| Wiskott–Aldrich syndrome | |
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| A) Multiple face petechiae and a hematoma under the right eye (left in image). B) Eczema of the foot. | |
| Specialty | Immunology  |
Wiskott–Aldrich syndrome (WAS) is a rareX-linked recessive disease characterized byeczema,thrombocytopenia (lowplatelet count),immune deficiency, and bloody diarrhea (secondary to the thrombocytopenia).[1] It is also sometimes called theeczema-thrombocytopenia-immunodeficiency syndrome in keeping with Aldrich's original description in 1954.[2] The WAS-related disorders ofX-linked thrombocytopenia (XLT) and X-linked congenital neutropenia (XLN) may present with similar but less severe symptoms and are caused by mutations of the same gene.
WAS occurs most often in males due to its X-linked recessive pattern of inheritance, affecting between 1 and 10 males per million.[1] The first signs are usuallypetechiae and bruising, resulting from a low platelet count (i.e.thrombocytopenia). Spontaneousnose bleeds and bloody diarrhea are also common andeczema typically develops within the first month of life. Recurrent bacterialinfections typically develop by three months of age. The majority of children with WAS develop at least oneautoimmune disorder, andcancers (mainlylymphoma andleukemia) develop in up to a third of patients.[3]Immunoglobulin M (IgM) levels are reduced,IgA andIgE are elevated, andIgG levels can be normal, reduced, or elevated.[4] In addition to thrombocytopenia, WAS patients have abnormally small platelets (i.e. microthrombocytes) and ~30% also have elevatedeosinophil counts (i.e.eosinophilia).[5]
The microthrombocytes seen in WAS patients have only been observed in one other condition,ARPC1B deficiency.[6] In both conditions the defective platelets are thought to be removed from circulation by thespleen 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 decreasedantibody production and the inability of immuneT cells to effectively combat infection.[7]
WAS is associated with mutations in agene on the short arm of theX chromosome (Xp11.23) that was originally termed theWiskott–Aldrich syndrome protein gene and is officially known asWAS (Gene ID: 7454).[8] X-linked thrombocytopenia (XLT) is also linked to pathogenic variants in theWAS 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 ofWAS mutations.[9]
The protein product ofWAS is known as WASp. It contains 502amino acids and is mainly expressed inhematopoietic 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 theArp2/3 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.[10] In T-cells, WASp is important because it is known to be activated viaT-cell receptor signaling pathways to induce cortical actincytoskeleton rearrangements that are responsible for forming theimmunological synapse.[11]
The severity of the symptoms produced by pathogenic variants in theWAS gene generally correlates with their effects on WASp.Missense variants generally are associated with less severe disease thantruncating variants that produce no protein due tononsense-mediated decay.[12] However, this correlation is not perfect, and sometimes the same variant can be seen both in XLT and in WAS (sometimes within two different members of the same family), a concept in genetics referred to asvariable expressivity.[13] Although autoimmune disease and malignancy may occur in both conditions, patients with loss of WASp are at higher risk. A defect in theCD43 molecule has also been found in WAS patients.[14] CD43, a transmembranesialoglycoprotein 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.[citation needed] 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-detectedB-cell lymphomas.
The diagnosis can be made on the basis of clinical findings, theperipheral blood smear, and lowimmunoglobulin levels. Typically, IgM levels are low, IgA levels are elevated, and IgE levels may be elevated;paraproteins are occasionally observed.[15] Skin immunologic testing (allergy testing) may reveal hyposensitivity. Individuals with Wiskott–Aldrich syndrome however are at higher risk for severe food allergies.[16] 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, andbone marrow biopsy may be performed. Decreased levels of WASp are typically observed. The current gold standard for diagnosis isDNA sequence analysis, which can detect WAS and the related disorders XLT and XLN in 95% of patients and carriers.[17]
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Jin et al. (2004) employ a numerical grading of severity:[12] This score, which ranges from 0 to 5, may have clinical utility for predicting disease severity.[20] Those with higher WAS scores (e.g., 5) at younger ages (e.g., age less than 5 years old), are thought to be at highest risk for increased morbidity and mortality related to their condition.[21] As individuals can develop more WAS-related symptoms (e.g. autoimmune disease, malignancy) 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 ashematopoietic stem cell transplant.[citation needed]
| Score | Definition | Clinical syndrome |
|---|---|---|
| 0 | Neutropenia (low white blood cell count) ormyelodysplasia only | X-linked neutropenia (XLN) |
| 0.5 | Intermittent thrombocytopenia (low platelet counts sometimes but not always) | X-linked thrombocytopenia (XLT) |
| 1 | Thrombocytopenia and small platelets (microthrombocytopenia) | 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 (WAS) |
| 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 |
Hematopoietic stem cell transplant
Treatment 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 (WAS score 3–5) the only widely available curative treatment currently available is ahematopoieticstem cell transplant (HCT). In this procedure stem cells are harvested fromumbilical 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 withHLA-identical or similar donors (often siblings). In cases of milder disease the potential benefits of HCT (>90% probability of cure if transplant occurs before age two) must be considered in the context of non-trivial risks presented by the procedure itself and the potential need for lifelongimmunosuppression to preventgraft-versus-host disease.[22][23] Generally outcomes are better if HCT occurs prior to the development ofautoimmune disease ormalignancy, however there are risks associated withchemotherapy (needed to make room for the new stem cells) especially in young infants (risk of a second cancer, orinfertility).[citation needed]
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 soaspirin and othernonsteroidal anti-inflammatory drugs that may interfere with already compromised platelet function should generally be avoided.[13]Circumcision, as well as elective surgeries, should generally be deferred in males withthrombocytopenia until after HCT if possible. Protective helmets can help protect children from life-threateningintracranial hemorrhage (brain bleed) which could result from head injuries. Patients may require platelet transfusions when there is extreme bloodloss (such as during surgery) or for very low plateletssplenectomy (removal of the spleen) may also be lifesaving.[24] However, splenectomy is generally considered palliative and is not universally recommended in WAS because it can increase the risk of life-threatening infections.[25][13] Post-splenectomy patients will require lifelongantibiotic prophyllaxis to prevent infections. Study ofeltrombopag, a thrombopoietic agent used to increase platelets inimmune thrombocytopenic purpura (ITP), in WAS concluded that although it increased platelet numbers it failed to increase platelet activation in most patients.[26] 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.[27]Anemia from bleeding may requireiron supplementation orblood transfusion. Regular surveillance of blood counts is recommended.
