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nord_271_3 | Affects of Chronic Lymphocytic Leukemia | Chronic lymphocytic leukemia is the most common type of leukemia found in multiple family members. It is twice as common in males as in females and the average age of onset in patients is 72. It is also more common in people that are white, or of Russian and Eastern European Jewish heritage. The rate of incidence of the disorder increases with age. CLL almost never affects children and is rare under the age of thirty. In the United States, it is thought that three out of every 100,000 people will develop CLL, but this may be an underestimate. | Affects of Chronic Lymphocytic Leukemia. Chronic lymphocytic leukemia is the most common type of leukemia found in multiple family members. It is twice as common in males as in females and the average age of onset in patients is 72. It is also more common in people that are white, or of Russian and Eastern European Jewish heritage. The rate of incidence of the disorder increases with age. CLL almost never affects children and is rare under the age of thirty. In the United States, it is thought that three out of every 100,000 people will develop CLL, but this may be an underestimate. | 271 | Chronic Lymphocytic Leukemia |
nord_271_4 | Related disorders of Chronic Lymphocytic Leukemia | Symptoms of the following disorders can be similar to those of chronic lymphocytic leukemia. Comparisons may be useful for a differential diagnosis.B cell prolymphocytic leukemia (PLL) is a rare, aggressive form of leukemia. Prolymphocytes are immature white blood cells whose primary function it is to secrete antibodies which fight bacteria and viruses. When fighting these toxins, cellular memories are usually developed, which is why humans do not usually contract chicken pox more than once, for example. A key feature of this disease is that this adaptive immunity is missing. This leukemia is characterized by overly large prolymphocytes, which can cause a swollen spleen, weight loss, tiredness, and high concentrations of prolymphocytes in the bone marrow and/or blood. Sometimes as CLL becomes more refractory, it shows evolution toward PLL.Richter’s syndrome develops in 3-15% of patients who have CLL. Richter’s syndrome is a very aggressive form of lymphoma. Usual symptoms a patient may experience when their CLL develops into Richter’s syndrome is increased swelling of the lymph nodes, spleen, and liver, a high fever, abdominal pain and even more weight loss. Blood counts will also worsen. The prognosis for Richter’s syndrome is very poor, but can be diagnosed with a lymph node biopsy. Treatment includes chemotherapy followed by stem cell transplant if possible.Hairy cell leukemia (HCL) is a rare type of blood cancer characterized by abnormal changes in white blood cells known as B lymphocytes. The bone marrow creates too many of these defective cells, known as “hairy cells” because of the thin hair-like projections found on their surface. Overproduction and accumulation of hairy cells causes a deficiency of normal blood cells (pancytopenia), including an abnormal decrease of certain white blood cells (neutrophils [neutropenia]), red blood cells (anemia) or platelets [thrombocytopenia]). Affected individuals usually exhibit fatigue and weakness due to anemia (abnormally low levels of red blood cells), fever, weight loss, and/or abdominal discomfort due to an abnormally enlarged spleen (splenomegaly). In addition, affected individuals may have a slightly enlarged liver (hepatomegaly) and may be unusually susceptible to bruising and/or severe infection. The exact cause of hairy cell leukemia is not known although almost all cases have a particular mutation in the B-raf gene. (For more information on this disorder, choose “leukemia, hairy cell” as your search term in the Rare Disease Database.)”Non-Hodgkin’s lymphomas (NHLs) are a group of cancers of the lymphatic system. Functioning as part of the immune system, the lymphatic system helps to protect the body against infection and disease. NHLs may be broadly classified into lymphomas that arise from abnormal B-lymphocytes (B-cell lymphomas) and those derived from abnormal T-lymphocytes (T-cell lymphomas). Abnormal, uncontrolled growth and multiplication (proliferation) of malignant lymphocytes may lead to enlargement of a specific lymph node region or regions, involvement of other lymphatic tissues, such as the spleen and bone marrow; and spread to other bodily tissues and organs, potentially resulting in life-threatening complications. The specific symptoms and physical findings may vary from person to person, depending upon the extent and region(s) of involvement and other factors. Groups of lymph nodes are located throughout the body, including in the neck, under the arms (axillae), at the elbows, and in the chest, abdomen, and groin. Symptoms of non-Hodgkin’s lymphomas may be anemia (abnormally low levels of red blood cells), weight loss, fever, night sweats, and weakness.Mantle cell lymphoma (MCL) belongs to the group of non-Hodgkin’s lymphomas. MCL is a B-cell lymphoma that develops from malignant B-lymphocytes within a region of the lymph node known as the mantle zone. According to various estimates, MCL represents approximately 2 to 7 percent of adult NHLs in the United States and Europe. It affects more men than women, and mostly over the age of 50 years. Many affected individuals have widespread disease at diagnosis, with involved regions often including multiple lymph nodes, the spleen, and, potentially, the bone marrow, the liver, and/or regions of the digestive (gastrointestinal) tract. (For more information on this disorder, choose “mantle cell lymphoma” as your search term in the Rare Disease Database.)Chronic myelogenous leukemia is a rare myeloproliferative disorder characterized by the excessive development of white blood cells in the spongy tissue found inside large bones of the body (bone marrow), spleen, liver and blood. As the disease progresses, the leukemic cells invade other areas of the body including the intestinal tract, kidneys, lungs, gonads and lymph nodes. (For more information on this disorder, choose “chronic myelogenous leukemia” as your search term in the Rare Disease Database.)Myelodysplastic syndromes (MDS) are a rare group of blood disorders that occur as a result of improper development of blood cells within the bone marrow. The three main types of blood cells (i.e., red blood cells, white blood cells and platelets) are affected. These improperly developed blood cells fail to develop normally and enter the bloodstream. As a result, individuals with MDS have abnormally low blood cell levels (low blood counts). General symptoms associated with MDS include fatigue, dizziness, weakness, bruising and bleeding, frequent infections, and headaches. In some patients, MDS may progress to life-threatening failure of the bone marrow or develop into an acute leukemia. (For more information on these disorders, choose “myelodysplastic syndromes” as your search term in the Rare Disease Database.) | Related disorders of Chronic Lymphocytic Leukemia. Symptoms of the following disorders can be similar to those of chronic lymphocytic leukemia. Comparisons may be useful for a differential diagnosis.B cell prolymphocytic leukemia (PLL) is a rare, aggressive form of leukemia. Prolymphocytes are immature white blood cells whose primary function it is to secrete antibodies which fight bacteria and viruses. When fighting these toxins, cellular memories are usually developed, which is why humans do not usually contract chicken pox more than once, for example. A key feature of this disease is that this adaptive immunity is missing. This leukemia is characterized by overly large prolymphocytes, which can cause a swollen spleen, weight loss, tiredness, and high concentrations of prolymphocytes in the bone marrow and/or blood. Sometimes as CLL becomes more refractory, it shows evolution toward PLL.Richter’s syndrome develops in 3-15% of patients who have CLL. Richter’s syndrome is a very aggressive form of lymphoma. Usual symptoms a patient may experience when their CLL develops into Richter’s syndrome is increased swelling of the lymph nodes, spleen, and liver, a high fever, abdominal pain and even more weight loss. Blood counts will also worsen. The prognosis for Richter’s syndrome is very poor, but can be diagnosed with a lymph node biopsy. Treatment includes chemotherapy followed by stem cell transplant if possible.Hairy cell leukemia (HCL) is a rare type of blood cancer characterized by abnormal changes in white blood cells known as B lymphocytes. The bone marrow creates too many of these defective cells, known as “hairy cells” because of the thin hair-like projections found on their surface. Overproduction and accumulation of hairy cells causes a deficiency of normal blood cells (pancytopenia), including an abnormal decrease of certain white blood cells (neutrophils [neutropenia]), red blood cells (anemia) or platelets [thrombocytopenia]). Affected individuals usually exhibit fatigue and weakness due to anemia (abnormally low levels of red blood cells), fever, weight loss, and/or abdominal discomfort due to an abnormally enlarged spleen (splenomegaly). In addition, affected individuals may have a slightly enlarged liver (hepatomegaly) and may be unusually susceptible to bruising and/or severe infection. The exact cause of hairy cell leukemia is not known although almost all cases have a particular mutation in the B-raf gene. (For more information on this disorder, choose “leukemia, hairy cell” as your search term in the Rare Disease Database.)”Non-Hodgkin’s lymphomas (NHLs) are a group of cancers of the lymphatic system. Functioning as part of the immune system, the lymphatic system helps to protect the body against infection and disease. NHLs may be broadly classified into lymphomas that arise from abnormal B-lymphocytes (B-cell lymphomas) and those derived from abnormal T-lymphocytes (T-cell lymphomas). Abnormal, uncontrolled growth and multiplication (proliferation) of malignant lymphocytes may lead to enlargement of a specific lymph node region or regions, involvement of other lymphatic tissues, such as the spleen and bone marrow; and spread to other bodily tissues and organs, potentially resulting in life-threatening complications. The specific symptoms and physical findings may vary from person to person, depending upon the extent and region(s) of involvement and other factors. Groups of lymph nodes are located throughout the body, including in the neck, under the arms (axillae), at the elbows, and in the chest, abdomen, and groin. Symptoms of non-Hodgkin’s lymphomas may be anemia (abnormally low levels of red blood cells), weight loss, fever, night sweats, and weakness.Mantle cell lymphoma (MCL) belongs to the group of non-Hodgkin’s lymphomas. MCL is a B-cell lymphoma that develops from malignant B-lymphocytes within a region of the lymph node known as the mantle zone. According to various estimates, MCL represents approximately 2 to 7 percent of adult NHLs in the United States and Europe. It affects more men than women, and mostly over the age of 50 years. Many affected individuals have widespread disease at diagnosis, with involved regions often including multiple lymph nodes, the spleen, and, potentially, the bone marrow, the liver, and/or regions of the digestive (gastrointestinal) tract. (For more information on this disorder, choose “mantle cell lymphoma” as your search term in the Rare Disease Database.)Chronic myelogenous leukemia is a rare myeloproliferative disorder characterized by the excessive development of white blood cells in the spongy tissue found inside large bones of the body (bone marrow), spleen, liver and blood. As the disease progresses, the leukemic cells invade other areas of the body including the intestinal tract, kidneys, lungs, gonads and lymph nodes. (For more information on this disorder, choose “chronic myelogenous leukemia” as your search term in the Rare Disease Database.)Myelodysplastic syndromes (MDS) are a rare group of blood disorders that occur as a result of improper development of blood cells within the bone marrow. The three main types of blood cells (i.e., red blood cells, white blood cells and platelets) are affected. These improperly developed blood cells fail to develop normally and enter the bloodstream. As a result, individuals with MDS have abnormally low blood cell levels (low blood counts). General symptoms associated with MDS include fatigue, dizziness, weakness, bruising and bleeding, frequent infections, and headaches. In some patients, MDS may progress to life-threatening failure of the bone marrow or develop into an acute leukemia. (For more information on these disorders, choose “myelodysplastic syndromes” as your search term in the Rare Disease Database.) | 271 | Chronic Lymphocytic Leukemia |
nord_271_5 | Diagnosis of Chronic Lymphocytic Leukemia | CLL is most commonly discovered when an abnormally high white blood cell count is noticed in routine blood work. A diagnosis can be made with one of the following tests:1. Complete blood cell count-This test will measure the count of every type of blood cell, white blood cells, red blood cells, and platelets. A high number of B-cells, a certain type of white blood cell, may indicate CLL.2. Flow cytometry-In this test, blood cells are examined with antibodies to determine if they are malignant (cancerous). This test establishes the diagnosis of CLL vs other related diseases.3. Bone marrow biopsy-This test is conducted by removing a sample of bone marrow and examining it to determine what time of leukemia is present. This is usually not required to make an initial diagnosis of CLL, since flow cytometry can be done on the blood. 4. Lymph node biopsy-A biopsy of the lymph nodes can determine whether cancer has spread to the lymphatic system.To predict the likely course of CLL, your doctor may also recommend more specialized tests. Specialized tests can predict response to treatment and the likelihood of relapse but the decision to treat is still based on clinical parameters – how you feel, your blood counts, lymph nodes, etc.Clinical Testing and Work-UpRegular blood tests and physical exams are used to carefully watch for signs of progression because early-stage CLL may take years to progress. Generally just blood tests and physical exams are all that is required for routine disease monitoring, along with blood chemistries and antibody tests. | Diagnosis of Chronic Lymphocytic Leukemia. CLL is most commonly discovered when an abnormally high white blood cell count is noticed in routine blood work. A diagnosis can be made with one of the following tests:1. Complete blood cell count-This test will measure the count of every type of blood cell, white blood cells, red blood cells, and platelets. A high number of B-cells, a certain type of white blood cell, may indicate CLL.2. Flow cytometry-In this test, blood cells are examined with antibodies to determine if they are malignant (cancerous). This test establishes the diagnosis of CLL vs other related diseases.3. Bone marrow biopsy-This test is conducted by removing a sample of bone marrow and examining it to determine what time of leukemia is present. This is usually not required to make an initial diagnosis of CLL, since flow cytometry can be done on the blood. 4. Lymph node biopsy-A biopsy of the lymph nodes can determine whether cancer has spread to the lymphatic system.To predict the likely course of CLL, your doctor may also recommend more specialized tests. Specialized tests can predict response to treatment and the likelihood of relapse but the decision to treat is still based on clinical parameters – how you feel, your blood counts, lymph nodes, etc.Clinical Testing and Work-UpRegular blood tests and physical exams are used to carefully watch for signs of progression because early-stage CLL may take years to progress. Generally just blood tests and physical exams are all that is required for routine disease monitoring, along with blood chemistries and antibody tests. | 271 | Chronic Lymphocytic Leukemia |
nord_271_6 | Therapies of Chronic Lymphocytic Leukemia | Treatment Treatment for CLL is based on the stage of the disease, symptoms, and prognosis. Patients with CLL may show no symptoms for years, and don’t require special care. However, in later stages of the disease, chemotherapy is a common choice of treatment. Another treatment option is monoclonal antibody therapy, which binds proteins to cancer cells, activating a mechanism that destroys them. Using both of these therapies together usually produces the highest treatment response. In especially aggressive or recurrent cases of CLL, a blood and marrow stem cell transplant has shown promise. All care of CLL patients, whether receiving specific therapy or not, includes what we call supportive care and includes platelet transfusions which are used for bleeding associated with a persistent decrease in the number blood platelets (thrombocytopenia). When anemia is present, transfusions of packed red blood cells are usually given. Antibiotics are used to combat bacterial infections usually related to a decrease in the number of leukocytes (lymphopenia) and a low level of gammaglobulin in the blood. Vaccinations are important and should include yearly influenza as well as the pneumococcal vaccines, prevnar and pneumovax. However, live virus vaccines like that against shingles can be dangerous. The Food and Drug Administration (FDA) approved the anti-cancer drug Rituxan (rituximab) in 2010 to treat certain patients with chronic lymphocytic leukemia. Rituxan is intended together with chemotherapy for patients with CLL who are beginning first line therapy. Rituxan is administered with two other chemotherapy drugs, Fludara (fludarabine) and Cytoxan (cyclophosphamide). Other antibodies with the same target as rituximab have been approved by the FDA for frontline therapy of CLL in combination with the oral chemotherapy pill Leukeran (chlorambucil): Gazyva (obinutuzumab) and Arzerra (ofatumumab) have been approved to combat CLL. Arzerra was initially approved to treat refractory patients, but more recently was approved for previously untreated patients in combination with Leukeran, and for patients who have had previous chemoimmunotherapy and are in remission. Treanda (bendamustine hydrochloride) has been approved by the FDA for treating CLL. It has been shown that Treanda can be effective when administered once every four weeks, similar to other chemotherapies. The last few years have seen an explosion of very effective small molecule inhibitors for CLL. These are tasken in pill form and generally well tolerated. Zydelig (idelalisib) was approved for relapsed CLL patients with comorbid medical problems in 2014. Also in 2014, Imbruvica (ibrutinib) was approved to treat chronic lymphocytic leukemia patients who have received at least one previous therapy as well as those with high risk del17p. In 2016 Imbruvica’s label was broadened to include all CLL patients, including those previously untreated. Venclexta (venetoclax) was approved just for relapsed 17p deleted CLL patients in 2016. In 2017, the combination drug Rituxan Hyecela (rituximab and hyaluronidase human) was approved for adults with CLL. Patients can only receive Rituxan Hyecela after they have received at least one intravenous treatment of Rituxan. In 2019, Calquence (acalabrutinib), a drug previous approved to treat patients with mantle cell lymphoma, was approved by FDA to treat CLL in adult patients. | Therapies of Chronic Lymphocytic Leukemia. Treatment Treatment for CLL is based on the stage of the disease, symptoms, and prognosis. Patients with CLL may show no symptoms for years, and don’t require special care. However, in later stages of the disease, chemotherapy is a common choice of treatment. Another treatment option is monoclonal antibody therapy, which binds proteins to cancer cells, activating a mechanism that destroys them. Using both of these therapies together usually produces the highest treatment response. In especially aggressive or recurrent cases of CLL, a blood and marrow stem cell transplant has shown promise. All care of CLL patients, whether receiving specific therapy or not, includes what we call supportive care and includes platelet transfusions which are used for bleeding associated with a persistent decrease in the number blood platelets (thrombocytopenia). When anemia is present, transfusions of packed red blood cells are usually given. Antibiotics are used to combat bacterial infections usually related to a decrease in the number of leukocytes (lymphopenia) and a low level of gammaglobulin in the blood. Vaccinations are important and should include yearly influenza as well as the pneumococcal vaccines, prevnar and pneumovax. However, live virus vaccines like that against shingles can be dangerous. The Food and Drug Administration (FDA) approved the anti-cancer drug Rituxan (rituximab) in 2010 to treat certain patients with chronic lymphocytic leukemia. Rituxan is intended together with chemotherapy for patients with CLL who are beginning first line therapy. Rituxan is administered with two other chemotherapy drugs, Fludara (fludarabine) and Cytoxan (cyclophosphamide). Other antibodies with the same target as rituximab have been approved by the FDA for frontline therapy of CLL in combination with the oral chemotherapy pill Leukeran (chlorambucil): Gazyva (obinutuzumab) and Arzerra (ofatumumab) have been approved to combat CLL. Arzerra was initially approved to treat refractory patients, but more recently was approved for previously untreated patients in combination with Leukeran, and for patients who have had previous chemoimmunotherapy and are in remission. Treanda (bendamustine hydrochloride) has been approved by the FDA for treating CLL. It has been shown that Treanda can be effective when administered once every four weeks, similar to other chemotherapies. The last few years have seen an explosion of very effective small molecule inhibitors for CLL. These are tasken in pill form and generally well tolerated. Zydelig (idelalisib) was approved for relapsed CLL patients with comorbid medical problems in 2014. Also in 2014, Imbruvica (ibrutinib) was approved to treat chronic lymphocytic leukemia patients who have received at least one previous therapy as well as those with high risk del17p. In 2016 Imbruvica’s label was broadened to include all CLL patients, including those previously untreated. Venclexta (venetoclax) was approved just for relapsed 17p deleted CLL patients in 2016. In 2017, the combination drug Rituxan Hyecela (rituximab and hyaluronidase human) was approved for adults with CLL. Patients can only receive Rituxan Hyecela after they have received at least one intravenous treatment of Rituxan. In 2019, Calquence (acalabrutinib), a drug previous approved to treat patients with mantle cell lymphoma, was approved by FDA to treat CLL in adult patients. | 271 | Chronic Lymphocytic Leukemia |
nord_272_0 | Overview of Chronic Myelogenous Leukemia | Summary Chronic myelogenous leukemia (CML) accounts of about 20% of all leukemias affecting adults. It typically affects middle-aged individuals and rarely adolescents or children. CML is a slowly progressing blood and bone marrow disorder, characterized by the excessive development of white blood cells in the spongy tissue found inside large bones of the body (bone marrow), spleen, liver and blood. As the disease progresses, the leukemic (blast) cells invade other areas of the body including the intestinal tract, kidneys, lungs, gonads and lymph nodes. These diseased cells do not grow old and eventually die like normal cells. They build up in huge numbers, overwhelm healthy blood cells and damage the bone marrow. Since CML progresses slowly, many people are first diagnosed during routine blood exams before they even show symptoms. There is no cure for CML because it is not possible to eliminate all of the diseased cells in the body, however, there are many approved treatments that can achieve a long-term remission. Patients respond best to treatment when CML is in its earliest stage, so it is important to diagnose the disease as early as possible. Possible symptoms that may indicate CML are fever, night sweats, fatigue, pain below the ribs on the left side, and inexplicable weight loss. If an individual is experiencing any of the above symptoms or other signs, it is important they make an appointment with their doctor to be tested for CML. Introduction There are three phases of chronic myelogenous leukemia.The first phase, or the chronic phase, is characterized by a slow, progressive overproduction of white blood cells. In chronic CML, fewer than 10% of the cells in the blood and bone marrow are blast (leukemic) cells. Patients in this phase have the best response to treatment. The next phase is transitional, and is called the accelerated phase, which occurs when 10%-19% of the cells are blast cells. The most advanced phase is the blastic phase. At this point, over 20% of the blood cells are blast cells). In the blastic phase, the leukemia is very aggressive and does not respond well to therapy. Approximately 85% of all individuals with chronic myelogenous leukemia enter this phase. | Overview of Chronic Myelogenous Leukemia. Summary Chronic myelogenous leukemia (CML) accounts of about 20% of all leukemias affecting adults. It typically affects middle-aged individuals and rarely adolescents or children. CML is a slowly progressing blood and bone marrow disorder, characterized by the excessive development of white blood cells in the spongy tissue found inside large bones of the body (bone marrow), spleen, liver and blood. As the disease progresses, the leukemic (blast) cells invade other areas of the body including the intestinal tract, kidneys, lungs, gonads and lymph nodes. These diseased cells do not grow old and eventually die like normal cells. They build up in huge numbers, overwhelm healthy blood cells and damage the bone marrow. Since CML progresses slowly, many people are first diagnosed during routine blood exams before they even show symptoms. There is no cure for CML because it is not possible to eliminate all of the diseased cells in the body, however, there are many approved treatments that can achieve a long-term remission. Patients respond best to treatment when CML is in its earliest stage, so it is important to diagnose the disease as early as possible. Possible symptoms that may indicate CML are fever, night sweats, fatigue, pain below the ribs on the left side, and inexplicable weight loss. If an individual is experiencing any of the above symptoms or other signs, it is important they make an appointment with their doctor to be tested for CML. Introduction There are three phases of chronic myelogenous leukemia.The first phase, or the chronic phase, is characterized by a slow, progressive overproduction of white blood cells. In chronic CML, fewer than 10% of the cells in the blood and bone marrow are blast (leukemic) cells. Patients in this phase have the best response to treatment. The next phase is transitional, and is called the accelerated phase, which occurs when 10%-19% of the cells are blast cells. The most advanced phase is the blastic phase. At this point, over 20% of the blood cells are blast cells). In the blastic phase, the leukemia is very aggressive and does not respond well to therapy. Approximately 85% of all individuals with chronic myelogenous leukemia enter this phase. | 272 | Chronic Myelogenous Leukemia |
nord_272_1 | Symptoms of Chronic Myelogenous Leukemia | Many individuals with CML show nonspecific symptoms at the time of diagnosis. The most common symptoms are fatigue, weakness, itchiness, night sweats, abdominal discomfort, and weight loss. An abnormally enlarged spleen (splenomegaly) is usually discovered upon physical examination. CML is commonly diagnosed when an affected individual is undergoing blood tests for a different reason. Sometimes, no symptoms are present at all.When the accelerated or blastic phase of CML occurs, an affected individual may experience severe weight loss, high fever, bone pain, enlargement of the liver and spleen, pain in the joints (arthralgia), and hemorrhages appearing as patches of purplish discoloration on the skin and mucous membranes. | Symptoms of Chronic Myelogenous Leukemia. Many individuals with CML show nonspecific symptoms at the time of diagnosis. The most common symptoms are fatigue, weakness, itchiness, night sweats, abdominal discomfort, and weight loss. An abnormally enlarged spleen (splenomegaly) is usually discovered upon physical examination. CML is commonly diagnosed when an affected individual is undergoing blood tests for a different reason. Sometimes, no symptoms are present at all.When the accelerated or blastic phase of CML occurs, an affected individual may experience severe weight loss, high fever, bone pain, enlargement of the liver and spleen, pain in the joints (arthralgia), and hemorrhages appearing as patches of purplish discoloration on the skin and mucous membranes. | 272 | Chronic Myelogenous Leukemia |
nord_272_2 | Causes of Chronic Myelogenous Leukemia | The exact cause of CML is not known. Blood samples of patients with CML show the presence of abnormal cells that reproduce more rapidly than normal cells. Ninety percent of these neoplastic cells show a consistent rearrangement of chromosomes. This rearrangement is the result of a transfer of genetic material from chromosome 22 to chromosome 9 and vice versa. As a result of this transference, chromosome 22 ends up shorter than normal. This shortened chromosome is known as the Philadelphia chromosome, and is present in the blood cells of 90% of people with CML. Formation of the Philadelphia chromosome results in a fused gene, called BCR-ABL. This gene contains instructions that make the disease blood cells produce far too much of a protein called tyrosine kinase. This protein causes the cancer by allowing the diseased blood cells to grow out of control.Family history is not a risk factor for CML. The chromosome rearrangement resulting in the Philadelphia chromosome is believed to be acquired, meaning it develops after birth. It is believed that in some cases, excessive exposure to radiation increases an individual’s chances of developing the disease. | Causes of Chronic Myelogenous Leukemia. The exact cause of CML is not known. Blood samples of patients with CML show the presence of abnormal cells that reproduce more rapidly than normal cells. Ninety percent of these neoplastic cells show a consistent rearrangement of chromosomes. This rearrangement is the result of a transfer of genetic material from chromosome 22 to chromosome 9 and vice versa. As a result of this transference, chromosome 22 ends up shorter than normal. This shortened chromosome is known as the Philadelphia chromosome, and is present in the blood cells of 90% of people with CML. Formation of the Philadelphia chromosome results in a fused gene, called BCR-ABL. This gene contains instructions that make the disease blood cells produce far too much of a protein called tyrosine kinase. This protein causes the cancer by allowing the diseased blood cells to grow out of control.Family history is not a risk factor for CML. The chromosome rearrangement resulting in the Philadelphia chromosome is believed to be acquired, meaning it develops after birth. It is believed that in some cases, excessive exposure to radiation increases an individual’s chances of developing the disease. | 272 | Chronic Myelogenous Leukemia |
nord_272_3 | Affects of Chronic Myelogenous Leukemia | CML is slightly more prevalent in males than in females. It may occur at any age, but predominantly affects people in their 40s and 50s. There are more than 4,000 new cases of the 30,000 new cases of leukemia, diagnosed each year. There is an increased incidence rate of CML among people who have been exposed to radiation, such as the survivors of the atomic bombs dropped in Nagasaki and Hiroshima.Although very rare in young patients, ages 20-29, CML may present itself in a more aggressive form, such as the accelerated phase or the blastic phase. | Affects of Chronic Myelogenous Leukemia. CML is slightly more prevalent in males than in females. It may occur at any age, but predominantly affects people in their 40s and 50s. There are more than 4,000 new cases of the 30,000 new cases of leukemia, diagnosed each year. There is an increased incidence rate of CML among people who have been exposed to radiation, such as the survivors of the atomic bombs dropped in Nagasaki and Hiroshima.Although very rare in young patients, ages 20-29, CML may present itself in a more aggressive form, such as the accelerated phase or the blastic phase. | 272 | Chronic Myelogenous Leukemia |
nord_272_4 | Related disorders of Chronic Myelogenous Leukemia | Symptoms of the following disorders can be similar to those of chronic myelogenous leukemia. Comparisons may be useful for a differential diagnosis:Polycythemia vera is a rare chronic myeloproliferative disorder characterized by overproduction of red blood cells and elements of the bone marrow involved in the formation of red blood cells (hematopoietic elements). In most cases, affected individuals may experience headaches, weakness, dizziness (vertigo), and/or a ringing noise in the ear (tinnitus). In some cases, individuals with polycythemia vera experience itching (pruritis), especially after a hot bath. Affected individuals often have an abnormally enlarged spleen (splenomegaly) and/or liver (hepatomegaly). In some cases, affected individuals may have associated conditions including high blood pressure (hypertension), the formation of blood clots (thrombosis), and/or rupturing of and loss of blood (hemorrhaging) from certain blood vessels. The exact cause of polycythemia vera is not known. (For more information on this disorder, choose “polcythemia vera” as your search term in the Rare Disease Database.)Primary myelofibrosis is a rare disorder in which the cause is not known (idiopathic). Myelofibrosis is a condition characterized by formation of scar or fibrous tissue (fibrosis) within the bone marrow. In idiopathic myelofibrosis, the ability of the bone marrow to produce red blood cells may be impaired. Symptoms of idiopathic myelofibrosis may include abnormally low levels of circulating red blood cells (anemia), an abnormally large spleen (splenomegaly), an abnormally large liver (hepatomegaly), weight loss, weakness and fatigue due to replacement of normal bone marrow cells, and/or episodes of severe pain in the abdomen, bones, and joints. In many cases, myelofibrosis occurs in association with increased bone density and the formation of small sharp pieces of bone (spicules) within the marrow cavity and increased bone density (osteosclerosis). (For more information on this disorder, choose “primary myelofibrosis” as your search term in the Rare Disease Database.)Many other types of leukemia may mimic CML. Leukemia is a general term that denotes cancer of the bone marrow. In leukemia, white bloods cells divide and grow uncontrollably causing problems in the bone marrow and affecting the production of other bone marrow cells (i.e., red blood cells, platelets, other white blood cells). A similar form of leukemia is chronic lymphocytic leukemia (CLL). In CLL, the abnormal cells arise from lymphocytes (immune system cells), instead of from myeloid cells such as the parent cells of granulocytes (bacteria-destroying cells),), like in CML. Symptoms of CLL are very similar to CML, and may include fever, pain from an enlarged spleen, night sweats, fatigue, weight loss, bacterial infections. Blood tests can determine CML from CLL. (For more information on this disorder, choose “Chronic Lymphocytic Leukemia” as your search term in the Rare Disease Database.) | Related disorders of Chronic Myelogenous Leukemia. Symptoms of the following disorders can be similar to those of chronic myelogenous leukemia. Comparisons may be useful for a differential diagnosis:Polycythemia vera is a rare chronic myeloproliferative disorder characterized by overproduction of red blood cells and elements of the bone marrow involved in the formation of red blood cells (hematopoietic elements). In most cases, affected individuals may experience headaches, weakness, dizziness (vertigo), and/or a ringing noise in the ear (tinnitus). In some cases, individuals with polycythemia vera experience itching (pruritis), especially after a hot bath. Affected individuals often have an abnormally enlarged spleen (splenomegaly) and/or liver (hepatomegaly). In some cases, affected individuals may have associated conditions including high blood pressure (hypertension), the formation of blood clots (thrombosis), and/or rupturing of and loss of blood (hemorrhaging) from certain blood vessels. The exact cause of polycythemia vera is not known. (For more information on this disorder, choose “polcythemia vera” as your search term in the Rare Disease Database.)Primary myelofibrosis is a rare disorder in which the cause is not known (idiopathic). Myelofibrosis is a condition characterized by formation of scar or fibrous tissue (fibrosis) within the bone marrow. In idiopathic myelofibrosis, the ability of the bone marrow to produce red blood cells may be impaired. Symptoms of idiopathic myelofibrosis may include abnormally low levels of circulating red blood cells (anemia), an abnormally large spleen (splenomegaly), an abnormally large liver (hepatomegaly), weight loss, weakness and fatigue due to replacement of normal bone marrow cells, and/or episodes of severe pain in the abdomen, bones, and joints. In many cases, myelofibrosis occurs in association with increased bone density and the formation of small sharp pieces of bone (spicules) within the marrow cavity and increased bone density (osteosclerosis). (For more information on this disorder, choose “primary myelofibrosis” as your search term in the Rare Disease Database.)Many other types of leukemia may mimic CML. Leukemia is a general term that denotes cancer of the bone marrow. In leukemia, white bloods cells divide and grow uncontrollably causing problems in the bone marrow and affecting the production of other bone marrow cells (i.e., red blood cells, platelets, other white blood cells). A similar form of leukemia is chronic lymphocytic leukemia (CLL). In CLL, the abnormal cells arise from lymphocytes (immune system cells), instead of from myeloid cells such as the parent cells of granulocytes (bacteria-destroying cells),), like in CML. Symptoms of CLL are very similar to CML, and may include fever, pain from an enlarged spleen, night sweats, fatigue, weight loss, bacterial infections. Blood tests can determine CML from CLL. (For more information on this disorder, choose “Chronic Lymphocytic Leukemia” as your search term in the Rare Disease Database.) | 272 | Chronic Myelogenous Leukemia |
nord_272_5 | Diagnosis of Chronic Myelogenous Leukemia | A diagnosis of CML is made based upon a thorough clinical evaluation, a detailed patient history and a variety of tests including blood tests, bone marrow examination, and chromosome analysis.Routine blood tests may reveal abnormally high levels of white blood cells along with high numbers of immature white blood cells. If this is the case, a complete blood count (CBC) will be conducted. This test can provide a more detailed account of the abnormalities in the blood cells.A sample of tissue taken from the bone marrow is needed to confirm a diagnosis. In individuals with advanced stage CML, the bone marrow has very little fat and numerous leukemic cells.A fluorescence in situ hybridization (FISH) analysis and a polymerase chain reaction (PCR) test can identify the Philadelphia chromosome or the fused BCR-ABL gene that results from the chromosome translocation.Clinical Testing and Work-Up
When treating CML, it is crucial to know what stage of the disease the individual is in. To determine staging, the following tests and procedures may be used:Cytogenetic analysis: A test in which cells in a sample of blood or bone marrow are viewed under a microscope to look for certain changes in the chromosomes, such as the Philadelphia chromosome.Bone marrow aspiration and biopsy: The removal of bone marrow, blood, and a small piece of bone by inserting a needing into the hipbone or breastbone. They are then screened by a pathologist for abnormal cells under a microscope. | Diagnosis of Chronic Myelogenous Leukemia. A diagnosis of CML is made based upon a thorough clinical evaluation, a detailed patient history and a variety of tests including blood tests, bone marrow examination, and chromosome analysis.Routine blood tests may reveal abnormally high levels of white blood cells along with high numbers of immature white blood cells. If this is the case, a complete blood count (CBC) will be conducted. This test can provide a more detailed account of the abnormalities in the blood cells.A sample of tissue taken from the bone marrow is needed to confirm a diagnosis. In individuals with advanced stage CML, the bone marrow has very little fat and numerous leukemic cells.A fluorescence in situ hybridization (FISH) analysis and a polymerase chain reaction (PCR) test can identify the Philadelphia chromosome or the fused BCR-ABL gene that results from the chromosome translocation.Clinical Testing and Work-Up
When treating CML, it is crucial to know what stage of the disease the individual is in. To determine staging, the following tests and procedures may be used:Cytogenetic analysis: A test in which cells in a sample of blood or bone marrow are viewed under a microscope to look for certain changes in the chromosomes, such as the Philadelphia chromosome.Bone marrow aspiration and biopsy: The removal of bone marrow, blood, and a small piece of bone by inserting a needing into the hipbone or breastbone. They are then screened by a pathologist for abnormal cells under a microscope. | 272 | Chronic Myelogenous Leukemia |
nord_272_6 | Therapies of Chronic Myelogenous Leukemia | TreatmentTyrosine kinase inhibitors (TKIs) are the frontline therapy for CML.In 2002, the FDA approved imatinib mesylate (Gleevec), as a therapeutic agent for CML. Gleevec uses a technique known as molecular targeting to block the action of the protein tyrosine kinase, thought to be responsible for most cases of CML. Because it targets the specific cause of the disease, the treatment does not alter healthy tissues, and is thought to be easier on patients than other forms of treatment, such as interferon injections, chemotherapy, and bone marrow transplant. Gleevec is manufactured by Novartis Pharmaceuticals Corporation.Other drugs that have recently been approved by the FDA are dasatinib (Sprycel) and nilotinib (Tasigna). They work in ways similar to Gleevec, by blocking tyrosine kinase.
