Wiskott-Aldrich syndrome: Difference between revisions

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{{SI}}
{{SI}}


{{Infobox_Disease |
{{CMG}}; {{AE}} {{CK}}; {{HK}}; {{CZ}}
  Name          = {{PAGENAME}} |
  Image          = |
  Caption        = |
  DiseasesDB    = 14176 |
  ICD10          = {{ICD10|D|82|0|d|80}} |
  ICD9          = {{ICD9|279.12}} |
  ICDO          = |
  OMIM          = 301000 |
  MedlinePlus    = |
  MeshID        = D014923 |
}}
 
{{CMG}}; {{AE}} {{CK}}
 
'''Associate Editor-In-Chief:''' {{CZ}}


{{SK}} Aldrich syndrome
{{SK}} Aldrich syndrome
==Patient Informtion==


==Overview==
==Overview==
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==Classification==
==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>
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
* Grade 0.5: intermittent [[Thrombocytopenia|thrombopenia]]
* 1.0: thrombopenia and small platelets
* Grade 1.0: [[Thrombocytopenia|thrombopenia]] and small platelets
* 2.0: thrombopenia and normally responsive eczema or occasional upper respiratory tract infections.
* Grade 2.0: [[Thrombocytopenia|thrombopenia]] and normally responsive [[eczema]] or occasional upper [[Respiratory tract infection|respiratory tract infections]].
* 2.5: thrombopenia and therapy-responsive but severe eczema or airway infections requiring antibiotics
* Grade 2.5: [[Thrombocytopenia|thrombopenia]] and therapy-responsive but severe [[eczema]] or airway infections requiring antibiotics
* 3.0: both eczema ''and'' airway infections requiring antibiotics
* Grade 3.0: both [[eczema]] ''and'' airway infections requiring antibiotics
* 4.0: eczema continuously requiring therapy and/or severe or life threatening infections
* Grade 4.0: [[eczema]] continuously requiring therapy and/or severe or life threatening infections
* 5.0: autoimmune disease or malignancy in an XLT/WAS patient.
* Grade 5.0: [[Autoimmunity|autoimmune]] disease or [[malignancy]] in an XLT/WAS patient.


==Pathophysiology==
==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.
In the Wiskott–Aldrich syndrome, the [[Platelet|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.
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'' [[Mutation|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). 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 ''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 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 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 [[Infection|infections]], particularly of the [[Ear|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. Although autoimmune disease and [[malignancy]] occur in both types of [[mutation]], those patients with truncated WASp carry a higher risk.
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. 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>
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>


==Causes==
==Causes==
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.
In Wiskott–Aldrich syndrome, the [[Platelet|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.
Wiskott–Aldrich syndrome was linked in 1994 to [[Mutation|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). 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 ''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 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 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 [[Ear|ears]] and [[sinuses]]. [[T cell|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. Although [[Autoimmunity|autoimmune]] disease and [[malignancy]] occur in both types of [[mutation]], those patients with truncated WASp carry a higher risk.
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. 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>
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>


