PET scan can determine whether cancer has spread to the bones. In the past, this required a bone scan, but when a PET scan is used, a bone scan is no longer necessary, but is mandatory if surgery is being considered. Staging
When an individual is diagnosed with esophageal cancer, 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. The common staging system used for esophageal cancer is called the Tumor Node Metastasis (TNM) Staging System, which is a universal staging system for cancer developed by the American Joint Committee on Cancer/Union for International Cancer Control. This system is based on the extent of the tumor (T), whether and to what extent cancer has spread to the lymph nodes (N), and whether cancer has spread (metastasized) to other areas of the body (M). It is a complex staging system. For more information on this staging system for esophageal cancer, visit the American Cancer Society: https://www.cancer.org/cancer/esophagus-cancer/detection-diagnosis-staging/staging.html | 427 | Esophageal Cancer |
nord_427_6 | Therapies of Esophageal Cancer | Treatment
The therapeutic management of individuals with esophageal cancer will require the coordinated efforts of a team of medical professionals such as physicians who specialize in the diagnosis and treatment of diseases of the digestive system (gastroenterologists), physicians who specialize in the diagnosis and treatment of cancer (medical oncologists), physicians who specialize in the diagnosis and treatment of cancer with surgery (surgical oncologists or thoracic surgeons), physicians who specialize in the use of radiation therapy for the treatment of cancer (radiation oncologists), oncology nurses, psychiatrists, nutritionists, and other healthcare specialists. Psychosocial support for the entire family is essential as well. Several of the organizations listed in the Resources section provide support and information on cancer. Individuals who have esophageal cancer and who still smoke are strongly encouraged to quit smoking. The importance of quitting smoking cannot be overemphasized and is mandatory in patients who wish to be considered for surgery. Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease stage; tumor size; specific cancer subtype; the presence or absence of certain symptoms; an individual’s age and general health; and/or other 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.In general, esophageal cancer can be treated with surgery, chemotherapy, and radiation therapy, usually in some combination. In very early stages of the disease, some people may be treated with surgery alone. However, most people are diagnosed when esophageal cancer has already spread. In people in whom cancer is only in the mucosal layer of the esophagus, the tumor can be removed by a surgical procedure called endoscopic mucosal resection. This involves using a thin, flexible tube called an endoscope. This tube is fed down the throat and allows surgeons inject a tumor with saline (saltwater), which allows a small tumor to be sucked out by the endoscope. An endoscope can also be used to cut away (resect) the tumor and any affected tissue. If the cancer is found early enough, sometimes this can be curative. Endoscopic mucosal resection is a minimally-invasively surgical procedure. If the cancer has spread beyond the mucosal layer, then a procedure called an esophagectomy may be necessary. This surgery involves removing a portion of the esophagus. Sometimes, a small portion of the stomach is removed as well. After the cancer is removed, the remaining portion of the esophagus is reconnected to the stomach (gastric pullup). Sometimes, the stomach must be pulled up to connect to the remaining portion of the esophagus. The exact location, size, and spread of the cancer will determine how much of the esophagus (and whether any of the stomach) needs to be removed. Nearby lymph nodes should also be surgically removed. Surgery for esophageal cancer carries risk including infection, bleeding, and leakage of the affected area, especially where the esophagus is reconnected to the stomach. Trouble swallowing, heartburn, and digestive problems are other potential side effects. Except for very early stage esophageal cancer, surgery is usually preceded by radiation therapy and chemotherapy. Some people may not be candidates for surgery and will receive chemotherapy and radiation therapy as their first treatment option. Chemotherapy is the use of certain medications to kill or stop the growth of cancer cells. Cancers cells grow and divide rapidly, which makes them susceptible to chemotherapy medications. Different combinations of medications may be used; this is called a chemotherapy regimen. Radiation therapy uses high-powered x-rays to directly destroy cancer cells. Chemotherapy and radiation therapy are often used in combination (chemoradiotherapy) to treat people with esophageal cancer.Targeted Therapies
