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nord_385_5 | Diagnosis of Duchenne Muscular Dystrophy | A diagnosis of DMD is made based upon a thorough clinical evaluation, a detailed patient history, and a variety of specialized tests including molecular genetic tests. If the genetic tests are not informative, surgical removal and microscopic examination (biopsy) of affected muscle tissue that may reveal characteristic changes to muscle fibers. Specialized blood tests (e.g. creatine kinase) that evaluate the presence and levels of certain proteins in muscle (immunohistochemistry) are also used.Molecular genetic tests involve the examination of deoxyribonucleic acid (DNA) to identify specific a genetic mutation including deletions, duplications or single point mutations. Samples of blood or muscles cells may be tested. These techniques can also be used to diagnosis DMD before birth (prenatally).Blood tests may reveal elevated levels of the creatine kinase (CK), an enzyme that is found in abnormally high levels when muscle is damaged. The detection of elevated CK levels (usually in the thousands or ten thousands range) can confirm that muscle is damaged or inflamed, but cannot confirm a diagnosis of DMD.In some cases, a specialized test can be performed on muscle biopsy samples that can determine the presence and levels of specific proteins within cells. Various techniques such as immunostaining, immunofluorescence or Western blot (immunoblot) can be used. These tests involve the use of certain antibodies that react to certain proteins such as dystrophin. Tissue samples from muscle biopsies are exposed to these antibodies and the results can determine whether a specific muscle protein is present in the cells and in what quantity or what size. | Diagnosis of Duchenne Muscular Dystrophy. A diagnosis of DMD is made based upon a thorough clinical evaluation, a detailed patient history, and a variety of specialized tests including molecular genetic tests. If the genetic tests are not informative, surgical removal and microscopic examination (biopsy) of affected muscle tissue that may reveal characteristic changes to muscle fibers. Specialized blood tests (e.g. creatine kinase) that evaluate the presence and levels of certain proteins in muscle (immunohistochemistry) are also used.Molecular genetic tests involve the examination of deoxyribonucleic acid (DNA) to identify specific a genetic mutation including deletions, duplications or single point mutations. Samples of blood or muscles cells may be tested. These techniques can also be used to diagnosis DMD before birth (prenatally).Blood tests may reveal elevated levels of the creatine kinase (CK), an enzyme that is found in abnormally high levels when muscle is damaged. The detection of elevated CK levels (usually in the thousands or ten thousands range) can confirm that muscle is damaged or inflamed, but cannot confirm a diagnosis of DMD.In some cases, a specialized test can be performed on muscle biopsy samples that can determine the presence and levels of specific proteins within cells. Various techniques such as immunostaining, immunofluorescence or Western blot (immunoblot) can be used. These tests involve the use of certain antibodies that react to certain proteins such as dystrophin. Tissue samples from muscle biopsies are exposed to these antibodies and the results can determine whether a specific muscle protein is present in the cells and in what quantity or what size. | 385 | Duchenne Muscular Dystrophy |
nord_385_6 | Therapies of Duchenne Muscular Dystrophy | Treatment
No curative treatment exists for DMD. Treatments are aimed at the specific symptoms present in each individual. Treatment options should include physical therapy and active and passive exercise to build muscle strength and prevent contractures. Surgery may be recommended in some patients to treat contractures or scoliosis. Braces may be used to prevent the development of contractures. The use of mechanical aids (e.g., canes, braces, and wheelchairs) may become necessary to aid walking (ambulation).Corticosteroids are used as standard of care to treat individuals with DMD. These drugs slow the progression of muscle weakness in affected individuals and delay the loss of ambulation by 2-3 years. Two common corticosteroid drugs used to treat individuals with DMD are prednisone and deflazacort (which is not available in the United States).In 2016, Exondys 51 (eteplirsen) injection was FDA approved to treat DMD and is the first drug approved for this condition. Exondys 51 is specifically indicated for patients who have a confirmed mutation of the dystrophin gene amenable to exon 51 skipping, which affects about 13 percent of the population with DMD. In 2017, Emflaza (deflazacort) was FDA approved to treat patients age 5 years and older with DMD. In 2019 and 2020 respectively, the FDA approved Vyondys 53 (golodirsen) and Viltepso (viltolarsen) to treat patients with DMD who have a confirmed mutation of the dystrophin gene that is amenable to exon 53 skipping, which affects about 8 percent of patients with DMD. In 2021, the FDA approved Amondys 45 (casimersen) to treat patients with DMD who have a confirmed mutation of the DMD gene that is amenable to exon 45 skipping. This mutation occurs in approximately 8 percent of patients with DMD. Amondys 45 is the first FDA-approved targeted treatment for patients with this type of mutation. In 2023, the FDA approved the first gene therapy for DMD. Elevidys was approved to treat children aged 4-5 who have a confirmed mutation in the DMD gene. Clinical Testing and Work-Up
Children diagnosed with DMD should be monitored regularly for potential heart involvement. In some individuals, severe respiratory distress may necessitate the use of ventilator to assist breathing.Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive. | Therapies of Duchenne Muscular Dystrophy. Treatment
No curative treatment exists for DMD. Treatments are aimed at the specific symptoms present in each individual. Treatment options should include physical therapy and active and passive exercise to build muscle strength and prevent contractures. Surgery may be recommended in some patients to treat contractures or scoliosis. Braces may be used to prevent the development of contractures. The use of mechanical aids (e.g., canes, braces, and wheelchairs) may become necessary to aid walking (ambulation).Corticosteroids are used as standard of care to treat individuals with DMD. These drugs slow the progression of muscle weakness in affected individuals and delay the loss of ambulation by 2-3 years. Two common corticosteroid drugs used to treat individuals with DMD are prednisone and deflazacort (which is not available in the United States).In 2016, Exondys 51 (eteplirsen) injection was FDA approved to treat DMD and is the first drug approved for this condition. Exondys 51 is specifically indicated for patients who have a confirmed mutation of the dystrophin gene amenable to exon 51 skipping, which affects about 13 percent of the population with DMD. In 2017, Emflaza (deflazacort) was FDA approved to treat patients age 5 years and older with DMD. In 2019 and 2020 respectively, the FDA approved Vyondys 53 (golodirsen) and Viltepso (viltolarsen) to treat patients with DMD who have a confirmed mutation of the dystrophin gene that is amenable to exon 53 skipping, which affects about 8 percent of patients with DMD. In 2021, the FDA approved Amondys 45 (casimersen) to treat patients with DMD who have a confirmed mutation of the DMD gene that is amenable to exon 45 skipping. This mutation occurs in approximately 8 percent of patients with DMD. Amondys 45 is the first FDA-approved targeted treatment for patients with this type of mutation. In 2023, the FDA approved the first gene therapy for DMD. Elevidys was approved to treat children aged 4-5 who have a confirmed mutation in the DMD gene. Clinical Testing and Work-Up
Children diagnosed with DMD should be monitored regularly for potential heart involvement. In some individuals, severe respiratory distress may necessitate the use of ventilator to assist breathing.Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive. | 385 | Duchenne Muscular Dystrophy |
nord_386_0 | Overview of Duodenal Atresia or Stenosis | Duodenal atresia or stenosis is a rare congenital digestive disorder that usually occurs for no apparent reason (sporadically). However, a few cases of duodenal atresia have been inherited as an autosomal recessive genetic trait.Duodenal atresia is a disease of newborn infants. Absence or complete closure (atresia) of a portion of the channel (lumen) within the first part of the small intestine (duodenum), or partial obstruction due to narrowing (stenosis) of the duodenum, is present. Other associated abnormalities may be found in over half of those affected with duodenal atresia or duodenal stenosis. | Overview of Duodenal Atresia or Stenosis. Duodenal atresia or stenosis is a rare congenital digestive disorder that usually occurs for no apparent reason (sporadically). However, a few cases of duodenal atresia have been inherited as an autosomal recessive genetic trait.Duodenal atresia is a disease of newborn infants. Absence or complete closure (atresia) of a portion of the channel (lumen) within the first part of the small intestine (duodenum), or partial obstruction due to narrowing (stenosis) of the duodenum, is present. Other associated abnormalities may be found in over half of those affected with duodenal atresia or duodenal stenosis. | 386 | Duodenal Atresia or Stenosis |
nord_386_1 | Symptoms of Duodenal Atresia or Stenosis | Duodenal atresia and duodenal stenosis are abnormalities in which there is an absence or complete closure (atresia) in the first part of the small intestines (duodenum) or narrowing (stenosis) of the duodenum. These obstructions in the digestive tract of infants prevent proper absorption of food.The defect in the duodenum may be located in the area where the pancreatic and bile ducts join as they open into the first part of the small intestines (ampulla of Vater,) or in the portion of the duodenum furthest from the opening of the ampulla of Vater. There may be an absence of the channel at the top of the small intestine, a ring or web in the duodenum, an abnormally small channel at the top of the small intestines, or the duodenum may end with just a short chord going to the bowel.Symptoms of a complete blockage of the duodenum may include bilious vomiting (a yellow-green secretion arising from the liver or in some cases a clear or light brown granular matter) typically beginning a few hours after birth, distention or swelling of the upper abdomen, constipation resistant to treatment, a yellow discoloration of the skin (jaundice) and/or an excess of amniotic fluid detected before birth (polyhydramnios) through ultrasound.Symptoms of partial duodenal blockage vary depending on the severity. They may wax and wane not appearing for weeks, months, or years. Prolonged vomiting along with dehydration may also occur.Other problems associated with this disorder may include intestines that are shorter than normal, low birth weight, premature birth, and/or an imbalance of electrolytes (the elements in the blood, tissue, and cell fluid needed in correct amounts for the use of energy).Associated abnormalities have been found in some infants with duodenal atresia or duodenal stenosis. Twenty to thirty percent of individuals affected with these disorders have Down syndrome and twenty-two percent have heart disease. An abnormal rotation of the colon, a ring shaped pancreas encircling a portion of the duodenum (annulas pancreas), an abnormal tubelike passage between the windpipe and esophagus (tracheoesophageal fistula), and/or kidney malformations can also be associated with these conditions. (For more information on these disorders choose “Esophageal Atresia”, “Down Syndrome”, and/or “Tracheoesophageal Fistula” as your search terms in the Rare Disease Database). | Symptoms of Duodenal Atresia or Stenosis. Duodenal atresia and duodenal stenosis are abnormalities in which there is an absence or complete closure (atresia) in the first part of the small intestines (duodenum) or narrowing (stenosis) of the duodenum. These obstructions in the digestive tract of infants prevent proper absorption of food.The defect in the duodenum may be located in the area where the pancreatic and bile ducts join as they open into the first part of the small intestines (ampulla of Vater,) or in the portion of the duodenum furthest from the opening of the ampulla of Vater. There may be an absence of the channel at the top of the small intestine, a ring or web in the duodenum, an abnormally small channel at the top of the small intestines, or the duodenum may end with just a short chord going to the bowel.Symptoms of a complete blockage of the duodenum may include bilious vomiting (a yellow-green secretion arising from the liver or in some cases a clear or light brown granular matter) typically beginning a few hours after birth, distention or swelling of the upper abdomen, constipation resistant to treatment, a yellow discoloration of the skin (jaundice) and/or an excess of amniotic fluid detected before birth (polyhydramnios) through ultrasound.Symptoms of partial duodenal blockage vary depending on the severity. They may wax and wane not appearing for weeks, months, or years. Prolonged vomiting along with dehydration may also occur.Other problems associated with this disorder may include intestines that are shorter than normal, low birth weight, premature birth, and/or an imbalance of electrolytes (the elements in the blood, tissue, and cell fluid needed in correct amounts for the use of energy).Associated abnormalities have been found in some infants with duodenal atresia or duodenal stenosis. Twenty to thirty percent of individuals affected with these disorders have Down syndrome and twenty-two percent have heart disease. An abnormal rotation of the colon, a ring shaped pancreas encircling a portion of the duodenum (annulas pancreas), an abnormal tubelike passage between the windpipe and esophagus (tracheoesophageal fistula), and/or kidney malformations can also be associated with these conditions. (For more information on these disorders choose “Esophageal Atresia”, “Down Syndrome”, and/or “Tracheoesophageal Fistula” as your search terms in the Rare Disease Database). | 386 | Duodenal Atresia or Stenosis |
nord_386_2 | Causes of Duodenal Atresia or Stenosis | The majority of cases of duodenal atresia or stenosis occur for no apparent reason (sporadically). There are two theories as to why the abnormalities may occur. Blood vessel defects in the embryo may cause the absence or closure of the duodenum by decreasing the blood supply in the affected area, or there may be an overgrowth of cells in the duodenum that obstruct the channel of the first part of the duodenum (lumen) occuring during the sixth or seventh week of fetal development.A few cases of duodenal atresia have been inherited as an autosomal recessive genetic trait. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother. In recessive disorders, the condition does not appear unless a person inherits the same defective gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease, but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy. | Causes of Duodenal Atresia or Stenosis. The majority of cases of duodenal atresia or stenosis occur for no apparent reason (sporadically). There are two theories as to why the abnormalities may occur. Blood vessel defects in the embryo may cause the absence or closure of the duodenum by decreasing the blood supply in the affected area, or there may be an overgrowth of cells in the duodenum that obstruct the channel of the first part of the duodenum (lumen) occuring during the sixth or seventh week of fetal development.A few cases of duodenal atresia have been inherited as an autosomal recessive genetic trait. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother. In recessive disorders, the condition does not appear unless a person inherits the same defective gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease, but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy. | 386 | Duodenal Atresia or Stenosis |
nord_386_3 | Affects of Duodenal Atresia or Stenosis | Duodenal atresia or stenosis is a rare disorder that occurs in approximately 1 of 7,500 live births to 1 of 40,000 live births. In Finland, the rate goes up to 1 case per 3,400 live births. Males and females are affected in equal numbers. | Affects of Duodenal Atresia or Stenosis. Duodenal atresia or stenosis is a rare disorder that occurs in approximately 1 of 7,500 live births to 1 of 40,000 live births. In Finland, the rate goes up to 1 case per 3,400 live births. Males and females are affected in equal numbers. | 386 | Duodenal Atresia or Stenosis |
nord_386_4 | Related disorders of Duodenal Atresia or Stenosis | Symptoms of the following disorders can be similar to those of duodenal atresia or stenosis. Comparisons may be useful for a differential diagnosis:Jejunal atresia is a birth defect in which there is a partial absence of the fold of the stomach membrane that connects the small intestine to the back wall of the abdomen. This abnormality causes a portion of the small intestine (the jejunal) to twist around one of the arteries of the colon. The appearance of this condition resembles a Christmas tree or apple peel when viewed by a surgeon. Jejunal atresia may be inherited as an autosomal recessive genetic trait, or may occur sporadically with no known cause. (For more information on this disorder, choose “Jejunal Atresia” as your search term in the Rare Disease Database.)Multiple intestinal atresia is a rare disorder in which there are multiple areas of the intestines with an absence of a normal opening or space. This causes an intestinal blockage. The atresias typically involve: the shortest, widest part of the small intestine that joins the stomach (duodenum); one of the three portions of the small intestines that connects with the duodenum (jejunum); or the portion of the small intestine that opens into the large intestine (ileum), and the rectum. Infants born with this condition may have persistent vomiting and may have swelling just below the breast bone, an empty anal canal, and a hollow or boat shaped abdomen (scaphoid abdomen).Pyloric stenosis is a digestive disorder that may be apparent soon after birth or during the first few months of life. It may also occur in adults. The development of forceful vomiting (projectile) immediately after eating or when the stomach is filled is one of the first symptoms. Because too little food reaches the intestines, constipation is a frequent complication, as is failure of the infant to gain weight. The signs and symptoms of adult pyloric stenosis are similar to those in the infant. | Related disorders of Duodenal Atresia or Stenosis. Symptoms of the following disorders can be similar to those of duodenal atresia or stenosis. Comparisons may be useful for a differential diagnosis:Jejunal atresia is a birth defect in which there is a partial absence of the fold of the stomach membrane that connects the small intestine to the back wall of the abdomen. This abnormality causes a portion of the small intestine (the jejunal) to twist around one of the arteries of the colon. The appearance of this condition resembles a Christmas tree or apple peel when viewed by a surgeon. Jejunal atresia may be inherited as an autosomal recessive genetic trait, or may occur sporadically with no known cause. (For more information on this disorder, choose “Jejunal Atresia” as your search term in the Rare Disease Database.)Multiple intestinal atresia is a rare disorder in which there are multiple areas of the intestines with an absence of a normal opening or space. This causes an intestinal blockage. The atresias typically involve: the shortest, widest part of the small intestine that joins the stomach (duodenum); one of the three portions of the small intestines that connects with the duodenum (jejunum); or the portion of the small intestine that opens into the large intestine (ileum), and the rectum. Infants born with this condition may have persistent vomiting and may have swelling just below the breast bone, an empty anal canal, and a hollow or boat shaped abdomen (scaphoid abdomen).Pyloric stenosis is a digestive disorder that may be apparent soon after birth or during the first few months of life. It may also occur in adults. The development of forceful vomiting (projectile) immediately after eating or when the stomach is filled is one of the first symptoms. Because too little food reaches the intestines, constipation is a frequent complication, as is failure of the infant to gain weight. The signs and symptoms of adult pyloric stenosis are similar to those in the infant. | 386 | Duodenal Atresia or Stenosis |
nord_386_5 | Diagnosis of Duodenal Atresia or Stenosis | Diagnosis of Duodenal Atresia or Stenosis. | 386 | Duodenal Atresia or Stenosis |
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nord_386_6 | Therapies of Duodenal Atresia or Stenosis | Duodenal atresia may be recognized through ultrasound by the presence of a "double bubble" which can be seen in the abdominal area. The earlier the disorder is recognized and surgery is performed, the better the outcome. Parenteral nutrition (food given through a vein or directly to the stomach, but not by mouth) may be needed for a period of time.The surgery most often performed is a duodenojejunostomy. This is a procedure in which a connection is formed between the duodenum and the jejunum.When the atresia is located in the first part of the duodenum, a gastrojejunostomy may be the treatment of choice. This is a procedure in which there is a surgical creation of a connection between the stomach and jejunum bypassing the obstruction.A duodenoduodenostomy is another surgical procedure sometimes used to create a connection or opening between the two portions of the divided duodenum.Genetic counseling may be of benefit for patients and their families with the hereditary form of the disorders. | Therapies of Duodenal Atresia or Stenosis. Duodenal atresia may be recognized through ultrasound by the presence of a "double bubble" which can be seen in the abdominal area. The earlier the disorder is recognized and surgery is performed, the better the outcome. Parenteral nutrition (food given through a vein or directly to the stomach, but not by mouth) may be needed for a period of time.The surgery most often performed is a duodenojejunostomy. This is a procedure in which a connection is formed between the duodenum and the jejunum.When the atresia is located in the first part of the duodenum, a gastrojejunostomy may be the treatment of choice. This is a procedure in which there is a surgical creation of a connection between the stomach and jejunum bypassing the obstruction.A duodenoduodenostomy is another surgical procedure sometimes used to create a connection or opening between the two portions of the divided duodenum.Genetic counseling may be of benefit for patients and their families with the hereditary form of the disorders. | 386 | Duodenal Atresia or Stenosis |
nord_387_0 | Overview of Dup15q Syndrome | SummaryChromosome 15q11.2-13.1 duplication syndrome (dup15q syndrome) is a clinically identifiable syndrome which results from duplications of the portion of 15q11.2-13.1 chromosome (also referred to as the Prader-Willi/Angelman critical region (PWACR). These duplications most commonly occur in one of two forms. These include an extra isodicentric 15 chromosome, abbreviated idic(15), or an interstitial duplication 15, abbreviated int dup(15). Dup15q syndrome is characterized by hypotonia and gross and fine motor delays, variable intellectual disability (ID), autism spectrum disorder (ASD), and epilepsy including infantile spasms. These clinical findings may differ significantly between people and is influenced by whether the duplication is inherited from an individual's mother or father (parent-of-origin) and number of copies of the PWACR. Those with a maternally-derived idic(15) and interstitial triplications are typically more severely affected than those with an int dup(15). However, the severity of features (phenotype) varies even among individuals within molecular groupings who have similar duplications based on breakpoints. Some phenotypic features, such as ASD, are more consistently observed in individuals with a maternal idic(15) or large (>5-Mb) interstitial duplications that extend beyond the PWACR. Idic(15) chromosomes reported to date are almost exclusively maternal in origin so the phenotype of a paternally derived idic(15) is unknown. Individuals with paternally derived int dup(15) typically do not manifest the full phenotype of dup15q syndrome (see below).IntroductionThis disorder was first characterized in the late 1990’s when maternally inherited supernumerary markers involving inverted duplications of PWS/AS region were linked to autism, ID and subtle but not yet recognizable clinical phenotype | Overview of Dup15q Syndrome. SummaryChromosome 15q11.2-13.1 duplication syndrome (dup15q syndrome) is a clinically identifiable syndrome which results from duplications of the portion of 15q11.2-13.1 chromosome (also referred to as the Prader-Willi/Angelman critical region (PWACR). These duplications most commonly occur in one of two forms. These include an extra isodicentric 15 chromosome, abbreviated idic(15), or an interstitial duplication 15, abbreviated int dup(15). Dup15q syndrome is characterized by hypotonia and gross and fine motor delays, variable intellectual disability (ID), autism spectrum disorder (ASD), and epilepsy including infantile spasms. These clinical findings may differ significantly between people and is influenced by whether the duplication is inherited from an individual's mother or father (parent-of-origin) and number of copies of the PWACR. Those with a maternally-derived idic(15) and interstitial triplications are typically more severely affected than those with an int dup(15). However, the severity of features (phenotype) varies even among individuals within molecular groupings who have similar duplications based on breakpoints. Some phenotypic features, such as ASD, are more consistently observed in individuals with a maternal idic(15) or large (>5-Mb) interstitial duplications that extend beyond the PWACR. Idic(15) chromosomes reported to date are almost exclusively maternal in origin so the phenotype of a paternally derived idic(15) is unknown. Individuals with paternally derived int dup(15) typically do not manifest the full phenotype of dup15q syndrome (see below).IntroductionThis disorder was first characterized in the late 1990’s when maternally inherited supernumerary markers involving inverted duplications of PWS/AS region were linked to autism, ID and subtle but not yet recognizable clinical phenotype | 387 | Dup15q Syndrome |
nord_387_1 | Symptoms of Dup15q Syndrome | Two individuals with similar dup15q chromosomes based on breakpoints (BP) may be very different in terms of their abilities. However, the following features are found to some degree in most individuals with dup15q syndrome.Hypotonia in newborns and infants with dup15q is associated with feeding difficulties and most children manifest gross and fine motor delays. Although low muscle tone (hypotonia) in childhood impairs motor development, most children achieve independent walking after age two to three years (younger in children with an interstitial duplication).A wide-based or ataxic gait is common. Delays and persistent impairment in both fine and gross motor skills affect adaptive living skills and distinguish children with dup15q syndrome from children with nonsyndromic ASD. Global developmental delay in early childhood is nearly universal. This can be more specifically diagnosed as intellectual disability after age five years.Most children and adults with dup15q function in the moderate to severe range of intellectual disability; however, there is some variability, with a higher range of cognitive abilities seen in those with an interstitial duplication.Speech and language development is particularly affected, with universal delays ranging from moderate to severe. Some individuals exhibit echolalia, pronoun reversal, and stereotyped utterances, while others may lack functional speech. Most children and adults with dup15q syndrome meet criteria for ASD. Manifestations of ASD, particularly difficulties with social interaction, may increase from early to late childhood.Compared to children with nonsyndromic ASD, children with dup15q/ASD demonstrate a distinctive behavioral profile, including preserved responsive social smile and directed facial expressions towards others – features that may inform behavioral interventions.More than half of individuals with dup15q syndrome have epilepsy, usually involving multiple seizure types including infantile spasms and myoclonic, tonic-clonic, absence, and focal seizures. Seizures most often begin between ages six months and nine years. As many as 40% of individuals with seizures present initially with infantile spasms; of this group, approximately 90% subsequently develop other seizure types. Alternatively, individuals with dup15q may present with focal seizures only.Dup15q is one of the most common known causes of infantile spasms. Infantile spasms in dup15q often progress to Lennox Gastaut syndrome and other complex seizure patterns that may be difficult to control. Intractable epilepsy in dup15q may result in disabling secondary effects, including falls or developmental regression. This occurs in more than half of individuals with frequent, uncontrolled seizures or non-convulsive status epilepticus. In a small study, children with epilepsy were found to have lower cognitive and adaptive function than those without epilepsy.Abnormal (dysmorphic) facial features often reported in dup15q include flattened nasal bridge with a short-upturned nose, long philtrum, anteverted nostrils, downslanting palpebral fissures, micrognathia, low-set ears, flat occiput, low forehead, high-arched palate, and full lips. These features are typically subtle and missed in infancy.Although maternal idic(15) has been reported in schizophrenia, psychosis is not a commonly ascertained comorbidity in dup15q – a finding that may reflect the difficulty of recognizing and diagnosing psychosis in individuals with low cognitive functioning and limited verbal skills. For instance, psychosis is a common comorbidity in Prader-Willi syndrome caused by uniparental disomy, which similarly involves a duplication of the maternally contributed 15q11.2-13.1. These individuals tend to have higher cognitive and verbal abilities than individuals with dup15q. Conversely, with a high rate of ASD in dup15q, psychosis related to mood disorder may be misdiagnosed as schizophrenia.Sudden unexpected death in epilepsy (SUDEP) occurs in a small but significant minority of individuals with dup15q. In dup15q, these deaths almost always occur during sleep and most (though not all) have occurred in teenagers and young adults with epilepsy.SUDEP also occurs in other neurodevelopmental disorders involving severe cognitive impairments and treatment-resistant epilepsy. The mechanism underlying SUDEP is not well understood; however, available evidence suggests that in most cases a tonic-clonic seizure is followed by a shut-down of brain function and cardio-respiratory arrest. SUDEP occurs in 9% of individuals with epilepsy; the rate of SUDEP in dup15q is unknown. | Symptoms of Dup15q Syndrome. Two individuals with similar dup15q chromosomes based on breakpoints (BP) may be very different in terms of their abilities. However, the following features are found to some degree in most individuals with dup15q syndrome.Hypotonia in newborns and infants with dup15q is associated with feeding difficulties and most children manifest gross and fine motor delays. Although low muscle tone (hypotonia) in childhood impairs motor development, most children achieve independent walking after age two to three years (younger in children with an interstitial duplication).A wide-based or ataxic gait is common. Delays and persistent impairment in both fine and gross motor skills affect adaptive living skills and distinguish children with dup15q syndrome from children with nonsyndromic ASD. Global developmental delay in early childhood is nearly universal. This can be more specifically diagnosed as intellectual disability after age five years.Most children and adults with dup15q function in the moderate to severe range of intellectual disability; however, there is some variability, with a higher range of cognitive abilities seen in those with an interstitial duplication.Speech and language development is particularly affected, with universal delays ranging from moderate to severe. Some individuals exhibit echolalia, pronoun reversal, and stereotyped utterances, while others may lack functional speech. Most children and adults with dup15q syndrome meet criteria for ASD. Manifestations of ASD, particularly difficulties with social interaction, may increase from early to late childhood.Compared to children with nonsyndromic ASD, children with dup15q/ASD demonstrate a distinctive behavioral profile, including preserved responsive social smile and directed facial expressions towards others – features that may inform behavioral interventions.More than half of individuals with dup15q syndrome have epilepsy, usually involving multiple seizure types including infantile spasms and myoclonic, tonic-clonic, absence, and focal seizures. Seizures most often begin between ages six months and nine years. As many as 40% of individuals with seizures present initially with infantile spasms; of this group, approximately 90% subsequently develop other seizure types. Alternatively, individuals with dup15q may present with focal seizures only.Dup15q is one of the most common known causes of infantile spasms. Infantile spasms in dup15q often progress to Lennox Gastaut syndrome and other complex seizure patterns that may be difficult to control. Intractable epilepsy in dup15q may result in disabling secondary effects, including falls or developmental regression. This occurs in more than half of individuals with frequent, uncontrolled seizures or non-convulsive status epilepticus. In a small study, children with epilepsy were found to have lower cognitive and adaptive function than those without epilepsy.Abnormal (dysmorphic) facial features often reported in dup15q include flattened nasal bridge with a short-upturned nose, long philtrum, anteverted nostrils, downslanting palpebral fissures, micrognathia, low-set ears, flat occiput, low forehead, high-arched palate, and full lips. These features are typically subtle and missed in infancy.Although maternal idic(15) has been reported in schizophrenia, psychosis is not a commonly ascertained comorbidity in dup15q – a finding that may reflect the difficulty of recognizing and diagnosing psychosis in individuals with low cognitive functioning and limited verbal skills. For instance, psychosis is a common comorbidity in Prader-Willi syndrome caused by uniparental disomy, which similarly involves a duplication of the maternally contributed 15q11.2-13.1. These individuals tend to have higher cognitive and verbal abilities than individuals with dup15q. Conversely, with a high rate of ASD in dup15q, psychosis related to mood disorder may be misdiagnosed as schizophrenia.Sudden unexpected death in epilepsy (SUDEP) occurs in a small but significant minority of individuals with dup15q. In dup15q, these deaths almost always occur during sleep and most (though not all) have occurred in teenagers and young adults with epilepsy.SUDEP also occurs in other neurodevelopmental disorders involving severe cognitive impairments and treatment-resistant epilepsy. The mechanism underlying SUDEP is not well understood; however, available evidence suggests that in most cases a tonic-clonic seizure is followed by a shut-down of brain function and cardio-respiratory arrest. SUDEP occurs in 9% of individuals with epilepsy; the rate of SUDEP in dup15q is unknown. | 387 | Dup15q Syndrome |
nord_387_2 | Causes of Dup15q Syndrome | Dup15q syndrome is caused by presence of at least one extra maternally derived copy of the PWACR within chromosome 15q11.2-q13.1. The extra copy or copies most commonly arise by one of two mechanisms:Duplications may vary in size and have been seen up to 12 Mb long (as seen here) but must contain the PWACR to be causative of dup15q syndrome.Although several genes of interest (e.g., ATP10A, CYFIP1, MAGEL2, NECDIN, SNRPN, UBE3A, snoRNAs, and a cluster of genes encoding GABAA receptor subunits) are within the 4.5- to 12-Mb recurrent duplication, no single gene that – when duplicated – causes dup15q has been identified. | Causes of Dup15q Syndrome. Dup15q syndrome is caused by presence of at least one extra maternally derived copy of the PWACR within chromosome 15q11.2-q13.1. The extra copy or copies most commonly arise by one of two mechanisms:Duplications may vary in size and have been seen up to 12 Mb long (as seen here) but must contain the PWACR to be causative of dup15q syndrome.Although several genes of interest (e.g., ATP10A, CYFIP1, MAGEL2, NECDIN, SNRPN, UBE3A, snoRNAs, and a cluster of genes encoding GABAA receptor subunits) are within the 4.5- to 12-Mb recurrent duplication, no single gene that – when duplicated – causes dup15q has been identified. | 387 | Dup15q Syndrome |
nord_387_3 | Affects of Dup15q Syndrome | The prevalence of dup15q in the general population is unknown but may be as high as 1:5000. Dup15q is one of the most common chromosome (cytogenetic) anomalies in persons with ASD. In patients referred for clinical chromosomal microarray analysis (CMA) testing due to developmental concerns (developmental delay, intellectual disability, or ASD) or multiple congenital anomalies, the prevalence of dup15q is approximately 1:508. In ASD cohorts, the prevalence of dup15q is 1:253-1:522. In intellectual disability cohorts, the prevalence of dup15q is 1:584. | Affects of Dup15q Syndrome. The prevalence of dup15q in the general population is unknown but may be as high as 1:5000. Dup15q is one of the most common chromosome (cytogenetic) anomalies in persons with ASD. In patients referred for clinical chromosomal microarray analysis (CMA) testing due to developmental concerns (developmental delay, intellectual disability, or ASD) or multiple congenital anomalies, the prevalence of dup15q is approximately 1:508. In ASD cohorts, the prevalence of dup15q is 1:253-1:522. In intellectual disability cohorts, the prevalence of dup15q is 1:584. | 387 | Dup15q Syndrome |
nord_387_4 | Related disorders of Dup15q Syndrome | Paternal interstitial duplications of 15q11.2-q13.1: Because this duplicated region is imprinted, the phenotypes resulting from paternal and maternal duplications differ: paternal interstitial duplications are associated with a more variable phenotype that includes sleep concerns such as parasomnia (abnormal or unusual behavior during sleep). Clinical findings, particularly autistic features, may be present in up to 50% of affected individuals [Urraca et al 2013]. Because there is some overlap in the phenotypic features of maternal and paternal duplications, parent-of-origin testing should be performed to determine whether a patient has dup15q syndrome or a paternal interstitial duplication.Prader-Willi syndrome (PWS): is caused by a deletion, uniparental disomy, or an imprinting defect that results in the loss of the paternally contributed 15q11.2-q13.1 region. Despite some phenotypic similarities, PWS is distinct from dup15q: individuals with PWS typically have characteristic facial features, infantile hypotonia, hypogonadism, mild intellectual disability, hyperphagia, and obsessive-compulsive behaviors [Cassidy & Driscoll 2009]. Individuals with PWS are also verbal and typically have milder cognitive impairment (average IQ: 60-70s) than individuals with dup15q [Cassidy & Driscoll 2009].Angelman syndrome (AS) is caused by a deletion, uniparental disomy, imprinting defect, or mutation of the UBE3A gene that results in a loss of function of the maternally contributed UBE3A gene. AS is distinct from both PWS and dup15q and is characterized by distinctive facial features, severe intellectual disability, profound expressive language impairment, seizures, ataxia, and an unusually happy or excitable disposition [Dagli et al 2012].Deletions involving 15q11.2 or 15q13.3 – both of which flank but do not include the PWACR – can be pathogenic with distinct neurobehavioral phenotypes.Duplications involving 15q11.2 or 15q13.3 but not the PWACR have been implicated in developmental delay and autism [Miller et al 2009, van Bon et al 2009, Burnside et al 2011], but are considered variants of uncertain significance [Kaminsky et al 2011, Chaste et al 2014].Differential Diagnosis
Classic Rett syndrome is a neurodevelopmental disorder caused by mutation of the X-linked gene MECP2 [Chahrour & Zoghbi 2007]. Rett syndrome is primarily seen in females and assumed to be fatal in most males. Features of classic Rett syndrome include normal development in the first six to 18 months of life followed by developmental stagnation, rapid regression of skills across developmental domains, and stabilization. A hallmark feature of Rett syndrome is the replacement of purposeful hand use with repetitive, stereotypic hand movements. Additional features include absent speech, bruxism (teeth grinding), disordered breathing, sleep disturbances, autistic features, seizures, and unprovoked crying or screaming.Findings similar to those of dup15q syndrome include motor and language impairments, autistic features, and seizures. However, individuals with dup15q:
Pathogenic variants in CDKL5, an X-linked gene, have been identified in (1) females with early-onset severe seizures who have poor cognitive development but little in the way of Rett syndrome-like features [Archer et al 2006, Bahi-Buisson et al 2008] and (2) males with severe-to-profound intellectual disability and early-onset intractable seizures [Elia et al 2008].
Individuals with dup15q and those with pathogenic CDKL5 variants can both present with severe cognitive delays, intellectual disability, and early-onset seizures; however, moderate-to-severe infantile hypotonia is more characteristic of dup15q. | Related disorders of Dup15q Syndrome. Paternal interstitial duplications of 15q11.2-q13.1: Because this duplicated region is imprinted, the phenotypes resulting from paternal and maternal duplications differ: paternal interstitial duplications are associated with a more variable phenotype that includes sleep concerns such as parasomnia (abnormal or unusual behavior during sleep). Clinical findings, particularly autistic features, may be present in up to 50% of affected individuals [Urraca et al 2013]. Because there is some overlap in the phenotypic features of maternal and paternal duplications, parent-of-origin testing should be performed to determine whether a patient has dup15q syndrome or a paternal interstitial duplication.Prader-Willi syndrome (PWS): is caused by a deletion, uniparental disomy, or an imprinting defect that results in the loss of the paternally contributed 15q11.2-q13.1 region. Despite some phenotypic similarities, PWS is distinct from dup15q: individuals with PWS typically have characteristic facial features, infantile hypotonia, hypogonadism, mild intellectual disability, hyperphagia, and obsessive-compulsive behaviors [Cassidy & Driscoll 2009]. Individuals with PWS are also verbal and typically have milder cognitive impairment (average IQ: 60-70s) than individuals with dup15q [Cassidy & Driscoll 2009].Angelman syndrome (AS) is caused by a deletion, uniparental disomy, imprinting defect, or mutation of the UBE3A gene that results in a loss of function of the maternally contributed UBE3A gene. AS is distinct from both PWS and dup15q and is characterized by distinctive facial features, severe intellectual disability, profound expressive language impairment, seizures, ataxia, and an unusually happy or excitable disposition [Dagli et al 2012].Deletions involving 15q11.2 or 15q13.3 – both of which flank but do not include the PWACR – can be pathogenic with distinct neurobehavioral phenotypes.Duplications involving 15q11.2 or 15q13.3 but not the PWACR have been implicated in developmental delay and autism [Miller et al 2009, van Bon et al 2009, Burnside et al 2011], but are considered variants of uncertain significance [Kaminsky et al 2011, Chaste et al 2014].Differential Diagnosis
Classic Rett syndrome is a neurodevelopmental disorder caused by mutation of the X-linked gene MECP2 [Chahrour & Zoghbi 2007]. Rett syndrome is primarily seen in females and assumed to be fatal in most males. Features of classic Rett syndrome include normal development in the first six to 18 months of life followed by developmental stagnation, rapid regression of skills across developmental domains, and stabilization. A hallmark feature of Rett syndrome is the replacement of purposeful hand use with repetitive, stereotypic hand movements. Additional features include absent speech, bruxism (teeth grinding), disordered breathing, sleep disturbances, autistic features, seizures, and unprovoked crying or screaming.Findings similar to those of dup15q syndrome include motor and language impairments, autistic features, and seizures. However, individuals with dup15q:
Pathogenic variants in CDKL5, an X-linked gene, have been identified in (1) females with early-onset severe seizures who have poor cognitive development but little in the way of Rett syndrome-like features [Archer et al 2006, Bahi-Buisson et al 2008] and (2) males with severe-to-profound intellectual disability and early-onset intractable seizures [Elia et al 2008].