==Differentiating ((Page name)) from Other Diseases==
==Differentiating Wiskott-Aldrich Syndrome From Other Disorders of Humoral Imuunodeficiency==
Wiskott-Aldrich Syndrome should be differentiated from other disorders leading to [[hypogammaglobulinemia]] and defects of [[humoral immunity]]. The following conditions may be considered as differentials:<ref name="pmid17910333">{{cite journal |vauthors=Agarwal S, Cunningham-Rundles C |title=Assessment and clinical interpretation of reduced IgG values |journal=Ann. Allergy Asthma Immunol. |volume=99 |issue=3 |pages=281–3 |date=September 2007 |pmid=17910333 |pmc=3099256 |doi=10.1016/S1081-1206(10)60665-5 |url=}}</ref><ref name="pmid7679206">{{cite journal |vauthors=Korthäuer U, Graf D, Mages HW, Brière F, Padayachee M, Malcolm S, Ugazio AG, Notarangelo LD, Levinsky RJ, Kroczek RA |title=Defective expression of T-cell CD40 ligand causes X-linked immunodeficiency with hyper-IgM |journal=Nature |volume=361 |issue=6412 |pages=539–41 |date=February 1993 |pmid=7679206 |doi=10.1038/361539a0 |url=}}</ref><ref name="pmid9255191">{{cite journal |vauthors=Levy J, Espanol-Boren T, Thomas C, Fischer A, Tovo P, Bordigoni P, Resnick I, Fasth A, Baer M, Gomez L, Sanders EA, Tabone MD, Plantaz D, Etzioni A, Monafo V, Abinun M, Hammarstrom L, Abrahamsen T, Jones A, Finn A, Klemola T, DeVries E, Sanal O, Peitsch MC, Notarangelo LD |title=Clinical spectrum of X-linked hyper-IgM syndrome |journal=J. Pediatr. |volume=131 |issue=1 Pt 1 |pages=47–54 |date=July 1997 |pmid=9255191 |doi= |url=}}</ref><ref name="pmid14663287">{{cite journal |vauthors=Winkelstein JA, Marino MC, Ochs H, Fuleihan R, Scholl PR, Geha R, Stiehm ER, Conley ME |title=The X-linked hyper-IgM syndrome: clinical and immunologic features of 79 patients |journal=Medicine (Baltimore) |volume=82 |issue=6 |pages=373–84 |date=November 2003 |pmid=14663287 |doi=10.1097/01.md.0000100046.06009.b0 |url=}}</ref><ref name="pmid10352287">{{cite journal |vauthors=Subauste CS, Wessendarp M, Sorensen RU, Leiva LE |title=CD40-CD40 ligand interaction is central to cell-mediated immunity against Toxoplasma gondii: patients with hyper IgM syndrome have a defective type 1 immune response that can be restored by soluble CD40 ligand trimer |journal=J. Immunol. |volume=162 |issue=11 |pages=6690–700 |date=June 1999 |pmid=10352287 |doi= |url=}}</ref><ref name="pmid8993019">{{cite journal |vauthors=Hayward AR, Levy J, Facchetti F, Notarangelo L, Ochs HD, Etzioni A, Bonnefoy JY, Cosyns M, Weinberg A |title=Cholangiopathy and tumors of the pancreas, liver, and biliary tree in boys with X-linked immunodeficiency with hyper-IgM |journal=J. Immunol. |volume=158 |issue=2 |pages=977–83 |date=January 1997 |pmid=8993019 |doi= |url=}}</ref><ref name="pmid20180797">{{cite journal |vauthors=Davies EG, Thrasher AJ |title=Update on the hyper immunoglobulin M syndromes |journal=Br. J. Haematol. |volume=149 |issue=2 |pages=167–80 |date=April 2010 |pmid=20180797 |pmc=2855828 |doi=10.1111/j.1365-2141.2010.08077.x |url=}}</ref><ref name="pmid20101521">{{cite journal |vauthors=Yel L |title=Selective IgA deficiency |journal=J. Clin. Immunol. |volume=30 |issue=1 |pages=10–6 |date=January 2010 |pmid=20101521 |pmc=2821513 |doi=10.1007/s10875-009-9357-x |url=}}</ref><ref name="pmid19153537">{{cite journal |vauthors=Suzuki H, Kaneko H, Fukao T, Jin R, Kawamoto N, Asano T, Matsui E, Kasahara K, Kondo N |title=Various expression patterns of alpha1 and alpha2 genes in IgA deficiency |journal=Allergol Int |volume=58 |issue=1 |pages=111–7 |date=March 2009 |pmid=19153537 |doi=10.2332/allergolint.O-08-549 |url=}}</ref><ref name="pmid11720003">{{cite journal |vauthors=Cunningham-Rundles C |title=Physiology of IgA and IgA deficiency |journal=J. Clin. Immunol. |volume=21 |issue=5 |pages=303–9 |date=September 2001 |pmid=11720003 |doi= |url=}}</ref><ref name="pmid15093556">{{cite journal |vauthors=Edwards E, Razvi S, Cunningham-Rundles C |title=IgA deficiency: clinical correlates and responses to pneumococcal vaccine |journal=Clin. Immunol. |volume=111 |issue=1 |pages=93–7 |date=April 2004 |pmid=15093556 |doi=10.1016/j.clim.2003.12.005 |url=}}</ref><ref name="pmid305332">{{cite journal |vauthors=Chipps BE, Talamo RC, Winkelstein JA |title=IgA deficiency, recurrent pneumonias, and bronchiectasis |journal=Chest |volume=73 |issue=4 |pages=519–26 |date=April 1978 |pmid=305332 |doi= |url=}}</ref><ref name="pmid5056860">{{cite journal |vauthors=Zinneman HH, Kaplan AP |title=The association of giardiasis with reduced intestinal secretory immunoglobulin A |journal=Am J Dig Dis |volume=17 |issue=9 |pages=793–7 |date=September 1972 |pmid=5056860 |doi= |url=}}</ref><ref name="pmid18683032">{{cite journal |vauthors=Aghamohammadi A, Cheraghi T, Gharagozlou M, Movahedi M, Rezaei N, Yeganeh M, Parvaneh N, Abolhassani H, Pourpak Z, Moin M |title=IgA deficiency: correlation between clinical and immunological phenotypes |journal=J. Clin. Immunol. |volume=29 |issue=1 |pages=130–6 |date=January 2009 |pmid=18683032 |doi=10.1007/s10875-008-9229-9 |url=}}</ref><ref name="pmid19541543">{{cite journal |vauthors=Janzi M, Kull I, Sjöberg R, Wan J, Melén E, Bayat N, Ostblom E, Pan-Hammarström Q, Nilsson P, Hammarström L |title=Selective IgA deficiency in early life: association to infections and allergic diseases during childhood |journal=Clin. Immunol. |volume=133 |issue=1 |pages=78–85 |date=October 2009 |pmid=19541543 |doi=10.1016/j.clim.2009.05.014 |url=}}</ref><ref name="pmid18202833">{{cite journal |vauthors=Jacob CM, Pastorino AC, Fahl K, Carneiro-Sampaio M, Monteiro RC |title=Autoimmunity in IgA deficiency: revisiting the role of IgA as a silent housekeeper |journal=J. Clin. Immunol. |volume=28 Suppl 1 |issue= |pages=S56–61 |date=May 2008 |pmid=18202833 |doi=10.1007/s10875-007-9163-2 |url=}}</ref><ref name="pmid10600329">{{cite journal |vauthors=Conley ME, Notarangelo LD, Etzioni A |title=Diagnostic criteria for primary immunodeficiencies. Representing PAGID (Pan-American Group for Immunodeficiency) and ESID (European Society for Immunodeficiencies) |journal=Clin. Immunol. |volume=93 |issue=3 |pages=190–7 |date=December 1999 |pmid=10600329 |doi=10.1006/clim.1999.4799 |url=}}</ref><ref name="pmid4012343">{{cite journal |vauthors=Mayer RJ, Schiffer CA, Peterson BA, Silver RT, Cornwell GG, McIntyre OR, Rai KR, Budman DR, Ellison RR, Maguire M |title=Intensive postremission therapy in adults with acute nonlymphocytic leukemia with ara-C by continuous infusion or bolus administration: preliminary results of a CALGB phase I study |journal=Semin. Oncol. |volume=12 |issue=2 Suppl 3 |pages=84–90 |date=June 1985 |pmid=4012343 |doi= |url=}}</ref><ref name="pmid23527602">{{cite journal |vauthors=Massaad MJ, Ramesh N, Geha RS |title=Wiskott-Aldrich syndrome: a comprehensive review |journal=Ann. N. Y. Acad. Sci. |volume=1285 |issue= |pages=26–43 |date=May 2013 |pmid=23527602 |doi=10.1111/nyas.12049 |url=}}</ref><ref name="pmid29086100">{{cite journal |vauthors=Candotti F |title=Clinical Manifestations and Pathophysiological Mechanisms of the Wiskott-Aldrich Syndrome |journal=J. Clin. Immunol. |volume=38 |issue=1 |pages=13–27 |date=January 2018 |pmid=29086100 |doi=10.1007/s10875-017-0453-z |url=}}</ref><ref name="pmid28851742">{{cite journal |vauthors=Sereni L, Castiello MC, Villa A |title=Platelets in Wiskott-Aldrich syndrome: Victims or executioners? |journal=J. Leukoc. Biol. |volume=103 |issue=3 |pages=577–590 |date=March 2018 |pmid=28851742 |doi=10.1189/jlb.5MR0617-257R |url=}}</ref><ref name="pmid21178275">{{cite journal |vauthors=Blundell MP, Worth A, Bouma G, Thrasher AJ |title=The Wiskott-Aldrich syndrome: The actin cytoskeleton and immune cell function |journal=Dis. Markers |volume=29 |issue=3-4 |pages=157–75 |date=2010 |pmid=21178275 |pmc=3835520 |doi=10.3233/DMA-2010-0735 |url=}}</ref><ref name="pmid19351959">{{cite journal |vauthors=Bosticardo M, Marangoni F, Aiuti A, Villa A, Grazia Roncarolo M |title=Recent advances in understanding the pathophysiology of Wiskott-Aldrich syndrome |journal=Blood |volume=113 |issue=25 |pages=6288–95 |date=June 2009 |pmid=19351959 |doi=10.1182/blood-2008-12-115253 |url=}}</ref><ref name="pmid11091267">{{cite journal |vauthors=Fischer A |title=Severe combined immunodeficiencies (SCID) |journal=Clin. Exp. 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Infect. Dis. |volume=46 |issue=10 |pages=1547–54 |date=May 2008 |pmid=18419489 |doi=10.1086/587669 |url=}}</ref><ref name="pmid3963038">{{cite journal |vauthors=Roifman CM, Rao CP, Lederman HM, Lavi S, Quinn P, Gelfand EW |title=Increased susceptibility to Mycoplasma infection in patients with hypogammaglobulinemia |journal=Am. J. Med. |volume=80 |issue=4 |pages=590–4 |date=April 1986 |pmid=3963038 |doi= |url=}}</ref><ref name="pmid21970952">{{cite journal |vauthors=Yong PF, Thaventhiran JE, Grimbacher B |title="A rose is a rose is a rose," but CVID is Not CVID common variable immune deficiency (CVID), what do we know in 2011? |journal=Adv. 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Immunol. |volume=27 |issue=3 |pages=308–16 |date=May 2007 |pmid=17510807 |doi=10.1007/s10875-007-9075-1 |url=}}</ref><ref name="pmid26564081">{{cite journal |vauthors=Nissenkorn A, Ben-Zeev B |title=Ataxia telangiectasia |journal=Handb Clin Neurol |volume=132 |issue= |pages=199–214 |date=2015 |pmid=26564081 |doi=10.1016/B978-0-444-62702-5.00014-7 |url=}}</ref><ref name="pmid27884168">{{cite journal |vauthors=Rothblum-Oviatt C, Wright J, Lefton-Greif MA, McGrath-Morrow SA, Crawford TO, Lederman HM |title=Ataxia telangiectasia: a review |journal=Orphanet J Rare Dis |volume=11 |issue=1 |pages=159 |date=November 2016 |pmid=27884168 |pmc=5123280 |doi=10.1186/s13023-016-0543-7 |url=}}</ref><ref name="pmid9874856">{{cite journal |vauthors=Crawford TO |title=Ataxia telangiectasia |journal=Semin Pediatr Neurol |volume=5 |issue=4 |pages=287–94 |date=December 1998 |pmid=9874856 |doi= |url=}}</ref><ref name="pmid2415689">{{cite journal |vauthors=Boder E |title=Ataxia-telangiectasia: an overview |journal=Kroc Found Ser |volume=19 |issue= |pages=1–63 |date=1985 |pmid=2415689 |doi= |url=}}</ref><ref name="pmid22614068">{{cite journal |vauthors=Hoche F, Seidel K, Theis M, Vlaho S, Schubert R, Zielen S, Kieslich M |title=Neurodegeneration in ataxia telangiectasia: what is new? What is evident? |journal=Neuropediatrics |volume=43 |issue=3 |pages=119–29 |date=June 2012 |pmid=22614068 |doi=10.1055/s-0032-1313915 |url=}}</ref><ref name="pmid13542097">{{cite journal |vauthors=BODER E, SEDGWICK RP |title=Ataxia-telangiectasia; a familial syndrome of progressive cerebellar ataxia, oculocutaneous telangiectasia and frequent pulmonary infection |journal=Pediatrics |volume=21 |issue=4 |pages=526–54 |date=April 1958 |pmid=13542097 |doi= |url=}}</ref><ref name="pmid24683014">{{cite journal |vauthors=Sahama I, Sinclair K, Pannek K, Lavin M, Rose S |title=Radiological imaging in ataxia telangiectasia: a review |journal=Cerebellum |volume=13 |issue=4 |pages=521–30 |date=August 2014 |pmid=24683014 |doi=10.1007/s12311-014-0557-4 |url=}}</ref><ref name="pmid23886747">{{cite journal |vauthors=Lin DD, Barker PB, Lederman HM, Crawford TO |title=Cerebral abnormalities in adults with ataxia-telangiectasia |journal=AJNR Am J Neuroradiol |volume=35 |issue=1 |pages=119–23 |date=January 2014 |pmid=23886747 |pmc=4106125 |doi=10.3174/ajnr.A3646 |url=}}</ref><ref name="pmid15069401">{{cite journal |vauthors=Nowak-Wegrzyn A, Crawford TO, Winkelstein JA, Carson KA, Lederman HM |title=Immunodeficiency and infections in ataxia-telangiectasia |journal=J. Pediatr. |volume=144 |issue=4 |pages=505–11 |date=April 2004 |pmid=15069401 |doi=10.1016/j.jpeds.2003.12.046 |url=}}</ref>
{|
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Disorder
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Mechanism
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Characteristic Features
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Clinical Presentation
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Laboratory Findings
|-
! align="center" style="background:#DCDCDC;" + |[[Wiskott-Aldrich syndrome|Wiskott-Aldrich Syndrome]]
| align="left" style="background:#F5F5F5;" + |
* [[Mutation]] in [[WAS]] [[gene]]
* [[T cells]] unable to reorganize [[actin]] [[microfilaments]] ([[microfilament]] defect)  
| align="left" style="background:#F5F5F5;" + |
* [[X-linked recessive]] pattern of inheritance
* Increased risk of [[autoimmune disease]] and [[malignancy]]
| align="left" style="background:#F5F5F5;" + |
* [[Thrombocytopenic purpura]]
* [[Eczema]]
* Recurrent [[infections]]
| align="left" style="background:#F5F5F5;" + |
* Decreased to normal [[Immunoglobulin G|IgG]] and [[Immunoglobulin M|IgM]]
* Increased [[Immunoglobulin E|IgE]] and [[IgA]]
* Fewer and smaller [[platelets]]
|-
! align="center" style="background:#DCDCDC;" + |[[X-linked agammaglobulinemia|X-Linked (Bruton) Agammaglobulinemia]]
| align="left" style="background:#F5F5F5;" + |
* Defect in [[tyrosine kinase]] [[gene]] ([[Bruton's tyrosine kinase|BTK]])
* [[B cells]] fail to mature
| align="left" style="background:#F5F5F5;" + |
* [[X-linked recessive]] pattern of inheritance
* Increased [[prevalence]] in [[males]]
| align="left" style="background:#F5F5F5;" + |
* Recurrent [[bacterial]] and [[enteroviral]] [[infections]] after 6 months of age
* Pre-disposition to development of [[infections]] by [[encapsulated organisms]]
* Pre-disposition to development of Giardia infections
* Absent lymph nodes and tonsils
| align="left" style="background:#F5F5F5;" + |
* Normal [[CD19|CD19+ B cell]] count
* Decreased pro-[[B cells]]
* Increased pre-[[B cells]]
* Decreased [[immunoglobulins]] of all classes
|-
! align="center" style="background:#DCDCDC;" + |[[IgA deficiency|Selective IgA Deficiency]]
| align="left" style="background:#F5F5F5;" + |
* [[Stem cell]] defect (Transferrable with [[Bone marrow transplant|marrow transplant]])
* Lack of [[Interleukin 4|IL-4]], [[Interleukin 6|IL-6]], [[Interleukin 7|IL-7]], [[Interleukin 10|IL-10]], [[TGF beta|TGF-β]], and [[Interleukin 21|IL-21]]
* [[Mutations]] in [[transmembrane]] activator and calcium-modulator and [[cyclophilin]] ligand interactor ([[TACI]], [[TNFRSF13B]])
| align="left" style="background:#F5F5F5;" + |
* Most common primary [[immune deficiency]]
| align="left" style="background:#F5F5F5;" + |
* Majority of the cases are [[asymptomatic]]
* Respiratory and [[gastrointestinal]] infections ([[mucosal]] infections)
* Associated with [[autoimmune diseases]]
* [[Atopy]]
* [[Anaphylaxis]] to [[IgA]] containing products
| align="left" style="background:#F5F5F5;" + |
* Serum [[IgA]] < 7 mg/dl
* Normal [[IgG]] and [[IgM]] levels
|-
! align="center" style="background:#DCDCDC;" + |[[Common variable immunodeficiency|Common Variable Immunodeficiency]]
| align="left" style="background:#F5F5F5;" + |
* Defective [[B cell]] differentiation
| align="left" style="background:#F5F5F5;" + |
* May be acquired in 20-30 years of age
| align="left" style="background:#F5F5F5;" + |
* May present with other [[autoimmune diseases]]
* Associated with [[bronchiectasis]]
* Associated with [[lymphoma]]
* Associated with sinopulmonary infections ([[Bacterial]], [[enteroviral]] and [[parasitic]] such as [[Giardia]])
| align="left" style="background:#F5F5F5;" + |
* Decreased [[plasma cells]]
* Decreased [[immunoglobulins]]
|-
! align="center" style="background:#DCDCDC;" + |[[Job's syndrome|Autosomal dominant hype IgE syndrome (Job's Syndrome)]]
| align="left" style="background:#F5F5F5;" + |
* Defieciency of [[T helper 17 cell|Th17 cells]] due to [[STAT3]] [[mutation]]
* Impaired [[neutrophils]] to sites of [[infection]]
| align="left" style="background:#F5F5F5;" + |
* Distinctive coarse facies
* Cold (non-inflammatory) Staphylococcal abscesses
* Retained primary teeth
* Eczema
| align="left" style="background:#F5F5F5;" + |
| align="left" style="background:#F5F5F5;" + |
* Increased levels of [[IgE]]
* Decreased levels of [[interferon gamma]] (IFN-gamma)
|-
! align="center" style="background:#DCDCDC;" + |[[Severe combined immunodeficiency|Severe combined immunodeficiency (SCID)]]
| align="left" style="background:#F5F5F5;" + |
* Defective [[Interleukin-2 receptor|interleukin-2 receptor gamma chain]]
* [[Adenosine deaminase]] deficiency
* Reg 1 and Reg 2 [[nonsense mutations]]
| align="left" style="background:#F5F5F5;" + |
* [[Interleukin 20 receptor, alpha subunit|IL-2R]] disease is [[X-linked]]
* [[Adenosine deaminase|ADA]] deficiency and reg mutations are typically [[autosomal recessive]]
| align="left" style="background:#F5F5F5;" + |
* [[Failure to thrive]]
* [[Chronic diarrhea]]
* [[Thrush]]
* Recurrent [[bacterial]], [[viral]] and [[protozoal]] infections
* Treatment is [[bone marrow]] [[transplant]]
| align="left" style="background:#F5F5F5;" + |
* Decreased [[T cell]] receptor excision circles (TRECs)
* Abscence of [[thymic]] shadow on [[Chest X-ray|chest X-Ray]]
* Absent [[germinal centers]] of [[lymph node biopsy]]
* Absent [[T cells]] on [[flow cytometry]]
|-
! align="center" style="background:#DCDCDC;" + |[[Ataxia telangiectasia|Ataxia Telangiectasia]]
| align="left" style="background:#F5F5F5;" + |
* Defect in [[ATM|ATM gene]]
* [[DNA]] double stranded breaks leading to [[cell cycle]] arrest
| align="left" style="background:#F5F5F5;" + |
* Hypersensitivity to [[X-Ray|X-Rays]]
| align="left" style="background:#F5F5F5;" + |
* Triad of:
** [[Ataxia]]
** Spider [[Angioma|angiomas]] (Nests of distended [[capillaries]])
** [[IgA deficiency]]
| align="left" style="background:#F5F5F5;" + |
* Increased [[alpha fetoprotein]] ([[Alpha-fetoprotein|AFP]])
* Decreased [[IgA]], [[IgG]] and [[IgE]]
* [[Lymphopenia]]
* [[Cerebellar]] atrophy
|-
! align="center" style="background:#DCDCDC;" + |[[Hyper IgM Syndrome Type 1|Hyper IgM Syndrome]]
| align="left" style="background:#F5F5F5;" + |
* Defective [[CD40L]] ([[CD40L|CD40 ligand]]) on [[T helper cell|Th cells]] leading to [[class switching]] defect
| align="left" style="background:#F5F5F5;" + |
* [[X-linked recessive]] pattern of inheritance
| align="left" style="background:#F5F5F5;" + |
* Severe pyogenic infections in early life
* Opportunistic infection with:
** [[Pneumocystis jiroveci]]
** [[Cryptosporidium]]
** [[Cytomegalovirus]] ([[Cytomegalovirus infection|CMV]])
| align="left" style="background:#F5F5F5;" + |
* Increased [[Immunoglobulin M|IgM]]
* Decreased [[Immunoglobulin G|IgG]], [[IgA]] and [[Immunoglobulin E|IgE]]
* No [[germinal centers]]
|}
:*Malignancy: can cause the reduction in the immunoglobulin production.
*Viral infections: such as Epstein-Barr virus, HIV, cytomegalovirus are other causes of hypogammaglobulinemia..
*Side effect of certain medications: Some drugs include systemic glucocorticoids, phenytoin, and carbamazepine, have been associated with IgG deficiency.
*Other causes of primary humoral immunodeficiencies.
*Smoking: may cause IgG2 subclass deficiency.
*Protein-losing conditions: enteropathies, nephrotic syndrome, burns, and other traumas may cause abnormal loss of immunoglobulins.


