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| '''Associate Editor-In-Chief:''' {{CZ}} | | '''Associate Editor-In-Chief:''' {{CZ}} |
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| ==Overview== | | ==[[Wiskott-Aldrich syndrome overview|Overview]]== |
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| '''Wiskott-Aldrich syndrome''' (WAS) is a rare [[sex-linked|X-linked]] [[recessive gene|recessive]] disease characterized by [[eczema]], [[thrombocytopenia]] (low [[platelet]] counts), [[immune deficiency]], and bloody diarrhea (due to the low platelet counts). It is also sometimes called the ''eczema-thrombocytopenia-immunodeficiency syndrome'' in keeping with Aldrich's original description in 1954.<ref name=Aldrich>{{cite journal |author=Aldrich RA, Steinberg AG, Campbell DC |title=Pedigree demonstrating a sex-linked recessive condition characterized by draining ears, eczematoid dermatitis and bloody diarrhea |journal=Pediatrics |volume=13 |issue=2 |pages=133-9 |year=1954 |pmid=13133561}}</ref> 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 historical perspective|Historical Perspective]]== |
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| ==Signs and symptoms== | | ==[[Wiskott-Aldrich syndrome classification|Classification]]== |
| WAS generally becomes symptomatic in children. Due to its mode of inheritance, the overwhelming majority are male. It is characterised by bruising caused by [[thrombocytopenia]] (low [[platelet]] counts), small platelet size on [[blood film]], [[eczema]], recurrent [[infection]]s, and a propensity for [[autoimmune disorder]]s and [[malignancy|malignancies]] (mainly [[lymphoma]] and [[leukemia]]).
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| In Wiskott-Aldrich syndrome, the platelets are small and do not function properly. They are removed by the [[spleen]], which leads to low platelet counts. Splenomegaly is not an uncommon finding. Also, patients develop a type of itchy rash called [[eczema]]. [[Autoimmune disorder]]s are also found in patients with WAS.
| | ==[[Wiskott-Aldrich syndrome pathophysiology|Pathophysiology]]== |
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| ==Diagnosis== | | ==[[Wiskott-Aldrich syndrome causes|Causes]]== |
| The diagnosis is made on the basis of clinical parameters, the [[blood film]] and low [[immunoglobulin]] levels. Typically, [[immunoglobulin M]] (IgM) levels are low and [[IgA]] and [[IgE]] levels are elevated; [[paraprotein]]s are occasionally observed.<ref>{{cite journal |author=Radl J, Dooren LH, Morell A, Skvaril F, Vossen JM, Uittenbogaart CH |title=Immunoglobulins and transient paraproteins in sera of patients with the Wiskott-Aldrich syndrome: a follow-up study |journal=Clin. Exp. Immunol. |volume=25 |issue=2 |pages=256-63 |year=1976 |pmid=954233}}</ref> Skin immunologic testing (allergy testing) may reveal hyposensitivity. It must be remembered that not all patients will have a family history, since they may be the first to harbor the gene mutation. Often, [[leukemia]] may initially be suspected on the basis of the low platelets and the infections, and [[bone marrow biopsy]] may be performed. Decreased levels of [[Wiskott-Aldrich syndrome protein]] and/or confirmation of a causative mutation provides the most definitive diagnosis.
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| ==Classification== | | ==[[Wiskott-Aldrich syndrome differential diagnosis|Differentiating Wiskott-Aldrich syndrome from other Diseases]]== |
| Jin et al (2004) employ a numerical grading of severity:<ref name=Jin>{{cite journal |author=Jin Y, Mazza C, Christie JR, ''et al'' |title=Mutations of the Wiskott-Aldrich Syndrome Protein (WASP): hotspots, effect on transcription, and translation and phenotype/genotype correlation |journal=Blood |volume=104 |issue=13 |pages=4010-9 |year=2004 |pmid=15284122 |doi=10.1182/blood-2003-05-1592}}</ref>
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| * 0.5: intermittent thrombopenia
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| * 1.0: thrombopenia and small platelets
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| * 2.0: thrombopenia and normally responsive eczema or occasional upper respiratory tract infections.
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| * 2.5: thrombopenia and therapy-responsive but severe eczema or airway infections requiring antibiotics
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| * 3.0: both eczema ''and'' airway infections requiring antibiotics
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| * 4.0: eczema continuously requiring therapy and/or severe or life threatening infections
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| * 5.0: autoimmune disease or malignancy in an XLT/WAS patient.
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| ==Pathophysiology== | | ==[[Wiskott-Aldrich syndrome epidemiology and demographics|Epidemiology and Demographics]]== |
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| |align="center"|[[Image:Xlinkrecessivefather.jpg|200px]]
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| In Wiskott–Aldrich syndrome, the platelets are small and do not function properly. They are removed by the [[spleen]], which leads to low platelet counts.