Individuals with dup15q and those with pathogenic CDKL5 variants can both present with severe cognitive delays, intellectual disability, and early-onset seizures; however, moderate-to-severe infantile hypotonia is more characteristic of dup15q. | 387 | Dup15q Syndrome |
nord_387_5 | Diagnosis of Dup15q Syndrome | The diagnosis of Ddup15q syndrome is established by detection of at least one extra maternally derived copy of the PWACR, a region approximately 5 Mb long within chromosome 15q11.2-q13.1.Dup 15q should be suspected in individuals with any of the following; moderate to severe hypotonia in infancy and motor delays, developmental delay which can manifest as ID and/or speech and language delays, ASD, seizures, particularly infantile spasms. Also seen frequently in individuals with dup15q are mild-to-moderate dysmorphic features including upturned nose, epicanthal folds, and downslanting palpebral fissures and behavioral difficulties including hyperactivity, anxiety, or emotional lability.Genomic testing methods that determine the copy number of sequences can include chromosomal microarray analysis (CMA) or targeted duplication analysis. Note: (1) Interstitial 15q11.2-q13.1 duplications cannot typically be identified by routine analysis of G-banded chromosomes or other conventional cytogenetic banding techniques; however, idic(15) and large interstitial duplications (>5 Mb) that extend beyond the PWACR can be identified through cytogenetic analysis. (2) The presence of two or more populations of cells with different genotypes in one individual (mosaicism) has been reported for idic(15) which may affect the phenotype and the sensitivity of genomic testing strategies used for diagnosis.Parent-of-origin of the 15q11.2-q13.1 duplication is identified by genotyping or methylation analysis, including PCR-based methylation analysis [Zielinski et al 1988, Urraca et al 2010] or identification of a 15q11.2-q13.1 interstitial duplication in a parental sample.Prenatal testing or preimplantation genetic diagnosis using CMA will detect the 15q interstitial duplication; however, prenatal test results cannot reliably predict the severity of the phenotype even in a pregnancy known to be at increased risk for dup15q. All families should be referred for qualified genetic counseling. | Diagnosis of Dup15q Syndrome. The diagnosis of Ddup15q syndrome is established by detection of at least one extra maternally derived copy of the PWACR, a region approximately 5 Mb long within chromosome 15q11.2-q13.1.Dup 15q should be suspected in individuals with any of the following; moderate to severe hypotonia in infancy and motor delays, developmental delay which can manifest as ID and/or speech and language delays, ASD, seizures, particularly infantile spasms. Also seen frequently in individuals with dup15q are mild-to-moderate dysmorphic features including upturned nose, epicanthal folds, and downslanting palpebral fissures and behavioral difficulties including hyperactivity, anxiety, or emotional lability.Genomic testing methods that determine the copy number of sequences can include chromosomal microarray analysis (CMA) or targeted duplication analysis. Note: (1) Interstitial 15q11.2-q13.1 duplications cannot typically be identified by routine analysis of G-banded chromosomes or other conventional cytogenetic banding techniques; however, idic(15) and large interstitial duplications (>5 Mb) that extend beyond the PWACR can be identified through cytogenetic analysis. (2) The presence of two or more populations of cells with different genotypes in one individual (mosaicism) has been reported for idic(15) which may affect the phenotype and the sensitivity of genomic testing strategies used for diagnosis.Parent-of-origin of the 15q11.2-q13.1 duplication is identified by genotyping or methylation analysis, including PCR-based methylation analysis [Zielinski et al 1988, Urraca et al 2010] or identification of a 15q11.2-q13.1 interstitial duplication in a parental sample.Prenatal testing or preimplantation genetic diagnosis using CMA will detect the 15q interstitial duplication; however, prenatal test results cannot reliably predict the severity of the phenotype even in a pregnancy known to be at increased risk for dup15q. All families should be referred for qualified genetic counseling. | 387 | Dup15q Syndrome |
nord_387_6 | Therapies of Dup15q Syndrome | To establish the extent of disease and needs in an individual diagnosed with dup15q syndrome a complete review of systems, a physical examination, assessments of possible feeding difficulties associated with hypotonia, neurologic examinations including assessment for seizure activity and baseline EEG and consultation with a clinical geneticist and/or genetic counselor are recommended. A need for ongoing specialist care is frequent.Treatment of Manifestations: It is suggested that a multidisciplinary team evaluate infants for motor and speech development and later assist in referrals for appropriate educational programs. Supportive care may include: occupational and physical therapy, alternative and augmentative communication, behavioral therapy (e.g., applied behavioral analysis therapy), psychotropic medications for behavioral manifestations, and standard management for seizures. It is also notable that behavioral changes may be indicators of physical problems such as constipation or pain and individuals should be carefully examined if there is acute change in behavior.Surveillance: Periodic: neurodevelopmental and/or developmental/behavioral assessments, and monitoring for evidence of seizures and/or change in seizure type.Agents/circumstances to avoid: Seizure triggers (e.g., sleep deprivation, stress) and failure to follow medication regimen.Evaluation of relatives at risk: Consider genetic testing of siblings of a patient (known to be at increased risk for an inherited maternal interstitial 15q11.2-q13.1 duplication) in order to refer those with the interstitial duplication promptly for multidisciplinary team evaluation. | Therapies of Dup15q Syndrome. To establish the extent of disease and needs in an individual diagnosed with dup15q syndrome a complete review of systems, a physical examination, assessments of possible feeding difficulties associated with hypotonia, neurologic examinations including assessment for seizure activity and baseline EEG and consultation with a clinical geneticist and/or genetic counselor are recommended. A need for ongoing specialist care is frequent.Treatment of Manifestations: It is suggested that a multidisciplinary team evaluate infants for motor and speech development and later assist in referrals for appropriate educational programs. Supportive care may include: occupational and physical therapy, alternative and augmentative communication, behavioral therapy (e.g., applied behavioral analysis therapy), psychotropic medications for behavioral manifestations, and standard management for seizures. It is also notable that behavioral changes may be indicators of physical problems such as constipation or pain and individuals should be carefully examined if there is acute change in behavior.Surveillance: Periodic: neurodevelopmental and/or developmental/behavioral assessments, and monitoring for evidence of seizures and/or change in seizure type.Agents/circumstances to avoid: Seizure triggers (e.g., sleep deprivation, stress) and failure to follow medication regimen.Evaluation of relatives at risk: Consider genetic testing of siblings of a patient (known to be at increased risk for an inherited maternal interstitial 15q11.2-q13.1 duplication) in order to refer those with the interstitial duplication promptly for multidisciplinary team evaluation. | 387 | Dup15q Syndrome |
nord_388_0 | Overview of Dyggve Melchior Clausen syndrome | Dyggve-Melchior-Clausen syndrome (DMC) is a rare, progressive genetic disorder characterized by abnormal skeletal development, microcephaly and intellectual disability. The condition was first reported by Dyggve, Melchior and Clausen in 1962 in three of eight siblings where the father was the mother's paternal uncle. Because of physical appearance and the present of acid mucopolysaccharides in the urine, these authors believed that their affected patients had Morquio-Ullrich disease (now Morquio syndrome). Skeletal abnormalities in this condition may include a barrel-shaped chest with a short truck, partial dislocation of the hips, genu valgum (knocked knees) or varum (bowed legs), and decreased joint mobility. In 11% of patients, there is atlantoaxial (upper neck vertebrae) instability that can lead to spinal cord compression, weakness and paralysis (Kandziora et al. 2002). Normally, there is growth deficiency resulting in short stature. Radiographic findings in older children and adults are pathognomonic for the disorder (Aglan at et. 2009). DMC results from mutations in the DYM (dymeclin) gene and is inherited in an autosomal recessive mode.A variant of DMC syndrome, Smith-McCort syndrome (SMS), which was first described by Smith and McCort in 1958, has identical skeletal abnormalities, but lacks both the intellectual disability and microcephaly (Burns et al. 2003; Neumann et al. 2006; Santos et al. 2009). SMS is also caused by mutations in DYM, and thus is allelic to DMC (Santos et al. 2009). Both are classified as osteochondrodysplasias, specifically a spondyloepimetaphyseal dysplasia; this latter category of dysplasias consists of 28 separate disorders (Lachman 2007, pp. 934-6). | Overview of Dyggve Melchior Clausen syndrome. Dyggve-Melchior-Clausen syndrome (DMC) is a rare, progressive genetic disorder characterized by abnormal skeletal development, microcephaly and intellectual disability. The condition was first reported by Dyggve, Melchior and Clausen in 1962 in three of eight siblings where the father was the mother's paternal uncle. Because of physical appearance and the present of acid mucopolysaccharides in the urine, these authors believed that their affected patients had Morquio-Ullrich disease (now Morquio syndrome). Skeletal abnormalities in this condition may include a barrel-shaped chest with a short truck, partial dislocation of the hips, genu valgum (knocked knees) or varum (bowed legs), and decreased joint mobility. In 11% of patients, there is atlantoaxial (upper neck vertebrae) instability that can lead to spinal cord compression, weakness and paralysis (Kandziora et al. 2002). Normally, there is growth deficiency resulting in short stature. Radiographic findings in older children and adults are pathognomonic for the disorder (Aglan at et. 2009). DMC results from mutations in the DYM (dymeclin) gene and is inherited in an autosomal recessive mode.A variant of DMC syndrome, Smith-McCort syndrome (SMS), which was first described by Smith and McCort in 1958, has identical skeletal abnormalities, but lacks both the intellectual disability and microcephaly (Burns et al. 2003; Neumann et al. 2006; Santos et al. 2009). SMS is also caused by mutations in DYM, and thus is allelic to DMC (Santos et al. 2009). Both are classified as osteochondrodysplasias, specifically a spondyloepimetaphyseal dysplasia; this latter category of dysplasias consists of 28 separate disorders (Lachman 2007, pp. 934-6). | 388 | Dyggve Melchior Clausen syndrome |
nord_388_1 | Symptoms of Dyggve Melchior Clausen syndrome | Affected newborns may be small at birth, but otherwise appear normal. With age, other characteristics develop. For instance, chest deformities, feeding difficulties and developmental delay usually are manifest by or before 18 months. Disproportionate short stature, with the arms and legs being disproportionately too long for the torso, typically is present after 18 months. Additional clinical features that may also develop include dolichocephaly (a long skull), microcephaly (a small head), coarse facial appearance, prognathism (a protruding lower jaw). Intellectual disability ranges from moderate to severe, and worsens with age (Dgyyve et al. 1977; Aglan et al. 2009. Microcephaly occurs in most individuals. Thinning of the corpus callosum has also been reported (Dupuis et al. 2015). The overall health of an affected person is generally good and survival into adulthood is usual.In addition to the skeletal abnormalities listed above, affected individuals can also develop a short neck and chest, pectus carinatum (protruding breastbone), flaring of the costal margins, kyphosis (excessive backward curvature of the spine), lumbar lordosis (abnormal forward curvature of the spine), scoliosis (side-to-side curvature of the spine), claw-like hands, other joint contractures especially of the elbows and hips, genu valgum and talipes equinovarus (clubbed feet) (Aglan et al. 2009). Further, the metacarpals (bones in the middle of the hand) and phalanges (other bones in the fingers and toes) are shortened. The carpal bones (bones of the wrist) may also be small and irregularly shaped. Rhizomelic shortening of the limbs (disproportionate shortening of the proximal portion of the limbs) may be present also. Histologically, both DMC and SMS exhibit deficient chondrocytic organization and differentiation, and columnar formation that contain populations of degenerating cells with rough endoplasmic reticulum inclusions (Horton and Scott 1982; Nakamura 1997). On electron microscopic exam, the chondrocytes contain widened cisternae of the rough endoplasmic reticulum, and the vesicles are coated with a smooth single-layered membrane (Engfeldt et al. 1983; El Ghouzzi et al. 2003). The above findings suggest that lack of dymeclin may lead to abnormal processing or defective synthesis of cartilage protein (El Ghouzzi et al. 2003; Kinning et al. 2005).Other radiographic abnormalities seen in DMC have been extensively reviewed by Spranger et al. (1975) and include a small skull, hypoplastic facial bones, malformed or absent carpal bones, cone-shaped epiphyses of the phalanges, brachydactyly, fifth finger clinodactyly, accessory bones in the hands, odontoid hypoplasia (underdevelopment of the peg-like projection of the second cervical vertebra) with atlantoaxial instability (Kandziora et al. 2002; Girisha et al. 2008), platyspondyly (flattened vertebral bodies), irregular superior and inferior edges of the vertebral bodies, anterior pointing of the vertebral bodies, hypoplastic ilia (small hipbones), narrow sacrosciatic notch, widen pubic symphysis, dysplastic acetabulum (malformation of the hip socket), small femoral heads (proximal ends of the femurs), and broad metaphyses of the long bones (Aglan et al. 2009). Bone maturation (bone age) is delayed (Aglan et al. 2009). Individuals with Smith-McCort syndrome have similar skeletal findings as those associated with DMC.Secondary problems resulting from the skeletal abnormalities associated with DMC may include spinal compression, dislocated hips and restricted joint mobility. These problems may in turn cause a waddling gait. When it occurs, spinal cord compression in the neck is usually caused by the hypoplasia of the odontoid process and to hyperlaxity of the longitudinal ligament of the upper cervical spine. The pathognomonic radiographic findings for DMC and SMS include constrictions in the middle third of the vertebral bodies (a double-humped appearance), and a lacy appearance of the upper portion of the iliac crest (hipbone) (Hall-Craggs and Chapman 1987). This latter feature because less prominent with time and disappears by adulthood (Dyggve et al. 1977).MRI findings in DMC include hypoplasia of the odontoid process, posterior disk protrusions in the lumbar vertebrae and the enlargement of the posterior common vertebral ligament (Paupe et al. 2004; Carbonell et al. 2005; Aglan et al. 2009). In most individuals with DMC, MRI analyses of the brain have been normal (Paupe et al. 2004; Aglan et al. 2009). However, one patient has been reported with cortical atrophy (Aglan et al. 2009) and another with thinning of the corpus callosum (Dupuis et al. 2015).Both DMC and SMS are progressive disorders. With the exception of reduced length, affected individuals usually are normal at birth. Skeletal findings often are recognized first between 1 and 18 months. The vertebral body constriction abnormalities and lacy pattern of the iliac crests appear by 3-4 years and may persist until adulthood. The vertebral body constrictions are most prominent between ages 8 and 12 years (Aglan et al. 2009). The microcephaly in DMC and short stature in both appear during childhood. Throughout childhood and as adults, thoracic kyphosis, scoliosis, lumbar lordosis, subluxation (partial dislocation) and frank dislocation of the hips, wide-based and waddling gait, genu valgum or varum, and restricted joint mobility appear and may worsen. The treatment of genu varum in this condition has been reported (Kenis et al. 2011). Adult height is severely reduced with height ranging from 82 cm to 128 cm (32 in to 50 in). Neurologic and behavioral complications in DMC may include hyperactivity, autistic-like behavior, lack of speech and mild to severe intellectual disability with IQ scores ranging from 25 to 65 (Paupe et al. 2004). Because of the of atlantoaxial instability found in DMC, cord compression is a concern. However, only a few cases have been reported with this complication (Naffah and Taleb 1974). Prenatal diagnosis of DMC has been accomplished by finding a pathogenic homozygous mutation in the DYM gene in a fetus with no detectable physical findings (Toru et al. 2015). | Symptoms of Dyggve Melchior Clausen syndrome. Affected newborns may be small at birth, but otherwise appear normal. With age, other characteristics develop. For instance, chest deformities, feeding difficulties and developmental delay usually are manifest by or before 18 months. Disproportionate short stature, with the arms and legs being disproportionately too long for the torso, typically is present after 18 months. Additional clinical features that may also develop include dolichocephaly (a long skull), microcephaly (a small head), coarse facial appearance, prognathism (a protruding lower jaw). Intellectual disability ranges from moderate to severe, and worsens with age (Dgyyve et al. 1977; Aglan et al. 2009. Microcephaly occurs in most individuals. Thinning of the corpus callosum has also been reported (Dupuis et al. 2015). The overall health of an affected person is generally good and survival into adulthood is usual.In addition to the skeletal abnormalities listed above, affected individuals can also develop a short neck and chest, pectus carinatum (protruding breastbone), flaring of the costal margins, kyphosis (excessive backward curvature of the spine), lumbar lordosis (abnormal forward curvature of the spine), scoliosis (side-to-side curvature of the spine), claw-like hands, other joint contractures especially of the elbows and hips, genu valgum and talipes equinovarus (clubbed feet) (Aglan et al. 2009). Further, the metacarpals (bones in the middle of the hand) and phalanges (other bones in the fingers and toes) are shortened. The carpal bones (bones of the wrist) may also be small and irregularly shaped. Rhizomelic shortening of the limbs (disproportionate shortening of the proximal portion of the limbs) may be present also. Histologically, both DMC and SMS exhibit deficient chondrocytic organization and differentiation, and columnar formation that contain populations of degenerating cells with rough endoplasmic reticulum inclusions (Horton and Scott 1982; Nakamura 1997). On electron microscopic exam, the chondrocytes contain widened cisternae of the rough endoplasmic reticulum, and the vesicles are coated with a smooth single-layered membrane (Engfeldt et al. 1983; El Ghouzzi et al. 2003). The above findings suggest that lack of dymeclin may lead to abnormal processing or defective synthesis of cartilage protein (El Ghouzzi et al. 2003; Kinning et al. 2005).Other radiographic abnormalities seen in DMC have been extensively reviewed by Spranger et al. (1975) and include a small skull, hypoplastic facial bones, malformed or absent carpal bones, cone-shaped epiphyses of the phalanges, brachydactyly, fifth finger clinodactyly, accessory bones in the hands, odontoid hypoplasia (underdevelopment of the peg-like projection of the second cervical vertebra) with atlantoaxial instability (Kandziora et al. 2002; Girisha et al. 2008), platyspondyly (flattened vertebral bodies), irregular superior and inferior edges of the vertebral bodies, anterior pointing of the vertebral bodies, hypoplastic ilia (small hipbones), narrow sacrosciatic notch, widen pubic symphysis, dysplastic acetabulum (malformation of the hip socket), small femoral heads (proximal ends of the femurs), and broad metaphyses of the long bones (Aglan et al. 2009). Bone maturation (bone age) is delayed (Aglan et al. 2009). Individuals with Smith-McCort syndrome have similar skeletal findings as those associated with DMC.Secondary problems resulting from the skeletal abnormalities associated with DMC may include spinal compression, dislocated hips and restricted joint mobility. These problems may in turn cause a waddling gait. When it occurs, spinal cord compression in the neck is usually caused by the hypoplasia of the odontoid process and to hyperlaxity of the longitudinal ligament of the upper cervical spine. The pathognomonic radiographic findings for DMC and SMS include constrictions in the middle third of the vertebral bodies (a double-humped appearance), and a lacy appearance of the upper portion of the iliac crest (hipbone) (Hall-Craggs and Chapman 1987). This latter feature because less prominent with time and disappears by adulthood (Dyggve et al. 1977).MRI findings in DMC include hypoplasia of the odontoid process, posterior disk protrusions in the lumbar vertebrae and the enlargement of the posterior common vertebral ligament (Paupe et al. 2004; Carbonell et al. 2005; Aglan et al. 2009). In most individuals with DMC, MRI analyses of the brain have been normal (Paupe et al. 2004; Aglan et al. 2009). However, one patient has been reported with cortical atrophy (Aglan et al. 2009) and another with thinning of the corpus callosum (Dupuis et al. 2015).Both DMC and SMS are progressive disorders. With the exception of reduced length, affected individuals usually are normal at birth. Skeletal findings often are recognized first between 1 and 18 months. The vertebral body constriction abnormalities and lacy pattern of the iliac crests appear by 3-4 years and may persist until adulthood. The vertebral body constrictions are most prominent between ages 8 and 12 years (Aglan et al. 2009). The microcephaly in DMC and short stature in both appear during childhood. Throughout childhood and as adults, thoracic kyphosis, scoliosis, lumbar lordosis, subluxation (partial dislocation) and frank dislocation of the hips, wide-based and waddling gait, genu valgum or varum, and restricted joint mobility appear and may worsen. The treatment of genu varum in this condition has been reported (Kenis et al. 2011). Adult height is severely reduced with height ranging from 82 cm to 128 cm (32 in to 50 in). Neurologic and behavioral complications in DMC may include hyperactivity, autistic-like behavior, lack of speech and mild to severe intellectual disability with IQ scores ranging from 25 to 65 (Paupe et al. 2004). Because of the of atlantoaxial instability found in DMC, cord compression is a concern. However, only a few cases have been reported with this complication (Naffah and Taleb 1974). Prenatal diagnosis of DMC has been accomplished by finding a pathogenic homozygous mutation in the DYM gene in a fetus with no detectable physical findings (Toru et al. 2015). | 388 | Dyggve Melchior Clausen syndrome |
nord_388_2 | Causes of Dyggve Melchior Clausen syndrome | Dyggve-Melchior-Clausen syndrome is inherited as an autosomal recessive trait. Normally, autosomal genes come in pair with an individual receiving one gene of the paired genes from his or her father, and the other from the mother. Recessive genetic disorders occur when an individual inherits an abnormal or mutated gene for the same trait from each parent. In autosomal recessive conditions, if an individual receives one normal gene and one gene for the disease, the person is a carrier for the disease, but usually will not have any clinical manifestations of the condition. The risk for two carrier parents to both pass on their defective genes to an offspring, 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. And the chance for a child to receive two normal genes from his or her parents and be genetically normal for that particular trait is 25%. Many children with DMC and SMS are offspring of consanguineous parents with many reported patients being from Morocco or other Mediterranean countries (Aglan et al. 2009; Santos et al. 2009).Smith-McCort syndrome is allelic to DMC, and also is inherited as an autosomal recessive trait. There has been some confusion about the inheritance of SMS because Yunis et al. (1980) reported a family with apparent SMS where the condition was inherited in an X-linked mode. . Subsequently, Spranger (1981) suggested that this family had spondyloepiphyseal dysplasia tarda, a well-established X-linked disorder.The gene that causes both DMC and SMS was first reported by Cohn et al. (2003), which they originally called FLJ90130. Subsequently, others proposed changing the gene’s name, and the protein it produces, to dymeclin (abbreviated from Dyggve-Melchior-Clausen). The gene now most commonly is referred to as DYM. The gene is located on the long arm (q) of chromosome 18 (18q12-q21.1), contains 17 exons and spans about 400 kb (Cahn et al. 2003; Kinning et al. 2005). The protein, dymeclin, is a protein of 669 amino acids, and is a protein involved in the Golgi apparatus (Dimitrov et at. 2009). Dymeclin’s functions in the homeostasis and organization of the Golgi apparatus, and in trafficking of vesicles and proteins into and out of this organelle (Osipovich et al. 2008). DMC appears to be produced mostly by premature truncation of the DYM product resulting in complete or nearly complete absence of dymeclin production from both DYM genes. Alternatively, there may be little or no production from one gene and production of a partially functioning protein from the other. A number of different types of mutations, i.e., frameshift, nonsense, missense mutations and etc., cause DMC (Cohn et al. 2003; Santos et al. 2009; Khalifa et al. 2011) and at least 58 different DYM mutations in multiple families from different ethnic groups have been reported (Dimitrov et al. 2009; Santos et al. 2009; Gupta et al. 2010; Khalifa et al. 2011). Some mutations in DYM appear to result in mis-localization and subsequent degradation of dymeclin with in the cell (Dimitrov et al. 2009). Interestingly, disease producing mutations in this gene are scattered throughout the gene (El Ghouzzi et al. 2003). Smith-McCort syndrome usually is the result of missense mutations in the same gene (Dimitrov et al. 2009; Khalifa et al. 2011). Mutational analysis of DYM currently is available (http://www.genetests.org).More recently a second gene, RAB33B, has been reported to causes SMS (Alshammari et al. 2012). These investigators reported on a Saudi inbred family with six affected individuals in two sibships all of whom had clinical and radiographic features consistent with DMC/SMS. Four tested children each had the same missense mutation in the RAB33B gene. The gene encodes for a Rab protein and the mutation lead to a marked deficiency of this protein. Like dymeclin, the Rab protein plays a critical role in Golgi transport. All four of the evaluated children had normal cognitive function and head size. Thus, it appears that the siblings had SMS rather than DMC has claimed by the authors. Another individual with SMS and a mutation in RAB33B has been reported (Dupuis et al. 2012). | Causes of Dyggve Melchior Clausen syndrome. Dyggve-Melchior-Clausen syndrome is inherited as an autosomal recessive trait. Normally, autosomal genes come in pair with an individual receiving one gene of the paired genes from his or her father, and the other from the mother. Recessive genetic disorders occur when an individual inherits an abnormal or mutated gene for the same trait from each parent. In autosomal recessive conditions, if an individual receives one normal gene and one gene for the disease, the person is a carrier for the disease, but usually will not have any clinical manifestations of the condition. The risk for two carrier parents to both pass on their defective genes to an offspring, 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. And the chance for a child to receive two normal genes from his or her parents and be genetically normal for that particular trait is 25%. Many children with DMC and SMS are offspring of consanguineous parents with many reported patients being from Morocco or other Mediterranean countries (Aglan et al. 2009; Santos et al. 2009).Smith-McCort syndrome is allelic to DMC, and also is inherited as an autosomal recessive trait. There has been some confusion about the inheritance of SMS because Yunis et al. (1980) reported a family with apparent SMS where the condition was inherited in an X-linked mode. . Subsequently, Spranger (1981) suggested that this family had spondyloepiphyseal dysplasia tarda, a well-established X-linked disorder.The gene that causes both DMC and SMS was first reported by Cohn et al. (2003), which they originally called FLJ90130. Subsequently, others proposed changing the gene’s name, and the protein it produces, to dymeclin (abbreviated from Dyggve-Melchior-Clausen). The gene now most commonly is referred to as DYM. The gene is located on the long arm (q) of chromosome 18 (18q12-q21.1), contains 17 exons and spans about 400 kb (Cahn et al. 2003; Kinning et al. 2005). The protein, dymeclin, is a protein of 669 amino acids, and is a protein involved in the Golgi apparatus (Dimitrov et at. 2009). Dymeclin’s functions in the homeostasis and organization of the Golgi apparatus, and in trafficking of vesicles and proteins into and out of this organelle (Osipovich et al. 2008). DMC appears to be produced mostly by premature truncation of the DYM product resulting in complete or nearly complete absence of dymeclin production from both DYM genes. Alternatively, there may be little or no production from one gene and production of a partially functioning protein from the other. A number of different types of mutations, i.e., frameshift, nonsense, missense mutations and etc., cause DMC (Cohn et al. 2003; Santos et al. 2009; Khalifa et al. 2011) and at least 58 different DYM mutations in multiple families from different ethnic groups have been reported (Dimitrov et al. 2009; Santos et al. 2009; Gupta et al. 2010; Khalifa et al. 2011). Some mutations in DYM appear to result in mis-localization and subsequent degradation of dymeclin with in the cell (Dimitrov et al. 2009). Interestingly, disease producing mutations in this gene are scattered throughout the gene (El Ghouzzi et al. 2003). Smith-McCort syndrome usually is the result of missense mutations in the same gene (Dimitrov et al. 2009; Khalifa et al. 2011). Mutational analysis of DYM currently is available (http://www.genetests.org).More recently a second gene, RAB33B, has been reported to causes SMS (Alshammari et al. 2012). These investigators reported on a Saudi inbred family with six affected individuals in two sibships all of whom had clinical and radiographic features consistent with DMC/SMS. Four tested children each had the same missense mutation in the RAB33B gene. The gene encodes for a Rab protein and the mutation lead to a marked deficiency of this protein. Like dymeclin, the Rab protein plays a critical role in Golgi transport. All four of the evaluated children had normal cognitive function and head size. Thus, it appears that the siblings had SMS rather than DMC has claimed by the authors. Another individual with SMS and a mutation in RAB33B has been reported (Dupuis et al. 2012). | 388 | Dyggve Melchior Clausen syndrome |
nord_388_3 | Affects of Dyggve Melchior Clausen syndrome | DMC and SMS syndromes are rare genetic disorders. As of 2007 there were over 90 individuals with DMC or SMS reported in the literature (Lachman, 2007, p 934) who were from a number of different ethnic groups (El Ghouzzi et al. 2003; Pogue et al. 2005; Aglan et al. 2009). | Affects of Dyggve Melchior Clausen syndrome. DMC and SMS syndromes are rare genetic disorders. As of 2007 there were over 90 individuals with DMC or SMS reported in the literature (Lachman, 2007, p 934) who were from a number of different ethnic groups (El Ghouzzi et al. 2003; Pogue et al. 2005; Aglan et al. 2009). | 388 | Dyggve Melchior Clausen syndrome |
nord_388_4 | Related disorders of Dyggve Melchior Clausen syndrome | Features in the following disorders can be similar to those found in DMC. Comparisons may be useful for a differential diagnosis:Morquio syndrome (mucopolysaccharidosis type IV; MPS IV) exists in two forms (Morquio syndromes A and B) and occurs because of a deficiency of the enzymes, N-acetylgalactosamine-6-sulfatase and beta-galactosidase, respectively. A deficiency of either enzyme leads to the accumulation of mucopolysaccharides in cells, cloudy corneas, deafness, abnormal skeletal development, and other features. Most individuals with Morquio syndrome have normal intelligence. The clinical features of Morquio syndrome type B are usually fewer and milder than those associated with Morquio syndrome type A. Findings in both types may also include growth retardation, mildly course facial appearance, glaucoma, a prominent lower face, an abnormally short neck, pectus carinatum, kyphoscoliosis, platyspondyly, irregular epiphyses (ends of the long bones), broad metaphyses (segments underneath the epiphyses), genu valgum, and flat feet. In some patients, hearing loss, leg weakness, and/or additional abnormalities also occur. In contrast to Morquio syndrome, individuals with DMC have normal hearing and teeth, lack cloudy corneas and lack the urinary mucopolysaccharides, but do have intellectual disability. (For more information, choose “Morquio syndrome” as a search term in the Rare Disease Database.)Pseudoachondroplasia is a rare, autosomal dominant inherited disorder characterized by skeletal malformations resulting in short legs and mild to moderate short stature (short-limbed dwarfism). Affected individuals also may have brachydactyly (short, stubby fingers), genu varum, and/or genu valgum. Often there are spinal abnormalities including lumbar lordosis and kyphosis. In someindividuals, ulnar deviation of the wrists (abnormal bending of the hand toward the fifth finger side of the hand), and limited flexibility the elbows and hips may occur. Pseudoachondroplasia is due to mutations of the cartilage oligomeric matrix protein (COMP) gene, and as such, is allelic to some cases of multiple epiphyseal dysplasia (i.e., caused by different mutations of the same disease gene). (For more information, choose “pseudoachondroplastic dysplasia” as a search term in the Rare Disease Database.)Spondyloepiphyseal dysplasia congenital is also a rare genetic disorder characterized by growth deficiency before birth (prenatally); spinal, hips, knees and other joint abnormalities; and/or abnormalities affecting the eyes. As affected individuals age, growth deficiency results in short stature (dwarfism), in part, due to a disproportionately short neck and trunk, and coxa vara (a hip deformity in which the femur [thigh bone] is angled toward the midline of the body). Most affected individuals also have hypotonia (diminished muscle tone), kyphoscoliosis, lumbar lordosis, and pectus carinatum. Affected individuals also have abnormalities affecting the eyes including myopia (nearsightedness) and, in approximately 50 percent of patients, retinal detachment. Although there usually is normal intelligence, there may be delay in waking and a waddling gait. Spondyloepiphyseal dysplasia congenital is inherited as an autosomal dominant trait and is produced by a mutation in the collagen II (COL2A1) gene. This gene is involved in the production of type 2 collagen, a connective tissue protein, which is essential for the normal development of bones and other connective tissues. Changes in the composition of this collagen lead to abnormal skeletal growth in this and related disorders. (For more information, choose “spondyloepiphyseal dysplasia congenital” as a search term in the Rare Disease Database.)Spondyloepiphyseal dysplasia tarda, an X-linked inherited disorder, is also a rare genetic disorder that primarily affects males and is characterized by short stature, kyphoscoliosis, and lumbar lordosis. Individuals with this condition are normal at birth with onset of features between ages 5 and 10 years. Affected individuals may also have flat facies, a short neck and barrel-shaped chest (a rounded, bulging chest) with pectus carinatum. With time, pain and stiffness of the shoulders, cervical and lumbar vertebrae and hips develops. (For more information, choose “spondyloepiphyseal dysplasia tarda” as a search term in the Rare Disease Database.)Metatropic dysplasia I is also a rare genetic disorder with major findings including extremely short stature with short arms and legs. Other features are a narrow thorax, short ribs and kyphoscoliosis, the latter contributing to the short trunk typical for this condition. The cause of the disorder is a mutation in the TRPV4 gene. (For more information, choose “metatropic dysplasia I” as a search term in the Rare Disease Database.)Kniest dysplasia features include cleft palate, short stature and enlarged joints. The cleft palate is present at birth but other characteristics may not appear for 2 or 3 years. Other features may include flat facies, myopia progressing to retinal detachment, kyphoscoliosis and platyspondyly. Kniest dysplasia is also caused by mutations in the COL2A1 gene. (For more information, choose “Kniest dysplasia” as a search term in the Rare Disease Database.)Spondylometaphyseal dysplasia, Kozlowski type, is a rare disorder characterized by short stature with a short neck and trunk, scoliosis or kyphoscoliosis, short hands and feet and limited joint movement associated with an abnormal gait. Radiographically, there is severe and generalized platyspondyly, widened and irregular metaphyses of the tubular bones, coxa vara, and delayed bone maturation. The condition is inherited in an autosomal dominant mode. The cause of the disorder also is produced from mutations in the TRPV4 gene. | Related disorders of Dyggve Melchior Clausen syndrome. Features in the following disorders can be similar to those found in DMC. Comparisons may be useful for a differential diagnosis:Morquio syndrome (mucopolysaccharidosis type IV; MPS IV) exists in two forms (Morquio syndromes A and B) and occurs because of a deficiency of the enzymes, N-acetylgalactosamine-6-sulfatase and beta-galactosidase, respectively. A deficiency of either enzyme leads to the accumulation of mucopolysaccharides in cells, cloudy corneas, deafness, abnormal skeletal development, and other features. Most individuals with Morquio syndrome have normal intelligence. The clinical features of Morquio syndrome type B are usually fewer and milder than those associated with Morquio syndrome type A. Findings in both types may also include growth retardation, mildly course facial appearance, glaucoma, a prominent lower face, an abnormally short neck, pectus carinatum, kyphoscoliosis, platyspondyly, irregular epiphyses (ends of the long bones), broad metaphyses (segments underneath the epiphyses), genu valgum, and flat feet. In some patients, hearing loss, leg weakness, and/or additional abnormalities also occur. In contrast to Morquio syndrome, individuals with DMC have normal hearing and teeth, lack cloudy corneas and lack the urinary mucopolysaccharides, but do have intellectual disability. (For more information, choose “Morquio syndrome” as a search term in the Rare Disease Database.)Pseudoachondroplasia is a rare, autosomal dominant inherited disorder characterized by skeletal malformations resulting in short legs and mild to moderate short stature (short-limbed dwarfism). Affected individuals also may have brachydactyly (short, stubby fingers), genu varum, and/or genu valgum. Often there are spinal abnormalities including lumbar lordosis and kyphosis. In someindividuals, ulnar deviation of the wrists (abnormal bending of the hand toward the fifth finger side of the hand), and limited flexibility the elbows and hips may occur. Pseudoachondroplasia is due to mutations of the cartilage oligomeric matrix protein (COMP) gene, and as such, is allelic to some cases of multiple epiphyseal dysplasia (i.e., caused by different mutations of the same disease gene). (For more information, choose “pseudoachondroplastic dysplasia” as a search term in the Rare Disease Database.)Spondyloepiphyseal dysplasia congenital is also a rare genetic disorder characterized by growth deficiency before birth (prenatally); spinal, hips, knees and other joint abnormalities; and/or abnormalities affecting the eyes. As affected individuals age, growth deficiency results in short stature (dwarfism), in part, due to a disproportionately short neck and trunk, and coxa vara (a hip deformity in which the femur [thigh bone] is angled toward the midline of the body). Most affected individuals also have hypotonia (diminished muscle tone), kyphoscoliosis, lumbar lordosis, and pectus carinatum. Affected individuals also have abnormalities affecting the eyes including myopia (nearsightedness) and, in approximately 50 percent of patients, retinal detachment. Although there usually is normal intelligence, there may be delay in waking and a waddling gait. Spondyloepiphyseal dysplasia congenital is inherited as an autosomal dominant trait and is produced by a mutation in the collagen II (COL2A1) gene. This gene is involved in the production of type 2 collagen, a connective tissue protein, which is essential for the normal development of bones and other connective tissues. Changes in the composition of this collagen lead to abnormal skeletal growth in this and related disorders. (For more information, choose “spondyloepiphyseal dysplasia congenital” as a search term in the Rare Disease Database.)Spondyloepiphyseal dysplasia tarda, an X-linked inherited disorder, is also a rare genetic disorder that primarily affects males and is characterized by short stature, kyphoscoliosis, and lumbar lordosis. Individuals with this condition are normal at birth with onset of features between ages 5 and 10 years. Affected individuals may also have flat facies, a short neck and barrel-shaped chest (a rounded, bulging chest) with pectus carinatum. With time, pain and stiffness of the shoulders, cervical and lumbar vertebrae and hips develops. (For more information, choose “spondyloepiphyseal dysplasia tarda” as a search term in the Rare Disease Database.)Metatropic dysplasia I is also a rare genetic disorder with major findings including extremely short stature with short arms and legs. Other features are a narrow thorax, short ribs and kyphoscoliosis, the latter contributing to the short trunk typical for this condition. The cause of the disorder is a mutation in the TRPV4 gene. (For more information, choose “metatropic dysplasia I” as a search term in the Rare Disease Database.)Kniest dysplasia features include cleft palate, short stature and enlarged joints. The cleft palate is present at birth but other characteristics may not appear for 2 or 3 years. Other features may include flat facies, myopia progressing to retinal detachment, kyphoscoliosis and platyspondyly. Kniest dysplasia is also caused by mutations in the COL2A1 gene. (For more information, choose “Kniest dysplasia” as a search term in the Rare Disease Database.)Spondylometaphyseal dysplasia, Kozlowski type, is a rare disorder characterized by short stature with a short neck and trunk, scoliosis or kyphoscoliosis, short hands and feet and limited joint movement associated with an abnormal gait. Radiographically, there is severe and generalized platyspondyly, widened and irregular metaphyses of the tubular bones, coxa vara, and delayed bone maturation. The condition is inherited in an autosomal dominant mode. The cause of the disorder also is produced from mutations in the TRPV4 gene. | 388 | Dyggve Melchior Clausen syndrome |
nord_388_5 | Diagnosis of Dyggve Melchior Clausen syndrome | A diagnosis of DMC syndrome may be suspected upon a thorough clinical evaluation, a detailed patient history, and identification of characteristic clinical findings, e.g., barrel chest and disproportionate short stature. Radiographs may confirm specific skeletal abnormalities and findings consistent with DMC syndrome and includes notching of the vertebral bodies, lacy appearance of the iliac crest, and small and malformed carpal bones. Alternatively, gene testing for mutations in DYM can be done. | Diagnosis of Dyggve Melchior Clausen syndrome. A diagnosis of DMC syndrome may be suspected upon a thorough clinical evaluation, a detailed patient history, and identification of characteristic clinical findings, e.g., barrel chest and disproportionate short stature. Radiographs may confirm specific skeletal abnormalities and findings consistent with DMC syndrome and includes notching of the vertebral bodies, lacy appearance of the iliac crest, and small and malformed carpal bones. Alternatively, gene testing for mutations in DYM can be done. | 388 | Dyggve Melchior Clausen syndrome |
nord_388_6 | Therapies of Dyggve Melchior Clausen syndrome | TreatmentTreatment of individuals with DMC syndrome is symptomatic and supportive. When there is hypoplasia of the odontoid process and partial dislocation of the cervical vertebrae (the segments of the spinal column at the top of the spine), spinal fusion of these vertebrae or other means of vertebral stabilization normally is indicated. These procedures should be done in order to prevent damage to the cervical spinal cord, which can result in cord-related weakness or paralysis. Additionally, surgical techniques may be used to correct various other skeletal abnormalities such as subluxation or dislocation of the shoulder and hip joints. In some individuals, hip replacement is required.Children with DMC syndrome may benefit from early intervention and special educational programs. Genetic counseling may be of benefit for affected individuals, their parents and other family. | Therapies of Dyggve Melchior Clausen syndrome. TreatmentTreatment of individuals with DMC syndrome is symptomatic and supportive. When there is hypoplasia of the odontoid process and partial dislocation of the cervical vertebrae (the segments of the spinal column at the top of the spine), spinal fusion of these vertebrae or other means of vertebral stabilization normally is indicated. These procedures should be done in order to prevent damage to the cervical spinal cord, which can result in cord-related weakness or paralysis. Additionally, surgical techniques may be used to correct various other skeletal abnormalities such as subluxation or dislocation of the shoulder and hip joints. In some individuals, hip replacement is required.Children with DMC syndrome may benefit from early intervention and special educational programs. Genetic counseling may be of benefit for affected individuals, their parents and other family. | 388 | Dyggve Melchior Clausen syndrome |
nord_389_0 | Overview of Dysautonomia, Familial | Familial dysautonomia is a rare genetic disorder of the autonomic nervous system (ANS) that primarily affects people of Eastern European Jewish heritage. It is characterized by diminished sensitivity to pain, lack of overflow tearing in the eyes, a decrease in the number of knob-like projections that cover the tongue (fungiform papillae), unusual fluctuations of body temperature, and unstable blood pressure. Symptoms of this disorder are apparent at birth. The autonomic nervous system controls vital involuntary body functions. | Overview of Dysautonomia, Familial. Familial dysautonomia is a rare genetic disorder of the autonomic nervous system (ANS) that primarily affects people of Eastern European Jewish heritage. It is characterized by diminished sensitivity to pain, lack of overflow tearing in the eyes, a decrease in the number of knob-like projections that cover the tongue (fungiform papillae), unusual fluctuations of body temperature, and unstable blood pressure. Symptoms of this disorder are apparent at birth. The autonomic nervous system controls vital involuntary body functions. | 389 | Dysautonomia, Familial |
nord_389_1 | Symptoms of Dysautonomia, Familial | An infant born with familial dysautonomia typically has poor sucking ability, impaired swallowing reflexes, poor muscle tone (hypotonia), and/or abnormally low body temperature (hypothermia). Infants with this disorder may have cold hands and feet and experience unstable body temperature (from 94 to 108 degrees) during the course of infectious diseases. Profuse sweating and drooling may also occur. Crying without tears is one of the most striking symptoms of familial dysautonomia. Sometimes a lack of tears and insensitivity of the eyes to pain from foreign objects (corneal anesthesia) can lead to inflammation of the corneas and ulcerations in the eyes.Children with familial dysautonomia have a decreased perception of pain and lack of sensitivity to hot and/or cold temperatures; this can result in unnoticed injuries to the skin. Unstable blood pressure is usually present in infants with familial dysautonomia. Blood pressure readings may vary greatly and may be abnormally high or low.Other symptoms of familial dysautonomia may include the absence of the sense of taste, impaired speech, and/or red blotches on the skin that appear with emotional excitement. Approximately 40 percent of children with this disorder experience episodes of vomiting. Occasionally there may be skeletal defects, absence of tendon reflexes, stunted height, and/or repeated episodes of pneumonia due to the inhalation of food (aspiration).By adolescence, 95 percent of individuals with familial dysautonomia have evidence of side-to side spinal curvature (scoliosis). In addition, they may experience increased sweating and an accelerated heart rate. A decreased awareness of pain makes it difficult for children with this disorder to be aware of injuries; bone fractures may go unrecognized. Other symptoms that may appear during adolescence include weakness, leg cramps, and/or difficulty concentrating. Personality changes may also occur including depression, irritability, inability to sleep (insomnia), and/or negativism.Approximately 20 percent of adults with familial dysautonomia over 20 years of age develop kidney insufficiency. Neurological deterioration also appears and unsteadiness in walking may become more apparent at this age.A medical test is available that can determine if an infant has familial dysautonomia. Histamine is injected under the skin and response is measured along nerve cell fibers (axon flare). A lack of response confirms the diagnosis of familial dysautonomia. | Symptoms of Dysautonomia, Familial. An infant born with familial dysautonomia typically has poor sucking ability, impaired swallowing reflexes, poor muscle tone (hypotonia), and/or abnormally low body temperature (hypothermia). Infants with this disorder may have cold hands and feet and experience unstable body temperature (from 94 to 108 degrees) during the course of infectious diseases. Profuse sweating and drooling may also occur. Crying without tears is one of the most striking symptoms of familial dysautonomia. Sometimes a lack of tears and insensitivity of the eyes to pain from foreign objects (corneal anesthesia) can lead to inflammation of the corneas and ulcerations in the eyes.Children with familial dysautonomia have a decreased perception of pain and lack of sensitivity to hot and/or cold temperatures; this can result in unnoticed injuries to the skin. Unstable blood pressure is usually present in infants with familial dysautonomia. Blood pressure readings may vary greatly and may be abnormally high or low.Other symptoms of familial dysautonomia may include the absence of the sense of taste, impaired speech, and/or red blotches on the skin that appear with emotional excitement. Approximately 40 percent of children with this disorder experience episodes of vomiting. Occasionally there may be skeletal defects, absence of tendon reflexes, stunted height, and/or repeated episodes of pneumonia due to the inhalation of food (aspiration).By adolescence, 95 percent of individuals with familial dysautonomia have evidence of side-to side spinal curvature (scoliosis). In addition, they may experience increased sweating and an accelerated heart rate. A decreased awareness of pain makes it difficult for children with this disorder to be aware of injuries; bone fractures may go unrecognized. Other symptoms that may appear during adolescence include weakness, leg cramps, and/or difficulty concentrating. Personality changes may also occur including depression, irritability, inability to sleep (insomnia), and/or negativism.Approximately 20 percent of adults with familial dysautonomia over 20 years of age develop kidney insufficiency. Neurological deterioration also appears and unsteadiness in walking may become more apparent at this age.A medical test is available that can determine if an infant has familial dysautonomia. Histamine is injected under the skin and response is measured along nerve cell fibers (axon flare). A lack of response confirms the diagnosis of familial dysautonomia. | 389 | Dysautonomia, Familial |
