Wiskott-Aldrich syndrome
Synonyms and keywords: Aldrich syndrome

# Overview
Wiskott-Aldrich syndrome (WAS) is a rare X-linked recessive disease characterized by eczema, thrombocytopenia (low platelet counts), immune deficiency, and bloody diarrhea (due to the low platelet counts).  It is also sometimes called the eczema-thrombocytopenia-immunodeficiency syndrome in keeping with Aldrich's original description in 1954. The WAS-related disorders of X-linked thrombocytopenia (XLT) and X-linked congenital neutropenia (XLN) may present similar but less severe symptoms and are caused by mutations of the same gene.

# Historical Perspective
The syndrome is named after Dr Robert Anderson Aldrich, an American pediatrician who described the disease in a family of Dutch-Americans in 1954, and Dr Alfred Wiskott, a German pediatrician who first noticed the syndrome in 1937. Wiskott described three brothers with a similar disease, whose sisters were unaffected. In 2006 a German research group analysed family members of Wiskott's three cases, and surmised that they probably shared a novel frameshift mutation of the first exon of the WAS gene.

# Classification
Jin et al (2004) employ a numerical grading of severity:
- Grade 0.5: intermittent thrombopenia
- Grade 1.0: thrombopenia and small platelets
- Grade 2.0: thrombopenia and normally responsive eczema or occasional upper respiratory tract infections.
- Grade 2.5: thrombopenia and therapy-responsive but severe eczema or airway infections requiring antibiotics
- Grade 3.0: both eczema and airway infections requiring antibiotics
- Grade 4.0: eczema continuously requiring therapy and/or severe or life threatening infections
- Grade 5.0: autoimmune disease or malignancy in an XLT/WAS patient.

# Pathophysiology
In the WiskottAldrich syndrome, the platelets are small and do not function properly. They are removed by the spleen, which leads to low platelet counts.
WiskottAldrich syndrome was linked in 1994 to mutations in a gene on the short arm of the X chromosome, which was termed Wiskott-Aldrich syndrome protein (WASp). It was later discovered that the disease X-linked thrombocytopenia (XLT) was also due to WASp mutations, but different ones from those that cause full-blown WiskottAldrich syndrome. Furthermore, the rare disorder X-linked neutropenia has been linked to particular mutations of the WASp gene.
The WASp gene codes for the protein by the same name, which is 502 amino acids long and is mainly expressed in hematopoietic cells (the cells in the bone marrow that develop into blood cells). The main function of WASp is to activate actin polymerization by binding to the Arp2/3 complex.  In T-cell, WASp is important because it is known to be activated via T-cell receptor (TCR) signaling pathways to induce cortical actin cytoskeleton rearrangements that are responsible for forming the immunological synapse.
The immune deficiency is caused by decreased antibody production, and an inability for T cells to become polarized  (making it a combined immunodeficiency). This leads to increased susceptibility to infections, particularly of the ears and sinuses. T cells are unable to reorganize their actin cytoskeleton. The type of mutation to the WASp gene correlates significantly with the degree of severity: those that led to the production of a truncated protein caused significantly more symptoms than those with a missense mutation but a normal-length WASp. Although autoimmune disease and malignancy occur in both types of mutation, those patients with truncated WASp carry a higher risk.
A defect in CD43 molecule has been found to be associated in patients with WiskottAldrich syndrome.

# Causes
In WiskottAldrich syndrome, the platelets are small and do not function properly. They are removed by the spleen, which leads to low platelet counts.
WiskottAldrich syndrome was linked in 1994 to mutations in a gene on the short arm of the X chromosome, which was termed Wiskott-Aldrich syndrome protein (WASp). It was later discovered that the disease X-linked thrombocytopenia (XLT) was also due to WASp mutations, but different ones from those that cause full-blown WiskottAldrich syndrome. Furthermore, the rare disorder X-linked neutropenia has been linked to particular mutations of the WASp gene.
The WASp gene codes for the protein by the same name, which is 502 amino acids long and is mainly expressed in hematopoietic cells (the cells in the bone marrow that develop into blood cells). The main function of WASp is to activate actin polymerization by binding to the Arp2/3 complex.  In T-cell, WASp is important because it is known to be activated via T-cell receptor (TCR) signaling pathways to induce cortical actin cytoskeleton rearrangements that are responsible for forming the immunological synapse.
The immune deficiency is caused by decreased antibody production, and an inability for T cells to become polarized  (making it a combined immunodeficiency). This leads to increased susceptibility to infections, particularly of the ears and sinuses. T-cells are unable to reorganize their actin cytoskeleton. The type of mutation to the WASp gene correlates significantly with the degree of severity: those that led to the production of a truncated protein caused significantly more symptoms than those with a missense mutation but a normal-length WASp. Although autoimmune disease and malignancy occur in both types of mutation, those patients with truncated WASp carry a higher risk.
A defect in CD43 molecule has been found to be associated in patients with WiskottAldrich syndrome.