In June of 2010, Tasigna was approved by the FDA to treat CML upon initial diagnosis. Tasigna is manufactured by Novartis Pharmaceuticals Corporation.Sprycel was approved in October of 2010 by the FDA to treat CML when other drugs, such as Gleevec, have been ineffective. Sprycel is manufactured by Bristol Myers Squibb.Bosulif (bosutinib) was approved by the FDA in 2012 as a treatment for patients with chronic, accelerated or blast phase Philadelphia chromosome positive CML who are resistant to or who cannot tolerate other therapies. Bosulif works by blocking the signal of the tyrosine kinase that promotes the development of abnormal and unhealthy granulocytes. Bosulif is manufactured by Pfizer. Synribo (omacetaxine mepesuccinate) was approved by the FDA in 2012 under its accelerated approval program to treat adults with CML. This is a new treatment option for patients who are resistant to or cannot tolerate other FDA-approved drugs for chronic or accelerated phases of CML. Synribo blocks certain proteins that promote the development of cancerous cells. Synribo is manufactured by Teva Pharmaceuticals. The following therapies have been used previously to treat CML:The orphan drug Idarubicin HCI for injection (Idamycin) was approved by the Food and Drug Administration (FDA) in 1990 for the treatment of CML.Interferon alfa-2a (Roferon A), administered by injection, received FDA approval for the treatment of CML in 1995.Drugs that inhibit bone marrow activity (myelosuppressive drugs) may slow the progression of the disease. Hydroxyurea, a medication used to treat CML patients, may lower the white cell count and therefore reduce symptoms.Radiation therapy of the spleen is another treatment option employed in only relatively few uncontrolled cases, either alone or in combination with chemotherapy, to slow the progression of the disease.Bone marrow transplant, when performed during the early phase of the disease, can lead to remission and cure of this disease. However, this mode of treatment is not appropriate for all patients and does present some risks. The likelihood of success appears greatest among younger patients who are treated in the early stages of the disease. | Therapies of Chronic Myelogenous Leukemia. TreatmentTyrosine kinase inhibitors (TKIs) are the frontline therapy for CML.In 2002, the FDA approved imatinib mesylate (Gleevec), as a therapeutic agent for CML. Gleevec uses a technique known as molecular targeting to block the action of the protein tyrosine kinase, thought to be responsible for most cases of CML. Because it targets the specific cause of the disease, the treatment does not alter healthy tissues, and is thought to be easier on patients than other forms of treatment, such as interferon injections, chemotherapy, and bone marrow transplant. Gleevec is manufactured by Novartis Pharmaceuticals Corporation.Other drugs that have recently been approved by the FDA are dasatinib (Sprycel) and nilotinib (Tasigna). They work in ways similar to Gleevec, by blocking tyrosine kinase.
In June of 2010, Tasigna was approved by the FDA to treat CML upon initial diagnosis. Tasigna is manufactured by Novartis Pharmaceuticals Corporation.Sprycel was approved in October of 2010 by the FDA to treat CML when other drugs, such as Gleevec, have been ineffective. Sprycel is manufactured by Bristol Myers Squibb.Bosulif (bosutinib) was approved by the FDA in 2012 as a treatment for patients with chronic, accelerated or blast phase Philadelphia chromosome positive CML who are resistant to or who cannot tolerate other therapies. Bosulif works by blocking the signal of the tyrosine kinase that promotes the development of abnormal and unhealthy granulocytes. Bosulif is manufactured by Pfizer. Synribo (omacetaxine mepesuccinate) was approved by the FDA in 2012 under its accelerated approval program to treat adults with CML. This is a new treatment option for patients who are resistant to or cannot tolerate other FDA-approved drugs for chronic or accelerated phases of CML. Synribo blocks certain proteins that promote the development of cancerous cells. Synribo is manufactured by Teva Pharmaceuticals. The following therapies have been used previously to treat CML:The orphan drug Idarubicin HCI for injection (Idamycin) was approved by the Food and Drug Administration (FDA) in 1990 for the treatment of CML.Interferon alfa-2a (Roferon A), administered by injection, received FDA approval for the treatment of CML in 1995.Drugs that inhibit bone marrow activity (myelosuppressive drugs) may slow the progression of the disease. Hydroxyurea, a medication used to treat CML patients, may lower the white cell count and therefore reduce symptoms.Radiation therapy of the spleen is another treatment option employed in only relatively few uncontrolled cases, either alone or in combination with chemotherapy, to slow the progression of the disease.Bone marrow transplant, when performed during the early phase of the disease, can lead to remission and cure of this disease. However, this mode of treatment is not appropriate for all patients and does present some risks. The likelihood of success appears greatest among younger patients who are treated in the early stages of the disease. | 272 | Chronic Myelogenous Leukemia |
nord_273_0 | Overview of Churg Strauss Syndrome | Churg-Strauss syndrome is a rare disorder that may affect multiple organ systems, especially the lungs. The disorder is characterized by the abnormal clustering of certain white blood cells (hypereosinophilia) in the blood and tissues, inflammation of blood vessels (vasculitis), and the development of inflammatory nodular lesions called granulomas (granulomatosis). Most affected individuals have a history of allergy. In addition, asthma and other associated lung (pulmonary) abnormalities (i.e., pulmonary infiltrates) often precede the development of the generalized (systemic) symptoms and findings seen in Churg-Strauss syndrome by as little as six months or as much as two decades. Asthma, a chronic respiratory disorder, is characterized by inflammation and narrowing of the lungs' airways, causing difficulties breathing (dyspnea), coughing, the production of a high-pitched whistling sound while breathing (wheezing), and/or other symptoms and findings.Nonspecific findings associated with Churg-Strauss syndrome typically include flu-like symptoms, such as fever, a general feeling of weakness and fatigue (malaise), loss of appetite (anorexia), weight loss, and muscle pain (myalgia). Additional symptoms and findings may vary depending upon the specific organ systems affected. The nerves outside the central nervous system (peripheral nerves), kidneys, or gastrointestinal tract are often involved. Without appropriate treatment, serious organ damage and potentially life-threatening complications may result. Although the exact cause of Churg-Strauss syndrome is unknown, many researchers indicate that abnormal functioning of the immune system plays an important role. | Overview of Churg Strauss Syndrome. Churg-Strauss syndrome is a rare disorder that may affect multiple organ systems, especially the lungs. The disorder is characterized by the abnormal clustering of certain white blood cells (hypereosinophilia) in the blood and tissues, inflammation of blood vessels (vasculitis), and the development of inflammatory nodular lesions called granulomas (granulomatosis). Most affected individuals have a history of allergy. In addition, asthma and other associated lung (pulmonary) abnormalities (i.e., pulmonary infiltrates) often precede the development of the generalized (systemic) symptoms and findings seen in Churg-Strauss syndrome by as little as six months or as much as two decades. Asthma, a chronic respiratory disorder, is characterized by inflammation and narrowing of the lungs' airways, causing difficulties breathing (dyspnea), coughing, the production of a high-pitched whistling sound while breathing (wheezing), and/or other symptoms and findings.Nonspecific findings associated with Churg-Strauss syndrome typically include flu-like symptoms, such as fever, a general feeling of weakness and fatigue (malaise), loss of appetite (anorexia), weight loss, and muscle pain (myalgia). Additional symptoms and findings may vary depending upon the specific organ systems affected. The nerves outside the central nervous system (peripheral nerves), kidneys, or gastrointestinal tract are often involved. Without appropriate treatment, serious organ damage and potentially life-threatening complications may result. Although the exact cause of Churg-Strauss syndrome is unknown, many researchers indicate that abnormal functioning of the immune system plays an important role. | 273 | Churg Strauss Syndrome |
nord_273_1 | Symptoms of Churg Strauss Syndrome | Because multiple organ systems can potentially be affected, the specific symptoms of Churg-Strauss syndrome vary widely from case to case. The disorder is separated into three distinct phases – prodromal, eosinophilic and vasculitic. These phases may or may not occur sequentially. Some affected individuals will not develop all three phases. With proper treatment Churg-Strauss syndrome can be successfully managed. Without treatment the disorder may progress to cause life-threatening complications. The prodromal (or allergic) phase is marked by various allergic reactions and is usually precedes the other first phases in individuals with Churg-Strauss syndrome. Affected individuals may develop late-onset asthma including a cough, wheezing, and shortness of breath (dyspnea). In individuals who have asthma, the condition may become worse. Some affected individuals develop hay fever (allergic rhinitis), a common condition in which allergic inflammation of the mucous membrane of the nose causes a runny nose, sneezing, itching and nasal obstruction. Hay fever may be a chronic, recurring condition. In some cases, repeated episodes of sinus inflammation may occur (sinusitis). Sinusitis may result in facial pain. Chronic inflammation of the nose may cause small benign growths (polyps) to form (polyposis) within the nose. The prodromal phase may last from months to many years. Respiratory symptoms are usually the first signs of Churg-Strauss syndrome and can precede the development of vasculitis by as little as six months or as much as two decades. The eosinophilic phase of Churg-Strauss syndrome is marked by the accumulation of eosinophils in various tissues of the body. Eosinophils are a specific type of white blood cell. The exact role of eosinophils in the body is unknown, but they are often produced in response to allergies. In individuals with Churg-Strauss syndrome, abnormally high numbers of eosinophils (hypereosinophilia) are produced and may accumulate in various tissues of the body especially the lungs, gastrointestinal tract and skin. The third phase of Churg-Strauss syndrome is known as the vasculitic phase and is marked by widespread inflammation of various blood vessels of the body (vasculitis). Chronic vasculitis may cause narrowing of affected blood vessels, blocking or slowing the flow of blood to various organs of the body. In addition, inflamed blood vessels may become thin and fragile, potentially rupturing and bleeding into surrounding tissue or the blood vessels may become stretched out or develop a bulge (aneurysm). As mentioned above the symptoms of Churg-Strauss syndrome vary widely in presentation, severity, duration and onset. Since different organ systems will be affected in different people, all of the symptoms discussed below will not occur in every case. The symptoms of Churg-Strauss syndrome vary depending upon the organ systems involved. Most individuals develop asthma-like symptoms (discussed above) usually before the onset of other symptoms. However, in some cases, individuals develop symptoms of vasculitis before respiratory symptoms. Individuals with Churg-Strauss syndrome often develop nonspecific symptoms that may be associated with various illnesses including fatigue, fever, weight loss, night sweats, abdominal pain, cough, joint pain (arthralgia), muscle pain (myalgia), and a general feeling of ill health (malaise). Swollen lymph nodes and generalized weakness have also been reported. Inner ear infections with fluid build up (serous otitis media) may also occur and can result in hearing loss. The moist membrane lining the surface of the eyelids (conjunctiva) may be inflamed as well. Neurological symptoms are common, affecting approximately 78 percent of individuals with Churg-Strauss syndrome. A condition called mononeuritis multiplex, in which two or more nerves in separate areas of the peripheral nervous system are affected, may occur. The peripheral nervous system refers to the nerves found outside the central nervous system (i.e., brain and spinal cord). Associated symptoms depend upon the specific nerves involved. A common symptom is pain, tingling or numbness and eventually weakness and muscle wasting in the hands and feet (extremities). Disease affecting multiple nerves in the same area of the body (polyneuropathy) may also occur. If untreated, serious neurological complications may develop including bleeding on the brain or lack of blood flow to the brain (stroke). Approximately half of individuals with Churg-Strauss syndrome develop skin abnormalities caused by the accumulation of eosinophils in skin tissue. Symptoms may include the development of purplish skin lesions due to bleeding (hemorrhaging) into tissues under the skin (purpura), a rash with hives (urticaria), and small bumps (nodules), especially on the elbows. Gastrointestinal involvement results in abdominal pain, nausea, vomiting, diarrhea, blood in the stools and inflammation of the membrane lining the colon (colitis).Individuals with Churg-Strauss syndrome may develop heart abnormalities including inflammation of the fibrous sac (pericardium) that surrounds the heart (percarditis), inflammation of the muscular wall (myocardium) of the heart (myocarditis), heart failure and potentially a heart attack. Symptoms associated with heart disease include fatigue, shortness of breath, irregular heartbeats, chest pain and fainting episodes. Heart abnormalities may be cause by inflammation of the blood vessels (vasculitis) and the development of inflammatory nodular lesions (granulomas) within heart tissue.The kidneys can become involved in some cases eventually resulting in glomerulonephritis, a condition characterized by inflammation and degeneration of the tiny clusters of blood vessels (capillaries) called renal glomeruli that filter the blood as it passes through the kidneys. Glomerulonephritis results in an impaired ability to remove waster and fluid products from the body, which then build up in the bloodstream. Although it is an extremely rare occurrence in individuals with Churg-Strauss syndrome, life-threatening kidney failure can occur. | Symptoms of Churg Strauss Syndrome. Because multiple organ systems can potentially be affected, the specific symptoms of Churg-Strauss syndrome vary widely from case to case. The disorder is separated into three distinct phases – prodromal, eosinophilic and vasculitic. These phases may or may not occur sequentially. Some affected individuals will not develop all three phases. With proper treatment Churg-Strauss syndrome can be successfully managed. Without treatment the disorder may progress to cause life-threatening complications. The prodromal (or allergic) phase is marked by various allergic reactions and is usually precedes the other first phases in individuals with Churg-Strauss syndrome. Affected individuals may develop late-onset asthma including a cough, wheezing, and shortness of breath (dyspnea). In individuals who have asthma, the condition may become worse. Some affected individuals develop hay fever (allergic rhinitis), a common condition in which allergic inflammation of the mucous membrane of the nose causes a runny nose, sneezing, itching and nasal obstruction. Hay fever may be a chronic, recurring condition. In some cases, repeated episodes of sinus inflammation may occur (sinusitis). Sinusitis may result in facial pain. Chronic inflammation of the nose may cause small benign growths (polyps) to form (polyposis) within the nose. The prodromal phase may last from months to many years. Respiratory symptoms are usually the first signs of Churg-Strauss syndrome and can precede the development of vasculitis by as little as six months or as much as two decades. The eosinophilic phase of Churg-Strauss syndrome is marked by the accumulation of eosinophils in various tissues of the body. Eosinophils are a specific type of white blood cell. The exact role of eosinophils in the body is unknown, but they are often produced in response to allergies. In individuals with Churg-Strauss syndrome, abnormally high numbers of eosinophils (hypereosinophilia) are produced and may accumulate in various tissues of the body especially the lungs, gastrointestinal tract and skin. The third phase of Churg-Strauss syndrome is known as the vasculitic phase and is marked by widespread inflammation of various blood vessels of the body (vasculitis). Chronic vasculitis may cause narrowing of affected blood vessels, blocking or slowing the flow of blood to various organs of the body. In addition, inflamed blood vessels may become thin and fragile, potentially rupturing and bleeding into surrounding tissue or the blood vessels may become stretched out or develop a bulge (aneurysm). As mentioned above the symptoms of Churg-Strauss syndrome vary widely in presentation, severity, duration and onset. Since different organ systems will be affected in different people, all of the symptoms discussed below will not occur in every case. The symptoms of Churg-Strauss syndrome vary depending upon the organ systems involved. Most individuals develop asthma-like symptoms (discussed above) usually before the onset of other symptoms. However, in some cases, individuals develop symptoms of vasculitis before respiratory symptoms. Individuals with Churg-Strauss syndrome often develop nonspecific symptoms that may be associated with various illnesses including fatigue, fever, weight loss, night sweats, abdominal pain, cough, joint pain (arthralgia), muscle pain (myalgia), and a general feeling of ill health (malaise). Swollen lymph nodes and generalized weakness have also been reported. Inner ear infections with fluid build up (serous otitis media) may also occur and can result in hearing loss. The moist membrane lining the surface of the eyelids (conjunctiva) may be inflamed as well. Neurological symptoms are common, affecting approximately 78 percent of individuals with Churg-Strauss syndrome. A condition called mononeuritis multiplex, in which two or more nerves in separate areas of the peripheral nervous system are affected, may occur. The peripheral nervous system refers to the nerves found outside the central nervous system (i.e., brain and spinal cord). Associated symptoms depend upon the specific nerves involved. A common symptom is pain, tingling or numbness and eventually weakness and muscle wasting in the hands and feet (extremities). Disease affecting multiple nerves in the same area of the body (polyneuropathy) may also occur. If untreated, serious neurological complications may develop including bleeding on the brain or lack of blood flow to the brain (stroke). Approximately half of individuals with Churg-Strauss syndrome develop skin abnormalities caused by the accumulation of eosinophils in skin tissue. Symptoms may include the development of purplish skin lesions due to bleeding (hemorrhaging) into tissues under the skin (purpura), a rash with hives (urticaria), and small bumps (nodules), especially on the elbows. Gastrointestinal involvement results in abdominal pain, nausea, vomiting, diarrhea, blood in the stools and inflammation of the membrane lining the colon (colitis).Individuals with Churg-Strauss syndrome may develop heart abnormalities including inflammation of the fibrous sac (pericardium) that surrounds the heart (percarditis), inflammation of the muscular wall (myocardium) of the heart (myocarditis), heart failure and potentially a heart attack. Symptoms associated with heart disease include fatigue, shortness of breath, irregular heartbeats, chest pain and fainting episodes. Heart abnormalities may be cause by inflammation of the blood vessels (vasculitis) and the development of inflammatory nodular lesions (granulomas) within heart tissue.The kidneys can become involved in some cases eventually resulting in glomerulonephritis, a condition characterized by inflammation and degeneration of the tiny clusters of blood vessels (capillaries) called renal glomeruli that filter the blood as it passes through the kidneys. Glomerulonephritis results in an impaired ability to remove waster and fluid products from the body, which then build up in the bloodstream. Although it is an extremely rare occurrence in individuals with Churg-Strauss syndrome, life-threatening kidney failure can occur. | 273 | Churg Strauss Syndrome |
nord_273_2 | Causes of Churg Strauss Syndrome | The exact cause of Churg-Strauss syndrome is unknown. Most researchers believe that several different factors (e.g., environmental, immunological, and genetic) all play a role in the development of the disorder. Churg-Strauss syndrome is classified as an autoimmune disorder. Autoimmune disorders are caused when the body's natural defenses against “foreign” or invading organisms begin to attack healthy tissue for unknown reasons. Researchers do not know what sets off or “triggers” the abnormal immune system response in individuals with Churg-Strauss syndrome. Approximately 39 to 59 percent of individuals with Churg-Strauss syndrome have detectable levels of antineutrophil cytoplasmic antibodies (ANCA). ANCAs have also been identified in related blood vessel disorders (vasculitides) including Wegener's granulomatosis. The exact role of these antibodies in the development of Churg-Strauss syndrome is unknown.The symptoms of Churg-Strauss syndrome are caused by an abnormal accumulation of large number of antibodies; increased numbers of certain white blood cells (eosinophilia), indicating an inflammatory or allergic response; inflammation of veins, capillaries, and small- and medium-sized arteries; and the development of inflammatory nodular lesions (granulomatosis) within certain tissues and the walls of blood vessels. Although the lungs are often predominantly affected, multiple organ systems may potentially be involved, including the skin, heart, and nerves outside the brain and spinal cord (peripheral nervous system).In some cases, Churg-Strauss syndrome has been associated with use of zafirlukast (Accolate), a nonsteroidal medication that was approved in 1996 as a therapy for the prevention and treatment of asthma in individuals 12 years of age and older. In July 1997, the Food and Drug Administration (FDA) issued a health advisory reporting that six individuals with asthma developed Churg-Strauss syndrome while receiving zafirlukast therapy. In all reported cases, therapy with steroidal asthma medications was discontinued or was being slowly lowered (tapered) during zafirlukast therapy. According to the FDA, the data do not definitively show that use of zafirlukast caused the condition. In addition, the FDA cautions that individuals who are receiving asthma medication should not discontinue their therapy without consulting with their physicians. New labeling for the medication zafirlukast indicates that physicians should carefully monitor affected individuals as corticosteroid dosages are lowered or such therapy is discontinued.Zafirlukast belongs to a class of medications known as leukotriene antagonists. Leukotrienes, which occur naturally in certain white blood cells (leukocytes), produce inflammatory or allergic responses and are thought to play some role in causing particular allergies and asthma. Leukotriene antagonists, also known as antileukotrienes, are medications that serve to block the action of leukotrienes. There have been some reports in the medical literature in which therapy with montelukast, another leukotriene antagonist, has been associated with the development of Churg-Strauss syndrome. In many of these cases, researchers now believe that the slow removal of steroid treatment revealed existing, but undiagnosed, cases of Churg-Strauss syndrome and that the disorder did not develop because of the drugs. However, the exact relationship, if any, between Churg-Strauss syndrome and leukotriene antagonists is unknown. | Causes of Churg Strauss Syndrome. The exact cause of Churg-Strauss syndrome is unknown. Most researchers believe that several different factors (e.g., environmental, immunological, and genetic) all play a role in the development of the disorder. Churg-Strauss syndrome is classified as an autoimmune disorder. Autoimmune disorders are caused when the body's natural defenses against “foreign” or invading organisms begin to attack healthy tissue for unknown reasons. Researchers do not know what sets off or “triggers” the abnormal immune system response in individuals with Churg-Strauss syndrome. Approximately 39 to 59 percent of individuals with Churg-Strauss syndrome have detectable levels of antineutrophil cytoplasmic antibodies (ANCA). ANCAs have also been identified in related blood vessel disorders (vasculitides) including Wegener's granulomatosis. The exact role of these antibodies in the development of Churg-Strauss syndrome is unknown.The symptoms of Churg-Strauss syndrome are caused by an abnormal accumulation of large number of antibodies; increased numbers of certain white blood cells (eosinophilia), indicating an inflammatory or allergic response; inflammation of veins, capillaries, and small- and medium-sized arteries; and the development of inflammatory nodular lesions (granulomatosis) within certain tissues and the walls of blood vessels. Although the lungs are often predominantly affected, multiple organ systems may potentially be involved, including the skin, heart, and nerves outside the brain and spinal cord (peripheral nervous system).In some cases, Churg-Strauss syndrome has been associated with use of zafirlukast (Accolate), a nonsteroidal medication that was approved in 1996 as a therapy for the prevention and treatment of asthma in individuals 12 years of age and older. In July 1997, the Food and Drug Administration (FDA) issued a health advisory reporting that six individuals with asthma developed Churg-Strauss syndrome while receiving zafirlukast therapy. In all reported cases, therapy with steroidal asthma medications was discontinued or was being slowly lowered (tapered) during zafirlukast therapy. According to the FDA, the data do not definitively show that use of zafirlukast caused the condition. In addition, the FDA cautions that individuals who are receiving asthma medication should not discontinue their therapy without consulting with their physicians. New labeling for the medication zafirlukast indicates that physicians should carefully monitor affected individuals as corticosteroid dosages are lowered or such therapy is discontinued.Zafirlukast belongs to a class of medications known as leukotriene antagonists. Leukotrienes, which occur naturally in certain white blood cells (leukocytes), produce inflammatory or allergic responses and are thought to play some role in causing particular allergies and asthma. Leukotriene antagonists, also known as antileukotrienes, are medications that serve to block the action of leukotrienes. There have been some reports in the medical literature in which therapy with montelukast, another leukotriene antagonist, has been associated with the development of Churg-Strauss syndrome. In many of these cases, researchers now believe that the slow removal of steroid treatment revealed existing, but undiagnosed, cases of Churg-Strauss syndrome and that the disorder did not develop because of the drugs. However, the exact relationship, if any, between Churg-Strauss syndrome and leukotriene antagonists is unknown. | 273 | Churg Strauss Syndrome |
nord_273_3 | Affects of Churg Strauss Syndrome | Churg-Strauss syndrome affects males and females in equal numbers, although some reports suggest that males may be affected slightly more often. The disorder can affect individuals of almost any age and has ranged from 15 to 70 years of age. Most cases occur in individuals between 30 and 50 years of age. The estimated mean annual incidence is 2.4 individuals per million. Some researchers believe that Churg-Strauss syndrome is underdiagnosed, making it difficult to determine its true frequency in the general population. | Affects of Churg Strauss Syndrome. Churg-Strauss syndrome affects males and females in equal numbers, although some reports suggest that males may be affected slightly more often. The disorder can affect individuals of almost any age and has ranged from 15 to 70 years of age. Most cases occur in individuals between 30 and 50 years of age. The estimated mean annual incidence is 2.4 individuals per million. Some researchers believe that Churg-Strauss syndrome is underdiagnosed, making it difficult to determine its true frequency in the general population. | 273 | Churg Strauss Syndrome |
nord_273_4 | Related disorders of Churg Strauss Syndrome | Symptoms of the following disorders can be similar to those of Churg-Strauss syndrome. Comparisons may be useful for a differential diagnosis.Wegener's granulomatosis is an uncommon disorder characterized by inflammation of blood vessels (vasculitis) that results in damage to various organ systems of the body, most often the respiratory tract and kidneys. Symptoms may include ulcerations of the mucous membranes in the nose with secondary bacterial infection, a persistent runny nose, sinus pain, and chronic middle ear infection (otitis media) potentially resulting in hearing loss. In some cases, kidney abnormalities may progress to kidney failure, a serious complication. If the lungs are affected, a cough, expectoration of blood (hemoptysis), and inflammation of the thin membrane lining the outside of the lungs and the inside of the lung may be present. The exact cause of Wegener's granulomatosis is not known. (For more information on this disorder, choose “Wegener's granulomatosis” as your search term in the Rare Disease Database.)Polyarteritis nodosa, a rare multisystem disorder that usually becomes apparent between the ages of 40 to 50 years, is characterized by widespread inflammation, weakening, and degeneration of small and medium-sized arteries. Blood vessels in any organ or organ system may be affected, including arteries supplying the kidneys, heart, intestine, nervous system, and/or skeletal muscles. Damage to affected arteries may result in abnormally increased blood pressure (hypertension), “ballooning” (aneurysm) of an arterial wall, the formation of blood clots (thrombosis), obstructed blood supply to certain tissues, and/or tissue damage and loss (necrosis) in certain affected areas. In many cases, affected individuals experience weight loss, fever, a general feeling of ill health (malaise), fatigue, weakness, headache, muscle aches (myalgias), and/or abdominal pain. Additional symptoms and findings are often present and depend upon which areas of the body are affected. Although the exact cause of polyarteritis nodosa is not known, many researchers suspect that the disorder is due to disturbances of the body's immune system. (For more information on this disorder, choose “polyarteritis nodosa” as your search term in the Rare Disease Database.)Guillain-Barre syndrome (GBS) is a rare, rapidly progressive disorder that consists of inflammation of the nerves (polyneuritis) and, usually, muscle weakness, often progressing to frank paralysis. Although the precise cause of GBS is unknown, a viral or respiratory infection precedes the onset of the syndrome in about half of the cases. This has led to the theory that GBS may be an autoimmune disease (caused by the body's own immune system). Damage to the covering of nerve cells (myelin) and nerve axons (the extension of the nerve cell that conducts impulses away from the nerve cell body) results in delayed nerve signal transmission. There is a corresponding weakness in the muscles that are supplied or innervated by the damaged nerves. The following variants of GBS (acute inflammatory neuropathy or acute inflammatory demyelinating polyradiculoneuropathy) are recognized: Miller Fisher syndrome, acute motor-sensory axonal polyneuropathy, acute motor axonal polyneuropathy, chronic inflammatory polyneuropathy, (chronic inflammatory demyelinating polyradiculoneuropathy; also called chronic relapsing or recurring inflammatory polyneuropathy), and chronic polyneuropathy with conduction block. (For more information on this disorder, choose “Guillain-Barre” as your search term in the Rare Disease Database.)A variety of additional disorders may have similar findings (e.g., eosinophilia, pulmonary infiltrates, vasculitis) as those of Churg-Strauss syndrome. These disorders include allergic bronchopulmonary aspergillosis, acute eosinophilic pneumonia, hypereosinophilic syndrome, microscopic angiitis, certain malignancies, and certain fungal or bacterial infections. Certain drug reactions may cause a similar clinical picture as that found in Churg-Strauss syndrome. | Related disorders of Churg Strauss Syndrome. Symptoms of the following disorders can be similar to those of Churg-Strauss syndrome. Comparisons may be useful for a differential diagnosis.Wegener's granulomatosis is an uncommon disorder characterized by inflammation of blood vessels (vasculitis) that results in damage to various organ systems of the body, most often the respiratory tract and kidneys. Symptoms may include ulcerations of the mucous membranes in the nose with secondary bacterial infection, a persistent runny nose, sinus pain, and chronic middle ear infection (otitis media) potentially resulting in hearing loss. In some cases, kidney abnormalities may progress to kidney failure, a serious complication. If the lungs are affected, a cough, expectoration of blood (hemoptysis), and inflammation of the thin membrane lining the outside of the lungs and the inside of the lung may be present. The exact cause of Wegener's granulomatosis is not known. (For more information on this disorder, choose “Wegener's granulomatosis” as your search term in the Rare Disease Database.)Polyarteritis nodosa, a rare multisystem disorder that usually becomes apparent between the ages of 40 to 50 years, is characterized by widespread inflammation, weakening, and degeneration of small and medium-sized arteries. Blood vessels in any organ or organ system may be affected, including arteries supplying the kidneys, heart, intestine, nervous system, and/or skeletal muscles. Damage to affected arteries may result in abnormally increased blood pressure (hypertension), “ballooning” (aneurysm) of an arterial wall, the formation of blood clots (thrombosis), obstructed blood supply to certain tissues, and/or tissue damage and loss (necrosis) in certain affected areas. In many cases, affected individuals experience weight loss, fever, a general feeling of ill health (malaise), fatigue, weakness, headache, muscle aches (myalgias), and/or abdominal pain. Additional symptoms and findings are often present and depend upon which areas of the body are affected. Although the exact cause of polyarteritis nodosa is not known, many researchers suspect that the disorder is due to disturbances of the body's immune system. (For more information on this disorder, choose “polyarteritis nodosa” as your search term in the Rare Disease Database.)Guillain-Barre syndrome (GBS) is a rare, rapidly progressive disorder that consists of inflammation of the nerves (polyneuritis) and, usually, muscle weakness, often progressing to frank paralysis. Although the precise cause of GBS is unknown, a viral or respiratory infection precedes the onset of the syndrome in about half of the cases. This has led to the theory that GBS may be an autoimmune disease (caused by the body's own immune system). Damage to the covering of nerve cells (myelin) and nerve axons (the extension of the nerve cell that conducts impulses away from the nerve cell body) results in delayed nerve signal transmission. There is a corresponding weakness in the muscles that are supplied or innervated by the damaged nerves. The following variants of GBS (acute inflammatory neuropathy or acute inflammatory demyelinating polyradiculoneuropathy) are recognized: Miller Fisher syndrome, acute motor-sensory axonal polyneuropathy, acute motor axonal polyneuropathy, chronic inflammatory polyneuropathy, (chronic inflammatory demyelinating polyradiculoneuropathy; also called chronic relapsing or recurring inflammatory polyneuropathy), and chronic polyneuropathy with conduction block. (For more information on this disorder, choose “Guillain-Barre” as your search term in the Rare Disease Database.)A variety of additional disorders may have similar findings (e.g., eosinophilia, pulmonary infiltrates, vasculitis) as those of Churg-Strauss syndrome. These disorders include allergic bronchopulmonary aspergillosis, acute eosinophilic pneumonia, hypereosinophilic syndrome, microscopic angiitis, certain malignancies, and certain fungal or bacterial infections. Certain drug reactions may cause a similar clinical picture as that found in Churg-Strauss syndrome. | 273 | Churg Strauss Syndrome |
nord_273_5 | Diagnosis of Churg Strauss Syndrome | The diagnosis of Churg-Strauss syndrome may be suspected based upon a thorough clinical evaluation, characteristic physical findings, and specialized tests. In 1990, the American College of Rheumatology established diagnostic criteria for Churg-Strauss syndrome. An individual is classified as having Churg-Strauss syndrome and not another form of vasculitis if four of the following six findings are identified: 1. asthma; 2. eosinophilia (defined as greater than 10 percent in the circulating blood); 3. mono- or polyneuropathy; 4. nonfixed pulmonary infiltrates; 5. abnormality of the paranasal sinuses; and 6. extravascular eosinophilia.Diagnostic procedures that may be used to aid in a diagnosis include surgical removal (biopsy) and microscopic examination of small samples of lung tissue, demonstrating inflammation of blood vessels and other associated changes. Chest x-rays and other specialized imaging techniques, such as computerized tomography (CT) scanning, typically reveal abnormalities in the lungs (i.e., pulmonary infiltrates). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of an organ's tissue structure. In addition, laboratory tests may be conducted, including tests that demonstrate elevated levels of certain white blood cells (eosinophils) and further suggest the presence of an inflammatory process. | Diagnosis of Churg Strauss Syndrome. The diagnosis of Churg-Strauss syndrome may be suspected based upon a thorough clinical evaluation, characteristic physical findings, and specialized tests. In 1990, the American College of Rheumatology established diagnostic criteria for Churg-Strauss syndrome. An individual is classified as having Churg-Strauss syndrome and not another form of vasculitis if four of the following six findings are identified: 1. asthma; 2. eosinophilia (defined as greater than 10 percent in the circulating blood); 3. mono- or polyneuropathy; 4. nonfixed pulmonary infiltrates; 5. abnormality of the paranasal sinuses; and 6. extravascular eosinophilia.Diagnostic procedures that may be used to aid in a diagnosis include surgical removal (biopsy) and microscopic examination of small samples of lung tissue, demonstrating inflammation of blood vessels and other associated changes. Chest x-rays and other specialized imaging techniques, such as computerized tomography (CT) scanning, typically reveal abnormalities in the lungs (i.e., pulmonary infiltrates). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of an organ's tissue structure. In addition, laboratory tests may be conducted, including tests that demonstrate elevated levels of certain white blood cells (eosinophils) and further suggest the presence of an inflammatory process. | 273 | Churg Strauss Syndrome |
nord_273_6 | Therapies of Churg Strauss Syndrome | TreatmentMost individuals with Churg-Strauss syndrome are first treated with corticosteroid medications such as prednisone or methylprednisonone, which suppress the activity of the immune system (immunosuppressive) and reduce inflammation. Individuals usually receive high-doses of corticosteroid initially and then after improvement is seen the dosage is slowly reduced (tapered off). Many affected individuals only need corticosteroids to achieve remission of their symptoms (monotherapy).If individuals do not respond to steroid therapy alone or if they have advanced disease (e.g., the presence of kidney or neurological disease), they may require treatment with drugs that inhibit the growth and spread (proliferation) of certain cells (cytotoxic medications) such as cyclophosphamide or azathioprine. In some cases, other therapies may be recommended. (For more information, please see the “Investigational Therapies” section below.) Other treatment for individuals with Churg-Strauss Syndrome is symptomatic and supportive.In 2017, Nucala (mepolizumab) was approved by the U.S. Food and Drug Administration (FDA) to treat adult patients with eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome). Nucala is manufactured by GlaxoSmithKline. | Therapies of Churg Strauss Syndrome. TreatmentMost individuals with Churg-Strauss syndrome are first treated with corticosteroid medications such as prednisone or methylprednisonone, which suppress the activity of the immune system (immunosuppressive) and reduce inflammation. Individuals usually receive high-doses of corticosteroid initially and then after improvement is seen the dosage is slowly reduced (tapered off). Many affected individuals only need corticosteroids to achieve remission of their symptoms (monotherapy).If individuals do not respond to steroid therapy alone or if they have advanced disease (e.g., the presence of kidney or neurological disease), they may require treatment with drugs that inhibit the growth and spread (proliferation) of certain cells (cytotoxic medications) such as cyclophosphamide or azathioprine. In some cases, other therapies may be recommended. (For more information, please see the “Investigational Therapies” section below.) Other treatment for individuals with Churg-Strauss Syndrome is symptomatic and supportive.In 2017, Nucala (mepolizumab) was approved by the U.S. Food and Drug Administration (FDA) to treat adult patients with eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome). Nucala is manufactured by GlaxoSmithKline. | 273 | Churg Strauss Syndrome |