nord_389_2 | Causes of Dysautonomia, Familial | Familial dysautonomia is inherited as a recessive genetic trait. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother. In recessive disorders, the condition does not appear unless a person inherits the same defective gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease, but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy.Researchers have identified the gene that causes familial dysautonomia. Two mutations of the gene known as IKBKAP can cause FD. A carrier test is now available for all Ashkenazi Jews. Consult your local physician for details. | Causes of Dysautonomia, Familial. Familial dysautonomia is inherited as a recessive genetic trait. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother. In recessive disorders, the condition does not appear unless a person inherits the same defective gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease, but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy.Researchers have identified the gene that causes familial dysautonomia. Two mutations of the gene known as IKBKAP can cause FD. A carrier test is now available for all Ashkenazi Jews. Consult your local physician for details. | 389 | Dysautonomia, Familial |
nord_389_3 | Affects of Dysautonomia, Familial | Familial dysautonomia is a rare genetic disorder that affects males and females in equal numbers. This disorder primarily affects infants of Ashkenazi Jewish or Eastern European ancestry; approximately 1 in 30 people of East European Jewish ancestry are thought to be carriers of the defective gene that causes this disorder. | Affects of Dysautonomia, Familial. Familial dysautonomia is a rare genetic disorder that affects males and females in equal numbers. This disorder primarily affects infants of Ashkenazi Jewish or Eastern European ancestry; approximately 1 in 30 people of East European Jewish ancestry are thought to be carriers of the defective gene that causes this disorder. | 389 | Dysautonomia, Familial |
nord_389_4 | Related disorders of Dysautonomia, Familial | Symptoms of the following disorders can be similar to those of familial dysautonomia. Comparisons may be useful for a differential diagnosis:Biemond congenital and familial analgesia is a genetic disorder characterized by symptoms that are similar to those of familial dysautonomia. The symptoms of this disorder include insensitivity to pain, a diminished sense of temperature and touch, and the absence of tendon reflexes.Congenital sensory neuropathy with anhidrosis (hereditary sensory and autonomic neuropathy or HSAN-IV) is a rare inherited disorder of the autonomic nervous system that is characterized by the loss of pain and temperature sensation and a lack of sweating. There may be wide variations in body temperature and recurrent episodes of unexplained high fevers. The symptoms of congenital sensory neuropathy with anhidrosis may initially be confused with familial dysautonomia.Hereditary sensory neuropathy (HSAN II) is a rare inherited disorder characterized by insensitivity to pain, a diminished sense of temperature and touch, and the absence of tendon reflexes. Children with this disorder typically have decreased but not absent tear flow. The lack of sweating and the absence of abnormally low blood pressure upon standing (orthostatic hypotension) helps to distinguish this disorder from familial dysautonomia. (For more information on this disorder, choose “Hereditary Sensory Neuropathy” as your search term in the Rare Disease Database.)“Dysautonomia,” when used as a general medical term, refers to the abnormal functioning of the autonomic nervous system and can be combined with other words to describe specific conditions such as “diabetic cardiac dysautonomia” or “postganglionic cholinergic dysautonomia.” There are many conditions characterized by the symptoms of dysautonomia. These should not be confused with the specific hereditary disorder of familial dysautonomia. | Related disorders of Dysautonomia, Familial. Symptoms of the following disorders can be similar to those of familial dysautonomia. Comparisons may be useful for a differential diagnosis:Biemond congenital and familial analgesia is a genetic disorder characterized by symptoms that are similar to those of familial dysautonomia. The symptoms of this disorder include insensitivity to pain, a diminished sense of temperature and touch, and the absence of tendon reflexes.Congenital sensory neuropathy with anhidrosis (hereditary sensory and autonomic neuropathy or HSAN-IV) is a rare inherited disorder of the autonomic nervous system that is characterized by the loss of pain and temperature sensation and a lack of sweating. There may be wide variations in body temperature and recurrent episodes of unexplained high fevers. The symptoms of congenital sensory neuropathy with anhidrosis may initially be confused with familial dysautonomia.Hereditary sensory neuropathy (HSAN II) is a rare inherited disorder characterized by insensitivity to pain, a diminished sense of temperature and touch, and the absence of tendon reflexes. Children with this disorder typically have decreased but not absent tear flow. The lack of sweating and the absence of abnormally low blood pressure upon standing (orthostatic hypotension) helps to distinguish this disorder from familial dysautonomia. (For more information on this disorder, choose “Hereditary Sensory Neuropathy” as your search term in the Rare Disease Database.)“Dysautonomia,” when used as a general medical term, refers to the abnormal functioning of the autonomic nervous system and can be combined with other words to describe specific conditions such as “diabetic cardiac dysautonomia” or “postganglionic cholinergic dysautonomia.” There are many conditions characterized by the symptoms of dysautonomia. These should not be confused with the specific hereditary disorder of familial dysautonomia. | 389 | Dysautonomia, Familial |
nord_389_5 | Diagnosis of Dysautonomia, Familial | Diagnosis of Dysautonomia, Familial. | 389 | Dysautonomia, Familial |
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nord_389_6 | Therapies of Dysautonomia, Familial | Drugs used to relieve the symptoms of familial dysautonomia include diazepam, metoclopramide, and chloral hydrate. Artificial tears may be needed to lubricate the eyes.Physical therapy, chest physiotherapy, occupational therapy, feeding facilitation, and/or speech therapy may also be useful to alleviate the symptoms of familial dysautonomia.People with familial dysautonomia may also benefit from a variety of other orthopedic and ocular (vision) aids.Genetic counseling will be of benefit for patients with familial dysautonomia and their families. | Therapies of Dysautonomia, Familial. Drugs used to relieve the symptoms of familial dysautonomia include diazepam, metoclopramide, and chloral hydrate. Artificial tears may be needed to lubricate the eyes.Physical therapy, chest physiotherapy, occupational therapy, feeding facilitation, and/or speech therapy may also be useful to alleviate the symptoms of familial dysautonomia.People with familial dysautonomia may also benefit from a variety of other orthopedic and ocular (vision) aids.Genetic counseling will be of benefit for patients with familial dysautonomia and their families. | 389 | Dysautonomia, Familial |
nord_390_0 | Overview of Dyskeratosis Congenita | Dyskeratosis congenita is a rare genetic form of bone marrow failure, the inability of the marrow to produce sufficient blood cells. Dyskeratosis is Latin and means the irreversible degeneration of skin tissue, and congenita means inborn. First described in the medical literature in 1906, dyskeratosis congenita was originally thought to be a skin disease that also affects the nails and the mouth. Only later in the sixties was it realized that patients with these skin changes almost always develop bone marrow failure. Thus, for the last 40 years or so, the bone marrow failure syndrome dyskeratosis congenita was diagnosed when patients presented with the triad of abnormal skin, malformation (dystrophy) of the nails, and white, thickened patches on the mucous membranes of the mouth (oral leukoplakia). The skin changes may be present before the development of bone marrow failure. Bone marrow failure is usually diagnosed by the low number of circulating blood cells including red blood cells, white blood cells, and platelets. Additional findings in patients with dyskeratosis congenita may include short stature, eye and tooth abnormalities, thin and early graying of the hair, lung (pulmonary) disease, liver disease, gut abnormalities, bone thinning (osteoporosis), infertility, learning difficulties, and delays in reaching developmental milestones. An increased incidence of leukemia and cancer has also been documented.Today, in addition to examining the skin, nails, and mouth for these classical changes, we also use other tests to diagnose dyskeratosis congenita including testing for the genetic abnormality responsible for the development of the disease. Using these more sensitive tests, we are beginning to realize, that only a minority of patients with the genetic abnormality actually develop the full clinical picture of dyskeratosis congenita as outlined above. We find that there are many more individuals with the genetic abnormality (mutation) who have only a mild form of the disease. Often these individuals may only show one or two of the clinical features and these only become obvious, late in life. Some never develop the classic skin abnormalities that coined the name of the disease. Whether the disease in these patients in the absence of skin manifestations should also be labeled with dyskeratosis congenita is controversial and often these individuals are referred to as having atypical dyskeratosis congenita. There are even individuals carrying the mutation who will never develop disease, however their children or grandchildren might. These individuals are often referred to as silent mutation carriers. This new knowledge is important for physicians and patients because much of what has previously been published about this disease may actually not apply anymore for all individuals newly diagnosed with dyskeratosis congenita. In addition to the many more mild manifestations of this disease we also realize that there are some rare but very severe forms of dyskeratosis congenita. These were previously known as the Hoyeraal-Hreidarsson syndrome and the Revesz syndrome but today we know that they have the same underlying abnormality and are caused at least in part by mutations in the same genes responsible for dyskeratosis congenita. These severe forms manifest early in life and are associated with additional clinical features that are usually not present in other forms of dyskeratosis congenita (see also below).In the majority of cases dyskeratosis congenita is inherited. The pattern of inheritance may be X-linked (Zinsser-Cole-Engleman syndrome), autosomal dominant (dyskeratosis congenita, Scoggins type) or autosomal recessive. However, in a large proportion of patients dyskeratosis congenita occurs sporadically, meaning that the parents do not show disease. In some patients with sporadic DC the genetic abnormality may have newly arisen (de novo mutation) and therefore is not present in either parent. | Overview of Dyskeratosis Congenita. Dyskeratosis congenita is a rare genetic form of bone marrow failure, the inability of the marrow to produce sufficient blood cells. Dyskeratosis is Latin and means the irreversible degeneration of skin tissue, and congenita means inborn. First described in the medical literature in 1906, dyskeratosis congenita was originally thought to be a skin disease that also affects the nails and the mouth. Only later in the sixties was it realized that patients with these skin changes almost always develop bone marrow failure. Thus, for the last 40 years or so, the bone marrow failure syndrome dyskeratosis congenita was diagnosed when patients presented with the triad of abnormal skin, malformation (dystrophy) of the nails, and white, thickened patches on the mucous membranes of the mouth (oral leukoplakia). The skin changes may be present before the development of bone marrow failure. Bone marrow failure is usually diagnosed by the low number of circulating blood cells including red blood cells, white blood cells, and platelets. Additional findings in patients with dyskeratosis congenita may include short stature, eye and tooth abnormalities, thin and early graying of the hair, lung (pulmonary) disease, liver disease, gut abnormalities, bone thinning (osteoporosis), infertility, learning difficulties, and delays in reaching developmental milestones. An increased incidence of leukemia and cancer has also been documented.Today, in addition to examining the skin, nails, and mouth for these classical changes, we also use other tests to diagnose dyskeratosis congenita including testing for the genetic abnormality responsible for the development of the disease. Using these more sensitive tests, we are beginning to realize, that only a minority of patients with the genetic abnormality actually develop the full clinical picture of dyskeratosis congenita as outlined above. We find that there are many more individuals with the genetic abnormality (mutation) who have only a mild form of the disease. Often these individuals may only show one or two of the clinical features and these only become obvious, late in life. Some never develop the classic skin abnormalities that coined the name of the disease. Whether the disease in these patients in the absence of skin manifestations should also be labeled with dyskeratosis congenita is controversial and often these individuals are referred to as having atypical dyskeratosis congenita. There are even individuals carrying the mutation who will never develop disease, however their children or grandchildren might. These individuals are often referred to as silent mutation carriers. This new knowledge is important for physicians and patients because much of what has previously been published about this disease may actually not apply anymore for all individuals newly diagnosed with dyskeratosis congenita. In addition to the many more mild manifestations of this disease we also realize that there are some rare but very severe forms of dyskeratosis congenita. These were previously known as the Hoyeraal-Hreidarsson syndrome and the Revesz syndrome but today we know that they have the same underlying abnormality and are caused at least in part by mutations in the same genes responsible for dyskeratosis congenita. These severe forms manifest early in life and are associated with additional clinical features that are usually not present in other forms of dyskeratosis congenita (see also below).In the majority of cases dyskeratosis congenita is inherited. The pattern of inheritance may be X-linked (Zinsser-Cole-Engleman syndrome), autosomal dominant (dyskeratosis congenita, Scoggins type) or autosomal recessive. However, in a large proportion of patients dyskeratosis congenita occurs sporadically, meaning that the parents do not show disease. In some patients with sporadic DC the genetic abnormality may have newly arisen (de novo mutation) and therefore is not present in either parent. | 390 | Dyskeratosis Congenita |
nord_390_1 | Symptoms of Dyskeratosis Congenita | The symptoms and onset of symptoms in patients with dyskeratosis congenita varies greatly depending on the gene mutated, the nature of the mutation, for how many generations the mutation has been inherited, and possibly other genetic and environmental factors. However, even among members of the same family the symptoms and onset may vary to some degree. In some families disease seems to become more severe and manifests earlier in life with subsequent generations. One of the characteristics is that, with the exception of the very severe forms (Hoyeraal-Hreidarsson and to some extent the Revesz syndrome), clinical symptoms are not present at birth, but develop during childhood, adolescence, and in some cases only late in life. In general, the earlier the disease becomes apparent, the more likely it is that the disease is severe and rapidly progressing. Likewise, the later in life clinical symptoms appear, the milder the form of disease and the slower the progression of disease. The exception to this is the risk of cancer and leukemia, which increases with age and is more common in patients with moderate to mild forms of disease. Patients with the classic form of dyskeratosis congenita are those who present with the originally described skin, nail and mouth abnormalities. In these patients the skin and nail abnormalities usually appear before 10 years of age and bone marrow failure by 20 years of age. In approximately 80-90 percent of patients with classic dyskeratosis congenita bone marrow failure occurs by age 30. In some cases, bone marrow failure appears before skin, nail or mucous membrane symptoms. Patients with the mild form of dyskeratosis congenita may have no apparent symptoms (asymptomatic) into their 30s or 40s and often present only with one of the clinical features associated with dyskeratosis congenita such as bone marrow failure, pulmonary fibrosis, liver fibrosis, or osteoporosis. Skin and nail changes, might be so mild that they are overlooked, or not noticed.The X-linked form and some of the sporadic forms often present as classic dyskeratosis congenita, whereas individuals with the autosomal dominant form of dyskeratosis congenita often tend to have fewer abnormalities and later onset of symptoms. The skin and mucous membranes abnormalities are usually milder in the autosomal dominant form. The autosomal recessive form can vary dramatically with some individuals experiencing bone marrow failure early during childhood, while others have no blood abnormalities into their 40s. Although these findings are typical of many cases, individual cases may turn out differently. Skin, nail, and mouth changesThe skin abnormalities associated with dyskeratosis congenita include abnormal dark discoloration of the skin with a distribution pattern that resembles a net (reticulate hyperpigmentation). Affected areas may appear as grayish, flat spots (macules) on a degenerated (atrophic) or light colored patch of skin. The face, neck and shoulders are most often affected. Nail abnormalities usually affect the fingernails before the toenails and are characterized by fissures, underdevelopment (hypoplasia) and eventually degeneration and distortion of the affected nails. Some individuals may ultimately lose the affected nails. The development of white, thickened patches on mucous membranes of the mouth (oral leukoplakia) usually develops slowly appearing anywhere during the second, third or fourth decade. Although the mouth is predominantly affected, the mucous membranes of the anus and the urethra may become involved in rare cases. Bone marrow failureMost individuals with dyskeratosis congenita eventually develop bone marrow failure marked by deficiency of all three of the main types of blood cells (i.e., red cells, white cells, and platelets) a condition called pancytopenia. The bone marrow produces specialized cells (hematopoietic stem cells) that grow and eventually develop into red blood cells (erythrocytes), white blood cells (leukocytes), and platelets. The cells are released into the bloodstream to travel throughout the body performing their specific functions. Red blood cells deliver oxygen to the body, white blood cells help in fighting off infections, and platelets allow the body to form clots to stop bleeding. The degree of bone marrow failure can greatly vary from very mild with only one type of blood cell affected to very severe with low counts in all blood cell lineages. Bone marrow examination shows a reduced number of blood cell producing progenitor cells (hyopcelular or empty bone marrow). Sometimes it is not only the blood counts that are abnormal but the blood cells themselves can show abnormalities, such as chromosomal (karyotypic) differences. These findings are usually described as myelodysplasia or myelodysplastic syndrome (MDS). Patients with MDS are at a higher risk of developing leukemia particularly if they are associated with certain karyotypic abnormities such as only one chromosome 7 (monosomy 7) over a long period of time. In rare cases MDS or leukemia may be the first manifestation of disease.Pancytopenia (low blood cell count of all blood cell lineages) may result in a variety of symptoms. Bruising, small red spots on the skin (petechiae), paleness of the skin (pallor) and frequent infections may be the first signs of bone marrow failure. The specific symptoms and progression of the disorder vary from case to case. Some individuals may have mild symptoms that remain stable for many years; others may have serious symptoms that can progress to life-threatening complications. Bone marrow failure may develop during childhood or not become severe until well into adulthood. Individuals with anemia may experience tiredness, increased need for sleep, weakness, lightheadedness, dizziness, irritability, headaches, pale skin color, difficulty breathing (dyspnea), and cardiac symptoms. Individuals with low white blood cell counts (leukopenia) have an increased risk of contracting bacterial and fungal infections. Individuals with low platelet counts (thrombocytopenia) are more susceptible to excessive bruising following minimal injury and to spontaneous bleeding from the mucous membranes, especially those of the gums and nose.Some patients with the same genetic abnormality responsible for dyskeratosis congenita may present with bone marrow failure only. The severity of bone marrow failure in these patients can vary greatly, from affecting only one or two blood values in peripheral blood, to the full picture with low blood counts in all blood cell lineages, a condition termed aplastic anemia. Features of the skin or other symptoms associated with dyskeratosis congenita may not be present or be so mild that they are not appreciated. These patients are often initially misdiagnosed as having idiopathic aplastic anemia (see also below). Whether patients with the genetic abnormality for dyskeratosis congenita but only showing bone marrow failure should be classified as having dyskeratosis congenita is controversial, alternative classifications used are atypical dyskeratosis congenita, or aplastic anemia with short telomeres. It is important that in these individuals the treatment plan, response to treatment, disease surveillance, and prognosis differs from patients with idiopathic aplastic anemia. In addition because of the inherited nature of the disease, members of the family of the affected individual may also be at risk.Leukemia and cancerIndividuals with dyskeratosis congenita also have a predisposition to develop leukemia and cancer (malignancy) especially squamous cell carcinoma of the head and neck, and especially at the site of leukoplakia. If cancer occurs, it usually does not develop until the age of about 30. Thus, leukemia and cancer are more common in individuals who have a moderate or milder form of dyskeratosis congenita. Individuals who underwent a stem cell or bone marrow transplant for the treatment of their bone marrow failure are also at risk of developing cancer later in life. In rare cases leukemia or cancer may be the first manifestation of disease.Lung diseaseThe development of lung disease (pulmonary fibrosis) is often found in patients with dyskeratosis congenita. It usually develops later than the skin abnormalities and bone marrow failure, however in some patients with mild disease pulmonary fibrosis may be the first or only obvious manifestation. In these patients disease usually manifest at the age of 50 to 60 years of age. The cause of pulmonary fibrosis in patients with dyskeratosis congenita is not fully understood. Breathing difficulties and a decreased lung function may be signs of lung disease. Smoking seems to accelerate the progression of pulmonary disease.Other symptomsA variety of additional symptoms have been reported in individuals with dyskeratosis congenita. These symptoms occur with much less frequency than the abovementioned symptoms. These less common symptoms include excessively watery eyes due to obstruction of the tear ducts (epiphora), excessive sweating (hyperhidrosis) of the palms of the hands and the soles of the feet, cavities and tooth loss, narrowing of the esophagus (esophageal stricture), urinary tract anomalies, especially hypospadism, early graying and premature hair loss, lung disease and short stature, liver disease, underdeveloped testes (hypogonadism), failure of the testes to descend into the scrotum, and skeletal abnormalities.Some affected children may experience delays in attaining developmental milestones and learning disabilities. Additional symptoms have been reported that occur in less than 10 percent of cases including deafness, or abnormalities of the eye retina.Hoyeraal-Hreidarsson syndrome Once considered a separate disorder, Hoyeraal-Hreidarsson syndrome is now identified as a severe variant of dyskeratosis congenita. Symptoms usually occur during the first year of life and include severe growth retardation that occurs before birth (intrauterine growth retardation), bone marrow failure, immune system deficiencies, underdevelopment of the cerebellum (cerebellar hypoplasia), clumsiness caused by the inability to coordinate voluntary movements (ataxia), and microcephaly, a condition that indicates that head circumference is smaller than would be expected for an infant’s age and sex. Abnormalities of the gut varying from malabsorbtion to severe inflammation with ulcers may be present in these children. Bone marrow failure and immune system deficiency may result in life-threatening complications. Because of the complexity and because multiple organs are severely impaired the prognosis of children diagnosed with Hoyeraal-Hreidarsson syndrome is usually poor. These children often die before they develop the characteristic nail and skin abnormalities.Revesz syndromeRevesz syndrome is another severe form of dyskeratosis congenita that may present similar to the Hoyeraal-Hreidarsson syndrome but in addition is associated with abnormalities of the eye (bilateral exudative retinopathy, Coats retinopathy). | Symptoms of Dyskeratosis Congenita. The symptoms and onset of symptoms in patients with dyskeratosis congenita varies greatly depending on the gene mutated, the nature of the mutation, for how many generations the mutation has been inherited, and possibly other genetic and environmental factors. However, even among members of the same family the symptoms and onset may vary to some degree. In some families disease seems to become more severe and manifests earlier in life with subsequent generations. One of the characteristics is that, with the exception of the very severe forms (Hoyeraal-Hreidarsson and to some extent the Revesz syndrome), clinical symptoms are not present at birth, but develop during childhood, adolescence, and in some cases only late in life. In general, the earlier the disease becomes apparent, the more likely it is that the disease is severe and rapidly progressing. Likewise, the later in life clinical symptoms appear, the milder the form of disease and the slower the progression of disease. The exception to this is the risk of cancer and leukemia, which increases with age and is more common in patients with moderate to mild forms of disease. Patients with the classic form of dyskeratosis congenita are those who present with the originally described skin, nail and mouth abnormalities. In these patients the skin and nail abnormalities usually appear before 10 years of age and bone marrow failure by 20 years of age. In approximately 80-90 percent of patients with classic dyskeratosis congenita bone marrow failure occurs by age 30. In some cases, bone marrow failure appears before skin, nail or mucous membrane symptoms. Patients with the mild form of dyskeratosis congenita may have no apparent symptoms (asymptomatic) into their 30s or 40s and often present only with one of the clinical features associated with dyskeratosis congenita such as bone marrow failure, pulmonary fibrosis, liver fibrosis, or osteoporosis. Skin and nail changes, might be so mild that they are overlooked, or not noticed.The X-linked form and some of the sporadic forms often present as classic dyskeratosis congenita, whereas individuals with the autosomal dominant form of dyskeratosis congenita often tend to have fewer abnormalities and later onset of symptoms. The skin and mucous membranes abnormalities are usually milder in the autosomal dominant form. The autosomal recessive form can vary dramatically with some individuals experiencing bone marrow failure early during childhood, while others have no blood abnormalities into their 40s. Although these findings are typical of many cases, individual cases may turn out differently. Skin, nail, and mouth changesThe skin abnormalities associated with dyskeratosis congenita include abnormal dark discoloration of the skin with a distribution pattern that resembles a net (reticulate hyperpigmentation). Affected areas may appear as grayish, flat spots (macules) on a degenerated (atrophic) or light colored patch of skin. The face, neck and shoulders are most often affected. Nail abnormalities usually affect the fingernails before the toenails and are characterized by fissures, underdevelopment (hypoplasia) and eventually degeneration and distortion of the affected nails. Some individuals may ultimately lose the affected nails. The development of white, thickened patches on mucous membranes of the mouth (oral leukoplakia) usually develops slowly appearing anywhere during the second, third or fourth decade. Although the mouth is predominantly affected, the mucous membranes of the anus and the urethra may become involved in rare cases. Bone marrow failureMost individuals with dyskeratosis congenita eventually develop bone marrow failure marked by deficiency of all three of the main types of blood cells (i.e., red cells, white cells, and platelets) a condition called pancytopenia. The bone marrow produces specialized cells (hematopoietic stem cells) that grow and eventually develop into red blood cells (erythrocytes), white blood cells (leukocytes), and platelets. The cells are released into the bloodstream to travel throughout the body performing their specific functions. Red blood cells deliver oxygen to the body, white blood cells help in fighting off infections, and platelets allow the body to form clots to stop bleeding. The degree of bone marrow failure can greatly vary from very mild with only one type of blood cell affected to very severe with low counts in all blood cell lineages. Bone marrow examination shows a reduced number of blood cell producing progenitor cells (hyopcelular or empty bone marrow). Sometimes it is not only the blood counts that are abnormal but the blood cells themselves can show abnormalities, such as chromosomal (karyotypic) differences. These findings are usually described as myelodysplasia or myelodysplastic syndrome (MDS). Patients with MDS are at a higher risk of developing leukemia particularly if they are associated with certain karyotypic abnormities such as only one chromosome 7 (monosomy 7) over a long period of time. In rare cases MDS or leukemia may be the first manifestation of disease.Pancytopenia (low blood cell count of all blood cell lineages) may result in a variety of symptoms. Bruising, small red spots on the skin (petechiae), paleness of the skin (pallor) and frequent infections may be the first signs of bone marrow failure. The specific symptoms and progression of the disorder vary from case to case. Some individuals may have mild symptoms that remain stable for many years; others may have serious symptoms that can progress to life-threatening complications. Bone marrow failure may develop during childhood or not become severe until well into adulthood. Individuals with anemia may experience tiredness, increased need for sleep, weakness, lightheadedness, dizziness, irritability, headaches, pale skin color, difficulty breathing (dyspnea), and cardiac symptoms. Individuals with low white blood cell counts (leukopenia) have an increased risk of contracting bacterial and fungal infections. Individuals with low platelet counts (thrombocytopenia) are more susceptible to excessive bruising following minimal injury and to spontaneous bleeding from the mucous membranes, especially those of the gums and nose.Some patients with the same genetic abnormality responsible for dyskeratosis congenita may present with bone marrow failure only. The severity of bone marrow failure in these patients can vary greatly, from affecting only one or two blood values in peripheral blood, to the full picture with low blood counts in all blood cell lineages, a condition termed aplastic anemia. Features of the skin or other symptoms associated with dyskeratosis congenita may not be present or be so mild that they are not appreciated. These patients are often initially misdiagnosed as having idiopathic aplastic anemia (see also below). Whether patients with the genetic abnormality for dyskeratosis congenita but only showing bone marrow failure should be classified as having dyskeratosis congenita is controversial, alternative classifications used are atypical dyskeratosis congenita, or aplastic anemia with short telomeres. It is important that in these individuals the treatment plan, response to treatment, disease surveillance, and prognosis differs from patients with idiopathic aplastic anemia. In addition because of the inherited nature of the disease, members of the family of the affected individual may also be at risk.Leukemia and cancerIndividuals with dyskeratosis congenita also have a predisposition to develop leukemia and cancer (malignancy) especially squamous cell carcinoma of the head and neck, and especially at the site of leukoplakia. If cancer occurs, it usually does not develop until the age of about 30. Thus, leukemia and cancer are more common in individuals who have a moderate or milder form of dyskeratosis congenita. Individuals who underwent a stem cell or bone marrow transplant for the treatment of their bone marrow failure are also at risk of developing cancer later in life. In rare cases leukemia or cancer may be the first manifestation of disease.Lung diseaseThe development of lung disease (pulmonary fibrosis) is often found in patients with dyskeratosis congenita. It usually develops later than the skin abnormalities and bone marrow failure, however in some patients with mild disease pulmonary fibrosis may be the first or only obvious manifestation. In these patients disease usually manifest at the age of 50 to 60 years of age. The cause of pulmonary fibrosis in patients with dyskeratosis congenita is not fully understood. Breathing difficulties and a decreased lung function may be signs of lung disease. Smoking seems to accelerate the progression of pulmonary disease.Other symptomsA variety of additional symptoms have been reported in individuals with dyskeratosis congenita. These symptoms occur with much less frequency than the abovementioned symptoms. These less common symptoms include excessively watery eyes due to obstruction of the tear ducts (epiphora), excessive sweating (hyperhidrosis) of the palms of the hands and the soles of the feet, cavities and tooth loss, narrowing of the esophagus (esophageal stricture), urinary tract anomalies, especially hypospadism, early graying and premature hair loss, lung disease and short stature, liver disease, underdeveloped testes (hypogonadism), failure of the testes to descend into the scrotum, and skeletal abnormalities.Some affected children may experience delays in attaining developmental milestones and learning disabilities. Additional symptoms have been reported that occur in less than 10 percent of cases including deafness, or abnormalities of the eye retina.Hoyeraal-Hreidarsson syndrome Once considered a separate disorder, Hoyeraal-Hreidarsson syndrome is now identified as a severe variant of dyskeratosis congenita. Symptoms usually occur during the first year of life and include severe growth retardation that occurs before birth (intrauterine growth retardation), bone marrow failure, immune system deficiencies, underdevelopment of the cerebellum (cerebellar hypoplasia), clumsiness caused by the inability to coordinate voluntary movements (ataxia), and microcephaly, a condition that indicates that head circumference is smaller than would be expected for an infant’s age and sex. Abnormalities of the gut varying from malabsorbtion to severe inflammation with ulcers may be present in these children. Bone marrow failure and immune system deficiency may result in life-threatening complications. Because of the complexity and because multiple organs are severely impaired the prognosis of children diagnosed with Hoyeraal-Hreidarsson syndrome is usually poor. These children often die before they develop the characteristic nail and skin abnormalities.Revesz syndromeRevesz syndrome is another severe form of dyskeratosis congenita that may present similar to the Hoyeraal-Hreidarsson syndrome but in addition is associated with abnormalities of the eye (bilateral exudative retinopathy, Coats retinopathy). | 390 | Dyskeratosis Congenita |
nord_390_2 | Causes of Dyskeratosis Congenita | To date six genes when mutated have been shown to be responsible for dyskeratosis congenita. However, mutations in these genes only account for about one half of patients with classical clinical manifestations of dyskeratosis congenita, suggesting that there are additional genes that when mutated cause dyskeratosis congenita. X-linked dyskeratosis congenita The first gene to be identified was DKC1. Mutations in DKC1 are responsible for the X-linked form and for about 20-25% of sporadic cases. Male patients with DKC1 gene mutations, almost always present with the classic form of dyskeratosis congenita (high disease penetrance). Mutations in DKC1 have also been found in patients with Hoyeraal-Hreidarsson syndrome.X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females have two X chromosomes but one of the X chromosomes is “turned off” and all of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder or only very mild ones, because it is usually the X chromosome with the abnormal gene that is “turned off”. A male has one X chromosome and if he inherits an X chromosome that contains a disease gene, he will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Female carriers of an X-linked disorder have a 25% chance with each pregnancy of having a carrier daughter like themselves, a 25% chance of having a non-carrier daughter, a 25% chance of having a son affected with the disease, and a 25% chance of having an unaffected son. Investigators have shown that in the majority of families with an X-linked inheritance pattern of dyskeratosis congenita the disease results from changes or disruptions (mutations) of the DKC1 gene located on the end (distal) portion of the long arm of the X chromosome (Xq28). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome Xq28” refers to band 28 on the long arm of the X chromosome. The numbered bands specify the location of the thousands of genes that are present on each chromosome.The DKC1 gene contains instructions for the synthesis of a protein known as dyskerin. Dyskerin plays a role in the creation (biogenesis) of certain small structures found within cells that assemble proteins (ribosomes) and in the maintenance of telomeres, structures found at the end of chromosomes that are essential in the replication and stability of chromosomes. Autosomal dominant dyskeratosis congenitaDominant genetic disorders occur when only one of the two copies of a gene needs to be mutated for the disease to occur. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child. Investigators have found mutations in three different genes can account for some cases of the dominant form of dyskeratosis congenita. These include the telomerase RNA gene TERC located on the long arm (q) of the chromosome 3 (3q26), the gene encoding the enzymatically active component of telomerase TERT, located on the short arm of chromosome 5 (5p15.33) and the TINF2 gene encoding the telomere-associated protein TIN2 located on the long arm of chromosome 14 (14q12). Patients how carry a TERC or TERT gene mutation have often milder form of the disease compared to the X-linked form and some mutation carrier may not show disease, or only very late in life (low disease penetrance). However in rare cases TERT gene mutations have been identified to be responsible for severe forms of the disease including in patients with Hoyeraal-Hreidarsson syndrome. Patients who have inherited two mutations (homozygous or compound heterozygous), one from each parent, have usually an earlier onset and more severe disease. Patients with certain TINF2 gene mutations, have usually an early onset and severe disease. Mutations in TINF2 have also been found in patients with Revesz syndrome.Autosomal recessive dyskeratosis congenitaThree genes have been associated with the recessive form of dyskeratosis congenita; these are the NOP10 (NOLA3) gene, located on the long arm of chromosome 15 (15q14-q15) the NHP2 (NOLA2) gene, located on the long arm of chromosome 5 (5q35.3), and the TERT gene on chromosome 5 (5p15.33). Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. In some cases the parents, who each have a mutation in one copy of the gene may show mild disease, whereas the affected child, who has a mutation in both gene copies, will have more severe disease. In this scenario the effects of the mutations are additive and the mutations are expressed co-dominantly.Sporadic dyskeratosis congenitaIn a significant proportion of patients with moderate or severe disease the mutation is not inherited but has newly arisen either in the germ cells of the parents or shortly after conception (de novo mutation). De novo mutations in DKC1 and TINF2 have been found to be responsible for spontaneous dyskeratosis congenita, whereas spontaneous mutations in TERT causing disease in the first generation are very rare. Spontaneous mutations in TERC with disease in the first generation have not been described. Patients with de novo mutation usually have moderate to severe and progressive disease. A significant proportion of individuals thought to have sporadic dyskeratosis congenita actually have inherited the mutation from their parents, but their parents do not show disease. Similarly their siblings may also not show disease despite having inherited the mutation. This is due to fact that the manifestation of disease may vary (variable penetrance) and that the symptoms of disease manifestation may vary (variable expressivity). Disease anticipationIn some families with autosomal dominant dyskeratosis congenita the disease seems to get more severe and to occur earlier in life with subsequent generations. This is known as disease anticipation. Disease anticipation in autosomal dominant dyskeratosis congenita is thought to be due to the fact that not only the mutation, but also the short telomeres are inherited, and that these get shorter with every generation. Common pathway of the genes mutatedAll six genes that have been found to be mutated in patients with dyskeratosis congenita are involved in the elongation and maintenance of telomeres. Telomeres are the ends of chromosomes. Telomeres can be thought of as being like the plastic tips on shoelaces because they prevent chromosomes from sticking together, becoming frayed or damaged and protect the vital genetic information on a chromosome. Premature accelerated telomere shortening is thought to be the underlying mechanism of disease. It has been proposed that the time point when telomeres become critically short greatly determines the clinical picture of disease. According to this model, in the severe forms of dyskeratosis congenita, Hoyeraal-Hreidarsson syndrome and the Revesz syndrome the telomeres become critically short early in life, in classic dyskeratosis congenita telomeres are getting critically short during childhood and adolescence, and in atypical dyskeratosis congenita, telomeres become critically short in adults.When normal cells divide, the telomeres become shorter. When telomeres become too short, the cell stops growing or dies. The enzyme telomerase adds length to the telomeres so that they do not become too short too fast. The genes that are mutated in dyskeratosis congenita are all in one way or the other important for the telomerase enzyme to do its job or for the telomere end to be available for the enzyme. Mutations in these genes jeopardize the activity of the enzyme at the end of telomeres. Thus, the telomeres become shorter more rapidly until they are so short that the cell stops growing or dies. This occurs in all tissues, but fast dividing tissues such as the bone marrow, skin, and gut cells are affected the most.Indeed, when bone marrow failure becomes apparent, patients with dyskeratosis congenita have much shorter telomeres then normal individuals. The measurement of telomere length in circulating blood cells is therefore being increasingly used to identify patients who have bone marrow failure due to dyskeratosis congenita. Amongst patients with bone marrow failure, the detection of very short telomeres is a very sensitive way to identify patients with dyskeratosis congenita. In the absence of bone marrow failure telomere length does not predict the presence or absence of a disease causing mutation. Thus, telomere length in individuals who do not have bone marrow failure has to be interpreted with great caution. | Causes of Dyskeratosis Congenita. To date six genes when mutated have been shown to be responsible for dyskeratosis congenita. However, mutations in these genes only account for about one half of patients with classical clinical manifestations of dyskeratosis congenita, suggesting that there are additional genes that when mutated cause dyskeratosis congenita. X-linked dyskeratosis congenita The first gene to be identified was DKC1. Mutations in DKC1 are responsible for the X-linked form and for about 20-25% of sporadic cases. Male patients with DKC1 gene mutations, almost always present with the classic form of dyskeratosis congenita (high disease penetrance). Mutations in DKC1 have also been found in patients with Hoyeraal-Hreidarsson syndrome.X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females have two X chromosomes but one of the X chromosomes is “turned off” and all of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder or only very mild ones, because it is usually the X chromosome with the abnormal gene that is “turned off”. A male has one X chromosome and if he inherits an X chromosome that contains a disease gene, he will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Female carriers of an X-linked disorder have a 25% chance with each pregnancy of having a carrier daughter like themselves, a 25% chance of having a non-carrier daughter, a 25% chance of having a son affected with the disease, and a 25% chance of having an unaffected son. Investigators have shown that in the majority of families with an X-linked inheritance pattern of dyskeratosis congenita the disease results from changes or disruptions (mutations) of the DKC1 gene located on the end (distal) portion of the long arm of the X chromosome (Xq28). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome Xq28” refers to band 28 on the long arm of the X chromosome. The numbered bands specify the location of the thousands of genes that are present on each chromosome.The DKC1 gene contains instructions for the synthesis of a protein known as dyskerin. Dyskerin plays a role in the creation (biogenesis) of certain small structures found within cells that assemble proteins (ribosomes) and in the maintenance of telomeres, structures found at the end of chromosomes that are essential in the replication and stability of chromosomes. Autosomal dominant dyskeratosis congenitaDominant genetic disorders occur when only one of the two copies of a gene needs to be mutated for the disease to occur. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child. Investigators have found mutations in three different genes can account for some cases of the dominant form of dyskeratosis congenita. These include the telomerase RNA gene TERC located on the long arm (q) of the chromosome 3 (3q26), the gene encoding the enzymatically active component of telomerase TERT, located on the short arm of chromosome 5 (5p15.33) and the TINF2 gene encoding the telomere-associated protein TIN2 located on the long arm of chromosome 14 (14q12). Patients how carry a TERC or TERT gene mutation have often milder form of the disease compared to the X-linked form and some mutation carrier may not show disease, or only very late in life (low disease penetrance). However in rare cases TERT gene mutations have been identified to be responsible for severe forms of the disease including in patients with Hoyeraal-Hreidarsson syndrome. Patients who have inherited two mutations (homozygous or compound heterozygous), one from each parent, have usually an earlier onset and more severe disease. Patients with certain TINF2 gene mutations, have usually an early onset and severe disease. Mutations in TINF2 have also been found in patients with Revesz syndrome.Autosomal recessive dyskeratosis congenitaThree genes have been associated with the recessive form of dyskeratosis congenita; these are the NOP10 (NOLA3) gene, located on the long arm of chromosome 15 (15q14-q15) the NHP2 (NOLA2) gene, located on the long arm of chromosome 5 (5q35.3), and the TERT gene on chromosome 5 (5p15.33). Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. In some cases the parents, who each have a mutation in one copy of the gene may show mild disease, whereas the affected child, who has a mutation in both gene copies, will have more severe disease. In this scenario the effects of the mutations are additive and the mutations are expressed co-dominantly.Sporadic dyskeratosis congenitaIn a significant proportion of patients with moderate or severe disease the mutation is not inherited but has newly arisen either in the germ cells of the parents or shortly after conception (de novo mutation). De novo mutations in DKC1 and TINF2 have been found to be responsible for spontaneous dyskeratosis congenita, whereas spontaneous mutations in TERT causing disease in the first generation are very rare. Spontaneous mutations in TERC with disease in the first generation have not been described. Patients with de novo mutation usually have moderate to severe and progressive disease. A significant proportion of individuals thought to have sporadic dyskeratosis congenita actually have inherited the mutation from their parents, but their parents do not show disease. Similarly their siblings may also not show disease despite having inherited the mutation. This is due to fact that the manifestation of disease may vary (variable penetrance) and that the symptoms of disease manifestation may vary (variable expressivity). Disease anticipationIn some families with autosomal dominant dyskeratosis congenita the disease seems to get more severe and to occur earlier in life with subsequent generations. This is known as disease anticipation. Disease anticipation in autosomal dominant dyskeratosis congenita is thought to be due to the fact that not only the mutation, but also the short telomeres are inherited, and that these get shorter with every generation. Common pathway of the genes mutatedAll six genes that have been found to be mutated in patients with dyskeratosis congenita are involved in the elongation and maintenance of telomeres. Telomeres are the ends of chromosomes. Telomeres can be thought of as being like the plastic tips on shoelaces because they prevent chromosomes from sticking together, becoming frayed or damaged and protect the vital genetic information on a chromosome. Premature accelerated telomere shortening is thought to be the underlying mechanism of disease. It has been proposed that the time point when telomeres become critically short greatly determines the clinical picture of disease. According to this model, in the severe forms of dyskeratosis congenita, Hoyeraal-Hreidarsson syndrome and the Revesz syndrome the telomeres become critically short early in life, in classic dyskeratosis congenita telomeres are getting critically short during childhood and adolescence, and in atypical dyskeratosis congenita, telomeres become critically short in adults.When normal cells divide, the telomeres become shorter. When telomeres become too short, the cell stops growing or dies. The enzyme telomerase adds length to the telomeres so that they do not become too short too fast. The genes that are mutated in dyskeratosis congenita are all in one way or the other important for the telomerase enzyme to do its job or for the telomere end to be available for the enzyme. Mutations in these genes jeopardize the activity of the enzyme at the end of telomeres. Thus, the telomeres become shorter more rapidly until they are so short that the cell stops growing or dies. This occurs in all tissues, but fast dividing tissues such as the bone marrow, skin, and gut cells are affected the most.Indeed, when bone marrow failure becomes apparent, patients with dyskeratosis congenita have much shorter telomeres then normal individuals. The measurement of telomere length in circulating blood cells is therefore being increasingly used to identify patients who have bone marrow failure due to dyskeratosis congenita. Amongst patients with bone marrow failure, the detection of very short telomeres is a very sensitive way to identify patients with dyskeratosis congenita. In the absence of bone marrow failure telomere length does not predict the presence or absence of a disease causing mutation. Thus, telomere length in individuals who do not have bone marrow failure has to be interpreted with great caution. | 390 | Dyskeratosis Congenita |