==Epidemiology and Demographics==
==Differentiating Wiskott-Aldrich Syndrome From Other Bleeding Diseases==
The combined incidence of WAS and XLT is about 4-10 in 1 million live births. There is no geographical factor.
* Wiskott-Aldrich syndrome must be differentiated from other bleeding disorders. Different causes of bleeding disorders can be differentiated based on their clinical manifestation and laboratory findings. These features have discussed in the below table:
{|
! rowspan="2" align="center" style="background:#4479BA; color: #FFFFFF;" + |Category
! rowspan="2" align="center" style="background:#4479BA; color: #FFFFFF;" + |Subcategory
! colspan="2" rowspan="2" align="center" style="background:#4479BA; color: #FFFFFF;" + |Disease
! rowspan="2" align="center" style="background:#4479BA; color: #FFFFFF;" + |History
! colspan="6" align="center" style="background:#4479BA; color: #FFFFFF;" + |Clinical manifestation
! colspan="5" align="center" style="background:#4479BA; color: #FFFFFF;" + |Laboratory testing
! rowspan="2" align="center" style="background:#4479BA; color: #FFFFFF;" + |Comments
|-
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Mucosal bleeding
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Petechia
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Ecchymoses
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Menorrhagia
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Hematoma
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Hemarthrosis
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Plt
! align="center" style="background:#4479BA; color: #FFFFFF;" + |BT
! align="center" style="background:#4479BA; color: #FFFFFF;" + |PT
! align="center" style="background:#4479BA; color: #FFFFFF;" + |PTT
! align="center" style="background:#4479BA; color: #FFFFFF;" + |TT
|-
! rowspan="15" style="background: #4479BA; color: #FFFFFF; text-align: center;" |Platelet disorders
! rowspan="6" align="center" style="padding: 5px 5px; background: #DCDCDC;" |Qualitative Disorders of [[Platelet]] Function
! rowspan="4" align="center" style="padding: 5px 5px; background: #DCDCDC;" |Inherited Disorders of [[Platelet]] Function
! align="center" style="padding: 5px 5px; background: #DCDCDC;" |[[Wiskott-Aldrich syndrome]]
| align="left" style="background:#F5F5F5;" |
* Positive family history
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | <nowiki>+</nowiki>
| align="center" style="background:#F5F5F5;" | <nowiki>+</nowiki>
| align="center" style="background:#F5F5F5;" | <nowiki>+</nowiki>
| align="center" style="background:#F5F5F5;" | −
| align="center" style="background:#F5F5F5;" | −
| align="center" style="background:#F5F5F5;" | Nl or ↓
| align="center" style="background:#F5F5F5;" | ↑
| align="center" style="background:#F5F5F5;" | Nl
| align="center" style="background:#F5F5F5;" | Nl
| align="center" style="background:#F5F5F5;" | Nl
| align="left" style="background:#F5F5F5;" |
* Anti-WASP antibody can be used to detect presence or absence of WAS protein
* In Wiskott–Aldrich syndrome, the [[Platelet|platelets]] are small and do not function properly. They are removed by the [[spleen]], which leads to low [[platelet]] counts.
|-
! align="center" style="padding: 5px 5px; background: #DCDCDC;" |[[Glanzmann's thrombasthenia|Glanzmann’s thrombasthenia]]
| align="left" style="background:#F5F5F5;" |
* Positive family history
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | −
| align="center" style="background:#F5F5F5;" | Rare
| align="center" style="background:#F5F5F5;" | Nl or ↓
| align="center" style="background:#F5F5F5;" | ↑
| align="center" style="background:#F5F5F5;" | Nl
| align="center" style="background:#F5F5F5;" | Nl
| align="center" style="background:#F5F5F5;" | Nl
| align="left" style="background:#F5F5F5;" |
* AR inheritance
* Absence of the platelet Gp IIb/IIIa receptor
* Diminished for GP 2B-3A on [[Flow cytometry|flow cytometry]]
|-
! align="center" style="padding: 5px 5px; background: #DCDCDC;" |[[Bernard-Soulier syndrome]]
| align="left" style="background:#F5F5F5;" |
* Positive family history
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | −
| align="center" style="background:#F5F5F5;" | −
| align="center" style="background:#F5F5F5;" | Nl or ↓
| align="center" style="background:#F5F5F5;" | ↑
| align="center" style="background:#F5F5F5;" | Nl
| align="center" style="background:#F5F5F5;" | Nl
| align="center" style="background:#F5F5F5;" | Nl
| align="left" style="background:#F5F5F5;" |
* AR inheritance
* Absence of the platelet Gp Ib-IX-V receptor
* On PBS: giant platelets
* Ristocetin - no aggregation
|-
! align="left" style="padding: 5px 5px; background: #DCDCDC;" |Platelet storage pool disorder:
*[[Hermansky-Pudlak syndrome]]
*[[Chediak-Higashi syndrome]]
*[[Gray platelet syndrome]]
| align="left" style="background:#F5F5F5;" |
* Positive family history
* [[Hairy cell leukemia]]
* [[Cardiovascular bypass]]
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | <nowiki>+</nowiki>
| align="center" style="background:#F5F5F5;" | <nowiki>+</nowiki>
| align="center" style="background:#F5F5F5;" | <nowiki>+</nowiki>
| align="center" style="background:#F5F5F5;" | −
| align="center" style="background:#F5F5F5;" | −
| align="center" style="background:#F5F5F5;" | Nl or ↓
| align="center" style="background:#F5F5F5;" | ↑
| align="center" style="background:#F5F5F5;" | Nl
| align="center" style="background:#F5F5F5;" | Nl
| align="center" style="background:#F5F5F5;" | Nl
| align="left" style="background:#F5F5F5;" |
* AD inheritance
* AbNlities of platelet granule formation
|-
! colspan="2" align="center" style="padding: 5px 5px; background: #DCDCDC;" |Acquired Disorders of [[Platelet]] Function
| align="left" style="background:#F5F5F5 " |
* [[Chronic renal failure pathophysiology|Uremia]]
* [[Cardiopulmonary bypass]]
* Hematologic disorders such as: [[Myeloproliferative disease|myeloproliferative]] and [[Myelodysplastic syndrome|myelodysplastic syndromes]]
| align="center" style="background:#F5F5F5;" | <nowiki>+</nowiki>
| align="center" style="background:#F5F5F5;" | <nowiki>+</nowiki>
| align="center" style="background:#F5F5F5;" | <nowiki>+</nowiki>
| align="center" style="background:#F5F5F5;" | <nowiki>+</nowiki>
| align="center" style="background:#F5F5F5;" |±
| align="center" style="background:#F5F5F5;" |±
| align="center" style="background:#F5F5F5;" | Nl or ↓
| align="center" style="background:#F5F5F5;" | ↑
| align="center" style="background:#F5F5F5;" | Nl
| align="center" style="background:#F5F5F5;" | Nl
| align="center" style="background:#F5F5F5;" | Nl
| align="center" style="background:#F5F5F5;" | −
|-
! colspan="2" align="center" style="padding: 5px 5px; background: #DCDCDC;" |[[Von Willebrand disease|Von Willebrand Disease]]
| align="left" style="background:#F5F5F5;" |
* Easy bruising
* [[Epistaxis]]
* Oral cavity bleeding
* Bleeding after dental extraction/surgery
* [[Menorrhagia]]
* [[Postpartum hemorrhage]]
| align="center" style="background:#F5F5F5;" | <nowiki>+</nowiki>
| align="center" style="background:#F5F5F5;" | <nowiki>+</nowiki>
| align="center" style="background:#F5F5F5;" | <nowiki>+</nowiki>
| align="center" style="background:#F5F5F5;" | <nowiki>+</nowiki>
| align="center" style="background:#F5F5F5;" |±
| align="center" style="background:#F5F5F5;" |±
| align="center" style="background:#F5F5F5;" | ↑
| align="center" style="background:#F5F5F5;" | Nl
| align="center" style="background:#F5F5F5;" | ↑
| align="center" style="background:#F5F5F5;" | ↑
| align="center" style="background:#F5F5F5;" | Nl
| align="center" style="background:#F5F5F5;" | See the table below for the details about different types.
|-
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Subcategory
! colspan="2" align="center" style="background:#4479BA; color: #FFFFFF;" + |Disease
! align="center" style="background:#4479BA; color: #FFFFFF;" + |History
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Mucosal bleeding
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Petechia
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Ecchymoses
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Menorrhagia
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Hematoma
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Hemarthrosis
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Plt
! align="center" style="background:#4479BA; color: #FFFFFF;" + |BT
! align="center" style="background:#4479BA; color: #FFFFFF;" + |PT
! align="center" style="background:#4479BA; color: #FFFFFF;" + |PTT
! align="center" style="background:#4479BA; color: #FFFFFF;" + |TT
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Comments
|-
! rowspan="7" align="center" style="padding: 5px 5px; background: #DCDCDC;" |[[Thrombocytopenia]]
! colspan="2" align="center" style="padding: 5px 5px; background: #DCDCDC;" |[[Infection]]-Induced [[thrombocytopenia]]
| align="left" style="background:#F5F5F5;" |
* History of prior infection
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | ↓
| align="center" style="background:#F5F5F5;" | ↑
| align="center" style="background:#F5F5F5;" | Nl
| align="center" style="background:#F5F5F5;" | Nl
| align="center" style="background:#F5F5F5;" | Nl
| align="center" style="background:#F5F5F5;" | −
|-
! colspan="2" align="center" style="padding: 5px 5px; background: #DCDCDC;" |[[Medication]]-Induced [[Thrombocytopenia|Thrombocytopenia]]
| align="left" style="background:#F5F5F5;" |
*History of [[Medication|medications]] such as:
** [[Furosemide]]
** [[Non-steroidal anti-inflammatory drug|Nonsteroidal anti-inflammatory drugs]] ([[Non-steroidal anti-inflammatory drug|NSAIDs]])
** [[Penicillin]]
** [[Quinidine]]
** [[Quinine]]
** [[Ranitidine]]
** [[Sulfonamide (medicine)|Sulfonamides]]
** [[Linezolid]]
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | ↓
| align="center" style="background:#F5F5F5;" | ↑
| align="center" style="background:#F5F5F5;" | Nl
| align="center" style="background:#F5F5F5;" | Nl
| align="center" style="background:#F5F5F5;" | Nl
| align="center" style="background:#F5F5F5;" | Most important part of treatment is discontinuing of the medication.
|-
! colspan="2" align="center" style="padding: 5px 5px; background: #DCDCDC;" |[[Heparin-Induced Thrombocytopenia|Heparin-Induced thrombocytopenia]]
| align="left" style="background:#F5F5F5;" |
* [[Thrombosis]]
* Unexplained [[thrombocytopenia]] up to 3 weeks after the end of [[heparin]] therapy
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | ↓
| align="center" style="background:#F5F5F5;" | ↑
| align="center" style="background:#F5F5F5;" | Nl
| align="center" style="background:#F5F5F5;" | Nl
| align="center" style="background:#F5F5F5;" | ↑
| align="center" style="background:#F5F5F5;" | For more information click here: [[Heparin-induced thrombocytopenia]].  
|-
! colspan="2" align="center" style="padding: 5px 5px; background: #DCDCDC;" |[[Idiopathic thrombocytopenic purpura|Immune Thrombocytopenic Purpura]]
| align="left" style="background:#F5F5F5;" |
* History of prior [[infection]] or no history
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | ↓
| align="center" style="background:#F5F5F5;" | ↑
| align="center" style="background:#F5F5F5;" | Nl
| align="center" style="background:#F5F5F5;" | Nl
| align="center" style="background:#F5F5F5;" | Nl
| align="center" style="background:#F5F5F5;" | −
|-
! colspan="2" align="center" style="padding: 5px 5px; background: #DCDCDC;" |Inherited [[Thrombocytopenia]]
| align="left" style="background:#F5F5F5;" |
* Positive family history
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | ↓
| align="center" style="background:#F5F5F5;" | ↑
| align="center" style="background:#F5F5F5;" | Nl
| align="center" style="background:#F5F5F5;" | Nl
| align="center" style="background:#F5F5F5;" | Nl
| align="center" style="background:#F5F5F5;" | −
|-
! colspan="2" align="center" style="padding: 5px 5px; background: #DCDCDC;" |[[Thrombotic thrombocytopenic purpura|Thrombotic Thrombocytopenic Purpura]]
| align="left" style="background:#F5F5F5;" | History of:
*[[Cancer]]
*[[Bone marrow transplantation]]
*[[Pregnancy]]
*[[Medication]]
**[[Platelet]] aggregation inhibitors ([[ticlopidine]] and [[clopidogrel]])
**Immunosuppressants ([[cyclosporine]], [[mitomycin]], [[tacrolimus]]/FK506, [[interferon|interferon-α]])
*[[HIV-1]] infection
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | ↓
| align="center" style="background:#F5F5F5;" | ↑
| align="center" style="background:#F5F5F5;" | Nl
| align="center" style="background:#F5F5F5;" | Nl
| align="center" style="background:#F5F5F5;" | Nl
| align="center" style="background:#F5F5F5;" | −
|-
! colspan="2" align="center" style="padding: 5px 5px; background: #DCDCDC;" |[[Hemolytic-uremic syndrome|Hemolytic Uremic Syndrome]]
| align="left" style="background:#F5F5F5;" |History of:
* [[Infections]]
* [[Malignancy]], [[chemotherapy]], and [[ionizing radiation]]
* [[Calcineurin inhibitor]]s and [[transplantation]]
* [[Pregnancy]], [[HELLP syndrome]], and [[oral contraceptive pill]]
* [[Systemic lupus erythematosis]] 
* [[Antiphospholipid syndrome|Antiphospholipid antibody syndrome]]
* [[Glomerulopathy]]
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | ↓
| align="center" style="background:#F5F5F5;" | ↑
| align="center" style="background:#F5F5F5;" | Nl
| align="center" style="background:#F5F5F5;" | Nl
| align="center" style="background:#F5F5F5;" | Nl
| align="center" style="background:#F5F5F5;" | −
|-
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Subcategory
! colspan="2" align="center" style="background:#4479BA; color: #FFFFFF;" + |Disease
! align="center" style="background:#4479BA; color: #FFFFFF;" + |History
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Mucosal bleeding
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Petechia
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Ecchymoses
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Menorrhagia
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Hematoma
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Hemarthrosis
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Plt
! align="center" style="background:#4479BA; color: #FFFFFF;" + |BT
! align="center" style="background:#4479BA; color: #FFFFFF;" + |PT
! align="center" style="background:#4479BA; color: #FFFFFF;" + |PTT
! align="center" style="background:#4479BA; color: #FFFFFF;" + |TT
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Comments
|-
! rowspan="2" style="background: #4479BA; color: #FFFFFF; text-align: center;" |Vessel wall disorders
! align="center" style="padding: 5px 5px; background: #DCDCDC;" |[[Metabolism|Metabolic]] and [[Inflammation|Inflammatory]] Disorders
! colspan="2" align="left" style="padding: 5px 5px; background: #DCDCDC;" |
* Acute febrile illnesses
* [[Cryoglobulinemia|Mixed cryoglobulinemia]]
* [[Monoclonal gammopathy|Monoclonal gammopathies]]
