Wiskott-Aldrich syndrome 1211445 225119881 2008-07-11T23:47:47Z Thijs!bot 1392310 robot Adding: [[nl:Syndroom van Wiskott-Aldrich]] {{Infobox_Disease | Name = {{PAGENAME}} | Image = | Caption = | DiseasesDB = 14176 | ICD10 = {{ICD10|D|82|0|d|80}} | ICD9 = {{ICD9|279.12}} | ICDO = | OMIM = 301000 | MedlinePlus = | eMedicineSubj = med | eMedicineTopic = 1162 | eMedicine_mult = {{eMedicine2|ped|2443}} {{eMedicine2|derm|702}} | MeshID = D014923 | }} '''Wiskott-Aldrich syndrome''' (WAS) is a rare [[sex-linked|X-linked]] [[recessive gene|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]].<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> ==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 [[infection]]s, and a propensity for [[autoimmune disorder]]s and [[malignancy|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 disorder]]s 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, [[IgA]] levels are elevated, and [[IgE]] levels may be 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}} {{PMC|1541349}}</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. ==Classification== 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> * 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== 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 acid]]s long and is mainly expressed in [[haematopoeisis|hematopoietic]] cells (the cells in the bone marrow that develop into blood cells). Its exact function is being investigated, but [[signal transduction]] and [[cytoskeleton]] maintenance have been suggested. The immune deficiency is caused by decreased [[antibody]] production, although [[T cell]]s are also affected<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 |format= |work=}}</ref> (making it a [[combined immunodeficiency]]). This leads to increased susceptibility to infections, particularly of the ears and sinuses. 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. ==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 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]]. 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 may be 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. ==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=''Famili&auml;rer, 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> == References == {{reflist|2}} ==External links== *[http://www.primaryimmune.org/pubs/book_pats/book_pats.htm Immune Deficiency Foundation] - Chapter VII, "The Wiskott-Aldrich Syndrome" {{Immune disorders}} [[Category:Genetic disorders]] [[Category:Immune system disorders]] [[Category:Blood disorders]] [[Category:Rare diseases]] [[de:Wiskott-Aldrich-Syndrom]] [[fr:Syndrome de Wiskott-Aldrich]] [[nl:Syndroom van Wiskott-Aldrich]] [[pl:Zespół Wiskotta-Aldricha]] [[pt:Síndrome de Wiskott-Aldrich]]