nord_390_3 | Affects of Dyskeratosis Congenita | The prevalence or incidence of dyskeratosis congenita is difficult to assess. In a population of patients with bone marrow failure about 2-5% of patients have bone marrow failure due to dyskeratosis congenita. In patients with pulmonary fibrosis similarly 2-5% are thought to be due to mutations in TERC or TERT. In families with an increased frequency of bone marrow failure and/or lung disease, dyskeratosis congenita should be excluded as a possible cause of their disease. | Affects of Dyskeratosis Congenita. The prevalence or incidence of dyskeratosis congenita is difficult to assess. In a population of patients with bone marrow failure about 2-5% of patients have bone marrow failure due to dyskeratosis congenita. In patients with pulmonary fibrosis similarly 2-5% are thought to be due to mutations in TERC or TERT. In families with an increased frequency of bone marrow failure and/or lung disease, dyskeratosis congenita should be excluded as a possible cause of their disease. | 390 | Dyskeratosis Congenita |
nord_390_4 | Related disorders of Dyskeratosis Congenita | Symptoms of the following disorders can be similar to those of dyskeratosis congenita. Comparisons may be useful for a differential diagnosis.Fanconi anemia, also known as aplastic anemia with congenital anomalies, is a rare genetic disorder that may be apparent at birth or during childhood. In some cases, Fanconi anemia might not be diagnosed until adulthood. It is an inherited predisposition to gene mutations, probably because of a poor ability to repair chromosome damage (chromosome instability). The disorder is characterized by a deficiency of all bone marrow elements including red blood cells, white blood cells, and platelets (pancytopenia). Fanconi anemia may also be associated with heart (cardiac), kidney (renal), and/or skeletal abnormalities. It is commonly accompanied by patchy, brown discolorations (pigmentation changes) of the skin. There are several different subtypes (complementation groups) of Fanconi anemia, each of which is thought to result from an abnormal change (mutation) in a different gene. Each subtype appears to share the same characteristic symptoms and findings (phenotype). Most cases of Fanconi anemia have autosomal recessive inheritance. Fanconi anemia is not related in any way to Fanconi syndrome, a rare kidney disorder. (For more information on this disorder, choose “Fanconi” as your search term in the Rare Disease Database.)Acquired aplastic anemia is a rare disorder caused by profound, almost complete bone marrow failure. Bone marrow is the spongy substance found in the center of the long bones of the body. The bone marrow produces specialized cells (hematopoietic stem cells) that grow and eventually develop into red blood cells, white blood cells, and platelets. In acquired aplastic anemia, an almost complete absence of hematopoietic stem cells eventually results in low levels of red and white blood cells and platelets (pancytopenia). Specific symptoms associated with acquired aplastic anemia may vary, but include fatigue, chronic infections, dizziness, weakness, headaches, and episodes of excessive bleeding. In some instances acquired aplastic anemia is secondary to other disorders, or exposures (for example certain medications, exposure to toxins, or radiation). However, in most cases the cause for the development of acquired aplastic anemia is unknown. These patients are usually classified as having “idiopathic aplastic anemia”. Idiopathic meaning of unknown cause. Genetic testing in patients with idiopathic aplastic anemia increasingly shows that some of these patients actually have genetic disease or have a genetic predisposition to develop aplastic anemia. About 2-5% of patients originally diagnosed with idiopathic acquired aplastic anemia (and some cases with myelodysplasia, MDS) have actually the same genetic abnormality as patients with dyskeratosis congenita, but at the time of diagnosis they lacked the other characteristic features of dyskeratosis congenita, or these were so mild that they may not have been recognized. It is controversial whether disease in patients should be classified as “dyskeratosis congenita”, or “atypical dyskeratosis congenita”, or “aplastic anemia with short telomeres”. The patient’s immune system seems to play a role in the persistence of many cases of aplastic anemia. Some researchers believe that the immune system is even the primary cause of many cases of idiopathic aplastic anemia. This is based on the response of approximately half of patients to immune suppression, for example to anti thymocyte globulin (ATG), cyclosporine, or cyclophosphamide. (For more information on this disorder, choose “aplastic anemia” as your search term in the Rare Disease Database.) | Related disorders of Dyskeratosis Congenita. Symptoms of the following disorders can be similar to those of dyskeratosis congenita. Comparisons may be useful for a differential diagnosis.Fanconi anemia, also known as aplastic anemia with congenital anomalies, is a rare genetic disorder that may be apparent at birth or during childhood. In some cases, Fanconi anemia might not be diagnosed until adulthood. It is an inherited predisposition to gene mutations, probably because of a poor ability to repair chromosome damage (chromosome instability). The disorder is characterized by a deficiency of all bone marrow elements including red blood cells, white blood cells, and platelets (pancytopenia). Fanconi anemia may also be associated with heart (cardiac), kidney (renal), and/or skeletal abnormalities. It is commonly accompanied by patchy, brown discolorations (pigmentation changes) of the skin. There are several different subtypes (complementation groups) of Fanconi anemia, each of which is thought to result from an abnormal change (mutation) in a different gene. Each subtype appears to share the same characteristic symptoms and findings (phenotype). Most cases of Fanconi anemia have autosomal recessive inheritance. Fanconi anemia is not related in any way to Fanconi syndrome, a rare kidney disorder. (For more information on this disorder, choose “Fanconi” as your search term in the Rare Disease Database.)Acquired aplastic anemia is a rare disorder caused by profound, almost complete bone marrow failure. Bone marrow is the spongy substance found in the center of the long bones of the body. The bone marrow produces specialized cells (hematopoietic stem cells) that grow and eventually develop into red blood cells, white blood cells, and platelets. In acquired aplastic anemia, an almost complete absence of hematopoietic stem cells eventually results in low levels of red and white blood cells and platelets (pancytopenia). Specific symptoms associated with acquired aplastic anemia may vary, but include fatigue, chronic infections, dizziness, weakness, headaches, and episodes of excessive bleeding. In some instances acquired aplastic anemia is secondary to other disorders, or exposures (for example certain medications, exposure to toxins, or radiation). However, in most cases the cause for the development of acquired aplastic anemia is unknown. These patients are usually classified as having “idiopathic aplastic anemia”. Idiopathic meaning of unknown cause. Genetic testing in patients with idiopathic aplastic anemia increasingly shows that some of these patients actually have genetic disease or have a genetic predisposition to develop aplastic anemia. About 2-5% of patients originally diagnosed with idiopathic acquired aplastic anemia (and some cases with myelodysplasia, MDS) have actually the same genetic abnormality as patients with dyskeratosis congenita, but at the time of diagnosis they lacked the other characteristic features of dyskeratosis congenita, or these were so mild that they may not have been recognized. It is controversial whether disease in patients should be classified as “dyskeratosis congenita”, or “atypical dyskeratosis congenita”, or “aplastic anemia with short telomeres”. The patient’s immune system seems to play a role in the persistence of many cases of aplastic anemia. Some researchers believe that the immune system is even the primary cause of many cases of idiopathic aplastic anemia. This is based on the response of approximately half of patients to immune suppression, for example to anti thymocyte globulin (ATG), cyclosporine, or cyclophosphamide. (For more information on this disorder, choose “aplastic anemia” as your search term in the Rare Disease Database.) | 390 | Dyskeratosis Congenita |
nord_390_5 | Diagnosis of Dyskeratosis Congenita | A diagnosis of dyskeratosis congenita may be suspected based upon a thorough clinical evaluation, detailed patient history, and identification of characteristic findings especially changes in the skin or mouth. In individuals who develop aplastic anemia as the first sign of the disorder or pulmonary fibrosis diagnosis is more difficult.Very short telomeres in peripheral blood cells may support the diagnosis of dyskeratosis in patients who present with bone marrow failure.Molecular genetic tests to determine mutations in the DKC1, TERC, TERT, TINF2 NHP2, or NOP10 gene can confirm a diagnosis of dyskeratosis congenita. However, clinical genetic testing is expensive and for some genes only available on a research basis. Furthermore, genetic testing usually does not test for large gene deletions, thus patients with disease due to a large gene deletion are usually missed. Difficult may also be the proof that the identified sequence variant is in fact responsible for disease might be difficult. Not all the mutations described in the literature are in fact responsible for disease (rare polymorphisms) or cause disease in all individuals (variable penetrance). In about 50% of patients no mutation is identified, despite the presence of classic clinical manifestations. | Diagnosis of Dyskeratosis Congenita. A diagnosis of dyskeratosis congenita may be suspected based upon a thorough clinical evaluation, detailed patient history, and identification of characteristic findings especially changes in the skin or mouth. In individuals who develop aplastic anemia as the first sign of the disorder or pulmonary fibrosis diagnosis is more difficult.Very short telomeres in peripheral blood cells may support the diagnosis of dyskeratosis in patients who present with bone marrow failure.Molecular genetic tests to determine mutations in the DKC1, TERC, TERT, TINF2 NHP2, or NOP10 gene can confirm a diagnosis of dyskeratosis congenita. However, clinical genetic testing is expensive and for some genes only available on a research basis. Furthermore, genetic testing usually does not test for large gene deletions, thus patients with disease due to a large gene deletion are usually missed. Difficult may also be the proof that the identified sequence variant is in fact responsible for disease might be difficult. Not all the mutations described in the literature are in fact responsible for disease (rare polymorphisms) or cause disease in all individuals (variable penetrance). In about 50% of patients no mutation is identified, despite the presence of classic clinical manifestations. | 390 | Dyskeratosis Congenita |
nord_390_6 | Therapies of Dyskeratosis Congenita | TreatmentThere is no consensus about how to treat patients with dyskeratosis congenita. The literature is biased toward treatment and treatment outcome of patients who present with the classical form of disease. Little is still known about the treatment and disease monitoring of individuals with atypical or silent disease.The treatment of dyskeratosis congenita is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, adult internists and hematologist, dermatologists, dental specialists, medical geneticist, cancer specialists (oncologists) and other healthcare professionals may need to systematically and comprehensively plan an affected individual's treatment.General treatment recommendations for individuals with dyskeratosis congenita include avoiding smoking and alcohol to preserve the lungs and liver and the use of moisturizing creams to prevent damage to the skin. Good dental hygiene may help to prevent early tooth loss and delay the development of malignancy of the tongue. In certain patients marrow failure and immunodeficiency transiently respond to androgens and hematopoietic growth hormones.Androgens (e.g., oxymetholone), which are artificial male hormones, may increase red blood cell and, less often, platelet production in some individuals. Androgen therapy may be supplemented with corticosteroid (e.g., prednisone) therapy, which may delay growth acceleration potentially associated with androgen therapy and reduce bleeding associated with thrombocytopenia.A class of drugs known as hematopoietic growth factors has been used to treat individuals with dyskeratosis congenita, specifically granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF). These growth factors may transiently increase the production of certain white blood cells (neutrophils). In rare cases, treatment with these drugs also increases red blood cell and platelet levels.In most cases, the benefits of androgens and growth factors are only temporary. The specific amount of time these treatments improve bone marrow function varies in each individual case.If a compatible donor can be located, hematopoietic stem cell transplantation can potentially cure the blood abnormalities associated with dyskeratosis congenita. Hematopoietic stem cell transplantation should be considered in patients who present with mainly bone marrow failure. Hematopoietic stem cell transplant does not improve tissues affected by dyskeratosis cogenita. Patients with dyskeratosis congenita have an increased sensitivity towards radiation and certain chemotherapy drugs. An alternative conditioning regiment is without irradiation or certain chemotherapy drugs such as busulfan or melphalan should be avoided. Pulmonary complications after hematopoietic stem cell transplantation are not uncommon and may be fatal.The hypersensitivity of individuals with dyskeratosis congenita to radiation and chemotherapy encumbers the treatment of cancer in these individuals. Surgical resection of the cancer is probably the first line of treatment.Affected individuals should be monitored for the development of lung disease and cancer. Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive. | Therapies of Dyskeratosis Congenita. TreatmentThere is no consensus about how to treat patients with dyskeratosis congenita. The literature is biased toward treatment and treatment outcome of patients who present with the classical form of disease. Little is still known about the treatment and disease monitoring of individuals with atypical or silent disease.The treatment of dyskeratosis congenita is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, adult internists and hematologist, dermatologists, dental specialists, medical geneticist, cancer specialists (oncologists) and other healthcare professionals may need to systematically and comprehensively plan an affected individual's treatment.General treatment recommendations for individuals with dyskeratosis congenita include avoiding smoking and alcohol to preserve the lungs and liver and the use of moisturizing creams to prevent damage to the skin. Good dental hygiene may help to prevent early tooth loss and delay the development of malignancy of the tongue. In certain patients marrow failure and immunodeficiency transiently respond to androgens and hematopoietic growth hormones.Androgens (e.g., oxymetholone), which are artificial male hormones, may increase red blood cell and, less often, platelet production in some individuals. Androgen therapy may be supplemented with corticosteroid (e.g., prednisone) therapy, which may delay growth acceleration potentially associated with androgen therapy and reduce bleeding associated with thrombocytopenia.A class of drugs known as hematopoietic growth factors has been used to treat individuals with dyskeratosis congenita, specifically granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF). These growth factors may transiently increase the production of certain white blood cells (neutrophils). In rare cases, treatment with these drugs also increases red blood cell and platelet levels.In most cases, the benefits of androgens and growth factors are only temporary. The specific amount of time these treatments improve bone marrow function varies in each individual case.If a compatible donor can be located, hematopoietic stem cell transplantation can potentially cure the blood abnormalities associated with dyskeratosis congenita. Hematopoietic stem cell transplantation should be considered in patients who present with mainly bone marrow failure. Hematopoietic stem cell transplant does not improve tissues affected by dyskeratosis cogenita. Patients with dyskeratosis congenita have an increased sensitivity towards radiation and certain chemotherapy drugs. An alternative conditioning regiment is without irradiation or certain chemotherapy drugs such as busulfan or melphalan should be avoided. Pulmonary complications after hematopoietic stem cell transplantation are not uncommon and may be fatal.The hypersensitivity of individuals with dyskeratosis congenita to radiation and chemotherapy encumbers the treatment of cancer in these individuals. Surgical resection of the cancer is probably the first line of treatment.Affected individuals should be monitored for the development of lung disease and cancer. Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive. | 390 | Dyskeratosis Congenita |
nord_391_0 | Overview of Dysplasia Epiphysealis Hemimelica | Dysplasia epiphysealis hemimelica (DEH), also known as Trevor’s disease, is a developmental bone disease of childhood. It is very rare and clinical experience with this condition is limited. It is extremely rare in adults. Most cases are diagnosed before 8 years of age. It is characterized by a benign, abnormal growth of cartilage arising most frequently from the pre-existing cartilage of the distal ends (epiphysis)of the long bones. The joints of the lower limbs are most frequently affected including the ankle, knee, hip joints and the foot bones. The upper limbs are less frequently affected. The abnormal cartilage produces an irregular mass with varying degrees of deformities of the bone and adjacent joints. DEH may affect a single bone (localized form), multiple bones in a single limb (classical form) or an entire limb (generalized) usually involving a leg from the pelvis to the foot. Approximately two-thirds of affected children have the classic form. The lesions are usually located on the same side of the limbs, mostly medial, and this is called hemimelia. DEH was first described in the medical literature in 1926. Trevor recognized this condition in 1950. The name, dysplasia epiphysealis hemimelica first appeared in the medical literature in 1956. | Overview of Dysplasia Epiphysealis Hemimelica. Dysplasia epiphysealis hemimelica (DEH), also known as Trevor’s disease, is a developmental bone disease of childhood. It is very rare and clinical experience with this condition is limited. It is extremely rare in adults. Most cases are diagnosed before 8 years of age. It is characterized by a benign, abnormal growth of cartilage arising most frequently from the pre-existing cartilage of the distal ends (epiphysis)of the long bones. The joints of the lower limbs are most frequently affected including the ankle, knee, hip joints and the foot bones. The upper limbs are less frequently affected. The abnormal cartilage produces an irregular mass with varying degrees of deformities of the bone and adjacent joints. DEH may affect a single bone (localized form), multiple bones in a single limb (classical form) or an entire limb (generalized) usually involving a leg from the pelvis to the foot. Approximately two-thirds of affected children have the classic form. The lesions are usually located on the same side of the limbs, mostly medial, and this is called hemimelia. DEH was first described in the medical literature in 1926. Trevor recognized this condition in 1950. The name, dysplasia epiphysealis hemimelica first appeared in the medical literature in 1956. | 391 | Dysplasia Epiphysealis Hemimelica |
nord_391_1 | Symptoms of Dysplasia Epiphysealis Hemimelica | The symptoms present in each child with DEH vary depending on the location and size of the cartilage mass. The most common is a painless mass or swelling on one side of an affected joint, mostly the medial side. Associated pain occurs at the beginning or at a later stage of the disease.Additional symptoms have been reported including decreased range of motion of affected joints, joint deformity, limb length discrepancy and muscle weakness in the involved area. Rarely, the joint may lock. Some children may limp due to damage of the involved joints of the lower extremities. If left untreated, the joint will develop degenerative arthritis.A small number of children with DEH have, in addition to the symptoms described above, calcified structures within the joints, which are described as “loose bodies” and are recognized by radiographs and CT studies. They represent osteocartilaginous fragments of DEH tissue, originally located in the distal end of the long bones, which has spread out into the adjacent joint. | Symptoms of Dysplasia Epiphysealis Hemimelica. The symptoms present in each child with DEH vary depending on the location and size of the cartilage mass. The most common is a painless mass or swelling on one side of an affected joint, mostly the medial side. Associated pain occurs at the beginning or at a later stage of the disease.Additional symptoms have been reported including decreased range of motion of affected joints, joint deformity, limb length discrepancy and muscle weakness in the involved area. Rarely, the joint may lock. Some children may limp due to damage of the involved joints of the lower extremities. If left untreated, the joint will develop degenerative arthritis.A small number of children with DEH have, in addition to the symptoms described above, calcified structures within the joints, which are described as “loose bodies” and are recognized by radiographs and CT studies. They represent osteocartilaginous fragments of DEH tissue, originally located in the distal end of the long bones, which has spread out into the adjacent joint. | 391 | Dysplasia Epiphysealis Hemimelica |
nord_391_2 | Causes of Dysplasia Epiphysealis Hemimelica | The cause of DEH is unknown. There is no evidence that hereditary factors play a role in the development of this disease. More research is necessary to determine the exact underlying cause(s) of this disorder. DEH is benign and there are no reports of malignant transformation of the cartilage abnormality. | Causes of Dysplasia Epiphysealis Hemimelica. The cause of DEH is unknown. There is no evidence that hereditary factors play a role in the development of this disease. More research is necessary to determine the exact underlying cause(s) of this disorder. DEH is benign and there are no reports of malignant transformation of the cartilage abnormality. | 391 | Dysplasia Epiphysealis Hemimelica |
nord_391_3 | Affects of Dysplasia Epiphysealis Hemimelica | DEH usually affects children between the ages of 1 and 15. Males are affected more often than females. The incidence of DEH has been estimated at 1 in 1,000,000 individuals in the general population. However, some authors consider that the incidence is probably higher because some patients may be misdiagnosed with other conditions. | Affects of Dysplasia Epiphysealis Hemimelica. DEH usually affects children between the ages of 1 and 15. Males are affected more often than females. The incidence of DEH has been estimated at 1 in 1,000,000 individuals in the general population. However, some authors consider that the incidence is probably higher because some patients may be misdiagnosed with other conditions. | 391 | Dysplasia Epiphysealis Hemimelica |
nord_391_4 | Related disorders of Dysplasia Epiphysealis Hemimelica | The following disorders can histologically resemble those of DEH:Osteochondroma is the most common benign tumor of bone and usually develops between 10 and 30 years of age. It frequently occurs near the ends of the long bones (metaphysis) of the arms and legs. Radiographs demonstrate a bony mass arising from the surface of the bone and is not related to the joint. Although osteochondroma may resemble DEH histologically, it is a separate disease and should not be mistaken for DEH. The latter occurs in younger children and usually arises in the bones within the joints.Synovial chondromatosis is a benign condition arising from synovium, the thin layer of tissue covering the inner surface of the joints. It consists of numerous cartilage nodules measuring from a few millimeters to 1-2 cm in size. Synovial chondromatosis occurs most frequently in the knee of middle-aged patients, although other joints can be affected. It is very rare in children.Intracapsular or para-articular chondroma is a rare benign tumor composed of cartilage that originates from the connective-tissue outside the large joints, such as the knee. This lesion is rare in children. | Related disorders of Dysplasia Epiphysealis Hemimelica. The following disorders can histologically resemble those of DEH:Osteochondroma is the most common benign tumor of bone and usually develops between 10 and 30 years of age. It frequently occurs near the ends of the long bones (metaphysis) of the arms and legs. Radiographs demonstrate a bony mass arising from the surface of the bone and is not related to the joint. Although osteochondroma may resemble DEH histologically, it is a separate disease and should not be mistaken for DEH. The latter occurs in younger children and usually arises in the bones within the joints.Synovial chondromatosis is a benign condition arising from synovium, the thin layer of tissue covering the inner surface of the joints. It consists of numerous cartilage nodules measuring from a few millimeters to 1-2 cm in size. Synovial chondromatosis occurs most frequently in the knee of middle-aged patients, although other joints can be affected. It is very rare in children.Intracapsular or para-articular chondroma is a rare benign tumor composed of cartilage that originates from the connective-tissue outside the large joints, such as the knee. This lesion is rare in children. | 391 | Dysplasia Epiphysealis Hemimelica |
nord_391_5 | Diagnosis of Dysplasia Epiphysealis Hemimelica | The diagnosis of DEH is made based on the child’s history and the evaluation of imaging studies which include plain radiographs (X-rays), computed tomography (CT) and particularly magnetic resonance imaging (MRI). If possible, the expert knowledge of a pediatric or bone radiologist is very important for the diagnosis of this very rare disorder. In early childhood, as the disease consists mainly of growing cartilage, initial radiographs of the joint may appear normal or show minimal changes. As the child grows older, there is progression of the disease, and the abnormal cartilage mass undergoes bone formation (osteocartilaginous mass) and will be recognized by radiographs and CT. MRI is the best technique to demonstrate the uncalcified cartilaginous component of the lesion and the extent of epiphyseal and joint involvement. MRI can also establish the diagnosis of DEH at an early stage of the disease.Once the diagnosis of DEH is made, other sites of involvement at initial presentation should be considered, and a radiographic skeletal survey (radiographs of all bones) may be indicated. Clinical observation until puberty is also recommended as new lesions may appear later. The lesion of DEH grows until skeletal maturation with closure of the epiphyseal growth plate. | Diagnosis of Dysplasia Epiphysealis Hemimelica. The diagnosis of DEH is made based on the child’s history and the evaluation of imaging studies which include plain radiographs (X-rays), computed tomography (CT) and particularly magnetic resonance imaging (MRI). If possible, the expert knowledge of a pediatric or bone radiologist is very important for the diagnosis of this very rare disorder. In early childhood, as the disease consists mainly of growing cartilage, initial radiographs of the joint may appear normal or show minimal changes. As the child grows older, there is progression of the disease, and the abnormal cartilage mass undergoes bone formation (osteocartilaginous mass) and will be recognized by radiographs and CT. MRI is the best technique to demonstrate the uncalcified cartilaginous component of the lesion and the extent of epiphyseal and joint involvement. MRI can also establish the diagnosis of DEH at an early stage of the disease.Once the diagnosis of DEH is made, other sites of involvement at initial presentation should be considered, and a radiographic skeletal survey (radiographs of all bones) may be indicated. Clinical observation until puberty is also recommended as new lesions may appear later. The lesion of DEH grows until skeletal maturation with closure of the epiphyseal growth plate. | 391 | Dysplasia Epiphysealis Hemimelica |
nord_391_6 | Therapies of Dysplasia Epiphysealis Hemimelica | TreatmentThe treatment of DEH is essentially surgical removal of the osteocartilaginous mass, usually by a pediatric orthopedic surgeon. If the child is free of pain or other symptoms and shows no evidence of joint deformity or any other abnormality, conservative treatment with close follow up and observation may be indicated. In children with a history of pain, swelling, joint deformity and limited function, surgery is recommended. During surgical resection, any damage of the pre-existing cartilage should be avoided. The presence in the MRI of cleavage or separation between the abnormal tissue and the normal cartilage may facilitate the removal of the lesion by the surgeon. Recurrence is infrequent but has been reported. DEH is a benign condition and there is no evidence of malignant transformation. Some children with incomplete resections may do well and do not require additional surgery.Children who present with loose bodies within the joints usually undergo arthroscopy (minimally invasive surgical procedure) in order to evaluate the conditions within the joint and also facilitate the removal of the loose bodies. If they are too large, the loose bodies are removed through a surgical incision.In some cases of DEH, other types of treatment may be necessary according to the location, size of the lesion and the duration of the disease. | Therapies of Dysplasia Epiphysealis Hemimelica. TreatmentThe treatment of DEH is essentially surgical removal of the osteocartilaginous mass, usually by a pediatric orthopedic surgeon. If the child is free of pain or other symptoms and shows no evidence of joint deformity or any other abnormality, conservative treatment with close follow up and observation may be indicated. In children with a history of pain, swelling, joint deformity and limited function, surgery is recommended. During surgical resection, any damage of the pre-existing cartilage should be avoided. The presence in the MRI of cleavage or separation between the abnormal tissue and the normal cartilage may facilitate the removal of the lesion by the surgeon. Recurrence is infrequent but has been reported. DEH is a benign condition and there is no evidence of malignant transformation. Some children with incomplete resections may do well and do not require additional surgery.Children who present with loose bodies within the joints usually undergo arthroscopy (minimally invasive surgical procedure) in order to evaluate the conditions within the joint and also facilitate the removal of the loose bodies. If they are too large, the loose bodies are removed through a surgical incision.In some cases of DEH, other types of treatment may be necessary according to the location, size of the lesion and the duration of the disease. | 391 | Dysplasia Epiphysealis Hemimelica |
nord_392_0 | Overview of Dystonia | SummaryDystonia is a general term for a large group of movement disorders that vary in their symptoms, causes, progression, and treatments. This group of neurological conditions is generally characterized by involuntary muscle contractions that force the body into abnormal, sometimes painful, movements and positions (postures). The muscular contractions may be sustained or come and go (intermittent). Movements may be patterned and twisting, and/or in some cases shaking or quivering (tremulous) resembling a tremor. Dystonia may occur or be worsened when an individual attempts a voluntary action. There are many different causes for dystonia. Genetic as well as non-genetic factors can contribute to the development of these disorders. In some cases, the exact, underlying cause is unknown (idiopathic). The most characteristic finding associated with most forms of dystonia is twisting, repetitive movements that affect the neck, torso, limbs, eyes, face, vocal chords, and/or a combination of these muscle groups. Certain forms such as laryngeal dystonia are not associated with abnormal postures. Dystonia causes varying degrees of disability that ranges from mild symptoms that come and go to severe, debilitating symptoms that can significantly affect a person’s quality of life. Only in some cases pain can be present. Usually there is no weakness in the affected muscle groups. In some cases dystonia can become progressively worse, while in others it remains unchanged or no longer worsens (plateaus). Dystonia may even spontaneously remit in rare cases. Treatment for dystonia depends upon several factors including the specific subtype present and can include medications, botulinum toxin injections, physical therapy and surgery.IntroductionDystonia was first described in the medical literature as far back as the 1800s. However, the classification of dystonia has always been complicated and controversial, resulting in confusion, not only for patients, but within the medical community as well. A new basis for classifying the dystonias has been proposed based on a consensus achieved by an international expert group of physicians (Albanese A, et al. 2013). This group has proposed to classify dystonia based on clinical features and etiology.Classifying dystonia by clinical features includes age of onset, body distribution, temporal pattern, and associated features. Age of onset is broken down into infancy (birth to 2 years), childhood (3-12 years), adolescence (13-20), early adulthood (21-40), and late adulthood (greater than 40 years). Dystonia that develops during infancy or childhood is more likely to have a known cause and to progress to become widespread.Classifying dystonia by the specific body part(s) affected is common to many classification systems. Generally, dystonia may be focal (affecting an isolated body part), segmental (affecting adjacent body areas), multifocal (two or more noncontiguous areas), generalized (affecting the trunk and two other body regions), and hemidystonia (affecting one side of the body).Temporal pattern helps to distinguish between dystonia that becomes progressively worse, in terms of intensity and/or involvement of other muscles groups, or remains unchanged (static). It also refers to the variability in disease expression in relation to other factors such as external triggers or voluntary actions. Temporal patterns can be broken down into four types: persistent, in which dystonia persists throughout the day without fluctuation; task-specific, in which dystonia occurs only during a specific action or task (e.g. writer’s cramp); diurnal fluctuations, in which dystonia fluctuates in severity at certain points throughout the day and often lessens during the night; and paroxysmal in which a sudden, temporary episode of dystonia occurs often as the result of a specific trigger.Dystonia can also be classified by whether or not dystonia occurs along with another movement disorder. Isolated dystonia is when dystonia is the only motor feature with the exception of tremor. Combined dystonia is used when another movement disorder such as Parkinsonism or myoclonus is also present.The etiology axis refers to whether degenerative changes or structural damage is present in the nervous system (nervous system pathology) and whether the disorder is inherited or acquired, or whether the underlying cause is unknown or unproven (idiopathic).The use of this new classification would deemphasize much of the current terminology used in describing dystonia. Some of the current terminology would be rendered obsolete. Current terminology used to categorize dystonia includes primary dystonia, secondary dystonia, dystonia plus syndromes, and heredodegenerative dystonia. Primary dystonia referred to cases in which dystonia was the only clinical features (isolated dystonia), there was no evidence of brain degeneration, and without an acquired cause. Primary dystonia may be inherited or occur for unknown reasons (idiopathic). Secondary dystonia referred to cases in which dystonia resulted from a broad range of causes including genetic mutations, birth injury, stroke, brain tumors, certain infections, and as a reaction to certain drugs. Dystonia plus syndromes referred to disorders in which dystonia occurred in conjunction with another neurological disorder such as myoclonus or Parkinsonism. Heredodegenerative dystonia referred to hereditary cases that were associated with neurodegeneration and occur with other neurological symptoms.Until a consistent, straightforward classification system is adopted by the medical community confusion regarding terminology in describing dystonia will persist. In addition, dystonia is a rapidly growing disease family and information about these disorders is constantly changing. | Overview of Dystonia. SummaryDystonia is a general term for a large group of movement disorders that vary in their symptoms, causes, progression, and treatments. This group of neurological conditions is generally characterized by involuntary muscle contractions that force the body into abnormal, sometimes painful, movements and positions (postures). The muscular contractions may be sustained or come and go (intermittent). Movements may be patterned and twisting, and/or in some cases shaking or quivering (tremulous) resembling a tremor. Dystonia may occur or be worsened when an individual attempts a voluntary action. There are many different causes for dystonia. Genetic as well as non-genetic factors can contribute to the development of these disorders. In some cases, the exact, underlying cause is unknown (idiopathic). The most characteristic finding associated with most forms of dystonia is twisting, repetitive movements that affect the neck, torso, limbs, eyes, face, vocal chords, and/or a combination of these muscle groups. Certain forms such as laryngeal dystonia are not associated with abnormal postures. Dystonia causes varying degrees of disability that ranges from mild symptoms that come and go to severe, debilitating symptoms that can significantly affect a person’s quality of life. Only in some cases pain can be present. Usually there is no weakness in the affected muscle groups. In some cases dystonia can become progressively worse, while in others it remains unchanged or no longer worsens (plateaus). Dystonia may even spontaneously remit in rare cases. Treatment for dystonia depends upon several factors including the specific subtype present and can include medications, botulinum toxin injections, physical therapy and surgery.IntroductionDystonia was first described in the medical literature as far back as the 1800s. However, the classification of dystonia has always been complicated and controversial, resulting in confusion, not only for patients, but within the medical community as well. A new basis for classifying the dystonias has been proposed based on a consensus achieved by an international expert group of physicians (Albanese A, et al. 2013). This group has proposed to classify dystonia based on clinical features and etiology.Classifying dystonia by clinical features includes age of onset, body distribution, temporal pattern, and associated features. Age of onset is broken down into infancy (birth to 2 years), childhood (3-12 years), adolescence (13-20), early adulthood (21-40), and late adulthood (greater than 40 years). Dystonia that develops during infancy or childhood is more likely to have a known cause and to progress to become widespread.Classifying dystonia by the specific body part(s) affected is common to many classification systems. Generally, dystonia may be focal (affecting an isolated body part), segmental (affecting adjacent body areas), multifocal (two or more noncontiguous areas), generalized (affecting the trunk and two other body regions), and hemidystonia (affecting one side of the body).Temporal pattern helps to distinguish between dystonia that becomes progressively worse, in terms of intensity and/or involvement of other muscles groups, or remains unchanged (static). It also refers to the variability in disease expression in relation to other factors such as external triggers or voluntary actions. Temporal patterns can be broken down into four types: persistent, in which dystonia persists throughout the day without fluctuation; task-specific, in which dystonia occurs only during a specific action or task (e.g. writer’s cramp); diurnal fluctuations, in which dystonia fluctuates in severity at certain points throughout the day and often lessens during the night; and paroxysmal in which a sudden, temporary episode of dystonia occurs often as the result of a specific trigger.Dystonia can also be classified by whether or not dystonia occurs along with another movement disorder. Isolated dystonia is when dystonia is the only motor feature with the exception of tremor. Combined dystonia is used when another movement disorder such as Parkinsonism or myoclonus is also present.The etiology axis refers to whether degenerative changes or structural damage is present in the nervous system (nervous system pathology) and whether the disorder is inherited or acquired, or whether the underlying cause is unknown or unproven (idiopathic).The use of this new classification would deemphasize much of the current terminology used in describing dystonia. Some of the current terminology would be rendered obsolete. Current terminology used to categorize dystonia includes primary dystonia, secondary dystonia, dystonia plus syndromes, and heredodegenerative dystonia. Primary dystonia referred to cases in which dystonia was the only clinical features (isolated dystonia), there was no evidence of brain degeneration, and without an acquired cause. Primary dystonia may be inherited or occur for unknown reasons (idiopathic). Secondary dystonia referred to cases in which dystonia resulted from a broad range of causes including genetic mutations, birth injury, stroke, brain tumors, certain infections, and as a reaction to certain drugs. Dystonia plus syndromes referred to disorders in which dystonia occurred in conjunction with another neurological disorder such as myoclonus or Parkinsonism. Heredodegenerative dystonia referred to hereditary cases that were associated with neurodegeneration and occur with other neurological symptoms.Until a consistent, straightforward classification system is adopted by the medical community confusion regarding terminology in describing dystonia will persist. In addition, dystonia is a rapidly growing disease family and information about these disorders is constantly changing. | 392 | Dystonia |