* [[Rocky Mountain spotted fever]]
* [[Vitamin C deficiency]]
* [[Cushing's syndrome|Cushing’s syndrome]]
* Chronic [[glucocorticoid]] therapy
* [[Vasculitis]] such as Henoch-Schönlein Purpura
| align="left" style="background:#F5F5F5;" |
* History of the underlying disease
| align="center" style="background:#F5F5F5;" |−
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" |±
| align="center" style="background:#F5F5F5;" |−
| align="center" style="background:#F5F5F5;" |−
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |Nl or ↑
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |−
|-
! align="center" style="padding: 5px 5px; background: #DCDCDC;" |Inherited Disorders of the [[Vessel wall|Vessel Wall]]
! colspan="2" align="left" style="background:#DCDCDC;" |
* [[Marfan's syndrome|Marfan’s syndrome]]
* [[Ehlers-Danlos syndrome]]
* [[Pseudoxanthoma elasticum]]
* [[Hereditary hemorrhagic telangiectasia]] ([[Hereditary hemorrhagic telangiectasia|HHT]], or [[Osler-Weber-Rendu|Osler-Weber-Rendu disease]])
| align="left" style="background:#F5F5F5;" |
* Positive family history
| align="center" style="background:#F5F5F5;" |−
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" |±
| align="center" style="background:#F5F5F5;" |−
| align="center" style="background:#F5F5F5;" |−
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |Nl or ↑
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |−
|-
! rowspan="15" style="background: #4479BA; color: #FFFFFF; text-align: center;" |Coagulation factor disorders
<ref name="pmid28966616" />
! align="center" style="padding: 5px 5px; background: #DCDCDC;" |[[Fibrinogen]] deficiency
! colspan="2" align="left" style="padding: 5px 5px; background: #DCDCDC;" |
Different types of the [[fibrinogen]] disorders:
* [[Fibrinogen#Congenital afibrinogenemia|Congenital afibrinogenemia]]
* [[Fibrinogen#Congenital hypofibrinogenemia|Congenital hypofibrinogenemia]]
* [[Fibrinogen#Fibrinogen storage disease|Fibrinogen storage disease]]
* [[Fibrinogen#Congenital dysfibrinogenemia|Congenital dysfibrinogenemia]]
* [[Fibrinogen#Hereditary fibrinogen A.CE.B1-Chain amyloidosis|Hereditary fibrinogen Aα-Chain amyloidosis]]
* [[Fibrinogen#Acquired dysfibrinogenemia|Acquired dysfibrinogenemia]]
| align="left" style="background:#F5F5F5;" |
* [[Epistaxis]]
* Easy [[Bruise|bruising]]
* [[Menorrhagia]]
* [[Muscle]] bleeds
* [[Hemarthrosis]]
* [[Bleeding]] from the [[umbilical cord]] stump after birth
* Bleeding after [[dental surgery]] or tooth extraction
* AbNl bleeding during or after injury, surgery, or childbirth
* [[Gastrointestinal tract|Gastrointestinal]] [[hemorrhage]]
* [[Cerebral hemorrhage]]
* [[Thrombosis]]
| align="center" style="background:#F5F5F5;" |−
| align="center" style="background:#F5F5F5;" |−
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" |±
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |↑
| align="center" style="background:#F5F5F5;" |↑
| align="center" style="background:#F5F5F5;" |↑
| align="center" style="background:#F5F5F5;" |↑
| align="left" style="background:#F5F5F5;" |
* Impaired fibrin cross-linking or clot dissolution
* Mild or severe bleeding idepend on levels of functional fibrinogen
* Variable age of onset
|-
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Subcategory
! colspan="2" align="center" style="background:#4479BA; color: #FFFFFF;" + |Disease
! align="center" style="background:#4479BA; color: #FFFFFF;" + |History
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Mucosal bleeding
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Petechia
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Ecchymoses
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Menorrhagia
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Hematoma
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Hemarthrosis
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Plt
! align="center" style="background:#4479BA; color: #FFFFFF;" + |BT
! align="center" style="background:#4479BA; color: #FFFFFF;" + |PT
! align="center" style="background:#4479BA; color: #FFFFFF;" + |PTT
! align="center" style="background:#4479BA; color: #FFFFFF;" + |TT
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Comments
|-
! colspan="3" align="center" style="padding: 5px 5px; background: #DCDCDC;" |[[Prothrombin deficiency]]
| align="left" style="background:#F5F5F5;" |
* [[Epistaxis]]
* Soft-tissue hemorrhage
* Excessive postoperative bleeding
* [[Menorrhagia]]
* Muscle [[Hematoma|hematomas]]
* [[Hemarthrosis]]
* [[Intracranial hemorrhage|Intracranial]] bleeding
| align="center" style="background:#F5F5F5;" | −
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | Nl
| align="center" style="background:#F5F5F5;" | Nl
| align="center" style="background:#F5F5F5;" | ↑
| align="center" style="background:#F5F5F5;" | ↑
| align="center" style="background:#F5F5F5;" | ↑
| align="center" style="background:#F5F5F5;" | −
|-
! colspan="3" rowspan="1" align="center" style="padding: 5px 5px; background: #DCDCDC;" |[[Factor V deficiency]]
| align="left" style="background:#F5F5F5;" |
* Excessive bruising with minor injuries
* [[Epistaxis]]
* [[Hemarthrosis]]
* [[Menorrhagia]]
* [[Intracerebral hemorrhage|Intracerebral hemorrhages]]
* [[Pulmonary hemorrhage]]
| align="center" style="background:#F5F5F5;" | −
| align="center" style="background:#F5F5F5;" | −
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |↑
| align="center" style="background:#F5F5F5;" |↑
| align="center" style="background:#F5F5F5;" |↑
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |
* The severity of bleeding related to the degree of factor V deficiency
|-
! colspan="3" rowspan="1" align="center" style="padding: 5px 5px; background: #DCDCDC;" |[[Factor VII deficiency]]
| align="left" style="background:#F5F5F5;" |
* Easy [[Bruise|bruising]]
* Mucosal bleeding
* Postoperative bleeding
* [[Menorrhagia]]
* Soft tissue hematomas
* [[Thrombosis]]
| align="center" style="background:#F5F5F5;" |
| align="center" style="background:#F5F5F5;" |
| align="center" style="background:#F5F5F5;" |
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |
| align="center" style="background:#F5F5F5;" |↑
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |Nl
| align="left" style="background:#F5F5F5;" |
* Thrombosis in inherited factor VII deficiency
* Treatment with the administration of factor VII replacement therapy
|-
! colspan="3" rowspan="1" align="center" style="padding: 5px 5px; background: #DCDCDC;" |[[Factor X deficiency]]
| align="left" style="background:#F5F5F5;" |
* Prolonged bleeding following circumcision
* Easy [[Bruise|bruising]]
* [[Hematuria]]
* [[Menorrhagia]]
* Abortion
* Postpartum hemorrhage
* Epistaxis
* Pseudotumors
* Intracranial bleeding
* Hemarthroses
| align="center" style="background:#F5F5F5;" |
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |↑
| align="center" style="background:#F5F5F5;" |↑
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |−
|-
! colspan="3" rowspan="1" align="center" style="padding: 5px 5px; background: #DCDCDC;" |[[Factor XII|Factor XII deficiency]]
| align="left" style="background:#F5F5F5;" |
* Asymptomatic
* Recurrent miscarriages
* Painful leg ulcers
| align="center" style="background:#F5F5F5;" |
| align="center" style="background:#F5F5F5;" |−
| align="center" style="background:#F5F5F5;" |−
| align="center" style="background:#F5F5F5;" |−
| align="center" style="background:#F5F5F5;" |−
| align="center" style="background:#F5F5F5;" |−
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |↑
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |
|-
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Subcategory
! colspan="2" align="center" style="background:#4479BA; color: #FFFFFF;" + |Disease
! align="center" style="background:#4479BA; color: #FFFFFF;" + |History
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Mucosal bleeding
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Petechia
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Ecchymoses
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Menorrhagia
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Hematoma
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Hemarthrosis
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Plt
! align="center" style="background:#4479BA; color: #FFFFFF;" + |BT
! align="center" style="background:#4479BA; color: #FFFFFF;" + |PT
! align="center" style="background:#4479BA; color: #FFFFFF;" + |PTT
! align="center" style="background:#4479BA; color: #FFFFFF;" + |TT
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Comments
|-
! colspan="3" align="center" style="padding: 5px 5px; background: #DCDCDC;" |[[High-molecular-weight kininogen|High molecular weight kininogen (HMWK)]] deficiency
| align="left" style="background:#F5F5F5;" |
* Positive family history of bleeding
| align="center" style="background:#F5F5F5;" |
| align="center" style="background:#F5F5F5;" |−
| align="center" style="background:#F5F5F5;" |−
| align="center" style="background:#F5F5F5;" |−
| align="center" style="background:#F5F5F5;" |−
| align="center" style="background:#F5F5F5;" |−
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |↑
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |
|-
! colspan="3" rowspan="1" align="center" style="padding: 5px 5px; background: #DCDCDC;" |[[Prekallikrein]] deficiency
| align="left" style="background:#F5F5F5;" |
* Positive family history of bleeding
| align="center" style="background:#F5F5F5;" |
| align="center" style="background:#F5F5F5;" |−
| align="center" style="background:#F5F5F5;" |−
| align="center" style="background:#F5F5F5;" |−
| align="center" style="background:#F5F5F5;" |−
| align="center" style="background:#F5F5F5;" |−
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |↑
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |
|-
! rowspan="1" align="center" style="padding: 5px 5px; background: #DCDCDC;" |[[Factor XIII deficiency]]
! colspan="2" align="center" style="padding: 5px 5px; background: #DCDCDC;" |
* Sub unit A mutation disease (more common)
* Sub unit B mutation disease
| align="left" style="background:#F5F5F5;" |
* Positive family history of bleeding
| align="center" style="background:#F5F5F5;" |±
| align="center" style="background:#F5F5F5;" |±
| align="center" style="background:#F5F5F5;" |±
| align="center" style="background:#F5F5F5;" |±
| align="center" style="background:#F5F5F5;" |±
| align="center" style="background:#F5F5F5;" |±
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |Nl or ↑
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |Nl
| align="left" style="background:#F5F5F5;" |
* Impaired fibrin cross-linking or clot dissolution
* The severity of factor XIII deficiency bleeds can be different in different patients
|-
! rowspan="3" align="center" style="padding: 5px 5px; background: #DCDCDC;" |[[Hemophilia]]
! colspan="2" align="center" style="padding: 5px 5px; background: #DCDCDC;" |Type A deficiency
| align="left" style="background:#F5F5F5;" |
* Eeasy [[Bruise|bruising]]
* Inadequate clotting in [[trauma]] or mild injury
* Spontaneous hemorrhage
* [[Hemarthrosis]]
* [[Epistaxis]]
* [[Gingival bleeding]]
| align="center" style="background:#F5F5F5;" |−
| align="center" style="background:#F5F5F5;" |−
| align="center" style="background:#F5F5F5;" |−
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |↑
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |−
|-
! colspan="2" align="center" style="padding: 5px 5px; background: #DCDCDC;" |Type B deficiency
| align="left" style="background:#F5F5F5;" |
* Neonatal bleeding
* Trauma-related soft tissue hemorrhage
* [[Hemarthrosis]] 
* [[Hematoma|Hematomas]]
| align="center" style="background:#F5F5F5;" |−
| align="center" style="background:#F5F5F5;" |−
| align="center" style="background:#F5F5F5;" |−
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |↑
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |−
|-
! colspan="2" align="center" style="padding: 5px 5px; background: #DCDCDC;" |Type C deficiency
| align="left" style="background:#F5F5F5;" |
* Positive family history
* Bleeding after surgery or injury
| align="center" style="background:#F5F5F5;" |−
| align="center" style="background:#F5F5F5;" |−
| align="center" style="background:#F5F5F5;" |−
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" |Rare
| align="center" style="background:#F5F5F5;" |Rare
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |↑
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |−
|-
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Subcategory
! colspan="2" align="center" style="background:#4479BA; color: #FFFFFF;" + |Disease
! align="center" style="background:#4479BA; color: #FFFFFF;" + |History
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Mucosal bleeding
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Petechia
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Ecchymoses
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Menorrhagia
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Hematoma
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Hemarthrosis
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Plt
! align="center" style="background:#4479BA; color: #FFFFFF;" + |BT
! align="center" style="background:#4479BA; color: #FFFFFF;" + |PT
! align="center" style="background:#4479BA; color: #FFFFFF;" + |PTT
! align="center" style="background:#4479BA; color: #FFFFFF;" + |TT
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Comments
|-
! rowspan="2" style="background: #4479BA; color: #FFFFFF; text-align: center;" |Rare diseases
! colspan="3" align="center" style="padding: 5px 5px; background: #DCDCDC;" |[[Disseminated intravascular coagulation|Disseminated Intravascular Coagulation]]
| align="left" style="background:#F5F5F5;" |
* [[Trauma]]
* [[Burn]]
* [[Crush injury]]
* [[Sepsis]]
* [[Malignancy]]
* Obstetric complication: abruption, amniotic fluid embolism
* [[Hemolytic anemia]]
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" |↓
| align="center" style="background:#F5F5F5;" |↑
| align="center" style="background:#F5F5F5;" |↑
| align="center" style="background:#F5F5F5;" |↑
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |−
|-
! colspan="3" align="center" style="padding: 5px 5px; background: #DCDCDC;" |[[Vitamin K Deficiency]]
| align="left" style="background:#F5F5F5;" |
* Bleeding after trauma
* [[Epistaxis]]
* [[Hematoma]]
* Gastrointestinal bleeding
* [[Menorrhagia]]
* [[Hematuria]]
* Gum bleeding
* Oozing from venipuncture sites
* Easy [[Bruise|bruisability]]
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" |−
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" | +
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |↑
| align="center" style="background:#F5F5F5;" |↑
| align="center" style="background:#F5F5F5;" |Nl or mildly prolonged
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |−
|}