nord_274_0 | Overview of Cicatricial Alopecia | Cicatricial alopecias are classified as primary or secondary. This discussion is confined to the primary cicatricial alopecias, in which the hair follicle is the target of a destructive inflammatory process. In secondary cicatricial alopecias, destruction of the hair follicle is incidental to a non-follicle-directed process or external injury, such as severe infections, burns, radiation, or tumors.Primary cicatricial alopecia refers to a diverse group of rare disorders that destroy the hair follicle, replace it with scar tissue, and cause permanent hair loss. Hair loss can be gradual, without symptoms, and unnoticed for long periods. In other cases, the hair loss may be associated with severe itching, pain and burning, and progress rapidly. Cicatricial alopecia occurs in otherwise healthy men and women of all ages and is seen worldwide. | Overview of Cicatricial Alopecia. Cicatricial alopecias are classified as primary or secondary. This discussion is confined to the primary cicatricial alopecias, in which the hair follicle is the target of a destructive inflammatory process. In secondary cicatricial alopecias, destruction of the hair follicle is incidental to a non-follicle-directed process or external injury, such as severe infections, burns, radiation, or tumors.Primary cicatricial alopecia refers to a diverse group of rare disorders that destroy the hair follicle, replace it with scar tissue, and cause permanent hair loss. Hair loss can be gradual, without symptoms, and unnoticed for long periods. In other cases, the hair loss may be associated with severe itching, pain and burning, and progress rapidly. Cicatricial alopecia occurs in otherwise healthy men and women of all ages and is seen worldwide. | 274 | Cicatricial Alopecia |
nord_274_1 | Symptoms of Cicatricial Alopecia | Affected areas of the scalp may have redness, scaling, increased or decreased pigmentation, pustules, or draining sinuses. Other cases may show little signs of inflammation. The inflammation that destroys the follicle is below the skin surface and there is usually no “scar” seen on the scalp, although the affected scalp is usually left bare and smooth without hair and without the usual pore markings.Cicatricial alopecias are further classified by the type of inflammatory cells that destroy the hair follicle during the active stage of the disease. The inflammation may involve predominantly lymphocytes or neutrophils.Cicatricial alopecias that involve predominantly lymphocytic inflammation include lichen planopilaris, frontal fibrosing alopecia, central centrifugal alopecia, and pseudopelade (Brocq). Cicatricial alopecias that are due to predominantly neutrophilic inflammation include folliculitis decalvans and tufted folliculitis. Sometimes the inflammation shifts from a predominantly neutrophilic process to a lymphocytic process. Cicatricial alopecias with a mixed inflammatory infiltrate include dissecting cellulitis and folliculitis keloidalis. | Symptoms of Cicatricial Alopecia. Affected areas of the scalp may have redness, scaling, increased or decreased pigmentation, pustules, or draining sinuses. Other cases may show little signs of inflammation. The inflammation that destroys the follicle is below the skin surface and there is usually no “scar” seen on the scalp, although the affected scalp is usually left bare and smooth without hair and without the usual pore markings.Cicatricial alopecias are further classified by the type of inflammatory cells that destroy the hair follicle during the active stage of the disease. The inflammation may involve predominantly lymphocytes or neutrophils.Cicatricial alopecias that involve predominantly lymphocytic inflammation include lichen planopilaris, frontal fibrosing alopecia, central centrifugal alopecia, and pseudopelade (Brocq). Cicatricial alopecias that are due to predominantly neutrophilic inflammation include folliculitis decalvans and tufted folliculitis. Sometimes the inflammation shifts from a predominantly neutrophilic process to a lymphocytic process. Cicatricial alopecias with a mixed inflammatory infiltrate include dissecting cellulitis and folliculitis keloidalis. | 274 | Cicatricial Alopecia |
nord_274_2 | Causes of Cicatricial Alopecia | The cause of the various cicatricial alopecias is not well understood. However, all types of cicatricial alopecias involve inflammation directed at the upper part of the hair follicle where the stem cells and sebaceous gland (oil gland) are located. If the stem cells and sebaceous gland are destroyed, there is no possibility for regeneration of the hair follicle, leading to permanent hair loss. Cicatricial alopecias are not contagious. | Causes of Cicatricial Alopecia. The cause of the various cicatricial alopecias is not well understood. However, all types of cicatricial alopecias involve inflammation directed at the upper part of the hair follicle where the stem cells and sebaceous gland (oil gland) are located. If the stem cells and sebaceous gland are destroyed, there is no possibility for regeneration of the hair follicle, leading to permanent hair loss. Cicatricial alopecias are not contagious. | 274 | Cicatricial Alopecia |
nord_274_3 | Affects of Cicatricial Alopecia | Cicatricial alopecias affect healthy men and women of all ages, although primary cicatricial alopecia is not usually seen in children. Cicatricial alopecias occur worldwide. Epidemiologic studies have not been performed to determine the incidence of cicatricial alopecias. In general, they are not common.There have been a few reports of cicatricial alopecia occurring in a family. However, the majority of patients with cicatricial alopecia have no family history of a similar condition. Central centrifugal alopecia most commonly affects women of African ancestry and may occur in more than one family member. Dissecting cellulitis looks like deep cystic acne involving the scalp, and it occurs primarily in dark-skinned men. While it is possible to have more than one type of hair loss condition, non-scarring forms of hair loss do not turn into scarring forms of hair loss. | Affects of Cicatricial Alopecia. Cicatricial alopecias affect healthy men and women of all ages, although primary cicatricial alopecia is not usually seen in children. Cicatricial alopecias occur worldwide. Epidemiologic studies have not been performed to determine the incidence of cicatricial alopecias. In general, they are not common.There have been a few reports of cicatricial alopecia occurring in a family. However, the majority of patients with cicatricial alopecia have no family history of a similar condition. Central centrifugal alopecia most commonly affects women of African ancestry and may occur in more than one family member. Dissecting cellulitis looks like deep cystic acne involving the scalp, and it occurs primarily in dark-skinned men. While it is possible to have more than one type of hair loss condition, non-scarring forms of hair loss do not turn into scarring forms of hair loss. | 274 | Cicatricial Alopecia |
nord_274_4 | Related disorders of Cicatricial Alopecia | Symptoms of the following disorder can be similar to those of cicatricial alopecia. Comparisons may be useful for a differential diagnosis:Chronic cutaneous lupus erythematosus (CCLE) is predominantly a cutaneous disease with few systemic complications. Scarring and disfiguring changes in the skin (discoid lesons) are commonly seen in this disease. It occurs more frequently in females than males and more commonly in adults than children. | Related disorders of Cicatricial Alopecia. Symptoms of the following disorder can be similar to those of cicatricial alopecia. Comparisons may be useful for a differential diagnosis:Chronic cutaneous lupus erythematosus (CCLE) is predominantly a cutaneous disease with few systemic complications. Scarring and disfiguring changes in the skin (discoid lesons) are commonly seen in this disease. It occurs more frequently in females than males and more commonly in adults than children. | 274 | Cicatricial Alopecia |
nord_274_5 | Diagnosis of Cicatricial Alopecia | A scalp biopsy for the diagnosis of cicatricial alopecia is the necessary first step. Findings of the biopsy, including the type of inflammation present, location and amount of inflammation, and other changes in the scalp, are necessary to diagnose the type of cicatricial alopecia, to determine the degree of activity, and to select appropriate therapy.The biopsy specimen is taken with a biopsy punch, which is an instrument that removes a sample of skin about the size and shape of a small pencil eraser, after anesthetizing the local area. One or two biopsy specimens are taken, and ideally are examined after sectioning the skin samples both horizontally and vertically.Clinical evaluation of the scalp is also important. Symptoms of itching, burning, pain, or tenderness usually signal ongoing activity. Signs of scalp inflammation include redness, scaling, and pustules. However, in some active cases there are few symptoms or signs and only the scalp biopsy demonstrates the active inflammation. The overall extent and pattern of hair loss is noted and, together with the biopsy findings, these enable the dermatologist to diagnose the specific cicatricial alopecia present. A hair pull test is performed to identify areas of active disease in which follicles are easily pulled out. The pulled hairs are mounted on a slide and the hair bulbs are viewed under low power with a light microscope to determine how many are growing (anagen) hairs and how many are resting (telogen) hairs. Normally, only telogen hairs pull out easily; in contrast, in sites of active scarring alopecia, growing hairs may also pull out easily. In addition, if pustules are present, cultures may be performed to identify which microbes, if any, may be contributing to the inflammation. A thorough evaluation that includes all of these parameters is important in diagnosing a cicatricial alopecia and in identifying features in individual patients that will help the selection of therapy.Evaluation should be done by a dermatologist with a special interest or expertise in scalp and hair disorders, and who is familiar with current diagnostic methods and therapies. | Diagnosis of Cicatricial Alopecia. A scalp biopsy for the diagnosis of cicatricial alopecia is the necessary first step. Findings of the biopsy, including the type of inflammation present, location and amount of inflammation, and other changes in the scalp, are necessary to diagnose the type of cicatricial alopecia, to determine the degree of activity, and to select appropriate therapy.The biopsy specimen is taken with a biopsy punch, which is an instrument that removes a sample of skin about the size and shape of a small pencil eraser, after anesthetizing the local area. One or two biopsy specimens are taken, and ideally are examined after sectioning the skin samples both horizontally and vertically.Clinical evaluation of the scalp is also important. Symptoms of itching, burning, pain, or tenderness usually signal ongoing activity. Signs of scalp inflammation include redness, scaling, and pustules. However, in some active cases there are few symptoms or signs and only the scalp biopsy demonstrates the active inflammation. The overall extent and pattern of hair loss is noted and, together with the biopsy findings, these enable the dermatologist to diagnose the specific cicatricial alopecia present. A hair pull test is performed to identify areas of active disease in which follicles are easily pulled out. The pulled hairs are mounted on a slide and the hair bulbs are viewed under low power with a light microscope to determine how many are growing (anagen) hairs and how many are resting (telogen) hairs. Normally, only telogen hairs pull out easily; in contrast, in sites of active scarring alopecia, growing hairs may also pull out easily. In addition, if pustules are present, cultures may be performed to identify which microbes, if any, may be contributing to the inflammation. A thorough evaluation that includes all of these parameters is important in diagnosing a cicatricial alopecia and in identifying features in individual patients that will help the selection of therapy.Evaluation should be done by a dermatologist with a special interest or expertise in scalp and hair disorders, and who is familiar with current diagnostic methods and therapies. | 274 | Cicatricial Alopecia |
nord_274_6 | Therapies of Cicatricial Alopecia | Primary cicatricial alopecias are classified by the predominant type of inflammatory cells that attack the hair follicles (i.e., lymphocytes, neutrophils, or mixed inflammatory cells), and treatment strategies are different for each subtype and each patient.Treatment of the lymphocytic group of cicatricial alopecias including lichen planopilaris, frontal fibrosing alopecia, central centrifugal alopecia, and pseudopelade (Brocq) involves use of anti-inflammatory medications. The goal of treatment is to decrease or eliminate the lymphocytic inflammatory cells that are attacking and destroying the hair follicle. Oral medications may include hydroxychloroquine, doxycycline, mycophenolate mofetil, cyclosporine, or pioglitazone. Topical medications may include corticosteroids, topical tacrolimus, topical pimecrolimus, or Derma-Smoothe/FS scalp oil. Triamcinolone acetonide (a corticosteroid) may be injected into inflamed, symptomatic areas of the scalp.Treatment of the neutrophilic group of cicatricial alopecias (folliculitis decalvans, tufted folliculitis) is directed at eliminating the predominant microbes that are invariably involved in the inflammatory process. Oral antibiotics are the mainstay of therapy. Topical antibiotics and anti-inflammatory medications may be used to supplement the oral antibiotics.Treatment of the mixed group of cicatricial alopecias (dissecting cellulitis, folliculitis keloidalis) may include antimicrobials, anti-inflammatory medications, isotretinoin (starting dose must be small). Infliximab may be helpful in treatment-resistant dissecting cellulitis.The course of cicatricial alopecia is usually prolonged. Treatment is continued until the symptoms and signs of scalp inflammation are decreased, and progression of the condition has been controlled. Itching, burning, pain, and tenderness, and scalp redness, scaling, and/or pustules, can usually be controlled by current treatments. Unfortunately, the progression of the hair loss may continue silently even when the symptoms and signs are cleared. Cicatricial alopecia may reactivate after a quiet period and treatment may have to be repeated.Surgical treatment for cosmetic benefit is an option in some affected individuals after the disease has been inactive for one to two or more years. Hair restoration surgery or scalp reduction may be considered in these instances.Hair will not regrow once the follicle is destroyed. However, it may be possible to treat the inflammation in and around surrounding follicles before they are destroyed, and for this reason it is important to begin the above treatment early to control the inflammatory process. In addition, minoxidil solution or foam (2% or 5%) applied twice daily to the scalp may be helpful to stimulate any small, remaining, unscarred follicles. The progression of hair loss is unpredictable. In some cases, progression is slow and minimal, and in other cases progression can be rapid and extensive. Usually there is sufficient hair remaining to cover the affected scalp areas; relatively few patients require a hair piece.Hair care products and shampoos are generally safe as long as they are non-irritating to the scalp. A dermatologist can recommend specific shampoos and products to decrease scalp symptoms, scaling and inflammation and will recommend frequency of their use. Hair pieces, wigs, hats, and scarves are all safe, will not aggravate your condition, and may be used freely. | Therapies of Cicatricial Alopecia. Primary cicatricial alopecias are classified by the predominant type of inflammatory cells that attack the hair follicles (i.e., lymphocytes, neutrophils, or mixed inflammatory cells), and treatment strategies are different for each subtype and each patient.Treatment of the lymphocytic group of cicatricial alopecias including lichen planopilaris, frontal fibrosing alopecia, central centrifugal alopecia, and pseudopelade (Brocq) involves use of anti-inflammatory medications. The goal of treatment is to decrease or eliminate the lymphocytic inflammatory cells that are attacking and destroying the hair follicle. Oral medications may include hydroxychloroquine, doxycycline, mycophenolate mofetil, cyclosporine, or pioglitazone. Topical medications may include corticosteroids, topical tacrolimus, topical pimecrolimus, or Derma-Smoothe/FS scalp oil. Triamcinolone acetonide (a corticosteroid) may be injected into inflamed, symptomatic areas of the scalp.Treatment of the neutrophilic group of cicatricial alopecias (folliculitis decalvans, tufted folliculitis) is directed at eliminating the predominant microbes that are invariably involved in the inflammatory process. Oral antibiotics are the mainstay of therapy. Topical antibiotics and anti-inflammatory medications may be used to supplement the oral antibiotics.Treatment of the mixed group of cicatricial alopecias (dissecting cellulitis, folliculitis keloidalis) may include antimicrobials, anti-inflammatory medications, isotretinoin (starting dose must be small). Infliximab may be helpful in treatment-resistant dissecting cellulitis.The course of cicatricial alopecia is usually prolonged. Treatment is continued until the symptoms and signs of scalp inflammation are decreased, and progression of the condition has been controlled. Itching, burning, pain, and tenderness, and scalp redness, scaling, and/or pustules, can usually be controlled by current treatments. Unfortunately, the progression of the hair loss may continue silently even when the symptoms and signs are cleared. Cicatricial alopecia may reactivate after a quiet period and treatment may have to be repeated.Surgical treatment for cosmetic benefit is an option in some affected individuals after the disease has been inactive for one to two or more years. Hair restoration surgery or scalp reduction may be considered in these instances.Hair will not regrow once the follicle is destroyed. However, it may be possible to treat the inflammation in and around surrounding follicles before they are destroyed, and for this reason it is important to begin the above treatment early to control the inflammatory process. In addition, minoxidil solution or foam (2% or 5%) applied twice daily to the scalp may be helpful to stimulate any small, remaining, unscarred follicles. The progression of hair loss is unpredictable. In some cases, progression is slow and minimal, and in other cases progression can be rapid and extensive. Usually there is sufficient hair remaining to cover the affected scalp areas; relatively few patients require a hair piece.Hair care products and shampoos are generally safe as long as they are non-irritating to the scalp. A dermatologist can recommend specific shampoos and products to decrease scalp symptoms, scaling and inflammation and will recommend frequency of their use. Hair pieces, wigs, hats, and scarves are all safe, will not aggravate your condition, and may be used freely. | 274 | Cicatricial Alopecia |
nord_275_0 | Overview of Ciguatera Fish Poisoning | Ciguatera fish poisoning is a rare disorder that occurs because of the ingestion of certain contaminated tropical and subtropical fish. When ingested, the toxin (ciguatoxin), which is present at high levels in these contaminated fish, may affect the digestive, muscular, and/or neurological systems. More than 400 different species of fish have been implicated as a cause of ciguatera fish poisoning, including many that are otherwise considered edible (i.e., sea bass, snapper, and perch). These fish typically inhabit low-lying shore areas or coral reefs in tropical or subtropical areas. In the United States, ciguatera fish poisoning has occurred more frequently in the last decade perhaps as a result of a general increase in fish consumption. | Overview of Ciguatera Fish Poisoning. Ciguatera fish poisoning is a rare disorder that occurs because of the ingestion of certain contaminated tropical and subtropical fish. When ingested, the toxin (ciguatoxin), which is present at high levels in these contaminated fish, may affect the digestive, muscular, and/or neurological systems. More than 400 different species of fish have been implicated as a cause of ciguatera fish poisoning, including many that are otherwise considered edible (i.e., sea bass, snapper, and perch). These fish typically inhabit low-lying shore areas or coral reefs in tropical or subtropical areas. In the United States, ciguatera fish poisoning has occurred more frequently in the last decade perhaps as a result of a general increase in fish consumption. | 275 | Ciguatera Fish Poisoning |
nord_275_1 | Symptoms of Ciguatera Fish Poisoning | The symptoms of acute ciguatera fish poisoning may begin as soon as 30 minutes after eating contaminated fish. The initial symptoms may include itching, tingling, and numbness of the lips, tongue, hands, and/or feet. Other symptoms during the first six to 17 hours are abdominal cramps, nausea, vomiting, diarrhea, and/or a red skin rash (pruritus). Chills, hot and cold temperature reversal, generalized weakness, restlessness, dizziness, wheezing, blurred vision, abnormal sensitivity to light (photophobia), muscle aches (myalgias), and/or joint pain (arthralgias) may also develop.The acute symptoms of ciguatera fish poisoning generally disappear within a few days. However, neurological symptoms may continue for several months. Some affected individuals experience abnormally low blood pressure upon standing from a seated position (orthostatic hypotension). In severe cases, there may be rapid progression to breathing difficulties (dyspnea) and muscular paralysis. Life-threatening complications (i.e., abnormally slow heartbeat, respiratory arrest, convulsions, or coma) may occur in these severe cases within 24 hours. | Symptoms of Ciguatera Fish Poisoning. The symptoms of acute ciguatera fish poisoning may begin as soon as 30 minutes after eating contaminated fish. The initial symptoms may include itching, tingling, and numbness of the lips, tongue, hands, and/or feet. Other symptoms during the first six to 17 hours are abdominal cramps, nausea, vomiting, diarrhea, and/or a red skin rash (pruritus). Chills, hot and cold temperature reversal, generalized weakness, restlessness, dizziness, wheezing, blurred vision, abnormal sensitivity to light (photophobia), muscle aches (myalgias), and/or joint pain (arthralgias) may also develop.The acute symptoms of ciguatera fish poisoning generally disappear within a few days. However, neurological symptoms may continue for several months. Some affected individuals experience abnormally low blood pressure upon standing from a seated position (orthostatic hypotension). In severe cases, there may be rapid progression to breathing difficulties (dyspnea) and muscular paralysis. Life-threatening complications (i.e., abnormally slow heartbeat, respiratory arrest, convulsions, or coma) may occur in these severe cases within 24 hours. | 275 | Ciguatera Fish Poisoning |
nord_275_2 | Causes of Ciguatera Fish Poisoning | Ciguatera fish poisoning is caused by a toxin (ciguatoxin) found in tropical or subtropical fish during certain times of the year. The source of the toxin responsible for ciguatera fish poisoning is found in high levels in a marine organism (dinoflagellate Gamabierdiscus toxicus) that typically inhabits low-lying tropical shore areas and coral reefs. As local fish feed on this organism, toxin accumulates in their bodies and ultimately causes ciguatera fish poisoning when humans consume the fish.No known method of cooking can destroy the ciguatoxin in contaminated fish. It is possible that more than one form of the toxin may be present in a fish. | Causes of Ciguatera Fish Poisoning. Ciguatera fish poisoning is caused by a toxin (ciguatoxin) found in tropical or subtropical fish during certain times of the year. The source of the toxin responsible for ciguatera fish poisoning is found in high levels in a marine organism (dinoflagellate Gamabierdiscus toxicus) that typically inhabits low-lying tropical shore areas and coral reefs. As local fish feed on this organism, toxin accumulates in their bodies and ultimately causes ciguatera fish poisoning when humans consume the fish.No known method of cooking can destroy the ciguatoxin in contaminated fish. It is possible that more than one form of the toxin may be present in a fish. | 275 | Ciguatera Fish Poisoning |
nord_275_3 | Affects of Ciguatera Fish Poisoning | Ciguatera fish poisoning is a rare disease that affects males and females in equal numbers. This disease occurs with the greatest frequency in tropical and subtropical countries, particularly those in the Pacific and Caribbean areas. All age groups are at risk for this disease. However, a longer duration and more severe symptoms of ciguatera fish poisoning may be associated with increasing age. Children seem to experience milder symptoms for a shorter period of time. More severe symptoms may also be associated with the ingestion of a larger quantity of contaminated fish.The presence of ciguatoxin has been reported in semen from affected males which can cause the symptoms of ciguatera fish poisoning in females after sexual intercourse. Since this toxin has also been identified in breast milk, it is also possible for affected mothers to pass this disease to their nursing children. | Affects of Ciguatera Fish Poisoning. Ciguatera fish poisoning is a rare disease that affects males and females in equal numbers. This disease occurs with the greatest frequency in tropical and subtropical countries, particularly those in the Pacific and Caribbean areas. All age groups are at risk for this disease. However, a longer duration and more severe symptoms of ciguatera fish poisoning may be associated with increasing age. Children seem to experience milder symptoms for a shorter period of time. More severe symptoms may also be associated with the ingestion of a larger quantity of contaminated fish.The presence of ciguatoxin has been reported in semen from affected males which can cause the symptoms of ciguatera fish poisoning in females after sexual intercourse. Since this toxin has also been identified in breast milk, it is also possible for affected mothers to pass this disease to their nursing children. | 275 | Ciguatera Fish Poisoning |
nord_275_4 | Related disorders of Ciguatera Fish Poisoning | Symptoms of the following disorders can be similar to those of ciguatera fish poisoning. Comparisons may be useful for a differential diagnosis:Tetraodon poisoning results from eating puffer fish that contain the tetraodon toxin. Symptoms are similar to those of ciguatera fish poisoning and may include abdominal cramps, nausea, vomiting, diarrhea, and/or a red itchy skin rash (pruritus). Chills, hot and cold temperature reversal, blurred vision, abnormal sensitivity to light (photophobia), and muscle aches (myalgias) may also occur. Life-threatening complications may develop in about 50 percent of cases.Scombroid fish poisoning is caused by a toxin formed during bacterial decay of fish, and is usually associated with inadequate refrigeration. Symptoms generally begin soon after ingestion of contaminated fish and resemble those of an allergic (histamine) reaction. Symptoms may include flushing, dizziness, burning, hives (urticaria), nausea, and/or vomiting. Some people may experience swelling in the throat and difficulty breathing due to spasms which can tighten the passageway to the lungs (bronchospasm). The toxin which causes this disease is known as histamine saurine and can be found in tuna, mackerel, bonito, skipjack, and mahi mahi.Physical Urticaria refers to a group of skin disorders characterized by red (erythematous) allergic skin lesions and itchiness (pruritus). This reaction may be produced by exposure to a variety of environmental or stress factors. The most common symptoms of Physical Urticaria are itching (pruritus) and hives consisting of red rings around white ridges (wheals). Sensitivity to cold is usually manifested by these eruptions on the skin, as well as itching, and swelling under the skin (angioedema). These symptoms develop most typically after exposure or during swimming or bathing. Contraction of the muscles around the bronchi (bronchospasm) and even shock may occur in extreme cases. (For more information on this disorder, choose “Urticaria” as your search term in the Rare Disease Database.) | Related disorders of Ciguatera Fish Poisoning. Symptoms of the following disorders can be similar to those of ciguatera fish poisoning. Comparisons may be useful for a differential diagnosis:Tetraodon poisoning results from eating puffer fish that contain the tetraodon toxin. Symptoms are similar to those of ciguatera fish poisoning and may include abdominal cramps, nausea, vomiting, diarrhea, and/or a red itchy skin rash (pruritus). Chills, hot and cold temperature reversal, blurred vision, abnormal sensitivity to light (photophobia), and muscle aches (myalgias) may also occur. Life-threatening complications may develop in about 50 percent of cases.Scombroid fish poisoning is caused by a toxin formed during bacterial decay of fish, and is usually associated with inadequate refrigeration. Symptoms generally begin soon after ingestion of contaminated fish and resemble those of an allergic (histamine) reaction. Symptoms may include flushing, dizziness, burning, hives (urticaria), nausea, and/or vomiting. Some people may experience swelling in the throat and difficulty breathing due to spasms which can tighten the passageway to the lungs (bronchospasm). The toxin which causes this disease is known as histamine saurine and can be found in tuna, mackerel, bonito, skipjack, and mahi mahi.Physical Urticaria refers to a group of skin disorders characterized by red (erythematous) allergic skin lesions and itchiness (pruritus). This reaction may be produced by exposure to a variety of environmental or stress factors. The most common symptoms of Physical Urticaria are itching (pruritus) and hives consisting of red rings around white ridges (wheals). Sensitivity to cold is usually manifested by these eruptions on the skin, as well as itching, and swelling under the skin (angioedema). These symptoms develop most typically after exposure or during swimming or bathing. Contraction of the muscles around the bronchi (bronchospasm) and even shock may occur in extreme cases. (For more information on this disorder, choose “Urticaria” as your search term in the Rare Disease Database.) | 275 | Ciguatera Fish Poisoning |
nord_275_5 | Diagnosis of Ciguatera Fish Poisoning | Diagnosis of Ciguatera Fish Poisoning. | 275 | Ciguatera Fish Poisoning |
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nord_275_6 | Therapies of Ciguatera Fish Poisoning | The treatment for ciguatera fish poisoning is usually the immediate pumping out of all stomach contents (gastric lavage). If this treatment is not available, then vomiting should be induced by the administration of syrup of ipecac. Persistent nausea and vomiting must be treated with the intravenous administration of fluids to avoid dehydration. If shock, convulsions or respiratory failure occurs, immediate appropriate medical measures must be instituted. Dextran (a polysaccharide drug), Normal Human Serum Albumin, or blood transfusion may be necessary to treat shock. Meperidine may also be prescribed for pain. Other treatment is symptomatic and supportive.Travelers to endemic areas should be cautioned about the risk of contracting ciguatera fish poisoning. Since travelers are at the same relative risk as people who normally live in endemic areas, they should be warned not to eat barracuda and should exercise caution when considering other fish such as grouper and red snapper. | Therapies of Ciguatera Fish Poisoning. The treatment for ciguatera fish poisoning is usually the immediate pumping out of all stomach contents (gastric lavage). If this treatment is not available, then vomiting should be induced by the administration of syrup of ipecac. Persistent nausea and vomiting must be treated with the intravenous administration of fluids to avoid dehydration. If shock, convulsions or respiratory failure occurs, immediate appropriate medical measures must be instituted. Dextran (a polysaccharide drug), Normal Human Serum Albumin, or blood transfusion may be necessary to treat shock. Meperidine may also be prescribed for pain. Other treatment is symptomatic and supportive.Travelers to endemic areas should be cautioned about the risk of contracting ciguatera fish poisoning. Since travelers are at the same relative risk as people who normally live in endemic areas, they should be warned not to eat barracuda and should exercise caution when considering other fish such as grouper and red snapper. | 275 | Ciguatera Fish Poisoning |
nord_276_0 | Overview of Citrullinemia Type 1 | Citrullinemia type I (CTLN1) is a rare autosomal recessive genetic disorder that includes a neonatal acute (classic) form, a milder late-onset form, a form that begins during or after pregnancy and an asymptomatic form.CTLN1 is caused by deficiency or absence of the enzyme argininosuccinate synthetase (ASS). ASS is one of six enzymes that play a role in the removal of nitrogen from the body, a process known as the urea cycle. The lack of this enzyme results in excessive accumulation of nitrogen, in the form of ammonia (hyperammonemia) in the blood and all body fluids.Infants with the classic form may experience vomiting, refusal to eat, progressive lethargy and show signs of increased intracranial pressure. Prompt treatment can prolong survival, but neurologic deficits are usually present. The course of the late-onset form is sometimes milder but episodes of hyperammonemia are similar to the classic form. | Overview of Citrullinemia Type 1. Citrullinemia type I (CTLN1) is a rare autosomal recessive genetic disorder that includes a neonatal acute (classic) form, a milder late-onset form, a form that begins during or after pregnancy and an asymptomatic form.CTLN1 is caused by deficiency or absence of the enzyme argininosuccinate synthetase (ASS). ASS is one of six enzymes that play a role in the removal of nitrogen from the body, a process known as the urea cycle. The lack of this enzyme results in excessive accumulation of nitrogen, in the form of ammonia (hyperammonemia) in the blood and all body fluids.Infants with the classic form may experience vomiting, refusal to eat, progressive lethargy and show signs of increased intracranial pressure. Prompt treatment can prolong survival, but neurologic deficits are usually present. The course of the late-onset form is sometimes milder but episodes of hyperammonemia are similar to the classic form. | 276 | Citrullinemia Type 1 |
nord_276_1 | Symptoms of Citrullinemia Type 1 | The severity of CTLN1 varies from patient to patient. The classic form, characterized by profound lack of ASS enzyme activity, displays symptoms shortly after birth (neonatal period). A milder form of the disorder, which is characterized by partial lack of the ASS enzyme, affects some infants later during infancy or childhood.The symptoms of CTLN1 are caused by the accumulation of ammonia in the blood and cerebrospinal fluid (CSF). The classic form occurs within 24-72 hours after birth, usually following a protein feeding and is initially characterized by refusal to eat, lethargy, lack of appetite, vomiting and irritability. Affected infants may also experience seizures, diminished muscle tone (hypotonia), respiratory distress, accumulation of fluid in the brain (cerebral edema) and liver failure.If untreated, CTLN1 may progress to coma due to high levels of ammonia in the CSF (hyperammonemic coma). Neurological abnormalities including developmental delays, intellectual disability and cerebral palsy may occur and are more severe in infants who are in hyperammonemic coma for more than three days. Increased intracranial pressure can result in increased muscle tone, spasticity, abnormal reflex movements of the foot (ankle clonus) and seizures. If left untreated, the disorder will result in life-threatening complications.In some patients, including those with partial enzyme deficiency, onset of the disorder may not occur until later during infancy or childhood. Symptoms may include failure to grow and gain weight at the expected rate (failure to thrive), avoidance of high-protein foods from the diet, inability to coordinate voluntary movements (ataxia), progressive lethargy and vomiting. Infants with the mild form may alternate between periods of wellness and hyperammonemia. Infants and children with this form of CTLN1 may also develop hyperammonemic coma and life-threatening complications.Another form of CTLN1 occurs during and after pregnancy. Affected women may experience migraine headaches, repeated episodes of vomiting, lethargy, seizures, confusion, hallucinations and potentially coma. Behavioral changes may also occur including manic episodes and psychosis. Affected women may also have accumulation of fluid in the brain (cerebral edema).Some individuals with CTLN1 do not experience symptoms or hyperammonemia. The basis for these milder variants is not established. | Symptoms of Citrullinemia Type 1. The severity of CTLN1 varies from patient to patient. The classic form, characterized by profound lack of ASS enzyme activity, displays symptoms shortly after birth (neonatal period). A milder form of the disorder, which is characterized by partial lack of the ASS enzyme, affects some infants later during infancy or childhood.The symptoms of CTLN1 are caused by the accumulation of ammonia in the blood and cerebrospinal fluid (CSF). The classic form occurs within 24-72 hours after birth, usually following a protein feeding and is initially characterized by refusal to eat, lethargy, lack of appetite, vomiting and irritability. Affected infants may also experience seizures, diminished muscle tone (hypotonia), respiratory distress, accumulation of fluid in the brain (cerebral edema) and liver failure.If untreated, CTLN1 may progress to coma due to high levels of ammonia in the CSF (hyperammonemic coma). Neurological abnormalities including developmental delays, intellectual disability and cerebral palsy may occur and are more severe in infants who are in hyperammonemic coma for more than three days. Increased intracranial pressure can result in increased muscle tone, spasticity, abnormal reflex movements of the foot (ankle clonus) and seizures. If left untreated, the disorder will result in life-threatening complications.In some patients, including those with partial enzyme deficiency, onset of the disorder may not occur until later during infancy or childhood. Symptoms may include failure to grow and gain weight at the expected rate (failure to thrive), avoidance of high-protein foods from the diet, inability to coordinate voluntary movements (ataxia), progressive lethargy and vomiting. Infants with the mild form may alternate between periods of wellness and hyperammonemia. Infants and children with this form of CTLN1 may also develop hyperammonemic coma and life-threatening complications.Another form of CTLN1 occurs during and after pregnancy. Affected women may experience migraine headaches, repeated episodes of vomiting, lethargy, seizures, confusion, hallucinations and potentially coma. Behavioral changes may also occur including manic episodes and psychosis. Affected women may also have accumulation of fluid in the brain (cerebral edema).Some individuals with CTLN1 do not experience symptoms or hyperammonemia. The basis for these milder variants is not established. | 276 | Citrullinemia Type 1 |
nord_276_2 | Causes of Citrullinemia Type 1 | CTLN1 is caused by changes (mutations or pathogenic variants) in the ASS1 gene that is responsible for production of the argininosuccinate synthetase (ASS) enzyme. The symptoms of CTLN1 develop due to deficiency of this enzyme, which is needed to detoxify ammonia in the body. Failure to properly remove ammonia via synthesis of urea leads to the abnormal accumulation of ammonia in the blood (hyperammonemia).CTLN1 is inherited as an autosomal recessive genetic condition. 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. | Causes of Citrullinemia Type 1. CTLN1 is caused by changes (mutations or pathogenic variants) in the ASS1 gene that is responsible for production of the argininosuccinate synthetase (ASS) enzyme. The symptoms of CTLN1 develop due to deficiency of this enzyme, which is needed to detoxify ammonia in the body. Failure to properly remove ammonia via synthesis of urea leads to the abnormal accumulation of ammonia in the blood (hyperammonemia).CTLN1 is inherited as an autosomal recessive genetic condition. 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. | 276 | Citrullinemia Type 1 |
