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<script type="text/javascript" src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.boots.min.js"> </script><title>WAS-Related Disorders - GeneReviews® - NCBI Bookshelf</title>
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<meta name="citation_title" content="WAS-Related Disorders">
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<meta name="citation_publisher" content="University of Washington, Seattle">
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<meta name="citation_date" content="2024/08/15">
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<meta name="citation_author" content="Sharat Chandra">
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<meta name="citation_author" content="Chinmayee B Nagaraj">
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<meta name="citation_author" content="Miao Sun">
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<meta name="citation_author" content="Shanmuganathan Chandrakasan">
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<meta name="citation_author" content="Kejian Zhang">
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<meta name="citation_keywords" content="Wiskott-Aldrich Syndrome">
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<meta name="citation_keywords" content="X-Linked Thrombocytopenia (XLT)">
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<meta name="citation_keywords" content="X-Linked Neutropenia (XLN)">
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<meta name="citation_keywords" content="Actin nucleation-promoting factor WAS">
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<meta name="DC.Contributor" content="Chinmayee B Nagaraj">
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<meta name="DC.Contributor" content="Miao Sun">
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<meta name="DC.Contributor" content="Shanmuganathan Chandrakasan">
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<meta name="DC.Contributor" content="Kejian Zhang">
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class="wsprkl btn" title="Jump to next match">▶</a></nav></nav></div><div id="jr-epub-interstitial" class="hidden"></div><div id="jr-content"><article data-type="main"><div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><div class="fm-sec"><h1 id="_NBK1178_"><span class="title" itemprop="name"><i>WAS</i>-Related Disorders</span></h1><p class="contribs">Chandra S, Nagaraj CB, Sun M, et al.</p><p class="fm-aai"><a href="#_NBK1178_pubdet_">Publication Details</a></p><p><em>Estimated reading time: 34 minutes</em></p></div></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="was.Summary" itemprop="description"><h2 id="_was_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p>The <i>WAS</i>-related disorders, which include Wiskott-Aldrich syndrome, X-linked thrombocytopenia (XLT), and X-linked neutropenia (XLN), are a spectrum of disorders of hematopoietic cells, with predominant defects of platelets and lymphocytes.</p><p>Wiskott-Aldrich syndrome usually presents in infancy. Affected males have thrombocytopenia with intermittent mucosal bleeding, bloody diarrhea, and intermittent or chronic petechiae and purpura; recurrent bacterial, viral, fungal, and/or opportunistic infections; and eczema. Approximately 25%-40% of those who survive the early complications develop one or more autoimmune conditions including hemolytic anemia, immune thrombocytopenic purpura, immune-mediated neutropenia, vasculitis, rheumatoid arthritis, and immune-mediated damage to the kidneys and liver. Individuals with a <i>WAS</i>-related disorder, particularly those who have been exposed to Epstein-Barr virus (EBV), are at increased risk of developing lymphomas, which often occur in unusual extranodal locations including the brain, lung, or gastrointestinal tract.</p><p>Males with XLT have small platelet volume and thrombocytopenia. Severe disease-related events include severe bleeding episodes (14%), autoimmunity (12%), life-threatening infections (7%), and malignancy (5%).</p><p>Males with XLN typically have congenital neutropenia associated with myelodysplasia, hyperactive neutrophils, increased myeloid cell apoptosis, and lymphoid cell abnormalities.</p></div><div><h4 class="inline">Diagnosis/testing.</h4><p>The diagnosis of a <i>WAS</i>-related disorder is established in a male proband with both congenital thrombocytopenia (<70,000 platelets/mm<sup>3</sup>) and small platelets; at least one of the following features: eczema, recurrent bacterial, viral, and fungal infections, autoimmune disease(s), malignancy, reduced WASP expression in a fresh blood sample, abnormal antibody response to polysaccharide antigens and/or low isohemagglutinins, or positive maternal family history of a <i>WAS</i>-related disorder; and a hemizygous <i>WAS</i> pathogenic variant identified by molecular genetic testing (necessary to confirm the diagnosis).</p><p>The diagnosis of a <i>WAS</i>-related disorder in a female is uncommon. It is usually established by identification of a heterozygous pathogenic variant in <i>WAS</i> by molecular genetic testing in a female with severe skewed X-chromosome inactivation and increased expression of the mutated <i>WAS</i> allele.</p></div><div><h4 class="inline">Management.</h4><p><i>Targeted therapy:</i> The only curative targeted therapy clinically available for Wiskott-Aldrich syndrome is allogeneic hematopoietic stem cell transplantation (HSCT). In those with XLT, decision to treat with HSCT is determined on an individual basis.</p><p><i>Treatment of manifestations:</i> In those with Wiskott-Aldrich syndrome and XLT, treatment is individualized based on disease manifestations and includes management of thrombocytopenia; prevention of infection with immunoglobulin replacement; topical steroids for eczema; antibiotics as needed for chronic skin infections; prophylactic antibiotics for <i>Pneumocystis jirovecii</i> in infants with Wiskott-Aldrich syndrome; intravenous immunoglobulin G; routine non-live immunizations; prompt evaluation and treatment for infection including empiric parenteral antibiotics and exhaustive search for source of infection; and judicious use of immunosuppressants for autoimmune disease prior to definitive treatment.</p><p>In those with XLN, treatment includes granulocyte colony-stimulating factor therapy; routine non-live immunizations; prompt evaluation and treatment for infection including empiric parenteral antibiotics and exhaustive search for source of infection; and treatment of myelodysplastic syndrome and acute myelogenous leukemia per hematologist/oncologist.</p><p><i>Surveillance</i>: Complete blood count including platelet count and size and assessment for complications associated with increased bleeding as recommended by hematologist; annual skin examination; assessment by immunologist including for recurrent infections with frequency as recommended by immunologist; annual clinical assessment for autoimmune dysfunction and for manifestations of lymphoma.</p><p><i>Agents/circumstances to avoid:</i> Circumcision of at-risk newborn males who have thrombocytopenia; use of medications that interfere with platelet function. Defer elective procedures until after HSCT.</p><p><i>Evaluation of relatives at risk:</i> Evaluation of at-risk newborn males so that morbidity and mortality can be reduced by early diagnosis and treatment. Evaluation of relatives considering stem cell donation to inform transplant donor decision making.</p></div><div><h4 class="inline">Genetic counseling.</h4><p><i>WAS</i>-related disorders are inherited in an X-linked manner. If the mother of the proband has a <i>WAS</i> pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be symptomatic. Females who inherit the pathogenic variant will be carriers and are typically asymptomatic. Males with a <i>WAS</i>-related disorder transmit the pathogenic variant to all of their daughters and none of their sons. Once the <i>WAS</i> pathogenic variant has been identified in a family member, molecular genetic testing to identify female heterozygotes and prenatal and preimplantation genetic testing are possible.</p></div></div><div id="was.GeneReview_Scope"><h2 id="_was_GeneReview_Scope_"><i>GeneReview</i> Scope</h2><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figwasTc"><a href="/books/NBK1178/table/was.Tc/?report=objectonly" target="object" title="Table" class="img_link icnblk_img" rid-ob="figobwasTc"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="was.Tc"><a href="/books/NBK1178/table/was.Tc/?report=objectonly" target="object" rid-ob="figobwasTc">Table</a></h4><p class="float-caption no_bottom_margin">Wiskott-Aldrich syndrome X-linked thrombocytopenia (XLT)</p></div></div></div><div id="was.Diagnosis"><h2 id="_was_Diagnosis_">Diagnosis</h2><div id="was.Suggestive_Findings"><h3>Suggestive Findings</h3><p><i>WAS</i>-related disorders include a phenotypic spectrum ranging from severe to mild. The phenotypes and their <a href="https://esid.org/Working-Parties/Clinical/Resources/Diagnostic-criteria-for-PID2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">diagnostic criteria</a>, modified from the recommendations of the European Society of Immunodeficiencies (ESID), are listed here.</p><p><b>Wiskott-Aldrich syndrome</b>
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<b>should be suspected</b> in a male with the following:</p><ul><li class="half_rhythm"><div>Profound thrombocytopenia (<70,000 platelets/mm<sup>3</sup>)</div></li><li class="half_rhythm"><div>Small platelet size (mean platelet volume >2 standard deviations [SD] below the mean for the laboratory)</div></li><li class="half_rhythm"><div>Recurrent bacterial, viral, fungal, and/or other opportunistic infections in infancy or early childhood</div></li><li class="half_rhythm"><div>Eczema</div></li><li class="half_rhythm"><div>Autoimmune disorder, such as hemolytic anemia, vasculitis, rheumatoid arthritis, or glomerulonephritis</div></li><li class="half_rhythm"><div>Increased risk of cancer, particularly lymphoma</div></li><li class="half_rhythm"><div>Family history of one or more maternally related males with a <i>WAS</i>-related disorder</div></li><li class="half_rhythm"><div>Absent or decreased Wiskott-Aldrich syndrome protein (WASP) in hematopoietic cells by flow cytometry or western blotting</div></li><li class="half_rhythm"><div>Abnormal lymphocytes:</div><ul><li class="half_rhythm"><div class="half_rhythm">Decreased T-cell subsets, especially proportion and absolute number of CD8<sup>+</sup> T cells</div></li><li class="half_rhythm"><div class="half_rhythm">Decreased NK cell function. Lymphocyte subsets, mitogen responses, and other tests of cell-mediated immunity can vary among individuals, and over time in the same individual.</div><div class="half_rhythm">Note: (1) Some individuals, particularly children, have normal lymphocyte numbers and normal function. (2) Although the proportion of CD8<sup>+</sup> cells is often decreased, it is occasionally increased.</div></li><li class="half_rhythm"><div class="half_rhythm">Abnormal immunoglobulin levels (decreased IgM, normal or decreased IgG, increased IgA, increased IgE)</div></li><li class="half_rhythm"><div class="half_rhythm">Absent isohemagglutinins</div><div class="half_rhythm">Note: Interpretation of the significance of isohemagglutinin titers is unreliable in children younger than age 18 years.</div></li><li class="half_rhythm"><div class="half_rhythm">Absent or greatly decreased antibody responses to polysaccharide antigens (e.g., Pneumovax<sup>®</sup>)</div></li></ul></li></ul><p><b>X-linked thrombocytopenia (XLT) should be suspected</b> in a male with the following:</p><ul><li class="half_rhythm"><div>Congenital thrombocytopenia (5,000-50,000 platelets/mm<sup>3</sup>)</div></li><li class="half_rhythm"><div>Small platelet size (platelet volume <7.5 fL)</div></li><li class="half_rhythm"><div>Absence of other clinical findings of Wiskott-Aldrich syndrome</div></li><li class="half_rhythm"><div>Family history of one or more maternally related males with a <i>WAS</i>-related phenotype or disorder</div></li><li class="half_rhythm"><div>Decreased or absent WASP by flow cytometry or western blotting</div><div>Note: Some affected individuals have near-normal amounts of WASP.</div></li></ul><p><b>X-linked neutropenia (XLN) should be suspected</b> in a male with the following:</p><ul><li class="half_rhythm"><div>Recurrent bacterial infections</div></li><li class="half_rhythm"><div>Persistent neutropenia</div></li><li class="half_rhythm"><div>Arrested development of the bone marrow in the absence of other clinical findings of Wiskott-Aldrich syndrome</div></li><li class="half_rhythm"><div>Normal WASP expression by flow cytometry or western blotting</div></li></ul></div><div id="was.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><p><b>Male proband.</b> The diagnosis of a <i>WAS</i>-related disorder <b>is established</b> in a male proband with:</p><ul><li class="half_rhythm"><div>BOTH of the following:</div><ul><li class="half_rhythm"><div>Thrombocytopenia (<70,000 platelets/mm<sup>3</sup>, confirmed with repeat examination)</div></li><li class="half_rhythm"><div>Small platelets (platelet volume <7 fL, or mean platelet volume >2 SD below the mean for the laboratory)</div></li></ul></li><li class="half_rhythm"><div>AND at least ONE of the following:</div><ul><li class="half_rhythm"><div>Eczema</div></li><li class="half_rhythm"><div>Recurrent bacterial, viral, and/or fungal infections</div></li><li class="half_rhythm"><div>Autoimmune disease(s) (including vasculitis)</div></li><li class="half_rhythm"><div>Malignancy</div></li><li class="half_rhythm"><div>Reduced WASP expression in a fresh blood sample</div></li><li class="half_rhythm"><div>Abnormal antibody response to polysaccharide antigens and/or low isohemagglutinins</div></li><li class="half_rhythm"><div>Positive maternal family history of a <i>WAS</i>-related disorder</div></li></ul></li><li class="half_rhythm"><div>AND a hemizygous <i>WAS</i> pathogenic (or likely pathogenic) variant identified by molecular genetic testing (necessary to confirm the diagnosis; see <a href="/books/NBK1178/table/was.T.molecular_genetic_testing_used_in/?report=objectonly" target="object" rid-ob="figobwasTmoleculargenetictestingusedin">Table 1</a>).</div></li></ul><p><b>Female proband.</b> The diagnosis of a <i>WAS</i>-related disorder <b>is usually established</b> in a female proband by identification of a heterozygous pathogenic (or likely pathogenic) variant in <i>WAS</i> by molecular genetic testing (see <a href="/books/NBK1178/table/was.T.molecular_genetic_testing_used_in/?report=objectonly" target="object" rid-ob="figobwasTmoleculargenetictestingusedin">Table 1</a>) along with clinical features consistent with a <i>WAS</i>-related disorder.</p><p>Note: (1) Females heterozygous for a <i>WAS</i> pathogenic variant are typically asymptomatic due to random X-chromosome inactivation that results in sufficient normal WASP expression. Blood cell populations can vary from normal WASP expression to severe skewed X-chromosome inactivation with expression of the mutated <i>WAS</i> allele [<a class="bibr" href="#was.REF.lutskiy.2002.2763" rid="was.REF.lutskiy.2002.2763">Lutskiy et al 2002</a>, <a class="bibr" href="#was.REF.boonyawat.2013.1150" rid="was.REF.boonyawat.2013.1150">Boonyawat et al 2013</a>, <a class="bibr" href="#was.REF.dazacajigal.2013.125" rid="was.REF.dazacajigal.2013.125">Daza-Cajigal et al 2013</a>, <a class="bibr" href="#was.REF.takimoto.2015.185" rid="was.REF.takimoto.2015.185">Takimoto et al 2015</a>, <a class="bibr" href="#was.REF.hou.2021.691524" rid="was.REF.hou.2021.691524">Hou et al 2021</a>]. (2) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [<a class="bibr" href="#was.REF.richards.2015.405" rid="was.REF.richards.2015.405">Richards et al 2015</a>]. Reference to "pathogenic variants" in this <i>GeneReview</i> is understood to include likely pathogenic variants. (3) Identification of a hemizygous or heterozygous <i>WAS</i> variant of uncertain significance does not establish or rule out the diagnosis.</p><p>Molecular testing approaches can include a combination of <b>gene-targeted testing</b> (single gene testing, multigene panel) and <b>comprehensive</b>
