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WAS-Related Disorders

, MD, MRCPCH, , PhD, , MS, and , MD, MBA.

Author Information

Initial Posting: ; Last Update: September 22, 2016.

Summary

Clinical characteristics.

The WAS-related disorders, which include Wiskott-Aldrich syndrome, X-linked thrombocytopenia (XLT), and X-linked congenital neutropenia (XLN), are a spectrum of disorders of hematopoietic cells, with predominant defects of platelets and lymphocytes caused by pathogenic variants in WAS.

  • WAS-related disorders usually present in infancy. Affected males have thrombocytopenia with intermittent mucosal bleeding, bloody diarrhea, and intermittent or chronic petechiae and purpura; eczema; and recurrent bacterial and viral infections, particularly of the ear. At least 40% of those who survive the early complications develop one or more autoimmune conditions including hemolytic anemia, immune thrombocytopenic purpura, immune-mediated neutropenia, rheumatoid arthritis, vasculitis, and immune-mediated damage to the kidneys and liver. Individuals with a WAS-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.
  • Males with XLT have thrombocytopenia with small platelets; other complications of Wiskott-Aldrich syndrome, including eczema and immune dysfunction, are usually mild or absent.
  • Males with XLN have congenital neutropenia, myeloid dysplasia, and lymphoid cell abnormalities.

Diagnosis/testing.

The diagnosis of a WAS-related disorder is established in a male proband with both congenital thrombocytopenia (<70,000 platelets/mm3) and small platelets, in addition to at least one of the following features: eczema, recurrent bacterial or viral 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 WAS-related disorder. Identification of a hemizygous WAS pathogenic variant on molecular genetic testing is necessary to confirm the diagnosis.

Management.

Treatment of manifestations: Treatment options depend on an individual's predicted disease burden; hematopoietic cell transplantation (HCT) is the only known curative treatment. Topical steroids for eczema; antibiotics for infected eczema; judicious use of immunosuppressants for autoimmune disease; granulocyte colony stimulating factor (G-CSF) and appropriate antibiotics for neutropenia.

Prevention of primary manifestations: Pneumocystis jiroveci (formerly known as Pneumocystis carinii pneumonia, or PCP) prophylaxis with Bactrim® (trimethoprim-sulfamethoxazole) or pentamidine, intravenous immunoglobulin (IVIgG) replacement therapy, routine childhood “non-live” immunizations; judicious use of platelet transfusions for significant bleeding and surgical procedures.

Surveillance: Routine monitoring of blood counts and adequacy of IVIgG replacement therapy.

Agents/circumstances to avoid: Circumcision of at-risk newborn males who have thrombocytopenia; use of medications that interfere with platelet function. Defer elective procedures until after HCT.

Evaluation of relatives at risk: Evaluation of at-risk newborn males so that morbidity and mortality can be reduced by early diagnosis and treatment.

Genetic counseling.

WAS-related disorders are inherited in an X-linked manner. If the mother is a carrier of a WAS pathogenic variant, the chance of transmitting the pathogenic variant in each pregnancy is 50%: males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be carriers. Males will pass the pathogenic variant to all of their daughters and none of their sons. Female carriers of a WAS pathogenic variant are usually asymptomatic and have no immunologic or biochemical markers of the disorder. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the pathogenic variant has been identified in the family.

GeneReview Scope

WAS-Related Disorders: Included Phenotypes 1
1.

For other genetic causes of these phenotypes see Differential Diagnosis.

Diagnosis

Suggestive Findings

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 should be suspected in a male with:

  • Profound thrombocytopenia (<70,000 platelets/mm3)
  • Small platelet size (mean platelet volume >2 SD below the mean for the laboratory)
  • Recurrent bacterial or viral infection or opportunistic infection in infancy or early childhood
  • Eczema
  • Autoimmune disorder
  • Lymphoma
  • Family history of one or more maternally related males with a WAS-related phenotype or disorder
  • Absent or decreased intracellular Wiskott-Aldrich syndrome protein (WASP) detection in hematopoietic cells as determined by flow cytometry or western blotting
  • Abnormal 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, normal or decreased IgG, increased IgA, increased IgE
    • Absent isohemagglutinins
      Note: Interpretation of the significance of isohemagglutinin titers is unreliable in children younger than age 18 years.
    • Absent or greatly decreased antibody responses to polysaccharide vaccines (e.g., Pneumovax®)

X-linked thrombocytopenia (XLT) should be suspected in a male with:

  • Congenital thrombocytopenia (5,000-50,000 platelets/mm3)
  • Small platelet size (platelet volume <7.5 fL)
  • Absence of other clinical findings of Wiskott-Aldrich syndrome
  • Family history of one or more maternally related males with a WAS-related phenotype or disorder
  • Decreased or absent WASP by flow cytometry or western blotting
    Note: Some affected individuals have near-normal amounts of WASP.