Targeted therapies are being explored as potential treatments for individuals with esophageal cancer. Targeted therapies are drugs and other substances that prevent the growth and spread of cancer by blocking or inhibiting certain specific molecules (often proteins) that are involved in the development of specific cancers. Generally, targeted therapies are less toxic than other treatments for cancer. A few targeted therapies have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of individuals with esophageal cancer.One type of targeted therapy is called immunotherapy. Immunotherapy is the most recent addition to therapy for cancer. It is designed to enlist the body’s immune system to act against cancer. Most forms of immunotherapy are monoclonal antibodies, which is are manmade (synthetic) version of an immune system protein.In 2011, the FDA approved trastuzumab (Herceptin®) for the treatment of individuals with HER2-positive gastroesophageal junction cancer. The gastroesophageal junction is the area where the esophagus connects to the stomach. Trastuzumab is an antibody, a specialized protein of the immune system that is targeted specifically for HER2-positive cells. Trastuzumab is used for cancer that has spread (metastasized) to other areas of the body. HER2 is a protein found on the surface of cancer cells that helps cancer cells grow and multiple. Trastuzumab blocks (inhibits) the HER2 protein. Only a small percentage of people with esophageal cancer have a HER2-positive form. In 2014, the FDA approved ramucirumab (Cyramza®), along with another drug called paclitaxel, for the treatment of advanced gastroesophageal junction adenocarcinoma in individuals who have been previously treated and that treatment failed or the cancer came back. Ramucirumab works by blocking a protein called VEGF, which helps the body make new blood vessels. Tumors require a strong blood supply to grown and spread. By blocking the VEGF protein, ramucirumab essentially cuts off the blood supply from the tumor. In 2017, the FDA approved pembrolizumab (Keytruda®) for the treatment of advanced or metastatic, gastric or gastroesophageal junction adenocarcinoma whose tumors express PD-L1 as determined by an FDA-approved test. Affected individuals must have disease progression or recurrence despite two other previous therapies. Pembrolizumab is a type of immunotherapy called anti-PD-LI therapy or PD-L1 blockade, which releases the “brakes” on the immune system that some cancers use to try to evade the immune cells. PD-L1 stands for programmed death-ligand 1, which is a protein produced by certain cancerous cells. In 2019, the FDA approved trifluridine/ tipiracil (Lonsurf®) for adult patients with metastatic gastric or gastroesophageal junction adenocarcinoma previously treated with at least two prior lines of chemotherapy. Additional and Supportive Therapies
Some affected individuals may be treated with photodynamic therapy. Photodynamic therapy, a procedure in which a drug known as a photosensitizer is used along with a special type light, has been used to treat some individuals with esophageal cancer. During photodynamic therapy, the drug is administered to an affected individual and absorbed by the affected cells. A specific wavelength of light is used to activate the drug which binds with oxygen creating a chemical that destroys the affected cells.Some affected individuals may be treated with electrocoagulation, in which heat created by an electrical current is used to destroy cancer cells. The electrical current is delivered through an electrode that is placed near the cancerous tissue. Some affected individuals may have a stent, a tiny wire mesh tube, placed into the throat to keep the esophagus open and allow the passage of food and liquids. Some affected individuals may need a gastrostomy tube, in which a small, thin tube that is inserted into the stomach through a small cut in the abdomen to allow the passage of food and liquid. Sometimes a J tube (jejunostomy tube) is used, typically for patients in which a gastric pullup is planned in order to avoid damage to the stomach before surgery. A jejunostomy tube is a soft, plastic tube inserted through the abdomen and into the middle segment of the small intestine. Medications and other methods are available for pain management. Screening
Screening is when doctors runs tests to see whether cancer is present, even though there are no symptoms of cancer. Screening for cancer usually depends on whether people have specific risk factors for a particular cancer. In the United States, there are no recommendations for screening individuals in the general population for esophageal cancer. There are established guidelines for follow up (surveillance) and assessment of people with Barrett esophagus because people with this condition are at a greater risk than the general population of developing esophageal adenocarcinoma cancer. | Therapies of Esophageal Cancer. Treatment
