Wiskott-Aldrich Syndrome

What is Wiskott-Aldrich Syndrome?

Wiskott-Aldrich syndrome is a rare genetic disorder related to the X-chromosome. It features a trio of distinct signs: immune system weakness, low platelet count (thrombocytopenia), and a skin condition called eczema. Its cause is a faulty gene, specifically that which creates the Wiskott-Aldrich syndrome protein (WASp), that disrupts the immune system and results in a weakened ability to fight infections.

The severity of the disease varies widely dependent on the specific mutation in the gene. This spectrum ranges from a severe form of the disease (known as classic WAS) to more mild versions known as X-linked thrombocytopenia (XLT, a condition characterized by low platelet count) and X-linked neutropenia (another condition that causes a low count of a specific type of white blood cell called neutrophils).

What Causes Wiskott-Aldrich Syndrome?

Wiskott-Aldrich syndrome is caused by changes or mutations in a specific gene known as the WAS gene. This gene is responsible for creating the WAS protein which plays a crucial role in cellular communication and the formation of immunological synapses (connections between immune cells). When mutations occur in the WAS gene, the shape of the WAS protein can change. This variability in the protein’s structure can lead to different characteristics of the disease showing up in different people.

Risk Factors and Frequency for Wiskott-Aldrich Syndrome

This disease, which is linked to the X chromosome, has an estimated occurrence rate of 1 in every 100,000 live births. It mainly affects males. It happens in all ethnic and geographical areas without any favoritism. Some milder cases might be under-reported because they are incorrectly identified as a different condition known as idiopathic thrombocytopenia purpura.

Signs and Symptoms of Wiskott-Aldrich Syndrome

This disease displays various symptoms, including:

Bleeding: Patients typically show bleeding and bruising, such as rashes, nosebleeds, blood in urine, and severe bleeding gums or from wounds. In newborns, there might be excessive bleeding from the umbilical stump or after circumcision. Some infants, especially those below 2 years old, may experience severe, uncontrollable bleeding. This can pose a life-threatening risk.
Immunodeficiency: The severity of a weak immune system varies based on the specific mutation in each patient. Generally, patients struggle with multiple recurring infections and growth issues. They are especially prone to diseases from encapsulated organisms. Common infections include ear infections, sinusitis, pneumonia, meningitis, sepsis, and colitis. Patients who have undergone spleen removal are at an even higher risk of severe infections and sepsis. This weakened immune system also leaves them prone to infections from Pneumocystis jirovecii, Molluscum contagiosum, varicella, and cytomegalovirus. They may also experience infrequent fungal infections, typically due to Candida albicans.
Eczema: About half of patients with this condition develop eczema within their first year of life. This skin inflammation closely resembles typical allergic dermatitis.
Autoimmune manifestations: There may be instances of autoimmune diseases such as anemia, neutropenia, vessel inflammation, inflammatory bowel disease, and kidney diseases. These patients may also generate a wide variety of autoantibodies.
Malignancies: Some patients may develop cancers, specifically B cell lymphoma and leukemia. These usually occur during adolescence or in young adulthood.

There are three primary clinical types of the disease:

Classic Wiskott-Aldrich syndrome: This severe variant typically manifests in early childhood with symptoms including excessive bleeding due to low platelet count, recurring infections, and severe eczema. Swelling of the lymph nodes is common, and there can also be an enlargement of the liver or spleen. These patients are at an increased risk of developing autoimmune diseases and lymphoma or other cancers, which often leads to premature death.
X-linked neutropenia: This variant primarily manifests as a low neutrophil count. These patients generally suffer from infections typical of those with a neutrophil deficit, but they may also experience infections associated with lymphocyte dysfunction. They also have a higher risk of certain blood disorders called myelodysplasia.
X-linked thrombocytopenia: This variant manifests as a birth condition that involves a low platelet count, which can sometimes fluctuate. The eczema symptom is usually mild. Overall, these patients usually have a fairly mild disease progression and good long-term survival rates. However, they still have a higher risk of life-threatening infections, severe bleeding, autoimmune complications, and cancer.

Testing for Wiskott-Aldrich Syndrome

Wiskott-Aldrich syndrome or X-linked thrombocytopenia (XLT) is a disease that should be considered if a male patient is showing signs such as petechiae (tiny red or purple spots on the skin caused by bleeding), bruises, and congenital (present at birth) or early-onset thrombocytopenia (low platelet count) associated with small plates in their blood. These small plates, known as platelets, are the part of our blood that helps with clotting.

Doctors confirm this diagnosis by identifying harmful alterations or mutations in a specific gene, called the WAS gene. The presence of mild or serious eczema (a skin condition) can also support this diagnosis. Patients with this condition may not show signs of infections and immunity abnormalities or they may have mild or severe symptoms. Autoimmune diseases (where the immune system attacks its own body) and cancer occur more often in patients with classic Wiskott-Aldrich syndrome than in those with XLT.