==Risk Factors==
==Risk Factors==
* Positive family history of Wiskott-Aldrich syndrome, can be considered as a risk factor.


==Screening==
==Screening==
*[[Flow cytometry]]:
*[[Flow cytometry]]:
** Anti-WASp antibody can be used to detect presence or absence of WAS protein. However, [[flow cytometry]] may not detect expression of mutated, reduced or poor WASp.<ref name="pmid29729304">{{cite journal |vauthors=Chiang SCC, Vergamini SM, Husami A, Neumeier L, Quinn K, Ellerhorst T, Sheppard L, Gifford C, Buchbinder D, Joshi A, Ifversen M, Kleiner GI, Bussel JB, Chandrakasan S, Pesek RD, Pozos TC, Rose MJ, Scurlock AM, Zhang K, Bryceson YT, Bleesing J, Marsh RA |title=Screening for Wiskott-Aldrich syndrome by flow cytometry |journal=J. Allergy Clin. Immunol. |volume=142 |issue=1 |pages=333–335.e8 |date=July 2018 |pmid=29729304 |doi=10.1016/j.jaci.2018.04.017 |url=}}</ref>
** Anti-WASp antibody can be used to detect presence or absence of WAS protein. However, [[flow cytometry]] may not detect expression of mutated, reduced or poor WASp.<ref name="pmid29729304">{{cite journal |vauthors=Chiang SCC, Vergamini SM, Husami A, Neumeier L, Quinn K, Ellerhorst T, Sheppard L, Gifford C, Buchbinder D, Joshi A, Ifversen M, Kleiner GI, Bussel JB, Chandrakasan S, Pesek RD, Pozos TC, Rose MJ, Scurlock AM, Zhang K, Bryceson YT, Bleesing J, Marsh RA |title=Screening for Wiskott-Aldrich syndrome by flow cytometry |journal=J. Allergy Clin. Immunol. |volume=142 |issue=1 |pages=333–335.e8 |date=July 2018 |pmid=29729304 |doi=10.1016/j.jaci.2018.04.017 |url=}}</ref>
* Identification of carriers: Known [[female]] carriers can be identified by using [[DNA]] mutation analysis of [[WAS gene]].
* Identification of carriers: Known [[female]] carriers can be identified by using [[DNA]] mutation analysis of WAS gene.
* Prenatal diagnosis: DNA analysis from [[chorionic villus sampling]] can be performed.<ref name="pmid10073904">{{cite journal |vauthors=Giliani S, Fiorini M, Mella P, Candotti F, Schumacher RF, Wengler GS, Lalatta F, Fasth A, Badolato R, Ugazio AG, Albertini A, Notarangelo LD |title=Prenatal molecular diagnosis of Wiskott-Aldrich syndrome by direct mutation analysis |journal=Prenat. Diagn. |volume=19 |issue=1 |pages=36–40 |date=January 1999 |pmid=10073904 |doi= |url=}}</ref>
* Prenatal diagnosis: [[DNA]] analysis from [[chorionic villus sampling]] can be performed.<ref name="pmid10073904">{{cite journal |vauthors=Giliani S, Fiorini M, Mella P, Candotti F, Schumacher RF, Wengler GS, Lalatta F, Fasth A, Badolato R, Ugazio AG, Albertini A, Notarangelo LD |title=Prenatal molecular diagnosis of Wiskott-Aldrich syndrome by direct mutation analysis |journal=Prenat. Diagn. |volume=19 |issue=1 |pages=36–40 |date=January 1999 |pmid=10073904 |doi= |url=}}</ref>


