Wiskott-Aldrich syndrome: Difference between revisions
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==Pathophysiology== | ==Pathophysiology== | ||
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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. | |||
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. | |||
The | 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]]. | ||
The type of [[mutation]] to the '' | 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. | ||
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. | |||
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> | |||
==Epidemiology== | ==Epidemiology== | ||
Revision as of 16:18, 21 September 2012
| Wiskott-Aldrich syndrome | |
| ICD-10 | D82.0 |
|---|---|
| ICD-9 | 279.12 |
| OMIM | 301000 |
| DiseasesDB | 14176 |
| eMedicine | med/1162 ped/2443 derm/702 |
| MeSH | D014923 |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2]
Overview
Wiskott-Aldrich syndrome (WAS) is a rare X-linked 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.[1]
Signs and symptoms
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 infections, and a propensity for autoimmune disorders and malignancies (mainly lymphoma and leukemia).
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 disorders are also found in patients with WAS.
Diagnosis
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; paraproteins are occasionally observed.[2] 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.
Classification
Jin et al (2004) employ a numerical grading of severity:[3]
- 0.5: intermittent thrombopenia
- 1.0: thrombopenia and small platelets
- 2.0: thrombopenia and normally responsive eczema or occasional upper respiratory tract infections.
- 2.5: thrombopenia and therapy-responsive but severe eczema or airway infections requiring antibiotics
- 3.0: both eczema and airway infections requiring antibiotics
- 4.0: eczema continuously requiring therapy and/or severe or life threatening infections
- 5.0: autoimmune disease or malignancy in an XLT/WAS patient.
Pathophysiology
|
|
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.
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.
The WASp gene codes for the protein by the same name, which is 502 amino acids long 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 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.
The immune deficiency is caused by decreased antibody production, and an inability for T cells to become polarized [4] (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. 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.[3] Although autoimmune disease and malignancy occur in both types of mutation, those patients with truncated WASp carry a higher risk.
A defect in CD43 molecule has been found to be associated in patients with Wiskott–Aldrich syndrome.[5]
Epidemiology
The combined incidence of WAS and XLT is about 4-10 in 1 million live births. There is no geographical factor.
Treatment
Treatment of Wiskott-Aldrich syndrome is based on correcting symptoms. Aspirin and other non-steroidal anti-inflammatory drugs should be avoided, since these may interfere with platelet function. 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 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.
As Wiskott-Aldrich syndrome is primarily a disorder of the blood-forming tissues, a 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 HLA-identical donors, matched sibling donors, or even in cases of incomplete matches if the patient is age 5 or under.
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,[1] and Dr Alfred Wiskott, a German pediatrician who first noticed the syndrome in 1937.[6] 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.[7]
References
- ↑ 1.0 1.1 Aldrich RA, Steinberg AG, Campbell DC (1954). "Pedigree demonstrating a sex-linked recessive condition characterized by draining ears, eczematoid dermatitis and bloody diarrhea". Pediatrics. 13 (2): 133–9. PMID 13133561.
- ↑ Radl J, Dooren LH, Morell A, Skvaril F, Vossen JM, Uittenbogaart CH (1976). "Immunoglobulins and transient paraproteins in sera of patients with the Wiskott-Aldrich syndrome: a follow-up study". Clin. Exp. Immunol. 25 (2): 256–63. PMID 954233.
- ↑ 3.0 3.1 Jin Y, Mazza C, Christie JR; et al. (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.
- ↑ "Wiskott-Aldrich Syndrome: Immunodeficiency Disorders: Merck Manual Professional". Retrieved 2008-03-01.
- ↑ PMID 1683685 (PMID 1683685)
Citation will be completed automatically in a few minutes. Jump the queue or expand by hand - ↑ 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 (2006). "The genotype of the original Wiskott phenotype". N. Engl. J. Med. 355 (17): 1790–3. doi:10.1056/NEJMoa062520. PMID 17065640.
External links
- Immune Deficiency Foundation - Chapter VII, "The Wiskott-Aldrich Syndrome"