X-linked congenital neutropenia (XLN) should be suspected in a male with:

  • Recurrent bacterial infections
  • Persistent neutropenia
  • Arrested development of the bone marrow in the absence of other clinical findings of Wiskott-Aldrich syndrome
  • Normal WASP expression by flow cytometry or western blotting

Establishing the Diagnosis

Male proband. The diagnosis of a WAS-related disorder is established in a male proband with:

  • BOTH of the following:
    • Thrombocytopenia (<100,000 platelets/mm3, confirmed with repeat examination)
    • Small platelets (platelet volume <7.5 fL)
  • AND at least ONE of the following:
    • Eczema
    • Recurrent bacterial or viral infections
    • Autoimmune disease(s) (including vasculitis)
    • Malignancy
    • Reduced WASP expression in a fresh blood sample
    • Abnormal antibody response to polysaccharide antigens and/or low isohemagglutinins
    • Positive maternal family history of a WAS-related disorder
  • AND identification of a hemizygous WAS pathogenic variant on molecular genetic testing (necessary to confirm the diagnosis; see Table 1).

Female proband. The diagnosis of a WAS-related disorder is usually established in a female proband by identification of a heterozygous pathogenic variant in WAS by molecular genetic testing (see Table 1) along with clinical features consistent with a WAS-related disorder.

Note: Female carriers of a pathogenic variant in WAS are typically asymptomatic due to skewed X chromosome inactivation which results in silencing of the mutated allele. Female carriers may in rare cases be symptomatic: blood cell populations can vary with either normal or abnormal WASP expression [Lutskiy et al 2002] or skewed X-chromosome inactivation may favor expression of the mutated allele [Boonyawat et al 2013, Daza-Cajigal et al 2013, Takimoto et al 2015].

Molecular testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing.

  • Single-gene testing. Sequence analysis of WAS is performed first and followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.
  • A multigene panel that includes WAS and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel provides the best opportunity to identify the genetic cause of the condition at the most reasonable cost while limiting identification of pathogenic variants in genes that do not explain the underlying phenotype. (3) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
  • More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered if serial singlegene testing (and/or use of a multigene panel that includes WAS) fails to confirm a diagnosis in an individual with features of WAS-related disorders. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation). For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in WAS-Related Disorders

Gene 1Test MethodProportion of Probands with a Pathogenic Variant 2 Detectable by This Method
WASSequence analysis 3, 4~95% 5
Gene-targeted deletion/duplication analysis 6~5% 7
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by gene-targeted deletion/duplication analysis.

5.

Sequencing of the entire coding region and intron/exon boundaries of WAS is estimated to detect approximately 95% of pathogenic variants [Lutskiy et al 2005; Proust et al 2007; Author, personal observation].

6.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

7.

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

Clinical Characteristics

Clinical Description

Wiskott-Aldrich syndrome, X-linked thrombocytopenia (XLT), and X-linked neutropenia (XLN) are a spectrum of disorders caused by WAS pathogenic variants 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 pathogenic variants 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 WASP, (3) the WAS clinical score (see following), or (4) type of WAS pathogenic variant; 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 [Beel & Vandenberghe 2009, Albert et al 2011, Buchbinder et al 2011].

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

The WAS clinical score is derived from a variety of clinical parameters, including the presence of thrombocytopenia, eczema, immunodeficiency, autoimmunity, and malignancy. WAS scores, which range between 0 and 5, facilitate the clinical categorization of individuals and may be useful in predicting disease severity [Albert et al 2011]. A WAS score of 0 is reserved for those individuals with XLN and/or myelodysplasia. A score of 1 or 2 defines individuals with XLT; a score of 3 to 4 identifies individuals with classic WAS; and a score of 5 is reserved for individuals with either XLT or WAS who develop autoimmunity and/or malignancies. Individuals with a higher WAS score (e.g., 5) at a younger age (e.g., during the first 2 years of life) may represent a group at high risk for morbidity and mortality [Mahlaoui et al 2013]. 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]) [Albert et al 2010].

Wiskott-Aldrich Syndrome

Wiskott-Aldrich syndrome usually presents in infancy. Although a triad of (1) bloody diarrhea, mucosal bleeding and/or petechiae; (2) eczema; and (3) recurrent middle-ear infections and purulent drainage from the ears was originally described [Aldrich et al 1954], this triad is identified in only 27% of children with Wiskott-Aldrich syndrome [Sullivan et al 1994].

Common manifestations of Wiskott-Aldrich syndrome include the following.

Thrombocytopenia 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. Life-threatening bleeding occurs in 30% of males prior to diagnosis and accounts for 23% of all non-hematopoietic cell transplantation (HCT)-related deaths [Sullivan et al 1994]. Platelet counts do not adequately represent bleeding risk in an individual with Wiskott-Aldrich syndrome [Albert et al 2010].