==Natural History, Complications, and Prognosis==
==Natural History, Complications, and Prognosis==
*If left untreated, [[Patient|patients]] with Wiscott-Aldrich syndrome may progress to develop manifestations associated with [[thrombocytopenia]], defective [[Innate immune system|innate]] and [[Adaptive immune system|adaptive immunity]] which include, severe [[bleeding]] (eg, [[epistaxis]], [[purpura]], life threatening [[Gastrointestinal tract|gastrointestinal]] and [[Intracranial hemorrhage|intracranial hemorrhages]]), recurrent and severe bronchopulmonary infections. Malignancy and [[autoimmunity]] risk has also increased. These conditions may increase the risk of death.<ref name="pmid7996359">{{cite journal |vauthors=Sullivan KE, Mullen CA, Blaese RM, Winkelstein JA |title=A multiinstitutional survey of the Wiskott-Aldrich syndrome |journal=J. Pediatr. |volume=125 |issue=6 Pt 1 |pages=876–85 |date=December 1994 |pmid=7996359 |doi= |url=}}</ref>
*If left untreated, [[Patient|patients]] with Wiscott-Aldrich syndrome may progress to develop manifestations associated with [[thrombocytopenia]], and abnormal platelet function, defective [[Innate immune system|innate]] and [[Adaptive immune system|adaptive immunity]] which include, severe [[bleeding]] (eg, [[epistaxis]], [[purpura]], life threatening [[Gastrointestinal tract|gastrointestinal]] and [[Intracranial hemorrhage|intracranial hemorrhages]]), recurrent and severe bronchopulmonary infections. Malignancy and [[autoimmunity]] risk has also increased. These conditions may increase the risk of death.<ref name="pmid7996359">{{cite journal |vauthors=Sullivan KE, Mullen CA, Blaese RM, Winkelstein JA |title=A multiinstitutional survey of the Wiskott-Aldrich syndrome |journal=J. Pediatr. |volume=125 |issue=6 Pt 1 |pages=876–85 |date=December 1994 |pmid=7996359 |doi= |url=}}</ref>
*Common complications of Wiscott-Aldrich syndrome include:
*Common complications of Wiscott-Aldrich syndrome include:
** Recurrent infections with [[Bacteria|bacterial]], [[Virus|viral]], [[Fungus|fungal]] and [[Opportunistic infection|opportunistic organisms]]. Most common clinical manifestations include [[otitis media]], [[Rhinosinusitis|sinusitis]], [[pneumonia]], [[meningitis]], [[Skin and soft-tissue infections|skin infections]], and [[sepsis]].<ref name="pmid14159941">{{cite journal |vauthors=WEINTRAUB HD, WILSON WJ |title=PNEUMOCYSTIS CARINII PNEUMONIA IN WISKOTT-ALDRICH SYNDROME |journal=Am. J. Dis. Child. |volume=108 |issue= |pages=198–200 |date=August 1964 |pmid=14159941 |doi= |url=}}</ref><ref name="pmid24007832">{{cite journal |vauthors=Blancas-Galicia L, Escamilla-Quiroz C, Yamazaki-Nakashimada MA |title=[Wiskott-Aldrich Syndrome: An updated review] |language=Spanish; Castilian |journal=Rev Alerg Mex |volume=58 |issue=4 |pages=213–8 |date=2011 |pmid=24007832 |doi= |url=}}</ref><ref name="pmid12969986">{{cite journal |vauthors=Imai K, Morio T, Zhu Y, Jin Y, Itoh S, Kajiwara M, Yata J, Mizutani S, Ochs HD, Nonoyama S |title=Clinical course of patients with WASP gene mutations |journal=Blood |volume=103 |issue=2 |pages=456–64 |date=January 2004 |pmid=12969986 |doi=10.1182/blood-2003-05-1480 |url=}}</ref>  
** Recurrent infections with [[Bacteria|bacterial]], [[Virus|viral]], [[Fungus|fungal]] and [[Opportunistic infection|opportunistic organisms]]. Most common clinical manifestations include [[otitis media]], [[Rhinosinusitis|sinusitis]], [[pneumonia]], [[meningitis]], [[Skin and soft-tissue infections|skin infections]], and [[sepsis]].<ref name="pmid14159941">{{cite journal |vauthors=WEINTRAUB HD, WILSON WJ |title=PNEUMOCYSTIS CARINII PNEUMONIA IN WISKOTT-ALDRICH SYNDROME |journal=Am. J. Dis. Child. |volume=108 |issue= |pages=198–200 |date=August 1964 |pmid=14159941 |doi= |url=}}</ref><ref name="pmid24007832">{{cite journal |vauthors=Blancas-Galicia L, Escamilla-Quiroz C, Yamazaki-Nakashimada MA |title=[Wiskott-Aldrich Syndrome: An updated review] |language=Spanish; Castilian |journal=Rev Alerg Mex |volume=58 |issue=4 |pages=213–8 |date=2011 |pmid=24007832 |doi= |url=}}</ref><ref name="pmid12969986">{{cite journal |vauthors=Imai K, Morio T, Zhu Y, Jin Y, Itoh S, Kajiwara M, Yata J, Mizutani S, Ochs HD, Nonoyama S |title=Clinical course of patients with WASP gene mutations |journal=Blood |volume=103 |issue=2 |pages=456–64 |date=January 2004 |pmid=12969986 |doi=10.1182/blood-2003-05-1480 |url=}}</ref>  
** [[Bleeding diathesis]] (eg, [[epistaxis]], [[Bruise|ecchymoses]], [[Petechia|petechiae]], [[Intracranial hemorrhage|intracranial]] and [[Gastrointestinal bleeding|gastrointestinal hemorrhages]])<ref name="pmid7996359">{{cite journal |vauthors=Sullivan KE, Mullen CA, Blaese RM, Winkelstein JA |title=A multiinstitutional survey of the Wiskott-Aldrich syndrome |journal=J. Pediatr. |volume=125 |issue=6 Pt 1 |pages=876–85 |date=December 1994 |pmid=7996359 |doi= |url=}}</ref><ref name="pmid23449611">{{cite journal |vauthors=Notarangelo LD |title=In Wiskott-Aldrich syndrome, platelet count matters |journal=Blood |volume=121 |issue=9 |pages=1484–5 |date=February 2013 |pmid=23449611 |doi=10.1182/blood-2013-01-475913 |url=}}</ref>
** [[Bleeding diathesis]] (eg, [[epistaxis]], [[Bruise|ecchymoses]], [[Petechia|petechiae]], [[hematemesis]], [[Intracranial hemorrhage|intracranial]] and [[Gastrointestinal bleeding|gastrointestinal hemorrhages]])<ref name="pmid7996359">{{cite journal |vauthors=Sullivan KE, Mullen CA, Blaese RM, Winkelstein JA |title=A multiinstitutional survey of the Wiskott-Aldrich syndrome |journal=J. Pediatr. |volume=125 |issue=6 Pt 1 |pages=876–85 |date=December 1994 |pmid=7996359 |doi= |url=}}</ref><ref name="pmid23449611">{{cite journal |vauthors=Notarangelo LD |title=In Wiskott-Aldrich syndrome, platelet count matters |journal=Blood |volume=121 |issue=9 |pages=1484–5 |date=February 2013 |pmid=23449611 |doi=10.1182/blood-2013-01-475913 |url=}}</ref>
** Autoimmune manifestations may occur in the form of [[autoimmune hemolytic anemia]], [[immune thrombocytopenic purpura]] and [[neutropenia]], [[vasculitis]] involving small and large vessels, [[inflammatory bowel disease]], and  immune-mediated damage to the [[Kidney|kidneys]] and [[Joint|joints]].<ref name="pmid12728121">{{cite journal |vauthors=Dupuis-Girod S, Medioni J, Haddad E, Quartier P, Cavazzana-Calvo M, Le Deist F, de Saint Basile G, Delaunay J, Schwarz K, Casanova JL, Blanche S, Fischer A |title=Autoimmunity in Wiskott-Aldrich syndrome: risk factors, clinical features, and outcome in a single-center cohort of 55 patients |journal=Pediatrics |volume=111 |issue=5 Pt 1 |pages=e622–7 |date=May 2003 |pmid=12728121 |doi= |url=}}</ref><ref name="pmid25877044">{{cite journal |vauthors=Chen N, Zhang ZY, Liu DW, Liu W, Tang XM, Zhao XD |title=The clinical features of autoimmunity in 53 patients with Wiskott-Aldrich syndrome in China: a single-center study |journal=Eur. J. Pediatr. |volume=174 |issue=10 |pages=1311–8 |date=October 2015 |pmid=25877044 |doi=10.1007/s00431-015-2527-3 |url=}}</ref><ref name="pmid29358862">{{cite journal |vauthors=Ohya T, Yanagimachi M, Iwasawa K, Umetsu S, Sogo T, Inui A, Fujisawa T, Ito S |title=Childhood-onset inflammatory bowel diseases associated with mutation of Wiskott-Aldrich syndrome protein gene |journal=World J. Gastroenterol. |volume=23 |issue=48 |pages=8544–8552 |date=December 2017 |pmid=29358862 |pmc=5752714 |doi=10.3748/wjg.v23.i48.8544 |url=}}</ref>
** Autoimmune manifestations may occur in the form of [[autoimmune hemolytic anemia]], [[immune thrombocytopenic purpura]] and [[neutropenia]], [[vasculitis]] involving small and large vessels, [[inflammatory bowel disease]], and  immune-mediated damage to the [[Kidney|kidneys]] and [[Joint|joints]].<ref name="pmid12728121">{{cite journal |vauthors=Dupuis-Girod S, Medioni J, Haddad E, Quartier P, Cavazzana-Calvo M, Le Deist F, de Saint Basile G, Delaunay J, Schwarz K, Casanova JL, Blanche S, Fischer A |title=Autoimmunity in Wiskott-Aldrich syndrome: risk factors, clinical features, and outcome in a single-center cohort of 55 patients |journal=Pediatrics |volume=111 |issue=5 Pt 1 |pages=e622–7 |date=May 2003 |pmid=12728121 |doi= |url=}}</ref><ref name="pmid25877044">{{cite journal |vauthors=Chen N, Zhang ZY, Liu DW, Liu W, Tang XM, Zhao XD |title=The clinical features of autoimmunity in 53 patients with Wiskott-Aldrich syndrome in China: a single-center study |journal=Eur. J. Pediatr. |volume=174 |issue=10 |pages=1311–8 |date=October 2015 |pmid=25877044 |doi=10.1007/s00431-015-2527-3 |url=}}</ref><ref name="pmid29358862">{{cite journal |vauthors=Ohya T, Yanagimachi M, Iwasawa K, Umetsu S, Sogo T, Inui A, Fujisawa T, Ito S |title=Childhood-onset inflammatory bowel diseases associated with mutation of Wiskott-Aldrich syndrome protein gene |journal=World J. Gastroenterol. |volume=23 |issue=48 |pages=8544–8552 |date=December 2017 |pmid=29358862 |pmc=5752714 |doi=10.3748/wjg.v23.i48.8544 |url=}}</ref>
** Increased risk of malignancy such as [[lymphoma]], [[Leukemia|leukaemia]] is a frequent occurence in Wiskott-Aldrich syndrome.<ref name="pmid3910193">{{cite journal |vauthors=Cotelingam JD, Witebsky FG, Hsu SM, Blaese RM, Jaffe ES |title=Malignant lymphoma in patients with the Wiskott-Aldrich syndrome |journal=Cancer Invest. |volume=3 |issue=6 |pages=515–22 |date=1985 |pmid=3910193 |doi= |url=}}</ref><ref name="pmid23023736">{{cite journal |vauthors=Yoshimi A, Kamachi Y, Imai K, Watanabe N, Nakadate H, Kanazawa T, Ozono S, Kobayashi R, Yoshida M, Kobayashi C, Hama A, Muramatsu H, Sasahara Y, Jakob M, Morio T, Ehl S, Manabe A, Niemeyer C, Kojima S |title=Wiskott-Aldrich syndrome presenting with a clinical picture mimicking juvenile myelomonocytic leukaemia |journal=Pediatr Blood Cancer |volume=60 |issue=5 |pages=836–41 |date=May 2013 |pmid=23023736 |doi=10.1002/pbc.24359 |url=}}</ref>  
** Increased risk of malignancy such as [[lymphoma]], [[Leukemia|leukaemia]] is a frequent occurence in Wiskott-Aldrich syndrome.<ref name="pmid3910193">{{cite journal |vauthors=Cotelingam JD, Witebsky FG, Hsu SM, Blaese RM, Jaffe ES |title=Malignant lymphoma in patients with the Wiskott-Aldrich syndrome |journal=Cancer Invest. |volume=3 |issue=6 |pages=515–22 |date=1985 |pmid=3910193 |doi= |url=}}</ref><ref name="pmid23023736">{{cite journal |vauthors=Yoshimi A, Kamachi Y, Imai K, Watanabe N, Nakadate H, Kanazawa T, Ozono S, Kobayashi R, Yoshida M, Kobayashi C, Hama A, Muramatsu H, Sasahara Y, Jakob M, Morio T, Ehl S, Manabe A, Niemeyer C, Kojima S |title=Wiskott-Aldrich syndrome presenting with a clinical picture mimicking juvenile myelomonocytic leukaemia |journal=Pediatr Blood Cancer |volume=60 |issue=5 |pages=836–41 |date=May 2013 |pmid=23023736 |doi=10.1002/pbc.24359 |url=}}</ref>  
Line 88: Line 927:
===Diagnostic Study of Choice===
===Diagnostic Study of Choice===
*The first laboratory test to be performed in the diagnosis of Wiskott-Aldrich syndrome is [[Complete blood count|complete blood count with differential]] and [[Blood film|peripheral blood smears]].
*The first laboratory test to be performed in the diagnosis of Wiskott-Aldrich syndrome is [[Complete blood count|complete blood count with differential]] and [[Blood film|peripheral blood smears]].
*The diagnosis of Wiskott-Aldrich syndrome is suspected if a male patient who presents with bruises, petechiae and the presence of [[thrombocytopenia]] with small [[platelet]] volume (micro thrombocytopenia) on the peripheral blood smear.
*The diagnosis of Wiskott-Aldrich syndrome is suspected if a [[male]] patient who presents with [[Bruise|bruises]], [[Petechia|petechiae]], [[eczema]], recurrent [[Infection|infections]] and the presence of congenital [[thrombocytopenia]](< 70 000/mm3) with small [[platelet]] volume <5·0fl  (micro thrombocytopenia) on the [[Blood film|peripheral blood smear]].
*Identification of  WAS gene mutations using DNA sequence analysis of WAS gene and detection of WASp expression by flow cytometry are necessary to confirm the diagnosis.<ref name="pmid15284122">{{cite journal |vauthors=Jin Y, Mazza C, Christie JR, Giliani S, Fiorini M, Mella P, Gandellini F, Stewart DM, Zhu Q, Nelson DL, Notarangelo LD, Ochs HD |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 |date=December 2004 |pmid=15284122 |doi=10.1182/blood-2003-05-1592 |url=}}</ref><ref name="pmid12969986">{{cite journal |vauthors=Imai K, Morio T, Zhu Y, Jin Y, Itoh S, Kajiwara M, Yata J, Mizutani S, Ochs HD, Nonoyama S |title=Clinical course of patients with WASP gene mutations |journal=Blood |volume=103 |issue=2 |pages=456–64 |date=January 2004 |pmid=12969986 |doi=10.1182/blood-2003-05-1480 |url=}}</ref>
*Identification of  WAS gene mutations using [[DNA]] sequence analysis of WAS gene and detection of WASp expression by [[flow cytometry]] are necessary to confirm the diagnosis.<ref name="pmid15284122">{{cite journal |vauthors=Jin Y, Mazza C, Christie JR, Giliani S, Fiorini M, Mella P, Gandellini F, Stewart DM, Zhu Q, Nelson DL, Notarangelo LD, Ochs HD |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 |date=December 2004 |pmid=15284122 |doi=10.1182/blood-2003-05-1592 |url=}}</ref><ref name="pmid12969986">{{cite journal |vauthors=Imai K, Morio T, Zhu Y, Jin Y, Itoh S, Kajiwara M, Yata J, Mizutani S, Ochs HD, Nonoyama S |title=Clinical course of patients with WASP gene mutations |journal=Blood |volume=103 |issue=2 |pages=456–64 |date=January 2004 |pmid=12969986 |doi=10.1182/blood-2003-05-1480 |url=}}</ref>


===History and Symptoms===
===History and Symptoms===
* Patients with Wiskott-Aldrich syndrome have


* Common symptoms of Wiskott-Aldrich syndrome include:
* Common symptoms of Wiskott-Aldrich syndrome include:
Line 98: Line 938:
** [[Purpura]]
** [[Purpura]]
** [[Eczema]]
** [[Eczema]]
** Prolonged and excessive bleeding after circumcision or from umbilical stump
** Prolonged and excessive [[bleeding]] after circumcision or from umbilical stump
** Recurrent [[Infection|infections]]  
** Recurrent [[Infection|infections]]  
** [[Epistaxis]] (Nose bleeds)
** [[Epistaxis]] (Nose bleeds)
Line 112: Line 952:
**[[Rales]] and [[Wheeze|wheezing]] on auscultation if there is an underlying [[Respiratory tract infection|lung infection]].
**[[Rales]] and [[Wheeze|wheezing]] on auscultation if there is an underlying [[Respiratory tract infection|lung infection]].
**[[Hepatosplenomegaly]]  
**[[Hepatosplenomegaly]]  
**ENT examination: Carefully examine sinuses to rule out [[Rhinosinusitis|sinusitis]], [[Ear|ears]] for any [[Eardrum|tympanic membrane]] abnormalities to rule out [[otitis media]] and throat for [[pharyngitis]] and other opportunistic infections such as [[Oral candidiasis|oral thrush]].
**ENT examination: Carefully examine sinuses to rule out [[Rhinosinusitis|sinusitis]], [[Ear|ears]] for any [[Eardrum|tympanic membrane]] abnormalities to rule out [[otitis media]] and throat for [[pharyngitis]] and other opportunistic infections such as oral thrush.  
** CNS examination may be performed for symptoms associated with [[intracranial hemorrhage]] and [[Infection|infections]].
**CNS examination may be performed for symptoms associated with [[intracranial hemorrhage]] and [[Infection|infections]].  