# Differentiating Wiskott-Aldrich Syndrome From Other Disorders of Humoral Imuunodeficiency
Wiskott-Aldrich Syndrome should be differentiated from other disorders leading to hypogammaglobulinemia and defects of humoral immunity. The following conditions may be considered as differentials:
- Malignancy: can cause the reduction in the immunoglobulin production.
- Viral infections: such as Epstein-Barr virus, HIV, cytomegalovirus are other causes of hypogammaglobulinemia..
- Side effect of certain medications: Some drugs include systemic glucocorticoids, phenytoin, and carbamazepine, have been associated with IgG deficiency.
- Other causes of primary humoral immunodeficiencies.
- Smoking: may cause IgG2 subclass deficiency.
- Protein-losing conditions: enteropathies, nephrotic syndrome, burns, and other traumas may cause abnormal loss of immunoglobulins.

# Differentiating Wiskott-Aldrich Syndrome From Other Bleeding Diseases
- Wiskott-Aldrich syndrome must be differentiated from other bleeding disorders. Different causes of bleeding disorders can be differentiated based on their clinical manifestation and laboratory findings. These features have discussed in the below table:

# Risk Factors
- Positive family history of Wiskott-Aldrich syndrome, can be considered as a risk factor.

# Screening
- Flow cytometry:
Anti-WASp antibody can be used to detect presence or absence of WAS protein. However, flow cytometry may not detect expression of mutated, reduced or poor WASp.
- Anti-WASp antibody can be used to detect presence or absence of WAS protein. However, flow cytometry may not detect expression of mutated, reduced or poor WASp.
- Identification of carriers: Known female carriers can be identified by using DNA mutation analysis of WAS gene.
- Prenatal diagnosis: DNA analysis from chorionic villus sampling can be performed.

# Natural History, Complications, and Prognosis
- If left untreated, patients with Wiscott-Aldrich syndrome may progress to develop manifestations associated with thrombocytopenia, and abnormal platelet function, defective innate and adaptive immunity which include, severe bleeding (eg, epistaxis, purpura, life threatening gastrointestinal and intracranial hemorrhages), recurrent and severe bronchopulmonary infections. Malignancy and autoimmunity risk has also increased. These conditions may increase the risk of death.
- Common complications of Wiscott-Aldrich syndrome include:
Recurrent infections with bacterial, viral, fungal and opportunistic organisms. Most common clinical manifestations include otitis media, sinusitis, pneumonia, meningitis, skin infections, and sepsis.
Bleeding diathesis (eg, epistaxis, ecchymoses, petechiae, hematemesis, intracranial and gastrointestinal hemorrhages)
Autoimmune manifestations may occur in the form of autoimmune hemolytic anemia, immune thrombocytopenic purpura and neutropenia, vasculitis involving small and large vessels, inflammatory bowel disease, and  immune-mediated damage to the kidneys and joints.
Increased risk of malignancy such as lymphoma, leukaemia is a frequent occurence in Wiskott-Aldrich syndrome.
- Recurrent infections with bacterial, viral, fungal and opportunistic organisms. Most common clinical manifestations include otitis media, sinusitis, pneumonia, meningitis, skin infections, and sepsis.
- Bleeding diathesis (eg, epistaxis, ecchymoses, petechiae, hematemesis, intracranial and gastrointestinal hemorrhages)
- Autoimmune manifestations may occur in the form of autoimmune hemolytic anemia, immune thrombocytopenic purpura and neutropenia, vasculitis involving small and large vessels, inflammatory bowel disease, and  immune-mediated damage to the kidneys and joints.
- Increased risk of malignancy such as lymphoma, leukaemia is a frequent occurence in Wiskott-Aldrich syndrome.
- Prognosis is generally poor. 5-year survival rates in patients with Wiscott-Aldrich syndrome who had received stem cell transplantation is approximately  73.7% to 80%.