nord_276_3 | Affects of Citrullinemia Type 1 | CTLN1 occurs in approximately 1/57,000 births. | Affects of Citrullinemia Type 1. CTLN1 occurs in approximately 1/57,000 births. | 276 | Citrullinemia Type 1 |
nord_276_4 | Related disorders of Citrullinemia Type 1 | Symptoms of the following disorders may be similar to those of citrullinemia type 1. Comparisons may be useful for a differential diagnosis:The urea cycle disorders are a group of rare disorders affecting the urea cycle, a series of biochemical processes in which waste nitrogen is converted into urea and removed from the body through the urine. Ammonia is a waste product of protein metabolism. The symptoms of all urea cycle disorders vary in severity and result from the excessive accumulation of ammonia in the blood and body tissues (hyperammonemia). Common symptoms include lack of appetite, vomiting, drowsiness, seizures, intolerance to protein and/or coma. The liver may be abnormally enlarged (hepatomegaly) in some patients. In severe cases, life-threatening complications often result. In addition to citrullinemia, the other urea cycle disorders are: carbamyl phosphate synthetase (CPS) deficiency; argininosuccinic acid lyase deficiency; ornithine transcarbamylase (OTC) deficiency; arginase deficiency and N-acetylglutamate synthetase (NAGS) deficiency. (For more information on these disorders, choose the specific disorder name as your search terms in the Rare Disease Database.)Organic acidemias are a rare group of inherited metabolic disorders characterized by deficiency of certain enzymes that are necessary to break down (metabolize) chemical “building blocks” (amino acids) of certain proteins. Failure to break down amino acids results in the excessive accumulation of acids in the blood. Symptoms may include abnormally diminished muscle tone (hypotonia), poor feeding, vomiting, lethargy and seizures. They also develop metabolic acidosis (too much acid in the blood). If left untreated, organic acidemias may progress to coma and life-threatening complications. These disorders are of a genetic origin and affect the urea cycle as a secondary phenomenon.Citrullinemia type II is caused by pathogenic variants in the SLC25A13 gene resulting in a deficiency of the citrin protein. In infants, this can cause a liver disorder called neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) characterized by a block in the flow of bile that prevents the body from processing certain nutrients properly. NICCD often resolves within a year, but those affected can later develop features of adult-onset citrullinemia type II. Symptoms of the adult-onset form include confusion, restlessness, memory loss, aggression, irritability and hyperactivity, seizures, and coma. | Related disorders of Citrullinemia Type 1. Symptoms of the following disorders may be similar to those of citrullinemia type 1. Comparisons may be useful for a differential diagnosis:The urea cycle disorders are a group of rare disorders affecting the urea cycle, a series of biochemical processes in which waste nitrogen is converted into urea and removed from the body through the urine. Ammonia is a waste product of protein metabolism. The symptoms of all urea cycle disorders vary in severity and result from the excessive accumulation of ammonia in the blood and body tissues (hyperammonemia). Common symptoms include lack of appetite, vomiting, drowsiness, seizures, intolerance to protein and/or coma. The liver may be abnormally enlarged (hepatomegaly) in some patients. In severe cases, life-threatening complications often result. In addition to citrullinemia, the other urea cycle disorders are: carbamyl phosphate synthetase (CPS) deficiency; argininosuccinic acid lyase deficiency; ornithine transcarbamylase (OTC) deficiency; arginase deficiency and N-acetylglutamate synthetase (NAGS) deficiency. (For more information on these disorders, choose the specific disorder name as your search terms in the Rare Disease Database.)Organic acidemias are a rare group of inherited metabolic disorders characterized by deficiency of certain enzymes that are necessary to break down (metabolize) chemical “building blocks” (amino acids) of certain proteins. Failure to break down amino acids results in the excessive accumulation of acids in the blood. Symptoms may include abnormally diminished muscle tone (hypotonia), poor feeding, vomiting, lethargy and seizures. They also develop metabolic acidosis (too much acid in the blood). If left untreated, organic acidemias may progress to coma and life-threatening complications. These disorders are of a genetic origin and affect the urea cycle as a secondary phenomenon.Citrullinemia type II is caused by pathogenic variants in the SLC25A13 gene resulting in a deficiency of the citrin protein. In infants, this can cause a liver disorder called neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) characterized by a block in the flow of bile that prevents the body from processing certain nutrients properly. NICCD often resolves within a year, but those affected can later develop features of adult-onset citrullinemia type II. Symptoms of the adult-onset form include confusion, restlessness, memory loss, aggression, irritability and hyperactivity, seizures, and coma. | 276 | Citrullinemia Type 1 |
nord_276_5 | Diagnosis of Citrullinemia Type 1 | A diagnosis of citrullinemia can be confirmed by a detailed patient/family history, identification of characteristic findings, and a variety of specialized tests. Excessive amounts of ammonia and citrulline in the blood strongly suggests the diagnosis of CTLN1. Molecular genetic testing for detection of pathogenic variants in the ASS1 gene is available to confirm the diagnosis.CTLN1 may also be diagnosed through newborn screening programs. Citrulline can be measured on the newborn blood spot by tandem mass spectroscopy. Every state in the U.S. screens every newborn for CTLN1. Early detection is important because prompt identification and treatment may prevent the hyperammonemia that causes brain damage.Carrier testing and prenatal diagnosis are available if the specific pathogenic variant has been identified in the family.Siblings of an affected child should be tested immediately after birth and those with elevated ammonia or citrulline should receive a low protein diet. | Diagnosis of Citrullinemia Type 1. A diagnosis of citrullinemia can be confirmed by a detailed patient/family history, identification of characteristic findings, and a variety of specialized tests. Excessive amounts of ammonia and citrulline in the blood strongly suggests the diagnosis of CTLN1. Molecular genetic testing for detection of pathogenic variants in the ASS1 gene is available to confirm the diagnosis.CTLN1 may also be diagnosed through newborn screening programs. Citrulline can be measured on the newborn blood spot by tandem mass spectroscopy. Every state in the U.S. screens every newborn for CTLN1. Early detection is important because prompt identification and treatment may prevent the hyperammonemia that causes brain damage.Carrier testing and prenatal diagnosis are available if the specific pathogenic variant has been identified in the family.Siblings of an affected child should be tested immediately after birth and those with elevated ammonia or citrulline should receive a low protein diet. | 276 | Citrullinemia Type 1 |
nord_276_6 | Therapies of Citrullinemia Type 1 | Treatment
Treatment of an individual with CTLN1 requires the coordinated efforts of a team of specialists. Biochemical geneticists, pediatricians, neurologists and dieticians are needed to work together to ensure a comprehensive approach to treatment. Management involves prompt diagnosis, control of hyperammonemia and control of intracranial pressure.Prompt treatment is necessary when individuals have extremely high ammonia levels (severe hyperammonemic episode). Prompt treatment can avoid hyperammonemic coma and associated neurological symptoms. However, in some patients, especially those with complete enzyme deficiency, prompt treatment will not prevent recurrent episodes of hyperammonemia and the potential development of serious complications.The treatment of CTLN1 is aimed at preventing excessive ammonia from being formed or for removing excessive ammonia during a hyperammonemic episode. Medications that assist in the removal of nitrogen from the body by providing an alternative means of waste nitrogen removal are employed. Available medications are Buphenyl, Ammonul, and Raviciti, as well as arginine.Dietary restrictions are aimed at limiting the amount of protein intake to avoid the development of excess ammonia. However, enough protein must be taken in by an affected infant to ensure proper growth. Infants are placed a low protein, high calorie diet supplemented by essential amino acids. A combination of a high biological value natural protein such as breast milk or cow’s milk formulate, an essential amino acid formula, and a calorie supplement without protein is often used.Multiple vitamins and calcium supplements may also be used.Aggressive treatment including hospitalization and protein restriction is needed in hyperammonemic episodes that have progressed to vomiting and increased lethargy. Affected individuals may also receive treatment with intravenous administration of arginine and a combination of sodium benzoate and sodium phenylacetate. Non-protein calories may be also provided as glucose.In patients where there is no improvement or in patients where hyperammonemic coma develops, the removal of ammonia by filtering an affected individual’s blood through a machine (hemodialysis) may be necessary. Hemodialysis is also used to treat infants, children and adults who are first diagnosed with CTLN1 during hyperammonemic coma.Affected children should be monitored to prevent increased intracranial pressure and to anticipate the onset of a hyperammonemic episode. Warning signs include mood changes, headaches, lethargy, nausea, vomiting, refusal to eat and ankle clonus. Affected individuals should receive periodic blood tests to determine the level of ammonia in the blood and to determine the concentration of plasma amino acids to assist in the management of the protein restricted diet. Detection of elevated levels of ammonia may allow treatment before clinical symptoms appear.Liver transplantation has been reported to improve quality of life and prolong survival in some patients. | Therapies of Citrullinemia Type 1. Treatment
Treatment of an individual with CTLN1 requires the coordinated efforts of a team of specialists. Biochemical geneticists, pediatricians, neurologists and dieticians are needed to work together to ensure a comprehensive approach to treatment. Management involves prompt diagnosis, control of hyperammonemia and control of intracranial pressure.Prompt treatment is necessary when individuals have extremely high ammonia levels (severe hyperammonemic episode). Prompt treatment can avoid hyperammonemic coma and associated neurological symptoms. However, in some patients, especially those with complete enzyme deficiency, prompt treatment will not prevent recurrent episodes of hyperammonemia and the potential development of serious complications.The treatment of CTLN1 is aimed at preventing excessive ammonia from being formed or for removing excessive ammonia during a hyperammonemic episode. Medications that assist in the removal of nitrogen from the body by providing an alternative means of waste nitrogen removal are employed. Available medications are Buphenyl, Ammonul, and Raviciti, as well as arginine.Dietary restrictions are aimed at limiting the amount of protein intake to avoid the development of excess ammonia. However, enough protein must be taken in by an affected infant to ensure proper growth. Infants are placed a low protein, high calorie diet supplemented by essential amino acids. A combination of a high biological value natural protein such as breast milk or cow’s milk formulate, an essential amino acid formula, and a calorie supplement without protein is often used.Multiple vitamins and calcium supplements may also be used.Aggressive treatment including hospitalization and protein restriction is needed in hyperammonemic episodes that have progressed to vomiting and increased lethargy. Affected individuals may also receive treatment with intravenous administration of arginine and a combination of sodium benzoate and sodium phenylacetate. Non-protein calories may be also provided as glucose.In patients where there is no improvement or in patients where hyperammonemic coma develops, the removal of ammonia by filtering an affected individual’s blood through a machine (hemodialysis) may be necessary. Hemodialysis is also used to treat infants, children and adults who are first diagnosed with CTLN1 during hyperammonemic coma.Affected children should be monitored to prevent increased intracranial pressure and to anticipate the onset of a hyperammonemic episode. Warning signs include mood changes, headaches, lethargy, nausea, vomiting, refusal to eat and ankle clonus. Affected individuals should receive periodic blood tests to determine the level of ammonia in the blood and to determine the concentration of plasma amino acids to assist in the management of the protein restricted diet. Detection of elevated levels of ammonia may allow treatment before clinical symptoms appear.Liver transplantation has been reported to improve quality of life and prolong survival in some patients. | 276 | Citrullinemia Type 1 |
nord_277_0 | Overview of Classic Hereditary Hemochromatosis | Hereditary hemochromatosis (HH) is a general term for several rare genetic disorders that are characterized by the accumulation of iron in various organs of the body such as the liver, heart and pancreas. The abnormally stored iron can damage affected organs, potentially causing a variety of different symptoms. The most common form of hemochromatosis is known by several different names including hemochromatosis type I, HFE-related hemochromatosis, hereditary hemochromatosis and classic hereditary hemochromatosis. Iron accumulation in classic hereditary hemochromatosis occurs slowly over many years. Eventually, iron accumulation causes tissue damage and impaired functioning of affected organs. In many affected individuals, symptoms may not become apparent until some point between 40-60 years of age. Onset is usually earlier for men compared to women. Common symptoms include abdominal pain, weakness, lethargy, and unintended weight loss. Without treatment, classic hereditary hemochromatosis can progress to cause serious, life-threatening complications including failure of affected organs.There are several different disorders associated with excess iron accumulation in the body. Collectively, these different disorders are grouped under the name iron overload disorders. These disorders are caused by mutations to different genes and have different clinical presentations. Classic hereditary hemochromatosis is caused by mutations of the HFE gene. This report primarily deals with classic hereditary hemochromatosis caused by mutation of the HFE gene. | Overview of Classic Hereditary Hemochromatosis. Hereditary hemochromatosis (HH) is a general term for several rare genetic disorders that are characterized by the accumulation of iron in various organs of the body such as the liver, heart and pancreas. The abnormally stored iron can damage affected organs, potentially causing a variety of different symptoms. The most common form of hemochromatosis is known by several different names including hemochromatosis type I, HFE-related hemochromatosis, hereditary hemochromatosis and classic hereditary hemochromatosis. Iron accumulation in classic hereditary hemochromatosis occurs slowly over many years. Eventually, iron accumulation causes tissue damage and impaired functioning of affected organs. In many affected individuals, symptoms may not become apparent until some point between 40-60 years of age. Onset is usually earlier for men compared to women. Common symptoms include abdominal pain, weakness, lethargy, and unintended weight loss. Without treatment, classic hereditary hemochromatosis can progress to cause serious, life-threatening complications including failure of affected organs.There are several different disorders associated with excess iron accumulation in the body. Collectively, these different disorders are grouped under the name iron overload disorders. These disorders are caused by mutations to different genes and have different clinical presentations. Classic hereditary hemochromatosis is caused by mutations of the HFE gene. This report primarily deals with classic hereditary hemochromatosis caused by mutation of the HFE gene. | 277 | Classic Hereditary Hemochromatosis |
nord_277_1 | Symptoms of Classic Hereditary Hemochromatosis | The symptoms of classic hereditary hemochromatosis develop gradually over many years because of the excess accumulation of iron in the body. Symptoms usually become apparent at some point between 40-60 years of age, but may develop early or later. Symptoms rarely develop before 20 years of age. The specific symptoms that occur may vary depending upon the specific organs affected. The severity of the disorder may also vary. Some individuals may have mild, undetected cases, while others have serious complications including organ failure.It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.Common early symptoms of classic hereditary hemochromatosis include joint inflammation and pain (arthritis) especially in the small joints of the fingers, fatigue, weakness, abdominal pain, unintended weight loss, and an abnormally enlarged liver (hepatomegaly). An abnormally enlarged spleen (splenomegaly) may also occur.Additional symptoms occur depending on the specific organs involved. In classic hereditary hemochromatosis the liver, pancreas, heart, and skin are most commonly affected and (if left untreated) can potentially lead to serious complications.Liver abnormalities associated with classic hereditary hemochromatosis include hepatomegaly, and scarring of the liver (cirrhosis), high blood pressure of the branches of the portal vein (portal hypertension), which is the main vein that carries blood from the intestines to the liver. Liver disease can eventually progress to cause liver failure. Early on, some affected individuals may have abnormal liver function tests (e.g., elevated liver enzymes) in the absence of any observable clinical signs. Individuals with classic hereditary hemochromatosis are at a greater risk of developing liver cancer than the general population. A specific form of liver cancer potentially associated with classic hereditary hemochromatosis is hepatocellular carcinoma.Some HH patients have type 2 diabetes with insulin resistance and high serum insulin. It has been rare to document low serum insulin dependent diabetes in hemochromatosis. In population based studies, there has been no evidence that diabetes is increased in affected individuals who have two copies of the C282Y mutation in the HFE gene.Individuals with classic hereditary hemochromatosis may experience a variety of heart abnormalities including irregular heart rhythms, enlargement of the heart and disease of the heart muscle (cardiomyopathy). Eventually, affected individuals may experience a limited ability to circulate blood to the lungs and the rest of the body resulting in fluid build-up in the heart, lungs and various body tissues (congestive heart failure).Progressive darkening of patches of skin (increased skin pigmentation), sometimes referred to as bronzing, is another common finding of classic hereditary hemochromatosis. This condition occurs due to the accumulation of melanin in the skin.Some men with classic hereditary hemochromatosis may also have underactive testes and some women may have underactive ovaries (hypogonadism). In such cases, the testes and ovaries fail to produce sufficient sex hormones. The pituitary gland may also be affected in individuals with classic hereditary hemochromatosis. In some individuals, the pituitary may fail to produce sufficient amounts of some or all of the hormones it normal produces (hypopituitarism). Hypopituitarism can cause a wide variety of symptoms including fatigue, headaches and abdominal pain. As a result of hormonal deficiencies affected males may experience impotence and affected women may experience loss of menstrual periods (amenorrhea) or early menopause. Some affected individuals may also have loss of interest in sex (decreased libido).Additional symptoms have been associated with classic hereditary hemochromatosis. These symptoms are common to all individuals as they age. It is not known whether classic hereditary hemochromatosis makes people more susceptible to such symptoms. Such symptoms include loss of the cartilage that normally cushions joints (osteoarthritis), general loss of bone mass (osteoporosis) that can predispose individuals to fractures, an underactive of the thyroid gland (hypothyroidism), shortness of breath, and loss of body hair (outside of normal male pattern baldness). | Symptoms of Classic Hereditary Hemochromatosis. The symptoms of classic hereditary hemochromatosis develop gradually over many years because of the excess accumulation of iron in the body. Symptoms usually become apparent at some point between 40-60 years of age, but may develop early or later. Symptoms rarely develop before 20 years of age. The specific symptoms that occur may vary depending upon the specific organs affected. The severity of the disorder may also vary. Some individuals may have mild, undetected cases, while others have serious complications including organ failure.It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.Common early symptoms of classic hereditary hemochromatosis include joint inflammation and pain (arthritis) especially in the small joints of the fingers, fatigue, weakness, abdominal pain, unintended weight loss, and an abnormally enlarged liver (hepatomegaly). An abnormally enlarged spleen (splenomegaly) may also occur.Additional symptoms occur depending on the specific organs involved. In classic hereditary hemochromatosis the liver, pancreas, heart, and skin are most commonly affected and (if left untreated) can potentially lead to serious complications.Liver abnormalities associated with classic hereditary hemochromatosis include hepatomegaly, and scarring of the liver (cirrhosis), high blood pressure of the branches of the portal vein (portal hypertension), which is the main vein that carries blood from the intestines to the liver. Liver disease can eventually progress to cause liver failure. Early on, some affected individuals may have abnormal liver function tests (e.g., elevated liver enzymes) in the absence of any observable clinical signs. Individuals with classic hereditary hemochromatosis are at a greater risk of developing liver cancer than the general population. A specific form of liver cancer potentially associated with classic hereditary hemochromatosis is hepatocellular carcinoma.Some HH patients have type 2 diabetes with insulin resistance and high serum insulin. It has been rare to document low serum insulin dependent diabetes in hemochromatosis. In population based studies, there has been no evidence that diabetes is increased in affected individuals who have two copies of the C282Y mutation in the HFE gene.Individuals with classic hereditary hemochromatosis may experience a variety of heart abnormalities including irregular heart rhythms, enlargement of the heart and disease of the heart muscle (cardiomyopathy). Eventually, affected individuals may experience a limited ability to circulate blood to the lungs and the rest of the body resulting in fluid build-up in the heart, lungs and various body tissues (congestive heart failure).Progressive darkening of patches of skin (increased skin pigmentation), sometimes referred to as bronzing, is another common finding of classic hereditary hemochromatosis. This condition occurs due to the accumulation of melanin in the skin.Some men with classic hereditary hemochromatosis may also have underactive testes and some women may have underactive ovaries (hypogonadism). In such cases, the testes and ovaries fail to produce sufficient sex hormones. The pituitary gland may also be affected in individuals with classic hereditary hemochromatosis. In some individuals, the pituitary may fail to produce sufficient amounts of some or all of the hormones it normal produces (hypopituitarism). Hypopituitarism can cause a wide variety of symptoms including fatigue, headaches and abdominal pain. As a result of hormonal deficiencies affected males may experience impotence and affected women may experience loss of menstrual periods (amenorrhea) or early menopause. Some affected individuals may also have loss of interest in sex (decreased libido).Additional symptoms have been associated with classic hereditary hemochromatosis. These symptoms are common to all individuals as they age. It is not known whether classic hereditary hemochromatosis makes people more susceptible to such symptoms. Such symptoms include loss of the cartilage that normally cushions joints (osteoarthritis), general loss of bone mass (osteoporosis) that can predispose individuals to fractures, an underactive of the thyroid gland (hypothyroidism), shortness of breath, and loss of body hair (outside of normal male pattern baldness). | 277 | Classic Hereditary Hemochromatosis |
nord_277_2 | Causes of Classic Hereditary Hemochromatosis | Classic hereditary hemochromatosis is caused by changes (mutations) of the HFE gene. This mutation is inherited in an autosomal recessive pattern. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25 percent. The risk is the same for males and females.Hepcidin is a specialized protein that is the primary regulator of iron absorption in the body, including regulating the uptake of iron by the gastrointestinal tract. Mutations of the HFE gene result in the deficient levels of functional hepcidin in the body, which in turn leads to excess absorption of iron in the gastrointestinal tract. Iron is a critical mineral that is found in all cells of the body and is essential for the body to function and grow properly. Iron is found many types of food including red meat, poultry, eggs and vegetables. Iron levels must remain in a specific range within the body, otherwise they can cause anemia (due to low iron levels) or damage affected organs (due to high iron levels). Excess levels of iron eventually accumulates in the tissues and organs of the body, potentially damaging the function of affected organs and ultimately leading to the characteristic symptoms of classic hereditary hemochromatosis.Several different mutations of the HFE gene have been identified as causing classic hereditary hemochromatosis. Most individuals with classic hereditary hemochromatosis inherit two copies of a specific HFE gene mutation known as “C282Y”. Although most people who inherit two C282Y mutations develop classic hereditary hemochromatosis, studies suggest that up to 30 percent of those with the mutations do not develop associated findings (variable penetrance and expressivity).Some other individuals with classic hereditary hemochromatosis inherit one copy of the C282Y mutation and one copy of a different HFE gene mutation known as “H63D” (compound heterozygotes for C282Y/H63D). Reports suggest that the presence of the second (i.e., H63D) mutation appears to predispose individuals to expression of the disease in some cases. However, the disorder does not appear to develop in those who inherit two copies of the H63D mutation (i.e., and no copies of the C282Y mutation). Therefore, the role of H63D mutations in causing or contributing to classic hereditary hemochromatosis is not fully understood.Because of the highly variable nature of classic hereditary hemochromatosis, it is likely that additional factors, including genetic, physiological and environmental ones, all play a role in the development and progression of the disorder in each individual. More research is necessary to determine the exact underlying mechanisms that are involved in the development and progression of classic hereditary hemochromatosis. | Causes of Classic Hereditary Hemochromatosis. Classic hereditary hemochromatosis is caused by changes (mutations) of the HFE gene. This mutation is inherited in an autosomal recessive pattern. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25 percent. The risk is the same for males and females.Hepcidin is a specialized protein that is the primary regulator of iron absorption in the body, including regulating the uptake of iron by the gastrointestinal tract. Mutations of the HFE gene result in the deficient levels of functional hepcidin in the body, which in turn leads to excess absorption of iron in the gastrointestinal tract. Iron is a critical mineral that is found in all cells of the body and is essential for the body to function and grow properly. Iron is found many types of food including red meat, poultry, eggs and vegetables. Iron levels must remain in a specific range within the body, otherwise they can cause anemia (due to low iron levels) or damage affected organs (due to high iron levels). Excess levels of iron eventually accumulates in the tissues and organs of the body, potentially damaging the function of affected organs and ultimately leading to the characteristic symptoms of classic hereditary hemochromatosis.Several different mutations of the HFE gene have been identified as causing classic hereditary hemochromatosis. Most individuals with classic hereditary hemochromatosis inherit two copies of a specific HFE gene mutation known as “C282Y”. Although most people who inherit two C282Y mutations develop classic hereditary hemochromatosis, studies suggest that up to 30 percent of those with the mutations do not develop associated findings (variable penetrance and expressivity).Some other individuals with classic hereditary hemochromatosis inherit one copy of the C282Y mutation and one copy of a different HFE gene mutation known as “H63D” (compound heterozygotes for C282Y/H63D). Reports suggest that the presence of the second (i.e., H63D) mutation appears to predispose individuals to expression of the disease in some cases. However, the disorder does not appear to develop in those who inherit two copies of the H63D mutation (i.e., and no copies of the C282Y mutation). Therefore, the role of H63D mutations in causing or contributing to classic hereditary hemochromatosis is not fully understood.Because of the highly variable nature of classic hereditary hemochromatosis, it is likely that additional factors, including genetic, physiological and environmental ones, all play a role in the development and progression of the disorder in each individual. More research is necessary to determine the exact underlying mechanisms that are involved in the development and progression of classic hereditary hemochromatosis. | 277 | Classic Hereditary Hemochromatosis |
nord_277_3 | Affects of Classic Hereditary Hemochromatosis | The exact prevalence of classic hereditary hemochromatosis is unknown. The disorder is thought to be the most common autosomal recessive disorder in Caucasian populations. In individuals of Northern European descent, the prevalence is estimated to be as high as 1 in 227 individuals in the general population. Approximately 10 percent of the Caucasian population is estimated to be a “carrier” for classic hereditary hemochromatosis (i.e., has one mutation of the HFE gene). Some individuals who have genetic mutations that cause classic hereditary hemochromatosis do not develop symptoms of the disorder, making it difficult to determine the true frequency of classic hereditary hemochromatosis in the general population.Hemochromatosis is seen more often (and tends to be more severe) in men than women. Some researchers believe that this may be due, in part, to a woman’s monthly blood loss through menstruation. Consequently, iron accumulation is slower in women than men, and the average age of diagnosis for women is approximately 10 years later than in men (usually after menopause). | Affects of Classic Hereditary Hemochromatosis. The exact prevalence of classic hereditary hemochromatosis is unknown. The disorder is thought to be the most common autosomal recessive disorder in Caucasian populations. In individuals of Northern European descent, the prevalence is estimated to be as high as 1 in 227 individuals in the general population. Approximately 10 percent of the Caucasian population is estimated to be a “carrier” for classic hereditary hemochromatosis (i.e., has one mutation of the HFE gene). Some individuals who have genetic mutations that cause classic hereditary hemochromatosis do not develop symptoms of the disorder, making it difficult to determine the true frequency of classic hereditary hemochromatosis in the general population.Hemochromatosis is seen more often (and tends to be more severe) in men than women. Some researchers believe that this may be due, in part, to a woman’s monthly blood loss through menstruation. Consequently, iron accumulation is slower in women than men, and the average age of diagnosis for women is approximately 10 years later than in men (usually after menopause). | 277 | Classic Hereditary Hemochromatosis |
nord_277_4 | Related disorders of Classic Hereditary Hemochromatosis | Symptoms of the following disorders can be similar to those of classic hereditary hemochromatosis. 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 juvenile hemochromatosis, atransferrinemia, neonatal hemochromatosis, and African iron overload disease. Hemochromatosis has been separated into four distinct disorders – hereditary (classic) hemochromatosis, also known as HFE-related hemochromatosis or hemochromatosis type I, hemochromatosis type 2 (juvenile hemochromatosis), hemochromatosis type 3, also known as TFR-related hemochromatosis; and hemochromatosis type 4, also known as ferroportin disease. The specific symptoms related to these disorders 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.)Secondary hemochromatosis refers to a group of disorders in which there is an increased intake and accumulation of iron in the body due to a known (primary) cause. Examples of secondary hemochromatosis include thalassemia major, sideroblastic anemia, chronic hemolytic anemias, Friedreich ataxia, and aceruloplasminemia. Individuals with chronic alcoholic liver disease may also develop iron overload. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | Related disorders of Classic Hereditary Hemochromatosis. Symptoms of the following disorders can be similar to those of classic hereditary hemochromatosis. 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 juvenile hemochromatosis, atransferrinemia, neonatal hemochromatosis, and African iron overload disease. Hemochromatosis has been separated into four distinct disorders – hereditary (classic) hemochromatosis, also known as HFE-related hemochromatosis or hemochromatosis type I, hemochromatosis type 2 (juvenile hemochromatosis), hemochromatosis type 3, also known as TFR-related hemochromatosis; and hemochromatosis type 4, also known as ferroportin disease. The specific symptoms related to these disorders 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.)Secondary hemochromatosis refers to a group of disorders in which there is an increased intake and accumulation of iron in the body due to a known (primary) cause. Examples of secondary hemochromatosis include thalassemia major, sideroblastic anemia, chronic hemolytic anemias, Friedreich ataxia, and aceruloplasminemia. Individuals with chronic alcoholic liver disease may also develop iron overload. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | 277 | Classic Hereditary Hemochromatosis |
nord_277_5 | Diagnosis of Classic Hereditary Hemochromatosis | A diagnosis of classic hereditary hemochromatosis is made based upon the identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests.According to the medical literature, early diagnosis based on clinical features can be difficult since some individuals may have iron overload of relatively moderate degree or short duration with only certain or no obvious characteristic symptoms. Therefore, it is important that the disorder is considered for any individuals with unexplained enlargement of the liver (hepatomegaly), scarring of the liver (cirrhosis), increased pigmentation of the skin, loss of sexual drive (libido), disease of the heart muscle (cardiomyopathy), diabetes mellitus, or joint inflammation (arthritis).When the disorder is suspected, blood tests are performed to detect abnormally increased levels of iron in the blood; elevated blood levels of an iron compound that is used as an indicator of the body’s iron stores (serum ferritin levels), and increased transferrin saturation. Transferrin is a protein involved in the transport of iron from the intestine into the bloodstream.A liver biopsy (needle biopsy through the skin and microscopic study of liver tissue) was once used to help obtain a diagnosis of classic hereditary hemochromatosis. However, liver biopsy has shifted from a diagnostic test to a prognostic test in typical C282Y homozygotes. In addition, a liver biopsy may be useful in establishing the presence and extent of cirrhosis.In addition, specialized imaging tests such as magnetic resonance imaging (MRI) may reveal increased density of the liver due to excess iron accumulation. MRI uses a magnetic field and radio waves to provide detailed cross-sectional images of certain organs and tissues such as the liver.A diagnosis of classic hereditary hemochromatosis can be confirmed by molecular genetic testing, which can detect characteristic mutations of the HFE gene that can cause the disorder.Family members of those with a confirmed diagnosis of classic hereditary hemochromatosis should also undergo diagnostic evaluation to help detect or rule out the disorder. | Diagnosis of Classic Hereditary Hemochromatosis. A diagnosis of classic hereditary hemochromatosis is made based upon the identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests.According to the medical literature, early diagnosis based on clinical features can be difficult since some individuals may have iron overload of relatively moderate degree or short duration with only certain or no obvious characteristic symptoms. Therefore, it is important that the disorder is considered for any individuals with unexplained enlargement of the liver (hepatomegaly), scarring of the liver (cirrhosis), increased pigmentation of the skin, loss of sexual drive (libido), disease of the heart muscle (cardiomyopathy), diabetes mellitus, or joint inflammation (arthritis).When the disorder is suspected, blood tests are performed to detect abnormally increased levels of iron in the blood; elevated blood levels of an iron compound that is used as an indicator of the body’s iron stores (serum ferritin levels), and increased transferrin saturation. Transferrin is a protein involved in the transport of iron from the intestine into the bloodstream.A liver biopsy (needle biopsy through the skin and microscopic study of liver tissue) was once used to help obtain a diagnosis of classic hereditary hemochromatosis. However, liver biopsy has shifted from a diagnostic test to a prognostic test in typical C282Y homozygotes. In addition, a liver biopsy may be useful in establishing the presence and extent of cirrhosis.In addition, specialized imaging tests such as magnetic resonance imaging (MRI) may reveal increased density of the liver due to excess iron accumulation. MRI uses a magnetic field and radio waves to provide detailed cross-sectional images of certain organs and tissues such as the liver.A diagnosis of classic hereditary hemochromatosis can be confirmed by molecular genetic testing, which can detect characteristic mutations of the HFE gene that can cause the disorder.Family members of those with a confirmed diagnosis of classic hereditary hemochromatosis should also undergo diagnostic evaluation to help detect or rule out the disorder. | 277 | Classic Hereditary Hemochromatosis |