===Laboratory Findings===
===Laboratory Findings===
Line 141: Line 981:
===MRI===
===MRI===
*There are no specific [[Magnetic resonance imaging|MRI]] findings associated with Wiskott-Aldrich syndrome.
*There are no specific [[Magnetic resonance imaging|MRI]] findings associated with Wiskott-Aldrich syndrome.
===Other Imaging Findings===
* There are no other imaging findings associated with Wiscott-Aldrich syndrome.
===Other Diagnostic Studies===
* There are no other diagnostic tests associated with Wiskott-Aldrich syndrome.


==Treatment==
==Treatment==
===Medical Therapy===
===Medical Therapy===
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]].
* Mainstay therapy for Wiskott-Aldrich syndrome is conservative therapy and supportive care, which includes:
** Prophylactic antimicrobial agents should be given to treat [[Bacteria|bacterial]], [[Virus|viral]], [[Fungus|fungal]] and [[Opportunistic infection|opportunistic infections]].<ref name="pmid8957959">{{cite journal |vauthors=Litzman J, Jones A, Hann I, Chapel H, Strobel S, Morgan G |title=Intravenous immunoglobulin, splenectomy, and antibiotic prophylaxis in Wiskott-Aldrich syndrome |journal=Arch. Dis. Child. |volume=75 |issue=5 |pages=436–9 |date=November 1996 |pmid=8957959 |pmc=1511781 |doi= |url=}}</ref><ref name="pmid27462353">{{cite journal |vauthors=Kim KR, Kim JM, Kang JM, Kim YJ |title=Pneumocystis jirovecii pneumonia in pediatric patients: an analysis of 15 confirmed consecutive cases during 14 years |journal=Korean J Pediatr |volume=59 |issue=6 |pages=252–5 |date=June 2016 |pmid=27462353 |pmc=4958702 |doi=10.3345/kjp.2016.59.6.252 |url=}}</ref>
***[[Sulfamethoxazole-Trimethoprim|Trimethoprim/sulfamethoxazole]]: 5mg/kg/day can be given to treat most [[Bacteria|bacterial]] and [[pneumocystis jirovecii pneumonia]].
***[[Acyclovir]]:  200mg/twice daily may be given to treat viral infections (eg, [[Herpes simplex|HSV-1]])<ref name="pmid8547009">{{cite journal |vauthors=Modiano P, Salloum E, Gillet-Terver MN, Barbaud A, Georges JC, Thouvenot D, Schmutz JL, Weber M |title=Acyclovir-resistant chronic cutaneous herpes simplex in Wiskott-Aldrich syndrome |journal=Br. J. Dermatol. |volume=133 |issue=3 |pages=475–8 |date=September 1995 |pmid=8547009 |doi= |url=}}</ref>
***[[Fluconazole]]:  3mg/kg/day may be given to treat [[Fungal infection|fungal infections]].
** [[Platelet]] transfusions:<ref name="pmid17654055">{{cite journal |vauthors=Ferrara M, Capozzi L, Coppola A, Save G, Coppola L |title=Prophylactic platelet transfusion in children with thrombocytopenic disorders: a retrospective review |journal=Hematology |volume=12 |issue=4 |pages=297–9 |date=August 2007 |pmid=17654055 |doi=10.1080/10245330701255213 |url=}}</ref>
*** [[Platelet]] transfusions can be given to treat [[bleeding]] episodes such as life-threatening gastrointestinal and intracranial [[Bleeding|hemorrhages]]. [[Platelet]] transfusions can also be given to patients who are undergoing any surgical procedure.
*** If a patient can be chosen for transfusion, [[Platelet|platelets]] and [[blood]] products should be irradiated and must be obtained from a [[Cytomegalovirus infection|CMV]] free donor.
** [[Intravenous immunoglobulin|Intravenous immunoglobulins]]:<ref name="pmid5096517">{{cite journal |vauthors=Blaese RM, Strober W, Levy AL, Waldmann TA |title=Hypercatabolism of IgG, IgA, IgM, and albumin in the Wiskott-Aldrich syndrome. A unique disorder of serum protein metabolism |journal=J. Clin. Invest. |volume=50 |issue=11 |pages=2331–8 |date=November 1971 |pmid=5096517 |pmc=292175 |doi=10.1172/JCI106731 |url=}}</ref>
*** Preferred regimen:  400 to 600 mg/kg can be given every three weeks
** [[Immunosuppressive agents]]:<ref name="pmid17498197">{{cite journal |vauthors=Kim JJ, Thrasher AJ, Jones AM, Davies EG, Cale CM |title=Rituximab for the treatment of autoimmune cytopenias in children with immune deficiency |journal=Br. J. Haematol. |volume=138 |issue=1 |pages=94–6 |date=July 2007 |pmid=17498197 |doi=10.1111/j.1365-2141.2007.06616.x |url=}}</ref> [[Rituximab]] can be given to treat autoimmune cytopenias such as [[hemolytic anemia]], [[neutropenia]], associated with Wiskott- Aldrich syndrome.
** [[Thrombopoietic agent|Thrombopoietic agents]]: [[Eltrombopag]] may be helpful in increasing [[platelet]] count in patients with Wiskott-Aldrich syndrome but it may not improve [[platelet]] surface activation.<ref name="pmid26224646">{{cite journal |vauthors=Gerrits AJ, Leven EA, Frelinger AL, Brigstocke SL, Berny-Lang MA, Mitchell WB, Revel-Vilk S, Tamary H, Carmichael SL, Barnard MR, Michelson AD, Bussel JB |title=Effects of eltrombopag on platelet count and platelet activation in Wiskott-Aldrich syndrome/X-linked thrombocytopenia |journal=Blood |volume=126 |issue=11 |pages=1367–78 |date=September 2015 |pmid=26224646 |pmc=4729539 |doi=10.1182/blood-2014-09-602573 |url=}}</ref>
** [[Gene therapy]]: [[Gene therapy]] is an alternative curative treatment for Wiskott-Aldrich syndrome, which is still going under trials.<ref name="pmid21067383">{{cite journal |vauthors=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 |title=Stem-cell gene therapy for the Wiskott-Aldrich syndrome |journal=N. Engl. J. Med. |volume=363 |issue=20 |pages=1918–27 |date=November 2010 |pmid=21067383 |pmc=3064520 |doi=10.1056/NEJMoa1003548 |url=}}</ref>


===Surgery===
===Surgery===
* Splenectomy: Splenectomy may be considered for some patients with Wiskott-Aldrich syndrome . Splenectomy may be found to improve platelet count as well as size of the platelets . However, sepsis is a life-threatening complication after splenectomy. Prophylactic antibiotics should always be used to prevent infections.<ref name="pmid6767187">{{cite journal |vauthors=Lum LG, Tubergen DG, Corash L, Blaese RM |title=Splenectomy in the management of the thrombocytopenia of the Wiskott-Aldrich syndrome |journal=N. Engl. J. Med. |volume=302 |issue=16 |pages=892–6 |date=April 1980 |pmid=6767187 |doi=10.1056/NEJM198004173021604 |url=}}</ref><ref name="pmid21906397">{{cite journal |vauthors=Syrigos KN, Makrilia N, Neidhart J, Moutsos M, Tsimpoukis S, Kiagia M, Saif MW |title=Prolonged survival after splenectomy in Wiskott-Aldrich syndrome: a case report |journal=Ital J Pediatr |volume=37 |issue= |pages=42 |date=September 2011 |pmid=21906397 |pmc=3179709 |doi=10.1186/1824-7288-37-42 |url=}}</ref>
* [[Hematopoietic stem cell transplantation]] ([[Hematopoietic stem cell transplantation|HSCT]]):<ref name="pmid4177931">{{cite journal |vauthors=Bach FH, Albertini RJ, Joo P, Anderson JL, Bortin MM |title=Bone-marrow transplantation in a patient with the Wiskott-Aldrich syndrome |journal=Lancet |volume=2 |issue=7583 |pages=1364–6 |date=December 1968 |pmid=4177931 |doi= |url=}}</ref><ref name="pmid12598139">{{cite journal |vauthors=Antoine C, Müller S, Cant A, Cavazzana-Calvo M, Veys P, Vossen J, Fasth A, Heilmann C, Wulffraat N, Seger R, Blanche S, Friedrich W, Abinun M, Davies G, Bredius R, Schulz A, Landais P, Fischer A |title=Long-term survival and transplantation of haemopoietic stem cells for immunodeficiencies: report of the European experience 1968-99 |journal=Lancet |volume=361 |issue=9357 |pages=553–60 |date=February 2003 |pmid=12598139 |doi= |url=}}</ref><ref name="pmid17710656">{{cite journal |vauthors=Muñoz A, Olivé T, Martinez A, Bureo E, Maldonado MS, Diaz de Heredia C, Sastre A, Gonzalez-Vicent M |title=Allogeneic hemopoietic stem cell transplantation (HSCT) for Wiskott-Aldrich syndrome: a report of the Spanish Working Party for Blood and Marrow Transplantation in Children (GETMON) |journal=Pediatr Hematol Oncol |volume=24 |issue=6 |pages=393–402 |date=September 2007 |pmid=17710656 |doi=10.1080/08880010701454404 |url=}}</ref>
* Hematopoietic stem cell transplantation (HSCT):<ref name="pmid4177931">{{cite journal |vauthors=Bach FH, Albertini RJ, Joo P, Anderson JL, Bortin MM |title=Bone-marrow transplantation in a patient with the Wiskott-Aldrich syndrome |journal=Lancet |volume=2 |issue=7583 |pages=1364–6 |date=December 1968 |pmid=4177931 |doi= |url=}}</ref><ref name="pmid12598139">{{cite journal |vauthors=Antoine C, Müller S, Cant A, Cavazzana-Calvo M, Veys P, Vossen J, Fasth A, Heilmann C, Wulffraat N, Seger R, Blanche S, Friedrich W, Abinun M, Davies G, Bredius R, Schulz A, Landais P, Fischer A |title=Long-term survival and transplantation of haemopoietic stem cells for immunodeficiencies: report of the European experience 1968-99 |journal=Lancet |volume=361 |issue=9357 |pages=553–60 |date=February 2003 |pmid=12598139 |doi= |url=}}</ref><ref name="pmid17710656">{{cite journal |vauthors=Muñoz A, Olivé T, Martinez A, Bureo E, Maldonado MS, Diaz de Heredia C, Sastre A, Gonzalez-Vicent M |title=Allogeneic hemopoietic stem cell transplantation (HSCT) for Wiskott-Aldrich syndrome: a report of the Spanish Working Party for Blood and Marrow Transplantation in Children (GETMON) |journal=Pediatr Hematol Oncol |volume=24 |issue=6 |pages=393–402 |date=September 2007 |pmid=17710656 |doi=10.1080/08880010701454404 |url=}}</ref>
** [[Hematopoietic stem cell transplantation|HSCT]] is the only standard curative treatment for Wiskott-Aldrich syndrome.
* HSCT is the only standard curative treatment for Wiskott-Aldrich syndrome.
* [[Splenectomy]]: Splenectomy may be considered for some patients with Wiskott-Aldrich syndrome . [[Splenectomy]] may be found to improve [[platelet]] count as well as size of the [[Platelet|platelets]] . However, [[sepsis]] is a life-threatening complication after [[splenectomy]]. Prophylactic [[Antibiotic|antibiotics]] should always be used to prevent [[Infection|infections]].<ref name="pmid6767187">{{cite journal |vauthors=Lum LG, Tubergen DG, Corash L, Blaese RM |title=Splenectomy in the management of the thrombocytopenia of the Wiskott-Aldrich syndrome |journal=N. Engl. J. Med. |volume=302 |issue=16 |pages=892–6 |date=April 1980 |pmid=6767187 |doi=10.1056/NEJM198004173021604 |url=}}</ref><ref name="pmid21906397">{{cite journal |vauthors=Syrigos KN, Makrilia N, Neidhart J, Moutsos M, Tsimpoukis S, Kiagia M, Saif MW |title=Prolonged survival after splenectomy in Wiskott-Aldrich syndrome: a case report |journal=Ital J Pediatr |volume=37 |issue= |pages=42 |date=September 2011 |pmid=21906397 |pmc=3179709 |doi=10.1186/1824-7288-37-42 |url=}}</ref>