# Diagnosis

## Diagnostic Study of Choice
- The first laboratory test to be performed in the diagnosis of Wiskott-Aldrich syndrome is complete blood count with differential and peripheral blood smears.
- The diagnosis of Wiskott-Aldrich syndrome is suspected if a male patient who presents with bruises, petechiae, eczema, recurrent infections and the presence of congenital thrombocytopenia(< 70 000/mm3) with small platelet volume <50fl  (micro thrombocytopenia) on the peripheral blood smear.
- Identification of  WAS gene mutations using DNA sequence analysis of WAS gene and detection of WASp expression by flow cytometry are necessary to confirm the diagnosis.

## History and Symptoms
- Patients with Wiskott-Aldrich syndrome have
- Common symptoms of Wiskott-Aldrich syndrome include:
Easy bruising
Petechiae
Purpura
Eczema
Prolonged and excessive bleeding after circumcision or from umbilical stump
Recurrent infections
Epistaxis (Nose bleeds)
Hematemesis
Hematuria
Melena
- Easy bruising
- Petechiae
- Purpura
- Eczema
- Prolonged and excessive bleeding after circumcision or from umbilical stump
- Recurrent infections
- Epistaxis (Nose bleeds)
- Hematemesis
- Hematuria
- Melena

## Physical Examination
- The following findings may be found in the physical examination of the patients with Wiscott-Aldrich syndrome. These include:
Failure to thrive
Skin examination shows bruises, petechiae, purpura, and eczema due to low platelet count. suppurative skin lesions may also be seen.
Lymphadenopathy
Rales and wheezing on auscultation if there is an underlying lung infection.
Hepatosplenomegaly
ENT examination: Carefully examine sinuses to rule out sinusitis, ears for any tympanic membrane abnormalities to rule out otitis media and throat for pharyngitis and other opportunistic infections such as oral thrush.
CNS examination may be performed for symptoms associated with intracranial hemorrhage and infections.
- Failure to thrive
- Skin examination shows bruises, petechiae, purpura, and eczema due to low platelet count. suppurative skin lesions may also be seen.
- Lymphadenopathy
- Rales and wheezing on auscultation if there is an underlying lung infection.
- Hepatosplenomegaly
- ENT examination: Carefully examine sinuses to rule out sinusitis, ears for any tympanic membrane abnormalities to rule out otitis media and throat for pharyngitis and other opportunistic infections such as oral thrush.
- CNS examination may be performed for symptoms associated with intracranial hemorrhage and infections.

## Laboratory Findings
- Laboratory findings consistent with the diagnosis of Wiscott-Aldrich syndrome include:
Complete blood count (CBC) and peripheral smear may show anemia, thrombocytopenia, decreased platelet size and volume.
Immunologic studies may show following findings:
Decreased levels of serum IgG and IgM and elevated levels of serum IgA and IgE antibodies.
Reduction in T lymphocyte count and their function.
Variable antibody response to  vaccines, protein and polysaccharide antigens.
Decreased or absent concentrations of isohemagglutinins.
Abnormal T and B lymphocyte proliferative response to mitogens.
Abnormal phagocytic response
Natural Killer cell defects may also be found.
- Complete blood count (CBC) and peripheral smear may show anemia, thrombocytopenia, decreased platelet size and volume.
- Immunologic studies may show following findings:
Decreased levels of serum IgG and IgM and elevated levels of serum IgA and IgE antibodies.
Reduction in T lymphocyte count and their function.
Variable antibody response to  vaccines, protein and polysaccharide antigens.
Decreased or absent concentrations of isohemagglutinins.
Abnormal T and B lymphocyte proliferative response to mitogens.
Abnormal phagocytic response
Natural Killer cell defects may also be found.
- Decreased levels of serum IgG and IgM and elevated levels of serum IgA and IgE antibodies.
- Reduction in T lymphocyte count and their function.
- Variable antibody response to  vaccines, protein and polysaccharide antigens.
- Decreased or absent concentrations of isohemagglutinins.
- Abnormal T and B lymphocyte proliferative response to mitogens.
- Abnormal phagocytic response
- Natural Killer cell defects may also be found.

## Electrocardiogram
- There are no specific electrocardiogram findings associated with Wiskott-Aldrich syndrome.

## X-ray
- There are no specific x-ray findings associated with Wiskott-Aldrich syndrome. However, a chest x-ray may be helpful in the diagnosis of complications, which include pneumonia.

## Echocardiography or Ultrasound
- There are no specific echocardiography/ ultrasound findings associated with Wiscott-Aldrich syndrome.

## CT scan
- There are no CT scan findings associated with Wiscott-Aldrich syndrome. However, a CT scan may be helpful in the diagnosis of complications of this syndrome, which include pneumonia, internal hemorrhage, to diagnose malignancy and to assess splenic enlargement.