nord_277_6 | Therapies of Classic Hereditary Hemochromatosis | TreatmentClassic hereditary hemochromatosis is treated by removing excess iron from the body. Since much of the iron in the body is present in red blood cells, therapy involves the regular removal of blood via a vein (phlebotomy) to reduce excess body iron. A phlebotomy is a simple and safe procedure. Initially, phlebotomy may be required about once or twice a week. Weekly phlebotomies may continue to be necessary for up to approximately two years. Once ferritin and transferrin saturation levels stabilize, phlebotomy may then be conducted periodically as required (e.g., approximately once every three months for men and once or twice a year for women), based upon ongoing assessment of iron storage levels. Generally, men require the removal of more blood than women.There is no agreement in the medical literature as to whether individuals who have abnormal laboratory tests (e.g., elevated serum ferritin concentration), but do not have associated clinical symptoms require treatment with phlebotomy. Because the disease is believed to run a benign course in many individuals who only have abnormal lab tests, some researchers prefer to hold off on phlebotomies and instead simply conduct regular follow up testing and observation.However, treatment to remove excess iron in individuals who already have clinical symptoms of classic hereditary hemochromatosis is crucial to help to prevent chronic disease, organ damage, and potentially life-threatening complications.In rare cases where phlebotomy therapy is not possible (e.g., in individuals with anemia, cardiac disease or advanced cirrhosis), the drug deferoxamine may be used to help reduce excess levels of iron in the body. Deferoxamine is an iron chelator, a drug that binds to iron in the body allowing it to be dissolved in water and excreted from the body through the kidneys. Another oral iron chelator, exjade, has been studied in classic hereditary hemochromatosis.Additional treatment for this disorder is symptomatic and supportive. Supportive therapy may be necessary for individuals who experience organ damage due to excess iron levels. For example, individuals with end stage liver disease may require a liver transplant.Genetic counseling is recommended for affected individuals and their families. | Therapies of Classic Hereditary Hemochromatosis. TreatmentClassic hereditary hemochromatosis is treated by removing excess iron from the body. Since much of the iron in the body is present in red blood cells, therapy involves the regular removal of blood via a vein (phlebotomy) to reduce excess body iron. A phlebotomy is a simple and safe procedure. Initially, phlebotomy may be required about once or twice a week. Weekly phlebotomies may continue to be necessary for up to approximately two years. Once ferritin and transferrin saturation levels stabilize, phlebotomy may then be conducted periodically as required (e.g., approximately once every three months for men and once or twice a year for women), based upon ongoing assessment of iron storage levels. Generally, men require the removal of more blood than women.There is no agreement in the medical literature as to whether individuals who have abnormal laboratory tests (e.g., elevated serum ferritin concentration), but do not have associated clinical symptoms require treatment with phlebotomy. Because the disease is believed to run a benign course in many individuals who only have abnormal lab tests, some researchers prefer to hold off on phlebotomies and instead simply conduct regular follow up testing and observation.However, treatment to remove excess iron in individuals who already have clinical symptoms of classic hereditary hemochromatosis is crucial to help to prevent chronic disease, organ damage, and potentially life-threatening complications.In rare cases where phlebotomy therapy is not possible (e.g., in individuals with anemia, cardiac disease or advanced cirrhosis), the drug deferoxamine may be used to help reduce excess levels of iron in the body. Deferoxamine is an iron chelator, a drug that binds to iron in the body allowing it to be dissolved in water and excreted from the body through the kidneys. Another oral iron chelator, exjade, has been studied in classic hereditary hemochromatosis.Additional treatment for this disorder is symptomatic and supportive. Supportive therapy may be necessary for individuals who experience organ damage due to excess iron levels. For example, individuals with end stage liver disease may require a liver transplant.Genetic counseling is recommended for affected individuals and their families. | 277 | Classic Hereditary Hemochromatosis |
nord_278_0 | Overview of Classic Infantile CLN1 Disease | SummaryClassic infantile CLN1 disease is a rare genetic disorder with an onset of symptoms between 6 and 24 months of age. CLN1 disease is characterized by delays in reaching developmental milestones (developmental delays), twitching or jerking of muscles (myoclonic jerks), seizures, and mild to moderate intellectual disability. As children age, the psychomotor abilities (abilities that require coordination of muscular and mental activity) will deteriorate. Progressive vision loss leading to blindness can also occur. The severe form of CLN1 disease is often fatal during childhood. However, some children do not become ill until later because their genetic defect does not completely abolish the function of the gene and their disease can appear very much like juvenile CLN3 disease.Classic infantile CLN1 disease belongs to a group of progressive degenerative neurometabolic disorders known as the neuronal ceroid lipofuscinoses (NCLs). These disorders share certain similar symptoms and are distinguished in part by the age at which such symptoms appear. Classic infantile CLN1 disease was previously called infantile neuronal ceroid lipofuscinosis or Santavuori disease. The NCLs are characterized by abnormal accumulation of certain fatty, granular substances (i.e., pigmented lipids [lipopigments] ceroid and lipofuscin) within nerve cells (neurons) of the brain as well as other tissues of the body that may result in progressive deterioration (atrophy) of certain areas of the brain, neurological impairment, and other characteristic symptoms and physical findings.The neuronal ceroid lipofuscinoses are further classified as lysosomal storage diseases. Lysosomal storage diseases are inherited metabolic diseases that are characterized by an abnormal build-up of various toxic materials in the body's cells because of enzyme deficiencies. There are more than 50 of these disorders altogether, and they may affect different parts of the body, including the skeleton, brain, skin, heart, and central nervous system. New lysosomal storage disorders continue to be identified. While clinical trials are in progress on possible treatments for some of these diseases, there is currently no approved treatment for many lysosomal storage diseases. | Overview of Classic Infantile CLN1 Disease. SummaryClassic infantile CLN1 disease is a rare genetic disorder with an onset of symptoms between 6 and 24 months of age. CLN1 disease is characterized by delays in reaching developmental milestones (developmental delays), twitching or jerking of muscles (myoclonic jerks), seizures, and mild to moderate intellectual disability. As children age, the psychomotor abilities (abilities that require coordination of muscular and mental activity) will deteriorate. Progressive vision loss leading to blindness can also occur. The severe form of CLN1 disease is often fatal during childhood. However, some children do not become ill until later because their genetic defect does not completely abolish the function of the gene and their disease can appear very much like juvenile CLN3 disease.Classic infantile CLN1 disease belongs to a group of progressive degenerative neurometabolic disorders known as the neuronal ceroid lipofuscinoses (NCLs). These disorders share certain similar symptoms and are distinguished in part by the age at which such symptoms appear. Classic infantile CLN1 disease was previously called infantile neuronal ceroid lipofuscinosis or Santavuori disease. The NCLs are characterized by abnormal accumulation of certain fatty, granular substances (i.e., pigmented lipids [lipopigments] ceroid and lipofuscin) within nerve cells (neurons) of the brain as well as other tissues of the body that may result in progressive deterioration (atrophy) of certain areas of the brain, neurological impairment, and other characteristic symptoms and physical findings.The neuronal ceroid lipofuscinoses are further classified as lysosomal storage diseases. Lysosomal storage diseases are inherited metabolic diseases that are characterized by an abnormal build-up of various toxic materials in the body's cells because of enzyme deficiencies. There are more than 50 of these disorders altogether, and they may affect different parts of the body, including the skeleton, brain, skin, heart, and central nervous system. New lysosomal storage disorders continue to be identified. While clinical trials are in progress on possible treatments for some of these diseases, there is currently no approved treatment for many lysosomal storage diseases. | 278 | Classic Infantile CLN1 Disease |
nord_278_1 | Symptoms of Classic Infantile CLN1 Disease | The signs and symptoms of classic infantile CLN1 disease usually become apparent between 2 and 24 months of age. Infants will develop normally initially, but then become to regress. Their mental and motor development levels off and then begins to decline. Many infants are never able to speak or walk. However, some children do not become ill until later because they still have residual enzyme activity. Initial symptoms can include signs of intellectual and motor decline including delays in reaching developmental milestones (developmental delays), twitching or jerking of muscles (myoclonic jerks), and seizures. Infants may fail to gain weight and grow as the expected rate (failure to thrive) and may have diminished muscle tone (hypotonia). They may be restless, irritable and have difficulty sleeping through the night. Some infants exhibit microcephaly, a condition that indicates that a child’s head circumference is smaller than would otherwise be expected based on age and gender. Affected infants and children may also exhibit rhythmic, repetitive, predictable movements of their hands called hand stereotypies. As children age, the psychomotor abilities (abilities that require coordination of muscular and mental activity) will deteriorate. Infants and children may lose interest in playing. Mild to moderate intellectual disability may be present. Some children will develop spasticity, where the muscles become tight and stiff and difficult to move and sometimes painful. Progressive vision loss leading to blindness can also occur. In infants and children with the severe form, the disorder is often fatal anywhere between the ages of 2 to 9. | Symptoms of Classic Infantile CLN1 Disease. The signs and symptoms of classic infantile CLN1 disease usually become apparent between 2 and 24 months of age. Infants will develop normally initially, but then become to regress. Their mental and motor development levels off and then begins to decline. Many infants are never able to speak or walk. However, some children do not become ill until later because they still have residual enzyme activity. Initial symptoms can include signs of intellectual and motor decline including delays in reaching developmental milestones (developmental delays), twitching or jerking of muscles (myoclonic jerks), and seizures. Infants may fail to gain weight and grow as the expected rate (failure to thrive) and may have diminished muscle tone (hypotonia). They may be restless, irritable and have difficulty sleeping through the night. Some infants exhibit microcephaly, a condition that indicates that a child’s head circumference is smaller than would otherwise be expected based on age and gender. Affected infants and children may also exhibit rhythmic, repetitive, predictable movements of their hands called hand stereotypies. As children age, the psychomotor abilities (abilities that require coordination of muscular and mental activity) will deteriorate. Infants and children may lose interest in playing. Mild to moderate intellectual disability may be present. Some children will develop spasticity, where the muscles become tight and stiff and difficult to move and sometimes painful. Progressive vision loss leading to blindness can also occur. In infants and children with the severe form, the disorder is often fatal anywhere between the ages of 2 to 9. | 278 | Classic Infantile CLN1 Disease |
nord_278_2 | Causes of Classic Infantile CLN1 Disease | Classic infantile CLN1 disease is caused by an alteration in the PPT1 gene (designated CLN1). Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.The PPT1 gene contains instructions for creating the enzyme palmitoyl-protein thioesterase 1. This enzyme is essential for the proper function of lysosomes. Lysosomes are the primary digestive units within cells. Enzymes within lysosomes break down or “digest” nutrients, such as fats and carbohydrates. In the lysosomal storage disorders, deficiency or improper functioning of particular lysosomal enzymes may lead to an abnormal accumulation of certain complex compounds consisting of fatty materials and/or carbohydrates within the cells of particular tissues of the body. Researchers suspect that classic infantile CLN1 disease is caused by alterations within the cell so that the body is unable to break down and recycle substances such as fats, and their associated sugars and proteins in the normal way in lysosomes. Some of these fats, sugars, and proteins then appear to form the lipopigments that accumulate in nerve and other tissue alongside the symptoms associated with this disorder. Although these substances accumulate in most cells, brain cells are affected first.The gene alterations that cause classic infantile CLN1 disease are inherited in an autosomal recessive manner. 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. | Causes of Classic Infantile CLN1 Disease. Classic infantile CLN1 disease is caused by an alteration in the PPT1 gene (designated CLN1). Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.The PPT1 gene contains instructions for creating the enzyme palmitoyl-protein thioesterase 1. This enzyme is essential for the proper function of lysosomes. Lysosomes are the primary digestive units within cells. Enzymes within lysosomes break down or “digest” nutrients, such as fats and carbohydrates. In the lysosomal storage disorders, deficiency or improper functioning of particular lysosomal enzymes may lead to an abnormal accumulation of certain complex compounds consisting of fatty materials and/or carbohydrates within the cells of particular tissues of the body. Researchers suspect that classic infantile CLN1 disease is caused by alterations within the cell so that the body is unable to break down and recycle substances such as fats, and their associated sugars and proteins in the normal way in lysosomes. Some of these fats, sugars, and proteins then appear to form the lipopigments that accumulate in nerve and other tissue alongside the symptoms associated with this disorder. Although these substances accumulate in most cells, brain cells are affected first.The gene alterations that cause classic infantile CLN1 disease are inherited in an autosomal recessive manner. 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. | 278 | Classic Infantile CLN1 Disease |
nord_278_3 | Affects of Classic Infantile CLN1 Disease | Classic infantile CLN1 disease affects males and females in equal numbers. In the United States, classic infantile CLN1 disease along with other forms of neuronal ceroid lipofuscinosis occurs in approximately three in 100,000 live births. Classic infantile CLN1 disease occurs with greater frequency in Finland where its prevalence is estimated to be 1 in 190,000. | Affects of Classic Infantile CLN1 Disease. Classic infantile CLN1 disease affects males and females in equal numbers. In the United States, classic infantile CLN1 disease along with other forms of neuronal ceroid lipofuscinosis occurs in approximately three in 100,000 live births. Classic infantile CLN1 disease occurs with greater frequency in Finland where its prevalence is estimated to be 1 in 190,000. | 278 | Classic Infantile CLN1 Disease |
nord_278_4 | Related disorders of Classic Infantile CLN1 Disease | Symptoms of the following disorders can be similar to those of classic infantile CLN1 disease. Comparisons may be useful for a differential diagnosis.CLN2 disease includes the classic late infantile form of neuronal ceroid lipofuscinosis (LINCL). The onset of symptoms associated with the disorder typically begins between the ages of two to four years of age, but some children do not become ill until an older age. In this variant form, symptoms tend to appear later, at approximately five to seven years of age, and tend to progress more slowly than in the classic form of the disorder. Juvenile CLN3 disease, a rare genetic disorder, belongs to a group of progressive degenerative neurometabolic disorders known as the neuronal ceroid lipofuscinoses. Juvenile CLN3 disease was previously called juvenile neuronal ceroid lipofuscinoses (NCLs). The symptoms of juvenile CLN3 disease usually become apparent between 5 and 15 years of age when progressive loss of vision, seizures, and progressive neurological degeneration develop. In some individuals, initial symptoms may be less obvious and include clumsiness, balance problems and behavioral or personality changes. Juvenile CLN3 disease is caused by changes (mutations) of the CLN3 gene and is inherited as an autosomal recessive trait. It is the most common form of NCL, is found worldwide, and is found particularly in families of Northern European or Scandinavian ancestry. (For more information, choose “juvenile CLN3” as your search term in the Rare Disease Database.)Lysosomal storage diseases are inherited metabolic diseases that are characterized by an abnormal build-up of various toxic materials in the body’s cells because of enzyme deficiencies. There are more than 50 of these disorders altogether, and they may affect different parts of the body, including the skeleton, brain, skin, heart, and central nervous system. New lysosomal storage disorders continue to be identified. While clinical trials are in progress on possible treatments for some of these diseases, there is currently no approved treatment for many lysosomal storage diseases. (For more information on this disorder, choose “lysosomal” as your search term in the Rare Disease Database.)Rett syndrome is a progressive neurodevelopmental disorder that almost exclusively affects females. Only in rare cases are males affected. Infants with Rett syndrome generally develop normally for about 7 to 18 months after birth. At this point, they lose previously acquired skills (developmental regression) such as purposeful hand movements and the ability to communicate. Additional abnormalities occur including impaired control of voluntary movements (ataxia) and the development of distinctive, uncontrolled hand movements such as hand clapping or rubbing. Some children also have slowing of head growth (acquired microcephaly), Affected children often develop autistic-like behaviors, breathing irregularities, feeding and swallowing difficulties, growth retardation, and seizures. Most Rett syndrome cases are caused by identifiable mutations of the MECP2 gene on the X chromosome and can present with a wide range of disability ranging from mild to severe. The course and severity of Rett syndrome is determined by the location, type and severity of the MECP2 mutation and the process of random X-inactivation (see Causes section below). Therefore, two girls of the same age with the same mutation can appear significantly different. (For more information on this disorder, choose “Rett” as your search term in the Rare Disease Database.)Classic infantile CLN1 disease should also be differentiated from other progressive neurological diseases that are present from birth. Such disorders include acid sphingomyelinase deficiency (Niemann-Pick diseases A and B), progressive leukodystrophies such as Krabbe disease, hexosaminidase A deficiency, Leigh syndrome and other mitochondrial disorders. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | Related disorders of Classic Infantile CLN1 Disease. Symptoms of the following disorders can be similar to those of classic infantile CLN1 disease. Comparisons may be useful for a differential diagnosis.CLN2 disease includes the classic late infantile form of neuronal ceroid lipofuscinosis (LINCL). The onset of symptoms associated with the disorder typically begins between the ages of two to four years of age, but some children do not become ill until an older age. In this variant form, symptoms tend to appear later, at approximately five to seven years of age, and tend to progress more slowly than in the classic form of the disorder. Juvenile CLN3 disease, a rare genetic disorder, belongs to a group of progressive degenerative neurometabolic disorders known as the neuronal ceroid lipofuscinoses. Juvenile CLN3 disease was previously called juvenile neuronal ceroid lipofuscinoses (NCLs). The symptoms of juvenile CLN3 disease usually become apparent between 5 and 15 years of age when progressive loss of vision, seizures, and progressive neurological degeneration develop. In some individuals, initial symptoms may be less obvious and include clumsiness, balance problems and behavioral or personality changes. Juvenile CLN3 disease is caused by changes (mutations) of the CLN3 gene and is inherited as an autosomal recessive trait. It is the most common form of NCL, is found worldwide, and is found particularly in families of Northern European or Scandinavian ancestry. (For more information, choose “juvenile CLN3” as your search term in the Rare Disease Database.)Lysosomal storage diseases are inherited metabolic diseases that are characterized by an abnormal build-up of various toxic materials in the body’s cells because of enzyme deficiencies. There are more than 50 of these disorders altogether, and they may affect different parts of the body, including the skeleton, brain, skin, heart, and central nervous system. New lysosomal storage disorders continue to be identified. While clinical trials are in progress on possible treatments for some of these diseases, there is currently no approved treatment for many lysosomal storage diseases. (For more information on this disorder, choose “lysosomal” as your search term in the Rare Disease Database.)Rett syndrome is a progressive neurodevelopmental disorder that almost exclusively affects females. Only in rare cases are males affected. Infants with Rett syndrome generally develop normally for about 7 to 18 months after birth. At this point, they lose previously acquired skills (developmental regression) such as purposeful hand movements and the ability to communicate. Additional abnormalities occur including impaired control of voluntary movements (ataxia) and the development of distinctive, uncontrolled hand movements such as hand clapping or rubbing. Some children also have slowing of head growth (acquired microcephaly), Affected children often develop autistic-like behaviors, breathing irregularities, feeding and swallowing difficulties, growth retardation, and seizures. Most Rett syndrome cases are caused by identifiable mutations of the MECP2 gene on the X chromosome and can present with a wide range of disability ranging from mild to severe. The course and severity of Rett syndrome is determined by the location, type and severity of the MECP2 mutation and the process of random X-inactivation (see Causes section below). Therefore, two girls of the same age with the same mutation can appear significantly different. (For more information on this disorder, choose “Rett” as your search term in the Rare Disease Database.)Classic infantile CLN1 disease should also be differentiated from other progressive neurological diseases that are present from birth. Such disorders include acid sphingomyelinase deficiency (Niemann-Pick diseases A and B), progressive leukodystrophies such as Krabbe disease, hexosaminidase A deficiency, Leigh syndrome and other mitochondrial disorders. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | 278 | Classic Infantile CLN1 Disease |
nord_278_5 | Diagnosis of Classic Infantile CLN1 Disease | A diagnosis of classic infantile CLN1 disease may be based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic physical findings, and a variety of specialized tests including enzyme assays and molecular genetic testing. Clinical Testing and Workup
An enzyme assay is a test that measures the activity of a specific enzyme. For infantile CLN1 disease, doctors will look for the activity of the enzyme palmitoyl-protein thioesterase 1 in white blood cells (leukocytes), a dried blood sample, or cultured fibroblasts. Cultured fibroblasts are connective tissue cells obtained from a skin sample and grown in a laboratory.Molecular genetic testing can confirm a diagnosis of classic infantile CLN1 disease. Molecular genetic testing looks for alterations (mutations) in the PPT1 gene known to cause the disorder, but is available only as a diagnostic service at specialized laboratories.In some instances, diagnosis may require the microscopic examination (i.e., electron microscopy) and study of the chemical components (histochemical examination) of samples of tissue (biopsy), usually from the skin. The study of such tissue samples reveals abnormal accumulations of deposits (i.e., pigmented lipids [lipopigments] ceroid and lipofuscin) in membrane-bound cavities within the body (cytoplasm) of cells (inclusion bodies). | Diagnosis of Classic Infantile CLN1 Disease. A diagnosis of classic infantile CLN1 disease may be based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic physical findings, and a variety of specialized tests including enzyme assays and molecular genetic testing. Clinical Testing and Workup
An enzyme assay is a test that measures the activity of a specific enzyme. For infantile CLN1 disease, doctors will look for the activity of the enzyme palmitoyl-protein thioesterase 1 in white blood cells (leukocytes), a dried blood sample, or cultured fibroblasts. Cultured fibroblasts are connective tissue cells obtained from a skin sample and grown in a laboratory.Molecular genetic testing can confirm a diagnosis of classic infantile CLN1 disease. Molecular genetic testing looks for alterations (mutations) in the PPT1 gene known to cause the disorder, but is available only as a diagnostic service at specialized laboratories.In some instances, diagnosis may require the microscopic examination (i.e., electron microscopy) and study of the chemical components (histochemical examination) of samples of tissue (biopsy), usually from the skin. The study of such tissue samples reveals abnormal accumulations of deposits (i.e., pigmented lipids [lipopigments] ceroid and lipofuscin) in membrane-bound cavities within the body (cytoplasm) of cells (inclusion bodies). | 278 | Classic Infantile CLN1 Disease |
nord_278_6 | Therapies of Classic Infantile CLN1 Disease | The treatment of classic infantile CLN1 disease is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, specialists who diagnose and treat eye disorders (ophthalmologists), specialists who diagnose and treat disorders of the central nervous system (neurologists), speech pathologists, a medical geneticist, a psychiatrist and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Psychosocial support for the entire family is essential as well. Genetic counseling is of benefit for affected individuals and their families. There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with neuronal ceroid lipofuscinosis. Specific therapies for affected infants includes anti-seizure medications called anti-convulsants and medications that relax the muscles to treat spasticity. Specific medications may be used to treat anxiety and sleep disorders. Myoclonus can be treated by medications called diazepines or valproate. Pain medications including opioids and transdermal fentanyl patches have been recommended. Affected children may benefit from occupational, physical, and speech therapy. Additional medical, social, and/or vocation services including special remedial education may be necessary. Some affected infants may require the insertion of a tube through a small opening in the stomach (gastronomy tube) to ensure they receive sufficient food and nutrition. | Therapies of Classic Infantile CLN1 Disease. The treatment of classic infantile CLN1 disease is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, specialists who diagnose and treat eye disorders (ophthalmologists), specialists who diagnose and treat disorders of the central nervous system (neurologists), speech pathologists, a medical geneticist, a psychiatrist and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Psychosocial support for the entire family is essential as well. Genetic counseling is of benefit for affected individuals and their families. There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with neuronal ceroid lipofuscinosis. Specific therapies for affected infants includes anti-seizure medications called anti-convulsants and medications that relax the muscles to treat spasticity. Specific medications may be used to treat anxiety and sleep disorders. Myoclonus can be treated by medications called diazepines or valproate. Pain medications including opioids and transdermal fentanyl patches have been recommended. Affected children may benefit from occupational, physical, and speech therapy. Additional medical, social, and/or vocation services including special remedial education may be necessary. Some affected infants may require the insertion of a tube through a small opening in the stomach (gastronomy tube) to ensure they receive sufficient food and nutrition. | 278 | Classic Infantile CLN1 Disease |
nord_279_0 | Overview of Cleidocranial Dysplasia | Cleidocranial dysplasia is a rare genetic disorder characterized by abnormal bone formation commonly affecting the skull, teeth and long bones. As a result, short stature, distinctive facial features and narrow, sloping shoulders caused by abnormally developed or absent collarbones (clavicles) may be present in affected individuals. Major features may include premature closing of the soft spot on the head (coronal), delayed closure of the space between the bones of the skull (fontanels), narrow and abnormally shaped pelvic and pubic bones and abnormalities in development of the chest (thoracic region). If not diagnosed at birth, clinical presentation of remarkable features may be most notable in early childhood or adolescence. Additionally, a high arched palate, failure of the lower jaw joints to unite, delayed eruption of teeth and fingers that are irregular in length may also be present. Cleidocranial dysplasia is inherited as an autosomal dominant genetic condition. Approximately 1,000 cases of this disorder have been reported in the medical literature. | Overview of Cleidocranial Dysplasia. Cleidocranial dysplasia is a rare genetic disorder characterized by abnormal bone formation commonly affecting the skull, teeth and long bones. As a result, short stature, distinctive facial features and narrow, sloping shoulders caused by abnormally developed or absent collarbones (clavicles) may be present in affected individuals. Major features may include premature closing of the soft spot on the head (coronal), delayed closure of the space between the bones of the skull (fontanels), narrow and abnormally shaped pelvic and pubic bones and abnormalities in development of the chest (thoracic region). If not diagnosed at birth, clinical presentation of remarkable features may be most notable in early childhood or adolescence. Additionally, a high arched palate, failure of the lower jaw joints to unite, delayed eruption of teeth and fingers that are irregular in length may also be present. Cleidocranial dysplasia is inherited as an autosomal dominant genetic condition. Approximately 1,000 cases of this disorder have been reported in the medical literature. | 279 | Cleidocranial Dysplasia |
nord_279_1 | Symptoms of Cleidocranial Dysplasia | Because affected individuals can present with an array of features related to cleidocranial dysplasia, it is not always diagnosed at birth. The most prominent feature of cleidocranial dysplasia is the absence of collarbones or narrow, drooping shoulders caused by complete or partial absence of the collarbones. There may be abnormalities of the muscles in the area of the collarbones associated with an irregularly wide range of shoulder movement in affected individuals with collarbone abnormalities. Another prominent feature is atypical skull formation or skull abnormalities, which may include a premature closure of the two soft spots on the head (fontanels) and the fibrous joints where bones of the skull meet (sutures) causing abnormal development of the skull. Distinct facial features typically include a prominent forehead, unusually wide face, prominent chin, small upper jaw (maxillary hypoplasia) and bulging of the skull cap. Most individuals with cleidocranial dysplasia have some but not necessarily all features listed above and are diagnosed between birth and adolescence as the child develops and abnormalities may become more noticeable over time (irregular growth of long bones or pelvis, atypical facial feature development, abnormal tooth or jaw formation, etc.).Other bone abnormalities that have been found in some patients with cleidocranial dysplasia may be: a wide pelvic joint, delayed growth of the pubic bone, a hip defect in which the thigh bone angles towards the center of the body (coxa vara), failure of the lower jaw bones to unite, a defect of the hip that causes the thigh bone to angle out to the side of the body (coxa valga), curvature of the spine (scoliosis), a small shoulder blade and/or curvature of the upper legs so that the knees appear unusually close together (genu valgum).Dental abnormalities may include: a delay in tooth eruption, incomplete development or absence of teeth, underdeveloped enamel and/or extra teeth. Cysts may form around the unerupted or displaced teeth in some people. A high-arch palate or a condition in which there is a hole in the roof of the mouth (cleft palate) may be present.Individuals with cleidocranial dysplasia have an increased risk for recurrent ear and sinus infections, upper respiratory complications and hearing loss. | Symptoms of Cleidocranial Dysplasia. Because affected individuals can present with an array of features related to cleidocranial dysplasia, it is not always diagnosed at birth. The most prominent feature of cleidocranial dysplasia is the absence of collarbones or narrow, drooping shoulders caused by complete or partial absence of the collarbones. There may be abnormalities of the muscles in the area of the collarbones associated with an irregularly wide range of shoulder movement in affected individuals with collarbone abnormalities. Another prominent feature is atypical skull formation or skull abnormalities, which may include a premature closure of the two soft spots on the head (fontanels) and the fibrous joints where bones of the skull meet (sutures) causing abnormal development of the skull. Distinct facial features typically include a prominent forehead, unusually wide face, prominent chin, small upper jaw (maxillary hypoplasia) and bulging of the skull cap. Most individuals with cleidocranial dysplasia have some but not necessarily all features listed above and are diagnosed between birth and adolescence as the child develops and abnormalities may become more noticeable over time (irregular growth of long bones or pelvis, atypical facial feature development, abnormal tooth or jaw formation, etc.).Other bone abnormalities that have been found in some patients with cleidocranial dysplasia may be: a wide pelvic joint, delayed growth of the pubic bone, a hip defect in which the thigh bone angles towards the center of the body (coxa vara), failure of the lower jaw bones to unite, a defect of the hip that causes the thigh bone to angle out to the side of the body (coxa valga), curvature of the spine (scoliosis), a small shoulder blade and/or curvature of the upper legs so that the knees appear unusually close together (genu valgum).Dental abnormalities may include: a delay in tooth eruption, incomplete development or absence of teeth, underdeveloped enamel and/or extra teeth. Cysts may form around the unerupted or displaced teeth in some people. A high-arch palate or a condition in which there is a hole in the roof of the mouth (cleft palate) may be present.Individuals with cleidocranial dysplasia have an increased risk for recurrent ear and sinus infections, upper respiratory complications and hearing loss. | 279 | Cleidocranial Dysplasia |
nord_279_2 | Causes of Cleidocranial Dysplasia | Cleidocranial dysplasia is caused by changes (mutations or pathogenic variants) in the RUNX2 gene (originally called the CBFA1 gene). This gene codes for a protein that affects bone development and the proliferation of healthy osteoblasts. Osteoblasts are the specific cell type that make up bones and contribute to proper bone formation in the body. RUNX2 is a transcription factor or regulator of osteoblast generation in the body termed osteogenesis. About 20-30% of individuals with cleidocranial dysplasia do not have a pathogenic variant in the RUNX2 gene. This suggests that there are other genetic causes of this condition.Cleidocranial dysplasia is a rare disorder that is usually inherited as an autosomal dominant genetic condition. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a changed (mutated) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females. | Causes of Cleidocranial Dysplasia. Cleidocranial dysplasia is caused by changes (mutations or pathogenic variants) in the RUNX2 gene (originally called the CBFA1 gene). This gene codes for a protein that affects bone development and the proliferation of healthy osteoblasts. Osteoblasts are the specific cell type that make up bones and contribute to proper bone formation in the body. RUNX2 is a transcription factor or regulator of osteoblast generation in the body termed osteogenesis. About 20-30% of individuals with cleidocranial dysplasia do not have a pathogenic variant in the RUNX2 gene. This suggests that there are other genetic causes of this condition.Cleidocranial dysplasia is a rare disorder that is usually inherited as an autosomal dominant genetic condition. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a changed (mutated) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females. | 279 | Cleidocranial Dysplasia |
nord_279_3 | Affects of Cleidocranial Dysplasia | Cleidocranial dysplasia is a very rare disorder that is apparent at birth and affects males and females in equal numbers. Approximately 1,000 cases of this disorder have been reported in the medical literature. The birth prevalence is approximately 1 in 1 million. | Affects of Cleidocranial Dysplasia. Cleidocranial dysplasia is a very rare disorder that is apparent at birth and affects males and females in equal numbers. Approximately 1,000 cases of this disorder have been reported in the medical literature. The birth prevalence is approximately 1 in 1 million. | 279 | Cleidocranial Dysplasia |
nord_279_4 | Related disorders of Cleidocranial Dysplasia | Symptoms of the following disorders can be similar to those of cleidocranial dysplasia. Comparisons may be useful for a differential diagnosis:Mandibuloacral dysplasia is a rare disorder that may be characterized by a limitation in joint movement, slowed growth of the jaw, atrophic skin, underdeveloped fingers, a wide space between the bones of the skull, limited joint movement, absent or underdeveloped collarbone and/or a hip defect in which the thigh bone angles out to the side of the body (coxa valga). Mandibuloacral dysplasia is thought to affect males and females equally. Although these features may overlap with those present in individuals with cleidocranial dysplasia, mandibuloacral dysplasia is inherited in an autosomal recessive manner.Pyknodysostosis is a very rare genetic disorder that may be characterized by a delay in closure of the skull bones, short stature, an increase in the density of the bones, an underdeveloped jaw and abnormalities of the fingers. A small receding chin, dental abnormalities and short arms and legs may also be present. This disorder affects males and females equally and is inherited in an autosomal recessive manner.Osteogenesis imperfecta (OI) is a group of rare disorders affecting the connective tissue and characterized by extremely fragile bones that break or fracture easily (brittle bones), often without apparent cause. Connective tissue is strong fibrous tissue that supports and joins other body tissues and parts. The specific symptoms and physical findings associated with OI vary greatly from person to person. The severity of OI varies even among individuals in the same family. OI may be a mild disorder or may result in severe complications. In most cases, osteogenesis imperfecta is inherited as an autosomal dominant condition.Hajdu-Cheney syndrome is a rare connective tissue disorder. The most distinctive feature of individuals with this disorder is the appearance of ulcerating lesions on the palms of the hands and soles of the feet accompanied by softening and destruction of bones (acroosteolysis). Abnormal development of bones, joints and teeth also occurs. A decrease in bone mass and changes in the skull and jawbone are also features of this syndrome. The majority of cases are of unknown cause, but multiple cases have been reported in families which suggests autosomal dominant genetic inheritance. | Related disorders of Cleidocranial Dysplasia. Symptoms of the following disorders can be similar to those of cleidocranial dysplasia. Comparisons may be useful for a differential diagnosis:Mandibuloacral dysplasia is a rare disorder that may be characterized by a limitation in joint movement, slowed growth of the jaw, atrophic skin, underdeveloped fingers, a wide space between the bones of the skull, limited joint movement, absent or underdeveloped collarbone and/or a hip defect in which the thigh bone angles out to the side of the body (coxa valga). Mandibuloacral dysplasia is thought to affect males and females equally. Although these features may overlap with those present in individuals with cleidocranial dysplasia, mandibuloacral dysplasia is inherited in an autosomal recessive manner.Pyknodysostosis is a very rare genetic disorder that may be characterized by a delay in closure of the skull bones, short stature, an increase in the density of the bones, an underdeveloped jaw and abnormalities of the fingers. A small receding chin, dental abnormalities and short arms and legs may also be present. This disorder affects males and females equally and is inherited in an autosomal recessive manner.Osteogenesis imperfecta (OI) is a group of rare disorders affecting the connective tissue and characterized by extremely fragile bones that break or fracture easily (brittle bones), often without apparent cause. Connective tissue is strong fibrous tissue that supports and joins other body tissues and parts. The specific symptoms and physical findings associated with OI vary greatly from person to person. The severity of OI varies even among individuals in the same family. OI may be a mild disorder or may result in severe complications. In most cases, osteogenesis imperfecta is inherited as an autosomal dominant condition.Hajdu-Cheney syndrome is a rare connective tissue disorder. The most distinctive feature of individuals with this disorder is the appearance of ulcerating lesions on the palms of the hands and soles of the feet accompanied by softening and destruction of bones (acroosteolysis). Abnormal development of bones, joints and teeth also occurs. A decrease in bone mass and changes in the skull and jawbone are also features of this syndrome. The majority of cases are of unknown cause, but multiple cases have been reported in families which suggests autosomal dominant genetic inheritance. | 279 | Cleidocranial Dysplasia |