A specialized test can be performed to look for WAS protein in a type of white blood cell called lymphocytes. This test uses an anti-WASp antibody and flow cytometry, an advanced method that analyzes cells.

In addition, a condition called XLN should be considered in any male patient presenting with severe congenital neutropenia (an extremely low level of a specific type of white blood cell).

Patients with Wiskott-Aldrich syndrome have been found to exhibit abnormal immune system findings which include a decreased number and function of T cells and regulatory T cells (types of white blood cells that play a key role in the immune system), abnormal immunoglobulin types (proteins in the blood that function as antibodies), and impaired functions of natural killer cells to fight infection.

Usually, in infancy, lymphocyte counts (types of white blood cells) are normal but T and B cell numbers (two main types of lymphocytes that help to fight infections) decrease later in life in patients with classic WAS. Also, fluctuations in the levels of Immunoglobulins are reported, such as normal levels of IgG (antibodies that characterize an adaptive immune response), decreased levels of IgM, and increased levels of IgA and IgE.

Abnormal findings are commonly found in lymphoreticular tissue (tissue related to immune response). This includes varying degrees of T cell zone depletion in lymph nodes and the spleen, decrease in the number of follicles and abnormal follicular formation, and regressive or “burnt out” germinal centers.

Patient’s blood tests who have mutations in the WAS gene, generally show thrombocytopenia associated with small platelets in their blood, except for those presenting with an XLN phenotype. Platelet counts are generally 20,000 to 50,000 per cubic millimeter (mm) which but may drop below 10,000 per mm.

Treatment Options for Wiskott-Aldrich Syndrome

Wiskott-Aldrich syndrome, a rare genetic disorder, is primarily managed with regular care including different types of medications. This condition often requires broad-spectrum antibiotics to treat bacterial infections, and antiviral or antifungal medications for viral and fungal infections. To help prevent bleeding, patients may need transfusions of platelets, a type of blood cell that aids in clotting. Additionally, topical steroids, which are creams or lotions, are utilized for managing eczema, a skin condition common in these patients.

Another treatment probability is a therapy called Intravenous Immunoglobin (IVIG) which can help those with severe antibody deficiency. Antibodies are the body’s defense forces against infections. This treatment involves directing beneficial antibodies into the body to enhance its immunity. While common in other immunity disorders, patients with Wiskott-Aldrich syndrome usually need a higher dose due to faster breakdown in their bodies. The same antibodies can also be given under the skin, though it’s a method that needs careful attention in these patients due to an increased risk of bleeding.

Eltrombopag, an approved medication for a type of low platelet count condition, might also help reduce chances of bleeding for those waiting for a particular cell transplant.

For autoimmune symptoms – conditions where the body’s immune system attacks its own cells – immunosuppressive treatments might be necessitated. In particular, autoimmune cytopenias, a group of conditions causing low blood cells, might react positively to a medication called rituximab, which is fairly safe for patients already undergoing IVIG treatment.

Another option is spleen removal or splenectomy, which might be chosen in certain cases to increase platelet count and reduce bleeding chances. However, individuals who undergo this procedure need to be on lifelong antibiotics to prevent infections and face a higher chance of getting blood poisoning (septicemia).

Hematopoietic cell transplantation (HCT), a type of stem cell transplant, is currently the only known cure for this condition. This process has seen promising results, especially for patients who have a matched human leukocyte antigen (HLA), a protein marker on cells that the immune system uses to recognize self cells, from a family member or unrelated donors, or partially matched cord-blood donors.

Additionally, gene therapy, a procedure of altering, introducing, removing or replacing a faulty gene, is also being explored as a possible cure for this disease.

There are several conditions that can look a lot like Wiskott-Aldrich Syndrome (WAS) or X-linked thrombocytopenia (XLT). These are conditions that also cause skin inflammation (eczema), higher than normal levels of a certain antibody (IgE) in the blood, and make a person more prone to infections. The conditions include:

Hyper Immunoglobulin E syndrome
Omenn Syndrome
Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX)
Atopic Dermatitis (a type of eczema)
Immune Thrombocytopenic Purpura (a bleeding disorder)
Congenital Neutropenia (a condition causing low levels of a type of white blood cell called neutrophils)

What to expect with Wiskott-Aldrich Syndrome

People with X-linked thrombocytopenia, a blood disorder, usually have a good prognosis – that means they can expect to live as long as the average person. However, those with a condition called Wiskott-Aldrich syndrome unfortunately face a lower life expectancy. This is mainly due to repeated infections, an over-activity of the immune system that harms healthy cells, and the possibility of developing cancer. In these patients, the most common cause of death is excessive bleeding.

Frequently asked questions

The prognosis for Wiskott-Aldrich Syndrome varies depending on the specific mutation in the gene. Individuals with X-linked thrombocytopenia, a milder form of the disease, usually have a good prognosis and can expect to live as long as the average person. However, individuals with Wiskott-Aldrich syndrome have a lower life expectancy due to repeated infections, over-activity of the immune system, and the possibility of developing cancer. Excessive bleeding is the most common cause of death in these patients.