Thrombocytopenia may be reversed by splenectomy; however, recurrent thrombocytopenia associated with the development of immune thrombocytopenia purpura (ITP) is observed in some splenectomized individuals.

Eczema occurs in about 80% of males with Wiskott-Aldrich syndrome [Sullivan et al 1994]. The severity varies from mild to severe, and tends to be worse in males with a family history of allergies and asthma.

Other skin disorders including impetigo, cellulitis, and abscesses are common.

Infection. Boys with Wiskott-Aldrich syndrome are susceptible to recurrent bacterial and viral infections, particularly recurrent ear infections. They have an increased risk of mortality secondary to bacterial sepsis from encapsulated organisms including Streptococcus pneumonia and Haemophilus influenza B.

Infections by opportunistic agents including cytomegalovirus (CMV), herpes simplex virus (HSV), Epstein-Barr virus (EBV), and adenovirus are common. Pneumocystis jiroveci pneumonia (formerly known as Pneumocystis carinii pneumonia, or PCP) is a possible early life-threatening complication.

Splenectomy, commonly performed in the past to increase platelet counts and reduce risk of fatal hemorrhage, increases the risk of overwhelming bacterial infection.

Autoimmune disorders. 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 [Sullivan et al 1994, Chen et al 2015]. For a comprehensive review of autoimmunity in Wiskott-Aldrich syndrome, see Schurman & Candotti [2003] and Catucci et al [2012].

High serum IgM concentration in young children prior to splenectomy may be a risk factor for the development of autoimmune hemolytic anemia [Dupuis-Girod et al 2003]; however, the predictive value of this finding awaits confirmation by other investigators.

The presence of an autoimmune disorder significantly increases the risk of developing lymphoma [Sullivan et al 1994, Schurman & Candotti 2003].

Allogeneic HCT corrects autoimmunity in individuals with Wiskott-Aldrich syndrome [Pai et al 2006].

Lymphoma. 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 13% of individuals with Wiskott-Aldrich syndrome develop lymphoma, at an average age of 9.5 years. The risk of developing lymphoma increases with age and in the presence of autoimmune disease [Schurman & Candotti 2003].

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 de novo lymphoma. Individuals with Wiskott-Aldrich syndrome and lymphoma should undergo allogeneic HCT to increase their chances of relapse-free survival.

Life span. The reported median survival of children with Wiskott-Aldrich syndrome who do not undergo successful allogeneic HCT is between eight and 14.5 years [Dupuis-Girod et al 2003]. The causes of non-HCT-related deaths include infection (44% of individuals), malignancy (26%), and bleeding (23%). Survival into adulthood occurs, particularly given the improvement in medical treatment of this disorder over the last 20 years. HCT provides a potential cure for Wiskott-Aldrich syndrome [Friedrich et al 2009].

X-Linked Thrombocytopenia (XLT)

Males with XLT have small platelet volume and thrombocytopenia that may be intermittent. Albert et al [2010] found that life expectancy was not significantly affected in males with XLT as a group; however, severe disease-related events including life-threatening infections, bleeding, autoimmune diseases, and malignancies were common.

X-Linked Neutropenia (XLN)

Males with XLN typically present with congenital neutropenia associated with myelodysplasia, increased myeloid cell apoptosis, and lymphoid cell abnormalities. Beel & Vandenberghe [2009] described two males with XLN who developed myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Boztug & Klein [2011] estimate that 20%-30% of males with XLN are at risk for MDS or AML.

Female Carriers for WAS-Related Disorders

Female carriers of a WAS 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. Females carriers for a WAS pathogenic variant can in rare cases present with typical features of Wiskott-Aldrich syndrome such as severe thrombocytopenia and/or immunologic dysfunction [Lutskiy et al 2002, Boonyawat et al 2013, Daza-Cajigal et al 2013, Takimoto et al 2015].

Genotype-Phenotype Correlations

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

While several reports described missense variants in association with XLT or mild disease and nonsense, frameshift, or splice site variants in severe disease [Zhu et al 1997, Notarangelo & Ochs 2003, Imai et al 2004, Liu et al 2015], other studies failed to find consistent correlation between a particular pathogenic variant and clinical outcome [Greer et al 1996, Schindelhauer et al 1996, Lemahieu et al 1999, Fillat et al 2001].

XLT is typically associated with WAS pathogenic missense variants and most males with XLT are able to produce WASP. Specific pathogenic variants are not universally associated with XLT and disease severity varies considerably within families [Albert et al 2011, Liu et al 2015].

