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Overview of Human Monocytic Ehrlichiosis (HME)
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Human Monocytic Ehrlichiosis (HME) is a rare infectious disease belonging to a group of diseases known as the Human Ehrlichioses. These diseases are caused by bacteria belonging to the “Ehrlichia” family. Several forms of Human Ehrlichioses have been identified, including Human Monocytic Ehrlichiosis, Sennetsu Fever, and Human Granulocytic Ehrlichiosis. Though caused by different strains of Ehrlichia bacteria, the disorders are characterized by similar symptoms.The symptoms of Human Monocytic Ehrlichiosis may include a sudden high fever, headache, muscle aches (myalgia), chills, and a general feeling of weakness and fatigue (malaise) within a few weeks after initial infection. In addition, in many cases, laboratory findings may indicate an abnormally low number of circulating blood platelets (thrombocytopenia), a decrease in white blood cells (leukopenia), and an abnormal increase in the level of certain liver enzymes (hepatic transaminases). In some individuals, symptoms may progress to include nausea, vomiting, diarrhea, weight loss, and/or confusion. If HME is left untreated, life-threatening symptoms, such as kidney failure and respiratory insufficiency, may develop in some cases. Human Monocytic Ehrlichiosis is caused by the bacteria Ehrlichia chaffeensis (or E. chaffeensis). E. chaffeensis is carried and transmitted by certain ticks (vectors), such as the Lone Star tick (Amblyomma americanum) and the American dog tick (Dermacentor variabilis).
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Overview of Human Monocytic Ehrlichiosis (HME). Human Monocytic Ehrlichiosis (HME) is a rare infectious disease belonging to a group of diseases known as the Human Ehrlichioses. These diseases are caused by bacteria belonging to the “Ehrlichia” family. Several forms of Human Ehrlichioses have been identified, including Human Monocytic Ehrlichiosis, Sennetsu Fever, and Human Granulocytic Ehrlichiosis. Though caused by different strains of Ehrlichia bacteria, the disorders are characterized by similar symptoms.The symptoms of Human Monocytic Ehrlichiosis may include a sudden high fever, headache, muscle aches (myalgia), chills, and a general feeling of weakness and fatigue (malaise) within a few weeks after initial infection. In addition, in many cases, laboratory findings may indicate an abnormally low number of circulating blood platelets (thrombocytopenia), a decrease in white blood cells (leukopenia), and an abnormal increase in the level of certain liver enzymes (hepatic transaminases). In some individuals, symptoms may progress to include nausea, vomiting, diarrhea, weight loss, and/or confusion. If HME is left untreated, life-threatening symptoms, such as kidney failure and respiratory insufficiency, may develop in some cases. Human Monocytic Ehrlichiosis is caused by the bacteria Ehrlichia chaffeensis (or E. chaffeensis). E. chaffeensis is carried and transmitted by certain ticks (vectors), such as the Lone Star tick (Amblyomma americanum) and the American dog tick (Dermacentor variabilis).
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Symptoms of Human Monocytic Ehrlichiosis (HME)
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Human Monocytic Ehrlichiosis (HME) was the first form of Human Ehrlichial infection recognized in the United States. The onset of symptoms usually occurs about three weeks after an individual has been bitten by a tick carrying the bacterium Ehrlichia chaffeensis. Symptoms may initially include fever, chills, headaches, muscle pain (myalgia), and a general feeling of weakness and fatigue (malaise). In some cases, a rash may appear on the skin. Symptoms may then progress to include nausea, vomiting, loss of appetite (anorexia), and/or weight loss. Some affected individuals may also experience coughing, diarrhea, sore throat (pharyngitis), and pain in the abdominal area.In most cases of HME, there is also an abnormal decrease in white blood cells (leukopenia), a low number of circulating blood platelets (thrombocytopenia), and/or an abnormal increase in the level of certain liver enzymes (hepatic transaminases). Some affected individuals may also experience inflammation of the liver (hepatitis).In some severe cases of Human Monocytic Ehrlichiosis, if appropriate treatment is not received, symptoms may include shortness of breath (dyspnea); abnormalities in the blood's ability to clot properly (coagulopathy), potentially resulting in gastrointestinal bleeding; and/or neurologic abnormalities due to involvement of the brain and the spinal cord (central nervous system [CNS]). Affected individuals with CNS involvement may develop abnormal tissue changes (lesions) in the brain, experience inflammation of the protective membranes covering the brain and spinal cord (meningitis), and/or have abnormalities in the fluid surrounding the brain and spinal cord (cerebrospinal fluid). Neurologic symptoms and findings may include confusion, abnormal sensitivity to light (photophobia), stiffness of the neck, episodes of uncontrolled electrical disturbances in the brain (seizures), and/or coma. Additional neurologic abnormalities may include exaggerated reflex responses (hyperreflexia), impaired coordination of voluntary movements (ataxia), and/or loss of some motor function in the facial area due to impairment of one or more of the 12 nerve pairs arising from the brain (cranial nerve palsy). In severe cases, if HME is left untreated, life-threatening complications may result, such as kidney (renal) and/or respiratory failure.Some affected individuals may have a milder form of Human Monocytic Ehrlichiosis, experiencing only some of the symptoms typically associated with the disorder. Such symptoms may include muscle aches (myalgia), joint pain (arthralgia), headache, and/or loss of appetite (anorexia). In addition, it is believed that some individuals affected with HME may demonstrate no obvious symptoms (asymptomatic).
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Symptoms of Human Monocytic Ehrlichiosis (HME). Human Monocytic Ehrlichiosis (HME) was the first form of Human Ehrlichial infection recognized in the United States. The onset of symptoms usually occurs about three weeks after an individual has been bitten by a tick carrying the bacterium Ehrlichia chaffeensis. Symptoms may initially include fever, chills, headaches, muscle pain (myalgia), and a general feeling of weakness and fatigue (malaise). In some cases, a rash may appear on the skin. Symptoms may then progress to include nausea, vomiting, loss of appetite (anorexia), and/or weight loss. Some affected individuals may also experience coughing, diarrhea, sore throat (pharyngitis), and pain in the abdominal area.In most cases of HME, there is also an abnormal decrease in white blood cells (leukopenia), a low number of circulating blood platelets (thrombocytopenia), and/or an abnormal increase in the level of certain liver enzymes (hepatic transaminases). Some affected individuals may also experience inflammation of the liver (hepatitis).In some severe cases of Human Monocytic Ehrlichiosis, if appropriate treatment is not received, symptoms may include shortness of breath (dyspnea); abnormalities in the blood's ability to clot properly (coagulopathy), potentially resulting in gastrointestinal bleeding; and/or neurologic abnormalities due to involvement of the brain and the spinal cord (central nervous system [CNS]). Affected individuals with CNS involvement may develop abnormal tissue changes (lesions) in the brain, experience inflammation of the protective membranes covering the brain and spinal cord (meningitis), and/or have abnormalities in the fluid surrounding the brain and spinal cord (cerebrospinal fluid). Neurologic symptoms and findings may include confusion, abnormal sensitivity to light (photophobia), stiffness of the neck, episodes of uncontrolled electrical disturbances in the brain (seizures), and/or coma. Additional neurologic abnormalities may include exaggerated reflex responses (hyperreflexia), impaired coordination of voluntary movements (ataxia), and/or loss of some motor function in the facial area due to impairment of one or more of the 12 nerve pairs arising from the brain (cranial nerve palsy). In severe cases, if HME is left untreated, life-threatening complications may result, such as kidney (renal) and/or respiratory failure.Some affected individuals may have a milder form of Human Monocytic Ehrlichiosis, experiencing only some of the symptoms typically associated with the disorder. Such symptoms may include muscle aches (myalgia), joint pain (arthralgia), headache, and/or loss of appetite (anorexia). In addition, it is believed that some individuals affected with HME may demonstrate no obvious symptoms (asymptomatic).
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Causes of Human Monocytic Ehrlichiosis (HME)
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The Human Ehrlichioses, including Human Monocytic Ehrlichiosis (HME), are caused by bacteria belonging to the “Ehrlichia” family. They are considered “gram-negative” bacteria. Bacteria may be considered “gram negative” or “gram positive,” depending upon the results of “Gram's stain,” a testing method in which bacteria are stained with various solutions to help identify and classify the bacteria. Such staining may be essential in identifying a specific bacterium responsible for an infectious disorder and determining appropriate, effective treatments.In most cases, it is believed that Human Ehrlichial infection results from tick bites. Certain types of ticks serve as “vectors,” carrying and then transmitting the Ehrlichia bacteria to humans. A vector is any organism that is infected with a particular disease agent (e.g., bacterium or virus), carries it, and later transmits it to another organism, which may then become infected by the disease agent in question.Human Monocytic Ehrlichiosis is caused by a bacterium named Ehrlichia chaffeensis (or E. chaffeensis). E. chaffeensis is transmitted by tick vectors, such as the Lone Star tick (Amblyomma americanum) and the American dog tick (Dermacentor variabilis). The genetic composition of E. chaffeensis is closely related to that of two other types of Ehrlichia bacteria, i.e., Ehrlichia canis and Ehrlichia ewingii. Both of these Ehrlichial bacteria are known to cause Ehrlichiosis in dogs. In addition, the E. ewingii bacterium has been found to cause a newly recognized form of Human Ehrlichiosis. (For more information, please see the “Related Disorders” section below.) In Human Monocytic Ehrlichiosis, the Ehrlichial bacterium (E. chaffeensis) spreads through blood and lymphatic vessels. Lymph, a body fluid, carries cells that help fight infection. E. chaffeensis then invades certain cells (monocytes and macrophages) that play an essential role in the body's immune system by engulfing and digesting microorganisms (phagocytosis), such as bacteria and other foreign materials. The invading Ehrlichial bacteria grow within membrane-bound cavities (vacuoles) in monocytes and macrophages in the blood and certain body tissues (e.g., bone marrow, lymph nodes, liver, spleen, kidneys, lungs, and the fluid that surrounds the brain and spinal cord [cerebrospinal fluid]).
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Causes of Human Monocytic Ehrlichiosis (HME). The Human Ehrlichioses, including Human Monocytic Ehrlichiosis (HME), are caused by bacteria belonging to the “Ehrlichia” family. They are considered “gram-negative” bacteria. Bacteria may be considered “gram negative” or “gram positive,” depending upon the results of “Gram's stain,” a testing method in which bacteria are stained with various solutions to help identify and classify the bacteria. Such staining may be essential in identifying a specific bacterium responsible for an infectious disorder and determining appropriate, effective treatments.In most cases, it is believed that Human Ehrlichial infection results from tick bites. Certain types of ticks serve as “vectors,” carrying and then transmitting the Ehrlichia bacteria to humans. A vector is any organism that is infected with a particular disease agent (e.g., bacterium or virus), carries it, and later transmits it to another organism, which may then become infected by the disease agent in question.Human Monocytic Ehrlichiosis is caused by a bacterium named Ehrlichia chaffeensis (or E. chaffeensis). E. chaffeensis is transmitted by tick vectors, such as the Lone Star tick (Amblyomma americanum) and the American dog tick (Dermacentor variabilis). The genetic composition of E. chaffeensis is closely related to that of two other types of Ehrlichia bacteria, i.e., Ehrlichia canis and Ehrlichia ewingii. Both of these Ehrlichial bacteria are known to cause Ehrlichiosis in dogs. In addition, the E. ewingii bacterium has been found to cause a newly recognized form of Human Ehrlichiosis. (For more information, please see the “Related Disorders” section below.) In Human Monocytic Ehrlichiosis, the Ehrlichial bacterium (E. chaffeensis) spreads through blood and lymphatic vessels. Lymph, a body fluid, carries cells that help fight infection. E. chaffeensis then invades certain cells (monocytes and macrophages) that play an essential role in the body's immune system by engulfing and digesting microorganisms (phagocytosis), such as bacteria and other foreign materials. The invading Ehrlichial bacteria grow within membrane-bound cavities (vacuoles) in monocytes and macrophages in the blood and certain body tissues (e.g., bone marrow, lymph nodes, liver, spleen, kidneys, lungs, and the fluid that surrounds the brain and spinal cord [cerebrospinal fluid]).
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Affects of Human Monocytic Ehrlichiosis (HME)
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Human Monocytic Ehrlichiosis was first recognized in the United States in 1986. At that time, a male who was approximately 50 years of age was bitten by a tick in Arkansas. He experienced the symptoms of Ehrlichial infection approximately two weeks after tick exposure. Studies were later conducted by the Centers for Disease Control (CDC) and state public health officials, demonstrating that many individuals in the United States who had originally been diagnosed with Rocky Mountain Spotted Fever or a related disorder may have actually experienced Human Ehrlichial infection. In 1991, when a soldier stationed at an army base in Arkansas experienced similar symptoms, the bacterium responsible for the infection was isolated. The bacterium, named “Ehrlichia chaffeensis” after the army base where the soldier was stationed (Fort Chaffee, Arkansas), is the cause of Human Monocytic Ehrlichiosis (HME).From 1986 to 1997, 742 cases of HME were reported to the CDC. Most cases have occurred in the mid-Atlantic and southeastern states in the United States, although some have been reported from other states, including Washington, Wyoming, and Utah, as well as other continents, including Europe and Africa. However, because some individuals with HME may demonstrate no obvious symptoms (asymptomatic), it may be difficult to determine the true frequency of this form of Human Ehrlichiosis in the general population.HME infection most commonly occurs in rural areas in the months of May, June, and July. In theory, this disease affects males and females in equal numbers. However, in observed cases, approximately 80 percent of affected individuals are male, while about 20 percent are female. Infection tends to occur when individuals participate in recreational or occupational activities that expose them to tick vectors.Researchers believe that the distinct geographic distributions of the Human Ehrlichioses may result from differences in the distribution of the various vectors (e.g., raw fish, Lone Star tick, American dog tick, deer tick) carrying and transmitting the different Ehrlichia bacterial strains.A recent report by the Centers for Disease Control and Prevention suggests that the incidence of both HME and Human Granulocytic Ehrlichiosis is underreported.
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Affects of Human Monocytic Ehrlichiosis (HME). Human Monocytic Ehrlichiosis was first recognized in the United States in 1986. At that time, a male who was approximately 50 years of age was bitten by a tick in Arkansas. He experienced the symptoms of Ehrlichial infection approximately two weeks after tick exposure. Studies were later conducted by the Centers for Disease Control (CDC) and state public health officials, demonstrating that many individuals in the United States who had originally been diagnosed with Rocky Mountain Spotted Fever or a related disorder may have actually experienced Human Ehrlichial infection. In 1991, when a soldier stationed at an army base in Arkansas experienced similar symptoms, the bacterium responsible for the infection was isolated. The bacterium, named “Ehrlichia chaffeensis” after the army base where the soldier was stationed (Fort Chaffee, Arkansas), is the cause of Human Monocytic Ehrlichiosis (HME).From 1986 to 1997, 742 cases of HME were reported to the CDC. Most cases have occurred in the mid-Atlantic and southeastern states in the United States, although some have been reported from other states, including Washington, Wyoming, and Utah, as well as other continents, including Europe and Africa. However, because some individuals with HME may demonstrate no obvious symptoms (asymptomatic), it may be difficult to determine the true frequency of this form of Human Ehrlichiosis in the general population.HME infection most commonly occurs in rural areas in the months of May, June, and July. In theory, this disease affects males and females in equal numbers. However, in observed cases, approximately 80 percent of affected individuals are male, while about 20 percent are female. Infection tends to occur when individuals participate in recreational or occupational activities that expose them to tick vectors.Researchers believe that the distinct geographic distributions of the Human Ehrlichioses may result from differences in the distribution of the various vectors (e.g., raw fish, Lone Star tick, American dog tick, deer tick) carrying and transmitting the different Ehrlichia bacterial strains.A recent report by the Centers for Disease Control and Prevention suggests that the incidence of both HME and Human Granulocytic Ehrlichiosis is underreported.
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Related disorders of Human Monocytic Ehrlichiosis (HME)
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Symptoms of the following disorders may be similar to those of Human Monocytic Ehrlichiosis (HME). Comparisons may be useful for a differential diagnosis:Human Granulocytic Ehrlichiosis (HGE), a rare infectious disease, is caused by a bacterium from the “Ehrlichia” family that has not yet been named. The bacterium, which is carried and transmitted by ticks (vectors), invades certain granular white blood cells (neutrophils) that play a role in engulfing bacteria, removing them from the blood, and destroying them (phagocytosis). In individuals with HGE, the onset of symptoms usually occurs approximately one week after an individual has been bitten by a tick carrying the Ehrlichia bacterium. In almost all cases, symptoms include fever, chills, muscle pain (myalgia), a general feeling of weakness and fatigue (malaise), and/or headaches. Some affected individuals may also experience coughing, nausea, vomiting, and/or confusion. In addition, in many cases, certain abnormal laboratory findings may occur including an abnormal increase in the level of certain liver enzymes (hepatic transaminases), an abnormal decrease in circulating blood platelets (thrombocytopenia), anemia, and/or a decrease in certain white blood cells (granulocytopenia). In some severe cases, if Human Granulocytic Ehrlichiosis is left untreated, life-threatening symptoms, such as kidney failure and respiratory insufficiency, may result. Most cases have affected individuals in the Northeastern and Midwestern United States. (For more information on this disorder, choose “Human Granulocytic Ehrlichiosis” as your search term in the Rare Disease Database.)Sennetsu Fever, a rare infectious disease that also belongs to the Human Ehrlichioses, is caused by the bacterium known as Ehrlichia sennetsu. The symptoms of Sennetsu Fever may include a sudden high fever, headache, and muscle aches (myalgia) within a few weeks after initial infection. Some affected individuals may also experience nausea, vomiting, and/or loss of appetite (anorexia). In addition, in many cases, abnormal laboratory findings may occur including a decrease in white blood cells (leukopenia) and/or an abnormal increase in the level of certain liver enzymes (hepatic transaminases). The vector (or carrier) for the E. sennetsu bacterium has not yet been determined; however, some researchers believe that infection may result from ingestion of raw fish. Reported cases of Sennetsu Fever appear to be limited to Western Japan and Malaysia. (For more information on this disease, choose “Sennetsu” as your search term in the Rare Disease Database.)The most recently identified form of Human Ehrlichiosis has been reported in four individuals in Missouri, all of whom experienced tick exposure several days prior to symptom onset. Based upon certain specialized laboratory tests, the four individuals tested positive for Ehrlichial infection yet negative for all known human forms of the disease (e.g., HME, HGE). Further tests revealed that the infection was caused by Ehrlichia ewingii, a bacterium that was previously thought only to cause Ehrlichial infection in dogs (Canine Granulocytic Ehrlichiosis). The researchers indicated that there is no evidence of direct disease transmission from dogs to humans. Rather, humans and dogs both appear to be hosts to the same tick vectors. Associated symptoms typically include fever, headache, joint and muscle pain, and a general feeling of ill health (malaise). In addition, as with other forms of Human Ehrlichiosis, abnormal laboratory findings may also be present, such as abnormally low levels of circulating platelets (thrombocytopenia) and a decrease in the level of white blood cells (leukopenia). Three of the four individuals with this form of Ehrlichiosis had been receiving therapy with medications that suppress the activities of the immune system (immunosuppressants). It is unclear whether infection with the E. ewingii bacterium usually does not affect individuals with sufficient immune system functioning (immunocompetence) or results in mild or no apparent symptoms (asymptomatic) in such cases. Therefore, the implications of such findings are not yet understood. All individuals with this form of Human Ehrlichiosis responded to treatment with the antibiotic doxycycline. (For more information on Human Ehrlichiosis treatment, please see the “Standard Therapies” section of this report below.)Lyme Disease is an infectious disorder caused by the spirochete bacterium Borrelia burgdorferi. The bacterium is carried and transmitted by deer ticks (Ixodes dammini). In most cases, Lyme Disease is first characterized by the appearance of a red skin lesion (erythema chronicum migrans), which begins as a small elevated round spot (papule) that expands to at least five centimeters in diameter. Symptoms may then progress to include low-grade fever, chills, muscle aches (myalgia), headache, a general feeling of weakness and fatigue (malaise), and/or pain and stiffness of the large joints (infectious arthritis), especially in the knees. Such symptoms may tend to occur in recurrent cycles. In severe cases, heart muscle (myocardial) and/or neurologic abnormalities may occur. Most cases of Lyme Disease occur in the northeastern United States. However, cases have occurred in other areas of the U.S. as well as other countries including China, Japan, Australia, and several countries in Europe. (For more information on this disorder, choose “Lyme” as your search term in the Rare Disease Database.)Babesiosis is a group of infectious diseases caused by single-celled microorganisms (protozoa) belonging to the “Babesia” family. It is believed that the Babesia protozoa are usually carried and transmitted by ticks (vectors). Babesiosis occurs primarily in animals; however, in rare cases, Babesiosis infection may occur in humans. Certain Babesia species are known to cause Babesiosis infection in humans (i.e., Babesia microti), and the deer tick (Ixodes dammini) is a known vector. Human Babesiosis infection may cause fever, chills, headache, nausea, vomiting, and/or muscle aches (myalgia). Additional features may include premature destruction of red blood cells (hemolytic anemia), an abnormal decrease in circulating blood platelets (thrombocytopenia) and white blood cells (leukopenia), and/or an enlarged spleen (splenomegaly). Symptoms may be mild in otherwise healthy people; some infected individuals may exhibit no symptoms (asymptomatic). A severe form of Babesiosis, which can be life-threatening if untreated, can occur in people who have had their spleens removed (splenectomized) or who have an impaired immune system. In the United States, Babesiosis is most common in the northeastern states. In rare cases, Babesiosis may occur in Europe. (For more information on this disorder, choose “Babesiosis” as your search term in the Rare Disease Database.)Rocky Mountain Spotted Fever is a rare infectious disorder caused by the bacterium Rickettsia rickettsii. The bacterium is carried and transmitted by tick vectors, such as the Lone Star tick (Amblyomma americanum) and the American dog tick (Dermacentor variabilis), which are also known vectors for Human Monocytic Ehrlichiosis. Rocky Mountain Spotted Fever is characterized by severe headache, high fever, chills, muscle aches (myalgia), and/or confusion. In most cases, a skin rash may appear approximately two to six days after tick exposure; the rash may first appear on the palms, wrists, soles, ankles, and forearms, later spreading to the face, trunk, and lower arms and legs. Some affected individuals may also experience nausea, vomiting, and/or abdominal pain. In some cases, without early diagnosis and appropriate treatment, symptoms may become life-threatening. Rocky Mountain Spotted Fever characteristically occurs in outbreaks in various areas of the Midwestern, Eastern, and Southeastern United States. (For more information on this disorder, choose “Rocky Mountain Spotted Fever” as your search term in the Rare Disease Database.)Meningococcal disease is an infectious disease caused by the bacterium Neisseria meningitidis in the bloodstream. The symptoms associated with meningococcal disease may vary greatly from case to case, with associated findings ranging from a short fever and upper respiratory illness to sudden, severe infection with potentially life-threatening complications. In some cases, affected individuals may progress from one manifestation to another. In some individuals with meningococcal disease, symptoms may include fever, chills, headache, generalized weakness, a general feeling of ill health (malaise), and/or low blood pressure (hypotension). Many affected individuals may also have areas of abnormal bleeding (hemorrhage) within skin layers, causing the appearance of small purplish spots on the skin (petechia). In addition, in those with meningococcal disease, laboratory findings may include abnormally elevated levels of white cells in the blood (lymphocytosis). In some severe cases, affected individuals may experience inflammation of the protective membranes covering the brain and spinal cord (meningococcal meningitis). Associated symptoms may include the sudden onset of severe fever, chills, nausea, vomiting, and/or stiff neck, followed by confusion, drowsiness, and loss of consciousness. In such cases, life-threatening complications may result without immediate, appropriate treatment. (For more information on this disease, choose “Meningococcemia” or “Meningitis, Meningococcal” as your search term in the Rare Disease Database.) There are other infectious disorders that may be characterized by sudden high fever (febrile disorders), headache, myalgia, nausea, vomiting, thrombocytopenia, leukopenia, and/or other symptoms associated with Human Monocytic Ehrlichiosis. (For more information on these disorders, choose the exact disease name in question as your search term in the Rare Disease Database.)
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Related disorders of Human Monocytic Ehrlichiosis (HME). Symptoms of the following disorders may be similar to those of Human Monocytic Ehrlichiosis (HME). Comparisons may be useful for a differential diagnosis:Human Granulocytic Ehrlichiosis (HGE), a rare infectious disease, is caused by a bacterium from the “Ehrlichia” family that has not yet been named. The bacterium, which is carried and transmitted by ticks (vectors), invades certain granular white blood cells (neutrophils) that play a role in engulfing bacteria, removing them from the blood, and destroying them (phagocytosis). In individuals with HGE, the onset of symptoms usually occurs approximately one week after an individual has been bitten by a tick carrying the Ehrlichia bacterium. In almost all cases, symptoms include fever, chills, muscle pain (myalgia), a general feeling of weakness and fatigue (malaise), and/or headaches. Some affected individuals may also experience coughing, nausea, vomiting, and/or confusion. In addition, in many cases, certain abnormal laboratory findings may occur including an abnormal increase in the level of certain liver enzymes (hepatic transaminases), an abnormal decrease in circulating blood platelets (thrombocytopenia), anemia, and/or a decrease in certain white blood cells (granulocytopenia). In some severe cases, if Human Granulocytic Ehrlichiosis is left untreated, life-threatening symptoms, such as kidney failure and respiratory insufficiency, may result. Most cases have affected individuals in the Northeastern and Midwestern United States. (For more information on this disorder, choose “Human Granulocytic Ehrlichiosis” as your search term in the Rare Disease Database.)Sennetsu Fever, a rare infectious disease that also belongs to the Human Ehrlichioses, is caused by the bacterium known as Ehrlichia sennetsu. The symptoms of Sennetsu Fever may include a sudden high fever, headache, and muscle aches (myalgia) within a few weeks after initial infection. Some affected individuals may also experience nausea, vomiting, and/or loss of appetite (anorexia). In addition, in many cases, abnormal laboratory findings may occur including a decrease in white blood cells (leukopenia) and/or an abnormal increase in the level of certain liver enzymes (hepatic transaminases). The vector (or carrier) for the E. sennetsu bacterium has not yet been determined; however, some researchers believe that infection may result from ingestion of raw fish. Reported cases of Sennetsu Fever appear to be limited to Western Japan and Malaysia. (For more information on this disease, choose “Sennetsu” as your search term in the Rare Disease Database.)The most recently identified form of Human Ehrlichiosis has been reported in four individuals in Missouri, all of whom experienced tick exposure several days prior to symptom onset. Based upon certain specialized laboratory tests, the four individuals tested positive for Ehrlichial infection yet negative for all known human forms of the disease (e.g., HME, HGE). Further tests revealed that the infection was caused by Ehrlichia ewingii, a bacterium that was previously thought only to cause Ehrlichial infection in dogs (Canine Granulocytic Ehrlichiosis). The researchers indicated that there is no evidence of direct disease transmission from dogs to humans. Rather, humans and dogs both appear to be hosts to the same tick vectors. Associated symptoms typically include fever, headache, joint and muscle pain, and a general feeling of ill health (malaise). In addition, as with other forms of Human Ehrlichiosis, abnormal laboratory findings may also be present, such as abnormally low levels of circulating platelets (thrombocytopenia) and a decrease in the level of white blood cells (leukopenia). Three of the four individuals with this form of Ehrlichiosis had been receiving therapy with medications that suppress the activities of the immune system (immunosuppressants). It is unclear whether infection with the E. ewingii bacterium usually does not affect individuals with sufficient immune system functioning (immunocompetence) or results in mild or no apparent symptoms (asymptomatic) in such cases. Therefore, the implications of such findings are not yet understood. All individuals with this form of Human Ehrlichiosis responded to treatment with the antibiotic doxycycline. (For more information on Human Ehrlichiosis treatment, please see the “Standard Therapies” section of this report below.)Lyme Disease is an infectious disorder caused by the spirochete bacterium Borrelia burgdorferi. The bacterium is carried and transmitted by deer ticks (Ixodes dammini). In most cases, Lyme Disease is first characterized by the appearance of a red skin lesion (erythema chronicum migrans), which begins as a small elevated round spot (papule) that expands to at least five centimeters in diameter. Symptoms may then progress to include low-grade fever, chills, muscle aches (myalgia), headache, a general feeling of weakness and fatigue (malaise), and/or pain and stiffness of the large joints (infectious arthritis), especially in the knees. Such symptoms may tend to occur in recurrent cycles. In severe cases, heart muscle (myocardial) and/or neurologic abnormalities may occur. Most cases of Lyme Disease occur in the northeastern United States. However, cases have occurred in other areas of the U.S. as well as other countries including China, Japan, Australia, and several countries in Europe. (For more information on this disorder, choose “Lyme” as your search term in the Rare Disease Database.)Babesiosis is a group of infectious diseases caused by single-celled microorganisms (protozoa) belonging to the “Babesia” family. It is believed that the Babesia protozoa are usually carried and transmitted by ticks (vectors). Babesiosis occurs primarily in animals; however, in rare cases, Babesiosis infection may occur in humans. Certain Babesia species are known to cause Babesiosis infection in humans (i.e., Babesia microti), and the deer tick (Ixodes dammini) is a known vector. Human Babesiosis infection may cause fever, chills, headache, nausea, vomiting, and/or muscle aches (myalgia). Additional features may include premature destruction of red blood cells (hemolytic anemia), an abnormal decrease in circulating blood platelets (thrombocytopenia) and white blood cells (leukopenia), and/or an enlarged spleen (splenomegaly). Symptoms may be mild in otherwise healthy people; some infected individuals may exhibit no symptoms (asymptomatic). A severe form of Babesiosis, which can be life-threatening if untreated, can occur in people who have had their spleens removed (splenectomized) or who have an impaired immune system. In the United States, Babesiosis is most common in the northeastern states. In rare cases, Babesiosis may occur in Europe. (For more information on this disorder, choose “Babesiosis” as your search term in the Rare Disease Database.)Rocky Mountain Spotted Fever is a rare infectious disorder caused by the bacterium Rickettsia rickettsii. The bacterium is carried and transmitted by tick vectors, such as the Lone Star tick (Amblyomma americanum) and the American dog tick (Dermacentor variabilis), which are also known vectors for Human Monocytic Ehrlichiosis. Rocky Mountain Spotted Fever is characterized by severe headache, high fever, chills, muscle aches (myalgia), and/or confusion. In most cases, a skin rash may appear approximately two to six days after tick exposure; the rash may first appear on the palms, wrists, soles, ankles, and forearms, later spreading to the face, trunk, and lower arms and legs. Some affected individuals may also experience nausea, vomiting, and/or abdominal pain. In some cases, without early diagnosis and appropriate treatment, symptoms may become life-threatening. Rocky Mountain Spotted Fever characteristically occurs in outbreaks in various areas of the Midwestern, Eastern, and Southeastern United States. (For more information on this disorder, choose “Rocky Mountain Spotted Fever” as your search term in the Rare Disease Database.)Meningococcal disease is an infectious disease caused by the bacterium Neisseria meningitidis in the bloodstream. The symptoms associated with meningococcal disease may vary greatly from case to case, with associated findings ranging from a short fever and upper respiratory illness to sudden, severe infection with potentially life-threatening complications. In some cases, affected individuals may progress from one manifestation to another. In some individuals with meningococcal disease, symptoms may include fever, chills, headache, generalized weakness, a general feeling of ill health (malaise), and/or low blood pressure (hypotension). Many affected individuals may also have areas of abnormal bleeding (hemorrhage) within skin layers, causing the appearance of small purplish spots on the skin (petechia). In addition, in those with meningococcal disease, laboratory findings may include abnormally elevated levels of white cells in the blood (lymphocytosis). In some severe cases, affected individuals may experience inflammation of the protective membranes covering the brain and spinal cord (meningococcal meningitis). Associated symptoms may include the sudden onset of severe fever, chills, nausea, vomiting, and/or stiff neck, followed by confusion, drowsiness, and loss of consciousness. In such cases, life-threatening complications may result without immediate, appropriate treatment. (For more information on this disease, choose “Meningococcemia” or “Meningitis, Meningococcal” as your search term in the Rare Disease Database.) There are other infectious disorders that may be characterized by sudden high fever (febrile disorders), headache, myalgia, nausea, vomiting, thrombocytopenia, leukopenia, and/or other symptoms associated with Human Monocytic Ehrlichiosis. (For more information on these disorders, choose the exact disease name in question as your search term in the Rare Disease Database.)
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Diagnosis of Human Monocytic Ehrlichiosis (HME)
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Human Monocytic Ehrlichiosis (HME) may be diagnosed based upon a thorough clinical evaluation, characteristic findings, and specialized laboratory tests. Blood tests may reveal findings often associated with the Human Ehrlichioses such as abnormally low levels of blood platelets (thrombocytopenia), low levels of certain white blood cells (leukopenia), and/or elevated levels of certain liver enzymes (such as aspartate aminotransferase [AST] and alanine aminotransferase [ALT]). In some cases, laboratory tests may reveal abnormalities of the cerebrospinal fluid. In addition, chest X-rays may reveal abnormalities in the lungs (e.g., pulmonary infiltrates, increased fluid in the lungs).Examination of blood smears under a microscope that uses an electron beam (electron microscopy) may reveal clusters of bacteria in membrane-bound cavities (vacuoles) within certain cells (e.g., monocytes); however, such clusters may not be apparent early in the course of infection. In some cases, additional specialized laboratory tests may then be conducted to help determine and/or to confirm a diagnosis of a specific bacterial infection.Specialized laboratory tests may include Indirect Immunofluorescence Assays (IFA) conducted on the fluid portion of an affected individual's blood (serum). Antibodies, which are proteins manufactured by certain white blood cells, help the body fight toxins and invading microorganisms. In Indirect Immunofluorescence Assays, human antibodies are marked with special fluorescent dyes and a microscope with ultraviolet light is used, enabling researchers to observe antibody response to certain microorganisms.IFA testing has been used in confirming a diagnosis of all known types of Human Ehrlichial infection. However, in Human Monocytic Ehrlichiosis (HME), the bacterium responsible for the infection (Ehrlichia chaffeensis) was not characterized and identified (isolated) until 1991. Therefore, for many years, HME infection was diagnosed by observing the antibody response in a patient's blood serum to the bacterium responsible for Canine Ehrlichiosis, Ehrlichia canis, a bacterium that is very genetically similar to E. chaffeensis. Since E. chaffeensis was isolated in 1991, cases of HME have been confirmed by IFA testing that measures antibody response either to E. chaffeensis itself or the closely-related E. canis.Measurable diagnostic rises in antibody response to the Ehrlichia bacteria may not occur until approximately three weeks after the onset of Human Monocytic Ehrlichiosis. As a result, initial IFA blood serum results may be negative in some cases. Therefore, more sensitive testing techniques that can help establish early diagnosis may be used in some cases.One such process, called Polymerase Chain Reaction (PCR), is a laboratory technique in which sequences of DNA (which contains the organism's genetic information) can be copied over and over again quickly. This enables close analysis of the DNA, aiding in the identification of the organism in question. PCR conducted on certain bacterial DNA sequences obtained from patients' blood samples may confirm Human Ehrlichial infection due to a particular strain of Ehrlichia. PCR has been used to establish an early diagnosis of Human Ehrlichial infection in some cases of HME.The information in the medical literature indicates that because it may be difficult to differentiate Human Ehrlichial infection, such as Human Monocytic Ehrlichiosis, from other illnesses that are also characterized by high fever (febrile illnesses), Ehrlichiosis should be considered in any patient with high fever, thrombocytopenia, and leukopenia who has recently been exposed to ticks. In addition, HME should be considered in individuals with high fever, severe headache, and neurologic symptoms, particularly in areas where HME infection is known to occur and during peak seasons for such infection.If HME is suspected, treatment should not be delayed until diagnosis has been confirmed by IFA testing, since a positive antibody response may not occur until several weeks after initial infection. Therapy should begin as soon as possible after the onset of symptoms.