nord_279_5 | Diagnosis of Cleidocranial Dysplasia | Diagnosis of Cleidocranial Dysplasia. | 279 | Cleidocranial Dysplasia |
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nord_279_6 | Therapies of Cleidocranial Dysplasia | TreatmentThere is no cure for cleidocranial dysplasia. However, certain symptoms and features may be treated as they become apparent. Head gear in the form of a baby helmet may be worn after birth to protect the skull bones until they close. If dental abnormalities are present, appropriate dental care should be provided such as attending to tooth deformation or mandibular abnormalities possibly with surgical intervention. If a cleft palate is present, surgery may also be performed to close or block the opening to improve quality of life. Hearing evaluations should be performed at birth and throughout childhood since hearing complications may be present in individuals with cleidocranial dysplasia.Affected individuals have an increased risk for sleep apnea, sinus infections and ear infections due to delayed craniofacial development and should be assessed for symptoms that may require treatment as needed. Overall bone density should also be monitored over time and treatment provided if indicated. Speech and language may need to be assessed by a speech pathologist.Genetic counseling is recommended for patients and their families. Other treatments are dependent on symptoms and supportive as needed due to the variety of effects this condition can have on the body as mentioned above. | Therapies of Cleidocranial Dysplasia. TreatmentThere is no cure for cleidocranial dysplasia. However, certain symptoms and features may be treated as they become apparent. Head gear in the form of a baby helmet may be worn after birth to protect the skull bones until they close. If dental abnormalities are present, appropriate dental care should be provided such as attending to tooth deformation or mandibular abnormalities possibly with surgical intervention. If a cleft palate is present, surgery may also be performed to close or block the opening to improve quality of life. Hearing evaluations should be performed at birth and throughout childhood since hearing complications may be present in individuals with cleidocranial dysplasia.Affected individuals have an increased risk for sleep apnea, sinus infections and ear infections due to delayed craniofacial development and should be assessed for symptoms that may require treatment as needed. Overall bone density should also be monitored over time and treatment provided if indicated. Speech and language may need to be assessed by a speech pathologist.Genetic counseling is recommended for patients and their families. Other treatments are dependent on symptoms and supportive as needed due to the variety of effects this condition can have on the body as mentioned above. | 279 | Cleidocranial Dysplasia |
nord_280_0 | Overview of Clostridial Myonecrosis | Clostridial myonecrosis is a serious, life-threatening bacterial infection caused by a small number of Clostridium species of bacteria. Clostridial myonecrosis is broken down into two main forms – traumatic and spontaneous – and the two species most commonly associated with this infection are Clostridium perfringens, which is the primary cause of the traumatic form, and Clostridium septicum, which is the primary cause of the spontaneous form. The traumatic form most often arises in individuals who have suffered an injury or trauma that hinders or limits blood supply to the area (vascular compromise). The spontaneous form is often associated with individuals whose immune system are weakened or suppressed usually due to an underlying medical condition, most often cancer of the colon or rectum. Other underlying conditions that can be associated with the spontaneous form include blood (hematological) cancers like leukemia, diabetes mellitus, cyclic neutropenia, or individuals whose immune system is suppressed for other reasons. Clostridium septicum is not part of the normal human gut microbiota. It is thought that the associated illnesses cause maladaptation and imbalance (dysbiosis) allows Clostridium septicum to populate the gut. The bacteria can exist within the gastrointestinal system, but are kept under control by the immune system. In some immune-suppressed individuals, the infection can become dangerous. Clostridial myonecrosis is the term used when these clostridial infections spread to affect deep muscle tissue. A variety of complications can develop including pain, gas gangrene (a condition in which gas production and build up within muscle tissue leads to tissue death [necrosis]), and sepsis, a severe blood infection. These infections eventually progress to cause toxic shock and multiple organ failure. Clostridial myonecrosis is a rapidly progressive, medical emergency that can be fatal despite treatment. Prompt diagnosis and aggressive treatment are essential. | Overview of Clostridial Myonecrosis. Clostridial myonecrosis is a serious, life-threatening bacterial infection caused by a small number of Clostridium species of bacteria. Clostridial myonecrosis is broken down into two main forms – traumatic and spontaneous – and the two species most commonly associated with this infection are Clostridium perfringens, which is the primary cause of the traumatic form, and Clostridium septicum, which is the primary cause of the spontaneous form. The traumatic form most often arises in individuals who have suffered an injury or trauma that hinders or limits blood supply to the area (vascular compromise). The spontaneous form is often associated with individuals whose immune system are weakened or suppressed usually due to an underlying medical condition, most often cancer of the colon or rectum. Other underlying conditions that can be associated with the spontaneous form include blood (hematological) cancers like leukemia, diabetes mellitus, cyclic neutropenia, or individuals whose immune system is suppressed for other reasons. Clostridium septicum is not part of the normal human gut microbiota. It is thought that the associated illnesses cause maladaptation and imbalance (dysbiosis) allows Clostridium septicum to populate the gut. The bacteria can exist within the gastrointestinal system, but are kept under control by the immune system. In some immune-suppressed individuals, the infection can become dangerous. Clostridial myonecrosis is the term used when these clostridial infections spread to affect deep muscle tissue. A variety of complications can develop including pain, gas gangrene (a condition in which gas production and build up within muscle tissue leads to tissue death [necrosis]), and sepsis, a severe blood infection. These infections eventually progress to cause toxic shock and multiple organ failure. Clostridial myonecrosis is a rapidly progressive, medical emergency that can be fatal despite treatment. Prompt diagnosis and aggressive treatment are essential. | 280 | Clostridial Myonecrosis |
nord_280_1 | Symptoms of Clostridial Myonecrosis | Pain is often the presenting symptom and may be severe and may develop rapidly. In individuals with Clostridium perfringens infection following surgery, pain may arise shortly after the surgical procedure and be disproportionately strong. In Clostridium septicum infection, there is often sudden, severe onset of muscle pain. Sometimes, there is a sensation of heaviness, pressure, or numbness. Some individuals with the spontaneous form may initially show signs of confusion or exhibit a general feeling of poor health (malaise). In addition to pain, general early signs and symptoms can include fever, fatigue, and dehydration. Clostridial myonecrosis can cause a specific condition called gas gangrene. Clostridial infection produces toxins in the body. These toxins produce a gas. This gas becomes trapped within deep muscle tissue, specifically the soft tissues. This contributes to tissue death and decay called necrosis. Because clostridial myonecrosis affects deep muscle tissue initially, the skin near the infection site may be unaffected at first. Eventually, the skin may become pale, and over time usually darkens to reddish or brownish color. Eventually, bullae may form. Bullae are air- or fluid-filled sacs that form under a thin layer of skin. Sometimes, air- or blood-filled blisters called blebs form. Ultimately, the skin may turn a black or dark green color. The affected area may be extremely painful or tender, and there may be a grating or crackling sound (crepitation) from underneath the skin. Other signs and symptoms can include a foul-smelling discharge from the infection site, localized hardening of affected soft tissue (induration), and swelling due to fluid accumulation (edema). Eventually, the skin may break down and liquify before shedding off (sloughing). Sometimes, an infection can spread to the aorta, the main artery of the body. This is called aortitis. The wall of the artery may balloon or bulge outward (aneurysm) and there is a risk of the aorta rupturing. As the infection progresses, sepsis may occur. Sepsis is a widespread blood infection, in which the infections spreads to other areas of the body. The body responds by releasing chemicals to fight off the infection. These chemicals bring about an inflammatory response in the body. Individuals with sepsis can develop a rapid heartbeat (tachycardia), abnormally rapid breathing (tachypnea), low blood pressure (hypotension), and changes in their mental status including greatly dulled awareness or consciousness (stupor). Sepsis can lead to toxic shock, a life-threatening condition characterized by a sudden, high fever, sore throat, vomiting, diarrhea, muscle aches, headaches, confusion, disorientation, a rash, and seizures. Ultimately, multiorgan failure can occur. | Symptoms of Clostridial Myonecrosis. Pain is often the presenting symptom and may be severe and may develop rapidly. In individuals with Clostridium perfringens infection following surgery, pain may arise shortly after the surgical procedure and be disproportionately strong. In Clostridium septicum infection, there is often sudden, severe onset of muscle pain. Sometimes, there is a sensation of heaviness, pressure, or numbness. Some individuals with the spontaneous form may initially show signs of confusion or exhibit a general feeling of poor health (malaise). In addition to pain, general early signs and symptoms can include fever, fatigue, and dehydration. Clostridial myonecrosis can cause a specific condition called gas gangrene. Clostridial infection produces toxins in the body. These toxins produce a gas. This gas becomes trapped within deep muscle tissue, specifically the soft tissues. This contributes to tissue death and decay called necrosis. Because clostridial myonecrosis affects deep muscle tissue initially, the skin near the infection site may be unaffected at first. Eventually, the skin may become pale, and over time usually darkens to reddish or brownish color. Eventually, bullae may form. Bullae are air- or fluid-filled sacs that form under a thin layer of skin. Sometimes, air- or blood-filled blisters called blebs form. Ultimately, the skin may turn a black or dark green color. The affected area may be extremely painful or tender, and there may be a grating or crackling sound (crepitation) from underneath the skin. Other signs and symptoms can include a foul-smelling discharge from the infection site, localized hardening of affected soft tissue (induration), and swelling due to fluid accumulation (edema). Eventually, the skin may break down and liquify before shedding off (sloughing). Sometimes, an infection can spread to the aorta, the main artery of the body. This is called aortitis. The wall of the artery may balloon or bulge outward (aneurysm) and there is a risk of the aorta rupturing. As the infection progresses, sepsis may occur. Sepsis is a widespread blood infection, in which the infections spreads to other areas of the body. The body responds by releasing chemicals to fight off the infection. These chemicals bring about an inflammatory response in the body. Individuals with sepsis can develop a rapid heartbeat (tachycardia), abnormally rapid breathing (tachypnea), low blood pressure (hypotension), and changes in their mental status including greatly dulled awareness or consciousness (stupor). Sepsis can lead to toxic shock, a life-threatening condition characterized by a sudden, high fever, sore throat, vomiting, diarrhea, muscle aches, headaches, confusion, disorientation, a rash, and seizures. Ultimately, multiorgan failure can occur. | 280 | Clostridial Myonecrosis |
nord_280_2 | Causes of Clostridial Myonecrosis | Clostridial myonecrosis is caused by infection with species of the Clostridium genera of bacteria. Clostridia are found throughout nature. They are found in soil and marine sediments and can be found in animal and human gastrointestinal tracts. Two specific species, Clostridium perfringens and Clostridium septicum account for most of the people who develop clostridial myonecrosis. These two species produce toxins that cause certain cells to breakdown prematurely and damage blood vessels. They may promote the formation of blood clots and decrease or depress heart muscle contractions. These toxins also produce a gas that becomes trapped within deep muscle tissue causing tissue death and decay (myonecrosis or gas gangrene). Clostridium infection can occur in individuals who have recently experienced trauma or surgery. This is known as the trauma and or wound-related form. It is most often caused by Clostridium perfringens. An individual is exposed to the bacteria through the open wound. However, the bacteria will not grow and spread unless the environment around the wound will support its growth and spread. These bacteria do not need oxygen to survive and, if the injury or wound limits or hinders blood supply to the affected area, this can create an environment that promotes the growth and spread of the bacteria. The bacteria will spread to surrounding tissue including deep muscle tissue. The traumatic form of clostridial myonecrosis is associated with a variety of traumatic conditions including gunshot or deep knife wounds, compound fractures, and intramuscular injections. It may also be associated with bowel and biliary tract surgery or abortions. Pregnant women who have a retained placenta or prolonged rupture of fetal membranes or experience the death of a fetus (intrauterine fetal demise) may also be at risk. The spontaneous form of infection occurs when there is no obvious route of infection. It is also called the nontraumatic or idiopathic form. It is usually caused by Clostridium septicum and usually develops in individuals with a suppressed immune system and cancer of the colon or rectum. It also occurs in individuals with blood cancers like leukemia, inflammatory bowel disease, diverticulitis, lymphoproliferative disorders, cyclic neutropenia, or acquired immune deficiency syndrome (AIDS). Individuals who have undergone radiation therapy or gastrointestinal surgery may also be at risk. It is thought, the infection enters the bloodstream through an injury or lesion within the gastrointestinal system where it is carried to other tissues of the body including deep muscle tissue (hematogenous muscle seeding). Clostridium septicum does not need a low oxygen environment to grow and spread in the body and it is more aerotolerant than Clostridium perfringens. | Causes of Clostridial Myonecrosis. Clostridial myonecrosis is caused by infection with species of the Clostridium genera of bacteria. Clostridia are found throughout nature. They are found in soil and marine sediments and can be found in animal and human gastrointestinal tracts. Two specific species, Clostridium perfringens and Clostridium septicum account for most of the people who develop clostridial myonecrosis. These two species produce toxins that cause certain cells to breakdown prematurely and damage blood vessels. They may promote the formation of blood clots and decrease or depress heart muscle contractions. These toxins also produce a gas that becomes trapped within deep muscle tissue causing tissue death and decay (myonecrosis or gas gangrene). Clostridium infection can occur in individuals who have recently experienced trauma or surgery. This is known as the trauma and or wound-related form. It is most often caused by Clostridium perfringens. An individual is exposed to the bacteria through the open wound. However, the bacteria will not grow and spread unless the environment around the wound will support its growth and spread. These bacteria do not need oxygen to survive and, if the injury or wound limits or hinders blood supply to the affected area, this can create an environment that promotes the growth and spread of the bacteria. The bacteria will spread to surrounding tissue including deep muscle tissue. The traumatic form of clostridial myonecrosis is associated with a variety of traumatic conditions including gunshot or deep knife wounds, compound fractures, and intramuscular injections. It may also be associated with bowel and biliary tract surgery or abortions. Pregnant women who have a retained placenta or prolonged rupture of fetal membranes or experience the death of a fetus (intrauterine fetal demise) may also be at risk. The spontaneous form of infection occurs when there is no obvious route of infection. It is also called the nontraumatic or idiopathic form. It is usually caused by Clostridium septicum and usually develops in individuals with a suppressed immune system and cancer of the colon or rectum. It also occurs in individuals with blood cancers like leukemia, inflammatory bowel disease, diverticulitis, lymphoproliferative disorders, cyclic neutropenia, or acquired immune deficiency syndrome (AIDS). Individuals who have undergone radiation therapy or gastrointestinal surgery may also be at risk. It is thought, the infection enters the bloodstream through an injury or lesion within the gastrointestinal system where it is carried to other tissues of the body including deep muscle tissue (hematogenous muscle seeding). Clostridium septicum does not need a low oxygen environment to grow and spread in the body and it is more aerotolerant than Clostridium perfringens. | 280 | Clostridial Myonecrosis |
nord_280_3 | Affects of Clostridial Myonecrosis | Clostridial myonecrosis is a rare infection. Approximately, one in 1,000-3,000 people are reported each year in the United States. Most affected individuals are adults, but these infections can occur in individuals of any age including children. About 80% of these infections are traumatic clostridial myonecrosis. Of these, about 70% are caused by Clostridium perfringens. | Affects of Clostridial Myonecrosis. Clostridial myonecrosis is a rare infection. Approximately, one in 1,000-3,000 people are reported each year in the United States. Most affected individuals are adults, but these infections can occur in individuals of any age including children. About 80% of these infections are traumatic clostridial myonecrosis. Of these, about 70% are caused by Clostridium perfringens. | 280 | Clostridial Myonecrosis |
nord_280_4 | Related disorders of Clostridial Myonecrosis | Symptoms of the following disorders can be similar to those of clostridial myonecrosis. Comparisons may be useful for a differential diagnosis.Necrotizing fasciitis (NF) is a rare infection that means “decaying infection of the fascia,” which is the soft tissue that is part of the connective tissue system that runs throughout the body. NF is caused by one or more bacteria that attacks the skin, the tissue just beneath the skin (subcutaneous tissue), and the fascia causing these tissues to die (necrosis). These infections can be sudden, vicious, and fast-spreading. If not treated quickly with antibiotics and/or debridement of the infected tissue, the patient may develop toxic shock syndrome or toxic shock-like syndrome, which may lead to multiple organ failure and death. (For more information on this disorder, choose “necrotizing fasciitis” as your search term in the Rare Disease Database.) Fournier gangrene is an acute necrotic infection of the scrotum; penis; or perineum. It is characterized by scrotum pain and redness with rapid progression to gangrene and sloughing of tissue. Fournier gangrene is usually secondary to perirectal or periurethral infections associated with local trauma, operative procedures, or urinary tract disease. Since 1950, more than 1,800 cases for study have been reported in English language medical literature. This disease occurs worldwide and, although it is recognized more frequently among male adults, has been identified also among women and children. Treatment usually consists of the surgical removal (debridement) of extensive areas of dead tissue (necrosis, necrotic) and the administration of broad-spectrum intravenous antibiotics. Surgical reconstruction may follow where necessary. (For more information on this disorder, choose “Fournier” as your search term in the Rare Disease Database.)There are several infectious diseases or conditions that can resemble clostridial myonecrosis. These conditions include infection due to group A Streptococcus bacteria and Staphylococcus aureus; wound infection due to Vibrio vulnificus; muscle infection characterized by muscle abscesses (pyomyositis); muscle infection due to viral agents (viral myositis); and rhabdomyolysis, a general condition of skeletal muscle breakdown due to a variety of causes. | Related disorders of Clostridial Myonecrosis. Symptoms of the following disorders can be similar to those of clostridial myonecrosis. Comparisons may be useful for a differential diagnosis.Necrotizing fasciitis (NF) is a rare infection that means “decaying infection of the fascia,” which is the soft tissue that is part of the connective tissue system that runs throughout the body. NF is caused by one or more bacteria that attacks the skin, the tissue just beneath the skin (subcutaneous tissue), and the fascia causing these tissues to die (necrosis). These infections can be sudden, vicious, and fast-spreading. If not treated quickly with antibiotics and/or debridement of the infected tissue, the patient may develop toxic shock syndrome or toxic shock-like syndrome, which may lead to multiple organ failure and death. (For more information on this disorder, choose “necrotizing fasciitis” as your search term in the Rare Disease Database.) Fournier gangrene is an acute necrotic infection of the scrotum; penis; or perineum. It is characterized by scrotum pain and redness with rapid progression to gangrene and sloughing of tissue. Fournier gangrene is usually secondary to perirectal or periurethral infections associated with local trauma, operative procedures, or urinary tract disease. Since 1950, more than 1,800 cases for study have been reported in English language medical literature. This disease occurs worldwide and, although it is recognized more frequently among male adults, has been identified also among women and children. Treatment usually consists of the surgical removal (debridement) of extensive areas of dead tissue (necrosis, necrotic) and the administration of broad-spectrum intravenous antibiotics. Surgical reconstruction may follow where necessary. (For more information on this disorder, choose “Fournier” as your search term in the Rare Disease Database.)There are several infectious diseases or conditions that can resemble clostridial myonecrosis. These conditions include infection due to group A Streptococcus bacteria and Staphylococcus aureus; wound infection due to Vibrio vulnificus; muscle infection characterized by muscle abscesses (pyomyositis); muscle infection due to viral agents (viral myositis); and rhabdomyolysis, a general condition of skeletal muscle breakdown due to a variety of causes. | 280 | Clostridial Myonecrosis |
nord_280_5 | Diagnosis of Clostridial Myonecrosis | A diagnosis of clostridial myonecrosis is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests including a culture positive patient sample. Certain physical signs may support a diagnosis of traumatic clostridial myonecrosis. These include pain at the site of a wound or surgery, and signs of systemic toxicity or gas in the soft tissues such as a grating or crackling sound (crepitation) from underneath the skin. Spontaneous clostridial myonecrosis may be suspected in individuals with rapid onset of pain and fever, particularly in the arms and legs, in the absence of trauma or injury. The traumatic form easier to diagnose. Clinical Testing and Workup
Blood tests can reveal findings that are indicative of clostridial myonecrosis. Muscle damage and loss can lead to elevated levels of aldolase, potassium, lactate dehydrogenase, and creatine phosphokinase levels. White blood cell levels may be low. Sometimes, anemia (low levels of red blood cells) is seen. X-rays may reveal fine gas bubbles in affected soft tissue and skin tissue. Specialized imaging techniques called computerized tomography (CT) scanning and magnetic resonance imaging (MRI) can reveal gas outside of the gastrointestinal tract (extraluminal gas). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily issues. CT scanning and MRIs can also be used to determine whether an infection is localized to one site of the body or has spread to other areas.Laboratory technicians will also run a test called a Gram stain. Bacteria may be classified as “Gram negative” or “Gram positive”, depending upon the results of the staining test. This method involves staining bacteria with various solutions and dyes that help to identify and classify the bacteria based on the composition of their cellular components. This rapid staining technique when combined with microscopy gives physicians early clues about the underlying cause of their patient’s conditions. In individuals with clostridial myonecrosis, a Gram stain of discharge from the wound may reveal “Gram positive” rods (rod-shaped bacteria) and the absence of polymorphonuclear cells. These cells are inflammatory cells that are normally found at the sites of injury within the body, but are not found when this clostridial infection is involved. Researchers believe that toxins produced by some members of the infectious Clostridia prevent polymorphonuclear cells from reaching infected tissue. Blood cultures, which are tests that can detect and classify bacteria found in the blood, may be useful for diagnosing spontaneous clostridial myonecrosis and Clostridial septicum infection. Bacteria in the blood usually precedes skin signs by several hours. Exploratory surgery of the wound may reveal characteristic findings including muscles that do not bleed or contract upon stimulation, swelling, and discoloration. A tissue sample may be removed and studied under a microscope (biopsy sample) to other characteristic changes in muscle tissue. | Diagnosis of Clostridial Myonecrosis. A diagnosis of clostridial myonecrosis is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests including a culture positive patient sample. Certain physical signs may support a diagnosis of traumatic clostridial myonecrosis. These include pain at the site of a wound or surgery, and signs of systemic toxicity or gas in the soft tissues such as a grating or crackling sound (crepitation) from underneath the skin. Spontaneous clostridial myonecrosis may be suspected in individuals with rapid onset of pain and fever, particularly in the arms and legs, in the absence of trauma or injury. The traumatic form easier to diagnose. Clinical Testing and Workup
Blood tests can reveal findings that are indicative of clostridial myonecrosis. Muscle damage and loss can lead to elevated levels of aldolase, potassium, lactate dehydrogenase, and creatine phosphokinase levels. White blood cell levels may be low. Sometimes, anemia (low levels of red blood cells) is seen. X-rays may reveal fine gas bubbles in affected soft tissue and skin tissue. Specialized imaging techniques called computerized tomography (CT) scanning and magnetic resonance imaging (MRI) can reveal gas outside of the gastrointestinal tract (extraluminal gas). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily issues. CT scanning and MRIs can also be used to determine whether an infection is localized to one site of the body or has spread to other areas.Laboratory technicians will also run a test called a Gram stain. Bacteria may be classified as “Gram negative” or “Gram positive”, depending upon the results of the staining test. This method involves staining bacteria with various solutions and dyes that help to identify and classify the bacteria based on the composition of their cellular components. This rapid staining technique when combined with microscopy gives physicians early clues about the underlying cause of their patient’s conditions. In individuals with clostridial myonecrosis, a Gram stain of discharge from the wound may reveal “Gram positive” rods (rod-shaped bacteria) and the absence of polymorphonuclear cells. These cells are inflammatory cells that are normally found at the sites of injury within the body, but are not found when this clostridial infection is involved. Researchers believe that toxins produced by some members of the infectious Clostridia prevent polymorphonuclear cells from reaching infected tissue. Blood cultures, which are tests that can detect and classify bacteria found in the blood, may be useful for diagnosing spontaneous clostridial myonecrosis and Clostridial septicum infection. Bacteria in the blood usually precedes skin signs by several hours. Exploratory surgery of the wound may reveal characteristic findings including muscles that do not bleed or contract upon stimulation, swelling, and discoloration. A tissue sample may be removed and studied under a microscope (biopsy sample) to other characteristic changes in muscle tissue. | 280 | Clostridial Myonecrosis |
nord_280_6 | Therapies of Clostridial Myonecrosis | Clostridial myonecrosis is a medical emergency. Early diagnosis and prompt therapy are essential for the best outcome. Treatment may require a team of specialists including a specialist in diagnosing and treating infectious diseases (infectious disease specialist); a specialist in diagnosing and treating skin disorders (dermatologists); general, trauma, or burn surgeons; plastic surgeons; social workers; and other healthcare professionals may need to systematically and comprehensively plan treatment. Psychosocial support for the entire family is essential as well. The initial treatment for infection includes urgent surgical removal of all affected dead (necrotic), damaged or infected skin and subcutaneously tissue involved. This allows the remaining healthy tissue to heal more effectively. This is called debridement or surgical debridement and may require repeated sessions to maintain the wound margins as necessary over time. In severe instances, debridement can lead to the removal of a large portion of skin or tissue, or, when there is a severe infection of an arm or leg, amputation of the affected limb in order to stop the spread of infection. Along with debridement affected individuals are prescribed broad-spectrum intravenous antibiotics as quickly as possible. Antibiotics are medications that inhibit the growth of and destroy bacteria and are essential in controlling sepsis and preventing the spread of the infection. Broad spectrum antibiotics works against both gram-positive and gram-negative bacteria (see Diagnosis above) and are recommended until a definitive diagnosis is reached. Large clinical trials to test the effectiveness of different antibiotic medication for the treatment of clostridial myonecrosis have not been conducted. In 2014, the Infectious Disease Society published practice guidelines for the diagnosis and management of skin and soft tissue infections (Stevens, et al 2014). Penicillin plus clindamycin or tetracycline, are the recommended antibiotic regimen for clostridial myonecrosis. Supportive therapies are also essential and can include intravenous fluids and supplemental oxygen. If affected individuals have not received immunization against tetanus within 10 years, then a booster vaccination against tetanus may be recommended. | Therapies of Clostridial Myonecrosis. Clostridial myonecrosis is a medical emergency. Early diagnosis and prompt therapy are essential for the best outcome. Treatment may require a team of specialists including a specialist in diagnosing and treating infectious diseases (infectious disease specialist); a specialist in diagnosing and treating skin disorders (dermatologists); general, trauma, or burn surgeons; plastic surgeons; social workers; and other healthcare professionals may need to systematically and comprehensively plan treatment. Psychosocial support for the entire family is essential as well. The initial treatment for infection includes urgent surgical removal of all affected dead (necrotic), damaged or infected skin and subcutaneously tissue involved. This allows the remaining healthy tissue to heal more effectively. This is called debridement or surgical debridement and may require repeated sessions to maintain the wound margins as necessary over time. In severe instances, debridement can lead to the removal of a large portion of skin or tissue, or, when there is a severe infection of an arm or leg, amputation of the affected limb in order to stop the spread of infection. Along with debridement affected individuals are prescribed broad-spectrum intravenous antibiotics as quickly as possible. Antibiotics are medications that inhibit the growth of and destroy bacteria and are essential in controlling sepsis and preventing the spread of the infection. Broad spectrum antibiotics works against both gram-positive and gram-negative bacteria (see Diagnosis above) and are recommended until a definitive diagnosis is reached. Large clinical trials to test the effectiveness of different antibiotic medication for the treatment of clostridial myonecrosis have not been conducted. In 2014, the Infectious Disease Society published practice guidelines for the diagnosis and management of skin and soft tissue infections (Stevens, et al 2014). Penicillin plus clindamycin or tetracycline, are the recommended antibiotic regimen for clostridial myonecrosis. Supportive therapies are also essential and can include intravenous fluids and supplemental oxygen. If affected individuals have not received immunization against tetanus within 10 years, then a booster vaccination against tetanus may be recommended. | 280 | Clostridial Myonecrosis |
nord_281_0 | Overview of CLOVES Syndrome | SummaryCLOVES syndrome is a recently described rare disorder characterized by tissue overgrowth and complex vascular anomalies. CLOVES stands for congenital lipomatous (fatty) overgrowth, vascular malformations, epidermal nevi and scoliosis/skeletal/spinal anomalies.IntroductionCLOVES syndrome was described independently by Saap and colleagues in 2007 and Alomari in 2009. A case report by the German physician Hermann Friedberg “gigantism of the right lower limb” published in 1867 is probably the first known written account of CLOVES syndrome. | Overview of CLOVES Syndrome. SummaryCLOVES syndrome is a recently described rare disorder characterized by tissue overgrowth and complex vascular anomalies. CLOVES stands for congenital lipomatous (fatty) overgrowth, vascular malformations, epidermal nevi and scoliosis/skeletal/spinal anomalies.IntroductionCLOVES syndrome was described independently by Saap and colleagues in 2007 and Alomari in 2009. A case report by the German physician Hermann Friedberg “gigantism of the right lower limb” published in 1867 is probably the first known written account of CLOVES syndrome. | 281 | CLOVES Syndrome |
nord_281_1 | Symptoms of CLOVES Syndrome | CLOVES syndrome belongs to the spectrum of overgrowth syndromes with complex vascular anomalies caused by mosaic mutations in the PIK3CA gene. CLOVES syndrome may affect the soft tissue, blood vessels, bone and internal organs. The manifestations are very variable ranging from mild to severe anomalies. These abnormalities are typically present at birth.The most common features are:1. Fatty overgrowth. Soft fatty masses of variable size are noted at birth and can be located in the back, flanks, axilla, abdomen and buttocks. These masses may affect one or both sides of the body. The skin over the mass is typically covered with a red-pinkish birthmark (capillary malformation or port-wine stain).2. Vascular anomalies: Dilated veins in the chest, upper and lower extremities may cause clot formation and occasionally serious pulmonary embolism (clot travelling from the vein to the lungs). Lymphatic malformations are abnormal, large spaces filled with lymph. These malformations are frequently noted within the fatty masses or in the abdomen, chest and extremities. A small subgroup of patients may suffer from the more aggressive arteriovenous malformation around the area of the spinal cord.3. Abnormal extremities (arms and legs) are common. Large wide hands or feet, large fingers or toes, wide space between digits (sandal gap toe) and uneven size of extremities are common.4. Spinal anomalies include scoliosis (curving of the spine), fatty masses and vessels pushing on the spinal cord and tethered cord (spinal cord fixed by abnormal band).5. Skin birthmarks include port-wine stains, prominent veins, lymphatic vesicles, moles and epidermal nevus (slightly raised areas of skin with light brownish color).6. Kidney anomalies: The size of the kidneys could be asymmetric (one is larger) and may show some abnormal features on imaging studies. Wilms tumor has been noted in a small number of young patients with CLOVES syndrome. This requires screening with serial ultrasound examinations during childhood.Additional findings can occur in CLOVES syndrome including bleeding from the intestine, urinary bladder and asymmetric face and head.Not all patients with CLOVES syndrome have all these signs, but rather a combination of abnormalities. Some can be subtle and a dedicated physical exam and proper imaging studies are required. | Symptoms of CLOVES Syndrome. CLOVES syndrome belongs to the spectrum of overgrowth syndromes with complex vascular anomalies caused by mosaic mutations in the PIK3CA gene. CLOVES syndrome may affect the soft tissue, blood vessels, bone and internal organs. The manifestations are very variable ranging from mild to severe anomalies. These abnormalities are typically present at birth.The most common features are:1. Fatty overgrowth. Soft fatty masses of variable size are noted at birth and can be located in the back, flanks, axilla, abdomen and buttocks. These masses may affect one or both sides of the body. The skin over the mass is typically covered with a red-pinkish birthmark (capillary malformation or port-wine stain).2. Vascular anomalies: Dilated veins in the chest, upper and lower extremities may cause clot formation and occasionally serious pulmonary embolism (clot travelling from the vein to the lungs). Lymphatic malformations are abnormal, large spaces filled with lymph. These malformations are frequently noted within the fatty masses or in the abdomen, chest and extremities. A small subgroup of patients may suffer from the more aggressive arteriovenous malformation around the area of the spinal cord.3. Abnormal extremities (arms and legs) are common. Large wide hands or feet, large fingers or toes, wide space between digits (sandal gap toe) and uneven size of extremities are common.4. Spinal anomalies include scoliosis (curving of the spine), fatty masses and vessels pushing on the spinal cord and tethered cord (spinal cord fixed by abnormal band).5. Skin birthmarks include port-wine stains, prominent veins, lymphatic vesicles, moles and epidermal nevus (slightly raised areas of skin with light brownish color).6. Kidney anomalies: The size of the kidneys could be asymmetric (one is larger) and may show some abnormal features on imaging studies. Wilms tumor has been noted in a small number of young patients with CLOVES syndrome. This requires screening with serial ultrasound examinations during childhood.Additional findings can occur in CLOVES syndrome including bleeding from the intestine, urinary bladder and asymmetric face and head.Not all patients with CLOVES syndrome have all these signs, but rather a combination of abnormalities. Some can be subtle and a dedicated physical exam and proper imaging studies are required. | 281 | CLOVES Syndrome |
nord_281_2 | Causes of CLOVES Syndrome | CLOVES syndrome is a nonhereditary disorder caused by a somatic (body cell) mutation in a gene known as PIK3CA. Mutations in this growth regulatory gene result in two sets of cells within the body (mosaic status): those with the mutation and those without the mutation. The mutated cells give rise to the abnormal tissue. | Causes of CLOVES Syndrome. CLOVES syndrome is a nonhereditary disorder caused by a somatic (body cell) mutation in a gene known as PIK3CA. Mutations in this growth regulatory gene result in two sets of cells within the body (mosaic status): those with the mutation and those without the mutation. The mutated cells give rise to the abnormal tissue. | 281 | CLOVES Syndrome |