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<b>genomic testing</b> (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see <a href="#was.Option_1">Option 1</a>), whereas comprehensive genomic testing does not (see <a href="#was.Option_2">Option 2</a>).</p><div id="was.Option_1"><h4>Option 1</h4><p><b>Single-gene testing.</b> Sequence analysis of <i>WAS</i> is performed first to detect missense, nonsense, and splice site variants and small intragenic deletions/insertions. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.</p><p><b>A multigene panel</b> that includes <i>WAS</i> and other genes of interest (see <a href="#was.Differential_Diagnosis">Differential Diagnosis</a>) may be considered to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this <i>GeneReview</i>. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome or genome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.</p><p>For an introduction to multigene panels click <a href="/books/n/gene/app5/?report=reader#app5.Multigene_Panels">here</a>. More detailed information for clinicians ordering genetic tests can be found <a href="/books/n/gene/app5/?report=reader#app5.Multigene_Panels_FAQs">here</a>.</p></div><div id="was.Option_2"><h4>Option 2</h4><p>When the diagnosis of a <i>WAS</i>-related disorder has not been considered because an individual has atypical phenotypic features, <b>comprehensive</b>
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<b>genomic testing</b> does not require the clinician to determine which gene is likely involved. <b>Exome sequencing</b> is most used; <b>genome sequencing</b> is also possible.</p><p>For an introduction to comprehensive genomic testing click <a href="/books/n/gene/app5/?report=reader#app5.Comprehensive_Genomic_Testing">here</a>. More detailed information for clinicians ordering genomic testing can be found <a href="/books/n/gene/app5/?report=reader#app5.Comprehensive_Genomic_Testing_1">here</a>.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figwasTmoleculargenetictestingusedin"><a href="/books/NBK1178/table/was.T.molecular_genetic_testing_used_in/?report=objectonly" target="object" title="Table 1. " class="img_link icnblk_img" rid-ob="figobwasTmoleculargenetictestingusedin"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="was.T.molecular_genetic_testing_used_in"><a href="/books/NBK1178/table/was.T.molecular_genetic_testing_used_in/?report=objectonly" target="object" rid-ob="figobwasTmoleculargenetictestingusedin">Table 1. </a></h4><p class="float-caption no_bottom_margin">Molecular Genetic Testing Used in <i>WAS</i>-Related Disorders </p></div></div></div></div></div><div id="was.Clinical_Characteristics"><h2 id="_was_Clinical_Characteristics_">Clinical Characteristics</h2><div id="was.Clinical_Description"><h3>Clinical Description</h3><p><i>WAS</i>-related disorders comprise a spectrum that includes Wiskott-Aldrich syndrome, X-linked thrombocytopenia (XLT), and X-linked neutropenia (XLN). There is considerable overlap between phenotypes. <i>WAS</i>-related disorders usually present in infancy with low platelet counts, small platelet size, significant risk of bleeding, and, in some individuals, eczema and/or abnormal lymphocyte function with susceptibility to serious bacterial, viral, and fungal infections. Autoimmune disorders and lymphomas are frequent. The clinical phenotype may worsen with age. The clinical complications can vary widely, even in the same kindred. The prognosis for individuals with <i>WAS</i>-related disorders has improved as a result of improved treatment.</p><p>The <b><i>WAS</i>-related disorders clinical score (WAS score)</b> is derived from clinical and laboratory features including thrombocytopenia, eczema, immunodeficiency, autoimmune disorders, and malignancy (see <a href="/books/NBK1178/table/was.T.wasrelated_disorders_clinical_scor/?report=objectonly" target="object" rid-ob="figobwasTwasrelateddisordersclinicalscor">Table 2</a>). WAS scores, which range between 0 and 5, facilitate the clinical categorization of individuals and may be useful in predicting disease severity [<a class="bibr" href="#was.REF.albert.2011.42" rid="was.REF.albert.2011.42">Albert et al 2011</a>]. Individuals with a higher WAS score (e.g., 5) at a younger age (e.g., during the first two years of life) may be at increased risk for morbidity and mortality [<a class="bibr" href="#was.REF.mahlaoui.2013.1510" rid="was.REF.mahlaoui.2013.1510">Mahlaoui et al 2013</a>]. As progression of the disease can occur at a later age, individuals may transition from a lower to a higher WAS score (e.g., some individuals originally diagnosed with XLT [score of 1 to 2] may develop autoimmunity or cancer later in life [score of 5]) [<a class="bibr" href="#was.REF.cavannaugh.2022.609" rid="was.REF.cavannaugh.2022.609">Cavannaugh et al 2022</a>].</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figwasTwasrelateddisordersclinicalscor"><a href="/books/NBK1178/table/was.T.wasrelated_disorders_clinical_scor/?report=objectonly" target="object" title="Table 2. " class="img_link icnblk_img" rid-ob="figobwasTwasrelateddisordersclinicalscor"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="was.T.wasrelated_disorders_clinical_scor"><a href="/books/NBK1178/table/was.T.wasrelated_disorders_clinical_scor/?report=objectonly" target="object" rid-ob="figobwasTwasrelateddisordersclinicalscor">Table 2. </a></h4><p class="float-caption no_bottom_margin"><i>WAS</i>-Related Disorders: Clinical Scoring System </p></div></div><div id="was.WiskottAldrich_Syndrome"><h4>Wiskott-Aldrich Syndrome</h4><p><b>Thrombocytopenia</b> is usually present at birth. However, near-normal platelet counts in the newborn period followed by chronic thrombocytopenia have been reported. Intracranial bleeding is a potential early life-threatening complication. Intermittent mucosal bleeding and bloody diarrhea are commonly observed, as are intermittent or chronic petechiae and purpura. The cumulative incidence of severe bleeding at age 15 and 30 years were 33% and 49%, respectively, and contributes to 23% of mortality in individuals with Wiskott-Aldrich syndrome [<a class="bibr" href="#was.REF.vall_e.2024.2504" rid="was.REF.vall_e.2024.2504">Vallée et al 2024</a>]. Platelet counts do not adequately represent bleeding risk in an individual with Wiskott-Aldrich syndrome [<a class="bibr" href="#was.REF.albert.2010.3231" rid="was.REF.albert.2010.3231">Albert et al 2010</a>].</p><p>Thrombocytopenia may be reversed by splenectomy; however, recurrent thrombocytopenia associated with the development of immune thrombocytopenia purpura (ITP) is observed in some splenectomized individuals, more so in those with Wiskott-Aldrich syndrome compared to those with XLT [<a class="bibr" href="#was.REF.rivers.2019a.1042" rid="was.REF.rivers.2019a.1042">Rivers et al 2019a</a>].</p><p><b>Eczema</b> occurs in about 80% of males with Wiskott-Aldrich syndrome [<a class="bibr" href="#was.REF.sullivan.1994.876" rid="was.REF.sullivan.1994.876">Sullivan et al 1994</a>]. The severity varies from mild to severe and tends to be worse in males with a family history of allergies and asthma.</p><p><b>Immunodeficiency.</b> Boys with Wiskott-Aldrich syndrome are susceptible to recurrent bacterial, viral, fungal, and opportunistic infections, particularly recurrent ear infections. Skin infections including impetigo, cellulitis, and abscesses are common. Infections by opportunistic agents including cytomegalovirus (CMV), herpes simplex virus (HSV), Epstein-Barr virus (EBV), and adenovirus are common. <i>Pneumocystis jirovecii</i> pneumonia is a possible early life-threatening complication.</p><p>The overall incidence of any severe infections is 0.11 per patient-year (0.10-0.13). About half of individuals with Wiskott-Aldrich syndrome have a severe infection by age 15 years, and severe infections contribute to 27% of the mortality in Wiskott-Aldrich syndrome [<a class="bibr" href="#was.REF.vall_e.2024.2504" rid="was.REF.vall_e.2024.2504">Vallée et al 2024</a>]. There is an increased risk of mortality secondary to bacterial sepsis from encapsulated organisms including <i>Streptococcus pneumonia,</i>
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<i>Haemophilus influenzae</i> type B, and opportunistic infections. Splenectomy, commonly performed in the past to increase platelet counts and reduce risk of fatal hemorrhage, increases the risk of overwhelming bacterial infection.</p><p><b>Autoimmune disorders.</b> The risk of developing an autoimmune disorder increases with age. Roughly 25%-40% of males who survive the early complications of Wiskott-Aldrich syndrome develop one or more autoimmune conditions including hemolytic anemia (destruction of red blood cells), immune thrombocytopenic purpura, immune-mediated neutropenia, rheumatoid arthritis, vasculitis of small and large vessels, and immune-mediated damage to the kidneys and liver [<a class="bibr" href="#was.REF.chen.2015.1311" rid="was.REF.chen.2015.1311">Chen et al 2015</a>, <a class="bibr" href="#was.REF.vall_e.2024.2504" rid="was.REF.vall_e.2024.2504">Vallée et al 2024</a>]. For a comprehensive review of autoimmunity in Wiskott-Aldrich syndrome, see <a class="bibr" href="#was.REF.schurman.2003.446" rid="was.REF.schurman.2003.446">Schurman & Candotti [2003]</a>, <a class="bibr" href="#was.REF.catucci.2012.209" rid="was.REF.catucci.2012.209">Catucci et al [2012]</a>, and <a class="bibr" href="#was.REF.sudhakar.2021.363" rid="was.REF.sudhakar.2021.363">Sudhakar et al [2021]</a>.</p><p>High serum immunoglobulin (Ig) M concentration in young children prior to splenectomy may be a risk factor for the development of autoimmune hemolytic anemia [<a class="bibr" href="#was.REF.dupuisgirod.2003.e622" rid="was.REF.dupuisgirod.2003.e622">Dupuis-Girod et al 2003</a>]; however, the predictive value of this finding awaits confirmation by other investigators.</p><p>The presence of an autoimmune disorder significantly increases the risk of developing lymphoma [<a class="bibr" href="#was.REF.sullivan.1994.876" rid="was.REF.sullivan.1994.876">Sullivan et al 1994</a>, <a class="bibr" href="#was.REF.schurman.2003.446" rid="was.REF.schurman.2003.446">Schurman & Candotti 2003</a>].</p><p>Allogeneic hematopoietic stem cell transplantation (HSCT) corrects autoimmunity in individuals with Wiskott-Aldrich syndrome [<a class="bibr" href="#was.REF.pai.2006.671" rid="was.REF.pai.2006.671">Pai et al 2006</a>, <a class="bibr" href="#was.REF.burroughs.2020.2094" rid="was.REF.burroughs.2020.2094">Burroughs et al 2020</a>, <a class="bibr" href="#was.REF.sudhakar.2021.363" rid="was.REF.sudhakar.2021.363">Sudhakar et al 2021</a>].</p><p><b>Lymphoma.</b> Individuals with Wiskott-Aldrich syndrome, particularly those who have been exposed to Epstein-Barr virus (EBV), have a high risk of developing lymphomas, which often occur in unusual extranodal locations such as the brain, lung, or gastrointestinal tract. Although B-cell lymphomas predominate, EBV-associated T-cell lymphomas and Hodgkin lymphomas have also been reported. Approximately 15% of individuals with Wiskott-Aldrich syndrome develop lymphoma at an average age of 30 years [<a class="bibr" href="#was.REF.vall_e.2024.2504" rid="was.REF.vall_e.2024.2504">Vallée et al 2024</a>]. The risk of developing lymphoma increases with age and in the presence of autoimmune disease [<a class="bibr" href="#was.REF.schurman.2003.446" rid="was.REF.schurman.2003.446">Schurman & Candotti 2003</a>, <a class="bibr" href="#was.REF.vall_e.2024.2504" rid="was.REF.vall_e.2024.2504">Vallée et al 2024</a>].</p><p>The prognosis of individuals with Wiskott-Aldrich syndrome following conventional chemotherapy is poorer than that of age-matched normal controls. Individuals with Wiskott-Aldrich syndrome have a significant risk of relapse or development of a second <i>de novo</i> lymphoma. Individuals with Wiskott-Aldrich syndrome and lymphoma should undergo allogeneic HSCT to increase their chances of relapse-free survival.</p><p>Only three other non-hematologic malignancies were reported in individuals with Wiskott-Aldrich syndrome, including glioma, acoustic neuroma, and testicular carcinoma. To date, it is unknown if the risk of non-hematologic malignancy is increased in individuals with Wiskott-Aldrich syndrome.</p><p><b>Life span.