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Diagnosis of Human Monocytic Ehrlichiosis (HME). Human Monocytic Ehrlichiosis (HME) may be diagnosed based upon a thorough clinical evaluation, characteristic findings, and specialized laboratory tests. Blood tests may reveal findings often associated with the Human Ehrlichioses such as abnormally low levels of blood platelets (thrombocytopenia), low levels of certain white blood cells (leukopenia), and/or elevated levels of certain liver enzymes (such as aspartate aminotransferase [AST] and alanine aminotransferase [ALT]). In some cases, laboratory tests may reveal abnormalities of the cerebrospinal fluid. In addition, chest X-rays may reveal abnormalities in the lungs (e.g., pulmonary infiltrates, increased fluid in the lungs).Examination of blood smears under a microscope that uses an electron beam (electron microscopy) may reveal clusters of bacteria in membrane-bound cavities (vacuoles) within certain cells (e.g., monocytes); however, such clusters may not be apparent early in the course of infection. In some cases, additional specialized laboratory tests may then be conducted to help determine and/or to confirm a diagnosis of a specific bacterial infection.Specialized laboratory tests may include Indirect Immunofluorescence Assays (IFA) conducted on the fluid portion of an affected individual's blood (serum). Antibodies, which are proteins manufactured by certain white blood cells, help the body fight toxins and invading microorganisms. In Indirect Immunofluorescence Assays, human antibodies are marked with special fluorescent dyes and a microscope with ultraviolet light is used, enabling researchers to observe antibody response to certain microorganisms.IFA testing has been used in confirming a diagnosis of all known types of Human Ehrlichial infection. However, in Human Monocytic Ehrlichiosis (HME), the bacterium responsible for the infection (Ehrlichia chaffeensis) was not characterized and identified (isolated) until 1991. Therefore, for many years, HME infection was diagnosed by observing the antibody response in a patient's blood serum to the bacterium responsible for Canine Ehrlichiosis, Ehrlichia canis, a bacterium that is very genetically similar to E. chaffeensis. Since E. chaffeensis was isolated in 1991, cases of HME have been confirmed by IFA testing that measures antibody response either to E. chaffeensis itself or the closely-related E. canis.Measurable diagnostic rises in antibody response to the Ehrlichia bacteria may not occur until approximately three weeks after the onset of Human Monocytic Ehrlichiosis. As a result, initial IFA blood serum results may be negative in some cases. Therefore, more sensitive testing techniques that can help establish early diagnosis may be used in some cases.One such process, called Polymerase Chain Reaction (PCR), is a laboratory technique in which sequences of DNA (which contains the organism's genetic information) can be copied over and over again quickly. This enables close analysis of the DNA, aiding in the identification of the organism in question. PCR conducted on certain bacterial DNA sequences obtained from patients' blood samples may confirm Human Ehrlichial infection due to a particular strain of Ehrlichia. PCR has been used to establish an early diagnosis of Human Ehrlichial infection in some cases of HME.The information in the medical literature indicates that because it may be difficult to differentiate Human Ehrlichial infection, such as Human Monocytic Ehrlichiosis, from other illnesses that are also characterized by high fever (febrile illnesses), Ehrlichiosis should be considered in any patient with high fever, thrombocytopenia, and leukopenia who has recently been exposed to ticks. In addition, HME should be considered in individuals with high fever, severe headache, and neurologic symptoms, particularly in areas where HME infection is known to occur and during peak seasons for such infection.If HME is suspected, treatment should not be delayed until diagnosis has been confirmed by IFA testing, since a positive antibody response may not occur until several weeks after initial infection. Therapy should begin as soon as possible after the onset of symptoms.
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Therapies of Human Monocytic Ehrlichiosis (HME)
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TreatmentThe treatment of Human Monocytic Ehrlichiosis usually entails standard doses of tetracycline antibiotics. Alternatively, doxycycline therapy may be administered. In severe cases of HME infection, hospitalization may be required. Other treatment is symptomatic and supportive.PreventionIndividuals in geographic areas who risk exposure to tick vectors for Ehrlichial infection should consider taking certain steps to prevent infection. Such steps should include wearing long-sleeved shirts, long pants, and hats; wearing light-colored clothing to make ticks more visible; using insect repellents; and carefully checking their clothing and skin (particularly the scalp and the back of the neck) after being in fields or wooded areas.
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Therapies of Human Monocytic Ehrlichiosis (HME). TreatmentThe treatment of Human Monocytic Ehrlichiosis usually entails standard doses of tetracycline antibiotics. Alternatively, doxycycline therapy may be administered. In severe cases of HME infection, hospitalization may be required. Other treatment is symptomatic and supportive.PreventionIndividuals in geographic areas who risk exposure to tick vectors for Ehrlichial infection should consider taking certain steps to prevent infection. Such steps should include wearing long-sleeved shirts, long pants, and hats; wearing light-colored clothing to make ticks more visible; using insect repellents; and carefully checking their clothing and skin (particularly the scalp and the back of the neck) after being in fields or wooded areas.
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Overview of Huntington’s Disease
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Huntington's disease is a genetic, progressive, neurodegenerative disorder characterized by the gradual development of involuntary muscle movements affecting the hands, feet, face, and trunk and progressive deterioration of cognitive processes and memory (dementia). Neurologic movement abnormalities may include uncontrolled, irregular, rapid, jerky movements (chorea) and athetosis, a condition characterized by relatively slow, writhing involuntary movements. Dementia is typically associated with progressive disorientation and confusion, personality disintegration, impairment of memory control, restlessness, agitation, and other symptoms and findings. In individuals with the disorder, disease duration may range from approximately 10 years up to 25 years or more. Life-threatening complications may result from pneumonia or other infections, injuries related to falls, or other associated developments.Huntington's disease is transmitted as an autosomal dominant trait. The disease results from changes (mutations) of a gene known as “huntington” located on the short arm (p) of chromosome 4 (4p16.3). In those with the disorder, the huntington gene contains errors in the coded “building blocks” (nucleotide bases) that make up the gene's instructions. The gene contains abnormally long repeats of coded instructions consisting of the basic chemicals cytosine, adenine, and guanine (CAG trinucleotide repeat expansion). The length of the expanded repeats may affect the age at symptom onset. The specific symptoms and physical features associated with Huntington's disease result from degeneration of nerve cells (neurons) within certain areas of the brain (e.g., basal ganglia, cerebral cortex).
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Overview of Huntington’s Disease. Huntington's disease is a genetic, progressive, neurodegenerative disorder characterized by the gradual development of involuntary muscle movements affecting the hands, feet, face, and trunk and progressive deterioration of cognitive processes and memory (dementia). Neurologic movement abnormalities may include uncontrolled, irregular, rapid, jerky movements (chorea) and athetosis, a condition characterized by relatively slow, writhing involuntary movements. Dementia is typically associated with progressive disorientation and confusion, personality disintegration, impairment of memory control, restlessness, agitation, and other symptoms and findings. In individuals with the disorder, disease duration may range from approximately 10 years up to 25 years or more. Life-threatening complications may result from pneumonia or other infections, injuries related to falls, or other associated developments.Huntington's disease is transmitted as an autosomal dominant trait. The disease results from changes (mutations) of a gene known as “huntington” located on the short arm (p) of chromosome 4 (4p16.3). In those with the disorder, the huntington gene contains errors in the coded “building blocks” (nucleotide bases) that make up the gene's instructions. The gene contains abnormally long repeats of coded instructions consisting of the basic chemicals cytosine, adenine, and guanine (CAG trinucleotide repeat expansion). The length of the expanded repeats may affect the age at symptom onset. The specific symptoms and physical features associated with Huntington's disease result from degeneration of nerve cells (neurons) within certain areas of the brain (e.g., basal ganglia, cerebral cortex).
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Symptoms of Huntington’s Disease
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Huntington's disease is characterized by rapid uncontrollable muscle movements such as tics or muscle jerks (choreiform movements or chorea). This disorder causes a loss of coordination and personality changes. As the disease progresses, the ability to speak may be impaired, memory may fade, and the involuntary jerky muscle movements (chorea) become more severe.Huntington's disease runs a ten to 25 year progressive course. As the disorder progresses, the chorea may subside and there may be an absence of movement (akinesia). Dementia gradually develops. Patients with Huntington's disease are at high risk of developing pneumonia as a result of being bedridden and undernourished.
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Symptoms of Huntington’s Disease. Huntington's disease is characterized by rapid uncontrollable muscle movements such as tics or muscle jerks (choreiform movements or chorea). This disorder causes a loss of coordination and personality changes. As the disease progresses, the ability to speak may be impaired, memory may fade, and the involuntary jerky muscle movements (chorea) become more severe.Huntington's disease runs a ten to 25 year progressive course. As the disorder progresses, the chorea may subside and there may be an absence of movement (akinesia). Dementia gradually develops. Patients with Huntington's disease are at high risk of developing pneumonia as a result of being bedridden and undernourished.
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Causes of Huntington’s Disease
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Huntington's disease is inherited as an autosomal dominant 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 dominant disorders, a single copy of the disease gene (received from either the mother or father) will be expressed “dominating” the other normal gene and resulting in the appearance of the disease. The risk of transmitting the disorder from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.Huntington's disease is caused by changes (mutations) of a gene that is located on the short arm (p) of chromosome 4 (4p16.3). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q.” Chromosomes are further subdivided into bands that are numbered.Known as huntingtin, the gene controls the production of a protein found in nerve cells (neurons) throughout the brain. However, the specific function of the huntingtin protein is not known. In individuals with the disorder, the huntingtin gene contains errors in the coded “building blocks” that make up its specific genetic instructions. The instructions within every gene consist of different arrangements of four basic chemicals (nucleotide bases) called adenine (A), cytosine (C), guanine (G), and thymine (T). In those with Huntington's Disease, the huntingtin gene contains abnormally long repeats of coded instructions consisting of cytosine, adenine, and guanine (CAG trinucleotide repeat expansion). For example, individuals with the disease have over 35 CAG repeats within the huntingtin gene, with most having more than 39. However, individuals without the disorder tend to have about 20 repeats in the gene. Expanded CAG repeats are unstable and may expand further over time and with successive generations. This is thought to be responsible for genetic anticipation, a phenomenon in which an individual with Huntington's disease may have symptom onset at a significantly earlier age than his or her affected parent. In addition, some researchers suggest that expanded CAG repeats of the huntingtin gene may become more unstable when the gene is transmitted from the father.The specific symptoms associated with Huntington's disease are caused by degenerative changes of nerve cells (neurons) within certain regions of the brain, including the basal ganglia and cerebral cortex. The basal ganglia are specialized nerve cells deep within the brain that play a role in regulating movements. The cerebral cortex, the outer region of the brain, is responsible for conscious thought and movement.
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Causes of Huntington’s Disease. Huntington's disease is inherited as an autosomal dominant 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 dominant disorders, a single copy of the disease gene (received from either the mother or father) will be expressed “dominating” the other normal gene and resulting in the appearance of the disease. The risk of transmitting the disorder from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.Huntington's disease is caused by changes (mutations) of a gene that is located on the short arm (p) of chromosome 4 (4p16.3). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q.” Chromosomes are further subdivided into bands that are numbered.Known as huntingtin, the gene controls the production of a protein found in nerve cells (neurons) throughout the brain. However, the specific function of the huntingtin protein is not known. In individuals with the disorder, the huntingtin gene contains errors in the coded “building blocks” that make up its specific genetic instructions. The instructions within every gene consist of different arrangements of four basic chemicals (nucleotide bases) called adenine (A), cytosine (C), guanine (G), and thymine (T). In those with Huntington's Disease, the huntingtin gene contains abnormally long repeats of coded instructions consisting of cytosine, adenine, and guanine (CAG trinucleotide repeat expansion). For example, individuals with the disease have over 35 CAG repeats within the huntingtin gene, with most having more than 39. However, individuals without the disorder tend to have about 20 repeats in the gene. Expanded CAG repeats are unstable and may expand further over time and with successive generations. This is thought to be responsible for genetic anticipation, a phenomenon in which an individual with Huntington's disease may have symptom onset at a significantly earlier age than his or her affected parent. In addition, some researchers suggest that expanded CAG repeats of the huntingtin gene may become more unstable when the gene is transmitted from the father.The specific symptoms associated with Huntington's disease are caused by degenerative changes of nerve cells (neurons) within certain regions of the brain, including the basal ganglia and cerebral cortex. The basal ganglia are specialized nerve cells deep within the brain that play a role in regulating movements. The cerebral cortex, the outer region of the brain, is responsible for conscious thought and movement.
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Affects of Huntington’s Disease
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About 30,000 people in the United States have Huntington's disease and another 200,000 are at risk of developing the condition. Symptoms commonly develop between ages 30 and 50. The disease progresses slowly and a person may live for another 15-20 years after the onset of symptoms.
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Affects of Huntington’s Disease. About 30,000 people in the United States have Huntington's disease and another 200,000 are at risk of developing the condition. Symptoms commonly develop between ages 30 and 50. The disease progresses slowly and a person may live for another 15-20 years after the onset of symptoms.
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Related disorders of Huntington’s Disease
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Symptoms of the following disorders can be similar to those of Huntington's disease. Comparisons may be useful for a differential diagnosis:Hallervorden-Spatz disease is a rare progressive disorder that affects muscle movement. It is associated with the degeneration of the nervous system. Hallervorden-Spatz Disease is characterized by uncontrolled muscle movements (dystonia), muscular rigidity, and the loss of cognitive abilities (dementia). The symptoms of this disease typically begin during childhood, although occasionally the disease begins in adulthood. Approximately one-third of people with Hallervorden-Spatz disease experience sudden jerky muscle movements. Other less frequent symptoms may include joint pain (dysarthria), mental retardation, facial grimacing, impaired speech (dysphasia), and impaired vision. (For more information on this disorder, choose “Hallervorden-Spatz” as your search term in the Rare Disease Database.)Multiple system atrophy (MSA) is a group of rare inherited disorders that are characterized by the progressive degeneration of the cerebellar cortex and other brain tissue. Several different types of multiple system atrophy have been identified, the symptoms of which vary widely depending on the MSA type present. Generally, these disorders are characterized by an impaired ability to coordinate muscle movement, tremors, involuntary jerky muscle movements, impaired speech (dysphasia), loss of cognitive abilities, and mental deterioration. A wide variety in severity and age of onset may be found in all types of MSA. (For more information on the disorders which make up MSA, choose “Multiple System Atrophy” as your search term in the Rare Disease Database.)Sydenham's chorea is a disorder of the nervous system that begins abruptly after a streptococcal infection such as strep throat or rheumatic fever. This disorder usually affects young children and adolescents. Sydenham's chorea is characterized by rapid, involuntary, non-repetitive muscle movements that may gradually become more severe and frequent. The muscles of the arms and legs are usually most affected. Speech may also be impaired. Other common symptoms may include clumsiness and facial grimacing. Chorea-like muscle movements tend to disappear with sleep. This disorder usually subsides in 3 to 6 months with no permanent neurological or muscle damage. (For more information on this disorder, choose “Sydenham” as your search term in the Rare Disease Database.)Wilson's disease is a rare genetic disorder characterized by excess copper stored in various body tissues, particularly the liver, brain, and corneas of the eyes. The disease is progressive and, if left untreated, it may cause liver (hepatic) disease, central nervous system dysfunction, and death. Early diagnosis and treatment may prevent serious long-term disability and life threatening complications. Treatment is aimed at reducing the amount of copper that has accumulated in the body and maintaining normal copper levels thereafter. (For more information on this disorder, choose “Wilson” as your search term in the Rare Disease Database.)Tourette syndrome is a neurological movement disorder that usually first appears between the ages of two and 16 years. Initial symptoms are often rapid eye blinking or facial grimaces, but many parts of the body may be affected. Symptoms wax and wane, with new symptoms replacing old ones that have disappeared. Tourette syndrome is not progressive nor degenerative, and patients live a normal life span. Muscle and vocal tics characterize this disorder. (For more information on this disorder, choose “Tourette” as your search term in the Rare Disease Database.)Dentatorubral-Pallidoluysian atrophy (DRPLA) is another spino-cerebellar degenerative disease the cause of which is linked to an abnormally high number of nucleotide repeats in the patient's DNA. The characteristics of DRPLA include shock-like epileptic contractions (myoclonic epilepsy) usually limited to the upper extremities of one side of the body (pallidoluysian); slow, continuous, sinuous motion of the arms and/or hands (choreoathetosis); uncontrollable, irregular, uncoordinated, muscle actions (ataxia); and dementia. Age of onset is usually in the patient's twenties, and inheritance is autosomal dominant. The disorder has been traced to a gene located at 16q24.3. Huntington's disease-like 2 (HDL-2) is an autosomal dominant disorder remarkably like Huntington's disease but characterized by a different trinucleotide repeat. Onset typically occurs in the fourth decade, with involuntary movements and abnormalities of voluntary movements, as well as dementia. This disorder was described based on the experiences of one family and, except for lower frequency of eye-movement and the absence of seizures, it is similar to juvenile-onset Huntington's disease. The gene has been traced to a site at 16q24.3 that is known as the JPH3 gene or junctophilin gene.
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Related disorders of Huntington’s Disease. Symptoms of the following disorders can be similar to those of Huntington's disease. Comparisons may be useful for a differential diagnosis:Hallervorden-Spatz disease is a rare progressive disorder that affects muscle movement. It is associated with the degeneration of the nervous system. Hallervorden-Spatz Disease is characterized by uncontrolled muscle movements (dystonia), muscular rigidity, and the loss of cognitive abilities (dementia). The symptoms of this disease typically begin during childhood, although occasionally the disease begins in adulthood. Approximately one-third of people with Hallervorden-Spatz disease experience sudden jerky muscle movements. Other less frequent symptoms may include joint pain (dysarthria), mental retardation, facial grimacing, impaired speech (dysphasia), and impaired vision. (For more information on this disorder, choose “Hallervorden-Spatz” as your search term in the Rare Disease Database.)Multiple system atrophy (MSA) is a group of rare inherited disorders that are characterized by the progressive degeneration of the cerebellar cortex and other brain tissue. Several different types of multiple system atrophy have been identified, the symptoms of which vary widely depending on the MSA type present. Generally, these disorders are characterized by an impaired ability to coordinate muscle movement, tremors, involuntary jerky muscle movements, impaired speech (dysphasia), loss of cognitive abilities, and mental deterioration. A wide variety in severity and age of onset may be found in all types of MSA. (For more information on the disorders which make up MSA, choose “Multiple System Atrophy” as your search term in the Rare Disease Database.)Sydenham's chorea is a disorder of the nervous system that begins abruptly after a streptococcal infection such as strep throat or rheumatic fever. This disorder usually affects young children and adolescents. Sydenham's chorea is characterized by rapid, involuntary, non-repetitive muscle movements that may gradually become more severe and frequent. The muscles of the arms and legs are usually most affected. Speech may also be impaired. Other common symptoms may include clumsiness and facial grimacing. Chorea-like muscle movements tend to disappear with sleep. This disorder usually subsides in 3 to 6 months with no permanent neurological or muscle damage. (For more information on this disorder, choose “Sydenham” as your search term in the Rare Disease Database.)Wilson's disease is a rare genetic disorder characterized by excess copper stored in various body tissues, particularly the liver, brain, and corneas of the eyes. The disease is progressive and, if left untreated, it may cause liver (hepatic) disease, central nervous system dysfunction, and death. Early diagnosis and treatment may prevent serious long-term disability and life threatening complications. Treatment is aimed at reducing the amount of copper that has accumulated in the body and maintaining normal copper levels thereafter. (For more information on this disorder, choose “Wilson” as your search term in the Rare Disease Database.)Tourette syndrome is a neurological movement disorder that usually first appears between the ages of two and 16 years. Initial symptoms are often rapid eye blinking or facial grimaces, but many parts of the body may be affected. Symptoms wax and wane, with new symptoms replacing old ones that have disappeared. Tourette syndrome is not progressive nor degenerative, and patients live a normal life span. Muscle and vocal tics characterize this disorder. (For more information on this disorder, choose “Tourette” as your search term in the Rare Disease Database.)Dentatorubral-Pallidoluysian atrophy (DRPLA) is another spino-cerebellar degenerative disease the cause of which is linked to an abnormally high number of nucleotide repeats in the patient's DNA. The characteristics of DRPLA include shock-like epileptic contractions (myoclonic epilepsy) usually limited to the upper extremities of one side of the body (pallidoluysian); slow, continuous, sinuous motion of the arms and/or hands (choreoathetosis); uncontrollable, irregular, uncoordinated, muscle actions (ataxia); and dementia. Age of onset is usually in the patient's twenties, and inheritance is autosomal dominant. The disorder has been traced to a gene located at 16q24.3. Huntington's disease-like 2 (HDL-2) is an autosomal dominant disorder remarkably like Huntington's disease but characterized by a different trinucleotide repeat. Onset typically occurs in the fourth decade, with involuntary movements and abnormalities of voluntary movements, as well as dementia. This disorder was described based on the experiences of one family and, except for lower frequency of eye-movement and the absence of seizures, it is similar to juvenile-onset Huntington's disease. The gene has been traced to a site at 16q24.3 that is known as the JPH3 gene or junctophilin gene.
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Diagnosis of Huntington’s Disease
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The diagnosis of Huntington's disease may be confirmed by a thorough clinical evaluation, detailed patient history, and a variety of specialized tests. Specialized x-ray studies such as computerized tomography (CT) scanning, magnetic resonance imaging (MRI), or electroencephalography (EEG) may help confirm the diagnosis of Huntington's Disease. During CT scanning, a computer and x-rays are used to create a file showing cross-sectional images of the brain. During MRI, a magnetic field and radio waves are used to create cross-sectional images of the brain. During an EEG, an instrument records electrical activity of the brain. Neuropsychological and/or genetic tests are also used to aid the diagnosis of Huntington's disease.
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Diagnosis of Huntington’s Disease. The diagnosis of Huntington's disease may be confirmed by a thorough clinical evaluation, detailed patient history, and a variety of specialized tests. Specialized x-ray studies such as computerized tomography (CT) scanning, magnetic resonance imaging (MRI), or electroencephalography (EEG) may help confirm the diagnosis of Huntington's Disease. During CT scanning, a computer and x-rays are used to create a file showing cross-sectional images of the brain. During MRI, a magnetic field and radio waves are used to create cross-sectional images of the brain. During an EEG, an instrument records electrical activity of the brain. Neuropsychological and/or genetic tests are also used to aid the diagnosis of Huntington's disease.
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Therapies of Huntington’s Disease
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TreatmentIn August 2008, the Food and Drug Administration (FDA) approved tetrabenazine (Xenazine) for the treatment of the repetitive, involuntary movements (chorea. associated with Huntington's disease. This is the first and only FDA-approved treatment specifically for any symptom of HD. Prestwick Pharmaceuticals, Inc., of Washington, DC, is the U.S. manufacturer of tetrabenezine. The drug has been available in Europe for several years.Other treatment for Huntington's disease is symptomatic and supportive. There are some treatments that may alleviate various symptoms temporarily. Neuroleptic medication such as haloperidon can partially suppress the involuntary movement, especially in the early stages. Other medication can often help depression and other emotional symptoms. Special high calorie food preparations may help an affected individual maintain weight and avoid choking during the later stages of Huntington's disease.Genetic counseling will be of benefit for affected individuals and their families. Family members of affected individuals should also receive clinical evaluations to detect any symptoms and physical characteristics that may be potentially associated with Huntington's disease.
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Therapies of Huntington’s Disease. TreatmentIn August 2008, the Food and Drug Administration (FDA) approved tetrabenazine (Xenazine) for the treatment of the repetitive, involuntary movements (chorea. associated with Huntington's disease. This is the first and only FDA-approved treatment specifically for any symptom of HD. Prestwick Pharmaceuticals, Inc., of Washington, DC, is the U.S. manufacturer of tetrabenezine. The drug has been available in Europe for several years.Other treatment for Huntington's disease is symptomatic and supportive. There are some treatments that may alleviate various symptoms temporarily. Neuroleptic medication such as haloperidon can partially suppress the involuntary movement, especially in the early stages. Other medication can often help depression and other emotional symptoms. Special high calorie food preparations may help an affected individual maintain weight and avoid choking during the later stages of Huntington's disease.Genetic counseling will be of benefit for affected individuals and their families. Family members of affected individuals should also receive clinical evaluations to detect any symptoms and physical characteristics that may be potentially associated with Huntington's disease.
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Overview of Hutchinson-Gilford Progeria Syndrome
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Progeria, or Hutchinson-Gilford progeria syndrome (HGPS), is a rare, fatal, genetic condition of childhood with striking features resembling premature aging. Children with progeria usually have a normal appearance in early infancy. At approximately nine to 24 months of age, affected children begin to experience profound growth delays, resulting in short stature and low weight. They also develop a distinctive facial appearance characterized by a disproportionately small face in comparison to the head; an underdeveloped jaw (micrognathia); malformation and crowding of the teeth; abnormally prominent eyes; a small nose; and a subtle blueness around the mouth. In addition, by the second year of life, the scalp hair, eyebrows, and eyelashes are lost (alopecia), and the scalp hair may be replaced by small, downy, white or blond hairs. Additional characteristic features include generalized atherosclerosis, cardiovascular disease and stroke, hip dislocations, unusually prominent veins of the scalp, loss of the layer of fat beneath the skin (subcutaneous adipose tissue), defects of the nails, joint stiffness, skeletal defects, and/or other abnormalities. Individuals with HGPS develop premature, widespread thickening and loss of elasticity of artery walls (arteriosclerosis), which result in life-threatening complications during childhood, adolescence, or early adulthood. Children with progeria die of heart disease (atherosclerosis) at an average age of 14.5 years. As with any person suffering from heart disease, children with progeria can experience high blood pressure, strokes, angina (chest pain due to poor blood flow to the heart itself), enlarged heart, and heart failure, all conditions associated with aging.Progeria is caused by a change (mutation) in the LMNA gene that codes for the lamin A protein. The lamin A protein is the scaffolding that holds the nucleus of a cell together. Researchers now believe that the defective lamin A protein makes the nucleus unstable. The cellular instability appears to lead to the process of premature aging in progeria.
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Overview of Hutchinson-Gilford Progeria Syndrome. Progeria, or Hutchinson-Gilford progeria syndrome (HGPS), is a rare, fatal, genetic condition of childhood with striking features resembling premature aging. Children with progeria usually have a normal appearance in early infancy. At approximately nine to 24 months of age, affected children begin to experience profound growth delays, resulting in short stature and low weight. They also develop a distinctive facial appearance characterized by a disproportionately small face in comparison to the head; an underdeveloped jaw (micrognathia); malformation and crowding of the teeth; abnormally prominent eyes; a small nose; and a subtle blueness around the mouth. In addition, by the second year of life, the scalp hair, eyebrows, and eyelashes are lost (alopecia), and the scalp hair may be replaced by small, downy, white or blond hairs. Additional characteristic features include generalized atherosclerosis, cardiovascular disease and stroke, hip dislocations, unusually prominent veins of the scalp, loss of the layer of fat beneath the skin (subcutaneous adipose tissue), defects of the nails, joint stiffness, skeletal defects, and/or other abnormalities. Individuals with HGPS develop premature, widespread thickening and loss of elasticity of artery walls (arteriosclerosis), which result in life-threatening complications during childhood, adolescence, or early adulthood. Children with progeria die of heart disease (atherosclerosis) at an average age of 14.5 years. As with any person suffering from heart disease, children with progeria can experience high blood pressure, strokes, angina (chest pain due to poor blood flow to the heart itself), enlarged heart, and heart failure, all conditions associated with aging.Progeria is caused by a change (mutation) in the LMNA gene that codes for the lamin A protein. The lamin A protein is the scaffolding that holds the nucleus of a cell together. Researchers now believe that the defective lamin A protein makes the nucleus unstable. The cellular instability appears to lead to the process of premature aging in progeria.
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Symptoms of Hutchinson-Gilford Progeria Syndrome
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Newborns with HGPS may have certain suspicious findings present at birth, such as unusually taut, shiny, hardened (i.e., “scleroderma-like”) skin over the buttocks, upper legs, and lower abdomen; bluish discoloration of the skin and mucous membranes within the mid-portion of the face (midfacial cyanosis); and/or a “sculptured” nose. Profound, progressive growth delay usually becomes evident by approximately 24 months of age, resulting in short stature and weight that remains extremely low for height. Affected children who are 10 years of age typically have a height approximating that of an average three-year-old child.By the second year of life, there is also underdevelopment (hypoplasia) of the facial bones and the lower jaw (micrognathia). The face appears disproportionately small in comparison to the head, and bones of the front and the sides of the skull (cranium) are unusually prominent (frontal and parietal bossing). Affected children typically have additional, characteristic facial features, including a small, thin, potentially pointed nose; unusually prominent eyes; small ears with absent lobes; and thin lips. Dental abnormalities may also be present, such as delayed eruption of the primary (deciduous) and secondary (permanent) teeth; irregularly formed, small, discolored, and/or absent teeth; and/or an unusually increased incidence of tooth decay (dental caries). In addition, abnormal smallness of the jaw may result in dental crowding.The scalp hair becomes sparse and is typically lost (alopecia) by approximately two years of age. Scalp hair may be replaced by fine, downy, white or blond hairs that, in some children, may persist throughout life. In addition, the eyebrows and eyelashes may also be lost during early childhood.HGPS is also characterized by distinctive skin abnormalities. As discussed above, newborns with the disorder may have “scleroderma-like” skin changes over the buttocks, thighs, and lower abdomen. In addition, beginning in infancy, there is a gradual, almost complete loss of the layer of fat beneath the skin (subcutaneous adipose tissue), and veins in certain areas of the body, particularly over the scalp and thighs, become abnormally prominent. The skin acquires an abnormally aged appearance with areas that are unusually thin, dry, and wrinkled and/or unusually shiny and taut. In addition, brownish skin blotches may tend to develop with increasing age over sun-exposed areas of the skin. Affected children also typically have defects of the nails, such as fingernails and toenails that are yellowish, thin, brittle, curved, and/or absent.Children with HGPS also have distinctive skeletal defects. These may include delayed closure of the “soft spot” at the front of the skull (anterior fontanelle), an abnormally thin “dome-like” portion of the skull (calvaria), and/or absence of certain air-filled cavities within the skull that open into the nose (paranasal or frontal sinuses). Affected children may also have short, thin collarbones (clavicles); narrow shoulders; thin ribs; and a narrow or “pear-shaped” chest (pyriform thorax) with a prominent abdomen. In addition, the long bones of the arms and legs may appear unusually thin and fragile and be prone to fractures, particularly the bones of the upper arms (humeri).In many children with HGPS, skeletal abnormalities include degenerative changes (osteolysis) that may affect the collarbones (clavicles); bones of the ends of the fingers (terminal phalanges), causing the fingers to appear unusually short and “tapered”; and/or the hip socket (acetabulum). Degenerative changes of the hip socket may result in a hip deformity in which there is an abnormal increase in the angle of the thigh bone (coxa valga), hip pain and hip dislocation. Many affected children have abnormal fibrous tissue that forms progressively around certain joints (periarticular fibrosis), such as those of the hands, feet, knees, elbows, and spine, causing unusual prominence, stiffness, and limited movement of affected joints. Due to stiffness of the knees, progressive hip deformity (coxa valga), and other associated musculoskeletal abnormalities, children with the disorder tend to have a characteristic, widely based, “horse-riding stance” and a shuffling manner of walking (gait). The disorder is also associated with generalized loss of bone density (osteoporosis), a condition that may cause or contribute to repeated fractures following minor trauma.Additional symptoms and findings may also be associated with HGPS. These may include a distinctive, high-pitched voice; absence of the breast or nipple; absence of sexual maturation; hearing impairment; and/or other abnormalities.Affected children as young as five years of age may develop widespread thickening and loss of elasticity of artery walls (arteriosclerosis). Such changes may be most evident in particular blood vessels, such as the arteries that transport oxygen-rich blood to heart muscle (coronary arteries) and the major artery of the body (aorta).Additional findings may include enlargement of the heart (cardiomegaly) and abnormal heart sounds (i.e., as heard during a physician’s examination with a stethoscope) due to altered blood flow through valves or chambers of the heart (cardiac murmurs). During childhood or adolescence, progressive arteriosclerosis may lead to episodes of chest pain due to deficient oxygen supply to heart muscle (anginal attacks); obstructed blood flow within blood vessels of the brain (cerebrovascular occlusion); progressive inability of the heart to effectively pump blood to the lungs and the rest of the body (heart failure); and/or localized loss of heart muscle caused by interruption of its blood supply (myocardial infarction or heart attack). Progressive arteriosclerosis and associated cardiovascular abnormalities may result in potentially life-threatening complications during childhood, adolescence, or young adulthood.