nord_392_1 | Symptoms of Dystonia | Early onset childhood dystonia (generalized dystonia) is a neurologic movement disorder that usually begins in childhood or adolescence. Symptoms start in one part of the body (usually an arm or leg) and may eventually spread to other parts of the body, causing contractions and spasms of muscles that twist the body into unnatural positions. This is the most common hereditary form of dystonia, in most cases caused by changes (mutations) the DYT1 gene. Specific symptoms can vary from one person to another even among individuals with the same subtype. Specific symptoms may occur based upon the specific part of the body involved, age of onset and the underlying cause. Dystonias with an earlier age of onset are more likely to progress from a focal presentation to a generalized one and are usually more severe. Adult onset forms of dystonia tend to exhibit a focal presentation and usually do not progress. Some affected individuals can temporarily interrupt dystonic movements or postures by performing a specific action or maneuver. This is known as ‘gestes antagoniste’ or a sensory trick. Usually, the action involves a body part not affected by dystonia, but often nearby the affected area. For example, some individuals can temporarily alleviate cervical dystonia by touching their chins. Changing the pattern of muscle activation can also improve certain dystonic postures. For example, in patients with foot dystonia causing an abnormal turning of one foot when walking, when asked to run or to walk backwards they can present a reduction of this abnormal posturing. Some of the better known forms of dystonia are briefly discussed below. NORD has individual reports on many of the specific dystonia subtypes. For more information, choose the specific disorder name as your search term in the Rare Disease Database.ISOLATED FOCAL DYSTONIA Isolated focal dystonias are the most common dystonias and can include benign essential blepharospasm, cervical dystonia, oromandibular dystonia, and laryngeal dystonia. These dystonias often have adult onset. NORD has individual reports on these forms of dystonia. Isolated limb dystonia may occur in adults and often affects the arms and/or hands. Many are occupational or task-specific. Occupational or task-specific dystonia are general terms that refer to focal dystonia associated with a particular, often repetitive, activity. Initially, affected individuals may exhibit a lack of dexterity when performing the activity in question. Eventually, the condition progresses to cause repetitive movements and abnormal postures. The most common form may be writer’s cramp, in which abnormal flexion, extension or rotation of the fingers and wrist occurs when an affected individual writes. In some cases writing with the unaffected hand (contralateral) can induce dystonic posturing in the affected hand. This phenomenon is called “mirror movements”.Musician’s dystonia is a form of task-specific dystonia that involves muscles that are involved with performance. Symptoms occur when musicians attempt to play an instrument. Focal hand dystonia and embouchure dystonia are the most common forms. Focal hand dystonia is characterized by painless loss of muscular control in relation to highly practiced movements (as seen with pianists, guitarists, etc.). Embouchure dystonia is a specific form of musician’s dystonia that affects individuals who play brass and woodwind instruments. This form of dystonia can affect the muscles of the mouth, face, jaw, and tongue. The muscular contractions that characterize embouchure dystonia may only occur when the musician is playing or blowing into the mouthpiece of the instrument. INHERITED DYSTONIA A genetic classification for dystonia was established that sub-classified dystonia based upon the specific genetic mutation/loci associated with the subtype. Disorders were given the official abbreviation DYT and a number (e.g. DYT1). The subtypes are numbered in the order they were identified in the medical literature. There have been approximately 28 forms identified. However, this classification has several problems. Designations were assigned without a known gene so that individuals with one form of dystonia were eventually found to have an existing form. For example, individuals with DYT14 were eventually determined to have DYT5. A new nomenclature has been proposed where different forms of dystonia are designated by the prefix DYT- followed by the name of causal gene (Marras et al., 2106). For example, instead of DYT1 dystonia, this form is now called DYT-TOR1A, Another issue is that some disorders included in this classification system do not have dystonia as the primary symptom, but rather another neurological finding such as myoclonus or parkinsonism. Furthermore, many genetically- determined disorders with dystonia as a feature are not included in the classification such as Lesch-Nyhan syndrome, Wilson’s disease and deafness-dystonia-optic neuronopathy syndrome. Some of the better known forms of inherited dystonia are described below. DYT-TOR1A-related dystonia (previously called DYT1) usually begins in childhood or adolescence. However, the disorder may also develop later during life. Symptoms usually start in one part of the body (usually an arm or leg) and may eventually spread to other parts of the body, causing contractions and spasms of muscles that twist the body into unnatural positions. Severity can vary greatly from one person to another, even among members of the same family. The disorder can potentially cause significant disability in childhood while, in other cases it can remain undiagnosed until adulthood with only mild symptoms. DYT1-related dystonia is the most common hereditary form of dystonia and is caused by the DYT1 (also known as TOR1A) gene. This form of dystonia is inherited in an autosomal dominant manner. DYT-KMT2B (or DYT28) dystonia is a genetic form of early onset generalizes dystonia. that it was identified in 2016. Although rare, this form of dystonia seems to account for almost 10% of genetic case of generalized pediatric dystonia. Dystonia is associated with a number of dysmorphic features (such as small stature, elongated face, broad nasal base and bulbous nasal tip) as well as systemic manifestations in some of the cases (intellectual disability and developmental delay, microcephaly, renal and respiratory involvement, dermatological changes, and ophthalmological symptoms) which can help guide the diagnosis in these patients. This disorder is caused by mutations in the KMT2B gene. In the majority of the cases patients harbor de novo mutations, which are genetic changes that spontaneously arose in patients and are not inherited from their parent. The disease is transmitted in an autosomal dominant manner.X-linked dystonia-parkinsonism (also known as “Lubag”, DYT/PARK-TAF1 or DYT3) is a form of dystonia found almost exclusively among men from the Philippine island of Panay. Most female carriers do not develop symptoms (asymptomatic). The symptoms and clinical course is highly variable. Affected individuals may develop symptoms associated with Parkinsonism including abnormal slowness of movement (bradykinesia), resting tremor, and an inability to remain in a stable or balanced position (postural instability). Eventually, dystonia develops that usually is focal, most commonly affecting the jaw, neck, trunk, or eyes. Some individuals only develop Parkinsonism, which tends to be slowly progressive. Parkinsonism can be more severe, eventually resulting in an unstable gait and recurrent falls. Dystonia tends to be progressive and can become generalized or multifocal. Individuals with a combination of dystonia and Parkinsonism can develop severe, life-threatening complications. The mean age of onset of X-linked dystonia-parkinsonism is 39 years of age. This disorder is caused by mutations in the TAF1 gene. Dopa-responsive dystonia (DRD) is a general term for a few disorders in which generalized dystonia and Parkinsonism are present and often dramatically respond to treatment with levodopa. Levodopa is an amino acid that is converted to dopamine. Dopamine is a brain chemical that serves as a neurotransmitter and is deficient in individuals with DRD. Affected individuals may be misdiagnosed as having cerebral palsy or Parkinson’s disease. Two main forms have been identified and are known as Segawa syndrome, due to mutations of the GTP cyclohydrolase 1 (GCH1) gene (called DYT/PARK-GCH1), and tyrosine hydroxylase (TH) deficiency (called DYT/PARK-TH), although many other disorders may mimic dopa-responsive dystonia, including juvenile Parkinsonism. Segawa syndrome is inherited in an autosomal dominant manner; tyrosine hydroxylase deficiency is inherited in an autosomal recessive manner. NORD has individual reports on both of these disorders. These disorders are also known as DYT5A and DYT5B. Recessive forms of dopa-responsive dystonia can be caused also by sepiapterin reductase (SPR) deficiency. DYT-THAP1 dystonia (previously called DYT6) is characterized by dystonia affecting the cranial, cervical and laryngeal areas. Dystonia tends to worsen and spread to other areas (generalized dystonia). Some individuals initially exhibit dystonia affecting the arms and later develop cranial and cervical dystonia symptoms. Most often, this disorder has a juvenile onset. DYT6-related dystonia is caused by mutations in the THAP1 gene and is inherited in an autosomal dominant manner. Paroxysmal nonkinesigenic dyskinesia (PKND) is a disorder characterized by episodes of dystonia and choreoathetosis. Choreoathetosis is characterized by irregular, rapid, jerky movements that may occur in association with slow, writhing motions. Episodes may last from minutes to hours and can recur multiple times per day or per month. Episodes are often triggered by alcohol, caffeine, hunger, fatigue, stress and nicotine. Movement does not trigger an episode. Onset of the disorder can vary from early childhood to early adulthood. The disorder can potentially be disabling because it can interfere with basic activities such as chewing, swallowing, speaking, walking and coordinating movements of the arms and hands. PNKD is caused by mutations in the MR1 gene (also called PNKD gene) and is inherited in an autosomal dominant manner. In some cases, the disorder occurs randomly, for unknown reasons (sporadically). The disorder is also known as PxMD-PNKD (previously called DYT8), paroxysmal dystonic choreoathetosis, or Mount-Reback syndrome. Paroxysmal kinesigenic dyskinesia (PKD), also known as PxMD-PRRT2 (previously named DYT10), is characterized by episodes of dystonia and choreoathetosis that are triggered by sudden movements or when startled. Episodes usually last seconds or minutes. In some cases, as many as 100 episodes can occur in a single day; in others as few as one a month may occur. In rare cases, jerky, flailing or swinging movements (ballism) may also be seen. Some affected individuals may experience abnormal sensations (aura) in the affected area just before an attack occurs. Age of onset is usually in childhood or adolescence, but the disorder has been reported in individuals ranging from 4 to 57 years of age. PKD is caused by mutations in the PRRT2 gene and is inherited in an autosomal dominant manner. Myoclonic dystonia, better known as DTY11, myoclonus-dystonia, or according to the updated nomenclature DYT-SGCE, is characterized by rapid, involuntary, jerking movements (myoclonus) with or without sustained dystonic postures. Myoclonus most often affects the neck, trunk and upper arms. Less commonly, the legs are involved. Myoclonus is caused by muscle contractions or muscle relaxation and cannot be controlled by the affected individual. Affected individuals may also develop focal or segmental dystonia (e.g. writer’s cramp or cervical dystonia). Generally, dystonia does not worsen or progress to other areas. Additional symptoms that have been reported include panic attacks, anxiety, depression and obsessive-compulsive disorder. Onset is usually during childhood or adolescence. Most cases of myoclonus-dystonia are caused by mutations in the SGCE gene. The disorder is inherited in an autosomal dominant manner. Rapid-onset dystonia-parkinsonism (RDP), also known as DYT12 or DYT/PARK-ATP1A3, is characterized by dystonic features and additional symptoms that resemble those seen in Parkinson’s disease (Parkinsonism). Classic features include involuntary dystonic muscle spasms in the arms more often than the legs and prominent involvement of speech and swallowing muscles. Parkinsonian symptoms include involuntary, rhythmic, quivering movements (tremors), bradykinesia, and postural instability. Seizures have been reported in some cases. As the name suggests, symptoms usually develop rapidly over a period of a few hours or days, and often after a triggering event such as emotional stress, alcoholic binge drinking, childbirth or certain forms of exercise such as running. RDP is caused by mutations in the ATP1A3 gene and is inherited in an autosomal dominant manner. RDP usually begins in adolescence or young adulthood and stabilizes within approximately 4 weeks, with little progression of the disorder thereafter, however the availability of genetic testing has revealed that the clinical spectrum of the disorder is wider than initially appreciated, including alternating hemiplegia of childhood (For more information on this condition, choose “alternating hemiplegia of childhood” in the Rare Disease Database.) Paroxysmal exertion-induced dyskinesia, also known as PxMD-SLC2A1 or DYT18, is characterized by the combination of chorea, athetosis, and dystonia that primarily affects excessively exercised areas of the body. The legs are most commonly affected. An episode may last from a few minutes to more than an hour and occurs after prolonged physical activity or exercise. In some cases, additional symptoms have been reported including seizures, hemolytic anemia and migraines Paroxysmal exertion-induced dyskinesia is caused by mutations in the SCL2A1 gene and is inherited in an autosomal dominant manner. ACQUIRED DYSTONIA Acquired dystonia may be the result of environmental or disease-related damage to a part of the brain or central nervous system (See Causes section below). Acquired dystonia often presents with other neurological findings such as Parkinsonism. The specific symptoms and severity of these disorders varies based upon the underlying causes, specific body areas involved, and other factors. A specific form of acquired dystonia is tardive dyskinesia, which encompasses forms of dystonia that are induced by the use of certain drugs. Tardive dyskinesia causes quick repetitive movements without sustained postures. Tardive dystonia is generally considered a severe form of tardive dyskinesia characterized by muscle contractions resulting in slower, writhing movements. NORD has an individual report on tardive dyskinesia. | Symptoms of Dystonia. Early onset childhood dystonia (generalized dystonia) is a neurologic movement disorder that usually begins in childhood or adolescence. Symptoms start in one part of the body (usually an arm or leg) and may eventually spread to other parts of the body, causing contractions and spasms of muscles that twist the body into unnatural positions. This is the most common hereditary form of dystonia, in most cases caused by changes (mutations) the DYT1 gene. Specific symptoms can vary from one person to another even among individuals with the same subtype. Specific symptoms may occur based upon the specific part of the body involved, age of onset and the underlying cause. Dystonias with an earlier age of onset are more likely to progress from a focal presentation to a generalized one and are usually more severe. Adult onset forms of dystonia tend to exhibit a focal presentation and usually do not progress. Some affected individuals can temporarily interrupt dystonic movements or postures by performing a specific action or maneuver. This is known as ‘gestes antagoniste’ or a sensory trick. Usually, the action involves a body part not affected by dystonia, but often nearby the affected area. For example, some individuals can temporarily alleviate cervical dystonia by touching their chins. Changing the pattern of muscle activation can also improve certain dystonic postures. For example, in patients with foot dystonia causing an abnormal turning of one foot when walking, when asked to run or to walk backwards they can present a reduction of this abnormal posturing. Some of the better known forms of dystonia are briefly discussed below. NORD has individual reports on many of the specific dystonia subtypes. For more information, choose the specific disorder name as your search term in the Rare Disease Database.ISOLATED FOCAL DYSTONIA Isolated focal dystonias are the most common dystonias and can include benign essential blepharospasm, cervical dystonia, oromandibular dystonia, and laryngeal dystonia. These dystonias often have adult onset. NORD has individual reports on these forms of dystonia. Isolated limb dystonia may occur in adults and often affects the arms and/or hands. Many are occupational or task-specific. Occupational or task-specific dystonia are general terms that refer to focal dystonia associated with a particular, often repetitive, activity. Initially, affected individuals may exhibit a lack of dexterity when performing the activity in question. Eventually, the condition progresses to cause repetitive movements and abnormal postures. The most common form may be writer’s cramp, in which abnormal flexion, extension or rotation of the fingers and wrist occurs when an affected individual writes. In some cases writing with the unaffected hand (contralateral) can induce dystonic posturing in the affected hand. This phenomenon is called “mirror movements”.Musician’s dystonia is a form of task-specific dystonia that involves muscles that are involved with performance. Symptoms occur when musicians attempt to play an instrument. Focal hand dystonia and embouchure dystonia are the most common forms. Focal hand dystonia is characterized by painless loss of muscular control in relation to highly practiced movements (as seen with pianists, guitarists, etc.). Embouchure dystonia is a specific form of musician’s dystonia that affects individuals who play brass and woodwind instruments. This form of dystonia can affect the muscles of the mouth, face, jaw, and tongue. The muscular contractions that characterize embouchure dystonia may only occur when the musician is playing or blowing into the mouthpiece of the instrument. INHERITED DYSTONIA A genetic classification for dystonia was established that sub-classified dystonia based upon the specific genetic mutation/loci associated with the subtype. Disorders were given the official abbreviation DYT and a number (e.g. DYT1). The subtypes are numbered in the order they were identified in the medical literature. There have been approximately 28 forms identified. However, this classification has several problems. Designations were assigned without a known gene so that individuals with one form of dystonia were eventually found to have an existing form. For example, individuals with DYT14 were eventually determined to have DYT5. A new nomenclature has been proposed where different forms of dystonia are designated by the prefix DYT- followed by the name of causal gene (Marras et al., 2106). For example, instead of DYT1 dystonia, this form is now called DYT-TOR1A, Another issue is that some disorders included in this classification system do not have dystonia as the primary symptom, but rather another neurological finding such as myoclonus or parkinsonism. Furthermore, many genetically- determined disorders with dystonia as a feature are not included in the classification such as Lesch-Nyhan syndrome, Wilson’s disease and deafness-dystonia-optic neuronopathy syndrome. Some of the better known forms of inherited dystonia are described below. DYT-TOR1A-related dystonia (previously called DYT1) usually begins in childhood or adolescence. However, the disorder may also develop later during life. Symptoms usually start in one part of the body (usually an arm or leg) and may eventually spread to other parts of the body, causing contractions and spasms of muscles that twist the body into unnatural positions. Severity can vary greatly from one person to another, even among members of the same family. The disorder can potentially cause significant disability in childhood while, in other cases it can remain undiagnosed until adulthood with only mild symptoms. DYT1-related dystonia is the most common hereditary form of dystonia and is caused by the DYT1 (also known as TOR1A) gene. This form of dystonia is inherited in an autosomal dominant manner. DYT-KMT2B (or DYT28) dystonia is a genetic form of early onset generalizes dystonia. that it was identified in 2016. Although rare, this form of dystonia seems to account for almost 10% of genetic case of generalized pediatric dystonia. Dystonia is associated with a number of dysmorphic features (such as small stature, elongated face, broad nasal base and bulbous nasal tip) as well as systemic manifestations in some of the cases (intellectual disability and developmental delay, microcephaly, renal and respiratory involvement, dermatological changes, and ophthalmological symptoms) which can help guide the diagnosis in these patients. This disorder is caused by mutations in the KMT2B gene. In the majority of the cases patients harbor de novo mutations, which are genetic changes that spontaneously arose in patients and are not inherited from their parent. The disease is transmitted in an autosomal dominant manner.X-linked dystonia-parkinsonism (also known as “Lubag”, DYT/PARK-TAF1 or DYT3) is a form of dystonia found almost exclusively among men from the Philippine island of Panay. Most female carriers do not develop symptoms (asymptomatic). The symptoms and clinical course is highly variable. Affected individuals may develop symptoms associated with Parkinsonism including abnormal slowness of movement (bradykinesia), resting tremor, and an inability to remain in a stable or balanced position (postural instability). Eventually, dystonia develops that usually is focal, most commonly affecting the jaw, neck, trunk, or eyes. Some individuals only develop Parkinsonism, which tends to be slowly progressive. Parkinsonism can be more severe, eventually resulting in an unstable gait and recurrent falls. Dystonia tends to be progressive and can become generalized or multifocal. Individuals with a combination of dystonia and Parkinsonism can develop severe, life-threatening complications. The mean age of onset of X-linked dystonia-parkinsonism is 39 years of age. This disorder is caused by mutations in the TAF1 gene. Dopa-responsive dystonia (DRD) is a general term for a few disorders in which generalized dystonia and Parkinsonism are present and often dramatically respond to treatment with levodopa. Levodopa is an amino acid that is converted to dopamine. Dopamine is a brain chemical that serves as a neurotransmitter and is deficient in individuals with DRD. Affected individuals may be misdiagnosed as having cerebral palsy or Parkinson’s disease. Two main forms have been identified and are known as Segawa syndrome, due to mutations of the GTP cyclohydrolase 1 (GCH1) gene (called DYT/PARK-GCH1), and tyrosine hydroxylase (TH) deficiency (called DYT/PARK-TH), although many other disorders may mimic dopa-responsive dystonia, including juvenile Parkinsonism. Segawa syndrome is inherited in an autosomal dominant manner; tyrosine hydroxylase deficiency is inherited in an autosomal recessive manner. NORD has individual reports on both of these disorders. These disorders are also known as DYT5A and DYT5B. Recessive forms of dopa-responsive dystonia can be caused also by sepiapterin reductase (SPR) deficiency. DYT-THAP1 dystonia (previously called DYT6) is characterized by dystonia affecting the cranial, cervical and laryngeal areas. Dystonia tends to worsen and spread to other areas (generalized dystonia). Some individuals initially exhibit dystonia affecting the arms and later develop cranial and cervical dystonia symptoms. Most often, this disorder has a juvenile onset. DYT6-related dystonia is caused by mutations in the THAP1 gene and is inherited in an autosomal dominant manner. Paroxysmal nonkinesigenic dyskinesia (PKND) is a disorder characterized by episodes of dystonia and choreoathetosis. Choreoathetosis is characterized by irregular, rapid, jerky movements that may occur in association with slow, writhing motions. Episodes may last from minutes to hours and can recur multiple times per day or per month. Episodes are often triggered by alcohol, caffeine, hunger, fatigue, stress and nicotine. Movement does not trigger an episode. Onset of the disorder can vary from early childhood to early adulthood. The disorder can potentially be disabling because it can interfere with basic activities such as chewing, swallowing, speaking, walking and coordinating movements of the arms and hands. PNKD is caused by mutations in the MR1 gene (also called PNKD gene) and is inherited in an autosomal dominant manner. In some cases, the disorder occurs randomly, for unknown reasons (sporadically). The disorder is also known as PxMD-PNKD (previously called DYT8), paroxysmal dystonic choreoathetosis, or Mount-Reback syndrome. Paroxysmal kinesigenic dyskinesia (PKD), also known as PxMD-PRRT2 (previously named DYT10), is characterized by episodes of dystonia and choreoathetosis that are triggered by sudden movements or when startled. Episodes usually last seconds or minutes. In some cases, as many as 100 episodes can occur in a single day; in others as few as one a month may occur. In rare cases, jerky, flailing or swinging movements (ballism) may also be seen. Some affected individuals may experience abnormal sensations (aura) in the affected area just before an attack occurs. Age of onset is usually in childhood or adolescence, but the disorder has been reported in individuals ranging from 4 to 57 years of age. PKD is caused by mutations in the PRRT2 gene and is inherited in an autosomal dominant manner. Myoclonic dystonia, better known as DTY11, myoclonus-dystonia, or according to the updated nomenclature DYT-SGCE, is characterized by rapid, involuntary, jerking movements (myoclonus) with or without sustained dystonic postures. Myoclonus most often affects the neck, trunk and upper arms. Less commonly, the legs are involved. Myoclonus is caused by muscle contractions or muscle relaxation and cannot be controlled by the affected individual. Affected individuals may also develop focal or segmental dystonia (e.g. writer’s cramp or cervical dystonia). Generally, dystonia does not worsen or progress to other areas. Additional symptoms that have been reported include panic attacks, anxiety, depression and obsessive-compulsive disorder. Onset is usually during childhood or adolescence. Most cases of myoclonus-dystonia are caused by mutations in the SGCE gene. The disorder is inherited in an autosomal dominant manner. Rapid-onset dystonia-parkinsonism (RDP), also known as DYT12 or DYT/PARK-ATP1A3, is characterized by dystonic features and additional symptoms that resemble those seen in Parkinson’s disease (Parkinsonism). Classic features include involuntary dystonic muscle spasms in the arms more often than the legs and prominent involvement of speech and swallowing muscles. Parkinsonian symptoms include involuntary, rhythmic, quivering movements (tremors), bradykinesia, and postural instability. Seizures have been reported in some cases. As the name suggests, symptoms usually develop rapidly over a period of a few hours or days, and often after a triggering event such as emotional stress, alcoholic binge drinking, childbirth or certain forms of exercise such as running. RDP is caused by mutations in the ATP1A3 gene and is inherited in an autosomal dominant manner. RDP usually begins in adolescence or young adulthood and stabilizes within approximately 4 weeks, with little progression of the disorder thereafter, however the availability of genetic testing has revealed that the clinical spectrum of the disorder is wider than initially appreciated, including alternating hemiplegia of childhood (For more information on this condition, choose “alternating hemiplegia of childhood” in the Rare Disease Database.) Paroxysmal exertion-induced dyskinesia, also known as PxMD-SLC2A1 or DYT18, is characterized by the combination of chorea, athetosis, and dystonia that primarily affects excessively exercised areas of the body. The legs are most commonly affected. An episode may last from a few minutes to more than an hour and occurs after prolonged physical activity or exercise. In some cases, additional symptoms have been reported including seizures, hemolytic anemia and migraines Paroxysmal exertion-induced dyskinesia is caused by mutations in the SCL2A1 gene and is inherited in an autosomal dominant manner. ACQUIRED DYSTONIA Acquired dystonia may be the result of environmental or disease-related damage to a part of the brain or central nervous system (See Causes section below). Acquired dystonia often presents with other neurological findings such as Parkinsonism. The specific symptoms and severity of these disorders varies based upon the underlying causes, specific body areas involved, and other factors. A specific form of acquired dystonia is tardive dyskinesia, which encompasses forms of dystonia that are induced by the use of certain drugs. Tardive dyskinesia causes quick repetitive movements without sustained postures. Tardive dystonia is generally considered a severe form of tardive dyskinesia characterized by muscle contractions resulting in slower, writhing movements. NORD has an individual report on tardive dyskinesia. | 392 | Dystonia |
nord_392_2 | Causes of Dystonia | In some cases, dystonia occurs due to a known specific cause (acquired dystonia). Other cases are genetic and occur due to specific genetic mutations. Other cases occur randomly for no apparent reason, without a family history of the disorder (sporadically). In many cases, the exact underlying cause of dystonia is unknown or unproven (idiopathic). Most likely, many cases of dystonia develop due to multiple factors including genetic and environmental ones. Conditions associated with acquired dystonia include brain injury (particularly due to lack of oxygen) during or around the time of birth (perinatal period), certain infections, reactions to certain drugs, brain trauma, or various vascular abnormalities such as stroke, arteriovenous malformations, or profuse, excessive bleeding (hemorrhaging). Dystonia can also result from other illnesses affecting the central nervous system. Multiple genes have been associated with inherited dystonia. Researchers are actively seeking to locate additional genes and gene markers. Genetic factors are also believed to play a role in idiopathic and acquired dystonia, especially in individuals who have a relative with another form of dystonia. These individuals may have a genetic susceptibility to developing the disorder. A person who is genetically predisposed to a disorder carries a gene (or genes) for the disease, but it may not be expressed unless it is triggered or activated by other genetic modifiers or environmental factors (complex genetics). Genetic mutations that have been identified to cause inherited forms of dystonia may be inherited in an autosomal recessive, autosomal dominant, X-linked or mitochondrial manner. Autosomal recessive genetic disorders occur when an individual inherits an abnormal copy of a gene from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (de novo 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.. Dominant genetic disorders may be marked by incomplete penetrance, which means that some individuals who inherit the gene for a dominant disorder will not be affected by the disorder. Variable expressivity can also occur, which means that widely varying signs and symptoms can occur among affected individuals with the same gene mutation. X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females have two X chromosomes but one of the X chromosomes is
“turned off” and all of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder because it is usually the X chromosome with the abnormal gene that is “turned off.” A male has one X-chromosome and if he inherits an X chromosome that contains a disease gene, he will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers if the other X chromosome from their mother is normal. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease, and a 25% chance to have an unaffected son. In some females, known as heterozygotes, which inherit a single copy of the disease gene for an X-linked disorder, disease traits on the X chromosome may not always be masked by the normal gene on the other X chromosome. As a result, these females may exhibit some of the symptoms associated with the disorder. Some forms of dystonia are also classified as mitochondrial diseases. These disorders are caused by errors (e.g. mutations) in the genetic material (DNA) of the mitochondria. Mitochondria, found by the hundreds within virtually every cell of the body, generate most of the cellular energy. Several theories exists that attempt to explain the underlying mechanism of dystonia including abnormal functioning of or subtle abnormalities affecting certain areas of the brain including the basal ganglia, cerebellum, cortex, brainstem, and thalamus. Imbalances in neurotransmitters have also been studied. Neurotransmitters are chemicals that modify, amplify, or transmit nerve impulses from one nerve cell (neuron) to another, enabling nerve cells to communicate. Although the underlying mechanisms and causes of dystonia are not well understood, research is ongoing to determine the specific roles that genetic, environmental and other factors ultimately play in the development of the disorder. | Causes of Dystonia. In some cases, dystonia occurs due to a known specific cause (acquired dystonia). Other cases are genetic and occur due to specific genetic mutations. Other cases occur randomly for no apparent reason, without a family history of the disorder (sporadically). In many cases, the exact underlying cause of dystonia is unknown or unproven (idiopathic). Most likely, many cases of dystonia develop due to multiple factors including genetic and environmental ones. Conditions associated with acquired dystonia include brain injury (particularly due to lack of oxygen) during or around the time of birth (perinatal period), certain infections, reactions to certain drugs, brain trauma, or various vascular abnormalities such as stroke, arteriovenous malformations, or profuse, excessive bleeding (hemorrhaging). Dystonia can also result from other illnesses affecting the central nervous system. Multiple genes have been associated with inherited dystonia. Researchers are actively seeking to locate additional genes and gene markers. Genetic factors are also believed to play a role in idiopathic and acquired dystonia, especially in individuals who have a relative with another form of dystonia. These individuals may have a genetic susceptibility to developing the disorder. A person who is genetically predisposed to a disorder carries a gene (or genes) for the disease, but it may not be expressed unless it is triggered or activated by other genetic modifiers or environmental factors (complex genetics). Genetic mutations that have been identified to cause inherited forms of dystonia may be inherited in an autosomal recessive, autosomal dominant, X-linked or mitochondrial manner. Autosomal recessive genetic disorders occur when an individual inherits an abnormal copy of a gene from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (de novo 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.. Dominant genetic disorders may be marked by incomplete penetrance, which means that some individuals who inherit the gene for a dominant disorder will not be affected by the disorder. Variable expressivity can also occur, which means that widely varying signs and symptoms can occur among affected individuals with the same gene mutation. X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females have two X chromosomes but one of the X chromosomes is
“turned off” and all of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder because it is usually the X chromosome with the abnormal gene that is “turned off.” A male has one X-chromosome and if he inherits an X chromosome that contains a disease gene, he will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers if the other X chromosome from their mother is normal. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease, and a 25% chance to have an unaffected son. In some females, known as heterozygotes, which inherit a single copy of the disease gene for an X-linked disorder, disease traits on the X chromosome may not always be masked by the normal gene on the other X chromosome. As a result, these females may exhibit some of the symptoms associated with the disorder. Some forms of dystonia are also classified as mitochondrial diseases. These disorders are caused by errors (e.g. mutations) in the genetic material (DNA) of the mitochondria. Mitochondria, found by the hundreds within virtually every cell of the body, generate most of the cellular energy. Several theories exists that attempt to explain the underlying mechanism of dystonia including abnormal functioning of or subtle abnormalities affecting certain areas of the brain including the basal ganglia, cerebellum, cortex, brainstem, and thalamus. Imbalances in neurotransmitters have also been studied. Neurotransmitters are chemicals that modify, amplify, or transmit nerve impulses from one nerve cell (neuron) to another, enabling nerve cells to communicate. Although the underlying mechanisms and causes of dystonia are not well understood, research is ongoing to determine the specific roles that genetic, environmental and other factors ultimately play in the development of the disorder. | 392 | Dystonia |
nord_392_3 | Affects of Dystonia | Dystonia can affect individuals of any age, gender, race, or ethnic background. It is estimated that as many as 300,000 people in North America may be affected by the various forms of dystonia. However, because many cases of dystonia go misdiagnosed or undiagnosed, determining the true frequency of dystonia in the general population is difficult. Focal forms of dystonia are approximately 10 times more common than generalized forms. | Affects of Dystonia. Dystonia can affect individuals of any age, gender, race, or ethnic background. It is estimated that as many as 300,000 people in North America may be affected by the various forms of dystonia. However, because many cases of dystonia go misdiagnosed or undiagnosed, determining the true frequency of dystonia in the general population is difficult. Focal forms of dystonia are approximately 10 times more common than generalized forms. | 392 | Dystonia |
nord_392_4 | Related disorders of Dystonia | Symptoms of the following disorders can be similar to those of dystonia. Comparisons may be useful for a differential diagnosis: Pseudodystonia is a general term for a group of conditions that can resemble dystonia. Such conditions include dystonic tics; spinal abnormalities such as forward flexion or bending of the trunk and spine (camptocormia) and abnormal side-to-side curvature of the spine (scoliosis); partial dislocation of the shoulder (shoulder subluxation); Chiari malformations; soft tissues masses; congenital muscular torticollis (wryneck), in which the muscles that extend down the side of the neck are abnormally tight and short; Klippel-Feil syndrome, a rare skeletal disorder primarily characterized by abnormal union or fusion of two or more bones of the spinal column within the neck (cervical vertebrae); Satoyoshi syndrome, a rare disorder characterized by progressive, painful muscle spasms; and Dupuytren’s contracture, a connective tissue disorder characterized by fixation of certain joints. In addition, various neuromuscular, orthopedic, and rheumatologic conditions can cause symptoms similar to those seen in dystonia. A wide variety of genetic disorders may have dystonia as a component either as a minor or major finding and/or as a frequent or rare complication. Such disorders include Wilson’s disease, Rett syndrome, neuroacanthocytosis, Lesch-Nyhan disease, mitochondrial membrane protein-associated neurodegeneration, Huntington disease, dentatorubral- pallidoluysian atrophy, neuroferritinopathy, pantothenate kinase-associated neurodegeneration (PKAN), glutaricaciduria I, methylmalonic aciduria, propionic aciduria, hypermanganesemia, familial idiopathic basal ganglia calcification, various mitochondrial diseases, and deafness-dystonia-optic neuronopathy syndrome. (For more information, choose the specific disorder name as your search term in the Rare Disease Database.) Essential tremor (ET) is a progressive, neurological disorder characterized by tremor, most often of the hands or arms. A tremor is an involuntary, rhythmic, movement of a body part. Tremor may be seen as involuntary shaking or trembling of the affected area. In individuals with ET, other motor symptoms may be present including an unsteady manner of walking due to an inability to coordinate voluntary movements (ataxia). In some cases, affected individuals may also develop a variety of non-motor symptoms including cognitive impairment or personality changes. ET can occur in childhood or adulthood. The exact, underlying cause of ET is not fully understood. In some cases, the disorder runs in families; in others, it occurs in individuals with no previous family history. The cause of ET is most likely multifactorial, which means that several factors, such as genetic and environmental ones, all play a role in the development of the disorder. (For more information, choose “essential tremor” as your search term in the Rare Disease Database.) Parkinson’s disease (PD) is a slowly progressive neurologic movement disorder characterized by involuntary, resting tremor (trembling), muscular stiffness or lack of flexibility (rigidity), slowness of movement (bradykinesia) and difficulty controlling voluntary movements. Degenerative changes occur in areas deep within the brain (substantia nigra and other pigmented regions of the brain), resulting in decreasing levels of the neurotransmitter dopamine in the brain. Dopamine is a highly specialized brain chemical that sends a signal to other nerve cells, and participates in the regulation of body movements. Symptoms similar to those of PD may also develop secondary to hydrocephalus (a condition in which excessive cerebrospinal fluid accumulates in the spaces in the brain [ventricles]. As a result, the fluid increases pressure in the brain, and the skull may become enlarged or bulge). Parkinsonian symptoms may also occur as a result of head trauma, inflammation of the brain (encephalitis), obstructions (infarcts), or tumors deep within the cerebral hemispheres (cerebrum) and base of the brain (i.e., basal ganglia), or exposure to certain drugs and toxins. Parkinson’s disease usually begins in late adulthood. It is slowly progressive; however, it may not become incapacitating for many years. Additional movement disorders including chorea, myoclonus, and tics may also need to be distinguished from dystonia. These movement disorders can occur as isolated findings or as part of larger syndromes. | Related disorders of Dystonia. Symptoms of the following disorders can be similar to those of dystonia. Comparisons may be useful for a differential diagnosis: Pseudodystonia is a general term for a group of conditions that can resemble dystonia. Such conditions include dystonic tics; spinal abnormalities such as forward flexion or bending of the trunk and spine (camptocormia) and abnormal side-to-side curvature of the spine (scoliosis); partial dislocation of the shoulder (shoulder subluxation); Chiari malformations; soft tissues masses; congenital muscular torticollis (wryneck), in which the muscles that extend down the side of the neck are abnormally tight and short; Klippel-Feil syndrome, a rare skeletal disorder primarily characterized by abnormal union or fusion of two or more bones of the spinal column within the neck (cervical vertebrae); Satoyoshi syndrome, a rare disorder characterized by progressive, painful muscle spasms; and Dupuytren’s contracture, a connective tissue disorder characterized by fixation of certain joints. In addition, various neuromuscular, orthopedic, and rheumatologic conditions can cause symptoms similar to those seen in dystonia. A wide variety of genetic disorders may have dystonia as a component either as a minor or major finding and/or as a frequent or rare complication. Such disorders include Wilson’s disease, Rett syndrome, neuroacanthocytosis, Lesch-Nyhan disease, mitochondrial membrane protein-associated neurodegeneration, Huntington disease, dentatorubral- pallidoluysian atrophy, neuroferritinopathy, pantothenate kinase-associated neurodegeneration (PKAN), glutaricaciduria I, methylmalonic aciduria, propionic aciduria, hypermanganesemia, familial idiopathic basal ganglia calcification, various mitochondrial diseases, and deafness-dystonia-optic neuronopathy syndrome. (For more information, choose the specific disorder name as your search term in the Rare Disease Database.) Essential tremor (ET) is a progressive, neurological disorder characterized by tremor, most often of the hands or arms. A tremor is an involuntary, rhythmic, movement of a body part. Tremor may be seen as involuntary shaking or trembling of the affected area. In individuals with ET, other motor symptoms may be present including an unsteady manner of walking due to an inability to coordinate voluntary movements (ataxia). In some cases, affected individuals may also develop a variety of non-motor symptoms including cognitive impairment or personality changes. ET can occur in childhood or adulthood. The exact, underlying cause of ET is not fully understood. In some cases, the disorder runs in families; in others, it occurs in individuals with no previous family history. The cause of ET is most likely multifactorial, which means that several factors, such as genetic and environmental ones, all play a role in the development of the disorder. (For more information, choose “essential tremor” as your search term in the Rare Disease Database.) Parkinson’s disease (PD) is a slowly progressive neurologic movement disorder characterized by involuntary, resting tremor (trembling), muscular stiffness or lack of flexibility (rigidity), slowness of movement (bradykinesia) and difficulty controlling voluntary movements. Degenerative changes occur in areas deep within the brain (substantia nigra and other pigmented regions of the brain), resulting in decreasing levels of the neurotransmitter dopamine in the brain. Dopamine is a highly specialized brain chemical that sends a signal to other nerve cells, and participates in the regulation of body movements. Symptoms similar to those of PD may also develop secondary to hydrocephalus (a condition in which excessive cerebrospinal fluid accumulates in the spaces in the brain [ventricles]. As a result, the fluid increases pressure in the brain, and the skull may become enlarged or bulge). Parkinsonian symptoms may also occur as a result of head trauma, inflammation of the brain (encephalitis), obstructions (infarcts), or tumors deep within the cerebral hemispheres (cerebrum) and base of the brain (i.e., basal ganglia), or exposure to certain drugs and toxins. Parkinson’s disease usually begins in late adulthood. It is slowly progressive; however, it may not become incapacitating for many years. Additional movement disorders including chorea, myoclonus, and tics may also need to be distinguished from dystonia. These movement disorders can occur as isolated findings or as part of larger syndromes. | 392 | Dystonia |
nord_392_5 | Diagnosis of Dystonia | A diagnosis of dystonia is based upon identification of characteristic symptoms, a detailed patient and family history, and a thorough clinical evaluation. Evaluation by a movement disorder specialist may help to confirm a diagnosis of dystonia. Various, specialized tests may be recommended to rule out other conditions. Laboratory testing is essential in acquired dystonia to determine the underlying cause. Molecular genetic testing can confirm a diagnosis of certain inherited forms of dystonia. Molecular genetic testing can detect mutations in the specific genes known to cause inherited dystonia, but is available only as a diagnostic service at specialized laboratories. | Diagnosis of Dystonia. A diagnosis of dystonia is based upon identification of characteristic symptoms, a detailed patient and family history, and a thorough clinical evaluation. Evaluation by a movement disorder specialist may help to confirm a diagnosis of dystonia. Various, specialized tests may be recommended to rule out other conditions. Laboratory testing is essential in acquired dystonia to determine the underlying cause. Molecular genetic testing can confirm a diagnosis of certain inherited forms of dystonia. Molecular genetic testing can detect mutations in the specific genes known to cause inherited dystonia, but is available only as a diagnostic service at specialized laboratories. | 392 | Dystonia |
nord_392_6 | Therapies of Dystonia | TreatmentAt this time, no curative therapies are available for dystonia. Current treatments target specific symptoms (symptomatic treatment) and are intended to relieve muscle spasms, pain and discomfort, and unnatural postures. No single treatment program is appropriate for every patient. There are essentially three treatment options: oral medications, botulinum toxin injections, and surgery. These treatments may be used alone or in combination. In addition, physical and speech therapy may provide a helpful complement to medical treatment in specific cases. There are no oral medications approved by the Food and Drug Administration (FDA) for use in dystonia. Among the oral medications used are those that affect the activity of neurotransmitters. Anticholinergic agents such as benztropine and trihexyphenidyl block the neurotransmitter acetylocholine, and benzodiazepines such as clonazepam, diazepam, or lorazepam block the neurotransmitter gamma-aminobutyric acid (GABA). These drugs are most effective in children with generalized dystonia. In adults, side effects are often dose limiting. Some individuals particularly those with dopa-responsive dystonia (DRD) respond to treatment with very low doses of levodopa, a synthetic version of the neurotransmitter dopamine. Levodopa increases dopamine levels. In other cases with certain different forms of dystonia, affected individuals may respond to medications that block the activity of dopamine (antidopaminergic agents). A muscle relaxant known as baclofen, which may help periodically to reduce muscle spasms, may be prescribed and delivered by means of an implantable pump that releases the drug directly into the area around the spinal cord. Baclofen can stimulate the body’s ability to process the neurotransmitter GABA. There is no standard treatment for rapid-onset dystonia-parkinsonism (RDP), although levodopa/carbidopa medications and dopamine agonists (drugs that stimulate dopamine receptors in the absence of dopamine) may provide mild improvement for some affected individuals. In complex syndrome caused by metabolic conditions where dystonia represents one of their manifestations, such as Wilson’s disease, different treatments specific for each condition can be attempted (summarized in tablet 5.5 in Jinnah et al., 2019 and Mohammad et al., 2019). Botulinum toxin therapy is often used for certain forms of dystonia, particularly certain focal dystonias such as cervical dystonia and laryngeal dystonia. Botulinum toxin is a neurotoxin that is injected into muscles in very small doses. After injection into a muscle, the action of botulinum toxin is to interrupt nerve messages to the muscle, preventing the release of the neurotransmitter acetylcholine, which stimulates muscular contractions, and giving rise to weakness of that muscle. The effect of botulinum toxin on the muscle begins approximately 2-3 days following injection, peaks at around 4 weeks, and provides relief for approximately 3-6 months. When the effect of botulinum toxin wears off, the symptoms of dystonia recur. The degree of effectiveness of botulinum toxin will differ in each individual case. Botulinum toxin is approved by the FDA for cervical dystonia and blepharospasm and is widely used off label to treat all forms of dystonia. Botulinum toxin is manufactured by Allergan Pharmaceuticals (as BOTOX®), Elan Pharmaceuticals (as MYOBLOC®), Ipsen Pharmaceuticals (as DYSPORT®), and Merz Pharmaceuticals (as XEOMIN®). These brands are not interchangeable, and each should be administered as a unique drug. The FDA has a “black box” warning concerning the use of any of these toxins. A black box warning denotes that a drug known to be effective for some individuals may cause serious side effects in others. Surgery is generally reserved for those patients with severe dystonia who do not respond to drug therapy or cannot tolerate side effects as well as those with severe dystonia who become non-responsive to drug treatment. Deep brain stimulation (DBS) with an implantable pulse generator may be performed for some types of dystonia. DBS involves the surgical placement of very thin electrodes into certain areas of the brain such as the globus pallidus. The leads from these electrodes are then connected to a small device called a neurostimulator that is surgically implanted usually near the collarbone. These stimulators send small electrical pulses to the brain. After the DBS is placed, the stimulators are programmed for the optimal outcome. The electrical pulses block or interfere with the nerve signals that cause the symptoms of dystonia. DBS has become the mainstay for surgical treatment of individuals with dystonia. Older surgical procedures such as thalamotomy or pallidotomy are rarely used anymore for the treatment of dystonia. These procedures involved the precise destruction of a tiny area of the brain in order to interrupt the nerve pathways responsible for the symptoms of dystonia. Selective peripheral denervation in which the nerves to the dystonic muscles are severed has been reported to benefit patients with cervical dystonia who fail other therapies. However, this surgery requires a surgeon who is extensively trained both in the evaluation cervical dystonia and in the surgical procedure. Side effects from the surgery are not uncommon and following surgery, there is a long period of rehabilitation. | Therapies of Dystonia. TreatmentAt this time, no curative therapies are available for dystonia. Current treatments target specific symptoms (symptomatic treatment) and are intended to relieve muscle spasms, pain and discomfort, and unnatural postures. No single treatment program is appropriate for every patient. There are essentially three treatment options: oral medications, botulinum toxin injections, and surgery. These treatments may be used alone or in combination. In addition, physical and speech therapy may provide a helpful complement to medical treatment in specific cases. There are no oral medications approved by the Food and Drug Administration (FDA) for use in dystonia. Among the oral medications used are those that affect the activity of neurotransmitters. Anticholinergic agents such as benztropine and trihexyphenidyl block the neurotransmitter acetylocholine, and benzodiazepines such as clonazepam, diazepam, or lorazepam block the neurotransmitter gamma-aminobutyric acid (GABA). These drugs are most effective in children with generalized dystonia. In adults, side effects are often dose limiting. Some individuals particularly those with dopa-responsive dystonia (DRD) respond to treatment with very low doses of levodopa, a synthetic version of the neurotransmitter dopamine. Levodopa increases dopamine levels. In other cases with certain different forms of dystonia, affected individuals may respond to medications that block the activity of dopamine (antidopaminergic agents). A muscle relaxant known as baclofen, which may help periodically to reduce muscle spasms, may be prescribed and delivered by means of an implantable pump that releases the drug directly into the area around the spinal cord. Baclofen can stimulate the body’s ability to process the neurotransmitter GABA. There is no standard treatment for rapid-onset dystonia-parkinsonism (RDP), although levodopa/carbidopa medications and dopamine agonists (drugs that stimulate dopamine receptors in the absence of dopamine) may provide mild improvement for some affected individuals. In complex syndrome caused by metabolic conditions where dystonia represents one of their manifestations, such as Wilson’s disease, different treatments specific for each condition can be attempted (summarized in tablet 5.5 in Jinnah et al., 2019 and Mohammad et al., 2019). Botulinum toxin therapy is often used for certain forms of dystonia, particularly certain focal dystonias such as cervical dystonia and laryngeal dystonia. Botulinum toxin is a neurotoxin that is injected into muscles in very small doses. After injection into a muscle, the action of botulinum toxin is to interrupt nerve messages to the muscle, preventing the release of the neurotransmitter acetylcholine, which stimulates muscular contractions, and giving rise to weakness of that muscle. The effect of botulinum toxin on the muscle begins approximately 2-3 days following injection, peaks at around 4 weeks, and provides relief for approximately 3-6 months. When the effect of botulinum toxin wears off, the symptoms of dystonia recur. The degree of effectiveness of botulinum toxin will differ in each individual case. Botulinum toxin is approved by the FDA for cervical dystonia and blepharospasm and is widely used off label to treat all forms of dystonia. Botulinum toxin is manufactured by Allergan Pharmaceuticals (as BOTOX®), Elan Pharmaceuticals (as MYOBLOC®), Ipsen Pharmaceuticals (as DYSPORT®), and Merz Pharmaceuticals (as XEOMIN®). These brands are not interchangeable, and each should be administered as a unique drug. The FDA has a “black box” warning concerning the use of any of these toxins. A black box warning denotes that a drug known to be effective for some individuals may cause serious side effects in others. Surgery is generally reserved for those patients with severe dystonia who do not respond to drug therapy or cannot tolerate side effects as well as those with severe dystonia who become non-responsive to drug treatment. Deep brain stimulation (DBS) with an implantable pulse generator may be performed for some types of dystonia. DBS involves the surgical placement of very thin electrodes into certain areas of the brain such as the globus pallidus. The leads from these electrodes are then connected to a small device called a neurostimulator that is surgically implanted usually near the collarbone. These stimulators send small electrical pulses to the brain. After the DBS is placed, the stimulators are programmed for the optimal outcome. The electrical pulses block or interfere with the nerve signals that cause the symptoms of dystonia. DBS has become the mainstay for surgical treatment of individuals with dystonia. Older surgical procedures such as thalamotomy or pallidotomy are rarely used anymore for the treatment of dystonia. These procedures involved the precise destruction of a tiny area of the brain in order to interrupt the nerve pathways responsible for the symptoms of dystonia. Selective peripheral denervation in which the nerves to the dystonic muscles are severed has been reported to benefit patients with cervical dystonia who fail other therapies. However, this surgery requires a surgeon who is extensively trained both in the evaluation cervical dystonia and in the surgical procedure. Side effects from the surgery are not uncommon and following surgery, there is a long period of rehabilitation. | 392 | Dystonia |