XLN is caused by rare pathogenic variants 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 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:

Some studies have focused on WASP expression as a better predictor of clinical severity of a WAS-related disorder than the pathogenic variant 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]. Similarly, Liu et al [2015] demonstrated that 75% of individuals diagnosed with XLT had detectable WASP while the majority of individuals with classic Wiskott-Aldrich syndrome did not express WASP in peripheral blood mononuclear cells.
  • 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 [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 pathogenic variants in WAS.

Penetrance

Penetrance is complete in males with a WAS pathogenic variant.

Prevalence

The estimated prevalence of WAS-related disorders is one to four per 1,000,000 live male births. About 1.2% of all individuals in the United States with primary immune deficiency have Wiskott-Aldrich syndrome [Buchbinder et al 2014].

The disorder occurs worldwide with no racial or ethnic predilection.

Differential Diagnosis

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.

Wiskott-Aldrich syndrome 2 (WAS2) (OMIM 614493) is a rare autosomal recessive immunodeficiency characterized by recurrent infections, eczema, and thrombocytopenia. Like individuals with WAS-related Wiskott-Aldrich syndrome, individuals with WAS2 show low numbers of B and T cells, defective T cell proliferation and chemotaxis, low NK cell function, and abnormal WASP. Unlike individuals with WAS-related Wiskott-Aldrich syndrome, individuals with WAS2 have normal platelet volumes. WAS2 is caused by biallelic pathogenic variants in WIPF1 [Lanzi et al 2012]. Molecular testing for WIPF1 pathogenic variants should be considered in symptomatic males (especially those with normal platelet volumes or in whom sequence analysis of WAS did not identify a pathogenic variant) and in symptomatic females.

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. In typical X-SCID lack of IL2RG function results in near-complete absence of T and natural killer (NK) lymphocytes and nonfunctional B lymphocytes. X-SCID is almost universally fatal in the first two years of life unless reconstitution of the immune system is achieved through bone marrow transplant or gene therapy. X-SCID is caused by a hemizygous pathogenic variant 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 pathogenic variants 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 pathogenic variants 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.

X-Linked Thrombocytopenia (XLT)

The differential diagnosis for XLT includes GATA1-related X-linked cytopenia, 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.

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. For a detailed review of congenital neutropenia, refer to the review article by Hauck & Klein [2013].

Management

Evaluations Following Initial Diagnosis

The following are appropriate:

  • Referral to immunologist for management
  • Platelet count and size
  • T-cell subsets
  • Immunoglobulin levels
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

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

Wiskott-Aldrich Syndrome

[Buchbinder et al 2014]

Hematopoietic cell transplantation (HCT). The only curative treatment clinically available for Wiskott-Aldrich syndrome is allogeneic HCT. Affected males who receive HCT from a matched healthy sib or closely matched unrelated donor before their second birthday have a greater than 90% probability of being cured of the disorder [Moratto et al 2011, Shin et al 2012].

Currently, males with a WAS pathogenic variant who meet the clinical diagnostic criteria for Wiskott-Aldrich syndrome (WAS score 3-5), have markedly decreased WASP expression, and have a suitably matched donor are candidates for HCT. Myeloablative conditioning prior to transplantation is the most widely used approach, as reduced-intensity conditioning increases the risk of partial engraftment, which may not be curative [Moratto et al 2011]. Some symptoms (e.g., autoimmune disease) may take months to resolve following complete engraftment.

Since the phenotype of Wiskott-Aldrich syndrome may evolve over time, optimal timing of transplantation is challenging. Individuals with absent intracellular WASP detection in hematopoietic cells are likely to develop Wiskott-Aldrich syndrome, although a minority will exhibit the milder X-linked thrombocytopenia (XLT) phenotype throughout their life span. HCT before development of autoimmunity and malignancy is highly desirable, and younger age at transplant is associated with improved long-term outcome following HCT; however, the use of multiple chemotherapeutic agents necessary to achieve myeloablation presents a risk in young infants.

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 Therapies Under Investigation).

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

Infection. For those individuals with clinical signs or symptoms of infection, prompt evaluation and treatment is necessary. The initiation of empiric parenteral antibiotic treatment is necessary in the majority of individuals. The evaluation should be exhaustive until the source of the infection is uncovered. This may include invasive assessments, as cultures and isolation of the offending organism should be sought in order to guide therapy. If HCT is being considered, attention to the prevention and treatment of infectious complications is necessary to limit pre-transplant morbidity.

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

X-Linked Thrombocytopenia (XLT)

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 [Albert et al 2010]. 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 HCT as a treatment option for such individuals. Given the excellent success in young children with classic Wiskott-Aldrich syndrome, HCT may be considered a viable option for individuals with XLT if an HLA–identical donor can be identified. 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, HCT in XLT needs to be decided on an individual basis.

