|Wiskott–Aldrich syndrome has an X-linked recessive pattern of inheritance.|
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.
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. .
Jin et al. (2004) employ a numerical grading of severity:
- 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 a 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 estimated incidence of Wiskott–Aldrich syndrome in the United States is one in 250,000 live male births. No geographical factor is present.
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.
- Reference, Genetics Home. "Wiskott-Aldrich syndrome". Genetics Home Reference. Retrieved 2016-06-26.
- Aldrich RA, Steinberg AG, Campbell DC (February 1954). "Pedigree demonstrating a sex-linked recessive condition characterized by draining ears, eczematoid dermatitis and bloody diarrhea". Pediatrics. 13 (2): 133–9. PMID 13133561.
- Wiskott-Aldrich Syndrome at eMedicine
- Sande MA, Wilson WP (2001). Current diagnosis & treatment in infectious diseases. New York: Lange Medical Books/McGraw-Hill. p. 361. ISBN 978-0-8385-1494-8.[page needed]
- Navabi B, Upton JE (2016). "Primary immunodeficiencies associated with eosinophilia". Allergy, Asthma, and Clinical Immunology. 12: 27. doi:10.1186/s13223-016-0130-4. PMC 4878059. PMID 27222657.
- Kahr WH, Pluthero FG, Elkadri A, Warner N, Drobac M, Chen CH, Lo RW, Li L, Li R, Li Q, Thoeni C, Pan J, Leung G, Lara-Corrales I, Murchie R, Cutz E, Laxer RM, Upton J, Roifman CM, Yeung RS, Brumell JH, Muise AM (April 2017). "Loss of the Arp2/3 complex component ARPC1B causes platelet abnormalities and predisposes to inflammatory disease". Nature Communications. 8: 14816. Bibcode:2017NatCo...814816K. doi:10.1038/ncomms14816. PMC 5382316. PMID 28368018.
- "Wiskott-Aldrich Syndrome: Immunodeficiency Disorders: Merck Manual Professional". Retrieved 2008-03-01.
- Derry JM, Ochs HD, Francke U (August 1994). "Isolation of a novel gene mutated in Wiskott-Aldrich syndrome". Cell. 78 (4): 635–44. doi:10.1016/0092-8674(94)90528-2. PMID 8069912.
- Westerberg LS, Meelu P, Baptista M, Eston MA, Adamovich DA, Cotta-de-Almeida V, Seed B, Rosen MK, Vandenberghe P, Thrasher AJ, Klein C, Alt FW, Snapper SB (June 2010). "Activating WASP mutations associated with X-linked neutropenia result in enhanced actin polymerization, altered cytoskeletal responses, and genomic instability in lymphocytes". The Journal of Experimental Medicine. 207 (6): 1145–52. doi:10.1084/jem.20091245. PMC 2882832. PMID 20513746.
- Falet H, Hoffmeister KM, Neujahr R, Hartwig JH (September 2002). "Normal Arp2/3 complex activation in platelets lacking WASp". Blood. 100 (6): 2113–22. PMID 12200375.
- Malinova D, Fritzsche M, Nowosad CR, Armer H, Munro PM, Blundell MP, Charras G, Tolar P, Bouma G, Thrasher AJ (May 2016). "WASp-dependent actin cytoskeleton stability at the dendritic cell immunological synapse is required for extensive, functional T cell contacts". Journal of Leukocyte Biology. 99 (5): 699–710. doi:10.1189/jlb.2a0215-050rr. PMC 5404712. PMID 26590149.
- Jin Y, Mazza C, Christie JR, Giliani S, Fiorini M, Mella P, Gandellini F, Stewart DM, Zhu Q, Nelson DL, Notarangelo LD, Ochs HD (December 2004). "Mutations of the Wiskott-Aldrich Syndrome Protein (WASP): hotspots, effect on transcription, and translation and phenotype/genotype correlation". Blood. 104 (13): 4010–9. doi:10.1182/blood-2003-05-1592. PMID 15284122.
- Rosenstein Y, Park JK, Hahn WC, Rosen FS, Bierer BE, Burakoff SJ (November 1991). "CD43, a molecule defective in Wiskott-Aldrich syndrome, binds ICAM-1". Nature. 354 (6350): 233–5. Bibcode:1991Natur.354..233R. doi:10.1038/354233a0. PMID 1683685.