===Primary Prevention===
'''Primary Prevention'''
*There are no established measures for the [[primary prevention]] of the Wiskott-Aldrich syndrome. However [[Genetic testing|genetic mutation analysis]] and [[Prenatal diagnosis|prenatal molecular diagnosis]] can be helpful.<ref name="pmid8069912">{{cite journal |vauthors=Derry JM, Ochs HD, Francke U |title=Isolation of a novel gene mutated in Wiskott-Aldrich syndrome |journal=Cell |volume=78 |issue=4 |pages=635–44 |date=August 1994 |pmid=8069912 |doi= |url=}}</ref><ref name="pmid10073904">{{cite journal |vauthors=Giliani S, Fiorini M, Mella P, Candotti F, Schumacher RF, Wengler GS, Lalatta F, Fasth A, Badolato R, Ugazio AG, Albertini A, Notarangelo LD |title=Prenatal molecular diagnosis of Wiskott-Aldrich syndrome by direct mutation analysis |journal=Prenat. Diagn. |volume=19 |issue=1 |pages=36–40 |date=January 1999 |pmid=10073904 |doi= |url=}}</ref>
*There are no established measures for the [[primary prevention]] of the Wiskott-Aldrich syndrome. However [[Genetic testing|genetic mutation analysis]] and [[Prenatal diagnosis|prenatal molecular diagnosis]] can be helpful in decreaing the occurance .<ref name="pmid8069912">{{cite journal |vauthors=Derry JM, Ochs HD, Francke U |title=Isolation of a novel gene mutated in Wiskott-Aldrich syndrome |journal=Cell |volume=78 |issue=4 |pages=635–44 |date=August 1994 |pmid=8069912 |doi= |url=}}</ref><ref name="pmid10073904">{{cite journal |vauthors=Giliani S, Fiorini M, Mella P, Candotti F, Schumacher RF, Wengler GS, Lalatta F, Fasth A, Badolato R, Ugazio AG, Albertini A, Notarangelo LD |title=Prenatal molecular diagnosis of Wiskott-Aldrich syndrome by direct mutation analysis |journal=Prenat. Diagn. |volume=19 |issue=1 |pages=36–40 |date=January 1999 |pmid=10073904 |doi= |url=}}</ref>


===Secondary Prevention===
===Secondary Prevention===

Latest revision as of 16:55, 14 December 2018

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Chandrakala Yannam, MD [2]; Syed Hassan A. Kazmi BSc, MD [3]; Cafer Zorkun, M.D., Ph.D. [4]

Synonyms and keywords: Aldrich syndrome

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] 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.

Historical Perspective

The syndrome is named after Dr Robert Anderson Aldrich, an American pediatrician who described the disease in a family of Dutch-Americans in 1954, and Dr Alfred Wiskott, a German pediatrician who first noticed the syndrome in 1937.[2] 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.[3]

Classification

Jin et al (2004) employ a numerical grading of severity:[4]

Pathophysiology

In the 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 [5] (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. 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.[6]

Causes

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 [5] (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. 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.[6]

Differentiating Wiskott-Aldrich Syndrome From Other Disorders of Humoral Imuunodeficiency

Wiskott-Aldrich Syndrome should be differentiated from other disorders leading to hypogammaglobulinemia and defects of humoral immunity. The following conditions may be considered as differentials:[7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][30][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56]

Disorder Mechanism Characteristic Features Clinical Presentation Laboratory Findings
Wiskott-Aldrich Syndrome
X-Linked (Bruton) Agammaglobulinemia
Selective IgA Deficiency
  • Serum IgA < 7 mg/dl
  • Normal IgG and IgM levels
Common Variable Immunodeficiency
  • Defective B cell differentiation
  • May be acquired in 20-30 years of age
Autosomal dominant hype IgE syndrome (Job's Syndrome)
  • Distinctive coarse facies
  • Cold (non-inflammatory) Staphylococcal abscesses
  • Retained primary teeth
  • Eczema
Severe combined immunodeficiency (SCID)
Ataxia Telangiectasia
Hyper IgM Syndrome
  • Malignancy: can cause the reduction in the immunoglobulin production.
  • Viral infections: such as Epstein-Barr virus, HIV, cytomegalovirus are other causes of hypogammaglobulinemia..
  • Side effect of certain medications: Some drugs include systemic glucocorticoids, phenytoin, and carbamazepine, have been associated with IgG deficiency.
  • Other causes of primary humoral immunodeficiencies.
  • Smoking: may cause IgG2 subclass deficiency.
  • Protein-losing conditions: enteropathies, nephrotic syndrome, burns, and other traumas may cause abnormal loss of immunoglobulins.

Differentiating Wiskott-Aldrich Syndrome From Other Bleeding Diseases

  • Wiskott-Aldrich syndrome must be differentiated from other bleeding disorders. Different causes of bleeding disorders can be differentiated based on their clinical manifestation and laboratory findings. These features have discussed in the below table:
Category Subcategory Disease History Clinical manifestation Laboratory testing Comments
Mucosal bleeding Petechia Ecchymoses Menorrhagia Hematoma Hemarthrosis Plt BT PT PTT TT
Platelet disorders Qualitative Disorders of Platelet Function Inherited Disorders of Platelet Function Wiskott-Aldrich syndrome
  • Positive family history
+ + + + Nl or ↓ Nl Nl Nl
  • Anti-WASP antibody can be used to detect presence or absence of WAS protein
  • 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.
Glanzmann’s thrombasthenia
  • Positive family history
+ + + + Rare Nl or ↓ Nl Nl Nl
  • AR inheritance
  • Absence of the platelet Gp IIb/IIIa receptor
  • Diminished for GP 2B-3A on flow cytometry
Bernard-Soulier syndrome
  • Positive family history
+ + + + Nl or ↓ Nl Nl Nl
  • AR inheritance
  • Absence of the platelet Gp Ib-IX-V receptor
  • On PBS: giant platelets
  • Ristocetin - no aggregation
Platelet storage pool disorder: + + + + Nl or ↓ Nl Nl Nl
  • AD inheritance
  • AbNlities of platelet granule formation
Acquired Disorders of Platelet Function + + + + ± ± Nl or ↓ Nl Nl Nl
Von Willebrand Disease + + + + ± ± Nl Nl See the table below for the details about different types.
Subcategory Disease History Mucosal bleeding Petechia Ecchymoses Menorrhagia Hematoma Hemarthrosis Plt BT PT PTT TT Comments
Thrombocytopenia Infection-Induced thrombocytopenia
  • History of prior infection
+ + + + + + Nl Nl Nl
Medication-Induced Thrombocytopenia + + + + + + Nl Nl Nl Most important part of treatment is discontinuing of the medication.
Heparin-Induced thrombocytopenia + + + + + + Nl Nl For more information click here: Heparin-induced thrombocytopenia.
Immune Thrombocytopenic Purpura + + + + + + Nl Nl Nl
Inherited Thrombocytopenia
  • Positive family history
+ + + + + + Nl Nl Nl
Thrombotic Thrombocytopenic Purpura History of: + + + + + + Nl Nl Nl
Hemolytic Uremic Syndrome History of: + + + + + + Nl Nl Nl
Subcategory Disease History Mucosal bleeding Petechia Ecchymoses Menorrhagia Hematoma Hemarthrosis Plt BT PT PTT TT Comments
Vessel wall disorders Metabolic and Inflammatory Disorders
  • History of the underlying disease
+ + ± Nl Nl or ↑ Nl Nl Nl
Inherited Disorders of the Vessel Wall
  • Positive family history
+ + ± Nl Nl or ↑ Nl Nl Nl
Coagulation factor disorders

[57]

Fibrinogen deficiency

Different types of the fibrinogen disorders:

+ + ± + Nl
  • Impaired fibrin cross-linking or clot dissolution
  • Mild or severe bleeding idepend on levels of functional fibrinogen
  • Variable age of onset
Subcategory Disease History Mucosal bleeding Petechia Ecchymoses Menorrhagia Hematoma Hemarthrosis Plt BT PT PTT TT Comments
Prothrombin deficiency + + + + + Nl Nl
Factor V deficiency + + + + Nl Nl
  • The severity of bleeding related to the degree of factor V deficiency
Factor VII deficiency + + + Nl Nl Nl
  • Thrombosis in inherited factor VII deficiency
  • Treatment with the administration of factor VII replacement therapy
Factor X deficiency
  • Prolonged bleeding following circumcision
  • Easy bruising
  • Hematuria
  • Menorrhagia
  • Abortion
  • Postpartum hemorrhage
  • Epistaxis
  • Pseudotumors
  • Intracranial bleeding
  • Hemarthroses
+ + + + + Nl Nl Nl
Factor XII deficiency
  • Asymptomatic
  • Recurrent miscarriages
  • Painful leg ulcers
Nl Nl Nl Nl
Subcategory Disease History Mucosal bleeding Petechia Ecchymoses Menorrhagia Hematoma Hemarthrosis Plt BT PT PTT TT Comments
High molecular weight kininogen (HMWK) deficiency
  • Positive family history of bleeding
Nl Nl Nl Nl
Prekallikrein deficiency
  • Positive family history of bleeding
Nl Nl Nl Nl
Factor XIII deficiency
  • Sub unit A mutation disease (more common)
  • Sub unit B mutation disease
  • Positive family history of bleeding
± ± ± ± ± ± Nl Nl Nl or ↑ Nl Nl
  • Impaired fibrin cross-linking or clot dissolution
  • The severity of factor XIII deficiency bleeds can be different in different patients
Hemophilia Type A deficiency + + + Nl Nl Nl Nl
Type B deficiency + + + Nl Nl Nl Nl
Type C deficiency
  • Positive family history
  • Bleeding after surgery or injury
+ Rare Rare Nl Nl Nl Nl
Subcategory Disease History Mucosal bleeding Petechia Ecchymoses Menorrhagia Hematoma Hemarthrosis Plt BT PT PTT TT Comments
Rare diseases Disseminated Intravascular Coagulation + + + + + + Nl
Vitamin K Deficiency + + + + + Nl Nl or mildly prolonged Nl

Risk Factors

  • Positive family history of Wiskott-Aldrich syndrome, can be considered as a risk factor.

Screening

  • Flow cytometry:
    • Anti-WASp antibody can be used to detect presence or absence of WAS protein. However, flow cytometry may not detect expression of mutated, reduced or poor WASp.[58]
  • Identification of carriers: Known female carriers can be identified by using DNA mutation analysis of WAS gene.
  • Prenatal diagnosis: DNA analysis from chorionic villus sampling can be performed.[59]

Natural History, Complications, and Prognosis

Diagnosis

Diagnostic Study of Choice

History and Symptoms

  • Patients with Wiskott-Aldrich syndrome have

Physical Examination

Laboratory Findings

Electrocardiogram

  • There are no specific electrocardiogram findings associated with Wiskott-Aldrich syndrome.

X-ray

  • There are no specific x-ray findings associated with Wiskott-Aldrich syndrome. However, a chest x-ray may be helpful in the diagnosis of complications, which include pneumonia.

Echocardiography or Ultrasound

CT scan

MRI

  • There are no specific MRI findings associated with Wiskott-Aldrich syndrome.

Treatment

Medical Therapy

Surgery

Primary Prevention

Secondary Prevention

References

  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.
  2. Wiskott, A (1937). "Familiärer, angeborener Morbus Werlhofii? ("Familial congenital Werlhof's disease?")". Montsschr Kinderheilkd. 68: 212–16.
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