</b> The reported overall survival was 78% at age 15 years (95% confidence interval [CI] = 74-82) and at age 30 years 65% (95% CI = 58-73) [<a class="bibr" href="#was.REF.vall_e.2024.2504" rid="was.REF.vall_e.2024.2504">Vallée et al 2024</a>]. The causes of deaths include infection (27% of individuals), bleeding (23%), HSCT-related adverse events (16%), and malignancy (7%) [<a class="bibr" href="#was.REF.vall_e.2024.2504" rid="was.REF.vall_e.2024.2504">Vallée et al 2024</a>]. Survival into adulthood occurs, particularly given the improvement in medical treatment of this disorder over the last 20 years. HSCT provides a potential cure for Wiskott-Aldrich syndrome, with a three-year overall survival of more than 85% [<a class="bibr" href="#was.REF.burroughs.2020.2094" rid="was.REF.burroughs.2020.2094">Burroughs et al 2020</a>, <a class="bibr" href="#was.REF.albert.2022.2066" rid="was.REF.albert.2022.2066">Albert et al 2022</a>].</p></div><div id="was.XLinked_Thrombocytopenia_XLT"><h4>X-Linked Thrombocytopenia (XLT)</h4><p>Males with XLT have small platelet volume and thrombocytopenia that may be intermittent. <a class="bibr" href="#was.REF.albert.2010.3231" rid="was.REF.albert.2010.3231">Albert et al [2010]</a> found that though the life expectancy was not significantly affected in males with XLT as a group, severe disease-related events were common, with severe bleeding episodes in 14% of affected individuals, autoimmunity in 12%, life-threatening infections in 7%, and malignancy in 5% of individuals with XLT. Hence, survival without a severe disease-related event was only 56% at age 30 years [<a class="bibr" href="#was.REF.albert.2022.2066" rid="was.REF.albert.2022.2066">Albert et al 2022</a>].</p></div><div id="was.XLinked_Neutropenia_XLN"><h4>X-Linked Neutropenia (XLN)</h4><p>Males with XLN typically present with congenital neutropenia associated with myelodysplasia, hyperactive neutrophils, increased myeloid cell apoptosis, and lymphoid cell abnormalities [<a class="bibr" href="#was.REF.keszei.2018.4115" rid="was.REF.keszei.2018.4115">Keszei et al 2018</a>, <a class="bibr" href="#was.REF.he.2022.1069" rid="was.REF.he.2022.1069">He et al 2022</a>]. <a class="bibr" href="#was.REF.beel.2009.1449" rid="was.REF.beel.2009.1449">Beel & Vandenberghe [2009]</a> described two males with XLN who developed myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). <a class="bibr" href="#was.REF.boztug.2011.21" rid="was.REF.boztug.2011.21">Boztug & Klein [2011]</a> estimate that 20%-30% of males with XLN are at risk for MDS or AML.</p></div><div id="was.Heterozygous_Females"><h4>Heterozygous Females</h4><p>Females heterozygous for a <i>WAS</i> pathogenic variant rarely have significant clinical symptoms and generally have no immunologic or biochemical markers of the disorder; however, mild thrombocytopenia is noted in a small proportion. Heterozygous females rarely present with typical features of Wiskott-Aldrich syndrome such as severe thrombocytopenia and/or immunologic dysfunction [<a class="bibr" href="#was.REF.takimoto.2015.185" rid="was.REF.takimoto.2015.185">Takimoto et al 2015</a>, <a class="bibr" href="#was.REF.hou.2021.691524" rid="was.REF.hou.2021.691524">Hou et al 2021</a>].</p></div></div><div id="was.GenotypePhenotype_Correlations"><h3>Genotype-Phenotype Correlations</h3><p>Individuals with Wiskott-Aldrich syndrome show remarkably variable expressivity of clinical findings.</p><p>At least 300 different disease-causing variants and six mutational hot spots in <i>WAS</i> have been described. Loss-of-function variants in <i>WAS</i> cause Wiskott-Aldrich syndrome and XLT, whereas gain-of-function variants in the region encoding the conserved GTPase binding domain of Wiskott-Aldrich syndrome protein (WASP) lead to XLN [<a class="bibr" href="#was.REF.stenson.2020.1197" rid="was.REF.stenson.2020.1197">Stenson et al 2020</a>].</p><p>Specific pathogenic variants are not universally associated with a specific clinical phenotype, and disease severity varies considerably within families, even between monozygotic twins [<a class="bibr" href="#was.REF.buchbinder.2011.773" rid="was.REF.buchbinder.2011.773">Buchbinder et al 2011</a>], which suggests epigenetic factors, other genetic alterations, and environmental factors (e.g., Epstein-Barr virus [EBV]) could contribute to the phenotypic heterogeneity [<a class="bibr" href="#was.REF.albert.2011.42" rid="was.REF.albert.2011.42">Albert et al 2011</a>, <a class="bibr" href="#was.REF.buchbinder.2014.55" rid="was.REF.buchbinder.2014.55">Buchbinder et al 2014</a>, <a class="bibr" href="#was.REF.liu.2015.1601" rid="was.REF.liu.2015.1601">Liu et al 2015</a>]. While several reports described missense and certain intronic pathogenic variants in association with XLT or mild disease and nonsense, frameshift, or splice site variants in individuals with severe disease [<a class="bibr" href="#was.REF.jin.2004.4010" rid="was.REF.jin.2004.4010">Jin et al 2004</a>, <a class="bibr" href="#was.REF.liu.2015.1601" rid="was.REF.liu.2015.1601">Liu et al 2015</a>, <a class="bibr" href="#was.REF.vall_e.2024.2504" rid="was.REF.vall_e.2024.2504">Vallée et al 2024</a>], other studies failed to find consistent correlation between a particular pathogenic variant type and clinical outcome [<a class="bibr" href="#was.REF.buchbinder.2011.773" rid="was.REF.buchbinder.2011.773">Buchbinder et al 2011</a>, <a class="bibr" href="#was.REF.liu.2021.e25527" rid="was.REF.liu.2021.e25527">Liu et al 2021</a>, <a class="bibr" href="#was.REF.udomkittivorakul.2022.792" rid="was.REF.udomkittivorakul.2022.792">Udomkittivorakul et al 2022</a>].</p><p>XLN is caused by rare gain-of-function variants in the GTPase binding domain, which cause constitutive activation of WASP in tissues to compensate the reduced myelopoiesis and extremely low number of circulating neutrophil in peripheral blood. Therefore, individuals with XLN are generally not at high risk of infections and do not require permanent granulocyte colony-stimulating factor support. Disease severity varies considerably within families [<a class="bibr" href="#was.REF.keszei.2018.4115" rid="was.REF.keszei.2018.4115">Keszei et al 2018</a>].</p><p>While predictions can sometimes be made based on groups of affected individuals or types of pathogenic variant, considerable caution must be exercised in assigning a phenotype to a young, newly diagnosed male based on genotype alone for the following reasons:</p><ul><li class="half_rhythm"><div>The phenotype of affected males in the same kindred can vary widely [<a class="bibr" href="#was.REF.keszei.2018.4115" rid="was.REF.keszei.2018.4115">Keszei et al 2018</a>].</div></li><li class="half_rhythm"><div>Splice site variants may allow production of multiple gene products, including normally spliced WASP [<a class="bibr" href="#was.REF.jin.2004.4010" rid="was.REF.jin.2004.4010">Jin et al 2004</a>].</div></li><li class="half_rhythm"><div>Reversion of an inherited pathogenic variant to a benign variant in a subpopulation of cells with improvement of clinical symptoms has been reported [<a class="bibr" href="#was.REF.xie.2015.406" rid="was.REF.xie.2015.406">Xie et al 2015</a>].</div></li><li class="half_rhythm"><div>It is likely that the clinical phenotype in <i>WAS</i>-related disorders is modified by a somatic <i>WAS</i> pathogenic variant involving the second allele [<a class="bibr" href="#was.REF.du.2006.370" rid="was.REF.du.2006.370">Du et al 2006</a>, <a class="bibr" href="#was.REF.boztug.2008.68" rid="was.REF.boztug.2008.68">Boztug et al 2008</a>], pathogenic variants in other genes (e.g., those modifying atopy), epigenetic [<a class="bibr" href="#was.REF.buchbinder.2011.773" rid="was.REF.buchbinder.2011.773">Buchbinder et al 2011</a>] and environmental factors, and/or encounters with ubiquitous or rare pathogens.</div></li></ul><p>Some studies have focused on WASP expression as a better predictor of clinical severity of a <i>WAS</i>-related disorder than the pathogenic variant alone [<a class="bibr" href="#was.REF.lemahieu.1999.54" rid="was.REF.lemahieu.1999.54">Lemahieu et al 1999</a>].</p><ul><li class="half_rhythm"><div>In one study, 74.2% of individuals who produced WASP had XLT, while 86.5% of individuals who produced no WASP had Wiskott-Aldrich syndrome [<a class="bibr" href="#was.REF.imai.2003.427" rid="was.REF.imai.2003.427">Imai et al 2003</a>]. Similarly, <a class="bibr" href="#was.REF.liu.2015.1601" rid="was.REF.liu.2015.1601">Liu et al [2015]</a> demonstrated that 75% of individuals diagnosed with XLT had detectable WASP, while the majority of individuals with Wiskott-Aldrich syndrome did not express WASP in peripheral blood mononuclear cells.</div></li><li class="half_rhythm"><div>As a group, individuals who expressed normal-sized mutated WASP were significantly less likely to develop autoimmune disease and/or malignancy than individuals who did not express WASP or who expressed only a truncated protein [<a class="bibr" href="#was.REF.jin.2004.4010" rid="was.REF.jin.2004.4010">Jin et al 2004</a>].</div></li><li class="half_rhythm"><div><a class="bibr" href="#was.REF.lutskiy.2005.1329" rid="was.REF.lutskiy.2005.1329">Lutskiy et al [2005]</a> proposed that clinical phenotype was dependent on the presence or absence of WASP, the level of protein expression, and the molecular structure of the protein; they documented good clinical correlation for five of the most common pathogenic variants in <i>WAS</i>.</div></li></ul></div><div id="was.Penetrance"><h3>Penetrance</h3><p>Penetrance is complete in males with a <i>WAS</i> pathogenic variant.</p></div><div id="was.Prevalence"><h3>Prevalence</h3><p>The estimated prevalence of <i>WAS</i>-related disorders is one to four in 1,000,000 live male births. About 1.2% of all individuals in the United States with primary immune deficiency have Wiskott-Aldrich syndrome [<a class="bibr" href="#was.REF.buchbinder.2014.55" rid="was.REF.buchbinder.2014.55">Buchbinder et al 2014</a>, <a class="bibr" href="#was.REF.quinn.2022.19" rid="was.REF.quinn.2022.19">Quinn et al 2022</a>].</p></div></div><div id="was.Genetically_Related_Allelic_Disorder"><h2 id="_was_Genetically_Related_Allelic_Disorder_">Genetically Related (Allelic) Disorders</h2><p>No phenotypes other than those discussed in this <i>GeneReview</i> are known to be associated with germline pathogenic variants in <i>WAS</i>.</p></div><div id="was.Differential_Diagnosis"><h2 id="_was_Differential_Diagnosis_">Differential Diagnosis</h2><div id="was.WiskottAldrich_Syndrome_1"><h3>Wiskott-Aldrich Syndrome</h3><p><b>Idiopathic thrombocytopenic purpura (ITP</b>) should be considered in the differential diagnosis of males presenting early in life with thrombocytopenia. In contrast to Wiskott-Aldrich syndrome, ITP is associated with increased platelet size and increased reticulated platelet count. ITP is usually transient and self-limited.</p><p>Genetic disorders of interest in the differential diagnosis Wiskott-Aldrich syndrome include those listed in <a href="/books/NBK1178/table/was.T.genetic_disorders_of_interest_in_t/?report=objectonly" target="object" rid-ob="figobwasTgeneticdisordersofinterestint">Table 3</a>.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figwasTgeneticdisordersofinterestint"><a href="/books/NBK1178/table/was.T.genetic_disorders_of_interest_in_t/?report=objectonly" target="object" title="Table 3. " class="img_link icnblk_img" rid-ob="figobwasTgeneticdisordersofinterestint"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="was.T.genetic_disorders_of_interest_in_t"><a href="/books/NBK1178/table/was.T.genetic_disorders_of_interest_in_t/?report=objectonly" target="object" rid-ob="figobwasTgeneticdisordersofinterestint">Table 3. </a></h4><p class="float-caption no_bottom_margin">Genetic Disorders of Interest in the Differential Diagnosis of Wiskott-Aldrich Syndrome </p></div></div><p>Human immunodeficiency virus (HIV) infection can also be considered in males who initially present with <i>Pneumocystis carinii</i> pneumonia. HIV infection results in gradual destruction of the immune system. Individuals infected with HIV are at risk for illness and death from opportunistic infections and neoplasms; however, persistent thrombocytopenia is rarely, if ever, seen in individuals with HIV infection.</p></div><div id="was.XLinked_Thrombocytopenia_XLT_1"><h3>X-Linked Thrombocytopenia (XLT)</h3><p>The differential diagnosis for XLT includes <a href="/books/n/gene/gata1/?report=reader"><i>GATA1</i>-related X-linked cytopenia</a>, which is characterized by thrombocytopenia and/or anemia ranging from mild to severe and one or more of the following: platelet dysfunction, mild beta-thalassemia, neutropenia, and congenital erythropoietic porphyria in males. Thrombocytopenia typically presents in infancy as a bleeding disorder with easy bruising and mucosal bleeding, such as epistaxis. Anemia ranges from minimal (mild dyserythropoiesis) to severe (hydrops fetalis requiring in utero transfusion). At the extreme end of the <i>GATA1</i>-related clinical spectrum, severe hemorrhage and/or erythrocyte transfusion dependence are lifelong; at the milder end, anemia and the risk for bleeding decrease spontaneously with age.</p></div><div id="was.XLinked_Neutropenia_XLN_1"><h3>X-Linked Neutropenia (XLN)</h3><p>The differential diagnosis for XLN is broad and includes autoimmune neutropenia and benign ethnic neutropenia in addition to several novel genetic causes of severe congenital neutropenia. For detailed reviews of congenital neutropenia, see <a class="bibr" href="#was.REF.furutani.2019.384" rid="was.REF.furutani.2019.384">Furutani et al [2019]</a> and <a class="bibr" href="#was.REF.spoor.2019.149" rid="was.REF.spoor.2019.149">Spoor et al [2019]</a>.</p></div></div><div id="was.Management"><h2 id="_was_Management_">Management</h2><p>No clinical practice guidelines for <i>WAS</i>-related disorders have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder.</p><div id="was.Evaluations_Following_Initial_Diagno"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease and needs in an individual diagnosed with a <i>WAS</i>-related disorder, the evaluations summarized in <a href="/books/NBK1178/table/was.T.wasrelated_disorders_recommended_e/?report=objectonly" target="object" rid-ob="figobwasTwasrelateddisordersrecommendede">Table 4</a> (if not performed as part of the evaluation that led to the diagnosis) are recommended.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figwasTwasrelateddisordersrecommendede"><a href="/books/NBK1178/table/was.T.wasrelated_disorders_recommended_e/?report=objectonly" target="object" title="Table 4. " class="img_link icnblk_img" rid-ob="figobwasTwasrelateddisordersrecommendede"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="was.T.wasrelated_disorders_recommended_e"><a href="/books/NBK1178/table/was.T.wasrelated_disorders_recommended_e/?report=objectonly" target="object" rid-ob="figobwasTwasrelateddisordersrecommendede">Table 4. </a></h4><p class="float-caption no_bottom_margin"><i>WAS</i>-Related Disorders: Recommended Evaluations Following Initial Diagnosis </p></div></div></div><div id="was.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><p>Treatment options vary based on the predicted disease burden in a particular individual. See <a class="bibr" href="#was.REF.buchbinder.2014.55" rid="was.REF.buchbinder.2014.55">Buchbinder et al [2014]</a> for a review of treatment options for Wiskott-Aldrich syndrome.</p><div id="was.Targeted_Therapy"><h4>Targeted Therapy</h4><p>
