Clinical Diagnosis

WAS-related disorders comprise a phenotypic spectrum of disordered hematopoietic cells ranging from severe to mild. Before the availability of molecular genetic testing, these phenotypes were thought to be distinct entities rather than a continuum. The phenotypes and their diagnostic criteria, modified from the recommendations of the European Society of Immunodeficiencies (ESID), are the following:

Wiskott-Aldrich syndrome. The diagnosis of Wiskott-Aldrich syndrome should be considered in a male with profound thrombocytopenia (<70,000 platelets/mm²) and small platelet size. Additional diagnostic criteria include the following:

• Recurrent bacterial or viral infection or opportunistic infection in infancy or early childhood

• Eczema

• Lymphoma

• Autoimmune disorder

• Family history of one or more maternally related males with a WAS-related phenotype or disorder

• Absent or decreased Wiskott-Aldrich syndrome protein (WASP) as determined by flow cytometry or western blotting

X-linked thrombocytopenia (XLT). The diagnosis of XLT should be considered in a male with congenital thrombocytopenia and small platelet size in the absence of other clinical findings of Wiskott-Aldrich syndrome. Additional diagnostic criteria include the following:

• Family history of one or more maternally related males with a WAS-related phenotype or disorder

• Decreased or absent Wiskott-Aldrich syndrome protein (WASP) as determined by flow cytometry or western blotting
  
  Note: Some affected individuals have near-normal amounts of WASP.

X-linked congenital neutropenia (XLN). The diagnosis of XLN should be considered in a male with recurrent bacterial infections, persistent neutropenia, and arrested development of the bone marrow in the absence of other clinical findings of Wiskott-Aldrich syndrome. WASP expression is normal in individuals with XLN.

Testing

Test results as follows suggest the diagnosis of WAS-related disorders.

Platelets

• Small platelet size (mean platelet volume >2 SD below the mean for the laboratory)

• Proportion and absolute numbers of reticulated platelets (>2 SD below the mean for the laboratory)

Lymphocytes

• Decreased T-cell subsets, especially proportion and absolute number of CD8+T cells

• 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.
  
  Note: (1) Some individuals, particularly children, have normal lymphocyte numbers and normal function. (2) Although the proportion of CD8+ cells is often decreased, it is occasionally increased.

• Abnormal immunoglobulin levels: decreased IgM, low IgG2; increased IgA, increased IgE
  
  Note: Quantitative immunoglobulin levels may be normal in some individuals, especially early in life, and can vary over time in the same individual.

• Absent isohemagglutinins
  
  Note: Interpretation of the significance of isohemagglutinin titers is unreliable in children younger than age 18 years.

• Absent or greatly decreased antibody production in response to pneumococcal vaccine (Pneumovax^®)

WASP expression

• Absent or decreased intracellular WASP detection in hematopoietic cells as determined by flow cytometry or western blotting. Such testing is available clinically (see ).

Molecular Genetic Testing

Gene. WAS is the only gene in which mutations cause the WAS-related disorders of Wiskott-Aldrich syndrome, X-linked thrombocytopenia (XLT), and X-linked congenital neutropenia (XLN).

Clinical testing

• Sequence analysis. Sequencing of the entire coding region and intron/exon boundaries of WAS is estimated to detect more than 98% of mutations in males and about 95% of mutations in female carriers [Derry et al 1994, Kwan et al 1995].
  
  Note: Large deletions, which comprise approximately 5% of mutations, are not detected by sequence analysis in female carriers.

• Deletion/duplication analysis

  • In the authors’ unpublished sample 6/94 unrelated individuals with Wiskott-Aldrich syndrome had exonic or whole-gene deletions [Author, personal observation].

  • Proust et al [2007] identified exonic and whole-gene deletions in 3/79 individuals with Wiskott-Aldrich syndrome.

  • Lutskiy et al [2005] described large deletions in 2/44 of individuals studied.