The therapeutic management of individuals with esophageal cancer will require the coordinated efforts of a team of medical professionals such as physicians who specialize in the diagnosis and treatment of diseases of the digestive system (gastroenterologists), physicians who specialize in the diagnosis and treatment of cancer (medical oncologists), physicians who specialize in the diagnosis and treatment of cancer with surgery (surgical oncologists or thoracic surgeons), physicians who specialize in the use of radiation therapy for the treatment of cancer (radiation oncologists), oncology nurses, psychiatrists, nutritionists, and other healthcare specialists. Psychosocial support for the entire family is essential as well. Several of the organizations listed in the Resources section provide support and information on cancer. Individuals who have esophageal cancer and who still smoke are strongly encouraged to quit smoking. The importance of quitting smoking cannot be overemphasized and is mandatory in patients who wish to be considered for surgery. Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease stage; tumor size; specific cancer subtype; the presence or absence of certain symptoms; an individual’s age and general health; and/or other 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.In general, esophageal cancer can be treated with surgery, chemotherapy, and radiation therapy, usually in some combination. In very early stages of the disease, some people may be treated with surgery alone. However, most people are diagnosed when esophageal cancer has already spread. In people in whom cancer is only in the mucosal layer of the esophagus, the tumor can be removed by a surgical procedure called endoscopic mucosal resection. This involves using a thin, flexible tube called an endoscope. This tube is fed down the throat and allows surgeons inject a tumor with saline (saltwater), which allows a small tumor to be sucked out by the endoscope. An endoscope can also be used to cut away (resect) the tumor and any affected tissue. If the cancer is found early enough, sometimes this can be curative. Endoscopic mucosal resection is a minimally-invasively surgical procedure. If the cancer has spread beyond the mucosal layer, then a procedure called an esophagectomy may be necessary. This surgery involves removing a portion of the esophagus. Sometimes, a small portion of the stomach is removed as well. After the cancer is removed, the remaining portion of the esophagus is reconnected to the stomach (gastric pullup). Sometimes, the stomach must be pulled up to connect to the remaining portion of the esophagus. The exact location, size, and spread of the cancer will determine how much of the esophagus (and whether any of the stomach) needs to be removed. Nearby lymph nodes should also be surgically removed. Surgery for esophageal cancer carries risk including infection, bleeding, and leakage of the affected area, especially where the esophagus is reconnected to the stomach. Trouble swallowing, heartburn, and digestive problems are other potential side effects. Except for very early stage esophageal cancer, surgery is usually preceded by radiation therapy and chemotherapy. Some people may not be candidates for surgery and will receive chemotherapy and radiation therapy as their first treatment option. Chemotherapy is the use of certain medications to kill or stop the growth of cancer cells. Cancers cells grow and divide rapidly, which makes them susceptible to chemotherapy medications. Different combinations of medications may be used; this is called a chemotherapy regimen. Radiation therapy uses high-powered x-rays to directly destroy cancer cells. Chemotherapy and radiation therapy are often used in combination (chemoradiotherapy) to treat people with esophageal cancer.Targeted Therapies
Targeted therapies are being explored as potential treatments for individuals with esophageal cancer. Targeted therapies are drugs and other substances that prevent the growth and spread of cancer by blocking or inhibiting certain specific molecules (often proteins) that are involved in the development of specific cancers. Generally, targeted therapies are less toxic than other treatments for cancer. A few targeted therapies have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of individuals with esophageal cancer.One type of targeted therapy is called immunotherapy. Immunotherapy is the most recent addition to therapy for cancer. It is designed to enlist the body’s immune system to act against cancer. Most forms of immunotherapy are monoclonal antibodies, which is are manmade (synthetic) version of an immune system protein.In 2011, the FDA approved trastuzumab (Herceptin®) for the treatment of individuals with HER2-positive gastroesophageal junction cancer. The gastroesophageal junction is the area where the esophagus connects to the stomach. Trastuzumab