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<i>In GeneReviews, a targeted therapy is one that addresses the specific underlying mechanism of disease causation (regardless of whether the therapy is significantly efficacious for one or more manifestation of the genetic condition); would otherwise not be considered without knowledge of the underlying genetic cause of the condition; or could lead to a cure</i>. —ED</p><p>
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<b>Hematopoietic stem cell transplantation (HSCT)</b>
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</p><ul><li class="half_rhythm"><div class="half_rhythm"><b>Wiskott-Aldrich syndrome.</b> The only curative targeted therapy clinically available for Wiskott-Aldrich syndrome is allogeneic HSCT. It is recommended for children with absent Wiskott-Aldrich syndrome protein (WASP) expression and a pathogenic variant consistent with Wiskott-Aldrich syndrome even prior to the emergence of a severe clinical phenotype. Outcomes following HSCT are excellent, with a five-year overall survival of 91%. Age at time of transplant affects outcome; individuals younger than age five years have a significantly better overall survival. Additionally, overall survival is excellent regardless of donor type, even in cord blood recipients (90%) [<a class="bibr" href="#was.REF.burroughs.2020.2094" rid="was.REF.burroughs.2020.2094">Burroughs et al 2020</a>].</div><div class="half_rhythm">Myeloablative conditioning prior to transplantation is the most widely used approach, although busulfan-based reduced-intensity or sub-myeloblative regimens can also be used and result in donor myeloid chimerism >50%, which is essential for resolution of thrombocytopenia associated with Wiskott-Aldrich syndrome. Non-busulfan-based reduced-intensity conditioning regimens, however, are associated with increased risk of mixed chimerism and more likely to result in donor myeloid chimerism <50% or graft failure [<a class="bibr" href="#was.REF.burroughs.2020.2094" rid="was.REF.burroughs.2020.2094">Burroughs et al 2020</a>, <a class="bibr" href="#was.REF.albert.2022.2066" rid="was.REF.albert.2022.2066">Albert et al 2022</a>]. Risk of graft-vs-host disease is low regardless of donor and stem cell source [<a class="bibr" href="#was.REF.albert.2022.2066" rid="was.REF.albert.2022.2066">Albert et al 2022</a>].</div><div class="half_rhythm">Individuals with Wiskott-Aldrich syndrome who do not have a suitably matched donor but who experience life-threatening complications are candidates for gene therapy (see <a href="#was.Therapies_Under_Investigation">Therapies Under Investigation</a>).</div></li><li class="half_rhythm"><div class="half_rhythm"><b>X-linked thrombocytopenia (XLT).</b> The primary management of individuals with XLT (WAS score 1-2) remains controversial. Although long-term survival is excellent with conservative management of presenting symptoms, event-free survival is reduced by the substantial risk of severe, life-threatening, or potentially debilitating complications [<a class="bibr" href="#was.REF.albert.2010.3231" rid="was.REF.albert.2010.3231">Albert et al 2010</a>]. Serious bleeding episodes are generally restricted to the first 30 years of life. In contrast, the risk of developing autoimmune disease, malignancy, or a life-threatening infectious episode is rather constant throughout the individual's lifetime. This persistent morbidity argues for HSCT as a treatment option for such individuals, especially if a human leukocyte antigen (HLA)-identical donor is available. While a wait-and-watch approach can also be adopted, it is important to have a low threshold for referral for HSCT if disease severity progresses (e.g., development of autoimmunity) [<a class="bibr" href="#was.REF.rivers.2019b.647" rid="was.REF.rivers.2019b.647">Rivers et al 2019b</a>]. HSCT before development of significant autoimmunity-related organ damage and malignancy is highly desirable, and younger age at transplant is associated with improved long-term outcome following HSCT. However, one needs to carefully weigh the advantage of a possible cure against the acute risks and long-term consequences of this procedure (e.g., risk of secondary malignancy, infertility). Thus, use of HSCT for XLT should be determined on an individual basis.</div></li></ul></div><div id="was.Supportive_Care"><h4>Supportive Care</h4><p>Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see <a href="/books/NBK1178/table/was.T.wiskottaldrich_syndrome_and_xlinke/?report=objectonly" target="object" rid-ob="figobwasTwiskottaldrichsyndromeandxlinke">Table 5a</a> and <a href="/books/NBK1178/table/was.T.xlinked_neutropenia_treatment_of_m/?report=objectonly" target="object" rid-ob="figobwasTxlinkedneutropeniatreatmentofm">5b</a>).</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figwasTwiskottaldrichsyndromeandxlinke"><a href="/books/NBK1178/table/was.T.wiskottaldrich_syndrome_and_xlinke/?report=objectonly" target="object" title="Table 5a. " class="img_link icnblk_img" rid-ob="figobwasTwiskottaldrichsyndromeandxlinke"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="was.T.wiskottaldrich_syndrome_and_xlinke"><a href="/books/NBK1178/table/was.T.wiskottaldrich_syndrome_and_xlinke/?report=objectonly" target="object" rid-ob="figobwasTwiskottaldrichsyndromeandxlinke">Table 5a. </a></h4><p class="float-caption no_bottom_margin">Wiskott-Aldrich Syndrome and X-Linked Thrombocytopenia: Treatment of Manifestations </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figwasTxlinkedneutropeniatreatmentofm"><a href="/books/NBK1178/table/was.T.xlinked_neutropenia_treatment_of_m/?report=objectonly" target="object" title="Table 5b. " class="img_link icnblk_img" rid-ob="figobwasTxlinkedneutropeniatreatmentofm"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="was.T.xlinked_neutropenia_treatment_of_m"><a href="/books/NBK1178/table/was.T.xlinked_neutropenia_treatment_of_m/?report=objectonly" target="object" rid-ob="figobwasTxlinkedneutropeniatreatmentofm">Table 5b. </a></h4><p class="float-caption no_bottom_margin">X-Linked Neutropenia: Treatment of Manifestations </p></div></div></div></div><div id="was.Surveillance"><h3>Surveillance</h3><p>To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in <a href="/books/NBK1178/table/was.T.wasrelated_disorders_recommended_s/?report=objectonly" target="object" rid-ob="figobwasTwasrelateddisordersrecommendeds">Table 6</a> are recommended.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figwasTwasrelateddisordersrecommendeds"><a href="/books/NBK1178/table/was.T.wasrelated_disorders_recommended_s/?report=objectonly" target="object" title="Table 6. " class="img_link icnblk_img" rid-ob="figobwasTwasrelateddisordersrecommendeds"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="was.T.wasrelated_disorders_recommended_s"><a href="/books/NBK1178/table/was.T.wasrelated_disorders_recommended_s/?report=objectonly" target="object" rid-ob="figobwasTwasrelateddisordersrecommendeds">Table 6. </a></h4><p class="float-caption no_bottom_margin"><i>WAS</i>-Related Disorders: Recommended Surveillance </p></div></div></div><div id="was.AgentsCircumstances_to_Avoid"><h3>Agents/Circumstances to Avoid</h3><p>Circumcision of an at-risk newborn male should not be undertaken in the presence of thrombocytopenia.</p><p>The use of over-the-counter medications should be discussed with a physician, as some medications can interfere with platelet function.</p><p>When possible, elective surgical procedures should be deferred until after HSCT.</p></div><div id="was.Evaluation_of_Relatives_at_Risk"><h3>Evaluation of Relatives at Risk</h3><p>It is appropriate to clarify the genetic status of at-risk male relatives of an affected individual so that morbidity and mortality can be reduced by early diagnosis and treatment. Of note, evaluation of newborn at-risk males is recommended before any elective procedure such as circumcision.</p><p>Rapid screening of at-risk males may be accomplished by WASP staining using flow cytometry. Definitive testing requires molecular genetic testing for the familial <i>WAS</i> pathogenic variant.</p><p><b>For hematopoietic stem cell donation.</b> Any relative considering stem cell donation should undergo WASP flow cytometry-based testing for WASP expression and, if needed, <i>WAS</i> molecular genetic testing to clarify their genetic status so that informed risk-vs-benefit discussions for both recipient and donor can be incorporated into transplant donor-option decision making.</p><p>See <a href="#was.Related_Genetic_Counseling_Issues">Genetic Counseling</a> for issues related to testing of at-risk relatives for genetic counseling purposes.</p></div><div id="was.Therapies_Under_Investigation"><h3>Therapies Under Investigation</h3><p><b>Gene therapy.</b> Lentiviral-mediated gene therapy for Wiskott-Aldrich syndrome is feasible and can result in significant benefit for treated individuals. However, long-term observation is warranted to confirm the superior safety of lentiviral gene transfer as an alternative treatment option for Wiskott-Aldrich syndrome.</p><p>Search <a href="https://clinicaltrials.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ClinicalTrials.gov</a> in the US and <a href="https://www.clinicaltrialsregister.eu/ctr-search/search" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">EU Clinical Trials Register</a> in Europe for access to information on clinical studies for a wide range of diseases and conditions.</p></div></div><div id="was.Genetic_Counseling"><h2 id="_was_Genetic_Counseling_">Genetic Counseling</h2><p>
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<i>Genetic counseling is the process of providing individuals and families with
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information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them
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make informed medical and personal decisions. The following section deals with genetic
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risk assessment and the use of family history and genetic testing to clarify genetic
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status for family members; it is not meant to address all personal, cultural, or
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ethical issues that may arise or to substitute for consultation with a genetics
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professional</i>. —ED.</p><div id="was.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p><i>WAS</i>-related disorders are inherited in an X-linked manner.</p></div><div id="was.Risk_to_Family_Members"><h3>Risk to Family Members</h3><p>
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<b>Parents of a male proband</b>
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</p><ul><li class="half_rhythm"><div class="half_rhythm">The father of an affected male will not have a <i>WAS</i>-related disorder nor will he be hemizygous for a <i>WAS</i> pathogenic variant; therefore, he does not require further evaluation/testing.</div></li><li class="half_rhythm"><div class="half_rhythm">In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the <i>WAS</i> pathogenic variant cannot be detected in her leukocyte DNA, she most likely has gonadal mosaicism. Note: Females who are heterozygous for a <i>WAS</i> pathogenic variant rarely have significant clinical symptoms.</div></li><li class="half_rhythm"><div class="half_rhythm">If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier), the affected male may have a <i>de novo</i>
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<i>WAS</i> pathogenic variant (in which case the mother is not a carrier), or the mother may have somatic/gonadal mosaicism [<a class="bibr" href="#was.REF.arveiler.1990.906" rid="was.REF.arveiler.1990.906">Arveiler et al 1990</a>]. About one third of affected males with no previous family history of the disorder have a <i>de novo</i> pathogenic variant.</div></li><li class="half_rhythm"><div class="half_rhythm">Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.</div><div class="half_rhythm">Note: Testing of maternal leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.</div></li></ul><p><b>Sibs of a male proband.</b> The risk to sibs of a male proband depends on the genetic status of the mother.</p><ul><li class="half_rhythm"><div>If the mother of the proband has a <i>WAS</i> pathogenic variant, the chance of transmitting it in each pregnancy is 50%.</div><ul><li class="half_rhythm"><div>Males who inherit the pathogenic variant will be symptomatic. The clinical presentation of males with a <i>WAS</i> pathogenic variant can vary widely even within the same family. In some families, males in their seventh decade may have mild manifestations such as chronic thrombocytopenia, whereas other male relatives with the condition may have severe symptoms in early infancy or childhood. Long-term prognosis varies based on the disease burden in a particular individual [<a class="bibr" href="#was.REF.beel.2009.1449" rid="was.REF.beel.2009.1449">Beel & Vandenberghe 2009</a>, <a class="bibr" href="#was.REF.albert.2011.42" rid="was.REF.albert.2011.42">Albert et al 2011</a>, <a class="bibr" href="#was.REF.buchbinder.2011.773" rid="was.REF.buchbinder.2011.773">Buchbinder et al 2011</a>].</div></li><li class="half_rhythm"><div>Females who inherit the pathogenic variant will be carriers and are typically asymptomatic due to random X-chromosome inactivation that results in sufficient normal Wiskott-Aldrich syndrome protein (WASP) expression. Mild thrombocytopenia is noted in a small proportion. Heterozygous females rarely present with typical features of Wiskott-Aldrich syndrome such as severe thrombocytopenia and/or immunologic dysfunction due to severe skewed X-chromosome inactivation with expression of the mutated <i>WAS</i> allele [<a class="bibr" href="#was.REF.lutskiy.2002.2763" rid="was.REF.lutskiy.2002.2763">Lutskiy et al 2002</a>, <a class="bibr" href="#was.REF.boonyawat.2013.1150" rid="was.REF.boonyawat.2013.1150">Boonyawat et al 2013</a>, <a class="bibr" href="#was.REF.dazacajigal.2013.125" rid="was.REF.dazacajigal.2013.125">Daza-Cajigal et al 2013</a>, <a class="bibr" href="#was.REF.takimoto.2015.185" rid="was.REF.takimoto.2015.185">Takimoto et al 2015</a>, <a class="bibr" href="#was.REF.hou.2021.691524" rid="was.REF.hou.2021.691524">Hou et al 2021</a>].