nord_393_0 | Overview of Eales Disease | Eales Disease is a rare disorder of sight that appears as an inflammation and white haze around the outercoat of the veins in the retina. The disorder is most prevalent among young males and normally affects both eyes. Usually, vision is suddenly blurred because the clear jelly that fills the eyeball behind the lens of the eye seeps out (vitreous hemorrhaging). | Overview of Eales Disease. Eales Disease is a rare disorder of sight that appears as an inflammation and white haze around the outercoat of the veins in the retina. The disorder is most prevalent among young males and normally affects both eyes. Usually, vision is suddenly blurred because the clear jelly that fills the eyeball behind the lens of the eye seeps out (vitreous hemorrhaging). | 393 | Eales Disease |
nord_393_1 | Symptoms of Eales Disease | Eales Disease usually presents as blurred vision resulting from oozing of the clear jelly-like substance from behind the lens of the eye. At the onset of the disorder, the small outer veins of the retina show sheathing (encapsulation or covering). As the disease progresses, the inflammation around the veins in the retina extends further behind the lens. Eales Disease may also be associated with peripheral retinal neovascularization which is the formation of new blood vessels on the outer part of the retina.The more advanced cases of Eales Disease are characterized by a non- inflammatory degenerative disease of the retina (retinopathy) and extensive bleeding in the retina. The colorless jelly that fills the eyeball behind the lens oozes from the retina (vitreous hemorrhage) and, in rare cases, the retina may become detached. A reddish discoloration of the iris may be present (rubeosis iridis), and there may be loss of vision and damage to the optic disk (neovascular glaucoma). Clouding of the lens of the eye that obstructs the passage of light (cataracts) may develop as the disease progresses. | Symptoms of Eales Disease. Eales Disease usually presents as blurred vision resulting from oozing of the clear jelly-like substance from behind the lens of the eye. At the onset of the disorder, the small outer veins of the retina show sheathing (encapsulation or covering). As the disease progresses, the inflammation around the veins in the retina extends further behind the lens. Eales Disease may also be associated with peripheral retinal neovascularization which is the formation of new blood vessels on the outer part of the retina.The more advanced cases of Eales Disease are characterized by a non- inflammatory degenerative disease of the retina (retinopathy) and extensive bleeding in the retina. The colorless jelly that fills the eyeball behind the lens oozes from the retina (vitreous hemorrhage) and, in rare cases, the retina may become detached. A reddish discoloration of the iris may be present (rubeosis iridis), and there may be loss of vision and damage to the optic disk (neovascular glaucoma). Clouding of the lens of the eye that obstructs the passage of light (cataracts) may develop as the disease progresses. | 393 | Eales Disease |
nord_393_2 | Causes of Eales Disease | The exact case of Eales Disease is not known. This disorder seems to occur spontaneously because no precipitating factors such as injury, infection, or heredity appear to be involved. | Causes of Eales Disease. The exact case of Eales Disease is not known. This disorder seems to occur spontaneously because no precipitating factors such as injury, infection, or heredity appear to be involved. | 393 | Eales Disease |
nord_393_3 | Affects of Eales Disease | Eales Disease is a rare disorder that affect males and females in equal numbers. | Affects of Eales Disease. Eales Disease is a rare disorder that affect males and females in equal numbers. | 393 | Eales Disease |
nord_393_4 | Related disorders of Eales Disease | Symptoms of the following disorders can be similar to those of Eales Disease. Comparisons may be useful for a differential diagnosis.Arteriosclerotic Retinopathy alludes to a series of changes in the retina caused by hardening of the arteries (arteriosclerosis) serving the retina. The characteristics of this disorder are bleeding in the retina, thick fluid oozing from the retina, impaired oxygenation of the retina, and hardening of the walls of the vision impairment. (For more information on this disorder, choose “arteriosclerosis” as your search term in the Rare Disease Database.) | Related disorders of Eales Disease. Symptoms of the following disorders can be similar to those of Eales Disease. Comparisons may be useful for a differential diagnosis.Arteriosclerotic Retinopathy alludes to a series of changes in the retina caused by hardening of the arteries (arteriosclerosis) serving the retina. The characteristics of this disorder are bleeding in the retina, thick fluid oozing from the retina, impaired oxygenation of the retina, and hardening of the walls of the vision impairment. (For more information on this disorder, choose “arteriosclerosis” as your search term in the Rare Disease Database.) | 393 | Eales Disease |
nord_393_5 | Diagnosis of Eales Disease | Diagnosis of Eales Disease. | 393 | Eales Disease |
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nord_393_6 | Therapies of Eales Disease | Treatment of Eales Disease is symptomatic and supportive. The surgical process of coagulating tissue with a laser beam (laser panretinal photocoagulation) may be used to eliminate the deficiency of blood in the retina caused by constriction of blood vessels and to slow down excessive formation of blood vessel tissue.Hemorrhaging of the clear jelly that is behind the lens of the eye (vitreous) and detachment of the retina) may be helped by the removal of the dark pigmented disk and jelly-like substance behind the retina (pars plana vitrectomy. | Therapies of Eales Disease. Treatment of Eales Disease is symptomatic and supportive. The surgical process of coagulating tissue with a laser beam (laser panretinal photocoagulation) may be used to eliminate the deficiency of blood in the retina caused by constriction of blood vessels and to slow down excessive formation of blood vessel tissue.Hemorrhaging of the clear jelly that is behind the lens of the eye (vitreous) and detachment of the retina) may be helped by the removal of the dark pigmented disk and jelly-like substance behind the retina (pars plana vitrectomy. | 393 | Eales Disease |
nord_394_0 | Overview of Ectodermal Dysplasias | The ectodermal dysplasias (EDs) are a heterogeneous group of nearly 100 inherited disorders characterized by anomalies in at least two of the structures derived from the embryonic ectoderm, with at least one involving the skin appendages (hair, nails, sweat glands) or teeth. Other tissues derived from the primitive ectoderm that can be involved in EDs include the mammary glands, adrenal medulla, central nervous system, inner ear, retina, optic lens, pigment cells and branchial arch cartilages. Advances in molecular genetics and developmental biology have led to the identification of the causative genes and developmental pathways in at least 80 of the EDs. | Overview of Ectodermal Dysplasias. The ectodermal dysplasias (EDs) are a heterogeneous group of nearly 100 inherited disorders characterized by anomalies in at least two of the structures derived from the embryonic ectoderm, with at least one involving the skin appendages (hair, nails, sweat glands) or teeth. Other tissues derived from the primitive ectoderm that can be involved in EDs include the mammary glands, adrenal medulla, central nervous system, inner ear, retina, optic lens, pigment cells and branchial arch cartilages. Advances in molecular genetics and developmental biology have led to the identification of the causative genes and developmental pathways in at least 80 of the EDs. | 394 | Ectodermal Dysplasias |
nord_394_1 | Symptoms of Ectodermal Dysplasias | Each of the nearly 100 EDs has its own set of clinical signs and symptoms. Commonly, the conditions will have one or more of the following associated findings: | Symptoms of Ectodermal Dysplasias. Each of the nearly 100 EDs has its own set of clinical signs and symptoms. Commonly, the conditions will have one or more of the following associated findings: | 394 | Ectodermal Dysplasias |
nord_394_2 | Causes of Ectodermal Dysplasias | The molecular causes of these diverse conditions involve many genes and multiple developmental pathways that are necessary for normal formation, structure and function of the ectodermal derivatives. This classification scheme does not include all disorders that affect two or more ectodermal derivatives. Genetic alterations of ED-associated genes that affect only one derivative of the ectoderm would be considered non-syndromic traits of the causative gene. Conditions already included as part of other classifications or groups of diseases (vesiculobullous disorders, palmoplantar keratodermas, etc.) are not included in the ED classification. Complex syndromes that have ED signs, but also major non-ED signs, such as trisomy 21, are also excluded from the ED classification scheme.The genetic causes of greater than 50% of the ED’s have been determined. The classification scheme clusters the disorders based on genotype, molecular pathway and physical characteristics (phenotype). Categories are:
Conditions that meet the definition of ED but of unknown cause are grouped with other EDs that share the most similar phenotype. Once their genetic cause is identified, they can be classified with the appropriate category or become the anchor of a new cluster, depending on molecular etiology.The reference listed below from Wright, et al provides a full listing of know ED conditions. | Causes of Ectodermal Dysplasias. The molecular causes of these diverse conditions involve many genes and multiple developmental pathways that are necessary for normal formation, structure and function of the ectodermal derivatives. This classification scheme does not include all disorders that affect two or more ectodermal derivatives. Genetic alterations of ED-associated genes that affect only one derivative of the ectoderm would be considered non-syndromic traits of the causative gene. Conditions already included as part of other classifications or groups of diseases (vesiculobullous disorders, palmoplantar keratodermas, etc.) are not included in the ED classification. Complex syndromes that have ED signs, but also major non-ED signs, such as trisomy 21, are also excluded from the ED classification scheme.The genetic causes of greater than 50% of the ED’s have been determined. The classification scheme clusters the disorders based on genotype, molecular pathway and physical characteristics (phenotype). Categories are:
Conditions that meet the definition of ED but of unknown cause are grouped with other EDs that share the most similar phenotype. Once their genetic cause is identified, they can be classified with the appropriate category or become the anchor of a new cluster, depending on molecular etiology.The reference listed below from Wright, et al provides a full listing of know ED conditions. | 394 | Ectodermal Dysplasias |
nord_394_3 | Affects of Ectodermal Dysplasias | ED’s have been reported from essentially all races, ethnic groups and geographic regions. | Affects of Ectodermal Dysplasias. ED’s have been reported from essentially all races, ethnic groups and geographic regions. | 394 | Ectodermal Dysplasias |
nord_394_4 | Related disorders of Ectodermal Dysplasias | Related disorders of Ectodermal Dysplasias. | 394 | Ectodermal Dysplasias |
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nord_394_5 | Diagnosis of Ectodermal Dysplasias | Diagnosis of Ectodermal Dysplasias. | 394 | Ectodermal Dysplasias |
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nord_394_6 | Therapies of Ectodermal Dysplasias | Treatment depends upon the specific disease manifestations in the affected individual, and is largely aimed at minimizing symptoms. For most of the ED’s, multidisciplinary management is required, with involvement of primary care physicians, geneticists, dermatologists, multiple dental specialists, nutritionists, speech therapists, otolaryngologists, ophthalmologists, orthopedic surgeons and/or plastic surgeons. | Therapies of Ectodermal Dysplasias. Treatment depends upon the specific disease manifestations in the affected individual, and is largely aimed at minimizing symptoms. For most of the ED’s, multidisciplinary management is required, with involvement of primary care physicians, geneticists, dermatologists, multiple dental specialists, nutritionists, speech therapists, otolaryngologists, ophthalmologists, orthopedic surgeons and/or plastic surgeons. | 394 | Ectodermal Dysplasias |
nord_395_0 | Overview of Ectrodactyly Ectodermal Dysplasia Cleft Lip/Palate | Ectrodactyly ectodermal dysplasia cleft lip/palate (EEC) syndrome is a rare genetic disorder. Symptoms can vary greatly from one person to another. Affected individuals often have abnormalities affecting the limbs including ectrodactyly, a condition in which part or all of the central digits (fingers or toes) are missing. Ectrodactyly often affects the middle fingers or toes, but can present differently in different people (or be absent altogether). A groove or gap in the upper lip (cleft lip) and a groove or gap in the roof of the mouth (cleft palate) may also occur. The ectodermal dysplasia component refers to abnormalities to structures that arise from the outermost layer of the embryo (ectoderm). In EEC syndrome, this generally affects the hair, teeth, nails, skin and sweat glands. Individuals with EEC syndrome can also develop a variety of additional symptoms including abnormalities of the genitourinary system and the eyes. Intelligence does not seem to be affected. Most cases of EEC syndrome are caused by mutations of the TP63 gene and are either new (spontaneous) mutations or are inherited as autosomal dominant disorders.IntroductionThere are at least four other syndromes caused by mutations of the TP63 gene including AEC/Hay-wells syndrome, Rapp-Hodgkin syndrome, limb-mammary syndrome, and ADULT syndrome. In addition, TP63 mutations have also been reported as the cause of nonsyndromic split hand/foot malformation and nonsyndromic cleft lip/palate (CL/P). There is considerable overlap among these disorders and some researchers consider them different expressions of one disease process. Despite the overlap, the TP63-associated syndromes have their own characteristic physical findings related, in part, to the specific mutation of the TP63gene present. These syndromes are further classified as forms of ectodermal dysplasia, a group of disorders characterized by abnormalities that occur during early embryonic development. Ectodermal dysplasias typically affect the hair, teeth, nails and/or skin. | Overview of Ectrodactyly Ectodermal Dysplasia Cleft Lip/Palate. Ectrodactyly ectodermal dysplasia cleft lip/palate (EEC) syndrome is a rare genetic disorder. Symptoms can vary greatly from one person to another. Affected individuals often have abnormalities affecting the limbs including ectrodactyly, a condition in which part or all of the central digits (fingers or toes) are missing. Ectrodactyly often affects the middle fingers or toes, but can present differently in different people (or be absent altogether). A groove or gap in the upper lip (cleft lip) and a groove or gap in the roof of the mouth (cleft palate) may also occur. The ectodermal dysplasia component refers to abnormalities to structures that arise from the outermost layer of the embryo (ectoderm). In EEC syndrome, this generally affects the hair, teeth, nails, skin and sweat glands. Individuals with EEC syndrome can also develop a variety of additional symptoms including abnormalities of the genitourinary system and the eyes. Intelligence does not seem to be affected. Most cases of EEC syndrome are caused by mutations of the TP63 gene and are either new (spontaneous) mutations or are inherited as autosomal dominant disorders.IntroductionThere are at least four other syndromes caused by mutations of the TP63 gene including AEC/Hay-wells syndrome, Rapp-Hodgkin syndrome, limb-mammary syndrome, and ADULT syndrome. In addition, TP63 mutations have also been reported as the cause of nonsyndromic split hand/foot malformation and nonsyndromic cleft lip/palate (CL/P). There is considerable overlap among these disorders and some researchers consider them different expressions of one disease process. Despite the overlap, the TP63-associated syndromes have their own characteristic physical findings related, in part, to the specific mutation of the TP63gene present. These syndromes are further classified as forms of ectodermal dysplasia, a group of disorders characterized by abnormalities that occur during early embryonic development. Ectodermal dysplasias typically affect the hair, teeth, nails and/or skin. | 395 | Ectrodactyly Ectodermal Dysplasia Cleft Lip/Palate |
nord_395_1 | Symptoms of Ectrodactyly Ectodermal Dysplasia Cleft Lip/Palate | The symptoms of EEC syndrome are highly variable, even among members of the same family. The variability is due, in part, to different mutations of the TP63 gene (e.g., certain mutations are more likely to be associated with certain symptoms). Affected individuals or their parents should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.Ectrodactyly, which is also known as split hand/foot malformation (SHFM), is a condition characterized by absence or malformation of one or more of the fingers or toes. Usually, the middle fingers or toes are affected. All four hands and feet may be affected in some individuals. However, some individuals have only mild malformation or are unaffected. Individuals with EEC may also exhibit webbing or fusion (syndactyly) of some of the fingers and/or toes. In some cases, syndactyly is the only limb defect that occurs.Affected individuals have cleft lip with or without cleft palate. Additional distinctive facial features can occur including an undeveloped upper jaw (maxillary hypoplasia), a broad nasal tip, an abnormally long groove (philtrum) between the nose and the upper lip, and narrowing or blockage of the nasal airways (choanal atresia).The type and severity of ectodermal dysplasia in individuals with EEC syndrome is highly variable. The skin, hair, teeth, and sweat glands are commonly affected. Affected individuals may have dry, discolored (hypopigmented) skin. The skin may also be itchy. In some patients, mildly thickened, scaly patches of skin (hyperkeratosis) may also develop. Individuals tend to be fair skinned and have sparse, coarse, slow-growing scalp hair. Eyelashes or eyebrows may be sparse or absent.Additional symptoms can include slow-growing, thin, malformed (dysplastic) nails and missing, malformed or underdeveloped teeth (hypodontia). Tooth decay (dental caries) is common and often severe. Tooth enamel may be abnormal. Some individuals experience reduced activity or absence of certain exocrine glands (glands that secrete into ducts) including the sweat, salivary, and small oil-producing (sebaceous) glands. Abnormality of the sweat glands can lead to a reduced ability to sweat (hypohidrosis), which can be associated with heat intolerance and fever. Abnormality of the salivary glands can lead to dry mouth (xerostomia).Some individuals have eye issues including abnormalities of the tear (lacrimal) ducts that can cause frequent tearing, increased susceptibility to eye infections and chronic inflammation of the delicate membranes that line the inside of the eyes (conjunctivitis), potentially causing vision impairment. Additional abnormalities affecting the eyes can occur including sensitivity to light (photophobia), corneal ulcerations, inflammation of the cornea (keratitis), and inflammation of the eyelashes and eyelids (blepharitis).In some cases, affected individuals may have genitourinary anomalies. Virtually any part of the genitourinary tract can be involved. Symptoms can include absence of the kidneys (renal agenesis), narrowing of the tubes that carry urine out of the body from the bladder (urethral atresia), and obstruction of the tubes (ureters) that carry urine from the kidney to the bladder, resulting in the accumulation of urine in the pelvis and kidney duct (hydronephrosis). An extremely uncommon genitourinary complication known as atrophic/dysplastic bladder epithelium has been reported in individuals with EEC syndrome. Epithelium refers to specific tissue that lines many of the cavities and structures within the body such as the bladder. In affected individuals, abnormal thinning of this lining within the bladder results in painful urination (dysuria), increased urgency to urinate and an increased frequency to urinate.Additional abnormalities have been reported in some cases including underdeveloped (hypoplastic) nipples. Some individuals with EEC syndrome have developed hearing loss. The ears can be abnormally small and the outer part of the ears (auricles) malformed. Some individuals may develop glandular abnormalities such as an underdeveloped thymus and reduced activity of the pituitary gland (hypopituitarism). Glandular abnormalities can result in growth hormone deficiency.Intelligence is usually unaffected in children with EEC syndrome. Language development, however, may be delayed due to certain associated abnormalities such as cleft lip/palate or hearing impairment. | Symptoms of Ectrodactyly Ectodermal Dysplasia Cleft Lip/Palate. The symptoms of EEC syndrome are highly variable, even among members of the same family. The variability is due, in part, to different mutations of the TP63 gene (e.g., certain mutations are more likely to be associated with certain symptoms). Affected individuals or their parents should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.Ectrodactyly, which is also known as split hand/foot malformation (SHFM), is a condition characterized by absence or malformation of one or more of the fingers or toes. Usually, the middle fingers or toes are affected. All four hands and feet may be affected in some individuals. However, some individuals have only mild malformation or are unaffected. Individuals with EEC may also exhibit webbing or fusion (syndactyly) of some of the fingers and/or toes. In some cases, syndactyly is the only limb defect that occurs.Affected individuals have cleft lip with or without cleft palate. Additional distinctive facial features can occur including an undeveloped upper jaw (maxillary hypoplasia), a broad nasal tip, an abnormally long groove (philtrum) between the nose and the upper lip, and narrowing or blockage of the nasal airways (choanal atresia).The type and severity of ectodermal dysplasia in individuals with EEC syndrome is highly variable. The skin, hair, teeth, and sweat glands are commonly affected. Affected individuals may have dry, discolored (hypopigmented) skin. The skin may also be itchy. In some patients, mildly thickened, scaly patches of skin (hyperkeratosis) may also develop. Individuals tend to be fair skinned and have sparse, coarse, slow-growing scalp hair. Eyelashes or eyebrows may be sparse or absent.Additional symptoms can include slow-growing, thin, malformed (dysplastic) nails and missing, malformed or underdeveloped teeth (hypodontia). Tooth decay (dental caries) is common and often severe. Tooth enamel may be abnormal. Some individuals experience reduced activity or absence of certain exocrine glands (glands that secrete into ducts) including the sweat, salivary, and small oil-producing (sebaceous) glands. Abnormality of the sweat glands can lead to a reduced ability to sweat (hypohidrosis), which can be associated with heat intolerance and fever. Abnormality of the salivary glands can lead to dry mouth (xerostomia).Some individuals have eye issues including abnormalities of the tear (lacrimal) ducts that can cause frequent tearing, increased susceptibility to eye infections and chronic inflammation of the delicate membranes that line the inside of the eyes (conjunctivitis), potentially causing vision impairment. Additional abnormalities affecting the eyes can occur including sensitivity to light (photophobia), corneal ulcerations, inflammation of the cornea (keratitis), and inflammation of the eyelashes and eyelids (blepharitis).In some cases, affected individuals may have genitourinary anomalies. Virtually any part of the genitourinary tract can be involved. Symptoms can include absence of the kidneys (renal agenesis), narrowing of the tubes that carry urine out of the body from the bladder (urethral atresia), and obstruction of the tubes (ureters) that carry urine from the kidney to the bladder, resulting in the accumulation of urine in the pelvis and kidney duct (hydronephrosis). An extremely uncommon genitourinary complication known as atrophic/dysplastic bladder epithelium has been reported in individuals with EEC syndrome. Epithelium refers to specific tissue that lines many of the cavities and structures within the body such as the bladder. In affected individuals, abnormal thinning of this lining within the bladder results in painful urination (dysuria), increased urgency to urinate and an increased frequency to urinate.Additional abnormalities have been reported in some cases including underdeveloped (hypoplastic) nipples. Some individuals with EEC syndrome have developed hearing loss. The ears can be abnormally small and the outer part of the ears (auricles) malformed. Some individuals may develop glandular abnormalities such as an underdeveloped thymus and reduced activity of the pituitary gland (hypopituitarism). Glandular abnormalities can result in growth hormone deficiency.Intelligence is usually unaffected in children with EEC syndrome. Language development, however, may be delayed due to certain associated abnormalities such as cleft lip/palate or hearing impairment. | 395 | Ectrodactyly Ectodermal Dysplasia Cleft Lip/Palate |
nord_395_2 | Causes of Ectrodactyly Ectodermal Dysplasia Cleft Lip/Palate | Most cases of EEC syndrome are caused by mutations of the TP63 gene. The protein product of the gene is known as p63. A small percentage of cases with features resembling EEC syndrome are caused by chromosomal abnormalities. EEC syndrome is inherited as an autosomal dominant trait. Some cases occur sporadically with no previous family history of the disorder (i.e., new mutations).Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.Investigators have determined that the TP63 gene is located on the long arm (q) of chromosome 3 (3q27). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 3q27” refers to band 27 on the long arm of chromosome 3. The numbered bands specify the location of the thousands of genes that are present on each chromosome.The TP63 gene contains instructions for synthesizing (encoding) a protein that is essential for the proper development of the limbs and structures derived from the ectoderm. Mutations of this gene lead to a reduction of functional levels of normally functioning p63 protein, which hinders the proper development of these structures.In rare cases, individuals with EEC syndrome carry chromosomal disruptions (deletions, translocations) on the long arm of chromosome 7 (7q11.2-q21.3).When EEC syndrome is caused by mutations of the TP63 gene it is sometimes referred to EEC syndrome type 3 (EEC3); when it caused by chromosomal abnormalities of chromosome 7 it is referred to as EEC syndrome type 1 (EEC1). A disorder formerly designated EEC syndrome type 2 no longer exists.In some patients, EEC syndrome may be due to gonadal mosaicism, a condition in which some of a parent’s reproductive cells (germ cells) carry the TP63 mutation, while others contain a normal cell line (mosaicism). The other cells (non-reproductive or somatic cells) in a parent’s body do not have the mutation. As a result, one or more of the parent’s children may inherit the gene mutation, potentially leading to development of EEC syndrome, while the parent does not have the disorder (asymptomatic carrier). Germline mosaicism may be suspected when an apparently unaffected parent has more than one child with the same genetic abnormality. The likelihood of a parent passing on a mosaic germline mutation to a child depends upon the percentage of the parent’s germ cells that carry the mutation versus the percentage that do not. There is no test for germline mosaicism before pregnancy. Testing during pregnancy may be available and is best discussed with a genetic specialist.The symptoms and physical findings of EEC syndrome can vary greatly in severity from one person to another (variable expressivity). In addition, individuals who inherited a defective gene for EEC syndrome will not develop all of the symptoms discussed above (reduced penetrance). Researchers have noted that specific features of EEC syndrome are more likely or only associated with specific mutations of the TP63 genes. In addition, other factors such as additional genes that modify the expression of a disorder (modifier genes) may play a role in the variable findings of EEC syndrome. | Causes of Ectrodactyly Ectodermal Dysplasia Cleft Lip/Palate. Most cases of EEC syndrome are caused by mutations of the TP63 gene. The protein product of the gene is known as p63. A small percentage of cases with features resembling EEC syndrome are caused by chromosomal abnormalities. EEC syndrome is inherited as an autosomal dominant trait. Some cases occur sporadically with no previous family history of the disorder (i.e., new mutations).Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.Investigators have determined that the TP63 gene is located on the long arm (q) of chromosome 3 (3q27). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 3q27” refers to band 27 on the long arm of chromosome 3. The numbered bands specify the location of the thousands of genes that are present on each chromosome.The TP63 gene contains instructions for synthesizing (encoding) a protein that is essential for the proper development of the limbs and structures derived from the ectoderm. Mutations of this gene lead to a reduction of functional levels of normally functioning p63 protein, which hinders the proper development of these structures.In rare cases, individuals with EEC syndrome carry chromosomal disruptions (deletions, translocations) on the long arm of chromosome 7 (7q11.2-q21.3).When EEC syndrome is caused by mutations of the TP63 gene it is sometimes referred to EEC syndrome type 3 (EEC3); when it caused by chromosomal abnormalities of chromosome 7 it is referred to as EEC syndrome type 1 (EEC1). A disorder formerly designated EEC syndrome type 2 no longer exists.In some patients, EEC syndrome may be due to gonadal mosaicism, a condition in which some of a parent’s reproductive cells (germ cells) carry the TP63 mutation, while others contain a normal cell line (mosaicism). The other cells (non-reproductive or somatic cells) in a parent’s body do not have the mutation. As a result, one or more of the parent’s children may inherit the gene mutation, potentially leading to development of EEC syndrome, while the parent does not have the disorder (asymptomatic carrier). Germline mosaicism may be suspected when an apparently unaffected parent has more than one child with the same genetic abnormality. The likelihood of a parent passing on a mosaic germline mutation to a child depends upon the percentage of the parent’s germ cells that carry the mutation versus the percentage that do not. There is no test for germline mosaicism before pregnancy. Testing during pregnancy may be available and is best discussed with a genetic specialist.The symptoms and physical findings of EEC syndrome can vary greatly in severity from one person to another (variable expressivity). In addition, individuals who inherited a defective gene for EEC syndrome will not develop all of the symptoms discussed above (reduced penetrance). Researchers have noted that specific features of EEC syndrome are more likely or only associated with specific mutations of the TP63 genes. In addition, other factors such as additional genes that modify the expression of a disorder (modifier genes) may play a role in the variable findings of EEC syndrome. | 395 | Ectrodactyly Ectodermal Dysplasia Cleft Lip/Palate |
nord_395_3 | Affects of Ectrodactyly Ectodermal Dysplasia Cleft Lip/Palate | EEC syndrome affects males and females in equal numbers. The exact incidence and prevalence of the disorder in the general population is unknown. | Affects of Ectrodactyly Ectodermal Dysplasia Cleft Lip/Palate. EEC syndrome affects males and females in equal numbers. The exact incidence and prevalence of the disorder in the general population is unknown. | 395 | Ectrodactyly Ectodermal Dysplasia Cleft Lip/Palate |
nord_395_4 | Related disorders of Ectrodactyly Ectodermal Dysplasia Cleft Lip/Palate | Symptoms of the following disorders can be similar to those of EEC syndrome. Comparisons may be useful for a differential diagnosis.Several disorders in addition to EEC syndrome are caused by mutations of the TP63 gene. These disorders are allelic, caused by different mutations to the same disease gene. Some researchers consider these disorders different expressions of the same disease process. However, other researchers have noted that associated symptoms tend to vary based upon the specific mutation present (genotype-phenotype correlation), resulting in distinct yet overlapping syndromes. These disorders include AEC/Hay-Wells syndrome, Rapp Hodgkin syndrome, ADULT syndrome, limb-mammary syndrome and nonsyndromic split hand/foot malformation. Some individuals with isolated (nonsyndrommic) cleft lip also have mutations of the TP63 gene. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)Lacrimo-auriculo-dento-digital (LADD) syndrome is an extremely rare genetic disorder characterized by abnormalities affecting the lacrimal and salivary glands and ducts, ears, teeth and fingers and toes. The most common findings involve malformations in the network of structures of the eye that secrete tears and drain them from the eyes (lacrimal apparatus) and abnormalities of the forearms and fingers. Specific symptoms may vary greatly from person to person. LADD syndrome may occur sporadically or be inherited as an autosomal dominant trait. (For more information on this disorder, choose “LADD” as your search term in the Rare Disease Database.)Ectodermal dysplasias (EDs) are a group of rare genetic multisystem disorders that typically affect structures that arise from the outermost layer of the embryo (ectoderm). EDs typically affect the hair, teeth, nails, and/or skin. Several other ectodermal dysplasia disorders may be characterized by sparse or absent hair, absence or improper functioning of sweat glands, skin abnormalities, malformations of the nose, and/or other abnormalities similar to those associated with EEC syndrome. (For more information on these disorders, choose the specific disorder name or “ectodermal dysplasias” as your search term in the Rare Disease Database.) | Related disorders of Ectrodactyly Ectodermal Dysplasia Cleft Lip/Palate. Symptoms of the following disorders can be similar to those of EEC syndrome. Comparisons may be useful for a differential diagnosis.Several disorders in addition to EEC syndrome are caused by mutations of the TP63 gene. These disorders are allelic, caused by different mutations to the same disease gene. Some researchers consider these disorders different expressions of the same disease process. However, other researchers have noted that associated symptoms tend to vary based upon the specific mutation present (genotype-phenotype correlation), resulting in distinct yet overlapping syndromes. These disorders include AEC/Hay-Wells syndrome, Rapp Hodgkin syndrome, ADULT syndrome, limb-mammary syndrome and nonsyndromic split hand/foot malformation. Some individuals with isolated (nonsyndrommic) cleft lip also have mutations of the TP63 gene. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)Lacrimo-auriculo-dento-digital (LADD) syndrome is an extremely rare genetic disorder characterized by abnormalities affecting the lacrimal and salivary glands and ducts, ears, teeth and fingers and toes. The most common findings involve malformations in the network of structures of the eye that secrete tears and drain them from the eyes (lacrimal apparatus) and abnormalities of the forearms and fingers. Specific symptoms may vary greatly from person to person. LADD syndrome may occur sporadically or be inherited as an autosomal dominant trait. (For more information on this disorder, choose “LADD” as your search term in the Rare Disease Database.)Ectodermal dysplasias (EDs) are a group of rare genetic multisystem disorders that typically affect structures that arise from the outermost layer of the embryo (ectoderm). EDs typically affect the hair, teeth, nails, and/or skin. Several other ectodermal dysplasia disorders may be characterized by sparse or absent hair, absence or improper functioning of sweat glands, skin abnormalities, malformations of the nose, and/or other abnormalities similar to those associated with EEC syndrome. (For more information on these disorders, choose the specific disorder name or “ectodermal dysplasias” as your search term in the Rare Disease Database.) | 395 | Ectrodactyly Ectodermal Dysplasia Cleft Lip/Palate |
nord_395_5 | Diagnosis of Ectrodactyly Ectodermal Dysplasia Cleft Lip/Palate | A diagnosis of EEC syndrome is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests.Clinical Testing and Work-UpA variety of tests may be used to evaluate individuals with EEC syndrome. Imaging techniques may include traditional x-rays can be used assess abnormalities of the limbs and face. A complete ophthalmological exam will be performed to detect potential eye complications associated with the disorder such as lacrimal duct obstruction. A kidney (renal) ultrasound will be performed to detect potential kidney complications. An ultrasound uses reflected sound waves to create an image of the organ(s) in question.Molecular examination of the small samples of skin tissue (skin biopsy) may reveal abnormal thinning of the outer layer of the skin (epidermis) and the absence of certain specialized structures normally located within the skin (e.g., sweat glands).Molecular genetic testing can confirm a diagnosis of EEC syndrome. Molecular genetic testing can detect mutations in the TP63 gene or chromosomal abnormalities that account for the phenotype. In clinically diagnosed EEC syndrome patients, mutation analysis of the TP63 gene is the first test to perform; if negative, testing for chromosomal abnormalities can be considered. Testing is available only on a clinical basis.Prenatal diagnosis of EEC syndrome can be suspected based upon identification of ectrodactyly, cleft lip/palate or other associated anomalies, which can be detected during a routine fetal ultrasound.Prenatal diagnosis is available for families with a known risk for having a baby with EEC syndrome. Molecular genetic testing can be performed on cells obtained from the fluid that surrounds the developing fetus (amniotic fluid). A test known as chorionic villi sampling can also be used to obtain a prenatal diagnosis of EEC syndrome in these cases. Chorionic villi are thin, hair-like structures found on the placenta. Molecular genetic testing can also be performed on these cells. | Diagnosis of Ectrodactyly Ectodermal Dysplasia Cleft Lip/Palate. A diagnosis of EEC syndrome is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests.Clinical Testing and Work-UpA variety of tests may be used to evaluate individuals with EEC syndrome. Imaging techniques may include traditional x-rays can be used assess abnormalities of the limbs and face. A complete ophthalmological exam will be performed to detect potential eye complications associated with the disorder such as lacrimal duct obstruction. A kidney (renal) ultrasound will be performed to detect potential kidney complications. An ultrasound uses reflected sound waves to create an image of the organ(s) in question.Molecular examination of the small samples of skin tissue (skin biopsy) may reveal abnormal thinning of the outer layer of the skin (epidermis) and the absence of certain specialized structures normally located within the skin (e.g., sweat glands).Molecular genetic testing can confirm a diagnosis of EEC syndrome. Molecular genetic testing can detect mutations in the TP63 gene or chromosomal abnormalities that account for the phenotype. In clinically diagnosed EEC syndrome patients, mutation analysis of the TP63 gene is the first test to perform; if negative, testing for chromosomal abnormalities can be considered. Testing is available only on a clinical basis.Prenatal diagnosis of EEC syndrome can be suspected based upon identification of ectrodactyly, cleft lip/palate or other associated anomalies, which can be detected during a routine fetal ultrasound.Prenatal diagnosis is available for families with a known risk for having a baby with EEC syndrome. Molecular genetic testing can be performed on cells obtained from the fluid that surrounds the developing fetus (amniotic fluid). A test known as chorionic villi sampling can also be used to obtain a prenatal diagnosis of EEC syndrome in these cases. Chorionic villi are thin, hair-like structures found on the placenta. Molecular genetic testing can also be performed on these cells. | 395 | Ectrodactyly Ectodermal Dysplasia Cleft Lip/Palate |
nord_395_6 | Therapies of Ectrodactyly Ectodermal Dysplasia Cleft Lip/Palate | TreatmentThe treatment of EEC syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, pediatric surgeons, plastic surgeons, orthopedic surgeons, orthopedists, dentists, speech therapists, specialists that are trained to deal with abnormalities of the eyes (ophthalmologists), ears (audiologists), and skin (dermatologists), and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment.Reconstructive surgery may be beneficial for individuals with all defects causing functional disability such as ectrodactyly, syndactyly, cleft lip or palate and other associated facial anomalies (e.g., underdeveloped jaw, malformed ears). Dental surgery and corrective devices may be used to treat misshapen teeth. If teeth are missing, dentures may be necessary. Affected individuals should pay particular attention to dental health to prevent tooth decay.Artificial tears may be necessary for individuals with lacrimal duct obstruction. Surgery may also be necessary for blocked lacrimal ducts. Emollients may be used to treat dry skin. If hearing impairment is present, hearing aids may be beneficial. Children with hypohidrosis should be monitored closely for signs of hyperthermia, particularly during periods of prolonged activity and or during summer months.When hydronephrosis is present, temporary drainage of the urine may be necessary. Surgery may be indicated when pain or infection is present or when kidney function is compromised.Genetic counseling may be of benefit for affected individuals and their families. | Therapies of Ectrodactyly Ectodermal Dysplasia Cleft Lip/Palate. TreatmentThe treatment of EEC syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, pediatric surgeons, plastic surgeons, orthopedic surgeons, orthopedists, dentists, speech therapists, specialists that are trained to deal with abnormalities of the eyes (ophthalmologists), ears (audiologists), and skin (dermatologists), and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment.Reconstructive surgery may be beneficial for individuals with all defects causing functional disability such as ectrodactyly, syndactyly, cleft lip or palate and other associated facial anomalies (e.g., underdeveloped jaw, malformed ears). Dental surgery and corrective devices may be used to treat misshapen teeth. If teeth are missing, dentures may be necessary. Affected individuals should pay particular attention to dental health to prevent tooth decay.Artificial tears may be necessary for individuals with lacrimal duct obstruction. Surgery may also be necessary for blocked lacrimal ducts. Emollients may be used to treat dry skin. If hearing impairment is present, hearing aids may be beneficial. Children with hypohidrosis should be monitored closely for signs of hyperthermia, particularly during periods of prolonged activity and or during summer months.When hydronephrosis is present, temporary drainage of the urine may be necessary. Surgery may be indicated when pain or infection is present or when kidney function is compromised.Genetic counseling may be of benefit for affected individuals and their families. | 395 | Ectrodactyly Ectodermal Dysplasia Cleft Lip/Palate |
nord_396_0 | Overview of EEF1A2-Related Neurodevelopmental Disorder | EEF1A2-related neurodevelopmental disorder is a very rare disorder caused by harmful variants in the EEF1A2 gene that have arisen spontaneously. There are many different types of these variants, and the effects are very variable, sometimes even in children with the same variant. Most children, but not all, will have epilepsy, developmental delay and intellectual disability. Some also have challenging behaviours and/or movement disorders. | Overview of EEF1A2-Related Neurodevelopmental Disorder. EEF1A2-related neurodevelopmental disorder is a very rare disorder caused by harmful variants in the EEF1A2 gene that have arisen spontaneously. There are many different types of these variants, and the effects are very variable, sometimes even in children with the same variant. Most children, but not all, will have epilepsy, developmental delay and intellectual disability. Some also have challenging behaviours and/or movement disorders. | 396 | EEF1A2-Related Neurodevelopmental Disorder |
nord_396_1 | Symptoms of EEF1A2-Related Neurodevelopmental Disorder | EEF1A2-related neurodevelopmental disorder has a variable presentation but almost always involves epileptic seizures, developmental delay and intellectual disability. Most children, but not all, will have onset of epileptic seizures of different types within the first four months of life. The most common seizure type are myoclonic seizures, with most children developing other seizure types. The seizures can be difficult to control, but in some children, the seizures respond well to treatment. Significant global developmental delay will be seen in most but not all. Early concerns about low muscle tone, even within the first month of life, are often reported. There are no consistent characteristic features on magnetic resonance imaging (MRI) imaging studies. There have been reports that some children have a broad nasal bridge, tented upper lip, everted lower lip and downturned corners of the mouth but this is not seen in all affected children. | Symptoms of EEF1A2-Related Neurodevelopmental Disorder. EEF1A2-related neurodevelopmental disorder has a variable presentation but almost always involves epileptic seizures, developmental delay and intellectual disability. Most children, but not all, will have onset of epileptic seizures of different types within the first four months of life. The most common seizure type are myoclonic seizures, with most children developing other seizure types. The seizures can be difficult to control, but in some children, the seizures respond well to treatment. Significant global developmental delay will be seen in most but not all. Early concerns about low muscle tone, even within the first month of life, are often reported. There are no consistent characteristic features on magnetic resonance imaging (MRI) imaging studies. There have been reports that some children have a broad nasal bridge, tented upper lip, everted lower lip and downturned corners of the mouth but this is not seen in all affected children. | 396 | EEF1A2-Related Neurodevelopmental Disorder |