is an antibody, a specialized protein of the immune system that is targeted specifically for HER2-positive cells. Trastuzumab is used for cancer that has spread (metastasized) to other areas of the body. HER2 is a protein found on the surface of cancer cells that helps cancer cells grow and multiple. Trastuzumab blocks (inhibits) the HER2 protein. Only a small percentage of people with esophageal cancer have a HER2-positive form. In 2014, the FDA approved ramucirumab (Cyramza®), along with another drug called paclitaxel, for the treatment of advanced gastroesophageal junction adenocarcinoma in individuals who have been previously treated and that treatment failed or the cancer came back. Ramucirumab works by blocking a protein called VEGF, which helps the body make new blood vessels. Tumors require a strong blood supply to grown and spread. By blocking the VEGF protein, ramucirumab essentially cuts off the blood supply from the tumor. In 2017, the FDA approved pembrolizumab (Keytruda®) for the treatment of advanced or metastatic, gastric or gastroesophageal junction adenocarcinoma whose tumors express PD-L1 as determined by an FDA-approved test. Affected individuals must have disease progression or recurrence despite two other previous therapies. Pembrolizumab is a type of immunotherapy called anti-PD-LI therapy or PD-L1 blockade, which releases the “brakes” on the immune system that some cancers use to try to evade the immune cells. PD-L1 stands for programmed death-ligand 1, which is a protein produced by certain cancerous cells. In 2019, the FDA approved trifluridine/ tipiracil (Lonsurf®) for adult patients with metastatic gastric or gastroesophageal junction adenocarcinoma previously treated with at least two prior lines of chemotherapy. Additional and Supportive Therapies
Some affected individuals may be treated with photodynamic therapy. Photodynamic therapy, a procedure in which a drug known as a photosensitizer is used along with a special type light, has been used to treat some individuals with esophageal cancer. During photodynamic therapy, the drug is administered to an affected individual and absorbed by the affected cells. A specific wavelength of light is used to activate the drug which binds with oxygen creating a chemical that destroys the affected cells.Some affected individuals may be treated with electrocoagulation, in which heat created by an electrical current is used to destroy cancer cells. The electrical current is delivered through an electrode that is placed near the cancerous tissue. Some affected individuals may have a stent, a tiny wire mesh tube, placed into the throat to keep the esophagus open and allow the passage of food and liquids. Some affected individuals may need a gastrostomy tube, in which a small, thin tube that is inserted into the stomach through a small cut in the abdomen to allow the passage of food and liquid. Sometimes a J tube (jejunostomy tube) is used, typically for patients in which a gastric pullup is planned in order to avoid damage to the stomach before surgery. A jejunostomy tube is a soft, plastic tube inserted through the abdomen and into the middle segment of the small intestine. Medications and other methods are available for pain management. Screening
Screening is when doctors runs tests to see whether cancer is present, even though there are no symptoms of cancer. Screening for cancer usually depends on whether people have specific risk factors for a particular cancer. In the United States, there are no recommendations for screening individuals in the general population for esophageal cancer. There are established guidelines for follow up (surveillance) and assessment of people with Barrett esophagus because people with this condition are at a greater risk than the general population of developing esophageal adenocarcinoma cancer. | 427 | Esophageal Cancer |
nord_428_0 | Overview of Essential Iris Atrophy | Essential iris atrophy is a very rare, progressive disorder of the eye characterized by a pupil that is out of place and/or distorted areas of degeneration on the iris (atrophy), and/or holes in the iris. This disorder most frequently affects only one eye (unilateral) and develops slowly over time. Attachment of portions of the iris to the cornea (peripheral anterior synechiae) and subsequent closure of the drainage angle may lead to secondary glaucoma and vision loss.Essential iris atrophy is one of three iridocorneal endothelial (ICE) syndromes, each of which usually affects one eye of young to middle-aged men and women. The ICE syndromes (essential iris atrophy, Chandler syndrome, and Cogan-Reese syndrome) are distinct from one another. However, these disorders all affect the eyeand some of their symptoms overlap, making it difficult to distinguish between them. (For more information about Chandler’s syndrome, and Cogan-Reese syndrome, see the Related Disorders section of this