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| Wiskott–Aldrich syndrome was linked in 1994 to mutations in a [[gene]] on the short arm of the [[X chromosome]], which was termed ''[[Wiskott-Aldrich syndrome protein]]'' (''WASp''). It was later discovered that the disease [[X-linked thrombocytopenia]] (XLT) was also due to ''WASp'' mutations, but different ones from those that cause full-blown Wiskott–Aldrich syndrome. Furthermore, the rare disorder [[X-linked neutropenia]] has been linked to particular mutations of the ''WASp'' gene.
| | ==[[Wiskott-Aldrich syndrome risk factors|Risk Factors]]== |
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| The ''WASp'' gene codes for the protein by the same name, which is 502 [[amino acid]]s long and is mainly expressed in [[haematopoeisis|hematopoietic]] cells (the cells in the bone marrow that develop into blood cells). The main function of WASp is to activate actin polymerization by binding to the [[Arp2/3 complex]]. In T-cell, WASp is important because it is known to be activated via [[T-cell receptor]] (TCR) signaling pathways to induce cortical actin [[cytoskeleton]] rearrangements that are responsible for forming the [[immunological synapse]].
| | ==[[Wiskott-Aldrich syndrome screening|Screening]]== |
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| The immune deficiency is caused by decreased [[antibody]] production, and an inability for [[T cell]]s to become polarized <ref name="titleWiskott-Aldrich Syndrome: Immunodeficiency Disorders: Merck Manual Professional">{{cite web |url=http://www.merck.com/mmpe/sec13/ch164/ch164n.html |title=Wiskott-Aldrich Syndrome: Immunodeficiency Disorders: Merck Manual Professional |accessdate=2008-03-01 |work=}}</ref> (making it a [[combined immunodeficiency]]). This leads to increased susceptibility to infections, particularly of the ears and sinuses. T cells are unable to reorganize their actin cytoskeleton.
| | ==[[Wiskott-Aldrich syndrome natural history, complications and prognosis|Natural History, Complications and Prognosis]]== |
| The type of [[mutation]] to the ''WASp'' gene correlates significantly with the degree of severity: those that led to the production of a truncated protein caused significantly more symptoms than those with a [[missense mutation]] but a normal-length WASp.<ref name=Jin/> Although autoimmune disease and malignancy occur in both types of mutation, those patients with truncated WASp carry a higher risk.
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| A defect in [[CD43]] molecule has been found to be associated in patients with Wiskott–Aldrich syndrome.<ref name="CD43 a defective molecule in Wiskott-Aldrich syndrome">{{cite pmid|1683685}}</ref>
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| ==Epidemiology==
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| The combined incidence of WAS and XLT is about 4-10 in 1 million live births. There is no geographical factor.
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| | ==Diagnosis== |
| | [[Wiskott-Aldrich syndrome history and symptoms|History and Symptoms]] | [[Wiskott-Aldrich syndrome physical examination|Physical Examination]] | [[Wiskott-Aldrich syndrome laboratory findings|Laboratory Findings]] | [[Wiskott-Aldrich syndrome other diagnostic studies|Other Diagnostic Studies]] |
| ==Treatment== | | ==Treatment== |
| Treatment of Wiskott-Aldrich syndrome is based on correcting symptoms. [[Aspirin]] and other [[non-steroidal anti-inflammatory drug]]s should be avoided, since these may interfere with platelet function. A protective helmet can protect children from [[intra-axial hematoma|bleeding into the brain]] which could result from head injuries. For severely low platelet counts, patients may require platelet transfusions or a [[splenectomy]]. 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]].
| | [[Wiskott-Aldrich syndrome medical therapy|Medical Therapy]] | [[Wiskott-Aldrich syndrome surgery|Surgery]] | [[Wiskott-Aldrich syndrome prevention|Prevention]] | [[Wiskott-Aldrich syndrome cost-effectiveness of therapy|Cost-Effectiveness of Therapy]] | [[Wiskott-Aldrich syndrome future or investigational therapies|Future or Investigational Therapies]] |
| | | ==Case Studies== |
| As Wiskott-Aldrich syndrome is primarily a disorder of the blood-forming tissues, a [[haematopoiesis|hematopoietic]] [[stem cell]] transplant, accomplished through a [[cord blood]] or [[bone marrow transplant]] offers the only hope of cure. This treatment is inherently fraught with risks, but is nonetheless recommended for patients with [[human leukocyte antigen|HLA]]-identical donors, matched sibling donors, or even in cases of incomplete matches if the patient is age 5 or under.
| | [[Wiskott-Aldrich syndrome case study one|Case #1]] |
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| ==History== | |
| The syndrome is named after Dr Robert Anderson Aldrich, an American pediatrician who described the disease in a family of Dutch-Americans in 1954,<ref name=Aldrich/> and Dr Alfred Wiskott, a German pediatrician who first noticed the syndrome in 1937.<ref>{{cite journal |last=Wiskott |first=A |year=1937 |month= |title=''Familiärer, angeborener Morbus Werlhofii?'' ("Familial congenital Werlhof's disease?") |journal=Montsschr Kinderheilkd |volume=68 |issue= |pages=212-16}}</ref> 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 that they probably shared a novel frameshift mutation of the first exon of the ''WAS'' gene.<ref>{{cite journal |author=Binder V, Albert MH, Kabus M, Bertone M, Meindl A, Belohradsky BH |title=The genotype of the original Wiskott phenotype |journal=N. Engl. J. Med. |volume=355 |issue=17 |pages=1790-3 |year=2006 |pmid=17065640 |doi=10.1056/NEJMoa062520}}</ref>
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| == References ==
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| <div class="references-small">
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| {{reflist|2}}
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| </div>
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| ==External links== | | ==External links== |
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| {{Immune disorders}} | | {{Immune disorders}} |
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| [[Category:Genetic disorders]] | | [[Category:Genetic disorders]] |