nord_396_2 | Causes of EEF1A2-Related Neurodevelopmental Disorder | EEF1A2-related neurodevelopmental disorder is usually caused by harmful heterozygous variants (called missense mutations); heterozygous means that each affected individual has one normal copy of the gene and one mutant copy. These harmful variants lead to changes in the eEF1A2 protein in nerve cells and muscles. In almost every child reported so far, the variants in the EEF1A2 gene are categorised as de novo, meaning they have arisen in either an egg or sperm cell. This means the variant has not been inherited and the risk of recurrence in future children of the same parents is low. Numerous different variants in the EEF1A2 gene have been reported, and many have only been seen once, so it is not easy to make associations between specific variants and specific symptoms, although some patterns are emerging. | Causes of EEF1A2-Related Neurodevelopmental Disorder. EEF1A2-related neurodevelopmental disorder is usually caused by harmful heterozygous variants (called missense mutations); heterozygous means that each affected individual has one normal copy of the gene and one mutant copy. These harmful variants lead to changes in the eEF1A2 protein in nerve cells and muscles. In almost every child reported so far, the variants in the EEF1A2 gene are categorised as de novo, meaning they have arisen in either an egg or sperm cell. This means the variant has not been inherited and the risk of recurrence in future children of the same parents is low. Numerous different variants in the EEF1A2 gene have been reported, and many have only been seen once, so it is not easy to make associations between specific variants and specific symptoms, although some patterns are emerging. | 396 | EEF1A2-Related Neurodevelopmental Disorder |
nord_396_3 | Affects of EEF1A2-Related Neurodevelopmental Disorder | The frequency of EEF1A2-related neurodevelopmental disorder has been estimated to be 2.92/100,000. Prevalence in specific populations is likely to be consistent since most cases have not been inherited but arisen de novo. | Affects of EEF1A2-Related Neurodevelopmental Disorder. The frequency of EEF1A2-related neurodevelopmental disorder has been estimated to be 2.92/100,000. Prevalence in specific populations is likely to be consistent since most cases have not been inherited but arisen de novo. | 396 | EEF1A2-Related Neurodevelopmental Disorder |
nord_396_4 | Related disorders of EEF1A2-Related Neurodevelopmental Disorder | There are many different conditions in which a child has seizures within the first few months and/or has significant developmental delay. These conditions include, but are not restricted to, all other developmental and epileptic encephalopathies (note that this condition is also known as developmental and epileptic encephalopathy-33).In very rare instances, children have been reported with two mutant copies of the EEF1A2 gene instead of having one normal copy of the gene and one mutant copy. These children inherited one mutant copy of the gene from each parent. In addition to seizures and global developmental delay, people with two mutant copies of the EEF1A2 gene develop a heart problem where the heart walls become thin, stretched and weak and the heart is unable to pump blood to the rest of the body (dilated cardiomyopathy), leading to early death. Dilated cardiomyopathy has also been reported in an individual with one mutant copy of EEF1A2, though this patient’s heart function improved with age. | Related disorders of EEF1A2-Related Neurodevelopmental Disorder. There are many different conditions in which a child has seizures within the first few months and/or has significant developmental delay. These conditions include, but are not restricted to, all other developmental and epileptic encephalopathies (note that this condition is also known as developmental and epileptic encephalopathy-33).In very rare instances, children have been reported with two mutant copies of the EEF1A2 gene instead of having one normal copy of the gene and one mutant copy. These children inherited one mutant copy of the gene from each parent. In addition to seizures and global developmental delay, people with two mutant copies of the EEF1A2 gene develop a heart problem where the heart walls become thin, stretched and weak and the heart is unable to pump blood to the rest of the body (dilated cardiomyopathy), leading to early death. Dilated cardiomyopathy has also been reported in an individual with one mutant copy of EEF1A2, though this patient’s heart function improved with age. | 396 | EEF1A2-Related Neurodevelopmental Disorder |
nord_396_5 | Diagnosis of EEF1A2-Related Neurodevelopmental Disorder | A diagnosis can only be confirmed through molecular genetic testing. This testing can be done on a blood sample and may be included in a panel test that looks for variants in many different genes that cause epilepsy. There are also other methods for genetic testing such as trio-based sequencing. This is when the child and both biological parents are tested to look for gene variants.Any child with seizures and/or developmental delay should be considered for testing for EEF1A2. This includes children with seizures that are well controlled on medication and/or have mild developmental delay. There have been some reports of children with EEF1A2-related neurodevelopmental disorder whose early development was normal but degenerative changes emerged later in life. | Diagnosis of EEF1A2-Related Neurodevelopmental Disorder. A diagnosis can only be confirmed through molecular genetic testing. This testing can be done on a blood sample and may be included in a panel test that looks for variants in many different genes that cause epilepsy. There are also other methods for genetic testing such as trio-based sequencing. This is when the child and both biological parents are tested to look for gene variants.Any child with seizures and/or developmental delay should be considered for testing for EEF1A2. This includes children with seizures that are well controlled on medication and/or have mild developmental delay. There have been some reports of children with EEF1A2-related neurodevelopmental disorder whose early development was normal but degenerative changes emerged later in life. | 396 | EEF1A2-Related Neurodevelopmental Disorder |
nord_396_6 | Therapies of EEF1A2-Related Neurodevelopmental Disorder | Multidisciplinary health, educational and social support is needed. No consistently effective antiseizure medication has been identified although there have been reports of good response with levetiracetam, clobazam and valproate. Similarly, treatment of movement disorders can be challenging but good response with tetrabenazine has been reported. Children with behavioural problems will often benefit from learning disability support/psychology intervention.Genetic counseling is recommended for families with an affected child. | Therapies of EEF1A2-Related Neurodevelopmental Disorder. Multidisciplinary health, educational and social support is needed. No consistently effective antiseizure medication has been identified although there have been reports of good response with levetiracetam, clobazam and valproate. Similarly, treatment of movement disorders can be challenging but good response with tetrabenazine has been reported. Children with behavioural problems will often benefit from learning disability support/psychology intervention.Genetic counseling is recommended for families with an affected child. | 396 | EEF1A2-Related Neurodevelopmental Disorder |
nord_397_0 | Overview of Ehlers Danlos Syndromes | SummaryThe Ehlers-Danlos syndromes (EDS) are a group of related disorders caused by different genetic defects in collagen. Collagen is one of the major structural components of the body. Collagen is a tough, fibrous, protein, and serves as a building block essential in both strengthening connective tissue (e.g. bones) and providing flexibility where needed (e.g. cartilage). The problems seen in patients with EDS can be due to either the poor strength of collagen. It may alternatively be due to the absence of sufficient amounts of structurally normal collagen. The primary complications seen in EDS involve the skin, muscles, skeleton, and blood vessels. Patients with EDS often have skin that can be describes as “velvety”, “loose”. This skin characteristic predisposes patients to problems with wound healing. Patients will often note that they develop “paper-thin” scars. Patients also have excessively flexible, loose joints. These ‘hypermobile’ joints can be easily and frequently dislocated. Finally, fragile blood vessels leave patients experiencing easy bruising, even an increased tendency to serious episodes of bleeding.Each subtype of EDS results from a distinct genetic change. Patients within each specific subtype share characteristics other than the primary problems described above, and are covered in detail below. There may be significant variation in the experiences of individuals within each subtype.IntroductionThe named subtypes of EDS have undergone extensive reorganization as more information becomes available. EDS was originally categorized under eleven Roman numeral designations (EDS I -EDS XI), based primarily on symptoms and mode of inheritance. Later, EDS was classified into six subtypes based on the characteristic features of each type. In 2017, the International Classification for the Ehlers-Danlos Syndromes was published, in which thirteen descriptive subtypes are recognized. The 2017 International Classification most recently outlines a classification based on underlying genetic causes (Group A-F) that is used for research purposes. | Overview of Ehlers Danlos Syndromes. SummaryThe Ehlers-Danlos syndromes (EDS) are a group of related disorders caused by different genetic defects in collagen. Collagen is one of the major structural components of the body. Collagen is a tough, fibrous, protein, and serves as a building block essential in both strengthening connective tissue (e.g. bones) and providing flexibility where needed (e.g. cartilage). The problems seen in patients with EDS can be due to either the poor strength of collagen. It may alternatively be due to the absence of sufficient amounts of structurally normal collagen. The primary complications seen in EDS involve the skin, muscles, skeleton, and blood vessels. Patients with EDS often have skin that can be describes as “velvety”, “loose”. This skin characteristic predisposes patients to problems with wound healing. Patients will often note that they develop “paper-thin” scars. Patients also have excessively flexible, loose joints. These ‘hypermobile’ joints can be easily and frequently dislocated. Finally, fragile blood vessels leave patients experiencing easy bruising, even an increased tendency to serious episodes of bleeding.Each subtype of EDS results from a distinct genetic change. Patients within each specific subtype share characteristics other than the primary problems described above, and are covered in detail below. There may be significant variation in the experiences of individuals within each subtype.IntroductionThe named subtypes of EDS have undergone extensive reorganization as more information becomes available. EDS was originally categorized under eleven Roman numeral designations (EDS I -EDS XI), based primarily on symptoms and mode of inheritance. Later, EDS was classified into six subtypes based on the characteristic features of each type. In 2017, the International Classification for the Ehlers-Danlos Syndromes was published, in which thirteen descriptive subtypes are recognized. The 2017 International Classification most recently outlines a classification based on underlying genetic causes (Group A-F) that is used for research purposes. | 397 | Ehlers Danlos Syndromes |
nord_397_1 | Symptoms of Ehlers Danlos Syndromes | Classical (cEDS)
cEDS (formerly EDSI and EDSII) is associated with the primary problems described above, skin hyperextensibility, joint laxity, and fragile blood vessels. Scars are very thin, discolored, and stretch with time. Such paper-like (papyraceous) scarring occurs especially over prominent bony pressure points such as the knees, elbows, shins and forehead. Joint hypermobility accidents (subluxations and dislocations) are generally easily managed. Additional findings may include the formation of small, fleshy, skin growths called ‘molluscoid pseudotumors’ or hard, round, movable lumps under the skin called ‘calcified spheroids’. Finally, some individuals with this subtype may have a deformity of heart valves (especially the mitral/bicuspid valve between the atrium and the ventricle of the left side). The heart’s valves function to keep blood flowing in one direction. Weak valves may be overcome by the blood flow across their leaflets and prolapse, allowing blood to leak in the backwards direction. Valve dysfunction can result in remodeling of the heart’s architecture and with time congestive heart failure (pump insufficiency). Another complication cEDS patients may experience is dilatation of the aorta. The aorta is the major blood vessel coming immediately off the heart, responsible for directing oxygenated blood towards body tissues. In cEDS there is an increased risk also for aortic dissection. Blood vessel walls are made up of three layers (intima, media, and the adventitia). Dissection describes the separation of the intima from the media and adventitia. This complication can compromise blood supply to tissues including the heart. Aortic dissection is an immediate emergency that can result in acute heart failure. Patients should immediately seek medical attention for any tearing chest pains. Classical-like (clEDS)
clEDS is similar in clinical course to cEDS (described immediately above). Genetic causes of cEDS and clEDS differ (described below). Cardiac-valvular type (cvEDS)
cvEDS is a rare subtype of EDS wherein patients may have minor signs of EDS with severe defects to their aorta, requiring surgical interventions.Vascular type (vEDS)
vEDS (formerly EDSIV), can be identified at birth with noticeable clubfoot deformities and dislocation of the hips. In childhood, inguinal hernia (partial slip of intestine beyond the abdominal wall) and pneumothorax (collection of air between the lung and chest wall, impairing proper lung inflation) are commonly experienced and are indicative of this syndrome. Individuals with vEDS may also have abnormally decreased levels of fatty tissue under skin layers (subcutaneous adipose tissue) of the hands, arms, legs, feet, and face. Thus, some affected individuals may have a characteristic facial appearance. Cheeks are often taught and hollow. Lips and nose are often thin. Eyes are relatively prominent. In addition, skin of the hands and feet may appear prematurely aged (acrogeria). vEDS is particularly associated with arterial dissection and rupture, intestinal perforation, and uterine rupture. Arterial dissections are ruptures along the layers of tissue that comprise the thickness of the artery and may be spontaneous or preceded by an aneurysm (abnormal bulge in a vessel diameter) or arterio-venous malformation (AVM, abnormal connection between arteries and veins in the body). These bleeds can be life-threatening. One common AVM EDS patients experience is a carotid-cavernous sinus fistula. This is an abnormal connection between the carotid artery (a major offshoot of the aorta that supplies oxygenated blood to the brain) and the cavernous sinuses (a pool of deoxygenated blood deep within the skull behind the eyes). AVM can result in severe headaches, seizures, and increases a patient’s risk for stroke. There is an early onset of varicose veins, unusually widened, twisted veins visible under the skin that may be painful. vEDS carries a risk for spontaneous rupture of certain membranes and tissues. Acute pain in the abdominal or flank area may indicate arterial or intestinal rupture; such symptoms require immediate emergency medical attention. Pregnancies should be considered higher risk and watch closely for arterial and uterine ruptures. In addition, affected individuals may be prone to experiencing certain complications during and after surgical procedures, such as separation of the layers of a surgical wound (dehiscence). The median life expectancy for vEDS is 50, but with careful surveillance and management of complications this age can be well extended.Hypermobility type (hEDS)
hEDS (formerly EDSIII) comes with a defined set of complications to be managed but is generally a less severe form of the syndrome. For example, aortic root dilation is usually minimal and does not significantly increase the risk for dissections. The major complications to patients with hEDS are musculoskeletal in nature. Frequent joint dislocation and degenerative joint disease are common and associated with a baseline chronic pain, which affects both physical and psychological wellbeing. Problems with the autonomic nervous system, responsible for regulating body functions and the fight-or-flight response, are common. For example, patients often experience orthostatic intolerance, significant lightheadedness on standing, due to a slowed response by their circulatory system to compensation against blood pressure and flow changes with shifts in body position. Bowel disorders are also more common with this condition, especially functional dyspepsia (indigestion), and irritable bowel syndrome. Patients with EDS hypermobility type have also frequently reported psychological impairment and mood problems.Arthrochalasia type (aEDS)
aEDS (formerly EDSVII, A and B) is associated with the lifelong risk for the dislocation of multiple major joints concurrently. This condition makes achieving mobility significantly challenging. It is important to identify as early in life as possible as it carries consequences of physical disability with older age. Newborns may demonstrate severe muscular hypotonia and a bilateral dislocation of the hips at birth and might be difficult to distinguish from kEDS (described below).Dermatosparaxis type (dEDS)
Patient with dEDS (formerly EDSVIIC) tend to show a set of common body features. These include a short stature and finger length, loose skin of the face, with comparatively full eyelids, blue-tinged whites of the eye (sclera), skin folds in the upper eyelids (epicanthal folds), downward slanting outer corners of the eyes (palpebral fissures) and a small jaw (micrognathia). A major complication of dEDS is herniation, the improper displacement of an organ through the tissues holding it in proper position. Hernias are especially common after certain surgeries, for example wherein there is an incision into the muscles of the abdomen. Due to the lengthy wound-healing process, intestinal contents may bulge through incisions. Patients with dEDS are also prone to ruptures in the diaphragm and bladder. For families with a suspected history of dEDS type, the parents of newborns should be advised that their child’s soft spots in the skull (fontanelles) may be delayed in their closure.Kyphoscoliotic type (kEDS)
kEDS is accompanied by scleral fragility, increasing the risk for rupture of the white globe of the eye. Microcornea, near-sightedness (myopia), glaucoma and detachment of the nerve-rich membrane in the back of the eye (retina) are common and can result in vision loss. Patients experiencing floaters, flashes or sudden curtains falling across their visual field should seek immediate medical attention. kEDS (formerly EDSVI) can be evident at birth. Newborns may demonstrate severe muscular weakness (hypotonia) or abnormal spinal rotations and curvatures (scoliosis). Despite progressive scoliosis, the survival of patients with kEDS is unaffected. The most severely affected adults may lose the ability to walk by their 20s-30s and it becomes important to watch that their scoliosis does not begin to impede normal breathing patterns.Brittle cornea syndrome (BCS)
BCS is a variant of EDS that also involves the eyes. People with variant risk ruptures to the cornea following minor injuries with scarring, degeneration of the cornea (keratoconus), and protrusion of the cornea (keratoglobus). Patients may have blue sclera. Spondylodysplastic type (spEDS)
spEDS, previously spondylocheirodysplastic type, describes an EDS variant with skeletal dysmorphology. It primarily involves the spine and the hands. Clinical presentation can include stunted growth, short stature, protuberant eyes with bluish sclera, wrinkled skin of the palms, atrophy of muscles at the base of the thumb (thenar muscles), and tapering fingers. Musculocontractural type (mcEDS)
mcEDS is characterized by progressive multisystem complications. This subtype is especially associated with developmental delay and muscular weakness plus hypotonia. Patients often have facial and cranial structural defects, congenital contractures of the fingers, severe kyphoscoliosis, muscular hypotonia, club foot deformity, and ocular problems.Myopathic type (mEDS)
mEDS is characterized by muscle hypotonia evident at birth with muscles that do not function properly (myopathy). Scoliosis and sensorineural hearing impairment may accompany this condition. It shares many features with the kyphoscoliotic form of EDS.Periodontal type (pEDS)
pEDS type (formerly EDS VII) has findings that include disease of the tissues surrounding and supporting the teeth (periodontal disease), potentially resulting in premature tooth loss.Some subtypes of EDS included within the original disease classification system have been redefined and are no longer part of the revised categorization (eg: previously known as EDS type IX has been redefined to occipital horn syndrome and EDSXI is now known as familial hypermobility syndrome). For more information on these disorders, please see the “Related Disorders” section of this report below. | Symptoms of Ehlers Danlos Syndromes. Classical (cEDS)
cEDS (formerly EDSI and EDSII) is associated with the primary problems described above, skin hyperextensibility, joint laxity, and fragile blood vessels. Scars are very thin, discolored, and stretch with time. Such paper-like (papyraceous) scarring occurs especially over prominent bony pressure points such as the knees, elbows, shins and forehead. Joint hypermobility accidents (subluxations and dislocations) are generally easily managed. Additional findings may include the formation of small, fleshy, skin growths called ‘molluscoid pseudotumors’ or hard, round, movable lumps under the skin called ‘calcified spheroids’. Finally, some individuals with this subtype may have a deformity of heart valves (especially the mitral/bicuspid valve between the atrium and the ventricle of the left side). The heart’s valves function to keep blood flowing in one direction. Weak valves may be overcome by the blood flow across their leaflets and prolapse, allowing blood to leak in the backwards direction. Valve dysfunction can result in remodeling of the heart’s architecture and with time congestive heart failure (pump insufficiency). Another complication cEDS patients may experience is dilatation of the aorta. The aorta is the major blood vessel coming immediately off the heart, responsible for directing oxygenated blood towards body tissues. In cEDS there is an increased risk also for aortic dissection. Blood vessel walls are made up of three layers (intima, media, and the adventitia). Dissection describes the separation of the intima from the media and adventitia. This complication can compromise blood supply to tissues including the heart. Aortic dissection is an immediate emergency that can result in acute heart failure. Patients should immediately seek medical attention for any tearing chest pains. Classical-like (clEDS)
clEDS is similar in clinical course to cEDS (described immediately above). Genetic causes of cEDS and clEDS differ (described below). Cardiac-valvular type (cvEDS)
cvEDS is a rare subtype of EDS wherein patients may have minor signs of EDS with severe defects to their aorta, requiring surgical interventions.Vascular type (vEDS)
vEDS (formerly EDSIV), can be identified at birth with noticeable clubfoot deformities and dislocation of the hips. In childhood, inguinal hernia (partial slip of intestine beyond the abdominal wall) and pneumothorax (collection of air between the lung and chest wall, impairing proper lung inflation) are commonly experienced and are indicative of this syndrome. Individuals with vEDS may also have abnormally decreased levels of fatty tissue under skin layers (subcutaneous adipose tissue) of the hands, arms, legs, feet, and face. Thus, some affected individuals may have a characteristic facial appearance. Cheeks are often taught and hollow. Lips and nose are often thin. Eyes are relatively prominent. In addition, skin of the hands and feet may appear prematurely aged (acrogeria). vEDS is particularly associated with arterial dissection and rupture, intestinal perforation, and uterine rupture. Arterial dissections are ruptures along the layers of tissue that comprise the thickness of the artery and may be spontaneous or preceded by an aneurysm (abnormal bulge in a vessel diameter) or arterio-venous malformation (AVM, abnormal connection between arteries and veins in the body). These bleeds can be life-threatening. One common AVM EDS patients experience is a carotid-cavernous sinus fistula. This is an abnormal connection between the carotid artery (a major offshoot of the aorta that supplies oxygenated blood to the brain) and the cavernous sinuses (a pool of deoxygenated blood deep within the skull behind the eyes). AVM can result in severe headaches, seizures, and increases a patient’s risk for stroke. There is an early onset of varicose veins, unusually widened, twisted veins visible under the skin that may be painful. vEDS carries a risk for spontaneous rupture of certain membranes and tissues. Acute pain in the abdominal or flank area may indicate arterial or intestinal rupture; such symptoms require immediate emergency medical attention. Pregnancies should be considered higher risk and watch closely for arterial and uterine ruptures. In addition, affected individuals may be prone to experiencing certain complications during and after surgical procedures, such as separation of the layers of a surgical wound (dehiscence). The median life expectancy for vEDS is 50, but with careful surveillance and management of complications this age can be well extended.Hypermobility type (hEDS)
hEDS (formerly EDSIII) comes with a defined set of complications to be managed but is generally a less severe form of the syndrome. For example, aortic root dilation is usually minimal and does not significantly increase the risk for dissections. The major complications to patients with hEDS are musculoskeletal in nature. Frequent joint dislocation and degenerative joint disease are common and associated with a baseline chronic pain, which affects both physical and psychological wellbeing. Problems with the autonomic nervous system, responsible for regulating body functions and the fight-or-flight response, are common. For example, patients often experience orthostatic intolerance, significant lightheadedness on standing, due to a slowed response by their circulatory system to compensation against blood pressure and flow changes with shifts in body position. Bowel disorders are also more common with this condition, especially functional dyspepsia (indigestion), and irritable bowel syndrome. Patients with EDS hypermobility type have also frequently reported psychological impairment and mood problems.Arthrochalasia type (aEDS)
aEDS (formerly EDSVII, A and B) is associated with the lifelong risk for the dislocation of multiple major joints concurrently. This condition makes achieving mobility significantly challenging. It is important to identify as early in life as possible as it carries consequences of physical disability with older age. Newborns may demonstrate severe muscular hypotonia and a bilateral dislocation of the hips at birth and might be difficult to distinguish from kEDS (described below).Dermatosparaxis type (dEDS)
Patient with dEDS (formerly EDSVIIC) tend to show a set of common body features. These include a short stature and finger length, loose skin of the face, with comparatively full eyelids, blue-tinged whites of the eye (sclera), skin folds in the upper eyelids (epicanthal folds), downward slanting outer corners of the eyes (palpebral fissures) and a small jaw (micrognathia). A major complication of dEDS is herniation, the improper displacement of an organ through the tissues holding it in proper position. Hernias are especially common after certain surgeries, for example wherein there is an incision into the muscles of the abdomen. Due to the lengthy wound-healing process, intestinal contents may bulge through incisions. Patients with dEDS are also prone to ruptures in the diaphragm and bladder. For families with a suspected history of dEDS type, the parents of newborns should be advised that their child’s soft spots in the skull (fontanelles) may be delayed in their closure.Kyphoscoliotic type (kEDS)
kEDS is accompanied by scleral fragility, increasing the risk for rupture of the white globe of the eye. Microcornea, near-sightedness (myopia), glaucoma and detachment of the nerve-rich membrane in the back of the eye (retina) are common and can result in vision loss. Patients experiencing floaters, flashes or sudden curtains falling across their visual field should seek immediate medical attention. kEDS (formerly EDSVI) can be evident at birth. Newborns may demonstrate severe muscular weakness (hypotonia) or abnormal spinal rotations and curvatures (scoliosis). Despite progressive scoliosis, the survival of patients with kEDS is unaffected. The most severely affected adults may lose the ability to walk by their 20s-30s and it becomes important to watch that their scoliosis does not begin to impede normal breathing patterns.Brittle cornea syndrome (BCS)
BCS is a variant of EDS that also involves the eyes. People with variant risk ruptures to the cornea following minor injuries with scarring, degeneration of the cornea (keratoconus), and protrusion of the cornea (keratoglobus). Patients may have blue sclera. Spondylodysplastic type (spEDS)
spEDS, previously spondylocheirodysplastic type, describes an EDS variant with skeletal dysmorphology. It primarily involves the spine and the hands. Clinical presentation can include stunted growth, short stature, protuberant eyes with bluish sclera, wrinkled skin of the palms, atrophy of muscles at the base of the thumb (thenar muscles), and tapering fingers. Musculocontractural type (mcEDS)
mcEDS is characterized by progressive multisystem complications. This subtype is especially associated with developmental delay and muscular weakness plus hypotonia. Patients often have facial and cranial structural defects, congenital contractures of the fingers, severe kyphoscoliosis, muscular hypotonia, club foot deformity, and ocular problems.Myopathic type (mEDS)
mEDS is characterized by muscle hypotonia evident at birth with muscles that do not function properly (myopathy). Scoliosis and sensorineural hearing impairment may accompany this condition. It shares many features with the kyphoscoliotic form of EDS.Periodontal type (pEDS)
pEDS type (formerly EDS VII) has findings that include disease of the tissues surrounding and supporting the teeth (periodontal disease), potentially resulting in premature tooth loss.Some subtypes of EDS included within the original disease classification system have been redefined and are no longer part of the revised categorization (eg: previously known as EDS type IX has been redefined to occipital horn syndrome and EDSXI is now known as familial hypermobility syndrome). For more information on these disorders, please see the “Related Disorders” section of this report below. | 397 | Ehlers Danlos Syndromes |
nord_397_2 | Causes of Ehlers Danlos Syndromes | EDS can be inherited as a dominant or recessive genetic condition. Human traits are the product of the interaction between two genes. Genes are received in sets of two, one from the father and another from the mother. 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 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.Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. When someone in the family is diagnosed with EDS, it is important to contact a physician for further evaluation and to determine the mode of inheritance in the family. Some of the genes associated with EDS provide the instructions on the synthesis of (encode) different subtypes of collagen (COL1A1, COL1A2, COL1A3, COL5A1, and COL5A2). Other genes (ADAMTS2, PLOD1, and TNXB) encode proteins associated with processing collagen or otherwise interacting with collagen. Defects in these genes have been associated with different EDS subtypes. Type-specific genetics are summarized below.Classical type (cEDS)
cEDS follows an autosomal dominant inheritance pattern of inheritance for mutations on two genes: COL5A1 and COL5A2. COL5A1 encodes the protein ‘pro-alpha1(V)chain’ and COL5A2 encodes ‘pro-alpha2(V)chain’. The “pro-” designation indicates that their final product must be acted on by an enzyme which activates the final structure. Procollagen is the product of three chain-like proteins. Procollagen is processed by extracellular enzymes to a mature product. The final collagen product will associate into fibrils with type 1 collagen and function to determine the width of the type 1 collagen fibrils.Classical-like (clEDS)
clEDS is follows an autosomal recessive inheritance pattern. It is caused by mutations in the gene TNXB. This gene product is found outside the cell and serves in maintaining the integrity of the scaffold in which the collagen lays down. Tenascin-x also functions to regulate the stability of the body’s elastic fibers.Cardiac valvular type (cvEDS)
cvEDS is a rare subtype that follows an autosomal recessive inheritance pattern and is also associated with mutations in the COL1A2 gene. COL1A2 encodes pro-apha2(I)chain. Two pro-alpha1(I) chains (encoded by COL1A1) and one pro-apha2(I)chain (encoded by COL1A2) associate to form type 1 procollagen fibrils. Vascular type (vEDS)
vEDS is inherited in an autosomal dominant manner and usually caused by mutations in the gene COL3A1. There have been some reports of bi-allelic inheritance, where an affected individual has two mutant genes. COL3A1 encodes pro-alpha1(III)chain. Three of these products associate to form type III procollagen. Mature type III collagen assembles into long, thin fibrils. Crosslinking lends important strength to this collagen subtype. Some patients with vEDS have COL1A1 gene mutations (described above).Hypermobility type (hEDS)
hEDS follows an autosomal dominant inheritance pattern but the causal genes have not yet been unidentified. A small number of affected individuals have been found to have a deficiency of tenascin-x, a protein encoded by the gene TNXB. This gene product is found outside the cell and serves in maintaining the integrity of the scaffold in which the collagen lays down. Tenascin-x also functions to regulate the stability of the body’s elastic fibers.Arthrochalasia type (aEDS)
aEDS follows autosomal dominant inheritance. This subtype is caused by mutations in the COL1A1 gene, or the COL1A2 gene. COL1A1 encodes pro-apha1(I)chain. COL1A2 encodes pro-apha2(I)chain (described above). Dermatosparaxis type (dEDS)
dEDS follows an autosomal recessive inheritance pattern and is associated with mutations in the gene ADAMTS2. The enzyme encoded by this gene modifies collagen products. It cleaves short amino acid chains from procollagen molecules into mature collagen.Kyphoscoliotic type (kEDS)
kEDS follows autosomal recessive inheritance and is caused by mutations in the PLOD1 or FKBP14 genes. Mutations in PLOD1 result in a deficiency of activity in the enzyme procollagen-lysine, 2-oxogluterate 5-dioxygenase 1, also known as lysyl hydroxylase 1. This hydroxylase enzyme converts the amino acid lysine into hydrolysine. Hydrolysine is a modified amino acid essential to forming cross-links between individual of collagen chains. The FKBP14 gene encodes FK506-binding protien-14, which does not have a clearly defined function in the cell.Brittle cornea syndrome (BCS)
There are two types of BCS, both inherited in an autosomal recessive manner. Type 1 BCS is caused by mutations in the ZNF469 gene. Zinc finger protein 469 is thought to act as a DNA transcription factor or extra-nuclear regulator for collagen fiber synthesis or organization. Type 2 BCS is caused by mutations in the PRDM5 gene. The encoded protein, PR/SET domain 5, is a transcription factor regulating protein synthesis. Spondylodysplastic type (spEDS)
spEDS is inherited as an autosomal recessive condition and is associated with mutations in the gene SLC39A13, encoding the protein product solute carrier family 39 member 13, responsible for the transport of zinc into the cell. Zinc is a metal element and essential to the healthy function of connective tissues. This subtype can also be attributed to genetic defects in the B4GALT6 and B4GALT7 genes. The beta-1,4-galactosyltransferase gene family is associated with the synthesis of different glycosylated and saccharide structures.Musculocontractural type (mcEDS)
mcEDS follows autosomal recessive inheritance pattern and can be caused by mutations in two genes. Mutations in the gene CHST14, which encodes the enzyme carbohydrate sulfotransferase 14, is involved in several chemical reactions involving the transfer of sulfate groups between different molecules. mcEDS may also be caused by mutations to the gene DSE. The gene product, dermatan sulfate epimerase, is important in the production of dermatan sulfate (also known as chondroitin sulfate B), a glycosaminoglycan. Glycosaminoglycans are important in filling in connective tissue gaps, lending cohesion and stability.Myopathic type (mEDS)
mEDS can follow an autosomal dominant or autosomal recessive pattern of inheritance. Mutations causing this subtype are found in the COL12A1 gene, encoding type XII collagen. This fibril is associated with type I collagen and is thought to modify the interactions it makes. mEDS can also be caused by mutations in the gene FKBP14. FK506-binding protien-14 does not have a clearly defined function in the cell.Periodontal type (pEDS)
pEDS follows autosomal dominant inheritance and is caused by mutations in the genes C1R and C1S, encoding complement subcomponents, important to immune function. | Causes of Ehlers Danlos Syndromes. EDS can be inherited as a dominant or recessive genetic condition. Human traits are the product of the interaction between two genes. Genes are received in sets of two, one from the father and another from the mother. 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 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.Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. When someone in the family is diagnosed with EDS, it is important to contact a physician for further evaluation and to determine the mode of inheritance in the family. Some of the genes associated with EDS provide the instructions on the synthesis of (encode) different subtypes of collagen (COL1A1, COL1A2, COL1A3, COL5A1, and COL5A2). Other genes (ADAMTS2, PLOD1, and TNXB) encode proteins associated with processing collagen or otherwise interacting with collagen. Defects in these genes have been associated with different EDS subtypes. Type-specific genetics are summarized below.Classical type (cEDS)
cEDS follows an autosomal dominant inheritance pattern of inheritance for mutations on two genes: COL5A1 and COL5A2. COL5A1 encodes the protein ‘pro-alpha1(V)chain’ and COL5A2 encodes ‘pro-alpha2(V)chain’. The “pro-” designation indicates that their final product must be acted on by an enzyme which activates the final structure. Procollagen is the product of three chain-like proteins. Procollagen is processed by extracellular enzymes to a mature product. The final collagen product will associate into fibrils with type 1 collagen and function to determine the width of the type 1 collagen fibrils.Classical-like (clEDS)
clEDS is follows an autosomal recessive inheritance pattern. It is caused by mutations in the gene TNXB. This gene product is found outside the cell and serves in maintaining the integrity of the scaffold in which the collagen lays down. Tenascin-x also functions to regulate the stability of the body’s elastic fibers.Cardiac valvular type (cvEDS)
cvEDS is a rare subtype that follows an autosomal recessive inheritance pattern and is also associated with mutations in the COL1A2 gene. COL1A2 encodes pro-apha2(I)chain. Two pro-alpha1(I) chains (encoded by COL1A1) and one pro-apha2(I)chain (encoded by COL1A2) associate to form type 1 procollagen fibrils. Vascular type (vEDS)
vEDS is inherited in an autosomal dominant manner and usually caused by mutations in the gene COL3A1. There have been some reports of bi-allelic inheritance, where an affected individual has two mutant genes. COL3A1 encodes pro-alpha1(III)chain. Three of these products associate to form type III procollagen. Mature type III collagen assembles into long, thin fibrils. Crosslinking lends important strength to this collagen subtype. Some patients with vEDS have COL1A1 gene mutations (described above).Hypermobility type (hEDS)
hEDS follows an autosomal dominant inheritance pattern but the causal genes have not yet been unidentified. A small number of affected individuals have been found to have a deficiency of tenascin-x, a protein encoded by the gene TNXB. This gene product is found outside the cell and serves in maintaining the integrity of the scaffold in which the collagen lays down. Tenascin-x also functions to regulate the stability of the body’s elastic fibers.Arthrochalasia type (aEDS)
aEDS follows autosomal dominant inheritance. This subtype is caused by mutations in the COL1A1 gene, or the COL1A2 gene. COL1A1 encodes pro-apha1(I)chain. COL1A2 encodes pro-apha2(I)chain (described above). Dermatosparaxis type (dEDS)
dEDS follows an autosomal recessive inheritance pattern and is associated with mutations in the gene ADAMTS2. The enzyme encoded by this gene modifies collagen products. It cleaves short amino acid chains from procollagen molecules into mature collagen.Kyphoscoliotic type (kEDS)
kEDS follows autosomal recessive inheritance and is caused by mutations in the PLOD1 or FKBP14 genes. Mutations in PLOD1 result in a deficiency of activity in the enzyme procollagen-lysine, 2-oxogluterate 5-dioxygenase 1, also known as lysyl hydroxylase 1. This hydroxylase enzyme converts the amino acid lysine into hydrolysine. Hydrolysine is a modified amino acid essential to forming cross-links between individual of collagen chains. The FKBP14 gene encodes FK506-binding protien-14, which does not have a clearly defined function in the cell.Brittle cornea syndrome (BCS)
There are two types of BCS, both inherited in an autosomal recessive manner. Type 1 BCS is caused by mutations in the ZNF469 gene. Zinc finger protein 469 is thought to act as a DNA transcription factor or extra-nuclear regulator for collagen fiber synthesis or organization. Type 2 BCS is caused by mutations in the PRDM5 gene. The encoded protein, PR/SET domain 5, is a transcription factor regulating protein synthesis. Spondylodysplastic type (spEDS)
spEDS is inherited as an autosomal recessive condition and is associated with mutations in the gene SLC39A13, encoding the protein product solute carrier family 39 member 13, responsible for the transport of zinc into the cell. Zinc is a metal element and essential to the healthy function of connective tissues. This subtype can also be attributed to genetic defects in the B4GALT6 and B4GALT7 genes. The beta-1,4-galactosyltransferase gene family is associated with the synthesis of different glycosylated and saccharide structures.Musculocontractural type (mcEDS)
mcEDS follows autosomal recessive inheritance pattern and can be caused by mutations in two genes. Mutations in the gene CHST14, which encodes the enzyme carbohydrate sulfotransferase 14, is involved in several chemical reactions involving the transfer of sulfate groups between different molecules. mcEDS may also be caused by mutations to the gene DSE. The gene product, dermatan sulfate epimerase, is important in the production of dermatan sulfate (also known as chondroitin sulfate B), a glycosaminoglycan. Glycosaminoglycans are important in filling in connective tissue gaps, lending cohesion and stability.Myopathic type (mEDS)
mEDS can follow an autosomal dominant or autosomal recessive pattern of inheritance. Mutations causing this subtype are found in the COL12A1 gene, encoding type XII collagen. This fibril is associated with type I collagen and is thought to modify the interactions it makes. mEDS can also be caused by mutations in the gene FKBP14. FK506-binding protien-14 does not have a clearly defined function in the cell.Periodontal type (pEDS)
pEDS follows autosomal dominant inheritance and is caused by mutations in the genes C1R and C1S, encoding complement subcomponents, important to immune function. | 397 | Ehlers Danlos Syndromes |
nord_397_3 | Affects of Ehlers Danlos Syndromes | Signs and symptoms of EDS may become apparent during childhood. However, depending upon the form and severity, age of diagnosis varies widely. Reported estimates for the incidence of all EDS types range from 1/ 2,500 to 1/5,000 births. hEDS is estimated to affect 1/10,000-1/15,000. cEDS is estimated to affect 1/20,000-1/40,0000. Because those with mild joint and skin manifestations may not seek medical attention they remain undiagnosed and it is difficult to determine the true frequency of EDS mutations in the general population. hEDS, clEDS, and vEDS are most common subtypes. Other subtypes (kEDS, aEDS, and dEDS) are much less common. Only about 60 individuals with kEDS have been identified. Only about 30 patients with aEDS have been reported. Only about 12 patients of dEDS have been described. Some named variants of EDS (e.g. X type or dysfibronectinemic type) have only been identified and reported in single individuals within one affected family. | Affects of Ehlers Danlos Syndromes. Signs and symptoms of EDS may become apparent during childhood. However, depending upon the form and severity, age of diagnosis varies widely. Reported estimates for the incidence of all EDS types range from 1/ 2,500 to 1/5,000 births. hEDS is estimated to affect 1/10,000-1/15,000. cEDS is estimated to affect 1/20,000-1/40,0000. Because those with mild joint and skin manifestations may not seek medical attention they remain undiagnosed and it is difficult to determine the true frequency of EDS mutations in the general population. hEDS, clEDS, and vEDS are most common subtypes. Other subtypes (kEDS, aEDS, and dEDS) are much less common. Only about 60 individuals with kEDS have been identified. Only about 30 patients with aEDS have been reported. Only about 12 patients of dEDS have been described. Some named variants of EDS (e.g. X type or dysfibronectinemic type) have only been identified and reported in single individuals within one affected family. | 397 | Ehlers Danlos Syndromes |
nord_397_4 | Related disorders of Ehlers Danlos Syndromes | Several disorders closely mimic EDS in clinical presentation. The following is a non-exhaustive list of conditions that may be considered in the differential diagnosis of a patient’s presentation.Hypermobility spectrum disorders (HSD)
This term aims to incorporate a recognized laxity and instability of the joints that was previously referred to as joint hypermobility syndrome into a spectrum with EDS. This term can help describe milder conditions wherein the joints are abnormally flexible beyond the expected range of motion. Symptoms will generally include pain in affected joints, however this pain usually will not require clinical intervention. HSD is believed to be a relatively common entity in comparison to EDS.Occipital horn syndrome (OHS)
OHS, also known as X-linked cutis laxa, (formerly EDS, type IX) is an X-linked recessive condition that leads to deficiency of the enzyme lysyl oxidase. Lysyl oxidase deficiency results in abnormalities of copper metabolism and excretion that cause deformations of connective tissue and the skeleton. Patients with OHS have abnormally loose skin that tends to hang in folds (cutis laxa), abnormalities of bladder musculature, and formation of “horn-like” bony protuberances on the occipital bone which composes the back of the skull. Other characteristics may include hypermobility of the fingers and toes along with limited extension of elbows and knees. Affected individuals may be described as having a hooked nose, sagging cheeks, and downward slanting palpebral fissures. Affected individuals may also have a mild intellectual disability.Loeys-Dietz syndrome (LDS)
LDS is an autosomal dominant connective tissue disorder due to mutations in several genes: TGFBR1, TGFBR2, SMAD3, and TGFB2. Patients present with highly variable symptoms but the major manifestations include widening course (tortuosity) of arterial vessels, widely spaced eyes (hypertelorism), a wide/split posterior of the soft palate of the mouth (uvula), and aortic aneurysms.Familial aortic aneurysm (FAA)
FAA may present with very mild connective tissue signs (long-thin features, hernias, scoliosis). FAA is also associated with an increased risk for developing blockages of small arteries, increasing the risk for heart attack and stroke. The genetic cause of this condition includes mutations in the ACTA2 and TGFBR2 genes but more are still being identified.Familial hypermobility syndrome (FHS)
FHS (formerly EDS, type XI) is an autosomal dominant condition characterized by laxity and excessive extension of the joints resulting in dislocation of certain joints, such as those of the shoulders and knees; and sometimes, dislocation of the hip joints at birth (congenital).Marfan syndrome (MFS)
Marfan syndrome is an autosomal dominant condition caused by mutations in the FBN1 gene. The protein product, fibrillin, is a major connective tissue element essential to the elastic fibers of the body. People with Marfan syndrome all share a similar body habitus (appearance). They tend to be tall, thin with long limbs, fingers and toes. Marfan syndrome is associated with hyperflexibility, scoliosis and risk to deterioration of vasculature, especially in the form of mitral valve prolapse and aortic aneurysm. The eyes, lungs, and spinal meninges (connective tissues overlaying the spine). (For more information on this disorder, choose “Marfan Syndrome” as your search term in the Rare Disease Database.)Brittle cornea syndrome 2 (BCS2)
BCS2 is associated with the PRDM5 gene and encodes a transcription factor involved in cellular differentiation, development into a specific function. BCS2 is associated with extreme corneal thinning and predisposition to rupture. Patients often have hyperelasticity of the skin and hypermobile joints. Their sclera often appears blue. | Related disorders of Ehlers Danlos Syndromes. Several disorders closely mimic EDS in clinical presentation. The following is a non-exhaustive list of conditions that may be considered in the differential diagnosis of a patient’s presentation.Hypermobility spectrum disorders (HSD)