X-Linked Neutropenia (XLN)

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

Prevention of Primary Manifestations

See Treatment of Manifestations for discussion of hematopoietic cell transplantation (HCT).

Infection

  • Antibiotic prophylaxis. 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. Individuals with recurrent bacterial sinopulmonary infections may benefit from prophylactic antibiotic use.
  • Intravenous immune globulin. Replacement therapy with IVIgG by age six months is administered every three to four weeks or subcutaneously, usually on a weekly basis. IVIgG is a highly purified blood derivative (a combination of many specific antimicrobial antibodies).
  • Routine childhood immunizations. Live vaccines should be avoided. Other “non-live” vaccinations can be given safely to individuals with a WAS-related disorder but may not generate protective levels of antibody.

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 2011] as well as in males with Wiskott-Aldrich syndrome who subsequently undergo 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).

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 HCT.

Evaluation of Relatives at Risk

Evaluation 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.

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 shows promise in the treatment of Wiskott-Aldrich syndrome, especially in severely affected males without an HLA-matched donor [Klein et al 2003, Qasim et al 2009, Boztug et al 2010]. However, initial attempts at gene therapy using a retroviral vector resulted in leukemic proliferation in several affected individuals.

More recent attempts using a lentiviral vector in two clinical trials are promising. In the first trial, Italian investigators showed improvement of platelet counts, immune function, and clinical manifestations of the disease in three individuals at one year or longer after gene therapy [Aiuti et al 2013]. In the second trial, six out of seven individuals treated in London and Paris also showed improvement of immune function and clinical manifestations six to 42 months after treatment, without evidence of clonal expansion [Hacein-Bey Abina et al 2015]. For reasons that are not yet clear, neither trial resulted in reconstitution of normal platelet numbers, although bleeding episodes significantly reduced in number and severity with individuals becoming independent from transfusion and need for thrombopoietin agonists. Thus far, no evidence of leukemic transformation has been reported with the use of the lentivirus vector [Aiuti et al 2013]. Based on these observations, it can be concluded that lentiviral-mediated gene therapy for Wiskott-Aldrich syndrome is feasible and can result in significant benefit for treated individuals. Clearly, however, long-term observation is warranted to confirm the superior safety of lentiviral gene transfer as an alternative treatment option for Wiskott-Aldrich syndrome.

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

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

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

Risk to Family Members

Parents of a proband

Sibs of a proband. The risk to sibs of a male proband depends on the genetic status of the mother.

Offspring of a proband. Affected males will pass the WAS pathogenic variant to:

Other family members. The proband's maternal aunts or other maternal relatives and their offspring may be at risk of being carriers of a WAS pathogenic variant, if female, or of being affected with a WAS-related disorder, if male.

Heterozygote (Carrier) Detection

Molecular genetic testing of at-risk female relatives to determine their genetic status is most informative if the pathogenic variant has been identified in the proband.

Note: (1) Females who are heterozygous (carriers) for this X-linked disorder may occasionally have mild thrombocytopenia (see Female Carriers for WAS-Related Disorders). (2) Identification of female heterozygotes requires either (a) prior identification of the WAS pathogenic variant in the family or, (b) if an affected male is not available for testing, molecular genetic testing first by sequence analysis, and if no pathogenic variant is identified, by gene-targeted 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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the WAS pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Canadian Immunodeficiencies Patient Organization (CIPO)
    362 Concession Road 12
    RR #2
    Hastings Ontario K0L 1Y0
    Canada
    Phone: 877-262-2476 (toll-free)
    Fax: 866-942-7651 (toll-free)
    Email: info@cipo.ca
  • Jeffrey Modell Foundation/National Primary Immunodeficiency Resource Center
    747 Third Avenue
    New York NY 10017
    Phone: 866-463-6474 (toll-free); 212-819-0200
    Fax: 212-764-4180
    Email: info@jmfworld.org
  • European Society for Immunodeficiencies (ESID) Registry
    Dr. Gerhard Kindle
    University Medical Center Freiburg Centre of Chronic Immunodeficiency
    Engesserstr. 4
    79106 Freiburg
    Germany
    Phone: 49-761-270-34450
    Email: esid-registry@uniklinik-freiburg.de
  • National Cancer Institute Inherited Bone Marrow Failure Syndromes (IBMFS) Cohort Registry
    Phone: 800-518-8474
    Email: NCI.IBMFS@westat.com
  • Primary Immunodeficiency Diseases Registry at USIDNET
    40 West Chesapeake Avenue
    Suite 308
    Towson MD 21204-4803
    Phone: 866-939-7568
    Fax: 410-321-0293
    Email: contact@usidnet.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

WAS-Related Disorders: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for WAS-Related Disorders (View All in OMIM)

300299NEUTROPENIA, SEVERE CONGENITAL, X-LINKED; SCNX
300392WAS GENE; WAS
301000WISKOTT-ALDRICH SYNDROME; WAS
313900THROMBOCYTOPENIA 1; THC1

Gene structure. WAS comprises 12 exons that span more than 9 kb of genomic DNA. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. More than 350 pathogenic WAS variants have been published. Pathogenic variants have been found in all 12 exons. About half of these pathogenic variants are missense variants that interfere with protein function or nonsense variants that lead to protein truncation. The remaining pathogenic variants are small deletions/insertions, splicing variants, gross deletions/insertions and complex rearrangements. See Table A.