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Symptoms of Hutchinson-Gilford Progeria Syndrome. Newborns with HGPS may have certain suspicious findings present at birth, such as unusually taut, shiny, hardened (i.e., “scleroderma-like”) skin over the buttocks, upper legs, and lower abdomen; bluish discoloration of the skin and mucous membranes within the mid-portion of the face (midfacial cyanosis); and/or a “sculptured” nose. Profound, progressive growth delay usually becomes evident by approximately 24 months of age, resulting in short stature and weight that remains extremely low for height. Affected children who are 10 years of age typically have a height approximating that of an average three-year-old child.By the second year of life, there is also underdevelopment (hypoplasia) of the facial bones and the lower jaw (micrognathia). The face appears disproportionately small in comparison to the head, and bones of the front and the sides of the skull (cranium) are unusually prominent (frontal and parietal bossing). Affected children typically have additional, characteristic facial features, including a small, thin, potentially pointed nose; unusually prominent eyes; small ears with absent lobes; and thin lips. Dental abnormalities may also be present, such as delayed eruption of the primary (deciduous) and secondary (permanent) teeth; irregularly formed, small, discolored, and/or absent teeth; and/or an unusually increased incidence of tooth decay (dental caries). In addition, abnormal smallness of the jaw may result in dental crowding.The scalp hair becomes sparse and is typically lost (alopecia) by approximately two years of age. Scalp hair may be replaced by fine, downy, white or blond hairs that, in some children, may persist throughout life. In addition, the eyebrows and eyelashes may also be lost during early childhood.HGPS is also characterized by distinctive skin abnormalities. As discussed above, newborns with the disorder may have “scleroderma-like” skin changes over the buttocks, thighs, and lower abdomen. In addition, beginning in infancy, there is a gradual, almost complete loss of the layer of fat beneath the skin (subcutaneous adipose tissue), and veins in certain areas of the body, particularly over the scalp and thighs, become abnormally prominent. The skin acquires an abnormally aged appearance with areas that are unusually thin, dry, and wrinkled and/or unusually shiny and taut. In addition, brownish skin blotches may tend to develop with increasing age over sun-exposed areas of the skin. Affected children also typically have defects of the nails, such as fingernails and toenails that are yellowish, thin, brittle, curved, and/or absent.Children with HGPS also have distinctive skeletal defects. These may include delayed closure of the “soft spot” at the front of the skull (anterior fontanelle), an abnormally thin “dome-like” portion of the skull (calvaria), and/or absence of certain air-filled cavities within the skull that open into the nose (paranasal or frontal sinuses). Affected children may also have short, thin collarbones (clavicles); narrow shoulders; thin ribs; and a narrow or “pear-shaped” chest (pyriform thorax) with a prominent abdomen. In addition, the long bones of the arms and legs may appear unusually thin and fragile and be prone to fractures, particularly the bones of the upper arms (humeri).In many children with HGPS, skeletal abnormalities include degenerative changes (osteolysis) that may affect the collarbones (clavicles); bones of the ends of the fingers (terminal phalanges), causing the fingers to appear unusually short and “tapered”; and/or the hip socket (acetabulum). Degenerative changes of the hip socket may result in a hip deformity in which there is an abnormal increase in the angle of the thigh bone (coxa valga), hip pain and hip dislocation. Many affected children have abnormal fibrous tissue that forms progressively around certain joints (periarticular fibrosis), such as those of the hands, feet, knees, elbows, and spine, causing unusual prominence, stiffness, and limited movement of affected joints. Due to stiffness of the knees, progressive hip deformity (coxa valga), and other associated musculoskeletal abnormalities, children with the disorder tend to have a characteristic, widely based, “horse-riding stance” and a shuffling manner of walking (gait). The disorder is also associated with generalized loss of bone density (osteoporosis), a condition that may cause or contribute to repeated fractures following minor trauma.Additional symptoms and findings may also be associated with HGPS. These may include a distinctive, high-pitched voice; absence of the breast or nipple; absence of sexual maturation; hearing impairment; and/or other abnormalities.Affected children as young as five years of age may develop widespread thickening and loss of elasticity of artery walls (arteriosclerosis). Such changes may be most evident in particular blood vessels, such as the arteries that transport oxygen-rich blood to heart muscle (coronary arteries) and the major artery of the body (aorta).Additional findings may include enlargement of the heart (cardiomegaly) and abnormal heart sounds (i.e., as heard during a physician’s examination with a stethoscope) due to altered blood flow through valves or chambers of the heart (cardiac murmurs). During childhood or adolescence, progressive arteriosclerosis may lead to episodes of chest pain due to deficient oxygen supply to heart muscle (anginal attacks); obstructed blood flow within blood vessels of the brain (cerebrovascular occlusion); progressive inability of the heart to effectively pump blood to the lungs and the rest of the body (heart failure); and/or localized loss of heart muscle caused by interruption of its blood supply (myocardial infarction or heart attack). Progressive arteriosclerosis and associated cardiovascular abnormalities may result in potentially life-threatening complications during childhood, adolescence, or young adulthood.
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Causes of Hutchinson-Gilford Progeria Syndrome
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HGPS is caused by a single-letter misspelling in a gene on chromosome 1 that codes for lamin A, a protein that is a key component of the membrane surrounding the cell’s nucleus. The abnormal lamin A protein produced in HGPS is called progerin.HGPS is not usually passed down in families. The gene change is almost always a chance occurrence that is extremely rare. Children with other types of progeroid syndromes which are not HGPS may have diseases that are passed down in families. However, HGPS is due to a sporadic autosomal dominant mutation – sporadic because it is a new change in that family, and dominant because only one copy of the gene needs to be changed in order to have the syndrome. For parents who have never had a child with progeria, the chance of having a child with progeria is 1 in 4 – 8 million. For parents who have already had a child with progeria, the chance of having another affected child is much higher – about 2-3%. This is due to a condition called mosaicism, where a parent has the genetic mutation for progeria in a small proportion of their cells, but does not have progeria.The specific underlying cause of the accelerated aging associated with HGPS is not yet known. Many researchers suggest that the abnormal aging process is due to cumulative cellular damage resulting from ongoing chemical (metabolic) processes within bodily cells. According to this theory, certain compounds called free radicals are produced during chemical reactions in the body. The increasing accumulation of free radicals within bodily tissues is thought to eventually cause damage to cells and impair functioning of cells, ultimately resulting in aging. Certain enzymes (antioxidant enzymes) are believed to play a role in keeping the aging process “in check” by promoting the elimination of damaging free radicals. Enzymes are proteins produced by cells that accelerate the rate of chemical reactions in the body. Some researchers suspect that reduced activity of certain enzymes may play a role in causing accelerated aging in individuals with HGPS. In one study, skin cells (fibroblasts) obtained from individuals with progeria were compared with skin cells from individuals without the disease. In the fibroblasts of people with progeria, the activity levels of certain primary antioxidant enzymes (e.g., gluthathione peroxidase [GPx], catalase [CAT]) were significantly lower than the levels present in healthy fibroblasts. Further research is necessary to determine the implications of these findings.Studies have revealed that progerin is produced at much lower levels by healthy individuals, but it builds up in the coronary arteries over a lifetime as people age. This finding supports the theory that progerin is a contributor to the risk of atherosclerosis in the general population, and merits examination as a potential new marker to help predict heart-disease risk. Researchers have confirmed the link between normal aging, heart disease and progeria, so finding a cure for progeria will not only help these special children, but might also help people who suffer from heart attacks, strokes and other aging-related conditions.
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Causes of Hutchinson-Gilford Progeria Syndrome. HGPS is caused by a single-letter misspelling in a gene on chromosome 1 that codes for lamin A, a protein that is a key component of the membrane surrounding the cell’s nucleus. The abnormal lamin A protein produced in HGPS is called progerin.HGPS is not usually passed down in families. The gene change is almost always a chance occurrence that is extremely rare. Children with other types of progeroid syndromes which are not HGPS may have diseases that are passed down in families. However, HGPS is due to a sporadic autosomal dominant mutation – sporadic because it is a new change in that family, and dominant because only one copy of the gene needs to be changed in order to have the syndrome. For parents who have never had a child with progeria, the chance of having a child with progeria is 1 in 4 – 8 million. For parents who have already had a child with progeria, the chance of having another affected child is much higher – about 2-3%. This is due to a condition called mosaicism, where a parent has the genetic mutation for progeria in a small proportion of their cells, but does not have progeria.The specific underlying cause of the accelerated aging associated with HGPS is not yet known. Many researchers suggest that the abnormal aging process is due to cumulative cellular damage resulting from ongoing chemical (metabolic) processes within bodily cells. According to this theory, certain compounds called free radicals are produced during chemical reactions in the body. The increasing accumulation of free radicals within bodily tissues is thought to eventually cause damage to cells and impair functioning of cells, ultimately resulting in aging. Certain enzymes (antioxidant enzymes) are believed to play a role in keeping the aging process “in check” by promoting the elimination of damaging free radicals. Enzymes are proteins produced by cells that accelerate the rate of chemical reactions in the body. Some researchers suspect that reduced activity of certain enzymes may play a role in causing accelerated aging in individuals with HGPS. In one study, skin cells (fibroblasts) obtained from individuals with progeria were compared with skin cells from individuals without the disease. In the fibroblasts of people with progeria, the activity levels of certain primary antioxidant enzymes (e.g., gluthathione peroxidase [GPx], catalase [CAT]) were significantly lower than the levels present in healthy fibroblasts. Further research is necessary to determine the implications of these findings.Studies have revealed that progerin is produced at much lower levels by healthy individuals, but it builds up in the coronary arteries over a lifetime as people age. This finding supports the theory that progerin is a contributor to the risk of atherosclerosis in the general population, and merits examination as a potential new marker to help predict heart-disease risk. Researchers have confirmed the link between normal aging, heart disease and progeria, so finding a cure for progeria will not only help these special children, but might also help people who suffer from heart attacks, strokes and other aging-related conditions.
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Affects of Hutchinson-Gilford Progeria Syndrome
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HGPS is a rare disorder that appears to affect males and females equally, and all races equally. The disorder was originally described in the medical literature in 1886 (J. Hutchinson) and 1897 (H. Gilford). The prevalence of HGPS is approximately 1 in 20 million, so at any given time, there are approximately 400 children living with progeria worldwide. Two sets of affected identical twins have been reported in the literature. As of December 2020, the Progeria Research Foundation International Progeria Registry has identified a total of 131 children and young adults living with progeria worldwide including 20 living in the US.
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Affects of Hutchinson-Gilford Progeria Syndrome. HGPS is a rare disorder that appears to affect males and females equally, and all races equally. The disorder was originally described in the medical literature in 1886 (J. Hutchinson) and 1897 (H. Gilford). The prevalence of HGPS is approximately 1 in 20 million, so at any given time, there are approximately 400 children living with progeria worldwide. Two sets of affected identical twins have been reported in the literature. As of December 2020, the Progeria Research Foundation International Progeria Registry has identified a total of 131 children and young adults living with progeria worldwide including 20 living in the US.
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Related disorders of Hutchinson-Gilford Progeria Syndrome
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Symptoms of the following disorders can be similar to those of HGPS. Comparisons may be useful for a differential diagnosis:Hallermann-Streiff syndrome is a rare genetic disorder that is primarily characterized by distinctive malformations of the skull and facial (craniofacial) region; sparse hair (hypotrichosis); eye (ocular) abnormalities; dental defects; degenerative skin changes (atrophy), particularly in the scalp and nasal regions; and/or short stature (i.e., dwarfism). Characteristic craniofacial features include a short, broad head (brachycephaly) with an unusually prominent forehead and/or sides of the skull (frontal and/or parietal bossing); a small, underdeveloped lower jaw (hypoplastic mandible); a narrow, highly arched roof of the mouth (palate); and a thin, pinched, tapering nose. Many affected individuals also have clouding of the lenses of the eyes at birth (congenital cataracts); unusually small eyes (microphthalmia); and/or other ocular abnormalities. Dental defects may include the presence of certain teeth at birth (natal teeth) and absence (hypodontia or partial adontia), malformation, and/or improper alignment of teeth. Hallermann-Streiff syndrome appears to occur randomly for unknown reasons (sporadically) and may be the result of a new dominant genetic mutation. (For more information on this disorder, choose “Hallermann-Streiff” as your search term in the Rare Disease Database.)Gottron’s syndrome (acrogeria) is a mild, inherited form of premature aging characterized by abnormally small hands and feet with thin and delicate skin. From infancy on, children with this disorder appear older than their actual age. The skin is unusually thin and parchment-like on the hands and feet. The hands and feet remain abnormally small into adulthood. (For more information on this disorder, choose “Gottron” as your search term in the Rare Disease Database.)Wiedemann-Rautenstrauch syndrome (WRS), also known as neonatal progeroid syndrome, is a very rare genetic disorder characterized by an aged appearance at birth, growth delays before and after birth (prenatal and postnatal growth delay); and deficiency or absence of the layer of fat under the skin (subcutaneous lipoatrophy). Most individuals with WRS have a decreased life expectancy but there are a few individuals who have lived well in to the teens and a few still live in their 20s. WRS is inherited in an autosomal recessive pattern, as several pairs of siblings have been reported in families with unaffected parents. (For more information on this disorder, choose “Wiedemann-Rautenstrauch” as your search term in the Rare Disease Database.)De Barsy syndrome is a rare disorder that is inherited in an autosomal recessive pattern. The main characteristics include degeneration of the elastic tissue in the skin (cutis laxa), involuntary movements of the arms and legs (athetosis), cloudy corneas of the eyes, large prominent ears, and loss of muscle tone. Other symptoms may include unusual flexibility of the small joints, a forehead that protrudes outward (frontal bossing), and/or short stature. The loss of elasticity of the skin leads to an aged wrinkled appearance. Newborn children with this disorder may look like newborns with HGPS. (For more information on this disorder, choose “De Barsy” as your search term in the Rare Disease Database.)Progeroid syndrome with Ehlers-Danlos features is an extremely rare genetic disorder characterized in newborns by a “progeria-like” (progeroid) appearance. The skin may be wrinkled leading to an aged appearance. Other symptoms include sparse eyebrows, scanty eyelashes, multiple birthmarks, and extremely fragile skin which bruises easily. Some children with this disorder may have low-set prominent ears, a receding chin, and/or irregular teeth.
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Related disorders of Hutchinson-Gilford Progeria Syndrome. Symptoms of the following disorders can be similar to those of HGPS. Comparisons may be useful for a differential diagnosis:Hallermann-Streiff syndrome is a rare genetic disorder that is primarily characterized by distinctive malformations of the skull and facial (craniofacial) region; sparse hair (hypotrichosis); eye (ocular) abnormalities; dental defects; degenerative skin changes (atrophy), particularly in the scalp and nasal regions; and/or short stature (i.e., dwarfism). Characteristic craniofacial features include a short, broad head (brachycephaly) with an unusually prominent forehead and/or sides of the skull (frontal and/or parietal bossing); a small, underdeveloped lower jaw (hypoplastic mandible); a narrow, highly arched roof of the mouth (palate); and a thin, pinched, tapering nose. Many affected individuals also have clouding of the lenses of the eyes at birth (congenital cataracts); unusually small eyes (microphthalmia); and/or other ocular abnormalities. Dental defects may include the presence of certain teeth at birth (natal teeth) and absence (hypodontia or partial adontia), malformation, and/or improper alignment of teeth. Hallermann-Streiff syndrome appears to occur randomly for unknown reasons (sporadically) and may be the result of a new dominant genetic mutation. (For more information on this disorder, choose “Hallermann-Streiff” as your search term in the Rare Disease Database.)Gottron’s syndrome (acrogeria) is a mild, inherited form of premature aging characterized by abnormally small hands and feet with thin and delicate skin. From infancy on, children with this disorder appear older than their actual age. The skin is unusually thin and parchment-like on the hands and feet. The hands and feet remain abnormally small into adulthood. (For more information on this disorder, choose “Gottron” as your search term in the Rare Disease Database.)Wiedemann-Rautenstrauch syndrome (WRS), also known as neonatal progeroid syndrome, is a very rare genetic disorder characterized by an aged appearance at birth, growth delays before and after birth (prenatal and postnatal growth delay); and deficiency or absence of the layer of fat under the skin (subcutaneous lipoatrophy). Most individuals with WRS have a decreased life expectancy but there are a few individuals who have lived well in to the teens and a few still live in their 20s. WRS is inherited in an autosomal recessive pattern, as several pairs of siblings have been reported in families with unaffected parents. (For more information on this disorder, choose “Wiedemann-Rautenstrauch” as your search term in the Rare Disease Database.)De Barsy syndrome is a rare disorder that is inherited in an autosomal recessive pattern. The main characteristics include degeneration of the elastic tissue in the skin (cutis laxa), involuntary movements of the arms and legs (athetosis), cloudy corneas of the eyes, large prominent ears, and loss of muscle tone. Other symptoms may include unusual flexibility of the small joints, a forehead that protrudes outward (frontal bossing), and/or short stature. The loss of elasticity of the skin leads to an aged wrinkled appearance. Newborn children with this disorder may look like newborns with HGPS. (For more information on this disorder, choose “De Barsy” as your search term in the Rare Disease Database.)Progeroid syndrome with Ehlers-Danlos features is an extremely rare genetic disorder characterized in newborns by a “progeria-like” (progeroid) appearance. The skin may be wrinkled leading to an aged appearance. Other symptoms include sparse eyebrows, scanty eyelashes, multiple birthmarks, and extremely fragile skin which bruises easily. Some children with this disorder may have low-set prominent ears, a receding chin, and/or irregular teeth.
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Diagnosis of Hutchinson-Gilford Progeria Syndrome
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HGPS is usually diagnosed during the second year of life or later, when progeroid features begin to be noticeable. The diagnosis is based upon a thorough clinical evaluation, characteristic physical findings, a careful patient history and diagnostic genetic testing which is available through the Progeria Research Foundation (www.progeriaresearch.org). More rarely, the disorder may be suspected at birth based upon recognition of certain suspicious findings (e.g., “scleroderma-like” skin over the buttocks, thighs, lower abdomen; midfacial cyanosis; “sculptured” nose).Specialized imaging tests may be conducted to confirm or characterize certain skeletal abnormalities potentially associated with the disorder, such as degenerative changes (osteolysis) of certain bones of the fingers (terminal phalanges) and/or the hip socket (acetabulum). In addition, thorough cardiac evaluations and ongoing monitoring may also be performed (e.g., clinical examinations, X-ray studies, specialized cardiac tests) to assess associated cardiovascular abnormalities and determine appropriate disease management.
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Diagnosis of Hutchinson-Gilford Progeria Syndrome. HGPS is usually diagnosed during the second year of life or later, when progeroid features begin to be noticeable. The diagnosis is based upon a thorough clinical evaluation, characteristic physical findings, a careful patient history and diagnostic genetic testing which is available through the Progeria Research Foundation (www.progeriaresearch.org). More rarely, the disorder may be suspected at birth based upon recognition of certain suspicious findings (e.g., “scleroderma-like” skin over the buttocks, thighs, lower abdomen; midfacial cyanosis; “sculptured” nose).Specialized imaging tests may be conducted to confirm or characterize certain skeletal abnormalities potentially associated with the disorder, such as degenerative changes (osteolysis) of certain bones of the fingers (terminal phalanges) and/or the hip socket (acetabulum). In addition, thorough cardiac evaluations and ongoing monitoring may also be performed (e.g., clinical examinations, X-ray studies, specialized cardiac tests) to assess associated cardiovascular abnormalities and determine appropriate disease management.
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Therapies of Hutchinson-Gilford Progeria Syndrome
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Treatment
In November 2020, the U.S. Food and Drug Administration (FDA) approved Zokinvy (lonafarnib), a type of farnesyltransferase inhibitor (FTI) originally developed to treat cancer, as the first treatment for Hutchinson-Gilford progeria syndrome. Zokinvy is now available by prescription for those with HGPS in the United States. The drug is also available in many other countries through Eiger Biopharmaceutical’s Managed Access Program. Before this recent approval, children with progeria could receive treatment with Zokinvy only through participation in a clinical trial run through the Progeria Research Foundation at Boston Children’s Hospital in the United States. Zokinvy has been used to treat over 90 progeria patients through four clinical trials since 2007.In April 2018, analyses of data collected in an observational cohort study supported by the Progeria Research Foundation compared patients treated with Zokinvy to untreated children and young adults. A lower mortality rate was found in the patients who were treated. Previously, in September 2012, the results of the first-ever clinical drug trial for children with progeria showed that Zokinvy was effective for progeria. Every child showed improvement in one or more of four ways: gaining additional weight, better hearing, improved bone structure and/or, most importantly, increased flexibility of blood vessels.In addition to the use of Zokinvy, the treatment of HGPS is directed toward the specific symptoms that are apparent in each individual. Management may require the coordinated efforts of a team of specialists who may need to systematically and comprehensively plan an affected child's treatment. Such specialists may include pediatricians; physicians who diagnose and treat disorders of the skeleton, muscles, joints, and other related tissues (orthopedists); physicians who diagnose and treat abnormalities of the heart and its major blood vessels; physical therapists; and/or other health care professionals.Specific therapies for individuals with HGPS are symptomatic and supportive. For example, in those with episodes of chest pain due to deficient oxygen supply to heart muscle (anginal attacks), treatment may include the use of certain medications that may help to minimize or manage such symptoms.
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Therapies of Hutchinson-Gilford Progeria Syndrome. Treatment
In November 2020, the U.S. Food and Drug Administration (FDA) approved Zokinvy (lonafarnib), a type of farnesyltransferase inhibitor (FTI) originally developed to treat cancer, as the first treatment for Hutchinson-Gilford progeria syndrome. Zokinvy is now available by prescription for those with HGPS in the United States. The drug is also available in many other countries through Eiger Biopharmaceutical’s Managed Access Program. Before this recent approval, children with progeria could receive treatment with Zokinvy only through participation in a clinical trial run through the Progeria Research Foundation at Boston Children’s Hospital in the United States. Zokinvy has been used to treat over 90 progeria patients through four clinical trials since 2007.In April 2018, analyses of data collected in an observational cohort study supported by the Progeria Research Foundation compared patients treated with Zokinvy to untreated children and young adults. A lower mortality rate was found in the patients who were treated. Previously, in September 2012, the results of the first-ever clinical drug trial for children with progeria showed that Zokinvy was effective for progeria. Every child showed improvement in one or more of four ways: gaining additional weight, better hearing, improved bone structure and/or, most importantly, increased flexibility of blood vessels.In addition to the use of Zokinvy, the treatment of HGPS is directed toward the specific symptoms that are apparent in each individual. Management may require the coordinated efforts of a team of specialists who may need to systematically and comprehensively plan an affected child's treatment. Such specialists may include pediatricians; physicians who diagnose and treat disorders of the skeleton, muscles, joints, and other related tissues (orthopedists); physicians who diagnose and treat abnormalities of the heart and its major blood vessels; physical therapists; and/or other health care professionals.Specific therapies for individuals with HGPS are symptomatic and supportive. For example, in those with episodes of chest pain due to deficient oxygen supply to heart muscle (anginal attacks), treatment may include the use of certain medications that may help to minimize or manage such symptoms.
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Hutchinson-Gilford Progeria Syndrome
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Overview of Hydranencephaly
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Hydranencephaly is a central nervous system disorder characterized by an enlarged head and neurological deficits. The exact cause of Hydranencephaly is not known. This extremely rare form of Hydrocephalus involves the absence of portions of the brain. Results of neurologic examination in newborns may be normal or abnormal. The head usually appears enlarged at birth. Vision impairment, lack of growth and intellectual deficits are symptomatic of this disorder.
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Overview of Hydranencephaly. Hydranencephaly is a central nervous system disorder characterized by an enlarged head and neurological deficits. The exact cause of Hydranencephaly is not known. This extremely rare form of Hydrocephalus involves the absence of portions of the brain. Results of neurologic examination in newborns may be normal or abnormal. The head usually appears enlarged at birth. Vision impairment, lack of growth and intellectual deficits are symptomatic of this disorder.
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Hydranencephaly
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Symptoms of Hydranencephaly
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Hydranencephaly can usually be detected at birth due to an enlarged head. Some infants may appear healthy at birth but may later fail to grow at a normal rate. Irritability, poor feeding, infantile spasms or seizures, and spasticity or rigidity of arms and legs are symptomatic of this disorder. Some affected individuals may experience an exaggeration of muscular reflexes (hyperreflexia) and/or increased muscle tone (hypertonia). Poor body temperature regulation, vision impairment and mental retardation may also occur.
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Symptoms of Hydranencephaly. Hydranencephaly can usually be detected at birth due to an enlarged head. Some infants may appear healthy at birth but may later fail to grow at a normal rate. Irritability, poor feeding, infantile spasms or seizures, and spasticity or rigidity of arms and legs are symptomatic of this disorder. Some affected individuals may experience an exaggeration of muscular reflexes (hyperreflexia) and/or increased muscle tone (hypertonia). Poor body temperature regulation, vision impairment and mental retardation may also occur.
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Hydranencephaly
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Causes of Hydranencephaly
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Hydranencephaly is suspected to be an inherited disorder although the mode of transmission remains unknown. Some researchers believe that prenatal blockage of the carotid artery where it enters the cranium may be a cause of this disorder. However, the reason for the blockage is not known.An autosomal recessive inheritance has been described in some cases. 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 occur unless an individual 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.
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Causes of Hydranencephaly. Hydranencephaly is suspected to be an inherited disorder although the mode of transmission remains unknown. Some researchers believe that prenatal blockage of the carotid artery where it enters the cranium may be a cause of this disorder. However, the reason for the blockage is not known.An autosomal recessive inheritance has been described in some cases. 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 occur unless an individual 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.
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Hydranencephaly
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Affects of Hydranencephaly
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Hydranencephaly is a rare disorder that affects males and females in equal numbers.
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Affects of Hydranencephaly. Hydranencephaly is a rare disorder that affects males and females in equal numbers.
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Hydranencephaly
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Related disorders of Hydranencephaly
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Porencephaly is a disorder of the central nervous system involving cerebral cysts or cavities in cortical brain tissue. The disorder can occur before or after birth. Fluid which can accumulate in the head can be drained through a surgical shunt procedure. The prognosis is variable. Some patients with this disorder may develop only minor neurological problems and have normal intelligence, while others may be severely disabled.Hydrocephalus is a term describing an accumulation of fluid in the brain cavity which usually causes increased pressure inside the skull. It is characterized by enlargement of the head and prominence of the forehead. This disorder may begin suddenly and can be congenital or acquired; it can be a symptom of another disorder or a primary condition. Treatment with a surgical shunt procedure is generally successful in relieving pressure on the brain by draining the fluid out of the head. (For more information on this disorder, choose “hydrocephalus” as your search term in the Rare Disease Database.)
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Related disorders of Hydranencephaly. Porencephaly is a disorder of the central nervous system involving cerebral cysts or cavities in cortical brain tissue. The disorder can occur before or after birth. Fluid which can accumulate in the head can be drained through a surgical shunt procedure. The prognosis is variable. Some patients with this disorder may develop only minor neurological problems and have normal intelligence, while others may be severely disabled.Hydrocephalus is a term describing an accumulation of fluid in the brain cavity which usually causes increased pressure inside the skull. It is characterized by enlargement of the head and prominence of the forehead. This disorder may begin suddenly and can be congenital or acquired; it can be a symptom of another disorder or a primary condition. Treatment with a surgical shunt procedure is generally successful in relieving pressure on the brain by draining the fluid out of the head. (For more information on this disorder, choose “hydrocephalus” as your search term in the Rare Disease Database.)
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Hydranencephaly
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Diagnosis of Hydranencephaly
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The diagnosis of Hydranencephaly may be confirmed based upon a thorough clinical evaluation, the identification of characteristic physical findings, a detailed patient history, and advanced imaging techniques, such as transillumination, an x-ray of the blood vessels using dye (angiogram), or computerized tomography (CT scan). During CT scanning, a computer and x-rays are used to create a file showing cross-sectional images of internal structures such as the brain.In some cases, the disorder may be diagnosed before birth (prenatally) using fetal ultrasonography to identify characteristic physical abnormalities. In fetal ultrasonography, an image of the developing fetus is created using sound waves.
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Diagnosis of Hydranencephaly. The diagnosis of Hydranencephaly may be confirmed based upon a thorough clinical evaluation, the identification of characteristic physical findings, a detailed patient history, and advanced imaging techniques, such as transillumination, an x-ray of the blood vessels using dye (angiogram), or computerized tomography (CT scan). During CT scanning, a computer and x-rays are used to create a file showing cross-sectional images of internal structures such as the brain.In some cases, the disorder may be diagnosed before birth (prenatally) using fetal ultrasonography to identify characteristic physical abnormalities. In fetal ultrasonography, an image of the developing fetus is created using sound waves.
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Hydranencephaly
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Therapies of Hydranencephaly
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TreatmentThere is no treatment for Hydranencephaly. A shunt may be recommended to facilitate the drainage of fluid from the brain.
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Therapies of Hydranencephaly. TreatmentThere is no treatment for Hydranencephaly. A shunt may be recommended to facilitate the drainage of fluid from the brain.
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Hydranencephaly
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Overview of Hydrocephalus
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Hydrocephalus is a condition in which abnormally widened (dilated) cerebral spaces in the brain (ventricles) inhibit the normal flow of cerebrospinal fluid (CSF). The cerebrospinal fluid accumulates in the skull and puts pressure on the brain tissue. An enlarged head in infants and increased cerebrospinal fluid pressure are frequent findings but are not necessary for the diagnosis of Hydrocephalus. There are several different forms of Hydrocephalus: communicating hydrocephalus, non-communicating hydrocephalus or obstructive hydrocephalus, internal hydrocephalus, normal pressure hydrocephalus, and benign hydrocephalus.
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Overview of Hydrocephalus. Hydrocephalus is a condition in which abnormally widened (dilated) cerebral spaces in the brain (ventricles) inhibit the normal flow of cerebrospinal fluid (CSF). The cerebrospinal fluid accumulates in the skull and puts pressure on the brain tissue. An enlarged head in infants and increased cerebrospinal fluid pressure are frequent findings but are not necessary for the diagnosis of Hydrocephalus. There are several different forms of Hydrocephalus: communicating hydrocephalus, non-communicating hydrocephalus or obstructive hydrocephalus, internal hydrocephalus, normal pressure hydrocephalus, and benign hydrocephalus.
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Hydrocephalus
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Symptoms of Hydrocephalus
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Hydrocephalus is characterized in children by an unusually large head (cephalomegaly); a thin, transparent scalp; a bulging forehead with prominent spaces between the bones of the skull (fontanelles); and a downward gaze. Other symptoms may include convulsions, abnormal reflexes, a slowed heartbeat and respiratory rate, headache, vomiting, irritability, weakness, and problems with vision. Blindness and continuing mental deterioration may occur if treatment is not administered.When hydrocephalus begins in an adolescent or a young adult, the facial abnormalities are less obvious than in children with congenital or early onset hydrocephalus. Many of the other mental and physiologic symptoms are the same; however, previously acquired skills requiring coordinated movement (motor coordination) may be lost. Affected children and adolescents may also exhibit symptoms associated with diminished activity of the pituitary gland (hypopituitarism), such as delayed growth, obesity, and general weakness.Hydrocephalus is subdivided according to the particular defect that exists in the brain and whether the cerebrospinal fluid pressure is high or normal.In “communicating hydrocephalus”, there is no blockage (obstruction) in the cerebral spaces of the brain (ventricular system); the cerebrospinal fluid flows readily into the subarachnoid space (the space between the arachnoid and pia mater membranes in the brain), but the fluid is not absorbed readily, or perhaps produced in too great a quantity to be absorbed.In “noncommunicating (obstructive) hydrocephalus”, the cerebrospinal fluid is blocked causing widening (dilation) of the pathways upstream of the block, leading to increased cerebrospinal fluid pressure in the skull.“Normal-pressure hydrocephalus”, which affects middle-aged and older persons, is characterized by dilated ventricles but normal pressure within the spinal column (lumbar pressure). Other symptoms of normal-pressure hydrocephalus include loss of memory and intellectual capacity (dementia), loss of muscle coordination (ataxia), and loss of bladder control (urinary incontinence). Additional symptoms may include lack of emotions (apathy), memory disturbances, the slowing of mental and motor functions, and/or a lack of awareness or indifference to the affected sides of an affected individual's body (anosognosia).
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Symptoms of Hydrocephalus. Hydrocephalus is characterized in children by an unusually large head (cephalomegaly); a thin, transparent scalp; a bulging forehead with prominent spaces between the bones of the skull (fontanelles); and a downward gaze. Other symptoms may include convulsions, abnormal reflexes, a slowed heartbeat and respiratory rate, headache, vomiting, irritability, weakness, and problems with vision. Blindness and continuing mental deterioration may occur if treatment is not administered.When hydrocephalus begins in an adolescent or a young adult, the facial abnormalities are less obvious than in children with congenital or early onset hydrocephalus. Many of the other mental and physiologic symptoms are the same; however, previously acquired skills requiring coordinated movement (motor coordination) may be lost. Affected children and adolescents may also exhibit symptoms associated with diminished activity of the pituitary gland (hypopituitarism), such as delayed growth, obesity, and general weakness.Hydrocephalus is subdivided according to the particular defect that exists in the brain and whether the cerebrospinal fluid pressure is high or normal.In “communicating hydrocephalus”, there is no blockage (obstruction) in the cerebral spaces of the brain (ventricular system); the cerebrospinal fluid flows readily into the subarachnoid space (the space between the arachnoid and pia mater membranes in the brain), but the fluid is not absorbed readily, or perhaps produced in too great a quantity to be absorbed.In “noncommunicating (obstructive) hydrocephalus”, the cerebrospinal fluid is blocked causing widening (dilation) of the pathways upstream of the block, leading to increased cerebrospinal fluid pressure in the skull.“Normal-pressure hydrocephalus”, which affects middle-aged and older persons, is characterized by dilated ventricles but normal pressure within the spinal column (lumbar pressure). Other symptoms of normal-pressure hydrocephalus include loss of memory and intellectual capacity (dementia), loss of muscle coordination (ataxia), and loss of bladder control (urinary incontinence). Additional symptoms may include lack of emotions (apathy), memory disturbances, the slowing of mental and motor functions, and/or a lack of awareness or indifference to the affected sides of an affected individual's body (anosognosia).
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Hydrocephalus
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Causes of Hydrocephalus
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The cause of hydrocephalus is not known. Very few cases are caused by a birth defect; others can follow hemorrhage, viral infection, or meningitis. A genetic predisposition has been proposed, with transmission through autosomal recessive or X-linked genes.Human traits, including the classic genetic diseases, are a 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.X-linked recessive disorders are conditions which are coded on the X chromosome. Females have two X chromosomes, but males have one X chromosome and one Y chromosome. Therefore, in females, disease traits on the X chromosome can be masked by the normal gene on the other X chromosome. Since males only have one X chromosome, if they inherit a gene for a disease present on the X, it will be expressed. Men with X-linked disorders transmit the gene to all their daughters, who are carriers, but never to their sons. Women who are carriers of an X-linked disorder have a fifty percent risk of transmitting the carrier condition to their daughters, and a fifty percent risk of transmitting the disease to their sons. Some cases of Hydrocephalus are believed to be caused by Dandy-Walker Cysts. (For more information on this disorder, choose “Dandy-Walker Malformation” as your search term in the Rare Disease Database.)