</div></li></ul></li><li class="half_rhythm"><div>If the proband represents a simplex case (i.e., a single occurrence in a family) and if the <i>WAS</i> pathogenic variant cannot be detected in the leukocyte DNA of the mother, sibs remain at increased risk because of the possibility of maternal gonadal mosaicism [<a class="bibr" href="#was.REF.arveiler.1990.906" rid="was.REF.arveiler.1990.906">Arveiler et al 1990</a>].</div></li></ul><p><b>Offspring of a male proband.</b> Males with a <i>WAS</i>-related disorder transmit the <i>WAS</i> pathogenic variant to:</p><ul><li class="half_rhythm"><div>All of their daughters, who will be carriers (see Clinical Description, <a href="#was.Heterozygous_Females">Heterozygous Females</a>); and</div></li><li class="half_rhythm"><div>None of their sons.</div></li></ul><p><b>Other family members.</b> The maternal aunts and maternal cousins of a male proband may be at risk of having a <i>WAS</i> pathogenic variant.</p><p>Note: Molecular genetic testing may be able to identify the family member in whom a <i>de novo</i> pathogenic variant arose, information that could help determine genetic risk status of the extended family.</p></div><div id="was.Carrier_Detection"><h3>Carrier Detection</h3><p><b>Molecular genetic testing.</b> Identification of female heterozygotes requires prior identification of the <i>WAS</i> pathogenic variant in the family.</p><p>Note: (1) Females who are heterozygous (carriers) for this X-linked disorder are typically asymptomatic (see Clinical Description, <a href="#was.Heterozygous_Females">Heterozygous Females</a>).</p><p><b>Flow cytometry.</b> In female carriers, flow cytometry has been shown to detect lower levels of WASP in monocytes but not lymphocytes (except in females with <i>WAS</i> pathogenic variants in distal exons); however, molecular genetic testing remains the gold standard for carrier detection [<a class="bibr" href="#was.REF.yamada.2000.1119" rid="was.REF.yamada.2000.1119">Yamada et al 2000</a>, <a class="bibr" href="#was.REF.basu.2024.e30972" rid="was.REF.basu.2024.e30972">Basu et al 2024</a>].</p></div><div id="was.Related_Genetic_Counseling_Issues"><h3>Related Genetic Counseling Issues</h3><p>See Management, <a href="#was.Evaluation_of_Relatives_at_Risk">Evaluation of Relatives at Risk</a> for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.</p><p>
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<b>Family planning</b>
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</p><ul><li class="half_rhythm"><div>The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.</div></li><li class="half_rhythm"><div>It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.</div></li></ul><p>Note: There is no evidence that cesarean section reduces the risk of morbidity and mortality in males with Wiskott-Aldrich syndrome.</p></div><div id="was.Prenatal_Testing_and_Preimplantation"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p>Once the <i>WAS</i> pathogenic variant has been identified in a family member, prenatal and preimplantation genetic testing are possible.</p><p>Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.</p></div></div><div id="was.Resources"><h2 id="_was_Resources_">Resources</h2><p>
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<i>GeneReviews staff has selected the following disease-specific and/or umbrella
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support organizations and/or registries for the benefit of individuals with this disorder
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and their families. GeneReviews is not responsible for the information provided by other
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organizations. For information on selection criteria, click <a href="/books/n/gene/app4/?report=reader">here</a>.</i></p>
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<ul><li class="half_rhythm"><div>
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<b>Wiskott-Aldrich Foundation</b>
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</div><div><b>Phone:</b> 919-641-7134 </div><div><b>Email:</b> info@wiskott.org</div><div>
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<a href="https://www.wiskott.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">wiskott.org</a>
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</div></li><li class="half_rhythm"><div>
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<b>ImmUnity Canada</b>
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</div><div>Canada</div><div><b>Phone:</b> 250-381-7134; 877 -607­-2476</div><div><b>Email:</b> info@immunitycanada.org</div><div>
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<a href="https://immunitycanada.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">immunitycanada.org</a>
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</div></li><li class="half_rhythm"><div>
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<b>Jeffrey Modell Foundation/National Primary Immunodeficiency Resource Center</b>
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</div><div><b>Email:</b> info@jmfworld.org</div><div>
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<a href="http://www.info4pi.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">info4pi.org</a>
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</div></li><li class="half_rhythm"><div>
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<b>European Society for Immunodeficiencies (ESID) Registry</b>
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</div><div><b>Email:</b> esid-registry@uniklinik-freiburg.de</div><div>
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<a href="https://esid.org/Working-Parties/Registry-Working-Party/ESID-Registry" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ESID Registry</a>
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</div></li><li class="half_rhythm"><div>
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<b>National Cancer Institute Inherited Bone Marrow Failure Syndromes (IBMFS) Cohort Registry</b>
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</div><div><b>Phone:</b> 800-518-8474</div><div><b>Email:</b> NCI.IBMFS@westat.com</div><div>
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<a href="https://www.marrowfailure.cancer.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">marrowfailure.cancer.gov</a>
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</div></li><li class="half_rhythm"><div>
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<b>United States Immunodeficiency Network (USIDNET) Registry</b>
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</div><div><b>Email:</b> contact@usidnet.org</div><div>
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<a href="https://usidnet.org/about-usidnet/enrolling-institutions/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Enrolling Institutions</a>
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</div></li></ul>
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</div><div id="was.Molecular_Genetics"><h2 id="_was_Molecular_Genetics_">Molecular Genetics</h2><p><i>Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —</i>ED.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figwasmolgenTA"><a href="/books/NBK1178/table/was.molgen.TA/?report=objectonly" target="object" title="Table A." class="img_link icnblk_img" rid-ob="figobwasmolgenTA"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="was.molgen.TA"><a href="/books/NBK1178/table/was.molgen.TA/?report=objectonly" target="object" rid-ob="figobwasmolgenTA">Table A.</a></h4><p class="float-caption no_bottom_margin">WAS-Related Disorders: Genes and Databases </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figwasmolgenTB"><a href="/books/NBK1178/table/was.molgen.TB/?report=objectonly" target="object" title="Table B." class="img_link icnblk_img" rid-ob="figobwasmolgenTB"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="was.molgen.TB"><a href="/books/NBK1178/table/was.molgen.TB/?report=objectonly" target="object" rid-ob="figobwasmolgenTB">Table B.</a></h4><p class="float-caption no_bottom_margin">OMIM Entries for WAS-Related Disorders (View All in OMIM) </p></div></div><div id="was.Molecular_Pathogenesis"><h3>Molecular Pathogenesis</h3><p><i>WAS</i> encodes actin nucleation-promoting factor WAS (also called Wiskott-Aldrich syndrome protein, or WASP), which is expressed exclusively in hematopoietic cells and has a role in signal transduction [<a class="bibr" href="#was.REF.cory.1996.3791" rid="was.REF.cory.1996.3791">Cory et al 1996</a>, <a class="bibr" href="#was.REF.snapper.1999.905" rid="was.REF.snapper.1999.905">Snapper & Rosen 1999</a>] and actin cytoskeleton organization in response to external stimuli in white blood cells [<a class="bibr" href="#was.REF.kolluri.1996.5615" rid="was.REF.kolluri.1996.5615">Kolluri et al 1996</a>, <a class="bibr" href="#was.REF.bompard.2004.957" rid="was.REF.bompard.2004.957">Bompard & Caron 2004</a>, <a class="bibr" href="#was.REF.stradal.2004.303" rid="was.REF.stradal.2004.303">Stradal et al 2004</a>]. WASP activity is regulated by interaction with activated guanosine triphosphate (GTP)-loaded Cdc42 [<a class="bibr" href="#was.REF.hemsath.2005.313" rid="was.REF.hemsath.2005.313">Hemsath et al 2005</a>] and post-translational modification (e.g., phosphorylation) [<a class="bibr" href="#was.REF.badour.2004.99" rid="was.REF.badour.2004.99">Badour et al 2004</a>]. In normal natural killer (NK) cells, WASP is expressed and localized to the activating immunologic synapse with filamentous actin, which presumably plays an important role in NK cell cytolytic function [<a class="bibr" href="#was.REF.orange.2002.11351" rid="was.REF.orange.2002.11351">Orange et al 2002</a>].</p><p>Because the actin cytoskeleton plays an important role in cell adhesion and migration, T and B lymphocytes, neutrophils, macrophages, and dendritic cells of males with <i>WAS</i>-related disorders exhibit defects in migration, anchoring, and localization [<a class="bibr" href="#was.REF.kolluri.1996.5615" rid="was.REF.kolluri.1996.5615">Kolluri et al 1996</a>, <a class="bibr" href="#was.REF.de_noronha.2005.1590" rid="was.REF.de_noronha.2005.1590">de Noronha et al 2005</a>, <a class="bibr" href="#was.REF.snapper.2005.993" rid="was.REF.snapper.2005.993">Snapper et al 2005</a>, <a class="bibr" href="#was.REF.gallego.2006.221" rid="was.REF.gallego.2006.221">Gallego et al 2006</a>].</p><p><b>Mechanism of disease causation</b>. Wiskott-Aldrich syndrome and XLT are caused by loss-of-function variants. XLN is caused by gain-of-function variants in the GTPase binding domain.</p></div></div><div id="was.Chapter_Notes"><h2 id="_was_Chapter_Notes_">Chapter Notes</h2><div id="was.Author_Notes"><h3>Author Notes</h3><p><b>Miao Sun, PhD.</b> Dr Sun's clinical work mainly focuses on exome and genome sequencing for rare germline-related conditions. Dr Sun is interested in immunodeficiency, metabolic disorders, and neurodevelopmental disease. Email: <a href="mailto:dev@null" data-email="ude.csu.alhc@nusoaim" class="oemail">ude.csu.alhc@nusoaim</a></p></div><div id="was.Author_History"><h3>Author History</h3><p>Lucas Bronicki, PhD; University of Cincinnati College of Medicine (2016-2024)<br />Sharat Chandra, MD (2016-present)<br />Shanmuganathan Chandrakasan, MD (2024-present)<br />Alexandra H Filipovich, MD; Cincinnati Children's Hospital Medical Center (2004-2016)<br />Judith Johnson, MS; Cincinnati Children's Hospital Medical Center (2004-2016)<br />Chinmayee B Nagaraj, MS (2016-present)<br />Miao Sun, PhD (2024-present)<br />Kejian Zhang, MD, MBA (2004-present)</p></div><div id="was.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>15 August 2024 (sw) Comprehensive update posted live</div></li><li class="half_rhythm"><div>22 September 2016 (sw) Comprehensive update posted live</div></li><li class="half_rhythm"><div>20 March 2014 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>28 July 2011 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>27 April 2007 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>30 September 2004 (me) Review posted live</div></li><li class="half_rhythm"><div>1 October 2003 (jj) Original submission</div></li></ul></div></div><div id="was.References"><h2 id="_was_References_">References</h2><div id="was.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><p><div class="bk_ref" id="was.REF.albert.2010.3231">Albert
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MH, Bittner
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TC, Nonoyama
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S, Notarangelo
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LD, Burns
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S, Imai
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K, Espanol
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T, Fasth
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A, Pellier
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I, Strauss
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G, Morio
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T, Gathmann
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B, Noordzij
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JG, Fillat
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C, Hoenig
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M, Nathrath
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M, Meindl
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A, Pagel
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P, Wintergerst
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U, Fischer
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A, Thrasher
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AJ, Belohradsky
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BH, Ochs
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HD. X-linked thrombocytopenia (XLT) due to WAS mutations: clinical characteristics, long-term outcome, and treatment options.