- Radl J, Dooren LH, Morell A, Skvaril F, Vossen JM, Uittenbogaart CH (August 1976). "Immunoglobulins and transient paraproteins in sera of patients with the Wiskott-Aldrich syndrome: a follow-up study". Clinical and Experimental Immunology. 25 (2): 256–63. PMC 1541349. PMID 954233.
- Galy A, Roncarolo MG, Thrasher AJ (February 2008). "Development of lentiviral gene therapy for Wiskott Aldrich syndrome". Expert Opinion on Biological Therapy. 8 (2): 181–90. doi:10.1517/147125188.8.131.52. PMC 2789278. PMID 18194074.
- Frecha C, Toscano MG, Costa C, Saez-Lara MJ, Cosset FL, Verhoeyen E, Martin F (June 2008). "Improved lentiviral vectors for Wiskott-Aldrich syndrome gene therapy mimic endogenous expression profiles throughout haematopoiesis". Gene Therapy. 15 (12): 930–41. doi:10.1038/gt.2008.20. PMID 18323794.
- Boztug K, Schmidt M, Schwarzer A, Banerjee PP, Díez IA, Dewey RA, Böhm M, Nowrouzi A, Ball CR, Glimm H, Naundorf S, Kühlcke K, Blasczyk R, Kondratenko I, Maródi L, Orange JS, von Kalle C, Klein C (November 2010). "Stem-cell gene therapy for the Wiskott-Aldrich syndrome". The New England Journal of Medicine. 363 (20): 1918–27. doi:10.1056/NEJMoa1003548. PMC 3064520. PMID 21067383.
- Dewey RA, Avedillo Díez I, Ballmaier M, Filipovich A, Greil J, Güngör T, Happel C, Maschan A, Noyan F, Pannicke U, Schwarz K, Snapper S, Welte K, Klein C (September 2006). "Retroviral WASP gene transfer into human hematopoietic stem cells reconstitutes the actin cytoskeleton in myeloid progeny cells differentiated in vitro". Experimental Hematology. 34 (9): 1161–9. doi:10.1016/j.exphem.2006.04.021. PMID 16939809.
- Aiuti A, Biasco L, Scaramuzza S, Ferrua F, Cicalese MP, Baricordi C, Dionisio F, Calabria A, Giannelli S, Castiello MC, Bosticardo M, Evangelio C, Assanelli A, Casiraghi M, Di Nunzio S, Callegaro L, Benati C, Rizzardi P, Pellin D, Di Serio C, Schmidt M, Von Kalle C, Gardner J, Mehta N, Neduva V, Dow DJ, Galy A, Miniero R, Finocchi A, Metin A, Banerjee PP, Orange JS, Galimberti S, Valsecchi MG, Biffi A, Montini E, Villa A, Ciceri F, Roncarolo MG, Naldini L (August 2013). "Lentiviral hematopoietic stem cell gene therapy in patients with Wiskott-Aldrich syndrome". Science. 341 (6148): 1233151. doi:10.1126/science.1233151. PMC 4375961. PMID 23845947.
- Gallagher, James (21 April 2015) Gene therapy: 'Tame HIV' used to cure disease BBC News, Health, Retrieved 21 April 2015
- Malech HL, Ochs HD (April 2015). "An emerging era of clinical benefit from gene therapy". JAMA. 313 (15): 1522–3. doi:10.1001/jama.2015.2055. PMID 25898049.
- Robert A Schwartz, MD, MPH; Chief Editor: Harumi Jyonouchi, MD. Pediatric Wiskott-Aldrich Syndrome
- Wiskott, A (1937). "Familiärer, angeborener Morbus Werlhofii? ("Familial congenital Werlhof's disease?")". Montsschr Kinderheilkd. 68: 212–16.
- Binder V, Albert MH, Kabus M, Bertone M, Meindl A, Belohradsky BH (October 2006). "The genotype of the original Wiskott phenotype". The New England Journal of Medicine. 355 (17): 1790–3. doi:10.1056/NEJMoa062520. PMID 17065640.
- 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 - Chapter VII, "The Wiskott-Aldrich Syndrome"