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Causes of Hydrocephalus. The cause of hydrocephalus is not known. Very few cases are caused by a birth defect; others can follow hemorrhage, viral infection, or meningitis. A genetic predisposition has been proposed, with transmission through autosomal recessive or X-linked genes.Human traits, including the classic genetic diseases, are a 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.X-linked recessive disorders are conditions which are coded on the X chromosome. Females have two X chromosomes, but males have one X chromosome and one Y chromosome. Therefore, in females, disease traits on the X chromosome can be masked by the normal gene on the other X chromosome. Since males only have one X chromosome, if they inherit a gene for a disease present on the X, it will be expressed. Men with X-linked disorders transmit the gene to all their daughters, who are carriers, but never to their sons. Women who are carriers of an X-linked disorder have a fifty percent risk of transmitting the carrier condition to their daughters, and a fifty percent risk of transmitting the disease to their sons. Some cases of Hydrocephalus are believed to be caused by Dandy-Walker Cysts. (For more information on this disorder, choose “Dandy-Walker Malformation” as your search term in the Rare Disease Database.)
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Hydrocephalus
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Affects of Hydrocephalus
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Most cases of Hydrocephalus are diagnosed in the first 2 years of life, but onset may occur at any age, depending on the cause. Most types of Hydrocephalus (with the exception of those caused by an X-linked genetic trait) seem to affect males and females equally.
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Affects of Hydrocephalus. Most cases of Hydrocephalus are diagnosed in the first 2 years of life, but onset may occur at any age, depending on the cause. Most types of Hydrocephalus (with the exception of those caused by an X-linked genetic trait) seem to affect males and females equally.
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Hydrocephalus
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Related disorders of Hydrocephalus
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The following disorders can occur in conjunction with Hydrocephalus. Comparisons may be useful for differential diagnosis.Spina Bifida is a condition in which the spinal cord is not properly closed; part of the contents of the spinal canal may protrude through this opening. In its mildest form, this condition may go undetected. The lack of closure may affect a very small area of the spine. In the more severe form of Spina Bifida, a sac (meningocele) may be present on the back containing parts of the spinal canal. Fluid may then accumulate in the cavities in the brain, leading to hydrocephalus. (For more information on this disorder, choose “Spina Bifida” as your search term in the Rare Disease Database.)Chiari Malformation is a rare disorder that is characterized by the displacement of the brain stem (distal medulla). The brain stem becomes elongated and flattened and protrudes into the area of the upper spinal canal. In infants, Chiari Malformation is associated with the presence of a sac or hernia (myelomeningocele) from the spinal cord, which may contain the spinal cord and the membranes that surround the spinal cord (meninges). Hydrocephalus is commonly present. In infants, vomiting, mental impairment, head and facial muscle weakness, and difficulties in swallowing may be present. (For more information on this disorder, choose “Arnold-Chiari” as your search term in the Rare Disease Database.)Epilepsy is a disorder of the central nervous system. It is characterized by recurrent electrical disturbances in the brain. Symptoms of this disorder may include loss of consciousness, convulsions, spasms, sensory confusion, and disturbances in the autonomic nervous system. Attacks are frequently preceded by a feeling of uneasiness, discomfort, or strange behavior. Hydrocephalus can occur with or possibly result in epilepsy. (For more information on this disorder, choose “Epilepsy” as your search term in the Rare Disease Database.)Meningitis is an infection that causes inflammation of the membranes that surround the brain (meninges). In its milder form, the cause is thought to be viral. Bacterial meningitis is generally a more severe disease. Symptoms may include a general feeling of ill health (malaise), nausea, abdominal pain, and stiffness in the back and neck. Meningitis can occur in conjunction with hydrocephalus. (For more information on this disorder, choose “Meningitis” as your search term in the Rare Disease Database.)Encephalocele is a rare disorder in which an infant is born with a gap in the skull. The membranes that cover the brain (meninges) and the brain tissue protrude through this gap. Infants with an encephalocele may develop hydrocephalus. (For more information on this disorder, choose “Encephalocele” as your search term in the Rare Disease Database.)Cardio-Facio-Cutaneous Syndrome is a rare disorder in which an infant is born with multiple physical deformities and mental retardation. The common symptoms of this disorder include abnormal skin conditions (including patchy and unusually dry skin), unusual facial characteristics, sparse and curly hair, and heart defects. Affected individuals may also exhibit hydrocephalus. (For more information on this disorder, choose “Cardio-Facio- Cutaneous” as your search term in the Rare Disease Database.)Walker-Warburg Syndrome, a very rare genetic disorder, is also known as HARD +/-E Syndrome, an acronym for (H)ydrocephalus, (A)gyria, (R)etinal (D)ysplasia and sometimes (E)ncephalocele. The most consistent features of this disorder are a lack of normal folds of the brain (lissencephaly), malformations of the back portion of the brain (cerebellum), abnormalities of the retina of the eye, and progressive degeneration and weakness of the voluntary muscles (congenital muscular dystrophy). (For more information on this disorder, choose “Walker-Warburg” as your search term in the Rare Disease Database.)
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Related disorders of Hydrocephalus. The following disorders can occur in conjunction with Hydrocephalus. Comparisons may be useful for differential diagnosis.Spina Bifida is a condition in which the spinal cord is not properly closed; part of the contents of the spinal canal may protrude through this opening. In its mildest form, this condition may go undetected. The lack of closure may affect a very small area of the spine. In the more severe form of Spina Bifida, a sac (meningocele) may be present on the back containing parts of the spinal canal. Fluid may then accumulate in the cavities in the brain, leading to hydrocephalus. (For more information on this disorder, choose “Spina Bifida” as your search term in the Rare Disease Database.)Chiari Malformation is a rare disorder that is characterized by the displacement of the brain stem (distal medulla). The brain stem becomes elongated and flattened and protrudes into the area of the upper spinal canal. In infants, Chiari Malformation is associated with the presence of a sac or hernia (myelomeningocele) from the spinal cord, which may contain the spinal cord and the membranes that surround the spinal cord (meninges). Hydrocephalus is commonly present. In infants, vomiting, mental impairment, head and facial muscle weakness, and difficulties in swallowing may be present. (For more information on this disorder, choose “Arnold-Chiari” as your search term in the Rare Disease Database.)Epilepsy is a disorder of the central nervous system. It is characterized by recurrent electrical disturbances in the brain. Symptoms of this disorder may include loss of consciousness, convulsions, spasms, sensory confusion, and disturbances in the autonomic nervous system. Attacks are frequently preceded by a feeling of uneasiness, discomfort, or strange behavior. Hydrocephalus can occur with or possibly result in epilepsy. (For more information on this disorder, choose “Epilepsy” as your search term in the Rare Disease Database.)Meningitis is an infection that causes inflammation of the membranes that surround the brain (meninges). In its milder form, the cause is thought to be viral. Bacterial meningitis is generally a more severe disease. Symptoms may include a general feeling of ill health (malaise), nausea, abdominal pain, and stiffness in the back and neck. Meningitis can occur in conjunction with hydrocephalus. (For more information on this disorder, choose “Meningitis” as your search term in the Rare Disease Database.)Encephalocele is a rare disorder in which an infant is born with a gap in the skull. The membranes that cover the brain (meninges) and the brain tissue protrude through this gap. Infants with an encephalocele may develop hydrocephalus. (For more information on this disorder, choose “Encephalocele” as your search term in the Rare Disease Database.)Cardio-Facio-Cutaneous Syndrome is a rare disorder in which an infant is born with multiple physical deformities and mental retardation. The common symptoms of this disorder include abnormal skin conditions (including patchy and unusually dry skin), unusual facial characteristics, sparse and curly hair, and heart defects. Affected individuals may also exhibit hydrocephalus. (For more information on this disorder, choose “Cardio-Facio- Cutaneous” as your search term in the Rare Disease Database.)Walker-Warburg Syndrome, a very rare genetic disorder, is also known as HARD +/-E Syndrome, an acronym for (H)ydrocephalus, (A)gyria, (R)etinal (D)ysplasia and sometimes (E)ncephalocele. The most consistent features of this disorder are a lack of normal folds of the brain (lissencephaly), malformations of the back portion of the brain (cerebellum), abnormalities of the retina of the eye, and progressive degeneration and weakness of the voluntary muscles (congenital muscular dystrophy). (For more information on this disorder, choose “Walker-Warburg” as your search term in the Rare Disease Database.)
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Hydrocephalus
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nord_604_5
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Diagnosis of Hydrocephalus
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The diagnosis of hydrocephalus may be confirmed based upon a thorough clinical evaluation, the identification of characteristic physical findings, a detailed patient history, and advanced imaging techniques, such as transillumination, an x-ray of the blood vessels using dye (angiogram), computerized tomography (CT scan), or magnetic resonance imaging (MRI). During CT scanning, a computer and x-rays are used to create a file showing cross-sectional images of internal structures such as the brain. During MRI, a magnetic field and radio waves are used to create cross-sectional images of certain structures.In some cases, hydrocephalus may be diagnosed before birth (prenatally) using fetal ultrasonography to identify characteristic physical abnormalities. In fetal ultrasonography, an image of the developing fetus is created using sound waves.Any one or more of several tests may be used to diagnose normal-pressure hydrocephalus (NPH). In addition to CT and MRI described above, such tests may include lumbar puncture or spinal tap, which permits the removal of up to 50 cc of spinal fluid and may temporarily relieve symptoms. Neurosurgeons often interpret even temporary relief as a result of a spinal tap to indicate that surgical treatment may be successful. The insertion of a lumbar catheter permits the continuous removal of spinal fluid and the continuous measurement of spinal fluid pressure. A positive response of patients to treatment by lumbar catheter is often interpreted as an indicator that the patient will respond to shunt surgery as well.Intracranial pressure monitoring is done in the hospital and involves the insertion of a pressure monitor into the brain or a ventricle of the brain.Central spinal fluid (CSF) outflow resistance is carried out only in a specialized hospital setting. Simultaneously, the brain is infused with artificial spinal fluid and the CSF pressure is recorded. The purpose of the test is to determine by how much the reabsorption of CSF back into the bloodstream is retarded.Isotopic cisternography permits the clinician to monitor the CSF over a 4-day period by scanning how and where an isotope injected into one of the hollow spaces of the lower bac. is absorbed over the surface of the brain or retained in the hollows. This technique has lost favor over the past few years since it does not reliably predict how a patient will respond to shunt surgery.
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Diagnosis of Hydrocephalus. The diagnosis of hydrocephalus may be confirmed based upon a thorough clinical evaluation, the identification of characteristic physical findings, a detailed patient history, and advanced imaging techniques, such as transillumination, an x-ray of the blood vessels using dye (angiogram), computerized tomography (CT scan), or magnetic resonance imaging (MRI). During CT scanning, a computer and x-rays are used to create a file showing cross-sectional images of internal structures such as the brain. During MRI, a magnetic field and radio waves are used to create cross-sectional images of certain structures.In some cases, hydrocephalus may be diagnosed before birth (prenatally) using fetal ultrasonography to identify characteristic physical abnormalities. In fetal ultrasonography, an image of the developing fetus is created using sound waves.Any one or more of several tests may be used to diagnose normal-pressure hydrocephalus (NPH). In addition to CT and MRI described above, such tests may include lumbar puncture or spinal tap, which permits the removal of up to 50 cc of spinal fluid and may temporarily relieve symptoms. Neurosurgeons often interpret even temporary relief as a result of a spinal tap to indicate that surgical treatment may be successful. The insertion of a lumbar catheter permits the continuous removal of spinal fluid and the continuous measurement of spinal fluid pressure. A positive response of patients to treatment by lumbar catheter is often interpreted as an indicator that the patient will respond to shunt surgery as well.Intracranial pressure monitoring is done in the hospital and involves the insertion of a pressure monitor into the brain or a ventricle of the brain.Central spinal fluid (CSF) outflow resistance is carried out only in a specialized hospital setting. Simultaneously, the brain is infused with artificial spinal fluid and the CSF pressure is recorded. The purpose of the test is to determine by how much the reabsorption of CSF back into the bloodstream is retarded.Isotopic cisternography permits the clinician to monitor the CSF over a 4-day period by scanning how and where an isotope injected into one of the hollow spaces of the lower bac. is absorbed over the surface of the brain or retained in the hollows. This technique has lost favor over the past few years since it does not reliably predict how a patient will respond to shunt surgery.
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Hydrocephalus
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nord_604_6
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Therapies of Hydrocephalus
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TreatmentStandard treatment for hydrocephalus is the insertion of a shunt or tube into the head cavity which drains the excess cerebrospinal fluid into a part of the body that can absorb it. In growing children, the shunt may have to be lengthened periodically. Complications may arise if the shunt becomes clogged or stops functioning. At times, a new shunt may have to be re-implanted.
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Therapies of Hydrocephalus. TreatmentStandard treatment for hydrocephalus is the insertion of a shunt or tube into the head cavity which drains the excess cerebrospinal fluid into a part of the body that can absorb it. In growing children, the shunt may have to be lengthened periodically. Complications may arise if the shunt becomes clogged or stops functioning. At times, a new shunt may have to be re-implanted.
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Hydrocephalus
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nord_605_0
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Overview of Hyper IgM Syndromes
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SummaryHyper IgM syndromes are a group of rare disorders in which the immune system does not function properly. They are classified as rare primary immunodeficiency disorders, which are a group of disorders characterized by irregularities in the cell development and/or cell maturation process of the immune system. The immune system is divided into several components, the combined actions of which are responsible for defending the body against different infectious agents. The T cell system is responsible for fighting yeast and fungi, several viruses, and some bacteria. The B cell system fights infection caused by other viruses and bacteria. It does so by secreting immune factors called antibodies (also known as immunoglobulins) into the fluid portion of the blood (serum) and body secretions (e.g., saliva). There are five classes of immunoglobulins known as IgA, IgD, IgE, IgG, and IgM. Antibodies can directly kill microorganisms or coat them so they are more easily destroyed by white blood cells (leukocytes). Hyper IgM syndromes are caused by very rare, one-in-a-million, and potentially life-threatening genetic mutations that severely compromise the immune system and resulting in the individual’s inability to produce antibodies. Patients with hyper IgM are at significant risk for opportunistic and repeated infections. In addition, the defect in the immune system results in a decreased ability to identify and fight cancer cells as well as an inability to produce a response to pathogens. Some individuals with hyper-IgM syndrome have abnormally high levels of immunoglobulin IgM in the fluid portion of the blood, which led to the term “hyper IgM” syndrome. However, researchers have determined that many affected individuals have normal levels of IgM. Affected individuals may have normal to high IgM, but cannot produce adequate levels of immunoglobulins IgG, IgA, and IgE because they cannot switch from the production of IgM to these other immunoglobulin classes. Because these other immunoglobulins are deficient, affected individuals are susceptible to recurrent episodes of certain pus-producing (pyogenic) bacterial infections. The gastrointestinal system is often involved causing recurrent, prolonged (protracted) diarrhea.Approximately 70% of people with hyper IgM syndrome inherit the disorder in an X-linked recessive pattern. This is called X-linked hyper IgM syndrome or XHIM and is the most common type. Because it is X-linked, the disorder predominately affects males. Less often, affected individuals inherit the disorder in an autosomal recessive pattern. There are at least four types of autosomal recessive hyper IgM syndrome; these forms affect men and women equally. They are known as hyper IgM syndromes type 2, 3, 4, and 5.
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Overview of Hyper IgM Syndromes. SummaryHyper IgM syndromes are a group of rare disorders in which the immune system does not function properly. They are classified as rare primary immunodeficiency disorders, which are a group of disorders characterized by irregularities in the cell development and/or cell maturation process of the immune system. The immune system is divided into several components, the combined actions of which are responsible for defending the body against different infectious agents. The T cell system is responsible for fighting yeast and fungi, several viruses, and some bacteria. The B cell system fights infection caused by other viruses and bacteria. It does so by secreting immune factors called antibodies (also known as immunoglobulins) into the fluid portion of the blood (serum) and body secretions (e.g., saliva). There are five classes of immunoglobulins known as IgA, IgD, IgE, IgG, and IgM. Antibodies can directly kill microorganisms or coat them so they are more easily destroyed by white blood cells (leukocytes). Hyper IgM syndromes are caused by very rare, one-in-a-million, and potentially life-threatening genetic mutations that severely compromise the immune system and resulting in the individual’s inability to produce antibodies. Patients with hyper IgM are at significant risk for opportunistic and repeated infections. In addition, the defect in the immune system results in a decreased ability to identify and fight cancer cells as well as an inability to produce a response to pathogens. Some individuals with hyper-IgM syndrome have abnormally high levels of immunoglobulin IgM in the fluid portion of the blood, which led to the term “hyper IgM” syndrome. However, researchers have determined that many affected individuals have normal levels of IgM. Affected individuals may have normal to high IgM, but cannot produce adequate levels of immunoglobulins IgG, IgA, and IgE because they cannot switch from the production of IgM to these other immunoglobulin classes. Because these other immunoglobulins are deficient, affected individuals are susceptible to recurrent episodes of certain pus-producing (pyogenic) bacterial infections. The gastrointestinal system is often involved causing recurrent, prolonged (protracted) diarrhea.Approximately 70% of people with hyper IgM syndrome inherit the disorder in an X-linked recessive pattern. This is called X-linked hyper IgM syndrome or XHIM and is the most common type. Because it is X-linked, the disorder predominately affects males. Less often, affected individuals inherit the disorder in an autosomal recessive pattern. There are at least four types of autosomal recessive hyper IgM syndrome; these forms affect men and women equally. They are known as hyper IgM syndromes type 2, 3, 4, and 5.
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Symptoms of Hyper IgM Syndromes
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The signs and symptoms of hyper IgM syndromes can vary from one person to another. This is true even among members of the same family. Affected individuals are more susceptible to developing various infections and cannot fight off infections well once they occur. Without treatment, these disorders can become life-threatening during childhood or adolescence. The initial symptoms of hyper IgM syndrome usually develop in the first or second year of life.X-LINKED HYPER IGM SYNDROME
Affected individuals are susceptible to recurrent episodes of certain pus-producing (pyogenic) bacterial infections that may affect the upper and lower respiratory tract including the sinuses (sinusitis) and/or the lungs (pneumonitis or pneumonia); the middle ear (otitis media); the external ear canal (otitis externa); the membrane that lines the eyelids and the white portions (sclera) of the eyes (conjunctivitis); the skin (pyoderma); and/or other areas. These infections usually begin during infancy, often in the first year or two of life. Affected individuals may also be unusually susceptible to “opportunistic” infections. The term “opportunistic” infection refers either to infections caused by microorganisms that usually do not cause disease in individuals with fully functioning immune systems or to widespread (systemic) overwhelming disease by microorganisms that typically cause only localized, mild infections. Pneumocystis carinii, a microorganism to which individuals with X-linked hyper IgM syndrome are particularly susceptible, causes a form of pneumonia characterized by fever, cough, abnormally rapid breathing (tachypnea), and/or a bluish discoloration (cyanosis) of the skin and mucous membranes. Affected individuals may also be susceptible to Histoplasma capsulatum, a fungus whose spores, when inhaled, may produce histoplasmosis, an infection characterized by fever; cough; a general feeling of ill health (malaise); and/or irregularities of the lymph nodes (lymphadenopathy). Chronic inflammation and swelling of the sinuses (sinusitis) and thickening, widening, and scarring of the small airway tubes of the lungs due to chronic inflammation and infection (bronchiectasis) are common.In addition, parasitic Cryptosporidium is sometimes found in the intestinal tract of affected individuals, causing persistent diarrhea. Cryptosporidium may also be associated with degenerative disease of the liver (cirrhosis) and inflammation, thickening and scarring of the bile ducts (sclerosing cholangitis). The bile ducts are the passages that carry bile from the liver. These conditions can be associated with abdominal pain, fever, chills, and/or persistent yellowing of the skin, mucous membranes, and whites of the eyes (jaundice). Some individuals may experience liver disease because of infection with cytomegalovirus. Other findings associated with X-linked hyper-IgM syndrome, some of which may become apparent at as early as six to nine months of age, may include chronic diarrhea that, in some people, may lead to impaired absorption of nutrients by the intestinal tract (malabsorption). Affected infants with intestinal malabsorption may fail to grow and gain weight at the expected rate (failure to thrive). Infants and children may also develop widespread warty growths (verruca vulgaris) on the skin and/or skin rashes consisting of discolored spots (macules) and small elevated areas (papules) on the face, the scalp, and the bending surfaces of certain joints. Individuals with X-linked hyper-IgM syndrome may also be prone to developing autoimmune disorders, especially those affecting certain elements of the blood. The term “autoimmune” refers to conditions in which the body’s natural defenses against invading microorganisms mistakenly attack healthy tissue. Affected individuals may experience recurrent (cyclic) or persistent (chronic), often severe neutropenia, a condition in which there is an abnormal decrease in the number of certain white blood cells (neutrophils). Neutrophils play a major role in detecting, destroying, and removing invading bacteria from the blood (phagocytosis). An abnormal decrease in neutrophils (neutropenia) is often associated with fever, inflammation of the gums (gingivitis), and/or inflammation and/or ulceration of the mucous membranes of the mouth (stomatitis). In some people, neutropenia may also result in weight loss and/or susceptibility to other infections. Other autoimmune disorders that can develop include hemolytic anemia, a condition resulting from autoimmune destruction of red blood cells, and/or thrombocytopenic purpura, a condition characterized by abnormally low levels of circulating blood platelets. Platelets are specialized blood cells that help prevent and stop bleeding. Decreased levels of circulating blood platelets (thrombocytopenia) may result in increased susceptibility to bruising, the appearance of small purplish spots (petechiae) on the skin, and/or abnormal bleeding into various tissues of the body. Other autoimmune complications that can develop in people with X-liked hyper IgM syndrome include arthritis, impairment function of the thyroid (hypothyroidism), inflammatory bowel disease, and kidney disease. In approximately 10-15% of affected individuals, neurological symptoms can develop because of infection of the central nervous system. In addition, affected individuals may be more prone to developing certain forms of cancer than the general population. Cancers associated with this disorder have included leukemias (a cancer of the blood), those occurring in the gastrointestinal tract (colon and liver), including cancer of the bile ducts (cholangiocarcinoma) and the most common type of liver cancer (hepatocarcinoma); and neuroectodermal tumors of the gastrointestinal tract and the pancreas. HYPER IGM SYNDROME TYPE 2
This form of hyper IgM syndrome is also known as activation-induced cytidine deaminase (AID) deficiency. The signs and symptoms are similar to those seen in individuals with X-linked hyper IgM syndrome. Affected individuals often develop bacterial infections, especially those of the sinuses and lungs (sinopulmonary infections). These infections usually begin very early in life. Chronic inflammation and swelling of the sinuses (sinusitis) and thickening, widening, and scarring of the small airway tubes of the lungs due to chronic inflammation and infection (bronchiectasis) are common. Gastrointestinal infections often due to Giardia lamblia or viruses are also common. Abnormal enlargement of the spleen (splenomegaly) and the lymph nodes (lymphadenopathy) because of an increase in the number of white blood cells within lymph nodes (lymphoid hyperplasia) are also common. The tonsils may become abnormally large and require surgical removal. Autoimmune conditions, such as autoimmune cytopenia as described, are more common in hyper IgM syndrome type 2 than the X-linked form. Low levels of red cells (anemia) and platelets (thrombocytopenia) are most common. Other autoimmune conditions can develop including inflammation of the liver (hepatitis), and in rare cases, inflammatory bowel syndrome and arthritis. Unlike X-linked hyper IgM syndrome, individuals with hyper IgM syndrome type 2 usually do not develop opportunistic infections. Generally, IgM levels in the blood are much higher than in the X-linked form. Some affected individuals have a mild disease that can go undiagnosed into the teen-aged years or 20s. HYPER IGM SYNDROME TYPE 3
This form of hyper IgM syndrome is also known as hyper IgM syndrome due to CD40 deficiency. This form of the disorder causes signs and symptoms that are virtually indistinguishable from X-linked hyper IgM syndrome described above. HYPER IGM SYNDROME TYPE 4
Affected individuals have developed infections of the sinuses and lungs (sinopulmonary infections), widespread infection of the blood (sepsis), inflammation and infection of the lymph nodes (lymphadenitis), and infection and inflammation of bone (osteomyelitis). Osteomyelitis can cause fever, chills, sweating, bone pain, and swelling and limited movement of nearby joints. Generally, individuals develop similar, but generally milder symptoms than individuals with hyper IgM syndrome type 2. Most affected individuals do not develop opportunistic infections. HYPER IGM SYNDROME TYPE 5
This form is also known as uracil-DNA-glycosylase deficiency. Affected individuals develop signs and symptoms that are similar to those seen in hyper IgM syndrome type 2 including a susceptibility to bacterial infections and lymphoid hyperplasia, and a lack of opportunistic infections.
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Symptoms of Hyper IgM Syndromes. The signs and symptoms of hyper IgM syndromes can vary from one person to another. This is true even among members of the same family. Affected individuals are more susceptible to developing various infections and cannot fight off infections well once they occur. Without treatment, these disorders can become life-threatening during childhood or adolescence. The initial symptoms of hyper IgM syndrome usually develop in the first or second year of life.X-LINKED HYPER IGM SYNDROME
Affected individuals are susceptible to recurrent episodes of certain pus-producing (pyogenic) bacterial infections that may affect the upper and lower respiratory tract including the sinuses (sinusitis) and/or the lungs (pneumonitis or pneumonia); the middle ear (otitis media); the external ear canal (otitis externa); the membrane that lines the eyelids and the white portions (sclera) of the eyes (conjunctivitis); the skin (pyoderma); and/or other areas. These infections usually begin during infancy, often in the first year or two of life. Affected individuals may also be unusually susceptible to “opportunistic” infections. The term “opportunistic” infection refers either to infections caused by microorganisms that usually do not cause disease in individuals with fully functioning immune systems or to widespread (systemic) overwhelming disease by microorganisms that typically cause only localized, mild infections. Pneumocystis carinii, a microorganism to which individuals with X-linked hyper IgM syndrome are particularly susceptible, causes a form of pneumonia characterized by fever, cough, abnormally rapid breathing (tachypnea), and/or a bluish discoloration (cyanosis) of the skin and mucous membranes. Affected individuals may also be susceptible to Histoplasma capsulatum, a fungus whose spores, when inhaled, may produce histoplasmosis, an infection characterized by fever; cough; a general feeling of ill health (malaise); and/or irregularities of the lymph nodes (lymphadenopathy). Chronic inflammation and swelling of the sinuses (sinusitis) and thickening, widening, and scarring of the small airway tubes of the lungs due to chronic inflammation and infection (bronchiectasis) are common.In addition, parasitic Cryptosporidium is sometimes found in the intestinal tract of affected individuals, causing persistent diarrhea. Cryptosporidium may also be associated with degenerative disease of the liver (cirrhosis) and inflammation, thickening and scarring of the bile ducts (sclerosing cholangitis). The bile ducts are the passages that carry bile from the liver. These conditions can be associated with abdominal pain, fever, chills, and/or persistent yellowing of the skin, mucous membranes, and whites of the eyes (jaundice). Some individuals may experience liver disease because of infection with cytomegalovirus. Other findings associated with X-linked hyper-IgM syndrome, some of which may become apparent at as early as six to nine months of age, may include chronic diarrhea that, in some people, may lead to impaired absorption of nutrients by the intestinal tract (malabsorption). Affected infants with intestinal malabsorption may fail to grow and gain weight at the expected rate (failure to thrive). Infants and children may also develop widespread warty growths (verruca vulgaris) on the skin and/or skin rashes consisting of discolored spots (macules) and small elevated areas (papules) on the face, the scalp, and the bending surfaces of certain joints. Individuals with X-linked hyper-IgM syndrome may also be prone to developing autoimmune disorders, especially those affecting certain elements of the blood. The term “autoimmune” refers to conditions in which the body’s natural defenses against invading microorganisms mistakenly attack healthy tissue. Affected individuals may experience recurrent (cyclic) or persistent (chronic), often severe neutropenia, a condition in which there is an abnormal decrease in the number of certain white blood cells (neutrophils). Neutrophils play a major role in detecting, destroying, and removing invading bacteria from the blood (phagocytosis). An abnormal decrease in neutrophils (neutropenia) is often associated with fever, inflammation of the gums (gingivitis), and/or inflammation and/or ulceration of the mucous membranes of the mouth (stomatitis). In some people, neutropenia may also result in weight loss and/or susceptibility to other infections. Other autoimmune disorders that can develop include hemolytic anemia, a condition resulting from autoimmune destruction of red blood cells, and/or thrombocytopenic purpura, a condition characterized by abnormally low levels of circulating blood platelets. Platelets are specialized blood cells that help prevent and stop bleeding. Decreased levels of circulating blood platelets (thrombocytopenia) may result in increased susceptibility to bruising, the appearance of small purplish spots (petechiae) on the skin, and/or abnormal bleeding into various tissues of the body. Other autoimmune complications that can develop in people with X-liked hyper IgM syndrome include arthritis, impairment function of the thyroid (hypothyroidism), inflammatory bowel disease, and kidney disease. In approximately 10-15% of affected individuals, neurological symptoms can develop because of infection of the central nervous system. In addition, affected individuals may be more prone to developing certain forms of cancer than the general population. Cancers associated with this disorder have included leukemias (a cancer of the blood), those occurring in the gastrointestinal tract (colon and liver), including cancer of the bile ducts (cholangiocarcinoma) and the most common type of liver cancer (hepatocarcinoma); and neuroectodermal tumors of the gastrointestinal tract and the pancreas. HYPER IGM SYNDROME TYPE 2
This form of hyper IgM syndrome is also known as activation-induced cytidine deaminase (AID) deficiency. The signs and symptoms are similar to those seen in individuals with X-linked hyper IgM syndrome. Affected individuals often develop bacterial infections, especially those of the sinuses and lungs (sinopulmonary infections). These infections usually begin very early in life. Chronic inflammation and swelling of the sinuses (sinusitis) and thickening, widening, and scarring of the small airway tubes of the lungs due to chronic inflammation and infection (bronchiectasis) are common. Gastrointestinal infections often due to Giardia lamblia or viruses are also common. Abnormal enlargement of the spleen (splenomegaly) and the lymph nodes (lymphadenopathy) because of an increase in the number of white blood cells within lymph nodes (lymphoid hyperplasia) are also common. The tonsils may become abnormally large and require surgical removal. Autoimmune conditions, such as autoimmune cytopenia as described, are more common in hyper IgM syndrome type 2 than the X-linked form. Low levels of red cells (anemia) and platelets (thrombocytopenia) are most common. Other autoimmune conditions can develop including inflammation of the liver (hepatitis), and in rare cases, inflammatory bowel syndrome and arthritis. Unlike X-linked hyper IgM syndrome, individuals with hyper IgM syndrome type 2 usually do not develop opportunistic infections. Generally, IgM levels in the blood are much higher than in the X-linked form. Some affected individuals have a mild disease that can go undiagnosed into the teen-aged years or 20s. HYPER IGM SYNDROME TYPE 3
This form of hyper IgM syndrome is also known as hyper IgM syndrome due to CD40 deficiency. This form of the disorder causes signs and symptoms that are virtually indistinguishable from X-linked hyper IgM syndrome described above. HYPER IGM SYNDROME TYPE 4
Affected individuals have developed infections of the sinuses and lungs (sinopulmonary infections), widespread infection of the blood (sepsis), inflammation and infection of the lymph nodes (lymphadenitis), and infection and inflammation of bone (osteomyelitis). Osteomyelitis can cause fever, chills, sweating, bone pain, and swelling and limited movement of nearby joints. Generally, individuals develop similar, but generally milder symptoms than individuals with hyper IgM syndrome type 2. Most affected individuals do not develop opportunistic infections. HYPER IGM SYNDROME TYPE 5
This form is also known as uracil-DNA-glycosylase deficiency. Affected individuals develop signs and symptoms that are similar to those seen in hyper IgM syndrome type 2 including a susceptibility to bacterial infections and lymphoid hyperplasia, and a lack of opportunistic infections.