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Blood.
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2010;115:3231–8.
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[<a href="https://pubmed.ncbi.nlm.nih.gov/20173115" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20173115</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="was.REF.albert.2011.42">Albert
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MH, Notarangelo
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LD, Ochs
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HD. Clinical spectrum, pathophysiology and treatment of the Wiskott-Aldrich syndrome.
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Curr Opin Hematol.
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2011;18:42–8.
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[<a href="https://pubmed.ncbi.nlm.nih.gov/21076297" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21076297</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="was.REF.albert.2022.2066">Albert
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MH, Slatter
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MA, Gennery
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AR, Gungor
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T, Bakunina
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K, Markovitch
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B, Hazelaar
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S, Sirait
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T, Courteille
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V, Aiuti
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A, Aleinikova
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OV, Balashov
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D, Bernardo
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ME, Bodova
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I, Bruno
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B, Cavazzana
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M, Chiesa
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R, Fischer
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A, Hauck
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F, Ifversen
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M, Kałwak
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K, Klein
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C, Kulagin
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A, Kupesiz
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A, Kuskonmaz
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B, Lindemans
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CA, Locatelli
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F, Lum
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SH, Maschan
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A, Meisel
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R, Moshous
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D, Porta
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F, Sauer
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MG, Sedlacek
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P, Schulz
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A, Suarez
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F, Vallée
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TC, Winiarski
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JH, Zecca
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M, Neven
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B, Veys
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P, Lankester
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AC. Hematopoietic stem cell transplantation for Wiskott-Aldrich syndrome: an EBMT Inborn Errors Working Party analysis.
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Blood.
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2022;139:2066-79.
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[<a href="https://pubmed.ncbi.nlm.nih.gov/35100336" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 35100336</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="was.REF.arveiler.1990.906">Arveiler
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B, de Saint-Basile
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K, Sakiyama
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Y. Determination of carrier status for the Wiskott-Aldrich syndrome by flow cytometric analysis of Wiskott-Aldrich syndrome protein expression in peripheral blood mononuclear cells.
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J Immunol.
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2000;165:1119-22.
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[<a href="https://pubmed.ncbi.nlm.nih.gov/10878391" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10878391</span></a>]</div></p></li></ul></div></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK1178_pubdet_">Publication Details</h2><h3>Author Information and Affiliations</h3><div class="contrib half_rhythm"><span itemprop="author">Sharat Chandra</span>, MD<div class="affiliation small">Associate Professor, Division of Bone Marrow Transplantation and Immune Deficiency<br />Cincinnati Children's Hospital Medical Center;<br />University of Cincinnati College of Medicine<br />Cincinnati, Ohio<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="gro.cmhcc@ardnahc.tarahs" class="oemail">gro.cmhcc@ardnahc.tarahs</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Chinmayee B Nagaraj</span>, MS<div class="affiliation small">Genetic Counselor, Division of Human Genetics<br />Cincinnati Children's Hospital Medical Center<br />Cincinnati, Ohio<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="gro.cmhcc@oaramihb.eeyamnihc" class="oemail">gro.cmhcc@oaramihb.eeyamnihc</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Miao Sun</span>, PhD<div class="affiliation small">Assistant Professor, Clinical Pathology<br />Division of Genomic Medicine<br />Department of Pathology and Laboratory Medicine<br />Children's Hospital Los Angeles;<br />Keck School of Medicine of USC<br />Los Angeles, California<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.csu.alhc@nusoaim" class="oemail">ude.csu.alhc@nusoaim</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Shanmuganathan Chandrakasan</span>, MD<div class="affiliation small">Associate Professor and Director<br />Immune dysregulation / Immunohematology and Immune Defects Transplant Programs<br />Aflac Cancer and Blood Disorders Center<br />Children's Healthcare of Atlanta;<br />Emory University School of Medicine<br />Atlanta, Georgia<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.yrome@13nahcs" class="oemail">ude.yrome@13nahcs</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Kejian Zhang</span>, MD, MBA<div class="affiliation small">GoBroad Healthcare Group<br />GoBroad Hospital<br />Beijing, China<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="moc.liamg@7102gnahz.naijek" class="oemail">moc.liamg@7102gnahz.naijek</a></div></div></div><h3>Publication History</h3><p class="small">Initial Posting: <span itemprop="datePublished">September 30, 2004</span>; Last Update: <span itemprop="dateModified">August 15, 2024</span>.</p><h3>Copyright</h3><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright</a> © 1993-2025, University of Washington, Seattle. GeneReviews is
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a registered trademark of the University of Washington, Seattle. All rights
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reserved.<p class="small">GeneReviews® chapters are owned by the University of Washington. Permission is
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Washington) are included with each copy; (ii) a link to the original material is provided
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whenever the material is published elsewhere on the Web; and (iii) reproducers,
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distributors, and/or translators comply with the <a href="https://www.ncbi.nlm.nih.gov/books/n/gene/GRcopyright_permiss/" ref="pagearea=meta&targetsite=external&targetcat=link&targettype=uri">GeneReviews® Copyright Notice and Usage
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Disclaimer</a>. No further modifications are allowed. For clarity, excerpts
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use.</p><p class="small">For more information, see the <a href="https://www.ncbi.nlm.nih.gov/books/n/gene/GRcopyright_permiss/" ref="pagearea=meta&targetsite=external&targetcat=link&targettype=uri">GeneReviews® Copyright Notice and Usage
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Disclaimer</a>.</p><p class="small">For questions regarding permissions or whether a specified use is allowed,
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contact: <a href="mailto:dev@null" data-email="ude.wu@tssamda" class="oemail">ude.wu@tssamda</a>.</p></div></div><h3>Publisher</h3><p><a href="http://www.washington.edu" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">University of Washington, Seattle</a>, Seattle (WA)</p><h3>NLM Citation</h3><p>Chandra S, Nagaraj CB, Sun M, et al. WAS-Related Disorders. 2004 Sep 30 [Updated 2024 Aug 15]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. <span class="bk_cite_avail"></span></p></div><div class="small-screen-prev"><a href="/books/n/gene/wars2-def/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M75,30 c-80,60 -80,0 0,60 c-30,-60 -30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Prev</text></svg></a></div><div class="small-screen-next"><a href="/books/n/gene/wdr26-id/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M25,30c80,60 80,0 0,60 c30,-60 30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Next</text></svg></a></div></article><article data-type="table-wrap" id="figobwasTc"><div id="was.Tc" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1178/table/was.Tc/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__was.Tc_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_was.Tc_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>WAS</i>-Related Disorders: Included Phenotypes <sup>1</sup></th></tr></thead><tbody><tr><td headers="hd_h_was.Tc_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Wiskott-Aldrich syndrome</div></li><li class="half_rhythm"><div>X-linked thrombocytopenia (XLT)</div></li><li class="half_rhythm"><div>X-linked neutropenia (XLN)</div></li></ul>
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</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="was.TF.c.1"><p class="no_margin">For other genetic causes of these phenotypes see <a href="#was.Differential_Diagnosis">Differential Diagnosis</a>.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobwasTmoleculargenetictestingusedin"><div id="was.T.molecular_genetic_testing_used_in" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Molecular Genetic Testing Used in <i>WAS</i>-Related Disorders</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1178/table/was.T.molecular_genetic_testing_used_in/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__was.T.molecular_genetic_testing_used_in_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_was.T.molecular_genetic_testing_used_in_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene <sup>1</sup></th><th id="hd_h_was.T.molecular_genetic_testing_used_in_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Method</th><th id="hd_h_was.T.molecular_genetic_testing_used_in_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Proportion of Pathogenic Variants <sup>2</sup> Identified by Method</th></tr></thead><tbody><tr><td headers="hd_h_was.T.molecular_genetic_testing_used_in_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>WAS</i>
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</td><td headers="hd_h_was.T.molecular_genetic_testing_used_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Sequence analysis <sup>3</sup></td><td headers="hd_h_was.T.molecular_genetic_testing_used_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~95% <sup>4</sup></td></tr><tr><td headers="hd_h_was.T.molecular_genetic_testing_used_in_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Gene-targeted deletion/duplication analysis <sup>5</sup></td><td headers="hd_h_was.T.molecular_genetic_testing_used_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~5% <sup>4</sup></td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="was.TF.1.1"><p class="no_margin">See <a href="/books/NBK1178/?report=reader#was.molgen.TA">Table A. Genes and Databases</a> for chromosome locus and protein.</p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="was.TF.1.2"><p class="no_margin">See <a href="#was.Molecular_Genetics">Molecular Genetics</a> for information on variants detected in this gene.</p></div></dd></dl><dl class="bkr_refwrap"><dt>3. </dt><dd><div id="was.TF.1.3"><p class="no_margin">Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click <a href="/books/n/gene/app2/?report=reader">here</a>.</p></div></dd></dl><dl class="bkr_refwrap"><dt>4. </dt><dd><div id="was.TF.1.4"><p class="no_margin">Data derived from the subscription-based professional view of Human Gene Mutation Database [<a class="bibr" href="#was.REF.stenson.2020.1197" rid="was.REF.stenson.2020.1197">Stenson et al 2020</a>]</p></div></dd></dl><dl class="bkr_refwrap"><dt>5. </dt><dd><div id="was.TF.1.5"><p class="no_margin">Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobwasTwasrelateddisordersclinicalscor"><div id="was.T.wasrelated_disorders_clinical_scor" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p><i>WAS</i>-Related Disorders: Clinical Scoring System</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1178/table/was.T.wasrelated_disorders_clinical_scor/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__was.T.wasrelated_disorders_clinical_scor_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_1_1" colspan="5" scope="colgroup" rowspan="1" style="text-align:center;vertical-align:middle;">Feature</th><th id="hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_1_2" rowspan="2" scope="col" colspan="1" headers="hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_1_2" style="text-align:left;vertical-align:middle;">Score</th><th id="hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_1_3" rowspan="2" scope="col" colspan="1" headers="hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_1_3" style="text-align:left;vertical-align:middle;">Phenotype</th></tr><tr><th headers="hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_1_1" id="hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_2_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Thrombocytopenia</th><th headers="hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_1_1" id="hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_2_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Eczema</th><th headers="hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_1_1" id="hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_2_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Immunodeficiency</th><th headers="hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_1_1" id="hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_2_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Autoimmune disorders</th><th headers="hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_1_1" id="hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_2_5" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Malignancy</th></tr></thead><tbody><tr><td headers="hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_1_1 hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_2_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Absent</td><td headers="hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_1_1 hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Absent</td><td headers="hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_1_1 hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Absent</td><td headers="hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_1_1 hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Absent</td><td headers="hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_1_1 hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_2_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Absent</td><td headers="hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0</td><td headers="hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">XLN / myelodysplasia</td></tr><tr><td headers="hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_1_1 hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_2_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Present</td><td headers="hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_1_1 hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Absent</td><td headers="hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_1_1 hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Absent</td><td headers="hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_1_1 hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Absent</td><td headers="hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_1_1 hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_2_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Absent</td><td headers="hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">1</td><td headers="hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_1_3" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">XLT</td></tr><tr><td headers="hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_1_1 hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_2_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Present</td><td headers="hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_1_1 hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Mild or transient</td><td headers="hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_1_1 hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Infrequent infections</td><td headers="hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_1_1 hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Absent</td><td headers="hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_1_1 hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_2_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Absent</td><td headers="hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">2</td></tr><tr><td