• X-chromosome inactivation studies. Although hematopoietic cells from obligate female carriers, particularly T cells and platelets, tend to demonstrate a non-random pattern of X-chromosome inactivation, X-chromosome inactivation studies are not adequate to determine carrier status in Wiskott-Aldrich syndrome.

Table 1. Summary of Molecular Genetic Testing Used in WAS-Related Disorders

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1		Test Availability
			Males	Heterozygous Females
WAS	Sequence analysis	Sequence variants 2	>~98% 3	~95% 4	Clinical
	Deletion / duplication analysis 5	Partial- and whole-gene deletions	~5% 6	~5% 6

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests™ Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

3. Lack of amplification by PCR prior to sequence analysis suggests a putative deletion of one or more exons or the entire X-linked gene in a male; confirmation may require additional testing by deletion/duplication analysis.

4. Sequence analysis of genomic DNA cannot detect deletion of one or more exons or the entire X-linked gene in a heterozygous female.

5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment. See array CGH.

6. Proust et al [2007]; Lutskiy et al [2005]; Author, personal observation

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To establish the diagnosis in a male proband

1.

Confirm the presence of thrombocytopenia and small platelet size.

2.

Assay for decreased T-cell subsets, decreased NK function, abnormal immunoglobulin levels, absent isohemagglutinin titers, and abnormal antibody production in response to vaccines.

3.

Assay for absent or decreased intracellular WAS protein expression.

4.

Perform sequence analysis of WAS, followed by deletion/duplication analysis as needed to confirm presence of large deletion suspected on sequence analysis

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutation in the family.

Note: (1) Carriers are heterozygotes for this X-linked disorder and may occasionally have mild thrombocytopenia [Parolini et al 1998, Inoue et al 2002, Lutskiy et al 2002, Andreu et al 2003]. (2) Identification of female carriers requires either (a) prior identification of the disease-causing mutation in the family or, (b) if an affected male is not available for testing, molecular genetic testing first by sequence analysis, and then, if no mutation is identified, by deletion/duplication analysis.

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

Wiskott-Aldrich syndrome, X-linked thrombocytopenia, and X-linked neutropenia are allelic disorders. No other phenotypes are known to be associated with mutations in WAS.

Natural History

Wiskott-Aldrich syndrome, X-linked thrombocytopenia (XLT), and X-linked neutropenia (XLN) are a spectrum of disorders caused by WAS mutations that result in deficiency of the Wiskott-Aldrich syndrome protein (WASP), leading to low platelet counts (with small platelet size) and significant risk of serious bleeding, and, in some individuals, abnormal lymphocyte function with susceptibility to serious bacterial, viral, and fungal infections. Autoimmune disorders and lymphomas are frequently encountered in individuals with mutations in WAS.

Attempts have been made to classify affected individuals as having either XLT or Wiskott-Aldrich syndrome based on (1) presence or absence of autoimmune or inflammatory complications, (2) presence or absence of WAS protein, (3) overall clinical scoring system, or (4) type of WAS mutation; however, it has not been possible to eliminate the considerable overlap between XLT and Wiskott-Aldrich syndrome, an observation that emphasizes the notion that the phenotypes comprising the WAS-related disorders comprise a spectrum, not discrete entities.

WAS-related disorders usually present in infancy; however, because the clinical phenotype may worsen with age, it is particularly difficult to predict eventual disease severity in an infant. The range of clinical complications experienced by affected males can vary widely, even in the same kindred. Long-term prognosis varies based on the predicted disease burden in a particular individual. In some families, adult males in their 60s have mild manifestations such as chronic thrombocytopenia, whereas other affected male relatives succumb from complications of severe manifestations in infancy and childhood [Filipovich, unpublished observation].

The prognosis for individuals with WAS-related disorders has improved in the last 20 years as a result of improved treatment (see Management).

Genotype-Phenotype Correlations

Individuals with Wiskott-Aldrich syndrome show remarkable variable expressivity of clinical findings.

Whether genotype-phenotype correlations exist in WAS-related disorders is debatable.