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Causes of Hyper IgM Syndromes
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Hyper IgM syndromes are caused by variations (mutations) in specific genes. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body. X-linked hyper IgM syndrome is caused by a variation in the CD40LG gene. Hyper IgM syndrome type 2 is caused by a variation in the AICDA (also called AID) gene. Hyper IgM syndrome type 3 is caused by a variation in the CD40 gene. The genetic cause of hyper IgM syndrome type 4 is unknown. Hyper IgM syndrome type 5 is caused by a variation in the UNG gene. The CD40LG gene responsible for X-linked hyper-IgM syndrome is located on the long arm (q) of chromosome X (Xq26). This gene creates (encodes) a specialized protein called CD40 ligand. Because of the variation in the CD40LG gene, the body does not produce enough CD40 ligand, or produces an abnormal form of the protein. Affected individuals lack functional levels of this protein. In affected individuals, the B cell immune response is deficient as a result of a T cell defect. The first response of the B cell system to an invader (antigen) is normally the production of immunoglobulin M (IgM) antibodies. Antigens are those substances, such as microorganisms, toxins, or other foreign substances, that may trigger production of particular antibodies as part of an immune response. The other classes of immunoglobulins (IgG, IgA, and IgE), each of which has its own defensive duties to perform, are then produced sequentially (in a process called “class switching”) in the normal progression of an immune response.Two “steps” or signals are necessary for the B cell system to switch from the production and secretion of IgM to the production and secretion of IgG, IgA, and IgE. Certain immune response proteins (e.g., interleukin-2, interleukin-4, etc.) produced by T cells must bind to their “companion” interleukin receptors on B cells, which signal B cells to switch from producing IgM to producing IgA, IgE, and IgM. In addition, a certain molecule (CD40) found on the surface of particular B cells must interact with a companion binding protein (CD40 ligand) on the surface of certain activated T cells. Because T cells of individuals with X-linked hyper-IgM syndrome cannot create or synthesize the CD40 ligand, the sequential production of immunoglobulins G, A, and E (i.e., “class-switching” signaling) is inhibited, which, in turn, results in the susceptibility of affected individuals to many infectious disorders. The CD40 gene responsible for hyper IgM syndrome type 3 is located on chromosome 20. This gene encodes CD40, which is a protein receptor. Receptors are found on the surface of certain cells and interact with other proteins such as CD40 ligand. The altered CD40 gene does not produce enough functional CD40 receptor protein, which prevents the binding of CD40 ligand. CD40 ligand has a role in other functions of T cells, such as cytotoxic T cells that identify and eliminate other cells that are damaged, stressed, or infected. Other cell types in the immune system also express CD40 including dendritic cells, monocytes, and macrophages. Another normal process in the “switching” of B cell production of IgM to the production other immunoglobins is called somatic hypermutation. During this process, frequent mutations occur in immunoglobulin genes. These mutations occur in response to an infectious agent and help B cells create specific antibodies that can target specific infectious or foreign materials in the body. Somatic hypermutation may also be affected in individuals with hyper IgM syndrome. Hyper IgM syndromes type 2 is caused by a variation in the AID gene. This gene is also called AICDA. Hyper IgM syndrome type 5 is caused by a variation in the UNG gene. These genes produce enzymes, activation-induced cytidine deaminase for type 2 and uracil nucleoside glycosylase for type 5, that are essential for the process of somatic hypermutation. Unlike X-linked hyper IgM syndrome or hyper IgM syndrome type 3, which affect both the T cell and B cell systems, these two forms of the disorder only affect the B cell system. INHERITANCE PATTERNS
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. X-linked hyper IgM syndrome is caused by an altered gene on the X chromosome and is inherited in an X-linked recessive pattern. Females have two X chromosomes in their cells, but one of the X chromosomes is “turned off” or inactivated during development, a process termed “lyonization,” and all of the genes on that chromosome are inactivated. Lyonization is a random process, and varies from tissue to tissue; within tissues it can also vary from cell to cell. Females who have a disease gene present on one X chromosome are carriers of that disorder. As the result of the lyonization process, most carrier females have about 50% of the normal X and 50% of the mutant X expressed in each tissue, and usually do not display symptoms of the disorder. Because of the randomness of the lyonization process, exceptions to this rule exist, particularly if the inactivation of one copy of the X chromosome is significantly “skewed” in favor of one of the copies. If the normal copy prevails, then female carriers can be and remain completely asymptomatic. If the mutant copy prevails, then carrier females can develop symptoms of the disorder. Unlike females, males have only one X chromosome. If a male inherits an X chromosome that contains a disease gene, he will develop the disease. A male with an X-linked disorder passes the disease gene to all of his daughters, and the daughters will be carriers. A male cannot pass an X-linked gene to his sons because the Y chromosome (not the X chromosome) is always passed to male offspring. A female carrier of an X-linked disorder has a 50% chance with each pregnancy of having a carrier daughter, a 50% chance of having a non-carrier daughter, a 50% chance of having a son affected with the disease, and a 50% chance of having an unaffected son. Hyper IgM types 2, 3, 4 and 5 are inherited in an autosomal recessive pattern. Disorders inherited in a recessive pattern occur when an individual inherits two variants in a gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
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Causes of Hyper IgM Syndromes. Hyper IgM syndromes are caused by variations (mutations) in specific genes. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body. X-linked hyper IgM syndrome is caused by a variation in the CD40LG gene. Hyper IgM syndrome type 2 is caused by a variation in the AICDA (also called AID) gene. Hyper IgM syndrome type 3 is caused by a variation in the CD40 gene. The genetic cause of hyper IgM syndrome type 4 is unknown. Hyper IgM syndrome type 5 is caused by a variation in the UNG gene. The CD40LG gene responsible for X-linked hyper-IgM syndrome is located on the long arm (q) of chromosome X (Xq26). This gene creates (encodes) a specialized protein called CD40 ligand. Because of the variation in the CD40LG gene, the body does not produce enough CD40 ligand, or produces an abnormal form of the protein. Affected individuals lack functional levels of this protein. In affected individuals, the B cell immune response is deficient as a result of a T cell defect. The first response of the B cell system to an invader (antigen) is normally the production of immunoglobulin M (IgM) antibodies. Antigens are those substances, such as microorganisms, toxins, or other foreign substances, that may trigger production of particular antibodies as part of an immune response. The other classes of immunoglobulins (IgG, IgA, and IgE), each of which has its own defensive duties to perform, are then produced sequentially (in a process called “class switching”) in the normal progression of an immune response.Two “steps” or signals are necessary for the B cell system to switch from the production and secretion of IgM to the production and secretion of IgG, IgA, and IgE. Certain immune response proteins (e.g., interleukin-2, interleukin-4, etc.) produced by T cells must bind to their “companion” interleukin receptors on B cells, which signal B cells to switch from producing IgM to producing IgA, IgE, and IgM. In addition, a certain molecule (CD40) found on the surface of particular B cells must interact with a companion binding protein (CD40 ligand) on the surface of certain activated T cells. Because T cells of individuals with X-linked hyper-IgM syndrome cannot create or synthesize the CD40 ligand, the sequential production of immunoglobulins G, A, and E (i.e., “class-switching” signaling) is inhibited, which, in turn, results in the susceptibility of affected individuals to many infectious disorders. The CD40 gene responsible for hyper IgM syndrome type 3 is located on chromosome 20. This gene encodes CD40, which is a protein receptor. Receptors are found on the surface of certain cells and interact with other proteins such as CD40 ligand. The altered CD40 gene does not produce enough functional CD40 receptor protein, which prevents the binding of CD40 ligand. CD40 ligand has a role in other functions of T cells, such as cytotoxic T cells that identify and eliminate other cells that are damaged, stressed, or infected. Other cell types in the immune system also express CD40 including dendritic cells, monocytes, and macrophages. Another normal process in the “switching” of B cell production of IgM to the production other immunoglobins is called somatic hypermutation. During this process, frequent mutations occur in immunoglobulin genes. These mutations occur in response to an infectious agent and help B cells create specific antibodies that can target specific infectious or foreign materials in the body. Somatic hypermutation may also be affected in individuals with hyper IgM syndrome. Hyper IgM syndromes type 2 is caused by a variation in the AID gene. This gene is also called AICDA. Hyper IgM syndrome type 5 is caused by a variation in the UNG gene. These genes produce enzymes, activation-induced cytidine deaminase for type 2 and uracil nucleoside glycosylase for type 5, that are essential for the process of somatic hypermutation. Unlike X-linked hyper IgM syndrome or hyper IgM syndrome type 3, which affect both the T cell and B cell systems, these two forms of the disorder only affect the B cell system. INHERITANCE PATTERNS
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. X-linked hyper IgM syndrome is caused by an altered gene on the X chromosome and is inherited in an X-linked recessive pattern. Females have two X chromosomes in their cells, but one of the X chromosomes is “turned off” or inactivated during development, a process termed “lyonization,” and all of the genes on that chromosome are inactivated. Lyonization is a random process, and varies from tissue to tissue; within tissues it can also vary from cell to cell. Females who have a disease gene present on one X chromosome are carriers of that disorder. As the result of the lyonization process, most carrier females have about 50% of the normal X and 50% of the mutant X expressed in each tissue, and usually do not display symptoms of the disorder. Because of the randomness of the lyonization process, exceptions to this rule exist, particularly if the inactivation of one copy of the X chromosome is significantly “skewed” in favor of one of the copies. If the normal copy prevails, then female carriers can be and remain completely asymptomatic. If the mutant copy prevails, then carrier females can develop symptoms of the disorder. Unlike females, males have only one X chromosome. If a male inherits an X chromosome that contains a disease gene, he will develop the disease. A male with an X-linked disorder passes the disease gene to all of his daughters, and the daughters will be carriers. A male cannot pass an X-linked gene to his sons because the Y chromosome (not the X chromosome) is always passed to male offspring. A female carrier of an X-linked disorder has a 50% chance with each pregnancy of having a carrier daughter, a 50% chance of having a non-carrier daughter, a 50% chance of having a son affected with the disease, and a 50% chance of having an unaffected son. Hyper IgM types 2, 3, 4 and 5 are inherited in an autosomal recessive pattern. Disorders inherited in a recessive pattern occur when an individual inherits two variants in a gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
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Affects of Hyper IgM Syndromes
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X-liked hyper IgM syndrome is estimated to affect about 2 in 1,000,000 newborn boys. The autosomal recessive forms of hyper IgM syndrome are extremely rare. Hyper IgM syndrome type 2 is estimated to affect fewer than 1 in 1,000,000 people in the general population. The other forms of hyper IgM syndrome have only been described in the medical literature in a very small number of people. Because rare disorders often go undiagnosed, determining their true frequency in the general population is difficult. The X-linked form predominately affects males; the autosomal recessive forms affect both males and females. X-linked hyper IgM syndrome accounts for about 70% of people with this disorder.
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Affects of Hyper IgM Syndromes. X-liked hyper IgM syndrome is estimated to affect about 2 in 1,000,000 newborn boys. The autosomal recessive forms of hyper IgM syndrome are extremely rare. Hyper IgM syndrome type 2 is estimated to affect fewer than 1 in 1,000,000 people in the general population. The other forms of hyper IgM syndrome have only been described in the medical literature in a very small number of people. Because rare disorders often go undiagnosed, determining their true frequency in the general population is difficult. The X-linked form predominately affects males; the autosomal recessive forms affect both males and females. X-linked hyper IgM syndrome accounts for about 70% of people with this disorder.
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Related disorders of Hyper IgM Syndromes
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Symptoms of the following disorders can be similar to those of hyper IgM syndromes. Comparisons may be useful for a differential diagnosis.X-linked ectodermal dysplasia associated with immunodeficiency is a rare genetic disorder that is also associated with elevated IgM levels because of a failure of B cells to switch to creating other immunoglobulin classes. This disorder is also called NEMO immunodeficiency syndrome because the gene associated with the disorder was once called NEMO, but is now called IKBKG. This disorder is sometimes referred to as hyper IgM syndrome type 6. Ectodermal dysplasias are a group of rare disorders in which the affected tissues primarily come from the ectodermal germ layer, one of the primary three layers of a fetus. Usually, there is abnormal development of the hair, skin, nails, teeth, and/or sweat glands. The most common symptoms of this disorder are thickened skin, misshapen teeth, absent sweat glands (which can lead to overheating, high fevers and seizures), and thin, sparse hair. Affected individuals are also susceptible to a variety of bacterial and opportunistic infections and can have a similar pattern of immunodeficiency as seen in hyper IgM syndrome. The specific signs and symptoms can vary greatly from one person to another. X-linked ectodermal dysplasia associated with immunodeficiency is caused by variations in the IKBKG gene and is inherited in an X-linked recessive manner. The disorder predominately affects males. There are conditions that are not genetic that cause elevated levels of IgM. These are referred to as acquired forms because they are “acquired” at some point during life and not present at birth. These conditions include congenital rubella syndrome, in which newborns are ill because the mother is infected with measles (rubella) and certain cancers (malignancies) such as multiple myeloma or lymphoma. These conditions are not inherited genetic forms of immunodeficiency and do not fall under the families of diseases known as hyper IgM syndromes. There are several, rare genetic disorders that are associated with an ability of the body to change from creating IgM to creating other immunoglobulin classes. These disorders are sometimes classified as forms of hyper IgM syndrome. They are extremely rare and include PMS2 deficiency, phosphoinositide 3-kinase (PI3K) deficiency, mutator S homolog 6 (MSH6) deficiency, and deficiency in INO80 chromatin remodeling complex. Other disorders that can have elevated IgM levels include common variable immunodeficiency (CVID), Nijmegen syndrome, and ataxia telangiectasia. NORD has reports on some of these disorders (For more information, choose the exact disorder name as your search term in the Rare Disease Database.)
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Related disorders of Hyper IgM Syndromes. Symptoms of the following disorders can be similar to those of hyper IgM syndromes. Comparisons may be useful for a differential diagnosis.X-linked ectodermal dysplasia associated with immunodeficiency is a rare genetic disorder that is also associated with elevated IgM levels because of a failure of B cells to switch to creating other immunoglobulin classes. This disorder is also called NEMO immunodeficiency syndrome because the gene associated with the disorder was once called NEMO, but is now called IKBKG. This disorder is sometimes referred to as hyper IgM syndrome type 6. Ectodermal dysplasias are a group of rare disorders in which the affected tissues primarily come from the ectodermal germ layer, one of the primary three layers of a fetus. Usually, there is abnormal development of the hair, skin, nails, teeth, and/or sweat glands. The most common symptoms of this disorder are thickened skin, misshapen teeth, absent sweat glands (which can lead to overheating, high fevers and seizures), and thin, sparse hair. Affected individuals are also susceptible to a variety of bacterial and opportunistic infections and can have a similar pattern of immunodeficiency as seen in hyper IgM syndrome. The specific signs and symptoms can vary greatly from one person to another. X-linked ectodermal dysplasia associated with immunodeficiency is caused by variations in the IKBKG gene and is inherited in an X-linked recessive manner. The disorder predominately affects males. There are conditions that are not genetic that cause elevated levels of IgM. These are referred to as acquired forms because they are “acquired” at some point during life and not present at birth. These conditions include congenital rubella syndrome, in which newborns are ill because the mother is infected with measles (rubella) and certain cancers (malignancies) such as multiple myeloma or lymphoma. These conditions are not inherited genetic forms of immunodeficiency and do not fall under the families of diseases known as hyper IgM syndromes. There are several, rare genetic disorders that are associated with an ability of the body to change from creating IgM to creating other immunoglobulin classes. These disorders are sometimes classified as forms of hyper IgM syndrome. They are extremely rare and include PMS2 deficiency, phosphoinositide 3-kinase (PI3K) deficiency, mutator S homolog 6 (MSH6) deficiency, and deficiency in INO80 chromatin remodeling complex. Other disorders that can have elevated IgM levels include common variable immunodeficiency (CVID), Nijmegen syndrome, and ataxia telangiectasia. NORD has reports on some of these disorders (For more information, choose the exact disorder name as your search term in the Rare Disease Database.)
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Diagnosis of Hyper IgM Syndromes
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A diagnosis of hyper IgM syndrome is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation, a variety of specialized tests, including laboratory testing that can detect a pattern of immune system defects. Clinical Testing and Workup
Blood tests will be ordered to determine the status of immunoglobulins in the blood, including normal or high levels of IgM and low levels of other immunoglobulin classes. Low levels of red and white blood cells or platelets can also be detected when autoimmune cytopenia is present. Most times an exam called flow cytometry is used. This is a technology that can analyze the physical and chemical characteristics of particles in a fluid. Flow cytometry of the peripheral blood means that the peripheral blood (the blood that is circulating through the body) is studied through a machine called a flow cytometer. The flow cytometer will be able to tell the number and percentage of cells in the blood sample. It can also determine the size, shape and unique characteristics of cells such as biomarkers on the cells’ surfaces including the number of B cells in various stages of development. A key reason to order flow cytometry is to show absent or decreased expression of CD40 ligand protein on the surface of T cells or decreased ability to T cells to bind CD40, which is indicative of X-linked hyper IgM syndrome. Hyper IgM syndrome type 3 can be indicated when assessing the expression of the CD40 receptor on B cells and a type of white blood cell call monocytes. If possible, molecular genetic testing should then be recommended to confirm a diagnosis. Molecular genetic testing can detect variations (mutations) in specific genes known to cause hyper IgM syndromes. These tests are the preferred diagnostic methods for hyper IgM syndromes, and although performed by specialized laboratories, these tests are becoming more available and more easily performed. X-linked hyper IgM syndrome and hyper IgM syndrome type 3 are mostly diagnosed by genetic testing. Hyper IgM syndromes type 2 and 5 are usually confirmed through genetic testing. Because the underlying genetic defect for hyper IgM syndrome type 4 is unknown, there is no test to confirm a diagnosis.
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Diagnosis of Hyper IgM Syndromes. A diagnosis of hyper IgM syndrome is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation, a variety of specialized tests, including laboratory testing that can detect a pattern of immune system defects. Clinical Testing and Workup
Blood tests will be ordered to determine the status of immunoglobulins in the blood, including normal or high levels of IgM and low levels of other immunoglobulin classes. Low levels of red and white blood cells or platelets can also be detected when autoimmune cytopenia is present. Most times an exam called flow cytometry is used. This is a technology that can analyze the physical and chemical characteristics of particles in a fluid. Flow cytometry of the peripheral blood means that the peripheral blood (the blood that is circulating through the body) is studied through a machine called a flow cytometer. The flow cytometer will be able to tell the number and percentage of cells in the blood sample. It can also determine the size, shape and unique characteristics of cells such as biomarkers on the cells’ surfaces including the number of B cells in various stages of development. A key reason to order flow cytometry is to show absent or decreased expression of CD40 ligand protein on the surface of T cells or decreased ability to T cells to bind CD40, which is indicative of X-linked hyper IgM syndrome. Hyper IgM syndrome type 3 can be indicated when assessing the expression of the CD40 receptor on B cells and a type of white blood cell call monocytes. If possible, molecular genetic testing should then be recommended to confirm a diagnosis. Molecular genetic testing can detect variations (mutations) in specific genes known to cause hyper IgM syndromes. These tests are the preferred diagnostic methods for hyper IgM syndromes, and although performed by specialized laboratories, these tests are becoming more available and more easily performed. X-linked hyper IgM syndrome and hyper IgM syndrome type 3 are mostly diagnosed by genetic testing. Hyper IgM syndromes type 2 and 5 are usually confirmed through genetic testing. Because the underlying genetic defect for hyper IgM syndrome type 4 is unknown, there is no test to confirm a diagnosis.
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Therapies of Hyper IgM Syndromes
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Treatment
The treatment of hyper IgM syndromes is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, physicians who specialize in the diagnosis and treatment of immune system disorders (immunologists), specialize in the diagnosis and treatment of blood disorders (hematologists), infectious diseases specialists, and other healthcare professionals may need to systematically and comprehensively plan treatment. Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well.Individuals with all forms of hyper IgM syndrome are treated with regular immunoglobulin replacement therapy. This can be administered by direct infusion into the vein in an arm (intravenously) or just below the surface of the skin (subcutaneously). These infusions contain antibodies (IgG) obtained from the fluid portion of the blood (plasma) from donors. This will restore the immunoglobulin levels to normal. This therapy can be very helpful for all forms of IgM. It markedly reduces the frequency of bacterial infections and reduces the likelihood of developing lymphoid hyperplasia. Immunoglobulin replacement therapy does not help with opportunistic infections that are seen in X-linked hyper IgM syndrome or hyper IgM syndrome type 3. In addition to immunoglobulin replacement therapy, individuals with these forms of the disorder will receive preventive (prophylactic) therapy with antibiotic medications such as trimethoprim-cotrimoxazole, a combination of antibiotics against specific bacterial infections such as Pneumocystis jirovecii, which causes pneumonia. Antibiotic medications, nitazoxanide and azithromycin, have been used to treat active Cryptosporidium infection. Hyper IgM syndrome types 2, 4, and 5 can often be treated with immunoglobulin replacement therapy alone. However, sometimes prophylactic antibiotic therapy will be recommended for individuals who develop chronic complications such as bronchiectasis or recurrent sinus infections. Affected individuals with chronic neutropenia have been treated with granulocyte-colony stimulating factor. This drug stimulates the production of neutrophils. When autoimmune disorders occur, they are treated as with people who do not have hyper IgM syndrome and develop an autoimmune disorder.The only curative therapy for hyper IgM syndrome is an allogeneic hematopoietic stem cell transplant. This therapy is generally considered for individuals with X-linked hyper IgM syndrome or hyper IgM syndrome type 3. Hematopoietic stem cells are specialized cells found in the bone marrow (the soft spongy material found in long bones). These blood stem cells grow and eventually develop into one of the three main types of blood cells– red blood cells, white blood cells or platelets. A transplant is done to replace the bone marrow (and consequently the whole blood system) of an affected individual with marrow from a person who does not have a particular disorder. The healthy cells produced by the new marrow contain sufficient levels of white blood cells and produce the proper levels of immunoglobulins (antibodies). The procedure is expensive and carries the risk of serious complications including graft-versus-host disease and other long-term and late effects.LIFESTYLE CHANGES
Individuals with hyper IgM syndromes will be advised to make certain lifestyle changes including only drinking water that has been boiled or filtered through a reverse osmosis process. Swimming in lakes or communal pools should be avoided. Some medical sources recommend that young children avoid daycare and preschool because children there are often sick, avoid contact with farm animals, and minimize contact with kittens and puppies.
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Therapies of Hyper IgM Syndromes. Treatment
The treatment of hyper IgM syndromes is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, physicians who specialize in the diagnosis and treatment of immune system disorders (immunologists), specialize in the diagnosis and treatment of blood disorders (hematologists), infectious diseases specialists, and other healthcare professionals may need to systematically and comprehensively plan treatment. Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well.Individuals with all forms of hyper IgM syndrome are treated with regular immunoglobulin replacement therapy. This can be administered by direct infusion into the vein in an arm (intravenously) or just below the surface of the skin (subcutaneously). These infusions contain antibodies (IgG) obtained from the fluid portion of the blood (plasma) from donors. This will restore the immunoglobulin levels to normal. This therapy can be very helpful for all forms of IgM. It markedly reduces the frequency of bacterial infections and reduces the likelihood of developing lymphoid hyperplasia. Immunoglobulin replacement therapy does not help with opportunistic infections that are seen in X-linked hyper IgM syndrome or hyper IgM syndrome type 3. In addition to immunoglobulin replacement therapy, individuals with these forms of the disorder will receive preventive (prophylactic) therapy with antibiotic medications such as trimethoprim-cotrimoxazole, a combination of antibiotics against specific bacterial infections such as Pneumocystis jirovecii, which causes pneumonia. Antibiotic medications, nitazoxanide and azithromycin, have been used to treat active Cryptosporidium infection. Hyper IgM syndrome types 2, 4, and 5 can often be treated with immunoglobulin replacement therapy alone. However, sometimes prophylactic antibiotic therapy will be recommended for individuals who develop chronic complications such as bronchiectasis or recurrent sinus infections. Affected individuals with chronic neutropenia have been treated with granulocyte-colony stimulating factor. This drug stimulates the production of neutrophils. When autoimmune disorders occur, they are treated as with people who do not have hyper IgM syndrome and develop an autoimmune disorder.The only curative therapy for hyper IgM syndrome is an allogeneic hematopoietic stem cell transplant. This therapy is generally considered for individuals with X-linked hyper IgM syndrome or hyper IgM syndrome type 3. Hematopoietic stem cells are specialized cells found in the bone marrow (the soft spongy material found in long bones). These blood stem cells grow and eventually develop into one of the three main types of blood cells– red blood cells, white blood cells or platelets. A transplant is done to replace the bone marrow (and consequently the whole blood system) of an affected individual with marrow from a person who does not have a particular disorder. The healthy cells produced by the new marrow contain sufficient levels of white blood cells and produce the proper levels of immunoglobulins (antibodies). The procedure is expensive and carries the risk of serious complications including graft-versus-host disease and other long-term and late effects.LIFESTYLE CHANGES
Individuals with hyper IgM syndromes will be advised to make certain lifestyle changes including only drinking water that has been boiled or filtered through a reverse osmosis process. Swimming in lakes or communal pools should be avoided. Some medical sources recommend that young children avoid daycare and preschool because children there are often sick, avoid contact with farm animals, and minimize contact with kittens and puppies.
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Overview of Hyperekplexia
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Hyperekplexia is a rare hereditary, neurological disorder that may affect infants as newborns (neonatal) or prior to birth (in utero). It may also affect children and adults. Individuals with this disorder have an excessive startle reaction (eye blinking or body spasms) to sudden unexpected noise, movement, or touch. Symptoms include extreme muscle tension (stiffness or hypertonia) that prevent voluntary movement and can cause the affected person to fall stiffly, like a log, without loss of consciousness. Exaggeration of reflexes (hyperreflexia), and an unstable way of walking (gait) may also occur. Hyperekplexia is usually inherited as an autosomal dominant trait, but autosomal recessive or rarely, X-linked inheritance, has also been reported.Hyperekplexia is frequently misdiagnosed as a form of epilepsy so the process of getting an accurate diagnosis may be prolonged Treatment is relatively uncomplicated and involves the use of anti-anxiety and anti-spastic medicines Physical and cognitive therapy are supplemental treatment options.
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Overview of Hyperekplexia. Hyperekplexia is a rare hereditary, neurological disorder that may affect infants as newborns (neonatal) or prior to birth (in utero). It may also affect children and adults. Individuals with this disorder have an excessive startle reaction (eye blinking or body spasms) to sudden unexpected noise, movement, or touch. Symptoms include extreme muscle tension (stiffness or hypertonia) that prevent voluntary movement and can cause the affected person to fall stiffly, like a log, without loss of consciousness. Exaggeration of reflexes (hyperreflexia), and an unstable way of walking (gait) may also occur. Hyperekplexia is usually inherited as an autosomal dominant trait, but autosomal recessive or rarely, X-linked inheritance, has also been reported.Hyperekplexia is frequently misdiagnosed as a form of epilepsy so the process of getting an accurate diagnosis may be prolonged Treatment is relatively uncomplicated and involves the use of anti-anxiety and anti-spastic medicines Physical and cognitive therapy are supplemental treatment options.
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Symptoms of Hyperekplexia
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There are major and minor forms of hyperekplexia. In the major form, hyperekplexia is characterized by an unusually extreme startle reaction to sudden unexpected noise, movement, or touch. Arching of the head (exaggerated head-retraction reflex or HRR), spastic jerking movements (myoclonic jerks) or falling stiffly to the ground (without losing consciousness) tend to occur when the individual is startled. The frequency and severity of the startle response can be increased by emotional tension, stress, or fatigue.Jerking movements can also occur when the patient is trying to fall asleep (hypnagogic myoclonic jerks; for more information on myoclonic jerks, choose “myoclonus” as your search term in the Rare Disease Database). Extreme muscle tension or stiffness (hypertonia) is common in infants with hyperexplexia, especially at birth. Affected babies may not move around much, and when they do, they tend to move slowly (hypokinesia). Other symptoms presented by infants as well as adults may include exaggeration of reflexes (hyperreflexia), interrupted breathing (intermittent apnea) and/or unstable walking (gait), usually with a mild wide-based stance. Some patients have a dislocation of the hip that is present at birth. Hernias are not uncommon in the lower abdomen (inguinal hernias). In the minor form, individuals with hyperekplexia usually experience only an inconstant exaggerated startle reaction with few or none of the other symptoms. In infants with the minor form, the reaction may be brought on by fever. In children and adults, intensity of the startle response may be affected by stress or anxiety. Onset of both major and minor forms of hyperekplexia is usually from birth, but in some patients it does not occur until adolescence or adulthood. Mild intellectual disability may also be observed.
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Symptoms of Hyperekplexia. There are major and minor forms of hyperekplexia. In the major form, hyperekplexia is characterized by an unusually extreme startle reaction to sudden unexpected noise, movement, or touch. Arching of the head (exaggerated head-retraction reflex or HRR), spastic jerking movements (myoclonic jerks) or falling stiffly to the ground (without losing consciousness) tend to occur when the individual is startled. The frequency and severity of the startle response can be increased by emotional tension, stress, or fatigue.Jerking movements can also occur when the patient is trying to fall asleep (hypnagogic myoclonic jerks; for more information on myoclonic jerks, choose “myoclonus” as your search term in the Rare Disease Database). Extreme muscle tension or stiffness (hypertonia) is common in infants with hyperexplexia, especially at birth. Affected babies may not move around much, and when they do, they tend to move slowly (hypokinesia). Other symptoms presented by infants as well as adults may include exaggeration of reflexes (hyperreflexia), interrupted breathing (intermittent apnea) and/or unstable walking (gait), usually with a mild wide-based stance. Some patients have a dislocation of the hip that is present at birth. Hernias are not uncommon in the lower abdomen (inguinal hernias). In the minor form, individuals with hyperekplexia usually experience only an inconstant exaggerated startle reaction with few or none of the other symptoms. In infants with the minor form, the reaction may be brought on by fever. In children and adults, intensity of the startle response may be affected by stress or anxiety. Onset of both major and minor forms of hyperekplexia is usually from birth, but in some patients it does not occur until adolescence or adulthood. Mild intellectual disability may also be observed.
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Causes of Hyperekplexia
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In most cases, hyperekplexia is inherited as an autosomal dominant trait, but can also follow autosomal recessive or X-linked inheritance. Mutations in the following genes are associated with the condition: GLRA1, SLC6A5, GLRB, GPHN, and ARHGEF9 (X-linked). Most affected individuals have a mutation in either the GLRA1, SLC6A5 gene and have an affected parent.The genes that cause hyperekplexia are involved in the production of the glycine protein Glycine diminishes the action of nerve cells in the brain and spinal cord. It is known as an “inhibitor transmitter”. If the glycine receptors are interfered with in some way or damaged, the nerve cells lack their inhibitions and thus react to stimuli too easily and excessively. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and manifest mostly in males. Females that have a defective gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the defective gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a defective gene he will develop the disease.Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son. If a male with an X-linked disorder is able to reproduce, he will pass the defective gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.
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Causes of Hyperekplexia. In most cases, hyperekplexia is inherited as an autosomal dominant trait, but can also follow autosomal recessive or X-linked inheritance. Mutations in the following genes are associated with the condition: GLRA1, SLC6A5, GLRB, GPHN, and ARHGEF9 (X-linked). Most affected individuals have a mutation in either the GLRA1, SLC6A5 gene and have an affected parent.The genes that cause hyperekplexia are involved in the production of the glycine protein Glycine diminishes the action of nerve cells in the brain and spinal cord. It is known as an “inhibitor transmitter”. If the glycine receptors are interfered with in some way or damaged, the nerve cells lack their inhibitions and thus react to stimuli too easily and excessively. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and manifest mostly in males. Females that have a defective gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the defective gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a defective gene he will develop the disease.Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son. If a male with an X-linked disorder is able to reproduce, he will pass the defective gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.
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Affects of Hyperekplexia
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Hyperekplexia is a rare genetic disorder that is most often present at birth and affects both males and females. In some individuals, onset of the disorder may be delayed until adolescence or adulthood. Hyperekplexia affects approximately one in 40,000 people in the United States.
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Affects of Hyperekplexia. Hyperekplexia is a rare genetic disorder that is most often present at birth and affects both males and females. In some individuals, onset of the disorder may be delayed until adolescence or adulthood. Hyperekplexia affects approximately one in 40,000 people in the United States.
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Related disorders of Hyperekplexia
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Symptoms of the following disorders can be similar to those of Hyperekplexia. Comparisons may be useful for a differential diagnosis: Neuropsychiatric startle symptoms in which behavioral and/or psychiatric symptoms may be observed in addition to startling. For example, Jumping Frenchmen of Maine is a disorder characterized by an extreme startle reaction consisting of jumping, raising the arms, yelling, hitting, obeying sudden commands, or involuntarily repeating sentences. (People with hyperekplexia do not have the imitative repetition of words or actions, or the forced obedience response found in “Jumping Frenchmen”). The intensity of the response may be affected by the frequency of being startled, fatigue and/or stress. The affected person must be startled by an unexpected event in order to elicit the reaction. It is suspected to be a genetic disorder and/or an extreme conditioned response to a particular situation possibly influenced by cultural factors. (For more information on this disorder, choose “Jumping Frenchmen” as your search term in the Rare Disease Database.) Startle Epilepsy is expressed as a brief muscular contraction predominating on one-half of the body in response to sudden noise or movement. These patients often fall when startled and also have other seizure manifestations. (For more information on this disorder, choose “Epilepsy” as your search term in the Rare Disease Database.)General anxiety or tic disorders as well as additional startle-induced conditions may also have similar symptomatology. For example stiff person syndrome (SPS) is observed in older individuals (typically between the ages of 40 and 60) and is often accompanied by prolonged and progressive stiffness and intermittent spasms.
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Related disorders of Hyperekplexia. Symptoms of the following disorders can be similar to those of Hyperekplexia. Comparisons may be useful for a differential diagnosis: Neuropsychiatric startle symptoms in which behavioral and/or psychiatric symptoms may be observed in addition to startling. For example, Jumping Frenchmen of Maine is a disorder characterized by an extreme startle reaction consisting of jumping, raising the arms, yelling, hitting, obeying sudden commands, or involuntarily repeating sentences. (People with hyperekplexia do not have the imitative repetition of words or actions, or the forced obedience response found in “Jumping Frenchmen”). The intensity of the response may be affected by the frequency of being startled, fatigue and/or stress. The affected person must be startled by an unexpected event in order to elicit the reaction. It is suspected to be a genetic disorder and/or an extreme conditioned response to a particular situation possibly influenced by cultural factors. (For more information on this disorder, choose “Jumping Frenchmen” as your search term in the Rare Disease Database.) Startle Epilepsy is expressed as a brief muscular contraction predominating on one-half of the body in response to sudden noise or movement. These patients often fall when startled and also have other seizure manifestations. (For more information on this disorder, choose “Epilepsy” as your search term in the Rare Disease Database.)General anxiety or tic disorders as well as additional startle-induced conditions may also have similar symptomatology. For example stiff person syndrome (SPS) is observed in older individuals (typically between the ages of 40 and 60) and is often accompanied by prolonged and progressive stiffness and intermittent spasms.
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Diagnosis of Hyperekplexia
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Hyperekplexia is one thing that should be considered when an infant has seizures. A family history is an important part of the diagnosis, because of the usual genetic linkage. The major features of hyperekplexia are an excessive startle reflex/response, stiffness at birth, and brief impaired voluntary movement following the startle responseTesting for hyperekplexia can include electromyography (records of electrical impulses produced by the muscles) and electroencephalography (EEG, or records of electrical activity in the brain).The first step in molecular genetic testing for an individual who meets the clinical criteria for the condition is to test for mutations in the GLRA1 and SLC6A5 genes. Sequence analysis of the ARHGEF9 gene may be considered in males without identified GLRA1 or SLC6A5 mutations, particularly if cognitive impairment and epilepsy are present. If mutations are not identified, molecular genetic testing for mutations in the GLRB and GPHN genes can be considered,
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Diagnosis of Hyperekplexia. Hyperekplexia is one thing that should be considered when an infant has seizures. A family history is an important part of the diagnosis, because of the usual genetic linkage. The major features of hyperekplexia are an excessive startle reflex/response, stiffness at birth, and brief impaired voluntary movement following the startle responseTesting for hyperekplexia can include electromyography (records of electrical impulses produced by the muscles) and electroencephalography (EEG, or records of electrical activity in the brain).The first step in molecular genetic testing for an individual who meets the clinical criteria for the condition is to test for mutations in the GLRA1 and SLC6A5 genes. Sequence analysis of the ARHGEF9 gene may be considered in males without identified GLRA1 or SLC6A5 mutations, particularly if cognitive impairment and epilepsy are present. If mutations are not identified, molecular genetic testing for mutations in the GLRB and GPHN genes can be considered,
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Therapies of Hyperekplexia
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TreatmentIn both infants and adults, hyperekplexia is treated most effectively with the anti-anxiety and anti-spastic drug clonazepam. Other drugs that may be used include carbamazepine, phenobarbital, phenytoin, diazepam, 5-hydroxytryptophan, piracetam, and sodium valproate.Genetic counseling may be of benefit for patients and their families. Other treatment, such as physical and/or cognitive therapy to reduce anxiety can be supportive.
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Therapies of Hyperekplexia. TreatmentIn both infants and adults, hyperekplexia is treated most effectively with the anti-anxiety and anti-spastic drug clonazepam. Other drugs that may be used include carbamazepine, phenobarbital, phenytoin, diazepam, 5-hydroxytryptophan, piracetam, and sodium valproate.Genetic counseling may be of benefit for patients and their families. Other treatment, such as physical and/or cognitive therapy to reduce anxiety can be supportive.
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Overview of Hyperferritinemia Cataract Syndrome
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Hyperferritinemia-cataract syndrome is an extremely rare genetic disorder characterized by the early onset of cataracts associated with persistently elevated levels of ferritin in the blood plasma. Ferritin is a protein that binds to iron and is used as an indicator of the body's iron stores. Cataracts are the only known complication associated with this disorder. Hyperferritinemia-cataract syndrome is caused by mutations to ferritin light chain (FTL) gene. This mutation is inherited as an autosomal dominant trait.