headers="hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_1_1 hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_2_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Present</td><td headers="hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_1_1 hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Persistent but responsive</td><td headers="hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_1_1 hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Recurrent infections</td><td headers="hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_1_1 hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Absent</td><td headers="hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_1_1 hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_2_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Absent</td><td headers="hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">3</td><td headers="hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_1_3" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">Wiskott-Aldrich syndrome</td></tr><tr><td headers="hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_1_1 hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_2_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Present</td><td headers="hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_1_1 hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Severe, not controlled</td><td headers="hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_1_1 hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Severe infections</td><td headers="hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_1_1 hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Absent</td><td headers="hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_1_1 hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_2_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Absent</td><td headers="hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">4</td></tr><tr><td headers="hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_1_1 hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_2_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Present</td><td headers="hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_1_1 hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Any</td><td headers="hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_1_1 hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Any</td><td headers="hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_1_1 hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Present</td><td headers="hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_1_1 hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_2_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Present</td><td headers="hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">5</td><td headers="hd_h_was.T.wasrelated_disorders_clinical_scor_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">XLT / Wiskott-Aldrich syndrome w/autoimmunity &/or malignancy</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">XLN = X-linked neutropenia; XLT = X-linked thrombocytopenia</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobwasTgeneticdisordersofinterestint"><div id="was.T.genetic_disorders_of_interest_in_t" class="table"><h3><span class="label">Table 3. </span></h3><div class="caption"><p>Genetic Disorders of Interest in the Differential Diagnosis of Wiskott-Aldrich Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1178/table/was.T.genetic_disorders_of_interest_in_t/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__was.T.genetic_disorders_of_interest_in_t_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_was.T.genetic_disorders_of_interest_in_t_1_1_1_1" rowspan="2" scope="col" colspan="1" headers="hd_h_was.T.genetic_disorders_of_interest_in_t_1_1_1_1" style="text-align:left;vertical-align:middle;">Gene</th><th id="hd_h_was.T.genetic_disorders_of_interest_in_t_1_1_1_2" rowspan="2" scope="col" colspan="1" headers="hd_h_was.T.genetic_disorders_of_interest_in_t_1_1_1_2" style="text-align:left;vertical-align:middle;">Disorder</th><th id="hd_h_was.T.genetic_disorders_of_interest_in_t_1_1_1_3" rowspan="2" scope="col" colspan="1" headers="hd_h_was.T.genetic_disorders_of_interest_in_t_1_1_1_3" style="text-align:left;vertical-align:middle;">MOI</th><th id="hd_h_was.T.genetic_disorders_of_interest_in_t_1_1_1_4" colspan="2" scope="colgroup" rowspan="1" style="text-align:center;vertical-align:middle;">Features of Disorder</th><th id="hd_h_was.T.genetic_disorders_of_interest_in_t_1_1_1_5" rowspan="2" scope="col" colspan="1" headers="hd_h_was.T.genetic_disorders_of_interest_in_t_1_1_1_5" style="text-align:left;vertical-align:middle;">Comment</th></tr><tr><th headers="hd_h_was.T.genetic_disorders_of_interest_in_t_1_1_1_4" id="hd_h_was.T.genetic_disorders_of_interest_in_t_1_1_2_1" colspan="1" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Overlapping w/Wiskott-Aldrich syndrome</th><th headers="hd_h_was.T.genetic_disorders_of_interest_in_t_1_1_1_4" id="hd_h_was.T.genetic_disorders_of_interest_in_t_1_1_2_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Distinguishing from Wiskott-Aldrich syndrome</th></tr></thead><tbody><tr><td headers="hd_h_was.T.genetic_disorders_of_interest_in_t_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>WIPF1</i>
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</td><td headers="hd_h_was.T.genetic_disorders_of_interest_in_t_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Wiskott-Aldrich syndrome 2 (OMIM <a href="https://omim.org/entry/614493" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">614493</a>)</td><td headers="hd_h_was.T.genetic_disorders_of_interest_in_t_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_was.T.genetic_disorders_of_interest_in_t_1_1_1_4 hd_h_was.T.genetic_disorders_of_interest_in_t_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Recurrent infections, eczema, & thrombocytopenia</div></li><li class="half_rhythm"><div>Low numbers of B & T cells, defective T-cell proliferation & chemotaxis, low NK cell function, & abnormal WASP</div></li></ul>
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</td><td headers="hd_h_was.T.genetic_disorders_of_interest_in_t_1_1_1_4 hd_h_was.T.genetic_disorders_of_interest_in_t_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Normal platelet volumes</td><td headers="hd_h_was.T.genetic_disorders_of_interest_in_t_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>WIPF1</i> molecular genetic testing should be considered in symptomatic males (esp those w/normal platelet volumes or in whom sequence analysis of <i>WAS</i> did not identify a pathogenic variant) & in symptomatic females.</td></tr><tr><td headers="hd_h_was.T.genetic_disorders_of_interest_in_t_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/ada/?report=reader"><i>ADA</i></a><br /><i>AK2</i><br /><i>CD247</i> (<i>CD3Z</i>)<br /><i>CD3D</i><br /><i>CD3E</i><br /><i>CORO1A</i><br /><i>DCLRE1C</i><br /><i>IL7R PTPRC</i><br /><i>JAK3</i><br /><i>LAT</i><br /><i>LCP2</i><br /><i>LIG4</i><br /><i>NHEJ1</i><br /><i>PRKDC</i><br /><i>RAG1</i><br /><i>RAG2</i></td><td headers="hd_h_was.T.genetic_disorders_of_interest_in_t_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR severe combined immunodeficiency <sup>1</sup></td><td headers="hd_h_was.T.genetic_disorders_of_interest_in_t_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_was.T.genetic_disorders_of_interest_in_t_1_1_1_4 hd_h_was.T.genetic_disorders_of_interest_in_t_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Recurrent infection, T- & B-cell dysfunction, & T-cell lymphopenia</td><td headers="hd_h_was.T.genetic_disorders_of_interest_in_t_1_1_1_4 hd_h_was.T.genetic_disorders_of_interest_in_t_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Variable other clinical features <sup>1</sup></td><td headers="hd_h_was.T.genetic_disorders_of_interest_in_t_1_1_1_5" rowspan="3" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Consider In males who initially present w/<i>Pneumocystis carinii</i> pneumonia.</div></li><li class="half_rhythm"><div>Note: Persistent thrombocytopenia is rarely, if ever, seen in these conditions.</div></li></ul>
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</td></tr><tr><td headers="hd_h_was.T.genetic_disorders_of_interest_in_t_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>CD40L</i>
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</td><td headers="hd_h_was.T.genetic_disorders_of_interest_in_t_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/xlhi/?report=reader">X-linked hyper IgM syndrome</a>
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</td><td headers="hd_h_was.T.genetic_disorders_of_interest_in_t_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">XL</td><td headers="hd_h_was.T.genetic_disorders_of_interest_in_t_1_1_1_4 hd_h_was.T.genetic_disorders_of_interest_in_t_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Recurrent infections, neutropenia, thrombocytopenia, & hemolytic anemia</div></li><li class="half_rhythm"><div>Dysfunction of B cells & defective T-cell activation (normal to low T-cell counts)</div></li><li class="half_rhythm"><div>Risk for lymphomas & other malignancies</div></li></ul>
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</td><td headers="hd_h_was.T.genetic_disorders_of_interest_in_t_1_1_1_4 hd_h_was.T.genetic_disorders_of_interest_in_t_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>IgM normal or high</div></li><li class="half_rhythm"><div>Serum IgG, IgA, & IgE severely deficient</div></li><li class="half_rhythm"><div>Gastrointestinal complications & neurologic deterioration</div></li></ul>
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</td></tr><tr><td headers="hd_h_was.T.genetic_disorders_of_interest_in_t_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>IL2RG</i>
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</td><td headers="hd_h_was.T.genetic_disorders_of_interest_in_t_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/x-scid/?report=reader">X-linked severe combined immunodeficiency</a> (X-SCID)</td><td headers="hd_h_was.T.genetic_disorders_of_interest_in_t_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">XL</td><td headers="hd_h_was.T.genetic_disorders_of_interest_in_t_1_1_1_4 hd_h_was.T.genetic_disorders_of_interest_in_t_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Severe & persistent infections, diarrhea, & poor growth</div></li><li class="half_rhythm"><div>T-B+NK-, nonfunctional B lymphocytes, & lymphocytopenia</div></li></ul>
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</td><td headers="hd_h_was.T.genetic_disorders_of_interest_in_t_1_1_1_4 hd_h_was.T.genetic_disorders_of_interest_in_t_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Agammaglobulinemia (gamma chain deficiency), atrophy of thymus</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">AR = autosomal recessive; Ig = immunoglobulin; MOI = mode of inheritance; T-B+NK- = low numbers of T & natural killer cells, normal number of B cells; WASP = Wiskott-Aldrich syndrome protein; XL = X-linked</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="was.TF.3.1"><p class="no_margin">See <a class="bibr" href="#was.REF.tangye.2022.1473" rid="was.REF.tangye.2022.1473">Tangye et al [2022]</a></p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobwasTwasrelateddisordersrecommendede"><div id="was.T.wasrelated_disorders_recommended_e" class="table"><h3><span class="label">Table 4. </span></h3><div class="caption"><p><i>WAS</i>-Related Disorders: Recommended Evaluations Following Initial Diagnosis</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1178/table/was.T.wasrelated_disorders_recommended_e/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__was.T.wasrelated_disorders_recommended_e_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_was.T.wasrelated_disorders_recommended_e_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_was.T.wasrelated_disorders_recommended_e_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_was.T.wasrelated_disorders_recommended_e_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment</th></tr></thead><tbody><tr><td headers="hd_h_was.T.wasrelated_disorders_recommended_e_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Thrombocytopenia</b>
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</td><td headers="hd_h_was.T.wasrelated_disorders_recommended_e_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Platelet count & size</div></li><li class="half_rhythm"><div>Assessment for complications assoc w/↑ bleeding</div></li><li class="half_rhythm"><div>Referral to hematologist for periodic CBCs to monitor platelet counts & assess for anemia assoc w/bleeding</div></li></ul>
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</td><td headers="hd_h_was.T.wasrelated_disorders_recommended_e_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Occasionally, mild-to-moderate thrombocytopenia can present later in childhood, mimicking ITP but w/o response to oral steroids.</td></tr><tr><td headers="hd_h_was.T.wasrelated_disorders_recommended_e_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Eczema</b>
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</td><td headers="hd_h_was.T.wasrelated_disorders_recommended_e_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Skin should be examined for eczema.</td><td headers="hd_h_was.T.wasrelated_disorders_recommended_e_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Eczema is a variable feature.</td></tr><tr><td headers="hd_h_was.T.wasrelated_disorders_recommended_e_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Immunodeficiency</b>
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</td><td headers="hd_h_was.T.wasrelated_disorders_recommended_e_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Referral to immunologist for assessment of immunodeficiency:</td><td headers="hd_h_was.T.wasrelated_disorders_recommended_e_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Recurrent infections are a variable feature.</td></tr><tr><td headers="hd_h_was.T.wasrelated_disorders_recommended_e_1_1_1_2" colspan="1" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>T-cell subsets</div></li><li class="half_rhythm"><div>Ig levels</div></li><li class="half_rhythm"><div>Vaccine titers</div></li><li class="half_rhythm"><div>WASP expression</div></li></ul>
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</td><td headers="hd_h_was.T.wasrelated_disorders_recommended_e_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_was.T.wasrelated_disorders_recommended_e_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Autoimmune disorders</b>
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</td><td headers="hd_h_was.T.wasrelated_disorders_recommended_e_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Clinical assessment for autoimmune dysfunction</td><td headers="hd_h_was.T.wasrelated_disorders_recommended_e_1_1_1_3" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">Rarely the presenting manifestation but can complicate disease course.</td></tr><tr><td headers="hd_h_was.T.wasrelated_disorders_recommended_e_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Malignancies</b>
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</td><td headers="hd_h_was.T.wasrelated_disorders_recommended_e_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Clinical assessment for manifestations of lymphoma</td></tr><tr><td headers="hd_h_was.T.wasrelated_disorders_recommended_e_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Genetic counseling</b>
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</td><td headers="hd_h_was.T.wasrelated_disorders_recommended_e_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By genetics professionals <sup>1</sup></td><td headers="hd_h_was.T.wasrelated_disorders_recommended_e_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To obtain a pedigree & inform affected persons & their families re nature, MOI, & implications of <i>WAS</i>-related disorders to facilitate medical & personal decision making</td></tr><tr><td headers="hd_h_was.T.wasrelated_disorders_recommended_e_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Family support</b>
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<br />
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<b>& resources</b>
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</td><td headers="hd_h_was.T.wasrelated_disorders_recommended_e_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By clinicians, wider care team, & family support organizations</td><td headers="hd_h_was.T.wasrelated_disorders_recommended_e_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assessment of family & social structure to determine need for:
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<ul><li class="half_rhythm"><div>Community or <a href="#was.Resources">online resources</a> such as <a href="https://www.p2pusa.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Parent to Parent</a></div></li><li class="half_rhythm"><div>Social work involvement for parental support</div></li><li class="half_rhythm"><div>Home nursing referral</div></li></ul>
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</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">CBC = complete blood count; Ig = immunoglobulin; ITP = idiopathic thrombocytopenic purpura; MOI = mode of inheritance; WASP = Wiskott-Aldrich syndrome protein</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="was.TF.4.1"><p class="no_margin">Medical geneticist, certified genetic counselor, certified advanced genetic nurse</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobwasTwiskottaldrichsyndromeandxlinke"><div id="was.T.wiskottaldrich_syndrome_and_xlinke" class="table"><h3><span class="label">Table 5a. </span></h3><div class="caption"><p>Wiskott-Aldrich Syndrome and X-Linked Thrombocytopenia: Treatment of Manifestations</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1178/table/was.T.wiskottaldrich_syndrome_and_xlinke/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__was.T.wiskottaldrich_syndrome_and_xlinke_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_was.T.wiskottaldrich_syndrome_and_xlinke_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Manifestation/Concern</th><th id="hd_h_was.T.wiskottaldrich_syndrome_and_xlinke_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment</th><th id="hd_h_was.T.wiskottaldrich_syndrome_and_xlinke_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Considerations/Other</th></tr></thead><tbody><tr><td headers="hd_h_was.T.wiskottaldrich_syndrome_and_xlinke_1_1_1_1" rowspan="3" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Thrombocytopenia</b>