While several earlier reports described missense mutations in association with XLT or mild disease and nonsense, frameshift, or splice site mutations in severe disease [Zhu et al 1997, Notarangelo & Ochs 2003, Imai et al 2004], other studies failed to find consistent correlation between a particular mutation and clinical outcome [Greer et al 1996, Schindelhauer et al 1996, Lemahieu et al 1999, Fillat et al 2001].

XLT is typically associated with missense WAS mutations and most males with XLT are able to produce WASP. Specific mutations are not universally associated with XLT and disease severity varies considerably within families [Albert et al 2010b].

X-linked congenital neutropenia (XLN) is caused by rare mutations in WAS, generally described in the GTPase binding domain, which cause constitutive activation of WASP and lead to increased formation of actin polymers and abnormal cell division. WASP expression in individuals with XLN is comparable to that of normal controls [Devriendt et al 2001]. Disease severity varies considerably within families [Beel & Vandenberghe 2009].

While predictions can sometimes be made based on groups of affected individuals or types of mutations, considerable caution must be exercised in assigning a phenotype to a young, newly diagnosed male based on genotype alone for the following reasons:

• The phenotype of affected males in the same kindred can vary widely [Beel & Vandenberghe 2009, Albert et al 2010b]

• Splice site mutations may allow production of multiple gene products, including normally spliced WASP [Jin et al 2004].

• Reversion of an inherited mutation to normal in a subpopulation of cells with improvement of clinical symptoms has been reported [Ariga et al 2001, Wada et al 2001, Wada et al 2003, Jin et al 2004].

• It is likely that the clinical phenotype in WAS-related disorders, as in many other monogenic disorders, is modified by other genes (e.g., those modifying atopy) and results, in part, from encounters with ubiquitous or rare pathogens.

Some studies have focused on WAS protein expression as a better predictor of clinical severity of a WAS-related disorder than mutation alone.

• In one study, 74.2% of individuals who produced WASP had the XLT phenotype, while 86.5% of individuals who produced no WASP had the Wiskott-Aldrich syndrome phenotype [Imai et al 2003].

• As a group, individuals who expressed a normal-sized mutated WAS protein 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 [Jin et al 2004].

• Lutskiy et al [2005] 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 mutations in WAS.

Penetrance

Penetrance is complete in males with a WAS mutation.

Anticipation

Anticipation has not been documented in WAS-related disorders.

Prevalence

The estimated prevalence of WAS-related disorders is between 1:1,000,000 and 1:100,000 males [Ochs & Thrasher 2006].

The disorder occurs worldwide with no racial or ethnic predilection.

Wiskott-Aldrich Syndrome

Idiopathic thrombocytopenic purpura (ITP) 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.

In males who initially present with Pneumocystis carinii pneumonia, the following conditions should be considered; however, persistent thrombocytopenia is rarely, if ever, seen in these conditions.

• X-linked severe combined immunodeficiency (X-SCID) typically presents within a few months after birth with persistent viral, bacterial, and fungal infections, lymphocytopenia, growth failure, and thymic hypoplasia. Affected individuals have a low number of T cells, variable number of B cells, low immunoglobulins, and no specific antibodies. X-SCID is caused by a mutation in the common gamma chain gene (IL2RG).

• X-linked hyper IgM syndrome typically presents as recurrent bacterial infections (e.g., otitis media, sinusitis, pneumonias) by age one year. Males with this condition often develop autoimmune hematologic disorders including neutropenia, thrombocytopenia, and hemolytic anemia. Other medical complications may include lymphomas and other malignancies, serious gastrointestinal complications, and neurologic deterioration. Elevated IgM in the absence of other immunoglobulins is diagnostic of this condition. X-linked hyper IgM syndrome is caused by mutations in CD40LG (CD40 ligand).

• Autosomal recessive severe combined immunodeficiencies, a group of conditions that present with T- and B-cell dysfunction, result in recurrent infections in addition to other variable clinical features, but rarely result in persistent thrombocytopenia. These disorders are caused by mutations in a number of different genes.

