Wiskott–Aldrich syndrome
Wiskott–Aldrich syndrome is a rare X-linked recessive disease characterized by eczema, thrombocytopenia, immune deficiency, and bloody diarrhea. 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 and X-linked congenital neutropenia may present with similar but less severe symptoms and are caused by mutations of the same gene.
Signs and symptoms
WAS occurs most often in males due to its X-linked recessive pattern of inheritance, affecting between 1 and 10 males per million. The first signs are usually petechiae and bruising, resulting from a low platelet count. Spontaneous nose bleeds and bloody diarrhea are also common and eczema typically develops within the first month of life. Recurrent bacterial infections typically develop by three months of age. The majority of children with WAS develop at least one autoimmune disorder, and cancers develop in up to a third of patients. Immunoglobulin M levels are reduced, IgA and IgE are elevated, and IgG levels can be normal, reduced, or elevated. In addition to thrombocytopenia, WAS patients have abnormally small platelets and ~30% also have elevated eosinophil counts.Pathophysiology
The microthrombocytes seen in WAS patients have only been observed in one other condition, ARPC1B deficiency. In both conditions the defective platelets are thought to be removed from circulation by the spleen and/or liver, leading to low platelet counts. WAS patients have increased susceptibility to infections, particularly of the ears and sinuses, and this immune deficiency has been linked to decreased antibody production and the inability of immune T cells to effectively combat infection.Genetics
WAS is associated with mutations in a gene on the short arm of the X chromosome that was originally termed the Wiskott–Aldrich syndrome protein gene and is officially known as WAS. X-linked thrombocytopenia is also linked to pathogenic variants in the WAS gene, although some variants tend to be more strongly associated with XLT versus others that are more associated with WAS. The rare disorder X-linked neutropenia has also been linked to a specific subset of WAS mutations.The protein product of WAS is known as WASp. It contains 502 amino acids and is mainly expressed in hematopoietic cells. The main function of WASp is to activate actin polymerization by serving as a nucleation-promoting factor for the Arp2/3 complex, which generates branched actin filaments. Several proteins can serve as NPFs, and it has been observed that in WAS platelets the Arp2/3 complex functions normally, indicating that WASp is not required for its activation in platelets. In T-cells, WASp is important because it is known to be activated via T-cell receptor signaling pathways to induce cortical actin cytoskeleton rearrangements that are responsible for forming the immunological synapse.
The severity of the symptoms produced by pathogenic variants in the WAS gene generally correlates with their effects on WASp. Missense variants generally are associated with less severe disease than truncating variants that produce no protein due to nonsense-mediated decay. However, this correlation is not perfect, and sometimes the same variant can be seen both in XLT and in WAS, a concept in genetics referred to as variable expressivity. Although autoimmune disease and malignancy may occur in both conditions, patients with loss of WASp are at higher risk. A defect in the CD43 molecule has also been found in WAS patients. CD43, a transmembrane sialoglycoprotein also known as a leukosialin, is part of a greater complex involved in T-cell activation and acts as a sensitive indicator of abnormal, malignant B cell populations. Defects in this molecule may be detrimental to WAS patients, who are at a much higher risk of autoimmune diseases that may be exacerbated in later-detected B-cell lymphomas.
Diagnosis
The diagnosis can be made on the basis of clinical findings, the peripheral blood smear, and low immunoglobulin levels. Typically, IgM levels are low, IgA levels are elevated, and IgE levels may be elevated; paraproteins are occasionally observed. Skin immunologic testing may reveal hyposensitivity. Individuals with Wiskott–Aldrich syndrome however are at higher risk for severe food allergies. Not all patients have a positive family history of the disorder; new mutations do occur. Often, leukemia may be suspected on the basis of low platelets and infections, and bone marrow biopsy may be performed. Decreased levels of WASp are typically observed. The current gold standard for diagnosis is DNA sequence analysis, which can detect WAS and the related disorders XLT and XLN in 95% of patients and carriers.| Mandatory criteria |
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| Definitive | |
| Probable | |
| Possible |
Classification
Jin et al. employ a numerical grading of severity: This score, which ranges from 0 to 5, may have clinical utility for predicting disease severity. Those with higher WAS scores at younger ages, are thought to be at highest risk for increased morbidity and mortality related to their condition. As individuals can develop more WAS-related symptoms with age, one's WAS score can increase over time. A lower WAS score may be more compatible with conservative management versus higher WAS scores that may favor intervention with treatments such as hematopoietic stem cell transplant.| Score | Definition | Clinical syndrome |
| 0 | Neutropenia or myelodysplasia only | X-linked neutropenia |
| 0.5 | Intermittent thrombocytopenia | X-linked thrombocytopenia |