This term aims to incorporate a recognized laxity and instability of the joints that was previously referred to as joint hypermobility syndrome into a spectrum with EDS. This term can help describe milder conditions wherein the joints are abnormally flexible beyond the expected range of motion. Symptoms will generally include pain in affected joints, however this pain usually will not require clinical intervention. HSD is believed to be a relatively common entity in comparison to EDS.Occipital horn syndrome (OHS)
OHS, also known as X-linked cutis laxa, (formerly EDS, type IX) is an X-linked recessive condition that leads to deficiency of the enzyme lysyl oxidase. Lysyl oxidase deficiency results in abnormalities of copper metabolism and excretion that cause deformations of connective tissue and the skeleton. Patients with OHS have abnormally loose skin that tends to hang in folds (cutis laxa), abnormalities of bladder musculature, and formation of “horn-like” bony protuberances on the occipital bone which composes the back of the skull. Other characteristics may include hypermobility of the fingers and toes along with limited extension of elbows and knees. Affected individuals may be described as having a hooked nose, sagging cheeks, and downward slanting palpebral fissures. Affected individuals may also have a mild intellectual disability.Loeys-Dietz syndrome (LDS)
LDS is an autosomal dominant connective tissue disorder due to mutations in several genes: TGFBR1, TGFBR2, SMAD3, and TGFB2. Patients present with highly variable symptoms but the major manifestations include widening course (tortuosity) of arterial vessels, widely spaced eyes (hypertelorism), a wide/split posterior of the soft palate of the mouth (uvula), and aortic aneurysms.Familial aortic aneurysm (FAA)
FAA may present with very mild connective tissue signs (long-thin features, hernias, scoliosis). FAA is also associated with an increased risk for developing blockages of small arteries, increasing the risk for heart attack and stroke. The genetic cause of this condition includes mutations in the ACTA2 and TGFBR2 genes but more are still being identified.Familial hypermobility syndrome (FHS)
FHS (formerly EDS, type XI) is an autosomal dominant condition characterized by laxity and excessive extension of the joints resulting in dislocation of certain joints, such as those of the shoulders and knees; and sometimes, dislocation of the hip joints at birth (congenital).Marfan syndrome (MFS)
Marfan syndrome is an autosomal dominant condition caused by mutations in the FBN1 gene. The protein product, fibrillin, is a major connective tissue element essential to the elastic fibers of the body. People with Marfan syndrome all share a similar body habitus (appearance). They tend to be tall, thin with long limbs, fingers and toes. Marfan syndrome is associated with hyperflexibility, scoliosis and risk to deterioration of vasculature, especially in the form of mitral valve prolapse and aortic aneurysm. The eyes, lungs, and spinal meninges (connective tissues overlaying the spine). (For more information on this disorder, choose “Marfan Syndrome” as your search term in the Rare Disease Database.)Brittle cornea syndrome 2 (BCS2)
BCS2 is associated with the PRDM5 gene and encodes a transcription factor involved in cellular differentiation, development into a specific function. BCS2 is associated with extreme corneal thinning and predisposition to rupture. Patients often have hyperelasticity of the skin and hypermobile joints. Their sclera often appears blue. | 397 | Ehlers Danlos Syndromes |
nord_397_5 | Diagnosis of Ehlers Danlos Syndromes | EDS is generally diagnosed based on patient history and clinical findings. Genetic testing can facilitate the diagnosis of some subtypes. Electron microscopic analysis of tissue samples can also sometimes reveal characteristic abnormalities in collagen structure seen in EDS.The clinical evaluation of individuals with suspected or diagnosed EDS typically includes assessments to detect and determine the extent of skin and joint hyperextensibility. For example, physicians may measure skin hyperextensibility by carefully pulling up skin at a neutral site until the point of resistance, and joint hyperextensibility may be evaluated using a clinical rating scale (i.e., Beighton scale). Often, specialized imaging tests, such as computerized tomography (CT) scanning, magnetic resonance imaging (MRI), and echocardiography, are used to detect and characterize mitral valve prolapse and aortic dilatation. During a CT scan, a computer and x-rays create a film showing cross-sectional images of certain bodily structures. MRI uses a magnetic field to create cross-sectional images of organs and tissues. During an echocardiogram sound waves are directed toward the heart enabling physicians to study cardiac function and motion. In addition, in some individuals with EDS, specialized x-ray studies may be used to characterize round movable lumps (calcified spheroids) under the skin, to detect and determine the extent of abnormal spinal curvature (scoliosis and/or kyphosis) and/or reduced bone mass (ostepenia) (e.g., in those with EDS kyphoscoliosis or arthrochalasia types), and/or to confirm and characterize certain other abnormalities.Genetic analysis is helpful in the diagnosis of many EDS subtypes, either in providing a positive finding (eg: mutations in COL5A1 for patients with cEDS) or negative finding. As the genetic source of hEDS is yet unidentified, it is important to rule out mutations that cause other EDS types. A kEDS diagnosis can also be confirmed by a laboratory test on either a urine sample and extrapolated ratio of deoxypyridinoline to pyridinoline cross-links, or on a skin biopsy sample and measurement of lysyl hydroxylase enzyme activity from skin fibroblast cells. | Diagnosis of Ehlers Danlos Syndromes. EDS is generally diagnosed based on patient history and clinical findings. Genetic testing can facilitate the diagnosis of some subtypes. Electron microscopic analysis of tissue samples can also sometimes reveal characteristic abnormalities in collagen structure seen in EDS.The clinical evaluation of individuals with suspected or diagnosed EDS typically includes assessments to detect and determine the extent of skin and joint hyperextensibility. For example, physicians may measure skin hyperextensibility by carefully pulling up skin at a neutral site until the point of resistance, and joint hyperextensibility may be evaluated using a clinical rating scale (i.e., Beighton scale). Often, specialized imaging tests, such as computerized tomography (CT) scanning, magnetic resonance imaging (MRI), and echocardiography, are used to detect and characterize mitral valve prolapse and aortic dilatation. During a CT scan, a computer and x-rays create a film showing cross-sectional images of certain bodily structures. MRI uses a magnetic field to create cross-sectional images of organs and tissues. During an echocardiogram sound waves are directed toward the heart enabling physicians to study cardiac function and motion. In addition, in some individuals with EDS, specialized x-ray studies may be used to characterize round movable lumps (calcified spheroids) under the skin, to detect and determine the extent of abnormal spinal curvature (scoliosis and/or kyphosis) and/or reduced bone mass (ostepenia) (e.g., in those with EDS kyphoscoliosis or arthrochalasia types), and/or to confirm and characterize certain other abnormalities.Genetic analysis is helpful in the diagnosis of many EDS subtypes, either in providing a positive finding (eg: mutations in COL5A1 for patients with cEDS) or negative finding. As the genetic source of hEDS is yet unidentified, it is important to rule out mutations that cause other EDS types. A kEDS diagnosis can also be confirmed by a laboratory test on either a urine sample and extrapolated ratio of deoxypyridinoline to pyridinoline cross-links, or on a skin biopsy sample and measurement of lysyl hydroxylase enzyme activity from skin fibroblast cells. | 397 | Ehlers Danlos Syndromes |
nord_397_6 | Therapies of Ehlers Danlos Syndromes | Treatment
The care of patients with EDS is generally focused on implementing preventative measures against serious or life-threatening complications. The primary complications seen in EDS involve the skin, musculoskeletal, and cardiovascular systems. Patient skin is velvety thin, loose, and stretchable. This predisposes patients to difficulties with wound healing. For both accidental and surgical wounds, deep stiches are applied generously. Superficial stiches are placed to carefully realign the skin to prevent scarring. Stiches are also left in for extended periods of time to allow best strengthening of the forming scar tissue. Ascorbic acid (Vitamin C) may be recommended to help reduce the easy bruising that accompanies EDS. Hypermobile joints easily dislocate. With each dislocation, subsequent dislocations are increasingly likely, therefore prevention is particularly important for quality of life. Heavy sports, lifting, and other strenuous efforts should be avoided due to the risk of inciting trauma. Blood vessel fragility increases the risk for serious bleeds and dissections. High blood pressure (hypertension) puts additional strain on the fragile vasculature and increases the risk for complications. Regular screening for hypertension and arterial disease should be conducted and treatment should be initiated early on. The best approaches to screening are by non-invasive technology: ultrasound, MRI, or CT. Arteriography, colonoscopy, and other similarly invasive screening procedures should be considered carefully for benefit versus risk. Surgery for non-life threatening conditions should also be carefully considered. Pregnancies should be followed by obstetricians that are well trained in dealing with high-risk pregnancies. Delivery can progress very quickly in EDS patients and it is yet unclear if there is an advantage to mothers to deliver by vaginal or cesarean routes. Expectant mothers with known aortic root dilations should have echocardiograms each trimester to observe for possible exacerbation. All EDS-affected individuals should seek immediate medical attention for any sudden or unexplained pains and consider wearing a MedicAlert bracelet to communicate their status as a patient with EDS should they lose consciousness. hEDS patients may especially benefit from physical therapy, low-resistance exercise, and assistive devices like braces, wheelchairs, and scooters. Comfortable writing utensils and a low-stress mattress serve an important role in reducing musculoskeletal pain. Pain management is tailored to the individual. Gastrointestinal and psychological complications are likewise managed per an individual’s needs. In addition to physical therapy and low-resistance exercise, calcium and vitamin D can help maximize bone density. DEXA bone density scans should be conducted every other year. kEDS patients should have routine eye exams as they are at risk for globus rupture, retinal detachment and glaucoma. dEDS patients may benefit from protective bandages over exposed areas such as the skin of the elbows and knees. | Therapies of Ehlers Danlos Syndromes. Treatment
The care of patients with EDS is generally focused on implementing preventative measures against serious or life-threatening complications. The primary complications seen in EDS involve the skin, musculoskeletal, and cardiovascular systems. Patient skin is velvety thin, loose, and stretchable. This predisposes patients to difficulties with wound healing. For both accidental and surgical wounds, deep stiches are applied generously. Superficial stiches are placed to carefully realign the skin to prevent scarring. Stiches are also left in for extended periods of time to allow best strengthening of the forming scar tissue. Ascorbic acid (Vitamin C) may be recommended to help reduce the easy bruising that accompanies EDS. Hypermobile joints easily dislocate. With each dislocation, subsequent dislocations are increasingly likely, therefore prevention is particularly important for quality of life. Heavy sports, lifting, and other strenuous efforts should be avoided due to the risk of inciting trauma. Blood vessel fragility increases the risk for serious bleeds and dissections. High blood pressure (hypertension) puts additional strain on the fragile vasculature and increases the risk for complications. Regular screening for hypertension and arterial disease should be conducted and treatment should be initiated early on. The best approaches to screening are by non-invasive technology: ultrasound, MRI, or CT. Arteriography, colonoscopy, and other similarly invasive screening procedures should be considered carefully for benefit versus risk. Surgery for non-life threatening conditions should also be carefully considered. Pregnancies should be followed by obstetricians that are well trained in dealing with high-risk pregnancies. Delivery can progress very quickly in EDS patients and it is yet unclear if there is an advantage to mothers to deliver by vaginal or cesarean routes. Expectant mothers with known aortic root dilations should have echocardiograms each trimester to observe for possible exacerbation. All EDS-affected individuals should seek immediate medical attention for any sudden or unexplained pains and consider wearing a MedicAlert bracelet to communicate their status as a patient with EDS should they lose consciousness. hEDS patients may especially benefit from physical therapy, low-resistance exercise, and assistive devices like braces, wheelchairs, and scooters. Comfortable writing utensils and a low-stress mattress serve an important role in reducing musculoskeletal pain. Pain management is tailored to the individual. Gastrointestinal and psychological complications are likewise managed per an individual’s needs. In addition to physical therapy and low-resistance exercise, calcium and vitamin D can help maximize bone density. DEXA bone density scans should be conducted every other year. kEDS patients should have routine eye exams as they are at risk for globus rupture, retinal detachment and glaucoma. dEDS patients may benefit from protective bandages over exposed areas such as the skin of the elbows and knees. | 397 | Ehlers Danlos Syndromes |
nord_398_0 | Overview of Eisenmenger Syndrome | General DiscussionEisenmenger syndrome is a rare condition that affects both the heart and the lungs. The disease is characterized by high blood pressure and abnormal blood flow through the heart. The type of high blood pressure experienced by affected individuals is called pulmonary artery hypertension, which affects the blood vessels in the lungs and the right heart chambers. Generally, patients with Eisenmenger syndrome are born with a heart defect (congenital heart defect) that was not corrected with surgery or other intervention at an early age.The normal heart has four chambers. The two upper chambers, known as atria, are separated from each other by a fibrous partition, known as the atrial septum. The two lower chambers are known as ventricles and are separated from each other by the ventricular septum. Valves connect the atria (left and right) to their respective ventricles. The valves allow for blood to be pumped through the chambers. Blood travels from the right ventricle through the pulmonary artery to the lungs where it receives oxygen. The blood returns to the heart through pulmonary veins and enters the left ventricle. The left ventricle sends the now oxygen-filled blood into the main artery of the body (aorta). The aorta carries the blood to the body.Individuals with Eisenmenger syndrome often have a ventricular septal defect or a “hole in the heart” between the left and right pumping chambers in the heart. This results in significant shunting of blood from the left side of the heart to the right at birth, which progresses to pulmonary vascular disease. Once pulmonary vascular disease has developed, the heart defect is no longer repairable. Eventually blood flow through the defect (shunt) can become bidirectional, which leads to cyanosis (reduced oxygen concentration in the blood). | Overview of Eisenmenger Syndrome. General DiscussionEisenmenger syndrome is a rare condition that affects both the heart and the lungs. The disease is characterized by high blood pressure and abnormal blood flow through the heart. The type of high blood pressure experienced by affected individuals is called pulmonary artery hypertension, which affects the blood vessels in the lungs and the right heart chambers. Generally, patients with Eisenmenger syndrome are born with a heart defect (congenital heart defect) that was not corrected with surgery or other intervention at an early age.The normal heart has four chambers. The two upper chambers, known as atria, are separated from each other by a fibrous partition, known as the atrial septum. The two lower chambers are known as ventricles and are separated from each other by the ventricular septum. Valves connect the atria (left and right) to their respective ventricles. The valves allow for blood to be pumped through the chambers. Blood travels from the right ventricle through the pulmonary artery to the lungs where it receives oxygen. The blood returns to the heart through pulmonary veins and enters the left ventricle. The left ventricle sends the now oxygen-filled blood into the main artery of the body (aorta). The aorta carries the blood to the body.Individuals with Eisenmenger syndrome often have a ventricular septal defect or a “hole in the heart” between the left and right pumping chambers in the heart. This results in significant shunting of blood from the left side of the heart to the right at birth, which progresses to pulmonary vascular disease. Once pulmonary vascular disease has developed, the heart defect is no longer repairable. Eventually blood flow through the defect (shunt) can become bidirectional, which leads to cyanosis (reduced oxygen concentration in the blood). | 398 | Eisenmenger Syndrome |
nord_398_1 | Symptoms of Eisenmenger Syndrome | The specific symptoms of Eisenmenger syndrome vary greatly from person to person. Although the heart defect is present at birth, Eisenmenger syndrome with cyanosis often develops around puberty, but may develop earlier or later depending on the location and severity of the congenital heart defect. The symptoms and complications result from a combination of the effects of the heart defect, reduced oxygen in the blood and high pressures in the lungs.The most notable symptom is called cyanosis, which is the bluish discoloration of the skin and mucous membranes. Individuals affected with Eisenmenger syndrome develop cyanosis, particularly of the lips, fingers and toes, which is more pronounced during physical efforts. Patients typically have an increased number of blood cells (red blood cells or erythrocytes) that transport oxygen to the body (i.e., erythrocytosis), compensating for the inadequate oxygen supply to tissues. Additional signs may include rounding of the tips of the fingers and toes (clubbing), shortness of breath, fatigue, lethargy or arrhythmias. Those with Eisenmenger syndrome are also at higher risk for stroke, coughing up blood (hemoptysis) or gout. | Symptoms of Eisenmenger Syndrome. The specific symptoms of Eisenmenger syndrome vary greatly from person to person. Although the heart defect is present at birth, Eisenmenger syndrome with cyanosis often develops around puberty, but may develop earlier or later depending on the location and severity of the congenital heart defect. The symptoms and complications result from a combination of the effects of the heart defect, reduced oxygen in the blood and high pressures in the lungs.The most notable symptom is called cyanosis, which is the bluish discoloration of the skin and mucous membranes. Individuals affected with Eisenmenger syndrome develop cyanosis, particularly of the lips, fingers and toes, which is more pronounced during physical efforts. Patients typically have an increased number of blood cells (red blood cells or erythrocytes) that transport oxygen to the body (i.e., erythrocytosis), compensating for the inadequate oxygen supply to tissues. Additional signs may include rounding of the tips of the fingers and toes (clubbing), shortness of breath, fatigue, lethargy or arrhythmias. Those with Eisenmenger syndrome are also at higher risk for stroke, coughing up blood (hemoptysis) or gout. | 398 | Eisenmenger Syndrome |
nord_398_2 | Causes of Eisenmenger Syndrome | Specific genes that cause Eisenmenger syndrome have not been identified and the condition is not thought to be inherited.Eisenmenger syndrome is caused by a defect in the structure of the heart, more specifically a ventricular septal defect (VSD) or other shunt. A VSD is a hole in the heart in the region that connects the left ventricle and the right ventricle. At birth, this hole allows large amounts of blood to flow between the two chambers, increase the volume of blood traveling to the lungs and increasing lung pressures, damaging the small blood vessels in the lungs. The rise in lung pressures due to often irreversible changes in the lung vessels (pulmonary vascular disease) is called pulmonary arterial hypertension. Without early surgical correction of the underlying defect, the damage in the small arteries within the lung leads to increasing resistance to blood flow. The increasing pressure in the right ventricle can surpass that of the left ventricle and, when this happens, “blue” blood flow from the right to the left ventricle through the VSD (bidirectional, reversed or right-to-left shunt), leading to insufficient oxygen supply to the body (hypoxia), bluish discoloration of the skin and mucous membranes (cyanosis), elevated levels of circulating red blood cells, and other findings characteristic of Eisenmenger syndrome. | Causes of Eisenmenger Syndrome. Specific genes that cause Eisenmenger syndrome have not been identified and the condition is not thought to be inherited.Eisenmenger syndrome is caused by a defect in the structure of the heart, more specifically a ventricular septal defect (VSD) or other shunt. A VSD is a hole in the heart in the region that connects the left ventricle and the right ventricle. At birth, this hole allows large amounts of blood to flow between the two chambers, increase the volume of blood traveling to the lungs and increasing lung pressures, damaging the small blood vessels in the lungs. The rise in lung pressures due to often irreversible changes in the lung vessels (pulmonary vascular disease) is called pulmonary arterial hypertension. Without early surgical correction of the underlying defect, the damage in the small arteries within the lung leads to increasing resistance to blood flow. The increasing pressure in the right ventricle can surpass that of the left ventricle and, when this happens, “blue” blood flow from the right to the left ventricle through the VSD (bidirectional, reversed or right-to-left shunt), leading to insufficient oxygen supply to the body (hypoxia), bluish discoloration of the skin and mucous membranes (cyanosis), elevated levels of circulating red blood cells, and other findings characteristic of Eisenmenger syndrome. | 398 | Eisenmenger Syndrome |
nord_398_3 | Affects of Eisenmenger Syndrome | Eisenmenger syndrome appears to affect males and females in relatively equal numbers. Individuals with Down syndrome represent between 25-50% of the adult Eisenmenger population. | Affects of Eisenmenger Syndrome. Eisenmenger syndrome appears to affect males and females in relatively equal numbers. Individuals with Down syndrome represent between 25-50% of the adult Eisenmenger population. | 398 | Eisenmenger Syndrome |
nord_398_4 | Related disorders of Eisenmenger Syndrome | Eisenmenger syndrome belongs to a group of conditions called “pulmonary arterial hypertension” (PAH) and also includes idiopathic PAH, PAH related to connective tissue diseases etc. It is a rare, progressive disorder, characterized by pulmonary vascular disease and high blood pressure (hypertension) in the arteries of the lungs (pulmonary artery), often for no apparent reason (idiopathic). The pulmonary arteries are the blood vessels that carry blood from the right side of the heart through the lungs. Symptoms of PAH include shortness of breath (dyspnea), especially during exercise, fatigue, chest pain, and fainting episodes. The exact cause of PAH is unknown and although it is treatable, there is no known cure for this condition. Idiopathic PAH usually affects women between the ages of 30-60 years. Individuals with PAH may remain undiagnosed for years because their symptoms are initially mild and nonspecific, resembling other conditions such as asthma. It is important to treat PAH as early as possible, to avoid heart failure. The progressive nature of this disease means that an individual may experience only mild symptoms at first, but will eventually require treatment and medical care to maintain a reasonable quality of life. PAH remains life threatening despite treatment. Approximately 15-20% of patients with PAH have heritable forms of PAH. People with heritable PAH have either: (1) an autosomal dominant genetic condition associated with mutations in the BMPR2 gene or other recently identified genes now associated with HPAH or other forms of PAH or associated conditions such as pulmonary capillary hemangiomatosis or pulmonary veno-occlusive disease, or (2) are members of a family in which PAH is known to occur for no obvious reason. (For more information on this disorder, choose “pulmonary arterial hypertension” as your search term in the Rare Disease Database.) | Related disorders of Eisenmenger Syndrome. Eisenmenger syndrome belongs to a group of conditions called “pulmonary arterial hypertension” (PAH) and also includes idiopathic PAH, PAH related to connective tissue diseases etc. It is a rare, progressive disorder, characterized by pulmonary vascular disease and high blood pressure (hypertension) in the arteries of the lungs (pulmonary artery), often for no apparent reason (idiopathic). The pulmonary arteries are the blood vessels that carry blood from the right side of the heart through the lungs. Symptoms of PAH include shortness of breath (dyspnea), especially during exercise, fatigue, chest pain, and fainting episodes. The exact cause of PAH is unknown and although it is treatable, there is no known cure for this condition. Idiopathic PAH usually affects women between the ages of 30-60 years. Individuals with PAH may remain undiagnosed for years because their symptoms are initially mild and nonspecific, resembling other conditions such as asthma. It is important to treat PAH as early as possible, to avoid heart failure. The progressive nature of this disease means that an individual may experience only mild symptoms at first, but will eventually require treatment and medical care to maintain a reasonable quality of life. PAH remains life threatening despite treatment. Approximately 15-20% of patients with PAH have heritable forms of PAH. People with heritable PAH have either: (1) an autosomal dominant genetic condition associated with mutations in the BMPR2 gene or other recently identified genes now associated with HPAH or other forms of PAH or associated conditions such as pulmonary capillary hemangiomatosis or pulmonary veno-occlusive disease, or (2) are members of a family in which PAH is known to occur for no obvious reason. (For more information on this disorder, choose “pulmonary arterial hypertension” as your search term in the Rare Disease Database.) | 398 | Eisenmenger Syndrome |
nord_398_5 | Diagnosis of Eisenmenger Syndrome | The diagnosis of Eisenmenger syndrome is not particularly complex but may require cardiac catheterization, an invasive procedure to measure pressures in the heart and lungs. Other tests include pulse oximetry, which checks oxygen levels in the blood, chest x-ray, EKG, pulmonary function test, iron levels and complete blood count (CBC). Echocardiography is fundamental in identifying the heart defect and raising the suspicion of high pressures in the lungs. Other imaging modalities (e.g. cardiac MRI) can provide valuable anatomic information. | Diagnosis of Eisenmenger Syndrome. The diagnosis of Eisenmenger syndrome is not particularly complex but may require cardiac catheterization, an invasive procedure to measure pressures in the heart and lungs. Other tests include pulse oximetry, which checks oxygen levels in the blood, chest x-ray, EKG, pulmonary function test, iron levels and complete blood count (CBC). Echocardiography is fundamental in identifying the heart defect and raising the suspicion of high pressures in the lungs. Other imaging modalities (e.g. cardiac MRI) can provide valuable anatomic information. | 398 | Eisenmenger Syndrome |
nord_398_6 | Therapies of Eisenmenger Syndrome | Treatment
The treatment of Eisenmenger syndrome should be managed by a medical team with expertise in both congenital heart disease (cardiologist) and pulmonary hypertension (cardiologist or pulmonologist), with help from other specialists, e.g. hematologists, radiologists, anesthetists etc. The goal of treatment is to minimize symptoms, and the treatment often aligns with patients who are being treated for other types of pulmonary arterial hypertension. Currently, Eisenmenger patients are treated with pulmonary arterial hypertension therapies aimed at reducing the lung resistances and increase the amount of blood flowing through the lungs, hence delivering more oxygen to the body and reducing the load to the heart. Additional medications used include diuretics that reduce the amount of fluid in the body and, at times, medication to prevent blood clots. Beta blockers and especially calcium channel blockers are avoided, because they have a negative effect on the right ventricle. Iron supplementation may be necessary for individuals with iron deficiency anemia. Affected individuals may have an increased risk of developing bacterial infections of the heart lining and valves (bacterial endocarditis); therefore, disease management includes the administration of appropriate antibiotics (antibiotic prophylaxis) prior to dental visits, for certain oral procedures. In addition, anesthesia and sedation carry significant risks and should be avoided. Careful monitoring during anesthesia is essential for any patients undergoing essential unavoidable surgical procedures, which should be performed in expert centers.
Pregnancy should be avoided in women with pulmonary hypertension and Eisenmenger syndrome since it carries significant risks for both the mother and the developing fetus. Thus, it is essential that affected women have a thorough understanding of such risks and receive information, support, and guidance from their physicians and other members of their healthcare team concerning appropriate options to prevent pregnancy. Oxygen therapy has also been met with controversial reviews. There is no data to support its use as a mean for increasing exercise capacity or survival in adult patients. However, it has been seen to help patients with advanced disease in need of a heart-lung transplant or for nocturnal support.Individuals with Eisenmenger syndrome should avoid dehydration, high altitudes, and activities that could cause a sudden drop in blood pressure such as saunas, steam rooms or hot tubs. Extreme physical exercise should also be limited. In severely affected patients with physical deterioration, a heart-lung transplant may be necessary. | Therapies of Eisenmenger Syndrome. Treatment
The treatment of Eisenmenger syndrome should be managed by a medical team with expertise in both congenital heart disease (cardiologist) and pulmonary hypertension (cardiologist or pulmonologist), with help from other specialists, e.g. hematologists, radiologists, anesthetists etc. The goal of treatment is to minimize symptoms, and the treatment often aligns with patients who are being treated for other types of pulmonary arterial hypertension. Currently, Eisenmenger patients are treated with pulmonary arterial hypertension therapies aimed at reducing the lung resistances and increase the amount of blood flowing through the lungs, hence delivering more oxygen to the body and reducing the load to the heart. Additional medications used include diuretics that reduce the amount of fluid in the body and, at times, medication to prevent blood clots. Beta blockers and especially calcium channel blockers are avoided, because they have a negative effect on the right ventricle. Iron supplementation may be necessary for individuals with iron deficiency anemia. Affected individuals may have an increased risk of developing bacterial infections of the heart lining and valves (bacterial endocarditis); therefore, disease management includes the administration of appropriate antibiotics (antibiotic prophylaxis) prior to dental visits, for certain oral procedures. In addition, anesthesia and sedation carry significant risks and should be avoided. Careful monitoring during anesthesia is essential for any patients undergoing essential unavoidable surgical procedures, which should be performed in expert centers.
Pregnancy should be avoided in women with pulmonary hypertension and Eisenmenger syndrome since it carries significant risks for both the mother and the developing fetus. Thus, it is essential that affected women have a thorough understanding of such risks and receive information, support, and guidance from their physicians and other members of their healthcare team concerning appropriate options to prevent pregnancy. Oxygen therapy has also been met with controversial reviews. There is no data to support its use as a mean for increasing exercise capacity or survival in adult patients. However, it has been seen to help patients with advanced disease in need of a heart-lung transplant or for nocturnal support.Individuals with Eisenmenger syndrome should avoid dehydration, high altitudes, and activities that could cause a sudden drop in blood pressure such as saunas, steam rooms or hot tubs. Extreme physical exercise should also be limited. In severely affected patients with physical deterioration, a heart-lung transplant may be necessary. | 398 | Eisenmenger Syndrome |
nord_399_0 | Overview of Elephantiasis | Elephantiasis is a condition characterized by gross enlargement of an area of the body, especially the limbs. Other areas commonly affected include the external genitals. Elephantiasis is caused by obstruction of the lymphatic system, which results in the accumulation of a fluid called lymph in the affected areas.Functioning as part of the immune system, the lymphatic system helps to protect the body against infection and disease. It consists of a network of tubular channels (lymph vessels) that drain a thin watery fluid known as lymph from different areas of the body into the bloodstream. Obstruction of these vessels first results in lymphedema, and then can slowly progress to massive swelling and gross enlargement characteristic of elephantiasis.In areas where filariasis is endemic, the most common cause of elephantiasis is a parasitic disease known as lymphatic filariasis and, in the medical literature, the terms lymphatic filariasis and elephantiasis should not be used interchangeably. In most areas, the lymphatic damage associated with elephantiasis has other causes including certain sexually transmitted diseases (e.g., lymphogranuloma venereum); tuberculosis; an infectious disease called leishmaniasis; repeated streptococcal infections; leprosy; and environmental factors such as exposure to certain minerals (e.g., silica). In some cases, no cause can be identified (idiopathic). | Overview of Elephantiasis. Elephantiasis is a condition characterized by gross enlargement of an area of the body, especially the limbs. Other areas commonly affected include the external genitals. Elephantiasis is caused by obstruction of the lymphatic system, which results in the accumulation of a fluid called lymph in the affected areas.Functioning as part of the immune system, the lymphatic system helps to protect the body against infection and disease. It consists of a network of tubular channels (lymph vessels) that drain a thin watery fluid known as lymph from different areas of the body into the bloodstream. Obstruction of these vessels first results in lymphedema, and then can slowly progress to massive swelling and gross enlargement characteristic of elephantiasis.In areas where filariasis is endemic, the most common cause of elephantiasis is a parasitic disease known as lymphatic filariasis and, in the medical literature, the terms lymphatic filariasis and elephantiasis should not be used interchangeably. In most areas, the lymphatic damage associated with elephantiasis has other causes including certain sexually transmitted diseases (e.g., lymphogranuloma venereum); tuberculosis; an infectious disease called leishmaniasis; repeated streptococcal infections; leprosy; and environmental factors such as exposure to certain minerals (e.g., silica). In some cases, no cause can be identified (idiopathic). | 399 | Elephantiasis |
nord_399_1 | Symptoms of Elephantiasis | The initial symptom of lymphatic dysfunction is a mild edema, which can gradually progress to elephantiasis if not treated.The main symptom of elephantiasis is gross enlargement and swelling of an area of the body because of the accumulation of fluid. The arms and legs are the areas most often affected. An entire arm or leg may swell to several times its normal size resembling the thick, round appearance of an elephant’s leg. The skin of the affected areas usually develops a dry, thickened, pebbly appearance and may become ulcerated, pitted and darkened (hyperkeratosis). Fever, chills, and a general feeling of ill health (malaise) may also be present.Elephantiasis may also affect the male and female external genital organs. In a male, there may be enlargement of the scrotum, and the penis may be retracted under skin which has become thickened, nonelastic, hot and painful. The spermatic cords may thicken. Affected individuals may experience pain and a burning sensation.The external parts of the female genital organs (vulva) may also be affected by elephantiasis. A tumorous mass covered by thickened and ulcerated skin may develop between the thighs and may be accompanied by enlarged lymph nodes (lymphadenopathy) of the legs. In some women the breasts may become enlarged.Underlying damage to the lymphatic system may leave individuals susceptible to secondary bacterial and fungal infections that can greatly worsen the condition. Although the legs, arms and external genitalia are most often affected, elephantiasis can affect any area of the body. | Symptoms of Elephantiasis. The initial symptom of lymphatic dysfunction is a mild edema, which can gradually progress to elephantiasis if not treated.The main symptom of elephantiasis is gross enlargement and swelling of an area of the body because of the accumulation of fluid. The arms and legs are the areas most often affected. An entire arm or leg may swell to several times its normal size resembling the thick, round appearance of an elephant’s leg. The skin of the affected areas usually develops a dry, thickened, pebbly appearance and may become ulcerated, pitted and darkened (hyperkeratosis). Fever, chills, and a general feeling of ill health (malaise) may also be present.Elephantiasis may also affect the male and female external genital organs. In a male, there may be enlargement of the scrotum, and the penis may be retracted under skin which has become thickened, nonelastic, hot and painful. The spermatic cords may thicken. Affected individuals may experience pain and a burning sensation.The external parts of the female genital organs (vulva) may also be affected by elephantiasis. A tumorous mass covered by thickened and ulcerated skin may develop between the thighs and may be accompanied by enlarged lymph nodes (lymphadenopathy) of the legs. In some women the breasts may become enlarged.Underlying damage to the lymphatic system may leave individuals susceptible to secondary bacterial and fungal infections that can greatly worsen the condition. Although the legs, arms and external genitalia are most often affected, elephantiasis can affect any area of the body. | 399 | Elephantiasis |
nord_399_2 | Causes of Elephantiasis | Elephantiasis is caused by under-treatment of lymphedema, and due to the obstruction of the lymph vessels of the lymphatic system. As lymph moves through the lymphatic system, it is filtered by a network of small structures known as lymph nodes that help to remove microorganisms (e.g., viruses, bacteria, etc.) and other foreign bodies. Groups of lymph nodes are located throughout the body, including in the neck, under the arms (axillae), at the elbows, and in the chest, abdomen, and groin. In addition to the lymph nodes, the lymphatic system includes the spleen, which filters worn-out red blood cells and produces lymphocytes, and the tonsils, which are masses of lymphoid tissue in the throat region that help to fight infection. Lymphatic tissues also include the thymus, a relatively small organ behind the breastbone that is thought to play an important role in the immune system until puberty, as well as the bone marrow, which is the spongy tissue inside the cavities of bones that manufactures blood cells. Lymphatic tissue may also be located in other regions of the body, such as the skin, small intestine, liver, and other organs.In underdeveloped regions of South America, Central Africa, Asia, the Pacific Islands and the Caribbean, obstruction can be caused by a parasitic disease known as lymphatic filariasis. Lymphatic filariasis is caused by three different species of worms known as Brugia malayi, Brugia timori and Wuchereria bancrofti. These worms cause damage and inflammation to the lymphatic system. The larval form of the worms is introduced into the human body through the bite of infected mosquitoes.Genital elephantiasis can also be caused by bacterial sexually transmitted diseases, specifically lymphogranuloma venereum (LGV) and donovanosis. The bacterium that results in LGV, Chlamydia trachomatis serovar L1-L3, damages the lympathic system resulting in lymphatic obstruction in the genitals. Chronic obstruction eventually results in genital elephantiasis. Donovanosis is caused by the bacterium Calymmatobacterium (Klebsiella) granulomatosis. Donovanosis causes genital elephantiasis because the body’s immune system response to the bacterium causes inflammation and narrowing (constriction) of the lymphatic vessels.Elephantiasis is also associated with a disorder known as podoconiosis. Podoconiosis, sometimes referred to as nonfilarial elephantiasis, is a disorder caused by the absorption of minute mineral particles from the soil through the feet of barefoot individuals. It is believed that the mineral particles cause an immune system response eventually resulting in the formation of inflammatory masses of nodules (granulomas) in the lymph vessels of the feet and legs.Additional causes of elephantiasis include a protozoan disease called leishmaniasis, tuberculosis, leprosy, and a repeated streptococcal infection. Elephantiasis may also occur secondary to trauma, surgery or radiation if lymphedema is not treated.. For example, treatment such as the surgical removal of lymph nodes to treat cancer may result in the accumulation of lymph and subsequent swelling (lymphedema). | Causes of Elephantiasis. Elephantiasis is caused by under-treatment of lymphedema, and due to the obstruction of the lymph vessels of the lymphatic system. As lymph moves through the lymphatic system, it is filtered by a network of small structures known as lymph nodes that help to remove microorganisms (e.g., viruses, bacteria, etc.) and other foreign bodies. Groups of lymph nodes are located throughout the body, including in the neck, under the arms (axillae), at the elbows, and in the chest, abdomen, and groin. In addition to the lymph nodes, the lymphatic system includes the spleen, which filters worn-out red blood cells and produces lymphocytes, and the tonsils, which are masses of lymphoid tissue in the throat region that help to fight infection. Lymphatic tissues also include the thymus, a relatively small organ behind the breastbone that is thought to play an important role in the immune system until puberty, as well as the bone marrow, which is the spongy tissue inside the cavities of bones that manufactures blood cells. Lymphatic tissue may also be located in other regions of the body, such as the skin, small intestine, liver, and other organs.In underdeveloped regions of South America, Central Africa, Asia, the Pacific Islands and the Caribbean, obstruction can be caused by a parasitic disease known as lymphatic filariasis. Lymphatic filariasis is caused by three different species of worms known as Brugia malayi, Brugia timori and Wuchereria bancrofti. These worms cause damage and inflammation to the lymphatic system. The larval form of the worms is introduced into the human body through the bite of infected mosquitoes.Genital elephantiasis can also be caused by bacterial sexually transmitted diseases, specifically lymphogranuloma venereum (LGV) and donovanosis. The bacterium that results in LGV, Chlamydia trachomatis serovar L1-L3, damages the lympathic system resulting in lymphatic obstruction in the genitals. Chronic obstruction eventually results in genital elephantiasis. Donovanosis is caused by the bacterium Calymmatobacterium (Klebsiella) granulomatosis. Donovanosis causes genital elephantiasis because the body’s immune system response to the bacterium causes inflammation and narrowing (constriction) of the lymphatic vessels.Elephantiasis is also associated with a disorder known as podoconiosis. Podoconiosis, sometimes referred to as nonfilarial elephantiasis, is a disorder caused by the absorption of minute mineral particles from the soil through the feet of barefoot individuals. It is believed that the mineral particles cause an immune system response eventually resulting in the formation of inflammatory masses of nodules (granulomas) in the lymph vessels of the feet and legs.Additional causes of elephantiasis include a protozoan disease called leishmaniasis, tuberculosis, leprosy, and a repeated streptococcal infection. Elephantiasis may also occur secondary to trauma, surgery or radiation if lymphedema is not treated.. For example, treatment such as the surgical removal of lymph nodes to treat cancer may result in the accumulation of lymph and subsequent swelling (lymphedema). | 399 | Elephantiasis |
nord_399_3 | Affects of Elephantiasis | Elephantiasis is present worldwide, but with greater frequency in poor third world regions, including Southeast Asia, India, Africa and South America, and not only as a manifestation of lymphatic filariasis.Elephantiasis due to other causes is not rare. Elephantiasis can affect men or women of any age. | Affects of Elephantiasis. Elephantiasis is present worldwide, but with greater frequency in poor third world regions, including Southeast Asia, India, Africa and South America, and not only as a manifestation of lymphatic filariasis.Elephantiasis due to other causes is not rare. Elephantiasis can affect men or women of any age. | 399 | Elephantiasis |
nord_399_4 | Related disorders of Elephantiasis | Symptoms of the following disorders can be similar to those of elephantiasis. Comparisons may be useful for a differential diagnosis.Hereditary lymphedema is an inherited disorder of the lymphatic system that is characterized by abnormal swelling of certain parts of the body. The lymphatic system is a circulatory network of vessels, ducts, and nodes that filter and distribute certain fluid (lymph) and blood cells throughout the body. Lymphatic fluid collects in the soft tissues in and under the skin (subcutaneous) due to the obstruction, malformation, or underdevelopment (hypoplasia) of various lymphatic vessels. There are three forms of hereditary lymphedema: congenital hereditary lymphedema or Milroy disease, lymphedema praecox or Meige disease, and lymphedema tarda. Symptoms include swelling of affected areas (lymphedema) and thickening and hardening of the skin in affected areas. In most cases, hereditary lymphedema is inherited as an autosomal dominant trait. (For more information on this disorder, choose “hereditary lymphedema” as your search term in the Rare Disease Database). | Related disorders of Elephantiasis. Symptoms of the following disorders can be similar to those of elephantiasis. Comparisons may be useful for a differential diagnosis.Hereditary lymphedema is an inherited disorder of the lymphatic system that is characterized by abnormal swelling of certain parts of the body. The lymphatic system is a circulatory network of vessels, ducts, and nodes that filter and distribute certain fluid (lymph) and blood cells throughout the body. Lymphatic fluid collects in the soft tissues in and under the skin (subcutaneous) due to the obstruction, malformation, or underdevelopment (hypoplasia) of various lymphatic vessels. There are three forms of hereditary lymphedema: congenital hereditary lymphedema or Milroy disease, lymphedema praecox or Meige disease, and lymphedema tarda. Symptoms include swelling of affected areas (lymphedema) and thickening and hardening of the skin in affected areas. In most cases, hereditary lymphedema is inherited as an autosomal dominant trait. (For more information on this disorder, choose “hereditary lymphedema” as your search term in the Rare Disease Database). | 399 | Elephantiasis |
nord_399_5 | Diagnosis of Elephantiasis | A diagnosis of elephantiasis is made based upon a thorough clinical evaluation, a detailed patient history and identification of characteristic symptoms. A variety of tests may be used to determine the underlying cause of lymphatic damage and subsequent elephantiasis. | Diagnosis of Elephantiasis. A diagnosis of elephantiasis is made based upon a thorough clinical evaluation, a detailed patient history and identification of characteristic symptoms. A variety of tests may be used to determine the underlying cause of lymphatic damage and subsequent elephantiasis. | 399 | Elephantiasis |
nord_399_6 | Therapies of Elephantiasis | TreatmentTreatment of elephantiasis always involves treating the underlying condition. Lymphatic filariasis is a chronic lymphedema, which should be treated in the early stages with good compression therapy and garments to prevent elephantiasis. Other signs are treated with diethylcarbamazine. LGV is treated with doxycycline. Donovanosis may be treated with azithromycin.However, in the majority cases, medical therapy alone is enough and surgery may be necessary as a last option. In cases where the male genitals have been affected, reconstructive surgery on the penis and scrotum has been successful. Anti-streptococcal antibiotics are used to relieve secondary infection. Lymphatic tissue may be removed by surgery or radiation therapy.
Other treatment is symptomatic and supportive. | Therapies of Elephantiasis. TreatmentTreatment of elephantiasis always involves treating the underlying condition. Lymphatic filariasis is a chronic lymphedema, which should be treated in the early stages with good compression therapy and garments to prevent elephantiasis. Other signs are treated with diethylcarbamazine. LGV is treated with doxycycline. Donovanosis may be treated with azithromycin.However, in the majority cases, medical therapy alone is enough and surgery may be necessary as a last option. In cases where the male genitals have been affected, reconstructive surgery on the penis and scrotum has been successful. Anti-streptococcal antibiotics are used to relieve secondary infection. Lymphatic tissue may be removed by surgery or radiation therapy.
Other treatment is symptomatic and supportive. | 399 | Elephantiasis |
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