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Overview of Hyperferritinemia Cataract Syndrome. Hyperferritinemia-cataract syndrome is an extremely rare genetic disorder characterized by the early onset of cataracts associated with persistently elevated levels of ferritin in the blood plasma. Ferritin is a protein that binds to iron and is used as an indicator of the body's iron stores. Cataracts are the only known complication associated with this disorder. Hyperferritinemia-cataract syndrome is caused by mutations to ferritin light chain (FTL) gene. This mutation is inherited as an autosomal dominant trait.
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Hyperferritinemia Cataract Syndrome
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Symptoms of Hyperferritinemia Cataract Syndrome
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The only known symptom of hyperferritinemia-cataract syndrome is the early onset of cataracts, usually between the second and fourth decades of life. However, onset of the disorder has been reported in children as young as five and adults more than 40. The overall prognosis of the disorder is very good. The severity of the hyperferritinemia-cataract syndrome can vary greatly from one person to another even among members of the same family. Some individuals with characteristic mutations of the FLT gene have not developed any symptoms (asymptomatic). Cataracts are characterized by a clouding (opacity) of the lenses of the eye and can affect vision. The lens of an eye is the clear front portion of the eye through which light passes. The light is focused on the retina, the thin nerve-rich membrane lining the back of the eye. The retina converts light into nerve impulses and relays the information along the optic nerve to the brain. Cataracts can potentially affect both eyes and may cause several symptoms. Evidence suggests that cataracts in hyperferritinemia-cataract syndrome may become progressively worse. Individuals with hyperferritinemia-cataract syndrome may experience glare symptoms that are worse when driving at night or in bright sunlight. Glare symptoms means that headlights, lamps, and other lights may appear too bright or have a halo form around them. Some affected individuals may be abnormally sensitive to light (photophobia) or experience blurred or hazy vision.
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Symptoms of Hyperferritinemia Cataract Syndrome. The only known symptom of hyperferritinemia-cataract syndrome is the early onset of cataracts, usually between the second and fourth decades of life. However, onset of the disorder has been reported in children as young as five and adults more than 40. The overall prognosis of the disorder is very good. The severity of the hyperferritinemia-cataract syndrome can vary greatly from one person to another even among members of the same family. Some individuals with characteristic mutations of the FLT gene have not developed any symptoms (asymptomatic). Cataracts are characterized by a clouding (opacity) of the lenses of the eye and can affect vision. The lens of an eye is the clear front portion of the eye through which light passes. The light is focused on the retina, the thin nerve-rich membrane lining the back of the eye. The retina converts light into nerve impulses and relays the information along the optic nerve to the brain. Cataracts can potentially affect both eyes and may cause several symptoms. Evidence suggests that cataracts in hyperferritinemia-cataract syndrome may become progressively worse. Individuals with hyperferritinemia-cataract syndrome may experience glare symptoms that are worse when driving at night or in bright sunlight. Glare symptoms means that headlights, lamps, and other lights may appear too bright or have a halo form around them. Some affected individuals may be abnormally sensitive to light (photophobia) or experience blurred or hazy vision.
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Causes of Hyperferritinemia Cataract Syndrome
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Hyperferritinemia-cataract syndrome is caused by mutations of the ferritin light chain (FTL) gene and is inherited as an autosomal dominant trait.Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy. 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.Mutations of the FTL gene in hyperferritinemia-cataract syndrome affect a region of the gene known as the iron regulatory element (IRE). A specialized protein called iron regulatory protein (IRP) normally binds to the IRE and suppresses the creation of ferritin. Mutations of the IRE prevent the binding of this protein and ultimately results in elevated levels of ferritin it the blood plasma. Ferritin is also commonly found in the lenses of the eyes. In individuals with hyperferritinemia-cataract syndrome, excess amounts of ferritin have been found in the lenses of the eyes and are believed to cause the development of cataracts.
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Causes of Hyperferritinemia Cataract Syndrome. Hyperferritinemia-cataract syndrome is caused by mutations of the ferritin light chain (FTL) gene and is inherited as an autosomal dominant trait.Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy. 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.Mutations of the FTL gene in hyperferritinemia-cataract syndrome affect a region of the gene known as the iron regulatory element (IRE). A specialized protein called iron regulatory protein (IRP) normally binds to the IRE and suppresses the creation of ferritin. Mutations of the IRE prevent the binding of this protein and ultimately results in elevated levels of ferritin it the blood plasma. Ferritin is also commonly found in the lenses of the eyes. In individuals with hyperferritinemia-cataract syndrome, excess amounts of ferritin have been found in the lenses of the eyes and are believed to cause the development of cataracts.
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Affects of Hyperferritinemia Cataract Syndrome
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Hyperferritinemia-cataract syndrome is an extremely rare disorder that affects males and females in equal numbers. More than 100 families with the disorder have been described in the medical literature. The prevalence of hyperferritinemia-cataract syndrome has been estimated at 1 in 200,000 people in the general population. Because the disorder is so rare, it often goes unrecognized or undiagnosed, making it difficult to determine the disorder's true frequency in the general population. Hyperferritinemia-cataract syndrome was first described in the medical literature in 1995.
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Affects of Hyperferritinemia Cataract Syndrome. Hyperferritinemia-cataract syndrome is an extremely rare disorder that affects males and females in equal numbers. More than 100 families with the disorder have been described in the medical literature. The prevalence of hyperferritinemia-cataract syndrome has been estimated at 1 in 200,000 people in the general population. Because the disorder is so rare, it often goes unrecognized or undiagnosed, making it difficult to determine the disorder's true frequency in the general population. Hyperferritinemia-cataract syndrome was first described in the medical literature in 1995.
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Related disorders of Hyperferritinemia Cataract Syndrome
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Symptoms of the following disorders can be similar to those of hyperferritinemia-cataract syndrome. Comparisons may be useful for a differential diagnosis. Primary disorders of iron overload are a group of rare disorders characterized by iron accumulation in the body. This group includes hemochromatosis, juvenile hemochromatosis, atransferrinemia, neonatal hemochromatosis, and African iron overload disease. These disorders often have additional symptoms that distinguish them from hyperferritinemia-cataract syndrome. Such symptoms can vary depending upon the location and extent of iron accumulation. Common symptoms include fatigue, abdominal pain, lack of sex drive, joint pain, and heart abnormalities. If left untreated, iron can build up in various organs in the body causing serious, life-threatening complications. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Related disorders of Hyperferritinemia Cataract Syndrome. Symptoms of the following disorders can be similar to those of hyperferritinemia-cataract syndrome. Comparisons may be useful for a differential diagnosis. Primary disorders of iron overload are a group of rare disorders characterized by iron accumulation in the body. This group includes hemochromatosis, juvenile hemochromatosis, atransferrinemia, neonatal hemochromatosis, and African iron overload disease. These disorders often have additional symptoms that distinguish them from hyperferritinemia-cataract syndrome. Such symptoms can vary depending upon the location and extent of iron accumulation. Common symptoms include fatigue, abdominal pain, lack of sex drive, joint pain, and heart abnormalities. If left untreated, iron can build up in various organs in the body causing serious, life-threatening complications. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Hyperferritinemia Cataract Syndrome
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Diagnosis of Hyperferritinemia Cataract Syndrome
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A diagnosis of hyperferritinemia-cataract syndrome is made based upon identification of characteristic symptoms (e.g., cataracts), a detailed patient history, a thorough clinical evaluation and a variety of specialized tests such as blood tests, which can reveal elevated levels of ferritin in the blood plasma.
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Diagnosis of Hyperferritinemia Cataract Syndrome. A diagnosis of hyperferritinemia-cataract syndrome is made based upon identification of characteristic symptoms (e.g., cataracts), a detailed patient history, a thorough clinical evaluation and a variety of specialized tests such as blood tests, which can reveal elevated levels of ferritin in the blood plasma.
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Therapies of Hyperferritinemia Cataract Syndrome
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TreatmentThere is no specific treatment for hyperferritinemia-cataract syndrome. Cataracts are the only known complication of the disorder. Individuals are treated with corrective glasses, contact lenses and, if vision is impaired to the point of interference with daily activities, then cataract surgery is performed. During cataract surgery, the cloudy lens inside the eye is replaced with a clear plastic lens. This surgery is technologically advanced and has a high success rate.Therapy involving the regular removal of blood via a vein (known as a venesection or phlebotomy) is a common therapy for disorders associated with excess iron in the blood, but is not recommended as a therapy for hyperferritinemia-cataract syndrome.Genetic counseling may be of benefit for affected individuals and their families.
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Therapies of Hyperferritinemia Cataract Syndrome. TreatmentThere is no specific treatment for hyperferritinemia-cataract syndrome. Cataracts are the only known complication of the disorder. Individuals are treated with corrective glasses, contact lenses and, if vision is impaired to the point of interference with daily activities, then cataract surgery is performed. During cataract surgery, the cloudy lens inside the eye is replaced with a clear plastic lens. This surgery is technologically advanced and has a high success rate.Therapy involving the regular removal of blood via a vein (known as a venesection or phlebotomy) is a common therapy for disorders associated with excess iron in the blood, but is not recommended as a therapy for hyperferritinemia-cataract syndrome.Genetic counseling may be of benefit for affected individuals and their families.
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Overview of Hyperlipoproteinemia Type III
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Hyperlipoproteinemia type III is a genetic disorder that causes the body to breakdown (metabolize) fats (lipids) incorrectly. This results in the buildup of lipids in the body (hyperlipidemia) and can lead to the development of multiple small, yellow skin growths (xanthomas). Affected individuals may also develop the buildup of fatty materials in the blood vessels (atherosclerosis) blocking blood flow and potentially leading to heart attack or stroke. Hyperlipoproteinemia type III affects 1-5,000 to 1 in 10,000 people in the general population. Without treatment, affected individuals are 5-10 times more likely to develop cardiovascular disease.
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Overview of Hyperlipoproteinemia Type III. Hyperlipoproteinemia type III is a genetic disorder that causes the body to breakdown (metabolize) fats (lipids) incorrectly. This results in the buildup of lipids in the body (hyperlipidemia) and can lead to the development of multiple small, yellow skin growths (xanthomas). Affected individuals may also develop the buildup of fatty materials in the blood vessels (atherosclerosis) blocking blood flow and potentially leading to heart attack or stroke. Hyperlipoproteinemia type III affects 1-5,000 to 1 in 10,000 people in the general population. Without treatment, affected individuals are 5-10 times more likely to develop cardiovascular disease.
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Hyperlipoproteinemia Type III
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Symptoms of Hyperlipoproteinemia Type III
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The symptoms of hyperlipoproteinemia type III may vary from person to person. Some individuals may not show any symptoms (asymptomatic). Symptoms of hyperlipoproteinemia type III often do not appear unless additional conditions are present such as diabetes, obesity, or hypothyroidism.The most common feature associated with hyperlipoproteinemia type III is the development of xanthomas, which are deposits of fatty materials (lipids) in the skin and appear as multiple yellow bumps (papules) on or just beneath the skin. Xanthomas may form on different parts of the body including the hands, elbows, knees, knuckles, arms, legs, and buttocks. Xanthomas on the palms of the hands, a condition called xanthoma striata palmaris, is specific to hyperlipoproteinemia type III and has not been reported in any other disorder. Xanthomas can also develop within the tendons of the rear lower legs (Achilles tendon) and occasionally on the fingers. Some affected individuals may have fatty deposits within the corneas of the eyes (arcus lidus corneae).The risk for developing coronary heart disease is 5-10 times higher for an individual with hyperlipoproteinemia type III compared to the general population. Individuals with hyperlipoproteinemia type III may develop thickening and blockage of various blood vessels (atherosclerosis) due to the buildup of fatty material (lipids). Atherosclerosis may result in coronary heart disease or peripheral vascular disease. Coronary heart disease results from blockage of the blood supply to the heart potentially resulting in chest pain (angina) and heart attack. Peripheral vascular disease is a general term for disease of the blood vessels outside of the heart and brain. It results from blockage of the blood flow to various organs and the extremities. Decreased blood flow to the legs may result in cramping and cause a limp (claudication). Some individuals may have an abnormally enlarged liver or spleen (hepatosplenomegaly).Individuals with hyperlipoproteinemia type III may eventually develop inflammation of the pancreas (pancreatitis). Chronic pancreatitis may result in back pain, diarrhea, yellow-colored skin (jaundice), and potentially the development of diabetes. Pancreatitis can also lead to the development of pancreatic cancer.
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Symptoms of Hyperlipoproteinemia Type III. The symptoms of hyperlipoproteinemia type III may vary from person to person. Some individuals may not show any symptoms (asymptomatic). Symptoms of hyperlipoproteinemia type III often do not appear unless additional conditions are present such as diabetes, obesity, or hypothyroidism.The most common feature associated with hyperlipoproteinemia type III is the development of xanthomas, which are deposits of fatty materials (lipids) in the skin and appear as multiple yellow bumps (papules) on or just beneath the skin. Xanthomas may form on different parts of the body including the hands, elbows, knees, knuckles, arms, legs, and buttocks. Xanthomas on the palms of the hands, a condition called xanthoma striata palmaris, is specific to hyperlipoproteinemia type III and has not been reported in any other disorder. Xanthomas can also develop within the tendons of the rear lower legs (Achilles tendon) and occasionally on the fingers. Some affected individuals may have fatty deposits within the corneas of the eyes (arcus lidus corneae).The risk for developing coronary heart disease is 5-10 times higher for an individual with hyperlipoproteinemia type III compared to the general population. Individuals with hyperlipoproteinemia type III may develop thickening and blockage of various blood vessels (atherosclerosis) due to the buildup of fatty material (lipids). Atherosclerosis may result in coronary heart disease or peripheral vascular disease. Coronary heart disease results from blockage of the blood supply to the heart potentially resulting in chest pain (angina) and heart attack. Peripheral vascular disease is a general term for disease of the blood vessels outside of the heart and brain. It results from blockage of the blood flow to various organs and the extremities. Decreased blood flow to the legs may result in cramping and cause a limp (claudication). Some individuals may have an abnormally enlarged liver or spleen (hepatosplenomegaly).Individuals with hyperlipoproteinemia type III may eventually develop inflammation of the pancreas (pancreatitis). Chronic pancreatitis may result in back pain, diarrhea, yellow-colored skin (jaundice), and potentially the development of diabetes. Pancreatitis can also lead to the development of pancreatic cancer.
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Hyperlipoproteinemia Type III
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Causes of Hyperlipoproteinemia Type III
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Hypolipoproteinemia type III is a genetic condition caused by changes in the APOE gene. The APOE gene provides instructions for making a protein called apolipoprotein E. This protein combines with fats (lipids) in the body to form molecules called lipoproteins. Lipoproteins are responsible for packaging cholesterol and other fats, carrying them through the bloodstream, and helping clear them from the bloodstream. There are different versions (alleles) of the APOE gene. The major versions are called e2, e3, and e4. Every person has two copies of the APOE gene in some combination of these different versions. The most common version is e3, which is found in more than half of the general population. The APOE e2 version has been shown to increase the risk of hyperlipoproteinemia type III. APO e2 clears dietary fats from the body at a slower rate than apo e3. Also, of note, the APOE gene is associated with Alzheimer’s disease. However, individuals with two copies of the APO e2 variant have a low risk to develop the disease. The presence of two APO e2 genes by itself usually does not result in the development of symptoms of hyperlipoproteinemia type III. In fact, about 10-15 percent of individuals with two copies of the APO e2 variant develop outward symptoms of hyperlipoproteinemia type III. Researchers believe that additional genetic, environmental, or hormonal factors play a role in the development of the disorder. These factors may include the presence of other disorders (e.g., hypothyroidism, diabetes), obesity, or age. In women, low estrogen levels may contribute to the development of symptoms, which is why the disorder occurs in women after menopause. Hyperlipoproteinemia type III is most often inherited in an autosomal recessive pattern. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. Parents who are close blood relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. About 10% of hyperlipoproteinemia type III is caused by versions of the APOE gene that are inherited in an autosomal dominant pattern. 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. 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.Individuals with the dominant forms of hyperlipoproteinemia type III may experience symptoms from birth. Additional genetic, environmental and hormonal factors may determine the severity of the disorder.
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Causes of Hyperlipoproteinemia Type III. Hypolipoproteinemia type III is a genetic condition caused by changes in the APOE gene. The APOE gene provides instructions for making a protein called apolipoprotein E. This protein combines with fats (lipids) in the body to form molecules called lipoproteins. Lipoproteins are responsible for packaging cholesterol and other fats, carrying them through the bloodstream, and helping clear them from the bloodstream. There are different versions (alleles) of the APOE gene. The major versions are called e2, e3, and e4. Every person has two copies of the APOE gene in some combination of these different versions. The most common version is e3, which is found in more than half of the general population. The APOE e2 version has been shown to increase the risk of hyperlipoproteinemia type III. APO e2 clears dietary fats from the body at a slower rate than apo e3. Also, of note, the APOE gene is associated with Alzheimer’s disease. However, individuals with two copies of the APO e2 variant have a low risk to develop the disease. The presence of two APO e2 genes by itself usually does not result in the development of symptoms of hyperlipoproteinemia type III. In fact, about 10-15 percent of individuals with two copies of the APO e2 variant develop outward symptoms of hyperlipoproteinemia type III. Researchers believe that additional genetic, environmental, or hormonal factors play a role in the development of the disorder. These factors may include the presence of other disorders (e.g., hypothyroidism, diabetes), obesity, or age. In women, low estrogen levels may contribute to the development of symptoms, which is why the disorder occurs in women after menopause. Hyperlipoproteinemia type III is most often inherited in an autosomal recessive pattern. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. Parents who are close blood relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. About 10% of hyperlipoproteinemia type III is caused by versions of the APOE gene that are inherited in an autosomal dominant pattern. 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. 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.Individuals with the dominant forms of hyperlipoproteinemia type III may experience symptoms from birth. Additional genetic, environmental and hormonal factors may determine the severity of the disorder.
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Hyperlipoproteinemia Type III
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Affects of Hyperlipoproteinemia Type III
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Hyperlipoproteinemia type III affects males more often than females. Of the 10-15% of people who develop symptoms, this most often happens in early adulthood. Most people begin to experience symptoms in early adulthood, although some individuals have symptoms begining in childhood or late adulthood. Women are rarely affected until after menopause.Hyperlipoproteinemia type III is estimated to affect approximately 1 in 5,000-10,000 people in the general population
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Affects of Hyperlipoproteinemia Type III. Hyperlipoproteinemia type III affects males more often than females. Of the 10-15% of people who develop symptoms, this most often happens in early adulthood. Most people begin to experience symptoms in early adulthood, although some individuals have symptoms begining in childhood or late adulthood. Women are rarely affected until after menopause.Hyperlipoproteinemia type III is estimated to affect approximately 1 in 5,000-10,000 people in the general population
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Hyperlipoproteinemia Type III
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Related disorders of Hyperlipoproteinemia Type III
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Symptoms of the following disorders can be similar to those of hyperlipoproteinemia type III:Hyperlipoproteinemias are a group of inherited fat (lipid) storage and transport disorders that are characterized by increased levels of certain fats (lipoproteins) in the blood. In addition to hyperlipoproteinemia type III, this group of disorders includes hyperlipoproteinemia type I (familial hyperchylomicronemia); hyperlipoproteinemia type II (familial hyperbetalipoproteinemia); familial hyperlipoproteinemia type IV (carbohydrate induced hyperlipemia); and hyperlipoproteinemia type V (fat and carbohydrate hyperlipemia). Symptoms of all of these forms of hyperlipoproteinemia include atherosclerosis and the presence of xanthomas on certain areas of the skin.
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Related disorders of Hyperlipoproteinemia Type III. Symptoms of the following disorders can be similar to those of hyperlipoproteinemia type III:Hyperlipoproteinemias are a group of inherited fat (lipid) storage and transport disorders that are characterized by increased levels of certain fats (lipoproteins) in the blood. In addition to hyperlipoproteinemia type III, this group of disorders includes hyperlipoproteinemia type I (familial hyperchylomicronemia); hyperlipoproteinemia type II (familial hyperbetalipoproteinemia); familial hyperlipoproteinemia type IV (carbohydrate induced hyperlipemia); and hyperlipoproteinemia type V (fat and carbohydrate hyperlipemia). Symptoms of all of these forms of hyperlipoproteinemia include atherosclerosis and the presence of xanthomas on certain areas of the skin.
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Hyperlipoproteinemia Type III
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Diagnosis of Hyperlipoproteinemia Type III
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A diagnosis of hyperlipoproteinemia type III can be made based upon a thorough clinical evaluation, a detailed patient and family history and identification of characteristic findings such as xanthoma striata palmaris. Arterial imaging and a cardiac stress test can identify signs of silent atherosclerosis in young adults. Certain tests can be performed that can identify increased blood levels of certain lipids (hyperlipidemia), specifically cholesterol and triglycerides, and increased blood levels of very low-density lipoproteins (VLDLs), a lipoprotein that is elevated in hyperlipoproteinemia type III. An increased ratio of VLDLs to plasma triglycerides is also suggestive of hyperlipoproteinemia type III. A test known as electrophoresis may be used to show abnormal lipoproteins. Electrophoresis is a laboratory test that measures protein levels in the blood or urine by using an electric current to separate proteins by molecular size.Genetic testing of the APOE gene can confirm diagnosis of hyperlipoproteinemia type III. If genetic testing identifies two e2 versions of the APOE gene in an individual who is experiencing symptoms (xanthomas, high cholesterol and triglycerides), then a diagnosis of hyperlipoproteinemia type III can be made.
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Diagnosis of Hyperlipoproteinemia Type III. A diagnosis of hyperlipoproteinemia type III can be made based upon a thorough clinical evaluation, a detailed patient and family history and identification of characteristic findings such as xanthoma striata palmaris. Arterial imaging and a cardiac stress test can identify signs of silent atherosclerosis in young adults. Certain tests can be performed that can identify increased blood levels of certain lipids (hyperlipidemia), specifically cholesterol and triglycerides, and increased blood levels of very low-density lipoproteins (VLDLs), a lipoprotein that is elevated in hyperlipoproteinemia type III. An increased ratio of VLDLs to plasma triglycerides is also suggestive of hyperlipoproteinemia type III. A test known as electrophoresis may be used to show abnormal lipoproteins. Electrophoresis is a laboratory test that measures protein levels in the blood or urine by using an electric current to separate proteins by molecular size.Genetic testing of the APOE gene can confirm diagnosis of hyperlipoproteinemia type III. If genetic testing identifies two e2 versions of the APOE gene in an individual who is experiencing symptoms (xanthomas, high cholesterol and triglycerides), then a diagnosis of hyperlipoproteinemia type III can be made.
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Hyperlipoproteinemia Type III
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Therapies of Hyperlipoproteinemia Type III
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Treatment
Most individuals with hyperlipoproteinemia type III respond well to dietary therapy that consists of a diet that is low in cholesterol and saturated fat. The reduction of the intake of dietary cholesterol and other fats generally prevents xanthomas and high lipid levels in the blood (hyperlipidemia). Exercise in addition to dietary therapy may help lower lipid levels.Certain drugs can also help lower lipid levels. Drugs that have shown to be effective for reducing lipid levels include statin, fibrates, and nicotinic acid. Other drugs, such as cholestyramine and colestipol are not effective for the treatment of hyperlipoproteinemia type III; they may actually raise blood levels of beta-lipoproteins.Xanthomas can sometimes be removed surgically. Cardiovascular disease is treated according to the symptoms that present. Because estrogen improves the clearance of specific lipids associated with hyperlipoproteinemia type III from the bloodstream, estrogen therapy may help some postmenopausal women with this disorder.Genetic counseling is recommended for people with hyperlipoproteinemia type III and their families. Other treatment is symptomatic and supportive.
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Therapies of Hyperlipoproteinemia Type III. Treatment
Most individuals with hyperlipoproteinemia type III respond well to dietary therapy that consists of a diet that is low in cholesterol and saturated fat. The reduction of the intake of dietary cholesterol and other fats generally prevents xanthomas and high lipid levels in the blood (hyperlipidemia). Exercise in addition to dietary therapy may help lower lipid levels.Certain drugs can also help lower lipid levels. Drugs that have shown to be effective for reducing lipid levels include statin, fibrates, and nicotinic acid. Other drugs, such as cholestyramine and colestipol are not effective for the treatment of hyperlipoproteinemia type III; they may actually raise blood levels of beta-lipoproteins.Xanthomas can sometimes be removed surgically. Cardiovascular disease is treated according to the symptoms that present. Because estrogen improves the clearance of specific lipids associated with hyperlipoproteinemia type III from the bloodstream, estrogen therapy may help some postmenopausal women with this disorder.Genetic counseling is recommended for people with hyperlipoproteinemia type III and their families. Other treatment is symptomatic and supportive.
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Hyperlipoproteinemia Type III
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Overview of Hyperostosis Frontalis Interna
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Hyperostosis Frontalis Interna is characterized by the thickening of the frontal bone of the skull. It is not clear that this disorder is actually rare. Some clinicians believe that it may be a common abnormality found in as many as 12 percent of the female population. The disorder may be found associated with a variety of conditions such as seizures, headaches, obesity, diabetes insipidus, excessive hair growth and sex gland disturbances. Increased serum alkaline phosphatase and elevated serum calcium may occur.
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Overview of Hyperostosis Frontalis Interna. Hyperostosis Frontalis Interna is characterized by the thickening of the frontal bone of the skull. It is not clear that this disorder is actually rare. Some clinicians believe that it may be a common abnormality found in as many as 12 percent of the female population. The disorder may be found associated with a variety of conditions such as seizures, headaches, obesity, diabetes insipidus, excessive hair growth and sex gland disturbances. Increased serum alkaline phosphatase and elevated serum calcium may occur.
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Hyperostosis Frontalis Interna
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Symptoms of Hyperostosis Frontalis Interna
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The major feature of Hyperostosis Frontalis Interna is excessive growth or thickening of the frontal bone of the head. This excess growth can only be seen in an x-ray. As a result, scientists feel that this condition may be much more prevalent than suspected, but often goes undetected. Many people have no apparent symptoms.Other conditions that may be found in patients with this disorder are: obesity, a condition in which secondary male sexual traits are acquired by a female (virilization); a central nervous system disorder characterized by a sudden, aimless, uncontrollable discharge of electrical energy in the brain causing a convulsion or loss of consciousness (epilepsy); decreased vision; headaches; disturbances of the ovaries and testes (sex glands or gonads); excessive body hair; and/or diabetes. (For more information on these disorders, choose “Epilepsy” and/or “Diabetes” as your search terms in the Rare Disease Database).
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Symptoms of Hyperostosis Frontalis Interna. The major feature of Hyperostosis Frontalis Interna is excessive growth or thickening of the frontal bone of the head. This excess growth can only be seen in an x-ray. As a result, scientists feel that this condition may be much more prevalent than suspected, but often goes undetected. Many people have no apparent symptoms.Other conditions that may be found in patients with this disorder are: obesity, a condition in which secondary male sexual traits are acquired by a female (virilization); a central nervous system disorder characterized by a sudden, aimless, uncontrollable discharge of electrical energy in the brain causing a convulsion or loss of consciousness (epilepsy); decreased vision; headaches; disturbances of the ovaries and testes (sex glands or gonads); excessive body hair; and/or diabetes. (For more information on these disorders, choose “Epilepsy” and/or “Diabetes” as your search terms in the Rare Disease Database).
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Hyperostosis Frontalis Interna
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Causes of Hyperostosis Frontalis Interna
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Hyperostosis Frontalis Interna has been found in multiple generations suggesting that the disorder may be inherited as a dominant trait. It is not known if the disorder is autosomal dominant or X-linked. There are no known cases of male-to-male (father to son) transmission.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 dominant disorders, a single copy of the disease gene (received from either the mother or father) will be expressed “dominating” the other normal gene and resulting in the appearance of the disease. The risk of transmitting the disorder from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.
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Causes of Hyperostosis Frontalis Interna. Hyperostosis Frontalis Interna has been found in multiple generations suggesting that the disorder may be inherited as a dominant trait. It is not known if the disorder is autosomal dominant or X-linked. There are no known cases of male-to-male (father to son) transmission.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 dominant disorders, a single copy of the disease gene (received from either the mother or father) will be expressed “dominating” the other normal gene and resulting in the appearance of the disease. The risk of transmitting the disorder from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.
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Affects of Hyperostosis Frontalis Interna
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Hyperostosis Frontalis Interna affects females 9 times more often than males. This disorder presents itself most often among the middle-aged and elderly but has also been found in adolescents.
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Affects of Hyperostosis Frontalis Interna. Hyperostosis Frontalis Interna affects females 9 times more often than males. This disorder presents itself most often among the middle-aged and elderly but has also been found in adolescents.
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Related disorders of Hyperostosis Frontalis Interna
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Symptoms of the following disorders can be similar to those of Hyperostosis Frontalis Interna. Comparisons may be useful for a differential diagnosis:Acromegaly is a slowly progressive, chronic metabolic disorder in which an excess of growth hormone causes abnormal enlargement of various tissues of the body and unusual height. Most conspicuously affected are the extremities, jaws, and face. The enlargement of soft tissue, especially of the heart, is a serious feature of this disorder. High blood pressure (hypertension) may be another serious consequence of Acromegaly. (For more information on this disorder choose “Acromegaly” as your search term in the Rare Disease Database.)Paget's Disease is a slowly progressive disease of the skeletal system characterized by abnormally rapid bone breakdown and formation, leading to the development of bones that are dense but fragile. This disorder usually affects middle-aged and elderly people and most frequently occurs in the spine, skull, pelvis, thighs and lower legs. When it occurs in the skull it can cause hearing loss. (For more information on this disorder choose “Paget's” as your search term in the Rare Disease Database.)Leontiasis Ossea or Virchow's Disease is a disorder in which there is an overgrowth of the bones of the face and sometimes of the cranium. This disorder causes a general enlargement and distortion of all the features.The following disorders have been found in association with Hyperostosis Frontalis Interna. They are not necessary for a differential diagnosis:Crouzon Disease is a genetic disorder characterized by abnormalities in the skull, face, and brain caused by premature hardening of the skull. The skull is made up of several bony plates initially joined by fibrous connective tissue which normally fuse together and harden over a period of several years after growth of the brain. Facial deformities are often present at birth and may progress with time. Vision disturbances and deafness may develop in some cases. (For more information on this disorder choose “Crouzon” as your search term in the Rare Disease Database.)Galactorrhea is a condition in which there is a spontaneous flow of milk from the nipple.Myotonic Dystrophy is an inherited disorder involving the muscles, vision, and endocrine glands. It can cause mental deficiency and loss of hair. Onset of this disorder commonly occurs during young adulthood although it can occur at any age and is extremely variable in degree of severity. Symptoms of this disorder may be tripping, falling, difficulty in moving the neck, lack of facial expression and a nasal sounding voice. (For more information on this disorder choose “Myotonic Dystrophy” as your search term in the Rare Disease Database.)Diabetes Insipidus is due to an abnormality of anti-diuretic hormone (vasopresin or ADH) originating in the posterior lobe of the pituitary gland. The lack of this hormone on the kidney causes excretion of excessive quantities of very dilute (but otherwise normal) urine. Excessive thirst is the major symptom of this disorder. (For more information on this disorder, choose “Diabetes Insipidus” as your search term in the Rare Disease Database.)
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Related disorders of Hyperostosis Frontalis Interna. Symptoms of the following disorders can be similar to those of Hyperostosis Frontalis Interna. Comparisons may be useful for a differential diagnosis:Acromegaly is a slowly progressive, chronic metabolic disorder in which an excess of growth hormone causes abnormal enlargement of various tissues of the body and unusual height. Most conspicuously affected are the extremities, jaws, and face. The enlargement of soft tissue, especially of the heart, is a serious feature of this disorder. High blood pressure (hypertension) may be another serious consequence of Acromegaly. (For more information on this disorder choose “Acromegaly” as your search term in the Rare Disease Database.)Paget's Disease is a slowly progressive disease of the skeletal system characterized by abnormally rapid bone breakdown and formation, leading to the development of bones that are dense but fragile. This disorder usually affects middle-aged and elderly people and most frequently occurs in the spine, skull, pelvis, thighs and lower legs. When it occurs in the skull it can cause hearing loss. (For more information on this disorder choose “Paget's” as your search term in the Rare Disease Database.)Leontiasis Ossea or Virchow's Disease is a disorder in which there is an overgrowth of the bones of the face and sometimes of the cranium. This disorder causes a general enlargement and distortion of all the features.The following disorders have been found in association with Hyperostosis Frontalis Interna. They are not necessary for a differential diagnosis:Crouzon Disease is a genetic disorder characterized by abnormalities in the skull, face, and brain caused by premature hardening of the skull. The skull is made up of several bony plates initially joined by fibrous connective tissue which normally fuse together and harden over a period of several years after growth of the brain. Facial deformities are often present at birth and may progress with time. Vision disturbances and deafness may develop in some cases. (For more information on this disorder choose “Crouzon” as your search term in the Rare Disease Database.)Galactorrhea is a condition in which there is a spontaneous flow of milk from the nipple.Myotonic Dystrophy is an inherited disorder involving the muscles, vision, and endocrine glands. It can cause mental deficiency and loss of hair. Onset of this disorder commonly occurs during young adulthood although it can occur at any age and is extremely variable in degree of severity. Symptoms of this disorder may be tripping, falling, difficulty in moving the neck, lack of facial expression and a nasal sounding voice. (For more information on this disorder choose “Myotonic Dystrophy” as your search term in the Rare Disease Database.)Diabetes Insipidus is due to an abnormality of anti-diuretic hormone (vasopresin or ADH) originating in the posterior lobe of the pituitary gland. The lack of this hormone on the kidney causes excretion of excessive quantities of very dilute (but otherwise normal) urine. Excessive thirst is the major symptom of this disorder. (For more information on this disorder, choose “Diabetes Insipidus” as your search term in the Rare Disease Database.)
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Diagnosis of Hyperostosis Frontalis Interna
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Diagnosis of Hyperostosis Frontalis Interna.
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Therapies of Hyperostosis Frontalis Interna
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There is no known treatment for Hyperostosis Frontalis Interna. Seizures and headaches can be treated with standard medications.Genetic counseling may be of benefit for patients and their families. Other treatment is symptomatic and supportive.
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Therapies of Hyperostosis Frontalis Interna. There is no known treatment for Hyperostosis Frontalis Interna. Seizures and headaches can be treated with standard medications.Genetic counseling may be of benefit for patients and their families. Other treatment is symptomatic and supportive.