Normal gene product. The 1.8 kb mRNA transcript encodes an intracellular 53-kd proline-rich protein of 502 amino acids termed WASP (Wiskott-Aldrich syndrome protein). WASP is expressed mainly in hematopoietic cells and has a role in signal transduction [Cory et al 1996, Snapper & Rosen 1999] and actin cytoskeleton organization in response to external stimuli [Kolluri et al 1996, Bompard & Caron 2004, Stradal et al 2004].

WASP activity is regulated by interaction with activated guanosine triphosphate (GTP)-loaded Cdc42 [Hemsath et al 2005] and post-translational modification (e.g., phosphorylation) [Badour et al 2004]. In normal NK cells, WASP is expressed and localized to the activating immunologic synapse with filamentous actin (F-actin), which presumably plays an important role in NK cell cytolytic function [Orange et al 2002].

Abnormal gene product. WAS pathogenic variants lead to changes in the amino acid sequence, truncation, or absence of WASP.

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 WAS-related disorders exhibit defects in migration, anchoring, and localization [Kolluri et al 1996, de Noronha et al 2005, Snapper et al 2005, Gallego et al 2006].

References

Published Guidelines/Consensus Statements

  • American Society of Human Genetics Social Issues Subcommittee on Familial Disclosure. ASHG statement. Professional disclosure of familial genetic information. Available online. 1998. Accessed 10-10-17. [PMC free article: PMC1376910] [PubMed: 9537923]
  • Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available online. 2013. Accessed 10-10-17. [PubMed: 23428972]
  • European Society for Immunodeficiencies (ESID). Diagnostic criteria for primary immunodeficiencies: Wiskott-Aldrich syndrome. Available online. 2006. Accessed 10-10-17.