• Human immunodeficiency virus (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.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to Wiskott-Aldrich syndrome, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

• Males

• Carrier females

X-Linked Neutropenia (XLN)

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. An algorithm for the diagnostic evaluation of patients with neutropenia has been published [Boztug & Klein 2011].

X-Linked Thrombocytopenia

GATA1-related cytopenia is characterized by thrombocytopenia and/or anemia ranging from mild to severe and one or more of the following: platelet dysfunction, mild β-thalassemia, neutropenia, and congenital erythropoietic porphyria (CEP) 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 clinical spectrum, severe hemorrhage and/or erythrocyte transfusion dependence are life long; at the milder end, anemia and the risk for bleeding decrease spontaneously with age.

Evaluations Following Initial Diagnosis

At initial diagnosis of Wiskott-Aldrich syndrome an inventory should be made regarding the following:

• Platelet count and size

• T-cell subsets

• Immunoglobulin levels

Treatment of Manifestations

Treatment options vary based on the predicted disease burden in a particular individual.

Bone marrow transplantation (BMT). The only curative treatment currently available for Wiskott-Aldrich syndrome is allogeneic BMT. The first successful BMT for Wiskott-Aldrich syndrome was performed in 1968. Currently, affected boys who receive BMT from a matched healthy sibling or closely matched unrelated donor before their fifth birthday have a greater than 85% probability of being cured of the disorder [Filipovich et al 2001, Pai et al 2006, Tsuji et al 2006, Friedrich et al 2009].

Eczema. Topical steroids are the mainstay of therapy. When chronic infections of the skin worsen eczema, antibiotics may be useful.

Autoimmune disease. Treatment usually consists of judicious use of immunosuppressants tailored to the individual's diagnosis.

Neutropenia. Treatment of XLN is with granulocyte colony-stimulating factor (G-CSF) and appropriate antibiotics.

Prevention of Primary Manifestations

Infection

• Antibiotic prophylaxis. Prophylaxis against PCP and antimicrobial therapy for infections

• Intravenous immune globulin. Replacement therapy with intravenous immunoglobulin every three to four weeks (because of the individual's inability to generate the full array of normal protective antibodies)

• Routine childhood immunizations

Bleeding

• Splenectomy. Splenectomy is palliative, and while it may be life-saving in an individual with severe bleeding, it does not prevent any of the other possible complications of the disorder [Mullen et al 1993]. In a survey of clinical immunologists performed by the European and Pan American Groups on Immunodeficiencies, respondents from centers treating the highest numbers of individuals with Wiskott-Aldrich syndrome did not recommend splenectomy [Conley et al 2003]. Because splenectomy significantly increases the risk of life-threatening infections in males with XLT [Albert et al 2010b] as well as in males with Wiskott-Aldrich syndrome who subsequently undergo hematopoietic cell transplantation (HCT) [Ozsahin et al 2008], it should be used with caution.
  Males who have had splenectomy must take antibiotics routinely for the rest of their lives because of the increased risk for overwhelming infection.

• Platelet transfusions. Platelet transfusions should be administered judiciously, e.g., for significant bleeding and surgical procedures.

Prevention of Secondary Complications

Prophylaxis for pneumonia secondary to Pneumocystis jiroveci, formerly known as Pneumocystis carinii (PCP), is indicated for infants with Wiskott-Aldrich syndrome as they are at risk of developing PCP. Typical prophylaxis is Bactrim^® (trimethoprim-sulfamethoxazole) orally or pentamidine by intravenous or inhalation therapy.

IVIgG replacement should be considered by the time the child is six months old, as individuals with Wiskott-Aldrich syndrome cannot generate antibodies to encapsulated bacteria naturally and are at risk for overwhelming infection from these organisms. IVIgG is a highly purified blood derivative (a combination of many specific antimicrobial antibodies) that is typically given every three to four weeks or can be administered subcutaneously, usually on a weekly basis.

Additional antibiotic prophylaxis should be considered on a case-by-case basis.

Surveillance

Regular follow-up is indicated to monitor blood counts, adequacy of the IVIgG replacement therapy, and other potential complications.