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Overview of Hyperprolinemia Type I
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SummaryHyperprolinemia type I (HPI) is an inherited metabolic disorder of proline metabolism, which is characterized by abnormally high levels of proline, hydroxyproline and glycine in the blood and the urine. The high level of blood proline is the result of a deficiency of the enzyme proline oxidase, also called POX or proline dehydrogenase (PRODH), which is essential to the normal breakdown (metabolism) of proline. There are often no clinical manifestations of HPI.IntroductionThere are two types of hyperprolinemia: type I (HPI) and type II (HPII). Each type is caused by an autosomal recessive inborn error of the proline metabolic pathway. Proline is abundant in nature and readily found in a variety of foods.HPII is another form of hyperprolinemia caused by a deficiency of a different enzyme, Δ-1-pyrroline-5-carboxylate (P5C) dehydrogenase, leading to high blood proline levels. Patients with HPII have higher plasma levels of proline than do people with HPI and it is associated with neurological problems such as seizures and intellectual disability.
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Overview of Hyperprolinemia Type I. SummaryHyperprolinemia type I (HPI) is an inherited metabolic disorder of proline metabolism, which is characterized by abnormally high levels of proline, hydroxyproline and glycine in the blood and the urine. The high level of blood proline is the result of a deficiency of the enzyme proline oxidase, also called POX or proline dehydrogenase (PRODH), which is essential to the normal breakdown (metabolism) of proline. There are often no clinical manifestations of HPI.IntroductionThere are two types of hyperprolinemia: type I (HPI) and type II (HPII). Each type is caused by an autosomal recessive inborn error of the proline metabolic pathway. Proline is abundant in nature and readily found in a variety of foods.HPII is another form of hyperprolinemia caused by a deficiency of a different enzyme, Δ-1-pyrroline-5-carboxylate (P5C) dehydrogenase, leading to high blood proline levels. Patients with HPII have higher plasma levels of proline than do people with HPI and it is associated with neurological problems such as seizures and intellectual disability.
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Symptoms of Hyperprolinemia Type I
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HPI does not usually cause symptoms, but patients with intellectual disability and/or generalized epilepsy have been reported. A relationship between adult schizophrenia or schizoaffective disorders and HPI has been discussed. Kidney (renal) symptoms have been reported in some affected people. Other symptoms include abnormal EEG readings, generalized low muscle tone (hypotonia), global developmental delay, aggressive behavior, hyperactivity and repetitive movements (stereotypy).
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Symptoms of Hyperprolinemia Type I. HPI does not usually cause symptoms, but patients with intellectual disability and/or generalized epilepsy have been reported. A relationship between adult schizophrenia or schizoaffective disorders and HPI has been discussed. Kidney (renal) symptoms have been reported in some affected people. Other symptoms include abnormal EEG readings, generalized low muscle tone (hypotonia), global developmental delay, aggressive behavior, hyperactivity and repetitive movements (stereotypy).
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Causes of Hyperprolinemia Type I
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Hyperprolinemia has been reported in patients with a microdeletion of the POX (PRODH) gene in the chromosome 22q11 region. Various mutations have been reported. This gene is involved in the initial steps of breaking down proline. The PRODH mutations have been divided into three groups: those leading to mild (<30%); moderate (30–70%); and severe (>70%) reductions of POX enzyme activity. Serum proline level seems to correlate with the severity of POX enzyme deficiency but not to be related with clinical severity.HPI is an autosomal recessive genetic disorder. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
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Causes of Hyperprolinemia Type I. Hyperprolinemia has been reported in patients with a microdeletion of the POX (PRODH) gene in the chromosome 22q11 region. Various mutations have been reported. This gene is involved in the initial steps of breaking down proline. The PRODH mutations have been divided into three groups: those leading to mild (<30%); moderate (30–70%); and severe (>70%) reductions of POX enzyme activity. Serum proline level seems to correlate with the severity of POX enzyme deficiency but not to be related with clinical severity.HPI is an autosomal recessive genetic disorder. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
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Affects of Hyperprolinemia Type I
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HPI is a very rare disorder that is present at birth. It affects males and females in equal numbers. There appears to be no differences across ethnicities. The prevalence is unknown, but current studies of different populations suggest rates of 1 in 310,000 to 1 in 700,000.
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Affects of Hyperprolinemia Type I. HPI is a very rare disorder that is present at birth. It affects males and females in equal numbers. There appears to be no differences across ethnicities. The prevalence is unknown, but current studies of different populations suggest rates of 1 in 310,000 to 1 in 700,000.
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Related disorders of Hyperprolinemia Type I
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Symptoms of the following disorders are similar to those of HPI. Comparisons may be useful for a differential diagnosis.Hyperprolinemia type II (HPII) is characterized by a level of proline in the blood greater than that in HPI. In addition, P5C is excreted in the urine only in HPII. Intellectual disability and seizures may also occur. (For more information, choose “Hyperprolinemia Type II” as your search term in the Rare Disease Database.). Enzyme activity and gene mutation analysis is helpful for differential diagnosis. 22q.11 deletion syndrome is caused by microdeletions on chromosome 22.q.11 and includes DiGeorge syndrome and velo-cardio-facial syndrome (VCFS). HPI is often not considered a 22.q.11 deletion syndrome despite the PRODH gene being in this location on chromosome 22. This may be because HPI does not show the same symptoms as the other 22.q.11 deletion syndromes (bluish skin, facial differences and cleft palate). However, other less common, symptoms can be shared by both disorders including schizophrenia, behavioral problems, hypotonia and developmental delays. (For more information, choose “22q.11 deletion syndrome” as your search term in the Rare Disease Database.)
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Related disorders of Hyperprolinemia Type I. Symptoms of the following disorders are similar to those of HPI. Comparisons may be useful for a differential diagnosis.Hyperprolinemia type II (HPII) is characterized by a level of proline in the blood greater than that in HPI. In addition, P5C is excreted in the urine only in HPII. Intellectual disability and seizures may also occur. (For more information, choose “Hyperprolinemia Type II” as your search term in the Rare Disease Database.). Enzyme activity and gene mutation analysis is helpful for differential diagnosis. 22q.11 deletion syndrome is caused by microdeletions on chromosome 22.q.11 and includes DiGeorge syndrome and velo-cardio-facial syndrome (VCFS). HPI is often not considered a 22.q.11 deletion syndrome despite the PRODH gene being in this location on chromosome 22. This may be because HPI does not show the same symptoms as the other 22.q.11 deletion syndromes (bluish skin, facial differences and cleft palate). However, other less common, symptoms can be shared by both disorders including schizophrenia, behavioral problems, hypotonia and developmental delays. (For more information, choose “22q.11 deletion syndrome” as your search term in the Rare Disease Database.)
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Diagnosis of Hyperprolinemia Type I
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HPI is diagnosed biochemically based on a high plasma proline level without urinary excretion of P5C. In contrast, the presence of P5C in the urine is indicative of HPII.The normal level of proline is approximately 450 units, but people with HPI may have levels of 1,900 to 2,000 units. These high levels of proline are often 2 to 10 fold, around 0.8-4.0 mmol/L of proline. Often, the diagnosis is made by exclusion. After failure to arrive at a diagnosis by other means, a blood proline level is ordered and this confirms the diagnosis. Newborn screening can also be used to test the blood proline levels and compare them to the standard. A pilot study for HPI newborn screening is currently underway in California and China.
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Diagnosis of Hyperprolinemia Type I. HPI is diagnosed biochemically based on a high plasma proline level without urinary excretion of P5C. In contrast, the presence of P5C in the urine is indicative of HPII.The normal level of proline is approximately 450 units, but people with HPI may have levels of 1,900 to 2,000 units. These high levels of proline are often 2 to 10 fold, around 0.8-4.0 mmol/L of proline. Often, the diagnosis is made by exclusion. After failure to arrive at a diagnosis by other means, a blood proline level is ordered and this confirms the diagnosis. Newborn screening can also be used to test the blood proline levels and compare them to the standard. A pilot study for HPI newborn screening is currently underway in California and China.
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Hyperprolinemia Type I
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Therapies of Hyperprolinemia Type I
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Treatment
Proline is common in food, and attempts to control blood proline levels by restrictive dieting have not succeeded. Because the medical consequences of HPI appear to be modest or inconsequential, many physicians do not take an aggressive approach toward treatment.
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Therapies of Hyperprolinemia Type I. Treatment
Proline is common in food, and attempts to control blood proline levels by restrictive dieting have not succeeded. Because the medical consequences of HPI appear to be modest or inconsequential, many physicians do not take an aggressive approach toward treatment.
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Overview of Hyperprolinemia Type II
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Two types of hyperprolinemia are recognized by physicians and clinical researchers. Each represents an inherited inborn error of metabolism involving the amino acid, proline.Hyperprolinemia Type I (HP-I) is characterized by high levels of proline in the blood resulting from a deficiency of the enzyme proline oxidase, which is key to the breakdown (metabolism) of proline. There are often no clinical manifestations of HP-1.Hyperprolinemia II (HP-II) is a rare metabolic disorder that results from the deficiency of the enzyme known as delta-pyrroline-5-carboxylate (P-5-C) dehydrogenase. This disorder results in more severe clinical manifestations than are seen in HP-I, and may be associated with mild mental retardation and seizures.
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Overview of Hyperprolinemia Type II. Two types of hyperprolinemia are recognized by physicians and clinical researchers. Each represents an inherited inborn error of metabolism involving the amino acid, proline.Hyperprolinemia Type I (HP-I) is characterized by high levels of proline in the blood resulting from a deficiency of the enzyme proline oxidase, which is key to the breakdown (metabolism) of proline. There are often no clinical manifestations of HP-1.Hyperprolinemia II (HP-II) is a rare metabolic disorder that results from the deficiency of the enzyme known as delta-pyrroline-5-carboxylate (P-5-C) dehydrogenase. This disorder results in more severe clinical manifestations than are seen in HP-I, and may be associated with mild mental retardation and seizures.
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Hyperprolinemia Type II
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Symptoms of Hyperprolinemia Type II
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Hyperprolinemia Type II is characterized by an abnormally high level of the amino acid proline in the blood. Fevers associated with seizures are common and mild mental retardation may be present.
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Symptoms of Hyperprolinemia Type II. Hyperprolinemia Type II is characterized by an abnormally high level of the amino acid proline in the blood. Fevers associated with seizures are common and mild mental retardation may be present.
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Causes of Hyperprolinemia Type II
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Hyperprolinemia Type II is an autosomal recessive disorder. The gene involved has been mapped to the short arm of chromosome 1 (1p36). Chromosomes, which are present in the nucleus of human cells, carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males, and two X chromosomes for females. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q”. Chromosomes are further subdivided into many bands that are numbered. For example, chromosome 1p36 refers to band 36 on the short arm of chromosome 1.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. All individuals carry 4 to 5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk of having children with a recessive genetic disorder.
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Causes of Hyperprolinemia Type II. Hyperprolinemia Type II is an autosomal recessive disorder. The gene involved has been mapped to the short arm of chromosome 1 (1p36). Chromosomes, which are present in the nucleus of human cells, carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males, and two X chromosomes for females. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q”. Chromosomes are further subdivided into many bands that are numbered. For example, chromosome 1p36 refers to band 36 on the short arm of chromosome 1.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. All individuals carry 4 to 5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk of having children with a recessive genetic disorder.
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Hyperprolinemia Type II
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Affects of Hyperprolinemia Type II
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Hyperprolinemia Type II is a very rare disorder that is present at birth. It affects males and females in equal numbers.
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Affects of Hyperprolinemia Type II. Hyperprolinemia Type II is a very rare disorder that is present at birth. It affects males and females in equal numbers.
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Hyperprolinemia Type II
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Related disorders of Hyperprolinemia Type II
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Symptoms of the following disorder are similar to those of Hyperprolinemia Type II. Comparisons may be useful for a differential diagnosis:Hyperprolinemia Type I is a hereditary condition characterized by an excessive level of proline in the blood. However, the levels of proline are lower than those in Type II Hyperprolinemia. This condition is caused by a deficiency of the enzyme proline dehydrogenase. It may be associated with kidney disease. (For more information, choose “Hyperprolinemia Type I” as your search term in the Rare Disease Database.)
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Related disorders of Hyperprolinemia Type II. Symptoms of the following disorder are similar to those of Hyperprolinemia Type II. Comparisons may be useful for a differential diagnosis:Hyperprolinemia Type I is a hereditary condition characterized by an excessive level of proline in the blood. However, the levels of proline are lower than those in Type II Hyperprolinemia. This condition is caused by a deficiency of the enzyme proline dehydrogenase. It may be associated with kidney disease. (For more information, choose “Hyperprolinemia Type I” as your search term in the Rare Disease Database.)
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Hyperprolinemia Type II
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Diagnosis of Hyperprolinemia Type II
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HP-II is recognized by elevated blood proline and elevated P-5-C levels in the urine. (Normal blood proline levels are about 450 units whereas elevated blood proline levels in subjects with HP-II reach 1900-2000 units.)
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Diagnosis of Hyperprolinemia Type II. HP-II is recognized by elevated blood proline and elevated P-5-C levels in the urine. (Normal blood proline levels are about 450 units whereas elevated blood proline levels in subjects with HP-II reach 1900-2000 units.)
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Therapies of Hyperprolinemia Type II
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TreatmentProline is abundant in nature and readily found in a variety of foods. As a result, attempts to control blood proline levels by restrictive dieting have not succeeded. Patients with childhood neurological manifestations appear to grow out of the pattern of fevers and seizures. Adult life appears to be symptom-free.
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Therapies of Hyperprolinemia Type II. TreatmentProline is abundant in nature and readily found in a variety of foods. As a result, attempts to control blood proline levels by restrictive dieting have not succeeded. Patients with childhood neurological manifestations appear to grow out of the pattern of fevers and seizures. Adult life appears to be symptom-free.
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Hyperprolinemia Type II
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Overview of Hypochondroplasia
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Hypochrondroplasia is a genetic disorder characterized by small stature and disproportionately short arms, legs, hands, and feet (short-limbed dwarfism). Short stature often is not recognized until early to mid childhood or, in some cases, as late as adulthood. In those with the disorder, bowing of the legs typically develops during early childhood but often improves spontaneously with age. Some affected individuals may also have an abnormally large head (macrocephaly), a relatively prominent forehead, and/or other physical abnormalities associated with the disorder. In addition, in about 10 percent of cases, mild mental retardation may be present.In some cases, hypochondroplasia appears to occur randomly for unknown reasons (sporadically) with no apparent family history. In other instances, the disorder is familial with autosomal dominant inheritance.
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Overview of Hypochondroplasia. Hypochrondroplasia is a genetic disorder characterized by small stature and disproportionately short arms, legs, hands, and feet (short-limbed dwarfism). Short stature often is not recognized until early to mid childhood or, in some cases, as late as adulthood. In those with the disorder, bowing of the legs typically develops during early childhood but often improves spontaneously with age. Some affected individuals may also have an abnormally large head (macrocephaly), a relatively prominent forehead, and/or other physical abnormalities associated with the disorder. In addition, in about 10 percent of cases, mild mental retardation may be present.In some cases, hypochondroplasia appears to occur randomly for unknown reasons (sporadically) with no apparent family history. In other instances, the disorder is familial with autosomal dominant inheritance.
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Hypochondroplasia
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Symptoms of Hypochondroplasia
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Hypochondroplasia is primarily characterized by small stature, disproportionately short arms and legs (limbs), mild to moderate shortness of the fingers and toes (brachydactyly), and broad, short hands and feet (i.e., short-limbed dwarfism). Slow growth often is not apparent at birth; as noted above, it may not be recognized until about two to three years of age, later during childhood, or as late as adulthood.In those with hypochondroplasia, shortening of the limbs may be relatively mild or moderate. During early childhood, outward bowing of the legs (i.e., bowlegs [genu varum]) typically appears that is pronounced during weight bearing. This condition often improves spontaneously later during childhood. Many affected individuals also have limited extension and rotation of the elbows. In addition, beginning in childhood, exercise may result in minor aching or discomfort of the elbows, knees, and/or ankles. In affected adults, such joint pain may extend to involve the lower back. Approximately one third may also have abnormally pronounced inward curvature of the spine of the lower back (lordosis). Some individuals with hypochondroplasia also have an abnormally large head (macrocephaly). In addition, the skull may be relatively broad and short (brachycephaly) or rectangular in shape with a slightly prominent forehead. However, the facial appearance is typically normal. Reports indicate that mild mental retardation may also be present in approximately 10 percent of affected individuals.
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Symptoms of Hypochondroplasia. Hypochondroplasia is primarily characterized by small stature, disproportionately short arms and legs (limbs), mild to moderate shortness of the fingers and toes (brachydactyly), and broad, short hands and feet (i.e., short-limbed dwarfism). Slow growth often is not apparent at birth; as noted above, it may not be recognized until about two to three years of age, later during childhood, or as late as adulthood.In those with hypochondroplasia, shortening of the limbs may be relatively mild or moderate. During early childhood, outward bowing of the legs (i.e., bowlegs [genu varum]) typically appears that is pronounced during weight bearing. This condition often improves spontaneously later during childhood. Many affected individuals also have limited extension and rotation of the elbows. In addition, beginning in childhood, exercise may result in minor aching or discomfort of the elbows, knees, and/or ankles. In affected adults, such joint pain may extend to involve the lower back. Approximately one third may also have abnormally pronounced inward curvature of the spine of the lower back (lordosis). Some individuals with hypochondroplasia also have an abnormally large head (macrocephaly). In addition, the skull may be relatively broad and short (brachycephaly) or rectangular in shape with a slightly prominent forehead. However, the facial appearance is typically normal. Reports indicate that mild mental retardation may also be present in approximately 10 percent of affected individuals.
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Hypochondroplasia
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Causes of Hypochondroplasia
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In some cases, hypochondroplasia appears to occur randomly for unknown reasons (sporadically) with no apparent family history of the disorder. According to researchers, such cases typically represent new (sporadic) genetic changes (mutations) that may be transmitted as an autosomal dominant trait (i.e., new dominant gene mutations). Investigators have noted increased age of the father (advanced paternal age) in some instances of apparently sporadic hypochondroplasia. Familial cases of the disorder have also been reported. In such instances, the disorder has autosomal dominant inheritance. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother. In dominant disorders, a single copy of the disease gene (received from either the mother or father) may be expressed “dominating” the other normal gene and resulting in the appearance of the disease. The risk of transmitting the disorder from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child. The risk is the same for each pregnancy.Researchers indicate that hypochondroplasia often appears to result from specific mutations of a gene known as “fibroblast growth factor receptor-3” (FGFR3). The FGFR3 gene is located on the short arm (p) of chromosome 4 (4p16.3). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q”. Chromosomes are further subdivided into bands that are numbered. Therefore, chromosome 4p16.3 refers to band 16.3 on the short arm of chromosome 4.Researchers also have found that different mutations of the same gene (i.e., FGFR3) may cause achondroplasia, indicating that hypochondroplasia and achondroplasia are allelic disorders. (An allele is one of two or more alternative forms of a gene that may occupy a particular chromosomal location.) Achondroplasia is a more severe form of short-limbed dwarfism that may be characterized by certain features similar to those seen in hypochondroplasia. (For further information, please see the “Related Disorders” section of this report below.)Genetic analysis has revealed that some individuals with hypochondroplasia do not have currently identified mutations of the FGFR3 gene. In such cases, researchers suggest that the disorder may result from mutations of different disease genes (genetic heterogeneity) or, possibly, from other, currently undetected FGFR3 gene mutations. Further research is necessary to learn more about the underlying genetic causes of hypochondroplasia.
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Causes of Hypochondroplasia. In some cases, hypochondroplasia appears to occur randomly for unknown reasons (sporadically) with no apparent family history of the disorder. According to researchers, such cases typically represent new (sporadic) genetic changes (mutations) that may be transmitted as an autosomal dominant trait (i.e., new dominant gene mutations). Investigators have noted increased age of the father (advanced paternal age) in some instances of apparently sporadic hypochondroplasia. Familial cases of the disorder have also been reported. In such instances, the disorder has autosomal dominant inheritance. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother. In dominant disorders, a single copy of the disease gene (received from either the mother or father) may be expressed “dominating” the other normal gene and resulting in the appearance of the disease. The risk of transmitting the disorder from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child. The risk is the same for each pregnancy.Researchers indicate that hypochondroplasia often appears to result from specific mutations of a gene known as “fibroblast growth factor receptor-3” (FGFR3). The FGFR3 gene is located on the short arm (p) of chromosome 4 (4p16.3). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q”. Chromosomes are further subdivided into bands that are numbered. Therefore, chromosome 4p16.3 refers to band 16.3 on the short arm of chromosome 4.Researchers also have found that different mutations of the same gene (i.e., FGFR3) may cause achondroplasia, indicating that hypochondroplasia and achondroplasia are allelic disorders. (An allele is one of two or more alternative forms of a gene that may occupy a particular chromosomal location.) Achondroplasia is a more severe form of short-limbed dwarfism that may be characterized by certain features similar to those seen in hypochondroplasia. (For further information, please see the “Related Disorders” section of this report below.)Genetic analysis has revealed that some individuals with hypochondroplasia do not have currently identified mutations of the FGFR3 gene. In such cases, researchers suggest that the disorder may result from mutations of different disease genes (genetic heterogeneity) or, possibly, from other, currently undetected FGFR3 gene mutations. Further research is necessary to learn more about the underlying genetic causes of hypochondroplasia.
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Hypochondroplasia
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Affects of Hypochondroplasia
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Hypochondroplasia appears to affect females and males in relatively equal numbers. The features of the disorder were originally reported in 1913; hypochondroplasia was described as a distinct disease entity in 1924. Over 100 cases have since been recorded in the medical literature, including isolated (sporadic) and familial cases. Hypochondroplasia is thought to have an incidence of approximately one-twelfth that of achondroplasia. (Incidence refers to the number of new cases of a particular disorder or condition during a specific period.) The estimated frequency of achondroplasia has ranged from about one in 15,000 to one in 35,000 births. (For further information on achondroplasia, please see the “Related Disorders” section of this report below.)
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Affects of Hypochondroplasia. Hypochondroplasia appears to affect females and males in relatively equal numbers. The features of the disorder were originally reported in 1913; hypochondroplasia was described as a distinct disease entity in 1924. Over 100 cases have since been recorded in the medical literature, including isolated (sporadic) and familial cases. Hypochondroplasia is thought to have an incidence of approximately one-twelfth that of achondroplasia. (Incidence refers to the number of new cases of a particular disorder or condition during a specific period.) The estimated frequency of achondroplasia has ranged from about one in 15,000 to one in 35,000 births. (For further information on achondroplasia, please see the “Related Disorders” section of this report below.)
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Related disorders of Hypochondroplasia
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Symptoms of the following disorders may be similar to those of hypochondroplasia. Comparisons may be useful for a differential diagnosis:Achondroplasia is a genetic disorder characterized by short-limbed dwarfism that is apparent at birth. Although hypochondroplasia has certain similar findings, experts indicate that it may be distinguished from achondroplasia by less severe skeletal malformations of the hands and spine; absence of pelvic involvement; lack of or relatively mild associated abnormalities of the skull and facial (craniofacial) region; and/or other differences as determined by clinical and x-ray (radiographic) evaluation. In individuals with achondroplasia, the regions of the limbs closest to the trunk (proximal regions), such as the upper arms and thighs, are typically disproportionately shorter than those distal to or furthest from the trunk (i.e., rhizomelic dwarfism). Additional characteristic findings include unusually short hands; a distinctive malformation in which the fingers assume a “three-pronged” (i.e., trident) position; and increased tilt of the pelvis, causing abnormal prominence of the abdomen and buttocks. Distinctive facial abnormalities are also typically present, including an unusually large head (macrocephaly); prominent forehead; depressed nasal bridge; narrow nasal passages; and/or unusually flat, underdeveloped midfacial regions (midfacial hypoplasia). Affected individuals may also have decreased extension and rotation of the elbows, abnormally pronounced inward curvature of the spine of the lower back (lordosis), and/or additional physical abnormalities. In some cases, the disorder may be associated with potentially severe neurologic complications. Achondroplasia usually appears to be due to new (sporadic) autosomal dominant gene mutations. Rarely, familial cases have been reported in which the disorder was inherited as an autosomal dominant trait. As noted above (see “Causes”), achondroplasia and hypochondroplasia may result from different mutations of the same gene (FGFR3). (For more information on this disorder, choose “achondroplasia” as your search term in the Rare Disease Database.)Additional genetic disorders may be characterized by short stature; disproportionately short arms and legs; broad, short hands and feet; abnormal enlargement of the head (macrocephaly); and/or other symptoms and findings similar to those potentially associated with hypochondroplasia. (For more information on these disorders, choose the exact disease name in question as your search term in the Rare Disease Database.)
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Related disorders of Hypochondroplasia. Symptoms of the following disorders may be similar to those of hypochondroplasia. Comparisons may be useful for a differential diagnosis:Achondroplasia is a genetic disorder characterized by short-limbed dwarfism that is apparent at birth. Although hypochondroplasia has certain similar findings, experts indicate that it may be distinguished from achondroplasia by less severe skeletal malformations of the hands and spine; absence of pelvic involvement; lack of or relatively mild associated abnormalities of the skull and facial (craniofacial) region; and/or other differences as determined by clinical and x-ray (radiographic) evaluation. In individuals with achondroplasia, the regions of the limbs closest to the trunk (proximal regions), such as the upper arms and thighs, are typically disproportionately shorter than those distal to or furthest from the trunk (i.e., rhizomelic dwarfism). Additional characteristic findings include unusually short hands; a distinctive malformation in which the fingers assume a “three-pronged” (i.e., trident) position; and increased tilt of the pelvis, causing abnormal prominence of the abdomen and buttocks. Distinctive facial abnormalities are also typically present, including an unusually large head (macrocephaly); prominent forehead; depressed nasal bridge; narrow nasal passages; and/or unusually flat, underdeveloped midfacial regions (midfacial hypoplasia). Affected individuals may also have decreased extension and rotation of the elbows, abnormally pronounced inward curvature of the spine of the lower back (lordosis), and/or additional physical abnormalities. In some cases, the disorder may be associated with potentially severe neurologic complications. Achondroplasia usually appears to be due to new (sporadic) autosomal dominant gene mutations. Rarely, familial cases have been reported in which the disorder was inherited as an autosomal dominant trait. As noted above (see “Causes”), achondroplasia and hypochondroplasia may result from different mutations of the same gene (FGFR3). (For more information on this disorder, choose “achondroplasia” as your search term in the Rare Disease Database.)Additional genetic disorders may be characterized by short stature; disproportionately short arms and legs; broad, short hands and feet; abnormal enlargement of the head (macrocephaly); and/or other symptoms and findings similar to those potentially associated with hypochondroplasia. (For more information on these disorders, choose the exact disease name in question as your search term in the Rare Disease Database.)
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Diagnosis of Hypochondroplasia
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As noted previously, in individuals with hypochondroplasia, short stature often may not be recognized until early or mid childhood or as late as adulthood. The disorder may be diagnosed based upon thorough clinical examination; identification of characteristic physical findings (e.g., short stature, brachydactyly, genu varum, macrocephaly); x-ray studies; and/or other diagnostic techniques.
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Diagnosis of Hypochondroplasia. As noted previously, in individuals with hypochondroplasia, short stature often may not be recognized until early or mid childhood or as late as adulthood. The disorder may be diagnosed based upon thorough clinical examination; identification of characteristic physical findings (e.g., short stature, brachydactyly, genu varum, macrocephaly); x-ray studies; and/or other diagnostic techniques.
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Hypochondroplasia
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Therapies of Hypochondroplasia
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TreatmentThe treatment of hypochondroplasia is directed toward the specific symptoms that are apparent in each individual. Such treatment may require the coordinated efforts of a team of medical professionals, such as pediatricians or internists; physicians who diagnose and treat disorders of the skeleton, joints, muscles, and related tissues (orthopedists); surgeons; physical therapists; and/or other health care professionals.Various orthopedic techniques, including surgery, may be recommended to help treat or correct certain skeletal abnormalities associated with the disorder. For example, as noted above, although outward bowing of the legs tends to improve during later childhood, surgical straightening may be advised in some cases.In women with hypochondroplasia who are pregnant, Cesarean section is often necessary for delivery.Early intervention may be important to help ensure that affected children reach their potential. Special services that may be beneficial may include special education, physical therapy, occupational therapy, and/or other medical, social, or vocational services.Genetic counseling will be of benefit for affected individuals and their families. Other treatment for this disorder is symptomatic and supportive.
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Therapies of Hypochondroplasia. TreatmentThe treatment of hypochondroplasia is directed toward the specific symptoms that are apparent in each individual. Such treatment may require the coordinated efforts of a team of medical professionals, such as pediatricians or internists; physicians who diagnose and treat disorders of the skeleton, joints, muscles, and related tissues (orthopedists); surgeons; physical therapists; and/or other health care professionals.Various orthopedic techniques, including surgery, may be recommended to help treat or correct certain skeletal abnormalities associated with the disorder. For example, as noted above, although outward bowing of the legs tends to improve during later childhood, surgical straightening may be advised in some cases.In women with hypochondroplasia who are pregnant, Cesarean section is often necessary for delivery.Early intervention may be important to help ensure that affected children reach their potential. Special services that may be beneficial may include special education, physical therapy, occupational therapy, and/or other medical, social, or vocational services.Genetic counseling will be of benefit for affected individuals and their families. Other treatment for this disorder is symptomatic and supportive.
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Hypochondroplasia
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Overview of Hypohidrotic Ectodermal Dysplasia
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Hypohidrotic ectodermal dysplasia (HED) is a rare inherited multisystem disorder that belongs to the group of diseases known as ectodermal dysplasias. Ectodermal dysplasias typically affect the hair, teeth, nails, sweat glands, and/or skin. HED is primarily characterized by partial or complete absence of certain sweat glands (eccrine glands), causing lack of or diminished sweating (anhidrosis or hypohidrosis), heat intolerance, and fever; abnormally sparse hair (hypotrichosis), and absence (hypodontia) and/or malformation of certain teeth. Many individuals with HED also have characteristic facial abnormalities including a prominent forehead, a sunken nasal bridge (so-called “saddle nose”), unusually thick lips, and/or a large chin. The skin on most of the body may be abnormally thin, dry, and soft with an abnormal lack of pigmentation (hypopigmentation). However, the skin around the eyes (periorbital) may be darkly pigmented (hyperpigmentation) and finely wrinkled, appearing prematurely aged. In many cases, affected infants and children may also exhibit underdevelopment (hypoplasia) or absence (aplasia) of mucous glands within the respiratory and gastrointestinal (GI) tracts and, in some cases, decreased function of certain components of the immune system (e.g., depressed lymphocyte function, and rarely cellular immune hypofunction), potentially causing an increased susceptibility to certain infections and/or allergic conditions. Many affected infants and children experience recurrent attacks of wheezing and breathlessness (asthma), respiratory infections; chronic inflammation of the nasal passages (atrophic rhinitis), scaling, itchy (pruritic) skin rashes (eczema), and/or other findings.HED is usually inherited as an X-linked recessive genetic trait and is caused by a mutation in the ectodysplasin-A (EDA) gene; in such cases, the disorder is fully expressed in males only. However, females who carry a single copy of the disease gene (heterozygote carriers) may exhibit some of the symptoms and findings associated with the disorder. These may include absence and/or malformation of certain teeth, sparse hair, and/or reduced sweating. HED can also be inherited as an autosomal dominant or autosomal recessive genetic trait, caused by mutations in the EDAR or EDARADD genes. In such cases, the disorder is fully expressed in both males and females.
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Overview of Hypohidrotic Ectodermal Dysplasia. Hypohidrotic ectodermal dysplasia (HED) is a rare inherited multisystem disorder that belongs to the group of diseases known as ectodermal dysplasias. Ectodermal dysplasias typically affect the hair, teeth, nails, sweat glands, and/or skin. HED is primarily characterized by partial or complete absence of certain sweat glands (eccrine glands), causing lack of or diminished sweating (anhidrosis or hypohidrosis), heat intolerance, and fever; abnormally sparse hair (hypotrichosis), and absence (hypodontia) and/or malformation of certain teeth. Many individuals with HED also have characteristic facial abnormalities including a prominent forehead, a sunken nasal bridge (so-called “saddle nose”), unusually thick lips, and/or a large chin. The skin on most of the body may be abnormally thin, dry, and soft with an abnormal lack of pigmentation (hypopigmentation). However, the skin around the eyes (periorbital) may be darkly pigmented (hyperpigmentation) and finely wrinkled, appearing prematurely aged. In many cases, affected infants and children may also exhibit underdevelopment (hypoplasia) or absence (aplasia) of mucous glands within the respiratory and gastrointestinal (GI) tracts and, in some cases, decreased function of certain components of the immune system (e.g., depressed lymphocyte function, and rarely cellular immune hypofunction), potentially causing an increased susceptibility to certain infections and/or allergic conditions. Many affected infants and children experience recurrent attacks of wheezing and breathlessness (asthma), respiratory infections; chronic inflammation of the nasal passages (atrophic rhinitis), scaling, itchy (pruritic) skin rashes (eczema), and/or other findings.HED is usually inherited as an X-linked recessive genetic trait and is caused by a mutation in the ectodysplasin-A (EDA) gene; in such cases, the disorder is fully expressed in males only. However, females who carry a single copy of the disease gene (heterozygote carriers) may exhibit some of the symptoms and findings associated with the disorder. These may include absence and/or malformation of certain teeth, sparse hair, and/or reduced sweating. HED can also be inherited as an autosomal dominant or autosomal recessive genetic trait, caused by mutations in the EDAR or EDARADD genes. In such cases, the disorder is fully expressed in both males and females.