## MRI
- There are no specific MRI findings associated with Wiskott-Aldrich syndrome.

# Treatment

## Medical Therapy
- Mainstay therapy for Wiskott-Aldrich syndrome is conservative therapy and supportive care, which includes:
Prophylactic antimicrobial agents should be given to treat bacterial, viral, fungal and opportunistic infections.
Trimethoprim/sulfamethoxazole: 5mg/kg/day can be given to treat most bacterial and pneumocystis jirovecii pneumonia.
Acyclovir:  200mg/twice daily may be given to treat viral infections (eg, HSV-1)
Fluconazole:  3mg/kg/day may be given to treat fungal infections.
Platelet transfusions:
Platelet transfusions can be given to treat bleeding episodes such as life-threatening gastrointestinal and intracranial hemorrhages. Platelet transfusions can also be given to patients who are undergoing any surgical procedure.
If a patient can be chosen for transfusion, platelets and blood products should be irradiated and must be obtained from a CMV free donor.
Intravenous immunoglobulins:
Preferred regimen:  400 to 600 mg/kg can be given every three weeks
Immunosuppressive agents: Rituximab can be given to treat autoimmune cytopenias such as hemolytic anemia, neutropenia, associated with Wiskott- Aldrich syndrome.
Thrombopoietic agents: Eltrombopag may be helpful in increasing platelet count in patients with Wiskott-Aldrich syndrome but it may not improve platelet surface activation.
Gene therapy: Gene therapy is an alternative curative treatment for Wiskott-Aldrich syndrome, which is still going under trials.
- Prophylactic antimicrobial agents should be given to treat bacterial, viral, fungal and opportunistic infections.
Trimethoprim/sulfamethoxazole: 5mg/kg/day can be given to treat most bacterial and pneumocystis jirovecii pneumonia.
Acyclovir:  200mg/twice daily may be given to treat viral infections (eg, HSV-1)
Fluconazole:  3mg/kg/day may be given to treat fungal infections.
- Trimethoprim/sulfamethoxazole: 5mg/kg/day can be given to treat most bacterial and pneumocystis jirovecii pneumonia.
- Acyclovir:  200mg/twice daily may be given to treat viral infections (eg, HSV-1)
- Fluconazole:  3mg/kg/day may be given to treat fungal infections.
- Platelet transfusions:
Platelet transfusions can be given to treat bleeding episodes such as life-threatening gastrointestinal and intracranial hemorrhages. Platelet transfusions can also be given to patients who are undergoing any surgical procedure.
If a patient can be chosen for transfusion, platelets and blood products should be irradiated and must be obtained from a CMV free donor.
- Platelet transfusions can be given to treat bleeding episodes such as life-threatening gastrointestinal and intracranial hemorrhages. Platelet transfusions can also be given to patients who are undergoing any surgical procedure.
- If a patient can be chosen for transfusion, platelets and blood products should be irradiated and must be obtained from a CMV free donor.
- Intravenous immunoglobulins:
Preferred regimen:  400 to 600 mg/kg can be given every three weeks
- Preferred regimen:  400 to 600 mg/kg can be given every three weeks
- Immunosuppressive agents: Rituximab can be given to treat autoimmune cytopenias such as hemolytic anemia, neutropenia, associated with Wiskott- Aldrich syndrome.
- Thrombopoietic agents: Eltrombopag may be helpful in increasing platelet count in patients with Wiskott-Aldrich syndrome but it may not improve platelet surface activation.
- Gene therapy: Gene therapy is an alternative curative treatment for Wiskott-Aldrich syndrome, which is still going under trials.

## Surgery
- Hematopoietic stem cell transplantation (HSCT):
HSCT is the only standard curative treatment for Wiskott-Aldrich syndrome.
- HSCT is the only standard curative treatment for Wiskott-Aldrich syndrome.
- Splenectomy: Splenectomy may be considered for some patients with Wiskott-Aldrich syndrome . Splenectomy may be found to improve platelet count as well as size of the platelets . However, sepsis is a life-threatening complication after splenectomy. Prophylactic antibiotics should always be used to prevent infections.
Primary Prevention
- There are no established measures for the primary prevention of the Wiskott-Aldrich syndrome. However genetic mutation analysis and prenatal molecular diagnosis can be helpful in decreaing the occurance .

## Secondary Prevention
- There are no established measures for the secondary prevention of the Wiskott-Aldrich syndrome.