Agents/Circumstances to Avoid

Circumcision of an at-risk newborn male should not be undertaken in the presence of thrombocytopenia.

The use of over-the-counter medications should be discussed with a physician as some medications can interfere with platelet function.

When possible, elective surgical procedures should be deferred until after bone marrow transplantation.

Evaluation of Relatives at Risk

Testing of newborn at-risk males is recommended before any elective procedure such as circumcision.

It is appropriate to test at-risk males so that morbidity and mortality can be reduced by early diagnosis and treatment. Rapid screening of at-risk males may be accomplished by WASP staining using flow cytometry; definitive testing is available by molecular genetic testing if the disease-causing mutation in the family is known.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

There is no evidence that C-section reduces the risk of morbidity and mortality in males with Wiskott-Aldrich syndrome.

Therapies Under Investigation

Gene therapy

• Dupre et al [2006] demonstrated the efficacy of using a lentiviral vector and an autologous promoter to induce expression of WASP in mice.

• Dewey et al [200]6 induced functional reconstitution of WASP-deficient human myeloid cells upon retroviral gene transfer.

• Marangoni et al [2009] demonstrated long-term efficacy and safety of gene therapy in mice.

• Gene therapy has been used clinically to treat a limited number of males with Wiskott-Aldrich syndrome who lack a suitable HLA-matched donor [Klein et al 2003, Qasim et al 2009, Boztug et al 2010].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Registries

Contact information for voluntary patient registries is provided by GeneReviews staff.

European Society for Immunodeficiencies (ESID) Registry
University Medical Center Freiburg Centre of Chronic Immunodeficiency
Phone: 49-761-270-34450
Email: registry@esid.org
Web: www.esid.org

NCI Inherited Bone Marrow Failure Syndromes (IBMFS) Cohort Registry
National Cancer Institute
Phone: 800-518-8474
Email: lisaleathwood@westat.com
Web: www.marrowfailure.cancer.gov

Primary Immunodeficiency Diseases Registry at USIDNET
Phone: 866-939-7568
Email: contact@usidnet.org
Web: www.usidnet.org

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

WAS-related disorders are inherited in an X-linked manner.

Risk to Family Members

Parents of a proband

• The father of an affected male will not have a WAS-related disorder nor will he be a carrier of a WAS mutation.

• In a family with more than one affected individual, the mother of an affected male is an obligate carrier. Female carriers of a WAS mutation are asymptomatic and have no immunologic or biochemical markers of the disorder.

• If pedigree analysis reveals that the proband is the only affected family member, the mother may be a carrier or the affected male may have a de novo gene mutation, in which case the mother is not a carrier.

  • A de novo mutation occurs in about one third of affected individuals with no previous family history of the disorder.

  • Therefore, the mother of an affected male who has no family history of a WAS-related disorder has a 2/3 chance of being a carrier of the mutation.

Sibs of a proband

• The risk to sibs depends on the carrier status of the mother.

• If the mother is a carrier of a WAS mutation, the chance of transmitting the disease-causing mutation in each pregnancy is 50%. Males who inherit the mutation will be affected; females who inherit the mutation will be carriers and may occasionally have mild thrombocytopenia [Parolini et al 1998, Inoue et al 2002, Lutskiy et al 2002, Andreu et al 2003].

• Germline mosaicism has been demonstrated in this condition. Thus, even if the disease-causing mutation found in the proband has not been identified in DNA extracted from the mother's leukocytes, the sibs remain at increased risk [Areveiler et al 1990].

Offspring of a proband

• Males will pass the disease-causing mutation to all of their daughters and none of their sons.

• Female carriers of a WAS mutation may occasionally have mild thrombocytopenia [Parolini et al 1998, Inoue et al 2002, Lutskiy et al 2002, Andreu et al 2003].

Other family members of a proband. The proband's maternal aunts or other maternal relatives and their offspring may be at risk of being carriers of a WAS mutation, if female, or of being affected with a WAS-related disorder, if male. The precise risk to the proband's maternal relatives depends on the family relationships.