Infections and autoimmune disease
For patients with frequent infections,intravenous immunoglobulins (IVIG) orsubcutaneous 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 fromantibiotic prophylaxis, for example by takingtrimethoprim-sulfamethoxazole to preventPneumocystis jirovecii-related pneumonia. Similarly, prophylactic antibiotic use may also be considered in patients with recurrent bacterialsinus orlung infections. When there are signs or symptoms of an infection, prompt and thorough evaluation is important includingblood cultures to guide therapy (often IV antibiotics).Live vaccines (such asMMR orrotavirus) 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 withtopical steroids, and if chronic skin infections exacerbate eczema an antibiotic may also be given.Autoimmune disease is managed with judicious use of appropriate immunosuppressants.[citation needed]
Gene therapy
Agene therapy for Wiskott Aldrich syndrome using alentivirus has been tested inclinical trials.[28][29] Proof-of-principle for successful hematopoietic stem cell gene therapy has been provided for patients with Wiskott–Aldrich syndrome.[30] In July 2013 the ItalianSan Raffaele Telethon Institute for Gene Therapy (HSR-TIGET) reported that three children with Wiskott–Aldrich syndrome showed significant improvement (improved platelet counts, immune functiona, and clinical symptoms) 20–30 months after being treated with a genetically modified lentivirus.[31] 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.[32][33][34] Importantly, neither study showed evidence of leukemic proliferation following treatment, a complication of early attempts at gene therapy using a retroviral vector.[35] 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.[31][32]
Etuvetidigene autotemcel (Waskyra) was approved for medical use in the United States in December 2025.[36][37] It is the first gene therapy developed by a non-profit to be approved in the US.[36]
Outcomes from Wiskott–Aldrich syndrome are variable and depend on how severely an individual is affected (the WAS score may be used to assess disease severity). The milder end of the disease spectrum associated with theWAS gene is referred to as X-linked neutropenia orX-linked thrombocytopenia, and the latter is thought to have a normal life expectancy with reports of minimally affected males surviving into their seventh decade without treatment.[20] Traditionally however Wiskott–Aldrich syndrome has been associated with premature death from causes including bleeding, infections, or malignancy.[38] Wiskott–Aldrich syndrome is a condition withvariable expressivity, meaning that even within the same family some may exhibit only chronic thrombocytopenia while others experience severe, life-threatening complications of Wiskott–Aldrich syndrome in infancy or childhood.[39][13] Given symptoms often progress with age, it is challenging to predict how affected a newly diagnosed infant will eventually be. There is some genotype-phenotype correlation, with most individuals with X-linked thrombocytopenia havingmissense variants in theWAS gene versus 86.5% of those that make noWAS protein having the classic Wiskott–Aldrich syndrome phenotype.[40][41] Overall the prognosis for individuals with Wiskott–Aldrich syndrome has improved considerably over the past decades due to earlier diagnoses and more access to treatments.
The estimated incidence of Wiskott–Aldrich syndrome in the United States is one in 250,000 live male births.[42] While still a rare disease, this makes it more common than many genetic immunodeficiency syndromes such ashyper-IgM syndrome orSCID, which have an estimated incidence of about one in 1,000,000 live births, and Wiskott–Aldrich syndrome is thought to account for 1.2% of all inherited immunodeficiencies in the United States.[43] WAS occurs worldwide and is not known to be more common in any particular ethnic group.
The syndrome is named after Dr. Alfred Wiskott (1898–1978), a German pediatrician who first noticed the syndrome in 1937,[44] and Dr. Robert Anderson Aldrich (1917–1998), an American pediatrician who described the disease in a family of Dutch-Americans in 1954.[2] Wiskott described three brothers with a similar disease, whose sisters were unaffected. In 2006, a German research group analyzed family members of Wiskott's three cases, and surmised they probably shared a novelframeshift mutation of the firstexon of theWASp gene.[45]
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