Literature Cited

  • Albert MH, Bittner TC, Nonoyama S, Notarangelo LD, Burns S, Imai K, Espanol T, Fasth A, Pellier I, Strauss G, Morio T, Gathmann B, Noordzij JG, Fillat C, Hoenig M, Nathrath M, Meindl A, Pagel P, Wintergerst U, Fischer A, Thrasher AJ, Belohradsky BH, Ochs HD. X-linked thrombocytopenia (XLT) due to WAS mutations: clinical characteristics, long-term outcome, and treatment options. Blood. 2010;115:3231–8. [PubMed: 20173115]
  • Albert MH, Notarangelo LD, Ochs HD. Clinical spectrum, pathophysiology and treatment of the Wiskott-Aldrich syndrome. Curr Opin Hematol. 2011;18:42–8. [PubMed: 21076297]
  • Aldrich RA, Steinberg AG, Campbell DC. Pedigree demonstrating a sex-linked recessive condition characterized by draining ears, eczematoid dermatitis and bloody diarrhea. Pediatrics. 1954;13:133–9. [PubMed: 13133561]
  • Andreu N, Pujol-Moix N, Martinez-Lostao L, Oset M, Muniz-Diaz E, Estivill X, Volpini V, Fillat C. Wiskott-Aldrich syndrome in a female with skewed X-chromosome inactivation. Blood Cells Mol Dis. 2003;31:332–7. [PubMed: 14636648]
  • Arveiler B, de Saint-Basile G, Fischer A, Griscelli C, Mandel JL. Germ-line mosaicism simulates genetic heterogeneity in Wiskott-Aldrich syndrome. Am J Hum Genet. 1990 May;46(5):906–11. [PMC free article: PMC1683605] [PubMed: 1971143]
  • Ariga T, Kondoh T, Yamaguchi K, Yamada M, Sasaki S, Nelson DL, Ikeda H, Kobayashi K, Moriuchi H, Sakiyama Y. Spontaneous in vivo reversion of an inherited mutation in the Wiskott-Aldrich syndrome. J Immunol. 2001;166:5245–9. [PubMed: 11290809]
  • Aiuti A, Biasco L, Scaramuzza S, Ferrua F, Cicalese MP, Baricordi C, Dionisio F, Calabria A, Giannelli S, Castiello MC, Bosticardo M, Evangelio C, Assanelli A, Casiraghi M, Di Nunzio S, Callegaro L, Benati C, Rizzardi P, Pellin D, Di Serio C, Schmidt M, Von Kalle C, Gardner J, Mehta N, Neduva V, Dow DJ, Galy A, Miniero R, Finocchi A, Metin A, Banerjee PP, Orange JS, Galimberti S, Valsecchi MG, Biffi A, Montini E, Villa A, Ciceri F, Roncarolo MG, Naldini L. Lentiviral hematopoietic stem cell gene therapy in patients with Wiskott-Aldrich syndrome. Science. 2013;341:1233151. [PMC free article: PMC4375961] [PubMed: 23845947]
  • Badour K, Zhang J, Shi F, Leng Y, Collins M, Siminovitch KA. Fyn and PTP-PEST-mediated regulation of Wiskott-Aldrich syndrome protein (WASp) tyrosine phosphorylation is required for coupling T cell antigen receptor engagement to WASp effector function and T cell activation. J Exp Med. 2004;199:99–112. [PMC free article: PMC1887720] [PubMed: 14707117]
  • Beel K, Vandenberghe P. G-CSF receptor (CSF3R) mutations in X-linked neutropenia evolving to acute myeloid leukemia or myelodysplasia. Haematologica. 2009;94:1449–52. [PMC free article: PMC2754963] [PubMed: 19794089]
  • Bompard G, Caron E. Regulation of WASP/WAVE proteins: making a long story short. J Cell Biol. 2004;166:957–62. [PMC free article: PMC2172026] [PubMed: 15452139]
  • Boonyawat B, Dhanraj S, Al Abbas F, Zlateska B, Grunenbaum E, Roifman CM, Steele L, Meyn S, Blanchette V, Scherer SW, Swierczek S, Prchal J, Zhu Q, Torgerson TR, Ochs HD, Dror Y. Combined de-novo mutation and non-random X-chromosome inactivation causing Wiskott-Aldrich syndrome in a female with thrombocytopenia. J Clin Immunol. 2013;33:1150–5. [PubMed: 23943155]
  • Boztug K, Klein C. Genetic etiologies of severe congenital neutropenia. Curr Opin Pediatr. 2011;23:21–6. [PubMed: 21206270]
  • Boztug K, Schmidt M, Schwarzer A, Banerjee PP, Díez IA, Dewey RA, Böhm M, Nowrouzi A, Ball CR, Glimm H, Naundorf S, Kühlcke K, Blasczyk R, Kondratenko I, Maródi L, Orange JS, von Kalle C, Klein C. Stem-cell gene therapy for the Wiskott-Aldrich syndrome. N Engl J Med. 2010;363:1918–27. [PMC free article: PMC3064520] [PubMed: 21067383]
  • Buchbinder D, Nadeau K, Nugent D. Monozygotic twin pair showing discordant phenotype for X-linked thrombocytopenia and Wiskott-Aldrich syndrome: a role for epigenetics? J Clin Immunol. 2011;31:773–7. [PubMed: 21710275]
  • Buchbinder D, Nugent DJ, Fillipovich AH. Wiskott-Aldrich syndrome: diagnosis, current management, and emerging treatments. Appl Clin Genet. 2014;7:55–66. [PMC free article: PMC4012343] [PubMed: 24817816]
  • Catucci M, Castiello MC, Pala F, Bosticardo M, Villa A. Autoimmunity in wiskott-Aldrich syndrome: an unsolved enigma. Front Immunol. 2012;3:209. [PMC free article: PMC3399097] [PubMed: 22826711]
  • Chen N, Zhang ZY, Liu DW, Liu W, Tang XM, Zhao XD. The clinical features of autoimmunity in 53 patients with Wiskott-Aldrich syndrome in China: a single-center study. Eur J Pediatr. 2015;174:1311–8. [PubMed: 25877044]