Carrier Detection

Carrier testing of at-risk female relatives is possible if the mutation has been identified in an affected male relative.

If an affected male is not available for testing, molecular genetic testing of at-risk female relatives is done first by sequence analysis, and then, if no mutation is identified, by deletion/duplication analysis.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.

• 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.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal testing is possible for pregnancies of women who are carriers of a WAS mutation. The usual procedure is to determine fetal sex by chromosome analysis of fetal cells obtained by amniocentesis usually performed at about 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at about ten to 12 weeks' gestation. If the karyotype is 46,XY and if the WAS mutation has been identified in a family member, DNA from fetal cells can be analyzed for the known disease-causing mutation.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Published Guidelines/Consensus Statements

1. American Society of Human Genetics and American College of Medical Genetics. Points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents. Available online. 1995. Accessed 3-30-12.
2. American Society of Human Genetics Social Issues Subcommittee on Familial Disclosure. ASHG statement. Professional disclosure of familial genetic information. Available online. Registration or institutional access required. 1998. Accessed 3-30-12.
3. European Society for Immunodeficiencies (ESID). Diagnostic criteria for primary immunodeficiencies. Available online. 2005. Accessed 3-30-12.

Literature Cited

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16. Devriendt K, Kim AS, Mathijs G, Frints SG, Schwartz M, Van Den Oord JJ, Verhoef GE, Boogaerts MA, Fryns JP, You D, Rosen MK, Vandenberghe P. Constitutively activating mutation in WASP causes X-linked severe congenital neutropenia. Nat Genet. 2001;27:313–7. [PubMed: 11242115]
17. Dewey RA, Avedillo Diez I, Ballmaier M, Filipovich A, Greil J, Gungor T, Happel C, Maschan A, Noyan F, Pannicke U, Schwarz K, Snapper S, Welte K, Klein C. Retroviral WASP gene transfer into human hematopoietic stem cells reconstitutes the actin cytoskeleton in myeloid progeny cells differentiated in vitro. Exp Hematol. 2006;34:1161–9. [PubMed: 16939809]
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Suggested Reading

1. Bosticardo M, Marangoni F, Aiuti A, Villa A, Roncarolo MG. Recent advances in understanding the pathophysiology of Wiskott-Aldrich syndrome. Blood. 2009;113(25):6288–6295. [PubMed: 19351959]
2. French DL, Newman PJ, Poncz M. Inherited disorders of platelets. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill; Chap 177. Available at www.ommbid.com. Accessed 7-21-11.
3. Gulacsy V, Freiberger T, Shcherbina A, Pac M, Chernyshova L, Avcin T, Kondratenko I, Kostyuchenko L, Prokofjeva T, Pasic S, Bernatowska E, Kutukculer N, Rascon J, Iagaru N, Mazza C, Toth B, Erdos M, van der Burg M. Marodi L Genetic characteristics of eighty-seven patients with the Wiskott-Aldrich syndrome. Mol Immunol. 48:788–792. [PubMed: 21185603]
4. Ochs HD, Thrasher AJ. The Wiskott-Aldrich syndrome. J Allergy Clin Immunol. 2006;117:725–38. [PubMed: 16630926]
5. Ochs HD, Rosen FS. The Wiskott-Aldrich syndrome. In: Ochs HD, Smith CIE, Puck JM, eds. Primary Immunodeficiency Diseases: A Molecular and Genetic Approach. New York, NY: Oxford University Press; 1999:292-305.
6. Pai SY, Notarangelo LD. Hematopoietic cell transplantation for Wiskott-Aldrich syndrome: advances in biology and future directions for treatment. Immunol Allergy Clin North Am. 2010;30:179–94. [PMC free article: PMC2930258] [PubMed: 20493395]

Revision History

• 28 July 2011 (me) Comprehensive update posted live

• 27 April 2007 (me) Comprehensive update posted to live Web site

• 30 September 2004 (me) Review posted to live Web site

• 1 October 2003 (jj) Original submission