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Hypohidrotic Ectodermal Dysplasia
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Symptoms of Hypohidrotic Ectodermal Dysplasia
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HED is characterized by lack of or diminished sweating (anhidrosis or hypohidrosis), abnormally sparse hair (hypotrichosis), and/or absence (hypodontia) and/or malformation of certain teeth. In addition, affected individuals often have characteristic facial abnormalities, irregularities of the skin, abnormalities of the mucous membranes lining the respiratory and gastrointestinal (GI) tracts, an increased tendency to develop certain infections and allergic conditions, and/or other abnormalities. The range and severity of the symptoms and findings associated with HED varies from case to case. A primary feature of HED is a lack of or diminished sweating (anhidrosis or hypohidrosis), resulting from underdevelopment of or partial or complete absence of certain sweat glands (eccrine glands). Because affected infants and children are unable to sweat appropriately when exposed to warm environments, they can experience repeated episodes of heat intolerance and “unexplained” high fevers that may remain unexplained until the disorder is diagnosed. In individuals with HED, exertion can result in elevated body temperature (hyperpyrexia). Eating hot foods may also cause extreme discomfort. In some cases, without appropriate treatment, episodes of hyperpyrexia may result in life-threatening complications; particularly during the first two years of life.Abnormal sparseness of hair (hypotrichosis) is also a primary characteristic of HED, and is due to incomplete formation and reduced numbers of hair follicles. Scalp hair is usually blond or lightly pigmented; abnormally sparse, short, and fine; and, in some cases, stiff, dry, and unruly. Abnormal bald patches on the scalp (alopecia) may also be present. In addition, the eyebrows and eyelashes are often scanty or absent, although, in some cases, the eyelashes may appear normal. After puberty, male patterns of hair growth (e.g., moustache and beard) can be normal, while in other cases, facial and pubic hair growth may be sparse. In affected males and females, pubic and underarm (axillary) hair is typically scant. In some cases, hair may be absent from the arms, legs, and/or trunk. The third primary characteristic typically associated with HED is the absence (hypodontia) and/or malformation of teeth. In most cases, the majority of the primary (deciduous) and secondary (permanent) teeth are absent. The teeth most often present include front teeth (central incisors), teeth normally located next to the incisors (canines), and/or, in some cases, one or more molars. In most cases, the teeth that are present are widely spaced, with front teeth being pointed or cone shaped. In some rare cases, individuals with HED may lack all upper and/or lower teeth (edentulous or anodontia). Some individuals can be missing all the teeth in one jaw and have some in the other jaw. As a result of missing teeth the bony ridge of the jaws (alveolar process) that holds the teeth in place often fails to form properly. In addition, due to hypodontia, the lips may protrude outward (everted) and appear abnormally thick, the gums may be abnormally small or degenerated (atrophic), and the normally exposed red portion of the upper and lower lips (vermilion border) may not be noticeable. Many individuals with HED have additional, characteristic facial features, including a prominent forehead (frontal bossing); underdeveloped nostrils (hypoplastic alae nasi) and a low or sunken nasal bridge (so-called “saddle nose”); and underdeveloped, sunken cheeks (malar hypoplasia). Distinctive skin changes may also be present. Many affected newborns have unusual scaling or peeling of the skin, while many children develop itchy (pruritic), scaling skin rashes (eczema). In the majority of individuals with HED, the skin on most of the body is unusually thin and soft and can lack normal pigmentation (hypopigmentation). However, the skin around the eyes (periorbital) may be darkly pigmented (hyperpigmentation) and finely wrinkled, appearing prematurely aged. The skin may be extremely dry due to underdevelopment (hypoplasia) or absence (aplasia) of oil-secreting glands (sebaceous glands). Additionally there may be abnormalities in the skin ridge patterns (dermatoglyphic patterns) on the fingers, toes, palms of the hands, and/or soles of the feet. Some individuals with the disorder have unusually thin and brittle nails. In many individuals with HED, mucous glands within the membrane lining the respiratory and gastrointestinal (GI) tracts (e.g., in the lung, pharynx, larynx, trachea, upper esophagus, stomach, intestines) are underdeveloped (hypoplastic) or absent (aplastic). There are several rare HED forms or subtypes that have abnormally decreased function of certain components of the immune system (e.g., depressed lymphocyte function, cellular immune hypofunction). The immune system works to protect the body against invading microorganisms, toxins, and other substances that are recognized as foreign to the body. In many infants and children with HED, such mucous gland abnormalities and/or immune system irregularities cause an increased susceptibility to certain infections and/or allergic conditions.Salivary glands can also be underdeveloped (hypoplastic), leading to abnormal dryness of the mouth and an altered sense of taste or smell. In addition, some individuals with HED are unable to produce tears due to underdevelopment of the glands that secrete tears (hypoplastic lacrimal glands), hypoplasia of the ducts through which the tears pass (lacrimal ducts), and/or abnormal narrowing of the small openings in the inner corners of the eyelids where tears normally drain (stenotic lacrimal puncta). Eye (ocular) abnormalities may be present, including loss of transparency of the lens of the eyes (cataracts) and/or clouding of the portion of the eyes through which light passes (corneal opacities). Females who carry a single copy of the mutated EDA gene for X-linked HED (heterozygote carriers) may have no symptoms or physical abnormalities or may have some of the characteristics associated with the disease. Approximately 70% of female carriers show symptoms that are typically milder than those associated with the fully expressed disorder. Female carriers of X-linked HED may have dental abnormalities such as absence of certain teeth (hypodontia) and/or abnormally small, pointed, conical teeth; sparse hair (hypotrichosis); reduced sweating; and/or irregular dermatoglyphic patterns. In some cases, abnormalities of the breasts and nipples have been reported, and approximately 80 percent of carriers may experience difficulties nursing.
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Symptoms of Hypohidrotic Ectodermal Dysplasia. HED is characterized by lack of or diminished sweating (anhidrosis or hypohidrosis), abnormally sparse hair (hypotrichosis), and/or absence (hypodontia) and/or malformation of certain teeth. In addition, affected individuals often have characteristic facial abnormalities, irregularities of the skin, abnormalities of the mucous membranes lining the respiratory and gastrointestinal (GI) tracts, an increased tendency to develop certain infections and allergic conditions, and/or other abnormalities. The range and severity of the symptoms and findings associated with HED varies from case to case. A primary feature of HED is a lack of or diminished sweating (anhidrosis or hypohidrosis), resulting from underdevelopment of or partial or complete absence of certain sweat glands (eccrine glands). Because affected infants and children are unable to sweat appropriately when exposed to warm environments, they can experience repeated episodes of heat intolerance and “unexplained” high fevers that may remain unexplained until the disorder is diagnosed. In individuals with HED, exertion can result in elevated body temperature (hyperpyrexia). Eating hot foods may also cause extreme discomfort. In some cases, without appropriate treatment, episodes of hyperpyrexia may result in life-threatening complications; particularly during the first two years of life.Abnormal sparseness of hair (hypotrichosis) is also a primary characteristic of HED, and is due to incomplete formation and reduced numbers of hair follicles. Scalp hair is usually blond or lightly pigmented; abnormally sparse, short, and fine; and, in some cases, stiff, dry, and unruly. Abnormal bald patches on the scalp (alopecia) may also be present. In addition, the eyebrows and eyelashes are often scanty or absent, although, in some cases, the eyelashes may appear normal. After puberty, male patterns of hair growth (e.g., moustache and beard) can be normal, while in other cases, facial and pubic hair growth may be sparse. In affected males and females, pubic and underarm (axillary) hair is typically scant. In some cases, hair may be absent from the arms, legs, and/or trunk. The third primary characteristic typically associated with HED is the absence (hypodontia) and/or malformation of teeth. In most cases, the majority of the primary (deciduous) and secondary (permanent) teeth are absent. The teeth most often present include front teeth (central incisors), teeth normally located next to the incisors (canines), and/or, in some cases, one or more molars. In most cases, the teeth that are present are widely spaced, with front teeth being pointed or cone shaped. In some rare cases, individuals with HED may lack all upper and/or lower teeth (edentulous or anodontia). Some individuals can be missing all the teeth in one jaw and have some in the other jaw. As a result of missing teeth the bony ridge of the jaws (alveolar process) that holds the teeth in place often fails to form properly. In addition, due to hypodontia, the lips may protrude outward (everted) and appear abnormally thick, the gums may be abnormally small or degenerated (atrophic), and the normally exposed red portion of the upper and lower lips (vermilion border) may not be noticeable. Many individuals with HED have additional, characteristic facial features, including a prominent forehead (frontal bossing); underdeveloped nostrils (hypoplastic alae nasi) and a low or sunken nasal bridge (so-called “saddle nose”); and underdeveloped, sunken cheeks (malar hypoplasia). Distinctive skin changes may also be present. Many affected newborns have unusual scaling or peeling of the skin, while many children develop itchy (pruritic), scaling skin rashes (eczema). In the majority of individuals with HED, the skin on most of the body is unusually thin and soft and can lack normal pigmentation (hypopigmentation). However, the skin around the eyes (periorbital) may be darkly pigmented (hyperpigmentation) and finely wrinkled, appearing prematurely aged. The skin may be extremely dry due to underdevelopment (hypoplasia) or absence (aplasia) of oil-secreting glands (sebaceous glands). Additionally there may be abnormalities in the skin ridge patterns (dermatoglyphic patterns) on the fingers, toes, palms of the hands, and/or soles of the feet. Some individuals with the disorder have unusually thin and brittle nails. In many individuals with HED, mucous glands within the membrane lining the respiratory and gastrointestinal (GI) tracts (e.g., in the lung, pharynx, larynx, trachea, upper esophagus, stomach, intestines) are underdeveloped (hypoplastic) or absent (aplastic). There are several rare HED forms or subtypes that have abnormally decreased function of certain components of the immune system (e.g., depressed lymphocyte function, cellular immune hypofunction). The immune system works to protect the body against invading microorganisms, toxins, and other substances that are recognized as foreign to the body. In many infants and children with HED, such mucous gland abnormalities and/or immune system irregularities cause an increased susceptibility to certain infections and/or allergic conditions.Salivary glands can also be underdeveloped (hypoplastic), leading to abnormal dryness of the mouth and an altered sense of taste or smell. In addition, some individuals with HED are unable to produce tears due to underdevelopment of the glands that secrete tears (hypoplastic lacrimal glands), hypoplasia of the ducts through which the tears pass (lacrimal ducts), and/or abnormal narrowing of the small openings in the inner corners of the eyelids where tears normally drain (stenotic lacrimal puncta). Eye (ocular) abnormalities may be present, including loss of transparency of the lens of the eyes (cataracts) and/or clouding of the portion of the eyes through which light passes (corneal opacities). Females who carry a single copy of the mutated EDA gene for X-linked HED (heterozygote carriers) may have no symptoms or physical abnormalities or may have some of the characteristics associated with the disease. Approximately 70% of female carriers show symptoms that are typically milder than those associated with the fully expressed disorder. Female carriers of X-linked HED may have dental abnormalities such as absence of certain teeth (hypodontia) and/or abnormally small, pointed, conical teeth; sparse hair (hypotrichosis); reduced sweating; and/or irregular dermatoglyphic patterns. In some cases, abnormalities of the breasts and nipples have been reported, and approximately 80 percent of carriers may experience difficulties nursing.
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Hypohidrotic Ectodermal Dysplasia
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Causes of Hypohidrotic Ectodermal Dysplasia
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In the majority of reported cases, HED is inherited as an X-linked recessive genetic trait and caused by a mutation of the EDA gene. The protein regulated (encoded) by this gene is a type II membrane protein that acts as a homotrimer (a protein with three identical units of polypeptide) and may be involved in cell-cell signaling during early embryonic development when ectodermal organs are beginning to be formed. The ectodermal germ cell layer normally forms the nervous system, tooth enamel, epidermis of the skin, lining of the mouth, anus, nose, sweat glands, hair, and nails, but a mutated EDA gene will disrupt the normal function of a number of these characteristics.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. X-linked recessive disorders are conditions that are coded on the X chromosome. Females have two X chromosomes, but males have one X chromosome and one Y chromosome. Therefore, in females, disease traits on the X chromosome may be masked by the normal gene on the other X chromosome. Since males only have one X chromosome, if they inherit a gene for a disease present on the X, it will be expressed. Men with X-linked disorders transmit the gene to all their daughters, who are carriers, but never to their sons. Women who are carriers of an X-linked disorder have a 50 percent risk of transmitting the carrier condition to their daughters, and a 50 percent risk of transmitting the disease to their sons. Thus, in summary, when HED is inherited as an X-linked recessive trait, the disorder is fully expressed in males only and it is transmitted through the maternal X chromosome. In some females who inherit a single copy of the disease gene (heterozygote carriers) for HED, the disease may not be “masked” by the normal gene on the other X chromosome. As a result, in such cases, some females exhibit some of the symptoms associated with the disorder. Researchers also have reported cases in which HED appears to be inherited as an autosomal dominant or recessive genetic trait, but these patterns of inheritance are less common. A mutation in the EDAR gene can have an autosomal dominant or autosomal recessive pattern of inheritance, while a mutation in the EDARADD gene has an autosomal recessive pattern of inheritance. Autosomal dominant inheritance means one copy of the altered gene in each cell is sufficient to cause the disorder. Autosomal recessive inheritance means two copies of the gene in each cell are altered. Most often, the parents of an individual with an autosomal recessive disorder are carriers of one copy of the altered gene but do not show signs and symptoms of the disorder. In such cases, the disorder is fully expressed in both males and females. The existence of an autosomal recessive form of HED is supported by reports in the medical literature of severely affected females with the fully expressed disorder and multiple affected family members with parents who are closely related by blood (consanguineous). If both parents carry the same disease gene, there is a higher than normal risk that their children may inherit the two genes necessary for the development of the disease.
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Causes of Hypohidrotic Ectodermal Dysplasia. In the majority of reported cases, HED is inherited as an X-linked recessive genetic trait and caused by a mutation of the EDA gene. The protein regulated (encoded) by this gene is a type II membrane protein that acts as a homotrimer (a protein with three identical units of polypeptide) and may be involved in cell-cell signaling during early embryonic development when ectodermal organs are beginning to be formed. The ectodermal germ cell layer normally forms the nervous system, tooth enamel, epidermis of the skin, lining of the mouth, anus, nose, sweat glands, hair, and nails, but a mutated EDA gene will disrupt the normal function of a number of these characteristics.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. X-linked recessive disorders are conditions that are coded on the X chromosome. Females have two X chromosomes, but males have one X chromosome and one Y chromosome. Therefore, in females, disease traits on the X chromosome may be masked by the normal gene on the other X chromosome. Since males only have one X chromosome, if they inherit a gene for a disease present on the X, it will be expressed. Men with X-linked disorders transmit the gene to all their daughters, who are carriers, but never to their sons. Women who are carriers of an X-linked disorder have a 50 percent risk of transmitting the carrier condition to their daughters, and a 50 percent risk of transmitting the disease to their sons. Thus, in summary, when HED is inherited as an X-linked recessive trait, the disorder is fully expressed in males only and it is transmitted through the maternal X chromosome. In some females who inherit a single copy of the disease gene (heterozygote carriers) for HED, the disease may not be “masked” by the normal gene on the other X chromosome. As a result, in such cases, some females exhibit some of the symptoms associated with the disorder. Researchers also have reported cases in which HED appears to be inherited as an autosomal dominant or recessive genetic trait, but these patterns of inheritance are less common. A mutation in the EDAR gene can have an autosomal dominant or autosomal recessive pattern of inheritance, while a mutation in the EDARADD gene has an autosomal recessive pattern of inheritance. Autosomal dominant inheritance means one copy of the altered gene in each cell is sufficient to cause the disorder. Autosomal recessive inheritance means two copies of the gene in each cell are altered. Most often, the parents of an individual with an autosomal recessive disorder are carriers of one copy of the altered gene but do not show signs and symptoms of the disorder. In such cases, the disorder is fully expressed in both males and females. The existence of an autosomal recessive form of HED is supported by reports in the medical literature of severely affected females with the fully expressed disorder and multiple affected family members with parents who are closely related by blood (consanguineous). If both parents carry the same disease gene, there is a higher than normal risk that their children may inherit the two genes necessary for the development of the disease.
| 613 |
Hypohidrotic Ectodermal Dysplasia
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nord_613_3
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Affects of Hypohidrotic Ectodermal Dysplasia
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X-linked HED is a rare disorder that is fully expressed in males only. However, females who carry a single copy of the disease gene (heterozygote carriers) may exhibit milder symptoms associated with the disorder. In those rare cases when HED is inherited as an autosomal recessive genetic trait, males and females are affected in equal numbers. Because the vast majority of cases of HED are thought to be X-linked, it is suspected that approximately 90 percent of affected individuals are male. HED is thought to occur in approximately 1 in 5,000-10,000 newborns. Although some symptoms and findings associated with the disorder are present shortly after birth such as heat intolerance, unexplained fever, and/or extensive peeling of the skin, the characteristic facial abnormalities may not be apparent in affected infants. Therefore, the disorder often is not recognized in affected infants and children until associated dental and hair abnormalities become apparent.
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Affects of Hypohidrotic Ectodermal Dysplasia. X-linked HED is a rare disorder that is fully expressed in males only. However, females who carry a single copy of the disease gene (heterozygote carriers) may exhibit milder symptoms associated with the disorder. In those rare cases when HED is inherited as an autosomal recessive genetic trait, males and females are affected in equal numbers. Because the vast majority of cases of HED are thought to be X-linked, it is suspected that approximately 90 percent of affected individuals are male. HED is thought to occur in approximately 1 in 5,000-10,000 newborns. Although some symptoms and findings associated with the disorder are present shortly after birth such as heat intolerance, unexplained fever, and/or extensive peeling of the skin, the characteristic facial abnormalities may not be apparent in affected infants. Therefore, the disorder often is not recognized in affected infants and children until associated dental and hair abnormalities become apparent.
| 613 |
Hypohidrotic Ectodermal Dysplasia
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nord_613_4
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Related disorders of Hypohidrotic Ectodermal Dysplasia
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Symptoms of the following disorders may be similar to those of hypohidrotic ectodermal dysplasia. Comparisons may be useful for a differential diagnosis: Hidrotic ectodermal dysplasia (Clouston type), one of the group of disorders classified as ectodermal dysplasias, is characterized by abnormalities involving the nails, hair, skin, and/or teeth. This form of ectodermal dysplasia is considered “hidrotic” due to the absence of abnormalities affecting the sweat glands. In individuals with hidrotic ectodermal dysplasia (Clouston Type), physical features may include abnormally developed (dysplastic), underdeveloped (hypoplastic), or absent (aplastic) nails; scanty eyebrows, eyelashes, and body hair (hypotrichosis) with abnormally thin, sparse scalp hair or baldness; and/or, in some cases, abnormally thick, rough skin on the palms of the hands and the soles of the feet (palmoplantar keratoderma). In some affected individuals, physical findings include absence of certain teeth and/or unusually small teeth that tend to decay easily and/or abnormally increased pigmentation (hyperpigmentation) over the knees, elbows, and knuckles. Hidrotic ectodermal dysplasia (Clouston type) is inherited as an autosomal dominant genetic trait. EEC syndrome, also known as ectrodactyly-ectodermal dysplasia-cleft lip/palate, is a rare genetic disorder that may be characterized by absence of all or a portion of one or more fingers and/or toes (ectrodactyly) or other digital malformations; incomplete closure of the roof of the mouth (cleft palate) and an abnormal groove in the upper lip (cleft lip); and/or other characteristic abnormalities. Additional symptoms and findings often include fine, sparse, abnormally light (hypopigmented) scalp hair and eyebrows; absent eyelashes; and/or abnormalities of the tear (lacrimal) ducts that may cause abnormal tearing, increased susceptibility to eye infections, and chronic inflammation of the delicate membranes that line the inside of the eyelids (conjunctivitis), potentially causing visual impairment. Affected individuals may also exhibit irregularities of the nails (nail dysplasia); absence and/or abnormal smallness of certain teeth (hypodontia and/or microdontia); a decreased number of hair follicles and/or sebaceous glands; and, in some cases, skin abnormalities including unusual dryness of the skin and scaling, itchy (pruritic) skin rashes. In many cases, additional symptoms and findings may be associated with EEC syndrome including absence of the mucous membrane normally lining the voice box (larynx), causing abnormal breathiness of the voice; abnormalities of the urinary tract; deafness; and/or other abnormalities. The range and severity of symptoms and physical findings associated with the disorder vary widely from case to case. EEC syndrome is thought to be inherited as an autosomal dominant genetic trait. (For more information on this disorder, choose “EEC Syndrome” as your search term in the Rare Disease Database.) The ectodermal dysplasias are a group of more than 150 related disorders that result from abnormalities during early embryonic development. The ectodermal dysplasias are inherited disorders, but the pattern of inheritance is varied. (For more information on these disorders, choose “ectodermal dysplasia” or the exact disease name in question as your search term in the Rare Disease Database.) There are additional disorders that may be characterized by dental abnormalities, hypotrichosis, skin irregularities, craniofacial abnormalities, and/or other symptoms and findings similar to those associated with HED. Individuals with such disorders usually have characteristic abnormalities not typically associated with HED. A few of these disorders include: Schopf-Schulz-Passarge syndrome, odonto-onycho-dermal dysplasia syndrome, Witkop tooth and nail syndrome, and tricho-dento-osseous syndrome.
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Related disorders of Hypohidrotic Ectodermal Dysplasia. Symptoms of the following disorders may be similar to those of hypohidrotic ectodermal dysplasia. Comparisons may be useful for a differential diagnosis: Hidrotic ectodermal dysplasia (Clouston type), one of the group of disorders classified as ectodermal dysplasias, is characterized by abnormalities involving the nails, hair, skin, and/or teeth. This form of ectodermal dysplasia is considered “hidrotic” due to the absence of abnormalities affecting the sweat glands. In individuals with hidrotic ectodermal dysplasia (Clouston Type), physical features may include abnormally developed (dysplastic), underdeveloped (hypoplastic), or absent (aplastic) nails; scanty eyebrows, eyelashes, and body hair (hypotrichosis) with abnormally thin, sparse scalp hair or baldness; and/or, in some cases, abnormally thick, rough skin on the palms of the hands and the soles of the feet (palmoplantar keratoderma). In some affected individuals, physical findings include absence of certain teeth and/or unusually small teeth that tend to decay easily and/or abnormally increased pigmentation (hyperpigmentation) over the knees, elbows, and knuckles. Hidrotic ectodermal dysplasia (Clouston type) is inherited as an autosomal dominant genetic trait. EEC syndrome, also known as ectrodactyly-ectodermal dysplasia-cleft lip/palate, is a rare genetic disorder that may be characterized by absence of all or a portion of one or more fingers and/or toes (ectrodactyly) or other digital malformations; incomplete closure of the roof of the mouth (cleft palate) and an abnormal groove in the upper lip (cleft lip); and/or other characteristic abnormalities. Additional symptoms and findings often include fine, sparse, abnormally light (hypopigmented) scalp hair and eyebrows; absent eyelashes; and/or abnormalities of the tear (lacrimal) ducts that may cause abnormal tearing, increased susceptibility to eye infections, and chronic inflammation of the delicate membranes that line the inside of the eyelids (conjunctivitis), potentially causing visual impairment. Affected individuals may also exhibit irregularities of the nails (nail dysplasia); absence and/or abnormal smallness of certain teeth (hypodontia and/or microdontia); a decreased number of hair follicles and/or sebaceous glands; and, in some cases, skin abnormalities including unusual dryness of the skin and scaling, itchy (pruritic) skin rashes. In many cases, additional symptoms and findings may be associated with EEC syndrome including absence of the mucous membrane normally lining the voice box (larynx), causing abnormal breathiness of the voice; abnormalities of the urinary tract; deafness; and/or other abnormalities. The range and severity of symptoms and physical findings associated with the disorder vary widely from case to case. EEC syndrome is thought to be inherited as an autosomal dominant genetic trait. (For more information on this disorder, choose “EEC Syndrome” as your search term in the Rare Disease Database.) The ectodermal dysplasias are a group of more than 150 related disorders that result from abnormalities during early embryonic development. The ectodermal dysplasias are inherited disorders, but the pattern of inheritance is varied. (For more information on these disorders, choose “ectodermal dysplasia” or the exact disease name in question as your search term in the Rare Disease Database.) There are additional disorders that may be characterized by dental abnormalities, hypotrichosis, skin irregularities, craniofacial abnormalities, and/or other symptoms and findings similar to those associated with HED. Individuals with such disorders usually have characteristic abnormalities not typically associated with HED. A few of these disorders include: Schopf-Schulz-Passarge syndrome, odonto-onycho-dermal dysplasia syndrome, Witkop tooth and nail syndrome, and tricho-dento-osseous syndrome.
| 613 |
Hypohidrotic Ectodermal Dysplasia
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nord_613_5
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Diagnosis of Hypohidrotic Ectodermal Dysplasia
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In most cases, HED is diagnosed during early childhood when characteristic dental and hair abnormalities become apparent and prompt further testing. Such diagnosis is based upon a thorough clinical evaluation, identification of characteristic physical findings, a detailed patient and family history, and specialized laboratory testing. In some cases, during the newborn period, heat intolerance, unexplained fevers, and/or extensive skin peeling may lead to an earlier diagnosis.Specialized diagnostic testing may include microscopic examination of small samples of skin tissue removed from the palm, confirming partial or complete absence of eccrine sweat glands. In some cases, other types of sweat testing may be used to determine the reduction or absence of perspiration. One such test that is particularly helpful in detecting females who carry a single copy of the disease gene for X-linked HED (heterozygotes) consists of the application of an iodine-in-alcohol solution over the entire back, followed by the application of a corn starch/castor oil suspension. During such testing, sweat glands become highlighted by a black dot. In heterozygous females, characteristic streaks will appear on the back in the shape of a "V", demonstrating those areas that are devoid of sweat glands. Another method frequently used is the counting of sweat pores by direct observation. In cases of X-linked HED, direct observation reveals no sweat pores in affected males and decreased numbers of sweat pores in female carriers. In males and females with the autosomal recessive form of HED, such a count will also reveal decreased number of sweat pores.Additional diagnostic tools are available and may include a test in which the sweat glands are stimulated by a drug called pilocarpine through the use of direct current (iontophoresis) and the resulting perspiration is measured and analyzed. In some cases, application of the substance o-phthalaldehyde may be applied directly to the skin (topically) of the palm. Such testing may reveal absence or reduction of sweating in affected individuals and female carriers.In addition, dental x-rays to verify the absence of certain teeth and to further characterize associated dental abnormalities play an essential role in helping to confirm a diagnosis of HED or identify carrier status.Molecular testing for mutations in the EDA, EDAR, and EDARADD genes is available to confirm the diagnosis. Carrier testing is available if the disease-causing mutation(s) have been identified in an affected family member.
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Diagnosis of Hypohidrotic Ectodermal Dysplasia. In most cases, HED is diagnosed during early childhood when characteristic dental and hair abnormalities become apparent and prompt further testing. Such diagnosis is based upon a thorough clinical evaluation, identification of characteristic physical findings, a detailed patient and family history, and specialized laboratory testing. In some cases, during the newborn period, heat intolerance, unexplained fevers, and/or extensive skin peeling may lead to an earlier diagnosis.Specialized diagnostic testing may include microscopic examination of small samples of skin tissue removed from the palm, confirming partial or complete absence of eccrine sweat glands. In some cases, other types of sweat testing may be used to determine the reduction or absence of perspiration. One such test that is particularly helpful in detecting females who carry a single copy of the disease gene for X-linked HED (heterozygotes) consists of the application of an iodine-in-alcohol solution over the entire back, followed by the application of a corn starch/castor oil suspension. During such testing, sweat glands become highlighted by a black dot. In heterozygous females, characteristic streaks will appear on the back in the shape of a "V", demonstrating those areas that are devoid of sweat glands. Another method frequently used is the counting of sweat pores by direct observation. In cases of X-linked HED, direct observation reveals no sweat pores in affected males and decreased numbers of sweat pores in female carriers. In males and females with the autosomal recessive form of HED, such a count will also reveal decreased number of sweat pores.Additional diagnostic tools are available and may include a test in which the sweat glands are stimulated by a drug called pilocarpine through the use of direct current (iontophoresis) and the resulting perspiration is measured and analyzed. In some cases, application of the substance o-phthalaldehyde may be applied directly to the skin (topically) of the palm. Such testing may reveal absence or reduction of sweating in affected individuals and female carriers.In addition, dental x-rays to verify the absence of certain teeth and to further characterize associated dental abnormalities play an essential role in helping to confirm a diagnosis of HED or identify carrier status.Molecular testing for mutations in the EDA, EDAR, and EDARADD genes is available to confirm the diagnosis. Carrier testing is available if the disease-causing mutation(s) have been identified in an affected family member.
| 613 |
Hypohidrotic Ectodermal Dysplasia
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nord_613_6
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Therapies of Hypohidrotic Ectodermal Dysplasia
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TreatmentThe treatment of HED is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists who need to systematically and comprehensively plan an affected individual's treatment. Such specialists may include pediatricians or internists, physicians who treat disorders of the skin (dermatologists), dental specialists, physicians who diagnose and treat disorders of the ears, nose, and throat (otolaryngologists), allergists, and/or other health care professionals.If possible, it is recommended that individuals with HED live in a cool climate. Physicians may carefully monitor affected infants and young children and recommend supportive measures to help prevent episodes of severely elevated body temperature (hyperpyrexia). For children and adults with the disorder, preventive and protective measures should include avoidance of physical exertion, protection from high temperatures, and, during warm weather, large amounts of dietary fluids, cooling by water such as use of cool cloths and sponge baths, air conditioning, and/or other supportive measures.Early dental intervention and restoration is also important. Artificial teeth and/or other devices (prosthetics) may be used to replace absent teeth. Braces, bridges, dental surgery, and/or other corrective measures may be used to help correct dental abnormalities and ensure appropriate nutrition. In addition, in affected individuals with alopecia, hairpieces or wigs may be helpful.Physicians may recommend that impacted nasal secretions be carefully removed on a regular basis to help prevent or limit the severity of rhinitis. Physicians may also regularly monitor affected infants and children to help prevent respiratory infections and to ensure prompt, aggressive treatment should such infections occur.In affected individuals with impaired tear secretion (alacrima), the use of artificial tears may help to prevent possible corneal damage.Early intervention is important to ensure that children with HED reach their potential. Special services that may be beneficial to affected children may include special education and special social support, and/or other medical, social, and/or vocational services.Genetic counseling will be of benefit for affected children and their families. Other treatment is symptomatic and supportive.
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Therapies of Hypohidrotic Ectodermal Dysplasia. TreatmentThe treatment of HED is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists who need to systematically and comprehensively plan an affected individual's treatment. Such specialists may include pediatricians or internists, physicians who treat disorders of the skin (dermatologists), dental specialists, physicians who diagnose and treat disorders of the ears, nose, and throat (otolaryngologists), allergists, and/or other health care professionals.If possible, it is recommended that individuals with HED live in a cool climate. Physicians may carefully monitor affected infants and young children and recommend supportive measures to help prevent episodes of severely elevated body temperature (hyperpyrexia). For children and adults with the disorder, preventive and protective measures should include avoidance of physical exertion, protection from high temperatures, and, during warm weather, large amounts of dietary fluids, cooling by water such as use of cool cloths and sponge baths, air conditioning, and/or other supportive measures.Early dental intervention and restoration is also important. Artificial teeth and/or other devices (prosthetics) may be used to replace absent teeth. Braces, bridges, dental surgery, and/or other corrective measures may be used to help correct dental abnormalities and ensure appropriate nutrition. In addition, in affected individuals with alopecia, hairpieces or wigs may be helpful.Physicians may recommend that impacted nasal secretions be carefully removed on a regular basis to help prevent or limit the severity of rhinitis. Physicians may also regularly monitor affected infants and children to help prevent respiratory infections and to ensure prompt, aggressive treatment should such infections occur.In affected individuals with impaired tear secretion (alacrima), the use of artificial tears may help to prevent possible corneal damage.Early intervention is important to ensure that children with HED reach their potential. Special services that may be beneficial to affected children may include special education and special social support, and/or other medical, social, and/or vocational services.Genetic counseling will be of benefit for affected children and their families. Other treatment is symptomatic and supportive.
| 613 |
Hypohidrotic Ectodermal Dysplasia
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nord_614_0
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Overview of Hypokalemia
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Hypokalemia is a metabolic imbalance characterized by extremely low potassium levels in the blood. It is a symptom of another disease or condition, or a side effect of diuretic drugs. The body needs potassium for the contraction of muscles (including the heart), and for the functioning of many complicated proteins (enzymes). Potassium is found primarily in the skeletal muscle and bone, and participates with sodium to contribute to the normal flow of body fluids between the cells in the body. The normal concentration of potassium in the body is regulated by the kidneys through the excretion of urine. When the kidneys are functioning normally, the amount of potassium in the diet is sufficient for use by the body and the excess is usually excreted through urine and sweat. Body chemicals and hormones such as aldosterone also regulate potassium balance. Secretion of the hormone insulin, which is normally stimulated by food, prevents a temporary diet-induced Hypokalemia by increasing cell absorption of potassium. When Hypokalemia occurs, there is an imbalance resulting from a dysfunction in this normal process, or the rapid loss of urine or sweat without replacement of sufficient potassium.
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Overview of Hypokalemia. Hypokalemia is a metabolic imbalance characterized by extremely low potassium levels in the blood. It is a symptom of another disease or condition, or a side effect of diuretic drugs. The body needs potassium for the contraction of muscles (including the heart), and for the functioning of many complicated proteins (enzymes). Potassium is found primarily in the skeletal muscle and bone, and participates with sodium to contribute to the normal flow of body fluids between the cells in the body. The normal concentration of potassium in the body is regulated by the kidneys through the excretion of urine. When the kidneys are functioning normally, the amount of potassium in the diet is sufficient for use by the body and the excess is usually excreted through urine and sweat. Body chemicals and hormones such as aldosterone also regulate potassium balance. Secretion of the hormone insulin, which is normally stimulated by food, prevents a temporary diet-induced Hypokalemia by increasing cell absorption of potassium. When Hypokalemia occurs, there is an imbalance resulting from a dysfunction in this normal process, or the rapid loss of urine or sweat without replacement of sufficient potassium.
| 614 |
Hypokalemia
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nord_614_1
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Symptoms of Hypokalemia
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Most often, hypokalemia is asymptomatic, with no obvious signs of the disorder. However, symptoms of hypokalemia may include attacks of severe muscle weakness, eventually leading to paralysis and possibly respiratory failure.Muscular malfunction may result in paralysis of the bowel, low blood pressure, muscle twitches and mineral deficiencies (tetany). Severe hypokalemia may also lead to disruption of skeletal muscle cells, particularly during exercise. The normal physical response to exercise requires the local release of potassium from muscle. In potassium depleted muscle, the lack of potassium prevents adequate widening of blood vessels, resulting in decreased muscle blood flow, cramps and the destruction of skeletal muscle.Hypokalemia may also impair the ability of the kidneys to concentrate urine, resulting in excessive urination (polyuria) and excessive thirst (polydipsia). Other symptoms may include loss of appetite, nausea and vomiting. There may also be heart irregularities seen in electrocardiograph changes, confusion, distention of the abdomen, a decrease in mental activity.
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Symptoms of Hypokalemia. Most often, hypokalemia is asymptomatic, with no obvious signs of the disorder. However, symptoms of hypokalemia may include attacks of severe muscle weakness, eventually leading to paralysis and possibly respiratory failure.Muscular malfunction may result in paralysis of the bowel, low blood pressure, muscle twitches and mineral deficiencies (tetany). Severe hypokalemia may also lead to disruption of skeletal muscle cells, particularly during exercise. The normal physical response to exercise requires the local release of potassium from muscle. In potassium depleted muscle, the lack of potassium prevents adequate widening of blood vessels, resulting in decreased muscle blood flow, cramps and the destruction of skeletal muscle.Hypokalemia may also impair the ability of the kidneys to concentrate urine, resulting in excessive urination (polyuria) and excessive thirst (polydipsia). Other symptoms may include loss of appetite, nausea and vomiting. There may also be heart irregularities seen in electrocardiograph changes, confusion, distention of the abdomen, a decrease in mental activity.
| 614 |
Hypokalemia
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