nord_281_3 | Affects of CLOVES Syndrome | CLOVES syndrome is rare and evident at birth. It affects males and females equally regardless of their race or ethnicity. Many of the patients with CLOVES syndrome are misdiagnosed as having other syndromes such as Klippel-Trenaunay syndrome or Proteus syndrome. | Affects of CLOVES Syndrome. CLOVES syndrome is rare and evident at birth. It affects males and females equally regardless of their race or ethnicity. Many of the patients with CLOVES syndrome are misdiagnosed as having other syndromes such as Klippel-Trenaunay syndrome or Proteus syndrome. | 281 | CLOVES Syndrome |
nord_281_4 | Related disorders of CLOVES Syndrome | PIK3CA-related overgrowth syndromes (PROS) refers to a group of disorders caused by PIK3CA gene mutations such as CLOVES and Klippel-Trenaunay syndrome.Symptoms of the following disorders can be similar to those of CLOVES syndrome:Klippel-Trenaunay syndrome (KTS) is a rare disorder that is present at birth (congenital) and is characterized by a triad of cutaneous capillary malformation (port-wine stain), lymphatic anomalies, and abnormal veins in association with variable overgrowth of soft tissue and bone. KTS occurs typically in the lower limb. KTS equally affects males and females. (For more information on this disorder, choose “Klippel-Trenaunay” as your search term in the Rare Disease Database.)Proteus syndrome is a rare disorder characterized by disorganized overgrowth of various tissues of the body. The cause of the disorder is a mosaic mutation in a gene called AKT1. Disproportionate, asymmetric overgrowth occurs in a mosaic pattern (i.e., a random “patchy” pattern of affected and unaffected areas). Affected individuals may experience a wide variety of complications that may include progressive skeletal malformations, benign and malignant tumors, malformations of blood vessels (vascular malformations), bullous pulmonary disease, and certain skin lesions. In some patients, life-threatening conditions relating to abnormal blood clotting may develop including deep vein thrombosis and pulmonary embolism. (For more information on this disorder, choose “Proteus” as your search term in the Rare Disease Database.) | Related disorders of CLOVES Syndrome. PIK3CA-related overgrowth syndromes (PROS) refers to a group of disorders caused by PIK3CA gene mutations such as CLOVES and Klippel-Trenaunay syndrome.Symptoms of the following disorders can be similar to those of CLOVES syndrome:Klippel-Trenaunay syndrome (KTS) is a rare disorder that is present at birth (congenital) and is characterized by a triad of cutaneous capillary malformation (port-wine stain), lymphatic anomalies, and abnormal veins in association with variable overgrowth of soft tissue and bone. KTS occurs typically in the lower limb. KTS equally affects males and females. (For more information on this disorder, choose “Klippel-Trenaunay” as your search term in the Rare Disease Database.)Proteus syndrome is a rare disorder characterized by disorganized overgrowth of various tissues of the body. The cause of the disorder is a mosaic mutation in a gene called AKT1. Disproportionate, asymmetric overgrowth occurs in a mosaic pattern (i.e., a random “patchy” pattern of affected and unaffected areas). Affected individuals may experience a wide variety of complications that may include progressive skeletal malformations, benign and malignant tumors, malformations of blood vessels (vascular malformations), bullous pulmonary disease, and certain skin lesions. In some patients, life-threatening conditions relating to abnormal blood clotting may develop including deep vein thrombosis and pulmonary embolism. (For more information on this disorder, choose “Proteus” as your search term in the Rare Disease Database.) | 281 | CLOVES Syndrome |
nord_281_5 | Diagnosis of CLOVES Syndrome | The diagnosis is evident at birth based on physical signs and symptoms. Confirmation of diagnosis can be done with molecular genetic testing for the PIK3CA gene mutation. Imaging studies include plain x-rays (radiography), magnetic resonance imaging (MRI) of the chest, abdomen, pelvis, spine and limbs and ultrasound for vascular anomalies and kidneys. Prenatal diagnosis with imaging tools is feasible. | Diagnosis of CLOVES Syndrome. The diagnosis is evident at birth based on physical signs and symptoms. Confirmation of diagnosis can be done with molecular genetic testing for the PIK3CA gene mutation. Imaging studies include plain x-rays (radiography), magnetic resonance imaging (MRI) of the chest, abdomen, pelvis, spine and limbs and ultrasound for vascular anomalies and kidneys. Prenatal diagnosis with imaging tools is feasible. | 281 | CLOVES Syndrome |
nord_281_6 | Therapies of CLOVES Syndrome | TreatmentThe management of CLOVES syndrome can be very challenging and requires an interdisciplinary team of physicians with experience in overgrowth and vascular anomalies. The treatment should address the specific problems in the affected child. Debulking operations are necessary to reduce the size of the significant overgrown tissue. Orthopedic procedures are usually necessary for large limb anomalies. Large veins and lymphatic malformations should be treated with minimally invasive procedures such as sclerotherapy, embolization and laser treatment before undergoing surgical procedures due to the risk of vein thrombosis. Tethered cord is treated surgically.Medical therapy with sirolimus demonstrated promising results; particularly for patients with lymphatic malformation and pain. The use of sirolimus or other medical therapies is rapidly changing in CLOVES syndrome and other vascular anomalies and should be guided by an experienced hematologist/oncologist.The “Clinical Practice Guidelines for Management of CLOVES Syndrome” based on the institutional experience of the Vascular Anomalies Center at Boston Children’s Hospital is available at this link: http://www.clovessyndrome.org/sites/default/files/CLOVES_Syndrome_Management_Guidelines_For_Families_6-21-2014-2.pdfClinical Testing and Work-Up
Screening for Wilms tumor with serial ultrasounds up to age 8 years is recommended. | Therapies of CLOVES Syndrome. TreatmentThe management of CLOVES syndrome can be very challenging and requires an interdisciplinary team of physicians with experience in overgrowth and vascular anomalies. The treatment should address the specific problems in the affected child. Debulking operations are necessary to reduce the size of the significant overgrown tissue. Orthopedic procedures are usually necessary for large limb anomalies. Large veins and lymphatic malformations should be treated with minimally invasive procedures such as sclerotherapy, embolization and laser treatment before undergoing surgical procedures due to the risk of vein thrombosis. Tethered cord is treated surgically.Medical therapy with sirolimus demonstrated promising results; particularly for patients with lymphatic malformation and pain. The use of sirolimus or other medical therapies is rapidly changing in CLOVES syndrome and other vascular anomalies and should be guided by an experienced hematologist/oncologist.The “Clinical Practice Guidelines for Management of CLOVES Syndrome” based on the institutional experience of the Vascular Anomalies Center at Boston Children’s Hospital is available at this link: http://www.clovessyndrome.org/sites/default/files/CLOVES_Syndrome_Management_Guidelines_For_Families_6-21-2014-2.pdfClinical Testing and Work-Up
Screening for Wilms tumor with serial ultrasounds up to age 8 years is recommended. | 281 | CLOVES Syndrome |
nord_282_0 | Overview of Coats Disease | Coats disease was first described in 1908 and is a rare disorder characterized by abnormal development of the blood vessels in the retina. The retina is a nerve-rich tissue lining the back of the eye that transmits light images to the brain, which allows a person to see. Therefore, affected individuals may experience loss of vision due to changes in the retina and, in severe cases, retinal detachment. In almost all people with Coats disease, only one eye is affected. Rarely, both eyes may be exhibit symptoms, however, one eye is often affected more than the other. The specific cause of Coats disease is not known. | Overview of Coats Disease. Coats disease was first described in 1908 and is a rare disorder characterized by abnormal development of the blood vessels in the retina. The retina is a nerve-rich tissue lining the back of the eye that transmits light images to the brain, which allows a person to see. Therefore, affected individuals may experience loss of vision due to changes in the retina and, in severe cases, retinal detachment. In almost all people with Coats disease, only one eye is affected. Rarely, both eyes may be exhibit symptoms, however, one eye is often affected more than the other. The specific cause of Coats disease is not known. | 282 | Coats Disease |
nord_282_1 | Symptoms of Coats Disease | Coats disease affects males more often than females in a ratio of 3:1. The disorder may occur at any age, but the majority of patients are diagnosed in the first two decades of life. Individuals affected with Coats disease may display few or no symptoms while others may have severe involvement. The most common features at presentation of Coats disease include loss of vision, misalignment of the eyes (strabismus), and/or the development of a white reflex rather than the normal red or orange color in the pupil when light is flashed into the pupil so that the pupil appears white (leukocoria).Eye symptoms result from a developmental malformation, known as telangiectasia, of the blood vessels in the retina. Telangiectasia (tele equals far or end, angio means blood vessel, and ectasia refers to dilation) occurs when there is abnormal widening of groups of small blood vessels, resulting in the leakage of proteins and lipids from the blood. When this occurs in the retina, it is termed exudative retinopathy. This leakage can lead to retinal detachment and the other symptoms discussed above.Over time, Coats disease may cause detachment of the retina and substantial loss of vision. Additional signs may appear as Coats disease progresses, including elevated pressure inside the eye (glaucoma), clouding of the lens of the eye (cataract), reddish discoloration in the iris due to the growth of new blood vessels in the iris (rubeosis iridis or neovascular glaucoma), shrinking of the affected eyeball (phthisis bulbi), and/or inflammation of eye (uveitis). | Symptoms of Coats Disease. Coats disease affects males more often than females in a ratio of 3:1. The disorder may occur at any age, but the majority of patients are diagnosed in the first two decades of life. Individuals affected with Coats disease may display few or no symptoms while others may have severe involvement. The most common features at presentation of Coats disease include loss of vision, misalignment of the eyes (strabismus), and/or the development of a white reflex rather than the normal red or orange color in the pupil when light is flashed into the pupil so that the pupil appears white (leukocoria).Eye symptoms result from a developmental malformation, known as telangiectasia, of the blood vessels in the retina. Telangiectasia (tele equals far or end, angio means blood vessel, and ectasia refers to dilation) occurs when there is abnormal widening of groups of small blood vessels, resulting in the leakage of proteins and lipids from the blood. When this occurs in the retina, it is termed exudative retinopathy. This leakage can lead to retinal detachment and the other symptoms discussed above.Over time, Coats disease may cause detachment of the retina and substantial loss of vision. Additional signs may appear as Coats disease progresses, including elevated pressure inside the eye (glaucoma), clouding of the lens of the eye (cataract), reddish discoloration in the iris due to the growth of new blood vessels in the iris (rubeosis iridis or neovascular glaucoma), shrinking of the affected eyeball (phthisis bulbi), and/or inflammation of eye (uveitis). | 282 | Coats Disease |
nord_282_2 | Causes of Coats Disease | The specific cause of Coats disease is not known. One theory is that a mutation of the Norrie disease protein (NDP) gene leads to Coats disease. This gene is an attractive candidate because it has been shown to play a vital role in retinal blood vessel development. One study showed some promise for involvement of the NDP gene in Coats disease, however further studies have not been able to verify this hypothesis. In general, Coats disease is considered a non-genetic, non-heritable condition. | Causes of Coats Disease. The specific cause of Coats disease is not known. One theory is that a mutation of the Norrie disease protein (NDP) gene leads to Coats disease. This gene is an attractive candidate because it has been shown to play a vital role in retinal blood vessel development. One study showed some promise for involvement of the NDP gene in Coats disease, however further studies have not been able to verify this hypothesis. In general, Coats disease is considered a non-genetic, non-heritable condition. | 282 | Coats Disease |
nord_282_3 | Affects of Coats Disease | It is estimated that about 69% of those affected are male. The average age at diagnosis is 8-16 years, although the disease has been diagnosed in patients as young as 4 months. About two-thirds of juvenile cases present before age 10. Approximately one-third of patients are 30 years or older before symptoms begin. | Affects of Coats Disease. It is estimated that about 69% of those affected are male. The average age at diagnosis is 8-16 years, although the disease has been diagnosed in patients as young as 4 months. About two-thirds of juvenile cases present before age 10. Approximately one-third of patients are 30 years or older before symptoms begin. | 282 | Coats Disease |
nord_282_4 | Related disorders of Coats Disease | Signs of the following disorders can be similar to those of Coats disease.Retinoblastoma is an extremely rare malignant tumor or form of cancer that develops in the retina. Patients are usually diagnosed before the age of three. Common presenting symptoms include the white reflex in the pupil (leukocoria) and strabismus or eye misalignment. The presentation of symptoms in retinoblastoma can be identical to those in Coats disease, therefore it is very important to correctly distinguish Coats disease from retinoblastoma since untreated retinoblastoma can be life threatening. In most cases, retinoblastomas occur spontaneously with no family history; however, approximately 20 percent of cases are transmitted as an autosomal dominant trait. (For more information on this disorder, choose “Retinoblastoma” as your search terms in the Rare Disease Database.)Norrie disease is a rare inherited disorder characterized by early onset blindness in both eyes shortly after birth. Some children with this disorder may experience developmental delay. Additional signs associated with Norrie disease include mild to profound hearing loss and other eye abnormalities. Cataracts may develop during early infancy and the eyeballs may shrink (phthisis bulbi). Norrie disease is inherited as an X-linked trait. (For more information on this disorder, choose “Norrie” as your search term in the Rare Disease Database.)Persistent fetal vasculature (PFV), formerly called persistent hyperplastic primary vitreous (PHPV), is a developmental disorder affecting the eye that is present at birth. The disorder is characterized by persistence of the fetal blood vessels in the vitreous gel in the middle of the eye, insertion of the blood vessels into the lens causing cataract, and loss of vision.Other disorders that might be confused with Coats disease include familial exudative vitreoretinopathy (FEVR) and macular telangiectasia, type I. | Related disorders of Coats Disease. Signs of the following disorders can be similar to those of Coats disease.Retinoblastoma is an extremely rare malignant tumor or form of cancer that develops in the retina. Patients are usually diagnosed before the age of three. Common presenting symptoms include the white reflex in the pupil (leukocoria) and strabismus or eye misalignment. The presentation of symptoms in retinoblastoma can be identical to those in Coats disease, therefore it is very important to correctly distinguish Coats disease from retinoblastoma since untreated retinoblastoma can be life threatening. In most cases, retinoblastomas occur spontaneously with no family history; however, approximately 20 percent of cases are transmitted as an autosomal dominant trait. (For more information on this disorder, choose “Retinoblastoma” as your search terms in the Rare Disease Database.)Norrie disease is a rare inherited disorder characterized by early onset blindness in both eyes shortly after birth. Some children with this disorder may experience developmental delay. Additional signs associated with Norrie disease include mild to profound hearing loss and other eye abnormalities. Cataracts may develop during early infancy and the eyeballs may shrink (phthisis bulbi). Norrie disease is inherited as an X-linked trait. (For more information on this disorder, choose “Norrie” as your search term in the Rare Disease Database.)Persistent fetal vasculature (PFV), formerly called persistent hyperplastic primary vitreous (PHPV), is a developmental disorder affecting the eye that is present at birth. The disorder is characterized by persistence of the fetal blood vessels in the vitreous gel in the middle of the eye, insertion of the blood vessels into the lens causing cataract, and loss of vision.Other disorders that might be confused with Coats disease include familial exudative vitreoretinopathy (FEVR) and macular telangiectasia, type I. | 282 | Coats Disease |
nord_282_5 | Diagnosis of Coats Disease | A diagnosis of Coats disease is made based upon a thorough clinical ophthalmic evaluation, a detailed patient history, and specialized tests, including retinal fluorescein angiography, diagnostic echography, and in some cases computed tomography imaging of the orbits. | Diagnosis of Coats Disease. A diagnosis of Coats disease is made based upon a thorough clinical ophthalmic evaluation, a detailed patient history, and specialized tests, including retinal fluorescein angiography, diagnostic echography, and in some cases computed tomography imaging of the orbits. | 282 | Coats Disease |
nord_282_6 | Therapies of Coats Disease | TreatmentThe treatment of Coats disease is directed toward the specific signs present in each individual. A procedure that uses extreme cold to create a scar around the abnormal blood vessels (cryotherapy), and/or a procedure that uses laser energy to heat and destroy abnormal blood vessels (photocoagulation) are used singly or in combination to treat Coats disease. In conjunction with these procedures, steroids or other medicines such as bevacizumab may be injected into the eye to control inflammation and leaking from blood vessels. Surgery to reattach the retina may also be necessary.Genetic counseling is not necessary if the diagnosis is accurate since this is a non-genetic malformation and the recurrence risk is the same as the background rate in the general population. | Therapies of Coats Disease. TreatmentThe treatment of Coats disease is directed toward the specific signs present in each individual. A procedure that uses extreme cold to create a scar around the abnormal blood vessels (cryotherapy), and/or a procedure that uses laser energy to heat and destroy abnormal blood vessels (photocoagulation) are used singly or in combination to treat Coats disease. In conjunction with these procedures, steroids or other medicines such as bevacizumab may be injected into the eye to control inflammation and leaking from blood vessels. Surgery to reattach the retina may also be necessary.Genetic counseling is not necessary if the diagnosis is accurate since this is a non-genetic malformation and the recurrence risk is the same as the background rate in the general population. | 282 | Coats Disease |
nord_283_0 | Overview of Cockayne Syndrome | Cockayne Syndrome (CS) is a rare genetic disorder characterized by short stature, an abnormally small head (microcephaly) and neurologic abnormalities that can lead to intellectual disability. Affected children may also have skin that is sensitive to light (photosensitivity); inflammation of peripheral nerves and destruction of the fatty covering (myelin sheath) of nerve fibers; vision abnormalities including cataracts; hearing loss; dental abnormalities and a face with a sunken appearance of the eyes.The four types of CS have specific characteristics and age of onset. Children with the classical form (CS type I) have growth delay and developmental delays in the first two years of life. Children with CS type II have growth failure noticed at birth and sometimes congenital cataracts and a lack of neurologic development. CS type III presents later in childhood and is generally a milder form of the disease. Children with COFS have severe developmental abnormalities that begin during fetal development and can include stiff joints (contractures) at birth and eyes that don’t fully develop (microphthalmia). | Overview of Cockayne Syndrome. Cockayne Syndrome (CS) is a rare genetic disorder characterized by short stature, an abnormally small head (microcephaly) and neurologic abnormalities that can lead to intellectual disability. Affected children may also have skin that is sensitive to light (photosensitivity); inflammation of peripheral nerves and destruction of the fatty covering (myelin sheath) of nerve fibers; vision abnormalities including cataracts; hearing loss; dental abnormalities and a face with a sunken appearance of the eyes.The four types of CS have specific characteristics and age of onset. Children with the classical form (CS type I) have growth delay and developmental delays in the first two years of life. Children with CS type II have growth failure noticed at birth and sometimes congenital cataracts and a lack of neurologic development. CS type III presents later in childhood and is generally a milder form of the disease. Children with COFS have severe developmental abnormalities that begin during fetal development and can include stiff joints (contractures) at birth and eyes that don’t fully develop (microphthalmia). | 283 | Cockayne Syndrome |
nord_283_1 | Symptoms of Cockayne Syndrome | CS type I, the classical form, is characterized by a normal appearing newborn with symptoms that become apparent in the first wo years of life. Vision, hearing and nervous system functioning gets worse over time, resulting in severe disability.CS type II, the congenital form, is more severe with obvious growth failure at birth and little or no neurological development after birth. Serious vision impairments (cataracts and other structural abnormalities of the eye) are usually present at birth.CS type III is characterized by essentially normal growth and mental development during the early years, with onset of the typical symptoms of CS later in childhood or teen years. Affected individuals may also have problems with coordination, balance and speech (ataxia) and photosensitivity. COFS syndrome includes the typical symptoms of CS as well as multiple joint contractures (arthrogryposis) and eye abnormalities. Brain MRI on children with Cockayne syndrome shows white matter demyelination and cerebellar atrophy. Children with Cockayne syndrome may have unusual physical features including an abnormally small head (microcephaly), unusually thin nose, “hollow” or sunken appearance to the eyes, large misshapen ears, poor eyelid closure and/or the abnormal forward projection of both the upper and lower jaws (prognathism). There may be an unusual amount of dental decay due to the abnormal placement of the teeth. Affected individuals typically have large hands and feet and unusually long arms and legs in proportion to the size of their body. Joints may also be abnormally large and remain in a fixed position, and the spine may be curved outward when viewed from the side (kyphosis). Other features of Cockayne syndrome may include decreased sweating (hypohidrosis), lack of proper tearing in the eyes and/or thin, dry hair.Neurological symptoms may include rhythmic, quivering movements (tremors), an unsteady gait (ataxia), and/or the inability to coordinate movement. Affected children may experience varying degrees of intellectual disability, partial loss of hearing, and/or the progressive loss of previously acquired intellectual abilities.The symptoms of Cockayne syndrome that affect the eyes may include progressive clouding of the lens of the eyes (cataracts), loss of vision because of the wasting of the nerve fibers within the eyes (optic atrophy), degeneration of the retina, and/or the abnormal accumulation of retinal coloration (pigmentation).Some people with Cockayne syndrome also have an enlarged liver or spleen (hepatosplenomegaly), abnormally high blood pressure (hypertension), premature accumulation of fatty plaques on the walls of the arteries around the heart (arteriosclerotic disease) kidney disease and/or diabetes. Sexual maturation may be delayed. | Symptoms of Cockayne Syndrome. CS type I, the classical form, is characterized by a normal appearing newborn with symptoms that become apparent in the first wo years of life. Vision, hearing and nervous system functioning gets worse over time, resulting in severe disability.CS type II, the congenital form, is more severe with obvious growth failure at birth and little or no neurological development after birth. Serious vision impairments (cataracts and other structural abnormalities of the eye) are usually present at birth.CS type III is characterized by essentially normal growth and mental development during the early years, with onset of the typical symptoms of CS later in childhood or teen years. Affected individuals may also have problems with coordination, balance and speech (ataxia) and photosensitivity. COFS syndrome includes the typical symptoms of CS as well as multiple joint contractures (arthrogryposis) and eye abnormalities. Brain MRI on children with Cockayne syndrome shows white matter demyelination and cerebellar atrophy. Children with Cockayne syndrome may have unusual physical features including an abnormally small head (microcephaly), unusually thin nose, “hollow” or sunken appearance to the eyes, large misshapen ears, poor eyelid closure and/or the abnormal forward projection of both the upper and lower jaws (prognathism). There may be an unusual amount of dental decay due to the abnormal placement of the teeth. Affected individuals typically have large hands and feet and unusually long arms and legs in proportion to the size of their body. Joints may also be abnormally large and remain in a fixed position, and the spine may be curved outward when viewed from the side (kyphosis). Other features of Cockayne syndrome may include decreased sweating (hypohidrosis), lack of proper tearing in the eyes and/or thin, dry hair.Neurological symptoms may include rhythmic, quivering movements (tremors), an unsteady gait (ataxia), and/or the inability to coordinate movement. Affected children may experience varying degrees of intellectual disability, partial loss of hearing, and/or the progressive loss of previously acquired intellectual abilities.The symptoms of Cockayne syndrome that affect the eyes may include progressive clouding of the lens of the eyes (cataracts), loss of vision because of the wasting of the nerve fibers within the eyes (optic atrophy), degeneration of the retina, and/or the abnormal accumulation of retinal coloration (pigmentation).Some people with Cockayne syndrome also have an enlarged liver or spleen (hepatosplenomegaly), abnormally high blood pressure (hypertension), premature accumulation of fatty plaques on the walls of the arteries around the heart (arteriosclerotic disease) kidney disease and/or diabetes. Sexual maturation may be delayed. | 283 | Cockayne Syndrome |
nord_283_2 | Causes of Cockayne Syndrome | Cockayne syndrome is caused by changes (pathogenic variants) in the ERCC6 and ERCC8 genes. Pathogenic variants in ERCC6 account for about 65% of cases and pathogenic variants in ERCC8 cause about 35% of cases. These genes are involved in the normal repair of DNA that occurs after damage from ultraviolet light, which is the body’s natural defense against sunburn. Exposure to the ultraviolet component of sunlight damages DNA and because the cells are no longer able to repair the damaged DNA, it accumulates in the cells.CS is inherited in an autosomal recessive pattern. 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. | Causes of Cockayne Syndrome. Cockayne syndrome is caused by changes (pathogenic variants) in the ERCC6 and ERCC8 genes. Pathogenic variants in ERCC6 account for about 65% of cases and pathogenic variants in ERCC8 cause about 35% of cases. These genes are involved in the normal repair of DNA that occurs after damage from ultraviolet light, which is the body’s natural defense against sunburn. Exposure to the ultraviolet component of sunlight damages DNA and because the cells are no longer able to repair the damaged DNA, it accumulates in the cells.CS is inherited in an autosomal recessive pattern. 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. | 283 | Cockayne Syndrome |
nord_283_3 | Affects of Cockayne Syndrome | Cockayne syndrome affects males and females in equal numbers and has been diagnosed in children from many different ethnic backgrounds. The incidence of CS has been estimated to be 2.7 per 1,000,000 births in western Europe, but it is probably underdiagnosed. | Affects of Cockayne Syndrome. Cockayne syndrome affects males and females in equal numbers and has been diagnosed in children from many different ethnic backgrounds. The incidence of CS has been estimated to be 2.7 per 1,000,000 births in western Europe, but it is probably underdiagnosed. | 283 | Cockayne Syndrome |
nord_283_4 | Related disorders of Cockayne Syndrome | Many different disorders have symptoms similar to those of Cockayne syndrome. Conditions that might be included in a differential diagnosis include Pelizaeus-Merzbacher disease; Cornelia deLange syndrome; Dubowitz syndrome; Hallerman-Streiff syndrome; Rubinstein-Taybi syndrome; Silver-Russell syndrome; Seckel syndrome; Wiedemann-Rautenstrauch syndrome; xeroderma pigmentosum, Bloom syndrome; Hutchinson-Gilford progeria syndrome; Werner syndrome; Rothmund-Thompson syndrome; Warburg micro syndrome; disorders of calcium and phosphate metabolism; and congenital infections (rubella, toxoplasmosis).For more information about these disorders, search for them in the Rare Disease Database. | Related disorders of Cockayne Syndrome. Many different disorders have symptoms similar to those of Cockayne syndrome. Conditions that might be included in a differential diagnosis include Pelizaeus-Merzbacher disease; Cornelia deLange syndrome; Dubowitz syndrome; Hallerman-Streiff syndrome; Rubinstein-Taybi syndrome; Silver-Russell syndrome; Seckel syndrome; Wiedemann-Rautenstrauch syndrome; xeroderma pigmentosum, Bloom syndrome; Hutchinson-Gilford progeria syndrome; Werner syndrome; Rothmund-Thompson syndrome; Warburg micro syndrome; disorders of calcium and phosphate metabolism; and congenital infections (rubella, toxoplasmosis).For more information about these disorders, search for them in the Rare Disease Database. | 283 | Cockayne Syndrome |
nord_283_5 | Diagnosis of Cockayne Syndrome | Cockayne syndrome is diagnosed by molecular genetic (DNA) testing for pathogenic variants in the ERCC6 or ERCC8 genes. If pathogenic variants in these genes are not found, a DNA repair assay on skin cells can be done to look for sensitivity to ultraviolet radiation. | Diagnosis of Cockayne Syndrome. Cockayne syndrome is diagnosed by molecular genetic (DNA) testing for pathogenic variants in the ERCC6 or ERCC8 genes. If pathogenic variants in these genes are not found, a DNA repair assay on skin cells can be done to look for sensitivity to ultraviolet radiation. | 283 | Cockayne Syndrome |
nord_283_6 | Therapies of Cockayne Syndrome | Treatment
Treatment of Cockayne syndrome is symptomatic and supportive. A supportive team approach can benefit for children with CS and may include special education, physical therapy, and other medical, social, and/or vocational services. Genetic counseling is recommended for family members. | Therapies of Cockayne Syndrome. Treatment
Treatment of Cockayne syndrome is symptomatic and supportive. A supportive team approach can benefit for children with CS and may include special education, physical therapy, and other medical, social, and/or vocational services. Genetic counseling is recommended for family members. | 283 | Cockayne Syndrome |
nord_284_0 | Overview of Coffin Lowry Syndrome | Coffin-Lowry syndrome (CLS) is a rare genetic disorder characterized by intellectual disability; abnormalities of the head and facial (craniofacial) area; large, soft hands with short, thin (tapered) fingers; short stature; and/or various skeletal abnormalities. Characteristic facial features may include an underdeveloped upper jawbone (maxillary hypoplasia), an abnormally prominent brow, downslanting eyelid folds (palpebral fissures), widely spaced eyes (hypertelorism), large ears, and/or unusually thick eyebrows. Skeletal abnormalities may include abnormal front-to-back and side-to-side curvature of the spine (kyphoscoliosis) and unusual prominence of the breastbone (sternum) (pectus carinatum). Coffin-Lowry syndrome is caused by changes (mutations) in the RPS6KA3 gene and is inherited in an X-linked dominant pattern. Males are usually more severely affected than females. | Overview of Coffin Lowry Syndrome. Coffin-Lowry syndrome (CLS) is a rare genetic disorder characterized by intellectual disability; abnormalities of the head and facial (craniofacial) area; large, soft hands with short, thin (tapered) fingers; short stature; and/or various skeletal abnormalities. Characteristic facial features may include an underdeveloped upper jawbone (maxillary hypoplasia), an abnormally prominent brow, downslanting eyelid folds (palpebral fissures), widely spaced eyes (hypertelorism), large ears, and/or unusually thick eyebrows. Skeletal abnormalities may include abnormal front-to-back and side-to-side curvature of the spine (kyphoscoliosis) and unusual prominence of the breastbone (sternum) (pectus carinatum). Coffin-Lowry syndrome is caused by changes (mutations) in the RPS6KA3 gene and is inherited in an X-linked dominant pattern. Males are usually more severely affected than females. | 284 | Coffin Lowry Syndrome |
nord_284_1 | Symptoms of Coffin Lowry Syndrome | The symptoms of Coffin-Lowry syndrome tend to be more severe in males, although symptoms in affected females can range from none to the same severity seen in males. The characteristic facial features seen in affected males become more easily identifiable in late childhood and adulthood. The face is characterized by a prominent forehead and eyebrows, narrowing of both temples, scarce hair on the scalp, thickened eyebrow ridges, downslanting eyelid slits, wide-set eyes, thickened upper eyelids, a broad nasal bridge with a thick dividing cartilage (septum), thick prominent lips, an open mouth, prominent chin and ears.Limb abnormalities may include large soft hands with double-jointed thick fingers that taper toward the tips, an unusual prominent transverse crease (hypothenar) and a shortened big toe. In males, the skin is loose and may stretch easily. Many bone abnormalities may also occur such as thickening of facial bones, shortening of the long bones, and pointed or sunken breast bone. Abnormal front-to-back and side-to-side curvature of the spine may also be present (kyphosis and scoliosis) and progresses with age. Affected individuals usually have short stature. A smaller than average head size (microcephaly) and dental abnormalities are common. Hearing loss is sometimes associated with Coffin-Lowry syndrome. In rare cases, vision loss may occur. Heart problems may be present and can be life threatening.Affected males may have severe to profound intellectual disability. Intelligence in affected females ranges from normal to profound intellectual disability. Severely affected children may have no speech development.Some affected individuals experience episodes of brief collapse without loss of consciousness (drop attacks) that occur following an unexpected noise or emotional event. | Symptoms of Coffin Lowry Syndrome. The symptoms of Coffin-Lowry syndrome tend to be more severe in males, although symptoms in affected females can range from none to the same severity seen in males. The characteristic facial features seen in affected males become more easily identifiable in late childhood and adulthood. The face is characterized by a prominent forehead and eyebrows, narrowing of both temples, scarce hair on the scalp, thickened eyebrow ridges, downslanting eyelid slits, wide-set eyes, thickened upper eyelids, a broad nasal bridge with a thick dividing cartilage (septum), thick prominent lips, an open mouth, prominent chin and ears.Limb abnormalities may include large soft hands with double-jointed thick fingers that taper toward the tips, an unusual prominent transverse crease (hypothenar) and a shortened big toe. In males, the skin is loose and may stretch easily. Many bone abnormalities may also occur such as thickening of facial bones, shortening of the long bones, and pointed or sunken breast bone. Abnormal front-to-back and side-to-side curvature of the spine may also be present (kyphosis and scoliosis) and progresses with age. Affected individuals usually have short stature. A smaller than average head size (microcephaly) and dental abnormalities are common. Hearing loss is sometimes associated with Coffin-Lowry syndrome. In rare cases, vision loss may occur. Heart problems may be present and can be life threatening.Affected males may have severe to profound intellectual disability. Intelligence in affected females ranges from normal to profound intellectual disability. Severely affected children may have no speech development.Some affected individuals experience episodes of brief collapse without loss of consciousness (drop attacks) that occur following an unexpected noise or emotional event. | 284 | Coffin Lowry Syndrome |
nord_284_2 | Causes of Coffin Lowry Syndrome | Coffin-Lowry syndrome is caused by changes (mutations) in the RPS6KA3 gene on the X chromosome. Some individuals with Coffin-Lowry syndrome do not have a detectable mutation in the RPS6KA3 gene.Coffin-Lowry syndrome is inherited in an X-linked dominant pattern. About 70-80% of those affected have no family history of the condition. Males with a RPS6KA3 gene mutation will be affected with Coffin-Lowry syndrome and females with a RPS6KA32 gene mutation have a high risk for developmental delay and mild physical symptoms of the disease. | Causes of Coffin Lowry Syndrome. Coffin-Lowry syndrome is caused by changes (mutations) in the RPS6KA3 gene on the X chromosome. Some individuals with Coffin-Lowry syndrome do not have a detectable mutation in the RPS6KA3 gene.Coffin-Lowry syndrome is inherited in an X-linked dominant pattern. About 70-80% of those affected have no family history of the condition. Males with a RPS6KA3 gene mutation will be affected with Coffin-Lowry syndrome and females with a RPS6KA32 gene mutation have a high risk for developmental delay and mild physical symptoms of the disease. | 284 | Coffin Lowry Syndrome |
nord_284_3 | Affects of Coffin Lowry Syndrome | Coffin-Lowry syndrome affects as many males as females. However, symptoms may be more severe in males. | Affects of Coffin Lowry Syndrome. Coffin-Lowry syndrome affects as many males as females. However, symptoms may be more severe in males. | 284 | Coffin Lowry Syndrome |