report.) | Overview of Essential Iris Atrophy. Essential iris atrophy is a very rare, progressive disorder of the eye characterized by a pupil that is out of place and/or distorted areas of degeneration on the iris (atrophy), and/or holes in the iris. This disorder most frequently affects only one eye (unilateral) and develops slowly over time. Attachment of portions of the iris to the cornea (peripheral anterior synechiae) and subsequent closure of the drainage angle may lead to secondary glaucoma and vision loss.Essential iris atrophy is one of three iridocorneal endothelial (ICE) syndromes, each of which usually affects one eye of young to middle-aged men and women. The ICE syndromes (essential iris atrophy, Chandler syndrome, and Cogan-Reese syndrome) are distinct from one another. However, these disorders all affect the eyeand some of their symptoms overlap, making it difficult to distinguish between them. (For more information about Chandler’s syndrome, and Cogan-Reese syndrome, see the Related Disorders section of this report.) | 428 | Essential Iris Atrophy |
nord_428_1 | Symptoms of Essential Iris Atrophy | Major symptoms of essential iris atrophy may include a displaced and/or distorted pupil, patchy areas of degeneration (atrophy) on the iris, and/or holes in the iris. The edge of the pupil may turn outward (ectropion uveae). The onset of this disorder is gradual, and the changes in the shape and placement of the pupil are usually noticed before any change in vision occurs. Degeneration and holes in the iris may develop over a period of several years.Other features of essential iris atrophy may include the attachment of portions of the iris to the cornea (peripheral anterior synechiae), swelling of the cornea (corneal edema), and/or abnormalities in the cells lining the cornea (corneal endothelium). These changes may lead to increased pressure in the eye (glaucoma) and vision loss. | Symptoms of Essential Iris Atrophy. Major symptoms of essential iris atrophy may include a displaced and/or distorted pupil, patchy areas of degeneration (atrophy) on the iris, and/or holes in the iris. The edge of the pupil may turn outward (ectropion uveae). The onset of this disorder is gradual, and the changes in the shape and placement of the pupil are usually noticed before any change in vision occurs. Degeneration and holes in the iris may develop over a period of several years.Other features of essential iris atrophy may include the attachment of portions of the iris to the cornea (peripheral anterior synechiae), swelling of the cornea (corneal edema), and/or abnormalities in the cells lining the cornea (corneal endothelium). These changes may lead to increased pressure in the eye (glaucoma) and vision loss. | 428 | Essential Iris Atrophy |
nord_428_2 | Causes of Essential Iris Atrophy | The cause of essential iris atrophy or any other of the iridocorneal endothelial syndromes is not known. They are thought to be the result of the same mechanism. The primary defect is believed to be a cellular membrane secreted by the abnormal endothelial cells. This membrane covers the iris and the drainage angle of the eye. The contraction of this membrane leads to pupillary changes and formation of peripheral anterior synechiae with resultant angle closure glaucoma.Other researchers suspect that inflammation or chronic infection may be the cause of the disease.There is a hypothesis that ICE syndromes stem from an in-vitro herpes infection localized in the endothelial layer. According to this theory, one eye is infected first and the second eye develops immunity before it can be affected. | Causes of Essential Iris Atrophy. The cause of essential iris atrophy or any other of the iridocorneal endothelial syndromes is not known. They are thought to be the result of the same mechanism. The primary defect is believed to be a cellular membrane secreted by the abnormal endothelial cells. This membrane covers the iris and the drainage angle of the eye. The contraction of this membrane leads to pupillary changes and formation of peripheral anterior synechiae with resultant angle closure glaucoma.Other researchers suspect that inflammation or chronic infection may be the cause of the disease.There is a hypothesis that ICE syndromes stem from an in-vitro herpes infection localized in the endothelial layer. According to this theory, one eye is infected first and the second eye develops immunity before it can be affected. | 428 | Essential Iris Atrophy |
nord_428_3 | Affects of Essential Iris Atrophy | Essential iris atrophy is a very rare disorder that predominantly affects females in the middle adult years. The prevalence is not known. | Affects of Essential Iris Atrophy. Essential iris atrophy is a very rare disorder that predominantly affects females in the middle adult years. The prevalence is not known. | 428 | Essential Iris Atrophy |
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