Wiskott-Aldrich syndrome is caused by changes or mutations in the WAS gene.

The signs and symptoms of Wiskott-Aldrich Syndrome include: - Bleeding: Patients with Wiskott-Aldrich Syndrome often experience bleeding and bruising, such as rashes, nosebleeds, blood in urine, and severe bleeding gums or from wounds. In newborns, there might be excessive bleeding from the umbilical stump or after circumcision. Some infants, especially those below 2 years old, may experience severe, uncontrollable bleeding, which can be life-threatening. - Immunodeficiency: Patients with Wiskott-Aldrich Syndrome have a weak immune system, which can lead to multiple recurring infections and growth issues. They are particularly prone to diseases from encapsulated organisms. Common infections include ear infections, sinusitis, pneumonia, meningitis, sepsis, and colitis. Patients who have had their spleen removed are at an even higher risk of severe infections and sepsis. They are also susceptible to infections from Pneumocystis jirovecii, Molluscum contagiosum, varicella, cytomegalovirus, and infrequent fungal infections. - Eczema: Approximately half of patients with Wiskott-Aldrich Syndrome develop eczema within their first year of life. This skin inflammation closely resembles typical allergic dermatitis. - Autoimmune manifestations: Patients with Wiskott-Aldrich Syndrome may experience autoimmune diseases such as anemia, neutropenia, vessel inflammation, inflammatory bowel disease, and kidney diseases. They may also generate a wide variety of autoantibodies. - Malignancies: Some patients with Wiskott-Aldrich Syndrome may develop cancers, specifically B cell lymphoma and leukemia. These malignancies usually occur during adolescence or young adulthood. In summary, the signs and symptoms of Wiskott-Aldrich Syndrome include bleeding, immunodeficiency, eczema, autoimmune manifestations, and a higher risk of malignancies.

The types of tests that are needed for Wiskott-Aldrich Syndrome include: 1. Genetic testing to identify harmful alterations or mutations in the WAS gene. 2. Specialized tests to look for the presence of WAS protein in lymphocytes, using an anti-WASp antibody and flow cytometry. 3. Blood tests to measure platelet counts, which are generally low in patients with Wiskott-Aldrich Syndrome. 4. Evaluation of immune system findings, such as T cell and regulatory T cell counts, immunoglobulin levels, and natural killer cell function. 5. Examination of lymphoreticular tissue for abnormal findings, such as T cell zone depletion and abnormal follicular formation. 6. Additional tests may be necessary to evaluate specific symptoms or complications, such as severe congenital neutropenia or autoimmune cytopenias.

Hyper Immunoglobulin E syndrome, Omenn Syndrome, Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX), Atopic Dermatitis (a type of eczema), Immune Thrombocytopenic Purpura (a bleeding disorder), Congenital Neutropenia (a condition causing low levels of a type of white blood cell called neutrophils)

When treating Wiskott-Aldrich Syndrome, there are potential side effects associated with the different treatment options. These side effects include: - Broad-spectrum antibiotics: There may be risks of antibiotic resistance and gastrointestinal issues. - Antiviral or antifungal medications: Possible side effects include nausea, vomiting, and liver toxicity. - Platelet transfusions: There is a risk of transfusion reactions and infections. - Topical steroids: Potential side effects include skin thinning and increased risk of infections. - Intravenous Immunoglobin (IVIG): Side effects can include headache, fever, and allergic reactions. - Eltrombopag: Possible side effects include headache, nausea, and diarrhea. - Immunosuppressive treatments: These treatments can increase the risk of infections and have other side effects. - Spleen removal (splenectomy): Side effects include an increased risk of infections and septicemia. - Hematopoietic cell transplantation (HCT): There are risks associated with the transplant procedure, such as graft-versus-host disease and infections. - Gene therapy: This is still being explored as a potential cure, and its side effects are not yet fully known.

An immunologist or a hematologist.

Wiskott-Aldrich Syndrome has an estimated occurrence rate of 1 in every 100,000 live births.

Wiskott-Aldrich Syndrome is primarily managed with regular care including different types of medications. Treatment options include broad-spectrum antibiotics for bacterial infections, antiviral or antifungal medications for viral and fungal infections, transfusions of platelets to prevent bleeding, and topical steroids for managing eczema. Intravenous Immunoglobulin (IVIG) therapy can be used to enhance immunity, and Eltrombopag may help reduce bleeding for those waiting for a cell transplant. Immunosuppressive treatments, such as rituximab, may be necessary for autoimmune symptoms. Spleen removal or splenectomy may be chosen in certain cases to increase platelet count and reduce bleeding chances. Hematopoietic cell transplantation (HCT) is currently the only known cure, and gene therapy is being explored as a possible cure.

Wiskott-Aldrich Syndrome is a rare genetic disorder characterized by immune system weakness, low platelet count, and a skin condition called eczema. It is caused by a faulty gene that disrupts the immune system and weakens the ability to fight infections.

Eczema Genetic Disorders Immunodeficiency Thrombocytopenia X-Linked Disorders