Wiskott–Aldrich syndrome (WAS) is a rare X-linked recessive disease characterized by eczema, thrombocytopenia (low platelet count), immune deficiency, and bloody diarrhea (secondary to the thrombocytopenia). 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.
|Wiskott–Aldrich syndrome has an X-linked recessive pattern of inheritance.|
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 (i.e. thrombocytopenia). Spontaneous nose bleeds and bloody diarrhea are also common and eczema typically develops within the first month of life. Recurrent bacterial infections develop by three months. The majority of children with WAS develop at least one autoimmune disorder, and cancers (mainly lymphoma and leukemia) develop in up to a third of patients. Immunoglobulin M (IgM) 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 (i.e. microthrombocytes) and ~30% also have elevated eosinophil counts (i.e. eosinophilia).
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.
WAS is associated with mutations in a gene on the short arm of the X chromosome (Xp11.23) that was originally termed the Wiskott-Aldrich syndrome protein gene and is officially known as WAS (Gene ID: 7454). X-linked thrombocytopenia is also linked to WAS mutations, although they differ from those that cause full-blown 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 cells in the bone marrow that develop into blood cells). The main function of WASp is to activate actin polymerization by serving as a nucleation-promoting factor (NPF) 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 WAS mutations correlate with their effects on WASp. Alleles that produce no or truncated protein have more severe effects than missense mutations. Although autoimmune disease and malignancy may occur with both types of mutations, patients with truncated WASp carry a higher risk. A defect in the CD43 molecule has also been found in WAS patients.
The diagnosis is made on the basis of clinical parameters, 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 (allergy testing) may reveal hyposensitivity. 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 genomic DNA sequence analysis, which can detect WAS and the related disorders XLT and XLN in the vast majority of patients and carriers. .
- 0.5: intermittent thrombocytopenia
- 1.0: thrombocytopenia and small platelets (microthrombocytopenia)
- 2.0: microthrombocytopenia plus normally responsive eczema or occasional upper respiratory tract infections
- 2.5: microthrombocytopenia plus therapy-responsive but severe eczema or airway infections requiring antibiotics
- 3.0: microthrombocytopenia plus both eczema and airway infections requiring antibiotics
- 4.0: microthrombocytopenia plus eczema continuously requiring therapy and/or severe or life-threatening infections
- 5.0: microthrombocytopenia plus autoimmune disease or malignancy
Treatment of Wiskott–Aldrich syndrome is currently based on correcting symptoms. Aspirin and other nonsteroidal anti-inflammatory drugs should be avoided, since these may interfere with platelet function which is already compromised. A protective helmet can protect children from bleeding into the brain which could result from head injuries. For severely low platelet counts, patients may require platelet transfusions or removal of the spleen. For patients with frequent infections, intravenous immunoglobulins (IVIG) can be given to boost the immune system. Anemia from bleeding may require iron supplementation or blood transfusion.
As WAS is primarily a disorder of the blood-forming tissues, a hematopoietic stem cell transplant, accomplished through an umbilical cord blood or bone marrow transplant offers the only current hope of cure. This may be recommended for patients with HLA-identical donors, matched sibling donors, or even in cases of incomplete matches if the patient is age 5 or under.
Studies of correcting Wiskott–Aldrich syndrome with gene therapy using a lentivirus have begun. Proof-of-principle for successful hematopoietic stem cell gene therapy has been provided for patients with Wiskott–Aldrich syndrome. Currently, many investigators continue to develop optimized gene therapy vectors. In July 2013 the Italian San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET) 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 where six children with Wiskott–Aldrich syndrome were treated with gene therapy were described as promising. Median follow-up time was 27 months.
The syndrome is named after Dr. Alfred Wiskott (1898–1978), a German pediatrician who first noticed the syndrome in 1937, and Dr. Robert Anderson Aldrich (1917–1998), an American pediatrician who described the disease in a family of Dutch-Americans in 1954. 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 they probably shared a novel frameshift mutation of the first exon of the WASp gene.
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