| 1 | Thrombocytopenia and small platelets | XLT |
| 2 | Microthrombocytopenia plus normally responsive eczema or occasional upper respiratory tract infections | XLT |
| 2.5 | Microthrombocytopenia plus therapy-responsive but severe eczema or airway infections requiring antibiotics | XLT/Wiskott–Aldrich syndrome |
| 3 | Microthrombocytopenia plus both eczema and airway infections requiring antibiotics | WAS |
| 4 | Microthrombocytopenia plus eczema continuously requiring therapy and/or severe or life-threatening infections | WAS |
| 5 | Microthrombocytopenia plus autoimmune disease or malignancy | XLT/WAS + autoimmune disease or cancer |
Treatment
Hematopoietic stem cell transplantTreatment of Wiskott–Aldrich syndrome depends on the severity of the disease. WAS is primarily a disorder of the blood-forming tissues, so in cases of severe disease the only widely available curative treatment currently available is a hematopoietic stem cell transplant. In this procedure stem cells are harvested from umbilical cord blood, bone marrow, or peripheral blood following treatment with medications that cause stem cells to leave the bone marrow and circulate systemically. The best outcomes are with HLA-identical or similar donors. In cases of milder disease the potential benefits of HCT must be considered in the context of non-trivial risks presented by the procedure itself and the potential need for lifelong immunosuppression to prevent graft-versus-host disease. Generally outcomes are better if HCT occurs prior to the development of autoimmune disease or malignancy, however there are risks associated with chemotherapy especially in young infants.
Bleeding complications
Otherwise WAS treatment is focused on managing symptoms and preventing complications. The greatest mortality risk in WAS before age 30 is from bleeding so aspirin and other nonsteroidal anti-inflammatory drugs that may interfere with already compromised platelet function should generally be avoided. Circumcision, as well as elective surgeries, should generally be deferred in males with thrombocytopenia until after HCT if possible. Protective helmets can help protect children from life-threatening intracranial hemorrhage which could result from head injuries. Patients may require platelet transfusions when there is extreme bloodloss or for very low platelets splenectomy may also be lifesaving. However, splenectomy is generally considered palliative and is not universally recommended in WAS because it can increase the risk of life-threatening infections. Post-splenectomy patients will require lifelong antibiotic prophyllaxis to prevent infections. Study of eltrombopag, a thrombopoietic agent used to increase platelets in immune thrombocytopenic purpura, in WAS concluded that although it increased platelet numbers it failed to increase platelet activation in most patients. It has since been proposed the eltrombopag may be used to bridge to HCT in patients with severe thrombocytopenia to normalize platelet numbers without transfusions and decrease bleeding events. Anemia from bleeding may require iron supplementation or blood transfusion. Regular surveillance of blood counts is recommended.
Infections and autoimmune disease
For patients with frequent infections, intravenous immunoglobulins or subcutaneous immunoglobulins can be regularly scheduled to boost the immune system. Adequacy of IVIG replacement can be assessed via periodic lab draws. WAS patients with immune system compromise may benefit from antibiotic prophylaxis, for example by taking trimethoprim-sulfamethoxazole to prevent Pneumocystis jirovecii-related pneumonia. Similarly, prophylactic antibiotic use may also be considered in patients with recurrent bacterial sinus or lung infections. When there are signs or symptoms of an infection, prompt and thorough evaluation is important including blood cultures to guide therapy. Live vaccines should be avoided during routine childhood vaccination. Inactivated vaccines may be given safely but may not provide protective levels of immunity. Eczema is generally treated with topical steroids, and if chronic skin infections exacerbate eczema an antibiotic may also be given. Autoimmune disease is managed with judicious use of appropriate immunosuppressants.
Gene therapy
A gene therapy for Wiskott Aldrich syndrome using a lentivirus has been tested in clinical trials. Proof-of-principle for successful hematopoietic stem cell gene therapy has been provided for patients with Wiskott–Aldrich syndrome. In July 2013 the Italian San Raffaele Telethon Institute for Gene Therapy reported that three children with Wiskott–Aldrich syndrome showed significant improvement 20–30 months after being treated with a genetically modified lentivirus. In April 2015 results from a follow-up British and French trial six out of seven individuals showed improvement of immune function and clinical symptoms an average of 27 months after treatment with gene therapy. Importantly, neither study showed evidence of leukemic proliferation following treatment, a complication of early attempts at gene therapy using a retroviral vector. It is unknown why these gene therapies did not restore normal platelet numbers, but gene therapy treatment was still associated with transfusion-independence and a significant reduction in bleeding events.
Etuvetidigene autotemcel was approved for medical use in the United States in December 2025. It is the first gene therapy developed by a non-profit to be approved in the US.