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</td><td headers="hd_h_was.T.wiskottaldrich_syndrome_and_xlinke_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>The mainstay of thrombocytopenia mgmt in Wiskott-Aldrich syndrome is early HSCT (see <a href="#was.Targeted_Therapy">Targeted Therapy</a>).</div></li><li class="half_rhythm"><div>Platelet transfusions should be administered judiciously (e.g., for significant bleeding & surgical procedures).</div></li></ul>
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</td><td headers="hd_h_was.T.wiskottaldrich_syndrome_and_xlinke_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_was.T.wiskottaldrich_syndrome_and_xlinke_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">For autoimmune thrombocytopenia:
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<ul><li class="half_rhythm"><div>IVIG & immune modulation w/steroids as first-line therapy</div></li><li class="half_rhythm"><div>Rituximab as second-line therapy</div></li></ul>
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</td><td headers="hd_h_was.T.wiskottaldrich_syndrome_and_xlinke_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Autoimmune thrombocytopenia can occur in addition to baseline thrombocytopenia & can lead to severe bleeding.</td></tr><tr><td headers="hd_h_was.T.wiskottaldrich_syndrome_and_xlinke_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Splenectomy may be lifesaving in persons refractory to treatment & w/severe bleeding.</td><td headers="hd_h_was.T.wiskottaldrich_syndrome_and_xlinke_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Splenectomy can also be considered for mgmt of XLT-related thrombocytopenia.</div></li><li class="half_rhythm"><div>Males who have had splenectomy must take antibiotics routinely for the rest of their lives because of ↑ risk for overwhelming infection.</div></li></ul>
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</td></tr><tr><td headers="hd_h_was.T.wiskottaldrich_syndrome_and_xlinke_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Eczema</b>
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</td><td headers="hd_h_was.T.wiskottaldrich_syndrome_and_xlinke_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Topical steroids</div></li><li class="half_rhythm"><div>Antibiotics may be needed for chronic skin infections that worsen eczema.</div></li></ul>
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</td><td headers="hd_h_was.T.wiskottaldrich_syndrome_and_xlinke_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_was.T.wiskottaldrich_syndrome_and_xlinke_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Immunodeficiency</b>
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</td><td headers="hd_h_was.T.wiskottaldrich_syndrome_and_xlinke_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Prophylaxis for <i>Pneumocystis jirovecii</i> in infants w/Wiskott-Aldrich syndrome (e.g., Bactrim<sup>®</sup> or pentamidine)</div></li><li class="half_rhythm"><div>Consider prophylactic antibiotics in persons w/recurrent bacterial sinopulmonary infections.</div></li><li class="half_rhythm"><div>IVIG starting by age 6 mos administered every 3-4 wks or subcutaneously, usually on a weekly basis. IVIG is a highly purified blood derivative (a combination of many specific antimicrobial antibodies).</div></li><li class="half_rhythm"><div>Routine immunizations. "Non-live" vaccinations can be given safely to persons w/a <i>WAS</i>-related disorder but may not generate protective levels of antibodies.</div></li></ul>
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</td><td headers="hd_h_was.T.wiskottaldrich_syndrome_and_xlinke_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_was.T.wiskottaldrich_syndrome_and_xlinke_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Infection</b>
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</td><td headers="hd_h_was.T.wiskottaldrich_syndrome_and_xlinke_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Prompt eval & treatment for infection</div></li><li class="half_rhythm"><div>Treatment w/empiric parenteral antibiotics is necessary in most persons.</div></li><li class="half_rhythm"><div>Exhaustive eval for source of infection, which may incl invasive assessments; identification of offending organism is needed to guide therapy.</div></li></ul>
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</td><td headers="hd_h_was.T.wiskottaldrich_syndrome_and_xlinke_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">If HSCT is being considered, prevention & treatment of infections is necessary to limit pre-transplant morbidity.</td></tr><tr><td headers="hd_h_was.T.wiskottaldrich_syndrome_and_xlinke_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Autoimmune disorders</b>
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</td><td headers="hd_h_was.T.wiskottaldrich_syndrome_and_xlinke_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Judicious use of immunosuppressants tailored to individual diagnosis</td><td headers="hd_h_was.T.wiskottaldrich_syndrome_and_xlinke_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_was.T.wiskottaldrich_syndrome_and_xlinke_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Lymphoma</b>
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</td><td headers="hd_h_was.T.wiskottaldrich_syndrome_and_xlinke_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment w/allogeneic HSCT w/additional mgmt per hematologist/oncologist</td><td headers="hd_h_was.T.wiskottaldrich_syndrome_and_xlinke_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Recommended to ↑ chance of relapse-free survival</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">HSCT = hematopoietic stem cell transplantation; IVIG = Intravenous immunoglobulin; XLT = X-linked thrombocytopenia</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobwasTxlinkedneutropeniatreatmentofm"><div id="was.T.xlinked_neutropenia_treatment_of_m" class="table"><h3><span class="label">Table 5b. </span></h3><div class="caption"><p>X-Linked Neutropenia: Treatment of Manifestations</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1178/table/was.T.xlinked_neutropenia_treatment_of_m/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__was.T.xlinked_neutropenia_treatment_of_m_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_was.T.xlinked_neutropenia_treatment_of_m_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Manifestation/Concern</th><th id="hd_h_was.T.xlinked_neutropenia_treatment_of_m_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment</th><th id="hd_h_was.T.xlinked_neutropenia_treatment_of_m_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Considerations/Other</th></tr></thead><tbody><tr><td headers="hd_h_was.T.xlinked_neutropenia_treatment_of_m_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Neutropenia / Recurrent bacterial infections</b>
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</td><td headers="hd_h_was.T.xlinked_neutropenia_treatment_of_m_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>G-CSF therapy</div></li><li class="half_rhythm"><div>Consider prophylactic antibiotics in persons w/recurrent bacterial sinopulmonary infections.</div></li><li class="half_rhythm"><div>Routine immunizations. "Non-live" vaccinations can be given safely to persons w/a <i>WAS</i>-related disorder but may not generate protective levels of antibodies.</div></li></ul>
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</td><td headers="hd_h_was.T.xlinked_neutropenia_treatment_of_m_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_was.T.xlinked_neutropenia_treatment_of_m_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Infection</b>
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</td><td headers="hd_h_was.T.xlinked_neutropenia_treatment_of_m_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Prompt eval & treatment for infection</div></li><li class="half_rhythm"><div>Treatment w/empiric parenteral antibiotics is necessary in most persons.</div></li><li class="half_rhythm"><div>Exhaustive eval for source of infection, which may incl invasive assessments; identification of offending organism is needed to guide therapy.</div></li></ul>
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</td><td headers="hd_h_was.T.xlinked_neutropenia_treatment_of_m_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_was.T.xlinked_neutropenia_treatment_of_m_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Myelodysplastic syndrome / AML</b>
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</td><td headers="hd_h_was.T.xlinked_neutropenia_treatment_of_m_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment per hematologist/oncologist</td><td headers="hd_h_was.T.xlinked_neutropenia_treatment_of_m_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">G-CSF = granulocyte colony-stimulating factor</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobwasTwasrelateddisordersrecommendeds"><div id="was.T.wasrelated_disorders_recommended_s" class="table"><h3><span class="label">Table 6. </span></h3><div class="caption"><p><i>WAS</i>-Related Disorders: Recommended Surveillance</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1178/table/was.T.wasrelated_disorders_recommended_s/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__was.T.wasrelated_disorders_recommended_s_lrgtbl__"><table><thead><tr><th id="hd_h_was.T.wasrelated_disorders_recommended_s_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_was.T.wasrelated_disorders_recommended_s_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_was.T.wasrelated_disorders_recommended_s_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Frequency</th></tr></thead><tbody><tr><td headers="hd_h_was.T.wasrelated_disorders_recommended_s_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Thrombocytopenia</b>
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</td><td headers="hd_h_was.T.wasrelated_disorders_recommended_s_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>CBC incl platelet count & size</div></li><li class="half_rhythm"><div>Assessment for complications assoc w/↑ bleeding</div></li></ul>
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</td><td headers="hd_h_was.T.wasrelated_disorders_recommended_s_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">As recommended by hematologist</td></tr><tr><td headers="hd_h_was.T.wasrelated_disorders_recommended_s_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Eczema</b>
|
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</td><td headers="hd_h_was.T.wasrelated_disorders_recommended_s_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Skin exam</td><td headers="hd_h_was.T.wasrelated_disorders_recommended_s_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Annually</td></tr><tr><td headers="hd_h_was.T.wasrelated_disorders_recommended_s_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<b>Immunodeficiency</b>
|
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</td><td headers="hd_h_was.T.wasrelated_disorders_recommended_s_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assessment w/immunologist</td><td headers="hd_h_was.T.wasrelated_disorders_recommended_s_1_1_1_3" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">As recommended by immunologist</td></tr><tr><td headers="hd_h_was.T.wasrelated_disorders_recommended_s_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Infection</b>
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</td><td headers="hd_h_was.T.wasrelated_disorders_recommended_s_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assessment for recurrent infections</td></tr><tr><td headers="hd_h_was.T.wasrelated_disorders_recommended_s_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<b>Autoimmune disease</b>
|
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</td><td headers="hd_h_was.T.wasrelated_disorders_recommended_s_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Clinical assessment for autoimmune dysfunction</td><td headers="hd_h_was.T.wasrelated_disorders_recommended_s_1_1_1_3" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">Annually</td></tr><tr><td headers="hd_h_was.T.wasrelated_disorders_recommended_s_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Malignancy</b>
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</td><td headers="hd_h_was.T.wasrelated_disorders_recommended_s_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Clinical assessment for manifestations of lymphoma</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobwasmolgenTA"><div id="was.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>WAS-Related Disorders: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1178/table/was.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__was.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_was.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_was.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_was.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_was.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">Locus-Specific Databases</th><th id="hd_b_was.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_was.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_was.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="/gene/7454" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
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<i>WAS</i>
|
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</a>
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</td><td headers="hd_b_was.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">
|
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<a href="https://www.ncbi.nlm.nih.gov/genome/gdv/?context=gene&acc=7454" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Xp11<wbr style="display:inline-block"></wbr>​.23</a>
|
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</td><td headers="hd_b_was.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="http://www.uniprot.org/uniprot/P42768" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Actin nucleation-promoting factor WAS</a>
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</td><td headers="hd_b_was.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="https://research.cchmc.org/LOVD2/home.php?select_db=WAS" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">CCHMC - Human Genetics Mutation Database (WAS)</a>
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<br />
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<a href="https://databases.lovd.nl/shared/genes/WAS" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">WAS database</a>
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</td><td headers="hd_b_was.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=WAS" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">WAS</a>
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</td><td headers="hd_b_was.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=WAS[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">WAS</a>
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</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div id="was.TFA.1"><p class="no_margin">Data are compiled from the following standard references: gene from
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<a href="http://www.genenames.org/index.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">HGNC</a>;
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chromosome locus from
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<a href="http://www.omim.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">OMIM</a>;
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protein from <a href="http://www.uniprot.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">UniProt</a>.
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For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
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<a href="/books/n/gene/app1/?report=reader">here</a>.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobwasmolgenTB"><div id="was.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for WAS-Related Disorders (<a href="/omim/300299,300392,301000,313900" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">View All in OMIM</a>) </p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1178/table/was.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__was.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
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<a href="/omim/300299" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">300299</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">NEUTROPENIA, SEVERE CONGENITAL, X-LINKED; SCNX</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="/omim/300392" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">300392</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">WASP ACTIN NUCLEATION PROMOTING FACTOR; WAS</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="/omim/301000" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">301000</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">WISKOTT-ALDRICH SYNDROME; WAS</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="/omim/313900" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">313900</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">THROMBOCYTOPENIA 1; THC1</td></tr></tbody></table></div></div></article></div><div id="jr-scripts"><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/libs.min.js"> </script><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.min.js"> </script><script type="text/javascript">if (typeof (jQuery) != 'undefined') { (function ($) { $(function () { var min = Math.ceil(1); var max = Math.floor(100000); var randomNum = Math.floor(Math.random() * (max - min)) + min; var surveyUrl = "/projects/Gene/portal/surveys/seqdbui-survey.js?rando=" + randomNum.toString(); $.getScript(surveyUrl, function () { try { ncbi.seqDbUISurvey.init(); } catch (err) { console.info(err); } }).fail(function (jqxhr, settings, exception) { console.info('Cannot load survey script', jqxhr); });; }); })(jQuery); };</script></div></div>
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