Wiskott–Aldrich syndrome
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 rare
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.
Pathophysiology
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 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.[7]
Genetics
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).[8] X-linked thrombocytopenia (XLT) 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.[9]
The protein product of WAS is known as WASp. It contains 502
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.[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 as variable expressivity.[13] 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.[14] 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.[15] 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
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Classification
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.[21] 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.[22] 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 as hematopoietic stem cell transplant.[citation needed]
Score | Definition | Clinical syndrome |
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0 | Neutropenia (low white blood cell count) or myelodysplasia only | X-linked neutropenia (XLN) |
0.5 | Intermittent thrombocytopenia (low platelet counts sometimes but not always) | X-linked thrombocytopenia (XLT)
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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 |
Treatment
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 a
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.[13] 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 (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 platelets splenectomy (removal of the spleen) may also be lifesaving.[25] However, splenectomy is generally considered palliative and is not universally recommended in WAS because it can increase the risk of life-threatening infections.[26][13] 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 (ITP), in WAS concluded that although it increased platelet numbers it failed to increase platelet activation in most patients.[27] 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.[28] 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,
Gene therapy
For severely affected males without an HLA-matched donor, studies of correcting Wiskott–Aldrich syndrome with gene therapy using a lentivirus are underway.[29][30] Proof-of-principle for successful hematopoietic stem cell gene therapy has been provided for patients with Wiskott–Aldrich syndrome.[31] 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 (improved platelet counts, immune functiona, and clinical symptoms) 20–30 months after being treated with a genetically modified lentivirus.[32] 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.[33][34][35] Importantly, neither study showed evidence of leukemic proliferation following treatment, a complication of early attempts at gene therapy using a retroviral vector.[36] 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.[32][33] A version of this treatment, OTL-103, is being developed by Orchard Therapeutics and (as of 28 June 2021[update]) is undergoing Phase I/II clinical trials.
Prognosis
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 the WAS gene is referred to as X-linked neutropenia or
Epidemiology
The estimated incidence of Wiskott–Aldrich syndrome in the United States is one in 250,000 live male births.[41] While still a rare disease, this makes it more common than many genetic immunodeficiency syndromes such as hyper-IgM syndrome or SCID, 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.[42] WAS occurs worldwide and is not known to be more common in any particular ethnic group.
History
The syndrome is named after Dr. Alfred Wiskott (1898–1978), a German pediatrician who first noticed the syndrome in 1937,[43] 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 novel frameshift mutation of the first exon of the WASp gene.[44]
References
- ^ a b "Wiskott–Aldrich syndrome". Genetics Home Reference. Retrieved 2016-06-26.
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- ^ "Wiskott–Aldrich Syndrome: Immunodeficiency Disorders: Merck Manual Professional". Retrieved 2008-03-01.
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- ^ "CD43 - an overview | ScienceDirect Topics". www.sciencedirect.com. Retrieved 2021-11-19.
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- PMID 20301357. Retrieved 2020-12-10.
- ^ "ESID - European Society for Immunodeficiencies". esid.org. Retrieved 2020-12-10.
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- ^ Gallagher, James (21 April 2015) Gene therapy: 'Tame HIV' used to cure disease BBC News, Health, Retrieved 21 April 2015
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- ^ Robert A Schwartz, MD, MPH; Chief Editor: Harumi Jyonouchi, MD. Pediatric Wiskott–Aldrich Syndrome
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- ^ Wiskott A (1937). "Familiärer, angeborener Morbus Werlhofii? ("Familial congenital Werlhof's disease?")". Montsschr Kinderheilkd. 68: 212–16.
- S2CID 30040802.
Further reading
- GeneReviews/NIH/NCBI/UW entry on WAS-Related Disorders including Wiskott–Aldrich syndrome WAS X-linked thrombocytopenia XLT and X-linked congenital neutropenia XLN
- Immune Deficiency Foundation - "Wiskott–Aldrich Syndrome"
- Wiskott–Aldrich Foundation