nord_284_4 | Related disorders of Coffin Lowry Syndrome | Symptoms of the following disorder can be similar to those of Coffin-Lowry syndrome. Comparisons may be useful for a differential diagnosis:Borjeson syndrome is a rare genetic disorder primarily characterized by an unusual facial appearance, intellectual disability, obesity, seizures, delayed sexual development, and/or poor muscle tone (hypotonia). The disorder is follows X-linked recessive inheritance and therefore is usually fully expressed in males only. However, females who carry a single copy of the disease gene may manifest certain, usually more variable features of the disorder. (For more information on this disorder, choose “Borjeson” as your search term in the Rare Disease Database.)Alpha-thalassemia x-linked intellectual disability (ATRX) syndrome is an X-linked recessive genetic disorder characterized by intellectual disability with short stature, microcephaly, abnormal head shape and facial features that include low muscle tone, widely spaced eyes, small nose, open mouth and prominent lips. Generalized low muscle tone and genital abnormalities may be present.Williams syndrome is a rare genetic disorder characterized by growth delays before and after birth, short stature, varying levels of intellectual disability, and distinctive facial abnormalities that typically become more pronounced with age. Characteristic facial features may include a round face, full cheeks, thick lips, a large mouth that is usually held open, and a broad nasal bridge with nostrils that flare forward (anteverted nares). Affected individuals may also have unusually short eyelid folds (palpebral fissures), flared eyebrows, a small lower jaw (mandible), and prominent ears. Dental abnormalities may also be present including abnormally small, underdeveloped teeth (hypodontia) with small, slender roots. Individuals with Williams syndrome have a deletion of 25 genes on chromosome 7. (For more information on this condition, choose “Williams” as your search term in the Rare Disease Database.) | Related disorders of Coffin Lowry Syndrome. Symptoms of the following disorder can be similar to those of Coffin-Lowry syndrome. Comparisons may be useful for a differential diagnosis:Borjeson syndrome is a rare genetic disorder primarily characterized by an unusual facial appearance, intellectual disability, obesity, seizures, delayed sexual development, and/or poor muscle tone (hypotonia). The disorder is follows X-linked recessive inheritance and therefore is usually fully expressed in males only. However, females who carry a single copy of the disease gene may manifest certain, usually more variable features of the disorder. (For more information on this disorder, choose “Borjeson” as your search term in the Rare Disease Database.)Alpha-thalassemia x-linked intellectual disability (ATRX) syndrome is an X-linked recessive genetic disorder characterized by intellectual disability with short stature, microcephaly, abnormal head shape and facial features that include low muscle tone, widely spaced eyes, small nose, open mouth and prominent lips. Generalized low muscle tone and genital abnormalities may be present.Williams syndrome is a rare genetic disorder characterized by growth delays before and after birth, short stature, varying levels of intellectual disability, and distinctive facial abnormalities that typically become more pronounced with age. Characteristic facial features may include a round face, full cheeks, thick lips, a large mouth that is usually held open, and a broad nasal bridge with nostrils that flare forward (anteverted nares). Affected individuals may also have unusually short eyelid folds (palpebral fissures), flared eyebrows, a small lower jaw (mandible), and prominent ears. Dental abnormalities may also be present including abnormally small, underdeveloped teeth (hypodontia) with small, slender roots. Individuals with Williams syndrome have a deletion of 25 genes on chromosome 7. (For more information on this condition, choose “Williams” as your search term in the Rare Disease Database.) | 284 | Coffin Lowry Syndrome |
nord_284_5 | Diagnosis of Coffin Lowry Syndrome | X-ray and neuroimaging studies may be helpful in confirming a diagnosis of Coffin-Lowry syndrome. Decreased ribosomal S6 kinase activity in cultured fibroblast or transformed lymphoblast cells from a male indicates Coffin-Lowry syndrome. Studies of enzyme activity cannot be used to diagnose an affected female.Molecular genetic testing on a blood specimen or cells from a cheek swab is available to identify mutations in the RPS6KA3 gene. This testing can be used to confirm but not rule out the diagnosis of Coffin-Lowry syndrome because not all affected individuals have a detectable mutation. | Diagnosis of Coffin Lowry Syndrome. X-ray and neuroimaging studies may be helpful in confirming a diagnosis of Coffin-Lowry syndrome. Decreased ribosomal S6 kinase activity in cultured fibroblast or transformed lymphoblast cells from a male indicates Coffin-Lowry syndrome. Studies of enzyme activity cannot be used to diagnose an affected female.Molecular genetic testing on a blood specimen or cells from a cheek swab is available to identify mutations in the RPS6KA3 gene. This testing can be used to confirm but not rule out the diagnosis of Coffin-Lowry syndrome because not all affected individuals have a detectable mutation. | 284 | Coffin Lowry Syndrome |
nord_284_6 | Therapies of Coffin Lowry Syndrome | Treatment
Treatment for Coffin-Lowry syndrome is symptomatic and supportive. Affected individuals should have regular cardiac, hearing and visual examinations. Patients should be monitored for progressive kyphoscoliosis which can be life threatening if the cardiorespiratory system becomes compromised. Antiepileptic medications such as clonazepam may be used to treat drop attacks.Genetic counseling is recommended for families. | Therapies of Coffin Lowry Syndrome. Treatment
Treatment for Coffin-Lowry syndrome is symptomatic and supportive. Affected individuals should have regular cardiac, hearing and visual examinations. Patients should be monitored for progressive kyphoscoliosis which can be life threatening if the cardiorespiratory system becomes compromised. Antiepileptic medications such as clonazepam may be used to treat drop attacks.Genetic counseling is recommended for families. | 284 | Coffin Lowry Syndrome |
nord_285_0 | Overview of Coffin Siris Syndrome | Coffin-Siris syndrome (CSS) is a rare genetic disorder that may be evident at birth (congenital). The disorder may be characterized by abnormalities of the head and facial (craniofacial) area, resulting in a coarse facial appearance. Craniofacial malformations may include an abnormally small head (microcephaly) or large head (macrocephaly); a wide nose with a low nasal bridge; a wide mouth with thick, prominent lips; thick eyebrows and eyelashes or excess hair growth in unusual places such as the back (hypertrichosis); and sparse scalp hair. In addition, affected infants and children may have short fifth fingers (“pinkies”) and toes with underdeveloped (hypoplastic) or absent nails; other malformations of the fingers and toes and eye abnormalities. Feeding difficulties and frequent respiratory infections during infancy, diminished muscle tone (hypotonia), abnormal looseness (laxity) of the joints, delayed bone age, developmental delays, hearing loss, and intellectual disability may also be present. The specific symptoms and severity can vary among affected individuals. Treatment is directed towards the symptoms that are present in an individual with CSS. Pathogenic gene variants (mutations) in seven different genes, ARID1A, ARID1B, ARID2, SMARCA4, SMARCB1, SMARCE1 and SOX11 have been found to cause CSS. Pathogenic variants in the DPF2 gene have also recently been described in individuals with a “Coffin-Siris like” appearance (phenotype). Researchers believe that CSS can be inherited in an autosomal dominant pattern, but most cases appear to be the result of a new mutation that is not inherited. | Overview of Coffin Siris Syndrome. Coffin-Siris syndrome (CSS) is a rare genetic disorder that may be evident at birth (congenital). The disorder may be characterized by abnormalities of the head and facial (craniofacial) area, resulting in a coarse facial appearance. Craniofacial malformations may include an abnormally small head (microcephaly) or large head (macrocephaly); a wide nose with a low nasal bridge; a wide mouth with thick, prominent lips; thick eyebrows and eyelashes or excess hair growth in unusual places such as the back (hypertrichosis); and sparse scalp hair. In addition, affected infants and children may have short fifth fingers (“pinkies”) and toes with underdeveloped (hypoplastic) or absent nails; other malformations of the fingers and toes and eye abnormalities. Feeding difficulties and frequent respiratory infections during infancy, diminished muscle tone (hypotonia), abnormal looseness (laxity) of the joints, delayed bone age, developmental delays, hearing loss, and intellectual disability may also be present. The specific symptoms and severity can vary among affected individuals. Treatment is directed towards the symptoms that are present in an individual with CSS. Pathogenic gene variants (mutations) in seven different genes, ARID1A, ARID1B, ARID2, SMARCA4, SMARCB1, SMARCE1 and SOX11 have been found to cause CSS. Pathogenic variants in the DPF2 gene have also recently been described in individuals with a “Coffin-Siris like” appearance (phenotype). Researchers believe that CSS can be inherited in an autosomal dominant pattern, but most cases appear to be the result of a new mutation that is not inherited. | 285 | Coffin Siris Syndrome |
nord_285_1 | Symptoms of Coffin Siris Syndrome | CSS is characterized by distinctive abnormalities of the head and facial (craniofacial) region with affected individuals often described as having coarse facial features that become more prominent with age. Affected individuals may have an unusually small or large head (micro- or macrocephaly); a wide mouth with full, prominent lips; a broad nasal tip; a low nasal bridge and an abnormally long vertical groove between the nose and the upper lip (philtrum). Additional features may include thick eyebrows, long eyelashes and generalized excessive hair growth (hypertrichosis) with the exception of the scalp hair, which tends to be relatively sparse (scalp hypotrichosis). Reports suggest that sparse scalp hair improves with age.Individuals with CSS may also have characteristic skeletal abnormalities. For example, certain fingers and toes (digits), particularly the fifth fingers (“pinkies”) and toes may be unusually short due to absence or underdevelopment (hypoplasia) of the end bones (terminal phalanges) within these digits. The fingernails and toenails may also be underdeveloped or absent. Additional abnormalities may include dislocation of the inner forearm bone (radius) at the elbow, deformity of the hip (coxa valga) or unusually small or absent kneecaps (patellae). However, there are individuals with CSS who do not have the classic fifth digit findings.Early in life, infants with CSS typically experience feeding difficulties, vomiting, slow growth and weight gain (failure to thrive) which may have begun while the infant was still in the womb (intrauterine growth retardation), and frequent respiratory infections. In addition, affected infants and children may have hypotonia, abnormally loose joints, delayed bone age (2 to 3 years behind the chronological age) and mild to severe intellectual disability. Affected infants and children may also have mild to severe speech delays, where expressive language is affected more severely than receptive language, as well as moderate to severe delays in motor skills such as sitting and walking. Reports suggest that on average, affected children learn to sit up at 12 months (typically occurs at 6 to 8 months), walk at 30 months (typically occurs at 9 to 18 months) and speak at 24 months (typically begins around 12 months).Affected individuals may also have eye (ophthalmologic) abnormalities. This can include drooping of the upper eyelid (ptosis), clouding of the lens of the eye (cataracts) and misalignment of the eyes (strabismus, commonly known as “lazy eye”).Some children with CSS have been reported to have kidney (renal) or genitourinary abnormalities. There have been reports of affected individuals with fused kidneys at the lower end (horseshoe kidney) and the urethra – the tube through which urine drains from the bladder to exit the body – opening on the underside of the penis instead of at the tip (hypospadias).Individuals with CSS may also have gastric abnormalities which may include one portion of the bowel sliding into the next like a telescope (intussusception) or an opening in the diaphragm allowing abdominal organs to push up into the chest cavity (diaphragmatic hernia).Less commonly, affected individuals may have additional physical abnormalities, such as choanal atresia, a malformation in which a bony or thin layer of tissue blocks the passageway between the nose and throat, leading to breathing difficulties. Some individuals with CSS may also have heart abnormalities at birth. In addition, a brain abnormality known as Dandy-Walker malformation has been reported in some children. This condition is characterized by cystic malformation and expansion of one of the cavities in the brain (fourth ventricle). Dandy-Walker malformation is usually associated with an abnormal accumulation of cerebrospinal fluid (CSF) in the skull (hydrocephalus), resulting in increased fluid pressure, a rapid increase in head size, abnormal prominence of the back region of the head (occiput) and/or other associated findings. Some individuals with CSS may also have partial or complete absence of the band of nerve fibers that joins the two hemispheres of the brain (agenesis of the corpus callosum) and fewer folds in their brain (gyral simplification). Some affected individuals may also experience hearing loss, seizures and tics. There have been reports of liver cancer (hepatoblastoma) in affected individuals, but the link between CSS and tumor risk needs to be further investigated. | Symptoms of Coffin Siris Syndrome. CSS is characterized by distinctive abnormalities of the head and facial (craniofacial) region with affected individuals often described as having coarse facial features that become more prominent with age. Affected individuals may have an unusually small or large head (micro- or macrocephaly); a wide mouth with full, prominent lips; a broad nasal tip; a low nasal bridge and an abnormally long vertical groove between the nose and the upper lip (philtrum). Additional features may include thick eyebrows, long eyelashes and generalized excessive hair growth (hypertrichosis) with the exception of the scalp hair, which tends to be relatively sparse (scalp hypotrichosis). Reports suggest that sparse scalp hair improves with age.Individuals with CSS may also have characteristic skeletal abnormalities. For example, certain fingers and toes (digits), particularly the fifth fingers (“pinkies”) and toes may be unusually short due to absence or underdevelopment (hypoplasia) of the end bones (terminal phalanges) within these digits. The fingernails and toenails may also be underdeveloped or absent. Additional abnormalities may include dislocation of the inner forearm bone (radius) at the elbow, deformity of the hip (coxa valga) or unusually small or absent kneecaps (patellae). However, there are individuals with CSS who do not have the classic fifth digit findings.Early in life, infants with CSS typically experience feeding difficulties, vomiting, slow growth and weight gain (failure to thrive) which may have begun while the infant was still in the womb (intrauterine growth retardation), and frequent respiratory infections. In addition, affected infants and children may have hypotonia, abnormally loose joints, delayed bone age (2 to 3 years behind the chronological age) and mild to severe intellectual disability. Affected infants and children may also have mild to severe speech delays, where expressive language is affected more severely than receptive language, as well as moderate to severe delays in motor skills such as sitting and walking. Reports suggest that on average, affected children learn to sit up at 12 months (typically occurs at 6 to 8 months), walk at 30 months (typically occurs at 9 to 18 months) and speak at 24 months (typically begins around 12 months).Affected individuals may also have eye (ophthalmologic) abnormalities. This can include drooping of the upper eyelid (ptosis), clouding of the lens of the eye (cataracts) and misalignment of the eyes (strabismus, commonly known as “lazy eye”).Some children with CSS have been reported to have kidney (renal) or genitourinary abnormalities. There have been reports of affected individuals with fused kidneys at the lower end (horseshoe kidney) and the urethra – the tube through which urine drains from the bladder to exit the body – opening on the underside of the penis instead of at the tip (hypospadias).Individuals with CSS may also have gastric abnormalities which may include one portion of the bowel sliding into the next like a telescope (intussusception) or an opening in the diaphragm allowing abdominal organs to push up into the chest cavity (diaphragmatic hernia).Less commonly, affected individuals may have additional physical abnormalities, such as choanal atresia, a malformation in which a bony or thin layer of tissue blocks the passageway between the nose and throat, leading to breathing difficulties. Some individuals with CSS may also have heart abnormalities at birth. In addition, a brain abnormality known as Dandy-Walker malformation has been reported in some children. This condition is characterized by cystic malformation and expansion of one of the cavities in the brain (fourth ventricle). Dandy-Walker malformation is usually associated with an abnormal accumulation of cerebrospinal fluid (CSF) in the skull (hydrocephalus), resulting in increased fluid pressure, a rapid increase in head size, abnormal prominence of the back region of the head (occiput) and/or other associated findings. Some individuals with CSS may also have partial or complete absence of the band of nerve fibers that joins the two hemispheres of the brain (agenesis of the corpus callosum) and fewer folds in their brain (gyral simplification). Some affected individuals may also experience hearing loss, seizures and tics. There have been reports of liver cancer (hepatoblastoma) in affected individuals, but the link between CSS and tumor risk needs to be further investigated. | 285 | Coffin Siris Syndrome |
nord_285_2 | Causes of Coffin Siris Syndrome | CSS is thus far known to be caused by pathogenic gene variants (mutations) in one of the following genes: ARID1A, ARID1B, ARID2, SMARCA4, SMARCB1, SMARCE1, SMARCC2, DPF2, SOX4 and SOX11. Genes provide instructions for creating proteins that play a critical role in many functions of the body. The ARID and SMARC genes linked to CSS provide the instructions to make several different protein complexes that are known as BRG-1 associated factor (BAF) complex in humans. SOX11 is involved with transcriptional regulation of the BAF complex. These protein complexes regulate gene activity by altering how tightly regions of DNA are packaged, which can affect gene expression. Subsequently, the BAF complex is involved in a variety of processes including cell growth, division, and differentiation and the replication and repairing of DNA. It is still unclear how these mutations affect the BAF complex, but researchers believe they alter DNA packaging, which can disrupt gene activity and cellular processes and lead to the symptoms of CSS.CSS appears to be inherited as an autosomal dominant condition. 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 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. With CSS, most mutations appear to be the result of a new (de novo) mutation that occurs during early development in the embryo rather than inherited.In some dominant disorders, including CSS, disease expression may be variable. If individuals inherit a mutated gene for the disease, the characteristics that are expressed may vary greatly and range in severity from person to person.Other researchers think that CSS may be inherited in an autosomal recessive pattern. In recessive disorders, the condition does not appear unless a person inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one abnormal gene, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the abnormal gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier is 50% with each pregnancy. The chance for a child to receive a normal gene from each parent for that particular trait is 25%. The risk is the same for males and females.All individuals carry 4-5 abnormal genes. Parents who are related by blood (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. Parents of some individuals with CSS have been closely related by blood.Not all affected individuals have mutations in the ARID1A, ARID1B, ARID2, SMARCA4, SMARCB1, SMARCE1, SMARCC2, DPF2, SOX4 or SOX11 genes. It is likely that there are additional genes that cause CSS. Some researchers also suggest that isolated (sporadic) and familial cases of CSS may be due to unknown chromosomal abnormalities.Mutations in the genes that cause CSS have also been linked to other disorders (allelic disorders). Mutations in the ARID1B gene have been reported in several individuals with isolated intellectual disability and absence of other physical features of CSS. Mutations in the SMARCA4 and SMARCB1 genes have been reported to carry a potential increased risk for the growth of rhabdoid tumors (tumors of muscle tissue) and atypical teratoid and rhabdoid tumors (tumors typically located in the brain and other areas of the central nervous system). Overall, the risk of tumor growth is very low; further research is required to better assess the cancer risk in individuals with these mutations. | Causes of Coffin Siris Syndrome. CSS is thus far known to be caused by pathogenic gene variants (mutations) in one of the following genes: ARID1A, ARID1B, ARID2, SMARCA4, SMARCB1, SMARCE1, SMARCC2, DPF2, SOX4 and SOX11. Genes provide instructions for creating proteins that play a critical role in many functions of the body. The ARID and SMARC genes linked to CSS provide the instructions to make several different protein complexes that are known as BRG-1 associated factor (BAF) complex in humans. SOX11 is involved with transcriptional regulation of the BAF complex. These protein complexes regulate gene activity by altering how tightly regions of DNA are packaged, which can affect gene expression. Subsequently, the BAF complex is involved in a variety of processes including cell growth, division, and differentiation and the replication and repairing of DNA. It is still unclear how these mutations affect the BAF complex, but researchers believe they alter DNA packaging, which can disrupt gene activity and cellular processes and lead to the symptoms of CSS.CSS appears to be inherited as an autosomal dominant condition. 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 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. With CSS, most mutations appear to be the result of a new (de novo) mutation that occurs during early development in the embryo rather than inherited.In some dominant disorders, including CSS, disease expression may be variable. If individuals inherit a mutated gene for the disease, the characteristics that are expressed may vary greatly and range in severity from person to person.Other researchers think that CSS may be inherited in an autosomal recessive pattern. In recessive disorders, the condition does not appear unless a person inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one abnormal gene, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the abnormal gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier is 50% with each pregnancy. The chance for a child to receive a normal gene from each parent for that particular trait is 25%. The risk is the same for males and females.All individuals carry 4-5 abnormal genes. Parents who are related by blood (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. Parents of some individuals with CSS have been closely related by blood.Not all affected individuals have mutations in the ARID1A, ARID1B, ARID2, SMARCA4, SMARCB1, SMARCE1, SMARCC2, DPF2, SOX4 or SOX11 genes. It is likely that there are additional genes that cause CSS. Some researchers also suggest that isolated (sporadic) and familial cases of CSS may be due to unknown chromosomal abnormalities.Mutations in the genes that cause CSS have also been linked to other disorders (allelic disorders). Mutations in the ARID1B gene have been reported in several individuals with isolated intellectual disability and absence of other physical features of CSS. Mutations in the SMARCA4 and SMARCB1 genes have been reported to carry a potential increased risk for the growth of rhabdoid tumors (tumors of muscle tissue) and atypical teratoid and rhabdoid tumors (tumors typically located in the brain and other areas of the central nervous system). Overall, the risk of tumor growth is very low; further research is required to better assess the cancer risk in individuals with these mutations. | 285 | Coffin Siris Syndrome |
nord_285_3 | Affects of Coffin Siris Syndrome | CSS occurs worldwide with no ethnic predisposition. Since the disorder was originally described in 1970 (G.S. Coffin), there are likely several thousand individuals with known CSS, however there are more individuals with CSS who have not yet undergone molecular testing or who have not come to medical attention. | Affects of Coffin Siris Syndrome. CSS occurs worldwide with no ethnic predisposition. Since the disorder was originally described in 1970 (G.S. Coffin), there are likely several thousand individuals with known CSS, however there are more individuals with CSS who have not yet undergone molecular testing or who have not come to medical attention. | 285 | Coffin Siris Syndrome |
nord_285_4 | Related disorders of Coffin Siris Syndrome | Symptoms of the following disorders may be similar to those of Coffin-Siris syndrome. Comparisons may be useful for a differential diagnosis:Mosaic trisomy 9 is a rare chromosomal disorder in which there are three copies (trisomy) of chromosome number 9 rather than twice in some cells of the body. The term “mosaic” indicates that some cells contain the extra chromosome 9, while others have the normal chromosomal pair. Associated symptoms and findings may vary greatly in range and severity, depending on the percentage of cells with the extra chromosome. However, common features include growth deficiency before birth (intrauterine growth retardation); intellectual disability; structural malformations of the heart that are present at birth (congenital heart defects) and/or distinctive abnormalities of the skull and facial (craniofacial) region, such as a sloping forehead, a bulbous nose, short eyelid folds (palpebral fissures), deeply set eyes and/or low-set, malformed ears. The syndrome may also be characterized by musculoskeletal, genital, kidney (renal) and/or additional physical abnormalities. Mosaic trisomy 9 may be caused by errors during the division of a parent’s reproductive cells or during the division of body tissue cells early in the development of the embryo. (For further information, choose “mosaic trisomy 9” as your search term in the Rare Disease Database.)Cornelia de Lange syndrome (CdLS) is a rare genetic disorder that is apparent at birth (congenital). Associated symptoms and findings typically include delays in physical development before and after birth (prenatal and postnatal growth retardation); characteristic craniofacial abnormalities, resulting in a distinctive facial appearance; malformations of the hands and arms (upper limbs); and mild to severe intellectual disability. Many infants and children with the disorder have an unusually small, short head (microbrachycephaly); an abnormally long vertical groove between the upper lip and nose (philtrum); a depressed nasal bridge; upturned nostrils (anteverted nares) and a protruding upper jaw (maxillary prognathism). Additional, characteristic facial abnormalities may include thin, downturned lips; low-set ears; arched, well-defined eyebrows that grow together across the base of the nose (synophrys); an unusually low hairline on the forehead and the back of the neck and abnormally curly, long eyelashes. Affected individuals may also have distinctive malformations of the limbs, such as unusually small hands and feet, inward deviation (clinodactyly) of the fifth fingers, or webbing (syndactyly) of certain toes. Less commonly, there may be absence of the forearms, hands and fingers. Infants with Cornelia de Lange syndrome may also have feeding and breathing difficulties; an increased susceptibility to respiratory infections; a low-pitched “growling” cry; heart defects; delayed skeletal maturation; hearing loss or other physical abnormalities. The range and severity of associated symptoms and findings may be extremely variable from person to person. Cornelia de Lange syndrome can be inherited as an autosomal dominant condition or an X-linked condition. The genes that have been found to be associated with Cornelia de Lange syndrome are NIPBL, located on chromosome 5 and the SMC1A gene on the X chromosome. Milder forms of Cornelia de Lange have been attributed to mutations in the SMC3 and RAD21 genes. Most affected individuals have an abnormal gene as a result of a new gene mutation and do not have an affected parent. Other genes may be found to be associated with Cornelia de Lange syndrome in the future. (For further information, choose “Cornelia de Lange” as your search term in the Rare Disease Database.)Coffin-Lowry syndrome is a rare genetic disorder characterized by intellectual disability; abnormalities of the head and facial (craniofacial) area; large, soft hands with short, thin (tapered) fingers; short stature and/or various skeletal abnormalities. Characteristic facial features may include an underdeveloped upper jawbone (maxillary hypoplasia), an abnormally prominent brow, downslanting eyelid folds (palpebral fissures), widely spaced eyes (hypertelorism), large ears and/or unusually thick eyebrows. Skeletal abnormalities may include abnormal front-to-back and side-to-side curvature of the spine (kyphoscoliosis) and unusual prominence of the breastbone (sternum) (pectus carinatum). Coffin-Lowry syndrome is caused by mutations in the RSK2 gene and is inherited in an X-linked dominant pattern. Males are usually more severely affected than females. (For further information, choose “Coffin Lowry syndrome” as your search term in the Rare Disease Database.)DOOR syndrome is a rare genetic disorder that may be recognized shortly after birth. “DOOR,” an acronym for characteristic abnormalities associated with the syndrome, stands for (D)eafness due to a defect of the inner ear or auditory nerve (sensorineural hearing loss); (O)nychodystrophy or malformation of the nails; (O)steodystrophy, meaning malformation of certain bones; and mild to profound mental (R)etardation. Some affected infants may have sudden episodes of uncontrolled electrical activity in the brain (seizures). Distinctive nail abnormalities may include underdeveloped, misshapen or absent fingernails and/or toenails, while characteristic bone malformations may consist of an extra small bone in the thumbs and/or great toes (triphalangy) and/or underdevelopment (hypoplasia) of bones in other fingers and/or toes. DOOR syndrome is inherited in an autosomal recessive pattern. (For further information, choose “DOOR syndrome” as your search term in the Rare Disease Database.)Nicolaides-Baraitster syndrome (NCBRS) is an extremely rare condition characterized by severe intellectual disability, sparse hair, short stature, early onset seizures and distinctive facial features. It was recently discovered that mutations in the SMARCA2 gene cause some cases of NBRS.Brachymorphism-onychodysplasia-dysphalangism (BOD) syndrome is a rare genetic condition characterized by short fifth fingers, short stature, underdeveloped nails, a broad nose, a wide mouth and normal intellect to mild intellectual disability. BOD is believed to follow an autosomal dominant inheritance pattern, but often occurs as the result of a new mutation and is not inherited. Fetal hydantoin syndrome is a rare disorder that is caused by exposure of a fetus to the anticonvulsant drug phenytoin (Dilantin). The symptoms of this disorder may include abnormalities of the skull and facial features, growth deficiencies, underdeveloped nails of the fingers and toes and/or mild developmental delays. Other findings occasionally associated with this syndrome include cleft lip and palate, an unusually small head (microcephaly) and brain malformations with more significant developmental delays. (For further information, choose “fetal hydantoin syndrome” as your search term in the Rare Diseases Database.)Mabry syndrome/hyperphosphatasia with intellectual disability syndrome type 1 is a genetic condition characterized by developmental delays, feeding problems, low muscle tone and underdeveloped fifth fingers. Affected individuals also have distinctive facial features such as a broad nose, downturned corners of the mouth and arched eyebrows. A characteristic lab value found in these individuals is an elevated alkaline phosphatase. The disorder is caused by a mutation in the PIGV gene and is inherited in an autosomal recessive manner.4q monosomy is a rare chromosomal disorder in which there is a single copy (monosomy) of a portion of the 4th chromosome. Associated symptoms and findings may be variable, depending upon the specific length and location of the deleted portion of chromosome 4. Characteristic features include growth deficiency after birth (postnatal growth retardation), varying degrees of intellectual disability, malformations of the skull and facial (craniofacial) region, structural heart defects, abnormalities of the hands and feet and/or other physical findings. 4q monosomy usually results from spontaneous (de novo) errors very early during embryonic development that occur for unknown reasons. (For further information, choose “distal 4q monosomy” as your search term in the Rare Diseases Database).Other chromosomal disorders may have features similar to those associated with CSS. Chromosomal testing is necessary to confirm the specific chromosomal abnormality present. (For further information on such disorders, choose the name of the specific chromosomal disorder in question or use “chromosome” as your search term in the Rare Disease Database.) | Related disorders of Coffin Siris Syndrome. Symptoms of the following disorders may be similar to those of Coffin-Siris syndrome. Comparisons may be useful for a differential diagnosis:Mosaic trisomy 9 is a rare chromosomal disorder in which there are three copies (trisomy) of chromosome number 9 rather than twice in some cells of the body. The term “mosaic” indicates that some cells contain the extra chromosome 9, while others have the normal chromosomal pair. Associated symptoms and findings may vary greatly in range and severity, depending on the percentage of cells with the extra chromosome. However, common features include growth deficiency before birth (intrauterine growth retardation); intellectual disability; structural malformations of the heart that are present at birth (congenital heart defects) and/or distinctive abnormalities of the skull and facial (craniofacial) region, such as a sloping forehead, a bulbous nose, short eyelid folds (palpebral fissures), deeply set eyes and/or low-set, malformed ears. The syndrome may also be characterized by musculoskeletal, genital, kidney (renal) and/or additional physical abnormalities. Mosaic trisomy 9 may be caused by errors during the division of a parent’s reproductive cells or during the division of body tissue cells early in the development of the embryo. (For further information, choose “mosaic trisomy 9” as your search term in the Rare Disease Database.)Cornelia de Lange syndrome (CdLS) is a rare genetic disorder that is apparent at birth (congenital). Associated symptoms and findings typically include delays in physical development before and after birth (prenatal and postnatal growth retardation); characteristic craniofacial abnormalities, resulting in a distinctive facial appearance; malformations of the hands and arms (upper limbs); and mild to severe intellectual disability. Many infants and children with the disorder have an unusually small, short head (microbrachycephaly); an abnormally long vertical groove between the upper lip and nose (philtrum); a depressed nasal bridge; upturned nostrils (anteverted nares) and a protruding upper jaw (maxillary prognathism). Additional, characteristic facial abnormalities may include thin, downturned lips; low-set ears; arched, well-defined eyebrows that grow together across the base of the nose (synophrys); an unusually low hairline on the forehead and the back of the neck and abnormally curly, long eyelashes. Affected individuals may also have distinctive malformations of the limbs, such as unusually small hands and feet, inward deviation (clinodactyly) of the fifth fingers, or webbing (syndactyly) of certain toes. Less commonly, there may be absence of the forearms, hands and fingers. Infants with Cornelia de Lange syndrome may also have feeding and breathing difficulties; an increased susceptibility to respiratory infections; a low-pitched “growling” cry; heart defects; delayed skeletal maturation; hearing loss or other physical abnormalities. The range and severity of associated symptoms and findings may be extremely variable from person to person. Cornelia de Lange syndrome can be inherited as an autosomal dominant condition or an X-linked condition. The genes that have been found to be associated with Cornelia de Lange syndrome are NIPBL, located on chromosome 5 and the SMC1A gene on the X chromosome. Milder forms of Cornelia de Lange have been attributed to mutations in the SMC3 and RAD21 genes. Most affected individuals have an abnormal gene as a result of a new gene mutation and do not have an affected parent. Other genes may be found to be associated with Cornelia de Lange syndrome in the future. (For further information, choose “Cornelia de Lange” as your search term in the Rare Disease Database.)Coffin-Lowry syndrome is a rare genetic disorder characterized by intellectual disability; abnormalities of the head and facial (craniofacial) area; large, soft hands with short, thin (tapered) fingers; short stature and/or various skeletal abnormalities. Characteristic facial features may include an underdeveloped upper jawbone (maxillary hypoplasia), an abnormally prominent brow, downslanting eyelid folds (palpebral fissures), widely spaced eyes (hypertelorism), large ears and/or unusually thick eyebrows. Skeletal abnormalities may include abnormal front-to-back and side-to-side curvature of the spine (kyphoscoliosis) and unusual prominence of the breastbone (sternum) (pectus carinatum). Coffin-Lowry syndrome is caused by mutations in the RSK2 gene and is inherited in an X-linked dominant pattern. Males are usually more severely affected than females. (For further information, choose “Coffin Lowry syndrome” as your search term in the Rare Disease Database.)DOOR syndrome is a rare genetic disorder that may be recognized shortly after birth. “DOOR,” an acronym for characteristic abnormalities associated with the syndrome, stands for (D)eafness due to a defect of the inner ear or auditory nerve (sensorineural hearing loss); (O)nychodystrophy or malformation of the nails; (O)steodystrophy, meaning malformation of certain bones; and mild to profound mental (R)etardation. Some affected infants may have sudden episodes of uncontrolled electrical activity in the brain (seizures). Distinctive nail abnormalities may include underdeveloped, misshapen or absent fingernails and/or toenails, while characteristic bone malformations may consist of an extra small bone in the thumbs and/or great toes (triphalangy) and/or underdevelopment (hypoplasia) of bones in other fingers and/or toes. DOOR syndrome is inherited in an autosomal recessive pattern. (For further information, choose “DOOR syndrome” as your search term in the Rare Disease Database.)Nicolaides-Baraitster syndrome (NCBRS) is an extremely rare condition characterized by severe intellectual disability, sparse hair, short stature, early onset seizures and distinctive facial features. It was recently discovered that mutations in the SMARCA2 gene cause some cases of NBRS.Brachymorphism-onychodysplasia-dysphalangism (BOD) syndrome is a rare genetic condition characterized by short fifth fingers, short stature, underdeveloped nails, a broad nose, a wide mouth and normal intellect to mild intellectual disability. BOD is believed to follow an autosomal dominant inheritance pattern, but often occurs as the result of a new mutation and is not inherited. Fetal hydantoin syndrome is a rare disorder that is caused by exposure of a fetus to the anticonvulsant drug phenytoin (Dilantin). The symptoms of this disorder may include abnormalities of the skull and facial features, growth deficiencies, underdeveloped nails of the fingers and toes and/or mild developmental delays. Other findings occasionally associated with this syndrome include cleft lip and palate, an unusually small head (microcephaly) and brain malformations with more significant developmental delays. (For further information, choose “fetal hydantoin syndrome” as your search term in the Rare Diseases Database.)Mabry syndrome/hyperphosphatasia with intellectual disability syndrome type 1 is a genetic condition characterized by developmental delays, feeding problems, low muscle tone and underdeveloped fifth fingers. Affected individuals also have distinctive facial features such as a broad nose, downturned corners of the mouth and arched eyebrows. A characteristic lab value found in these individuals is an elevated alkaline phosphatase. The disorder is caused by a mutation in the PIGV gene and is inherited in an autosomal recessive manner.4q monosomy is a rare chromosomal disorder in which there is a single copy (monosomy) of a portion of the 4th chromosome. Associated symptoms and findings may be variable, depending upon the specific length and location of the deleted portion of chromosome 4. Characteristic features include growth deficiency after birth (postnatal growth retardation), varying degrees of intellectual disability, malformations of the skull and facial (craniofacial) region, structural heart defects, abnormalities of the hands and feet and/or other physical findings. 4q monosomy usually results from spontaneous (de novo) errors very early during embryonic development that occur for unknown reasons. (For further information, choose “distal 4q monosomy” as your search term in the Rare Diseases Database).Other chromosomal disorders may have features similar to those associated with CSS. Chromosomal testing is necessary to confirm the specific chromosomal abnormality present. (For further information on such disorders, choose the name of the specific chromosomal disorder in question or use “chromosome” as your search term in the Rare Disease Database.) | 285 | Coffin Siris Syndrome |
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