  • Conley ME, Saragoussi D, Notarangelo L, Etzioni A, Casanova JL. An international study examining therapeutic options used in treatment of Wiskott-Aldrich syndrome. Clin Immunol. 2003;109:272–7. [PubMed: 14697741]
  • Cory GO, MacCarthy-Morrogh L, Banin S, Gout I, Brickell PM, Levinsky RJ, Kinnon C, Lovering RC. Evidence that the Wiskott-Aldrich syndrome protein may be involved in lymphoid cell signaling pathways. J Immunol. 1996;157:3791–5. [PubMed: 8892607]
  • Davis BR, Candotti F. Revertant somatic mosaicism in the Wiskott-Aldrich syndrome. Immunol Res. 2009;44:127–31. [PubMed: 19129986]
  • Daza-Cajigal V, Martínez-Pomar N, Garcia-Alonso A, Heine-Suñer D, Torres S, Vega AK, Molina IJ, Matamoros N. X-linked thrombocytopenia in a female with a complex familial pattern of X-chromosome inactivation. Blood Cells Mol Dis. 2013 Aug;51(2):125–9. [PubMed: 23689198]
  • de Noronha S, Hardy S, Sinclair J, Blundell MP, Strid J, Schulz O, Zwirner J, Jones GE, Katz DR, Kinnon C, Thrasher AJ. Impaired dendritic-cell homing in vivo in the absence of Wiskott-Aldrich syndrome protein. Blood. 2005;105:1590–7. [PubMed: 15494425]
  • 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]
  • Dupuis-Girod S, Medioni J, Haddad E, Quartier P, Cavazzana-Calvo M, Le Deist F, de Saint Basile G, Delaunay J, Schwarz K, Casanova JL, Blanche S, Fischer A. Autoimmunity in Wiskott-Aldrich syndrome: risk factors, clinical features, and outcome in a single-center cohort of 55 patients. Pediatrics. 2003;111:e622–7. [PubMed: 12728121]
  • Fillat C, Espanol T, Oset M, Ferrando M, Estivill X, Volpini V. Identification of WASP mutations in 14 Spanish families with Wiskott-Aldrich syndrome. Am J Med Genet. 2001;100:116–21. [PubMed: 11298372]
  • Friedrich W, Schütz C, Schulz A, Benninghoff U, Hönig M. Results and long-term outcome in 39 patients with Wiskott-Aldrich syndrome transplanted from HLA-matched and -mismatched donors. Immunol Res. 2009;44:18–24. [PubMed: 18846321]
  • Gallego MD, de la Fuente MA, Anton IM, Snapper S, Fuhlbrigge R, Geha RS. WIP and WASP play complementary roles in T cell homing and chemotaxis to SDF-1alpha. Int Immunol. 2006;18:221–32. [PubMed: 16141245]
  • Greer WL, Shehabeldin A, Schulman J, Junker A, Siminovitch KA. Identification of WASP mutations, mutation hotspots and genotype-phenotype disparities in 24 patients with the Wiskott-Aldrich syndrome. Hum Genet. 1996;98:685–90. [PubMed: 8931701]
  • Hauck F, Klein C. Curr Opin Allergy Clin Immunol. 2013;13:596–606. Pathogenic mechanisms and clinical implications of congenital neutropenia syndromes. [PubMed: 24145314]
  • Hacein-Bey Abina S, Gaspar HB, Blondeau J, Caccavelli L, Charrier S, Buckland K, Picard C, Six E, Himoudi N, Gilmour K, McNicol AM, Hara H, Xu-Bayford J, Rivat C, Touzot F, Mavilio F, Lim A, Treluyer JM, Héritier S, Lefrère F, Magalon J, Pengue-Koyi I, Honnet G, Blanche S, Sherman EA, Male F, Berry C, Malani N, Bushman FD, Fischer A, Thrasher AJ, Galy A, Cavazzana M. Outcomes following gene therapy in patients with severe Wiskott-Aldrich syndrome. JAMA. 2015;313:1550–63. [PMC free article: PMC4942841] [PubMed: 25898053]
  • Hemsath L, Dvorsky R, Fiegen D, Carlier MF, Ahmadian MR. An electrostatic steering mechanism of Cdc42 recognition by Wiskott-Aldrich syndrome proteins. Mol Cell. 2005;20:313–24. [PubMed: 16246732]
  • Imai K, Morio T, Zhu Y, Jin Y, Itoh S, Kajiwara M, Yata J, Mizutani S, Ochs HD, Nonoyama S. Clinical course of patients with WASP gene mutations. Blood. 2004;103:456–64. [PubMed: 12969986]
  • Imai K, Nonoyama S, Ochs HD. WASP (Wiskott-Aldrich syndrome protein) gene mutations and phenotype. Curr Opin Allergy Clin Immunol. 2003;3:427–36. [PubMed: 14612666]
  • Inoue H, Kurosawa H, Nonoyama S, Imai K, Kumazaki H, Matsunaga T, Sato Y, Sugita K, Eguchi M. X-linked thrombocytopenia in a girl. Br J Haematol. 2002;118:1163–5. [PubMed: 12199801]
  • Jin Y, Mazza C, Christie JR, Giliani S, Fiorini M, Mella P, Gandellini F, Stewart DM, Zhu Q, Nelson DL, Notarangelo LD, Ochs HD. Mutations of the Wiskott-Aldrich Syndrome Protein (WASP): hotspots, effect on transcription, and translation and phenotype/genotype correlation. Blood. 2004;104:4010–9. [PubMed: 15284122]
  • Klein C, Nguyen D, Liu CH, Mizoguchi A, Bhan AK, Miki H, Takenawa T, Rosen FS, Alt FW, Mulligan RC, Snapper SB. Gene therapy for Wiskott-Aldrich syndrome: rescue of T-cell signaling and amelioration of colitis upon transplantation of retrovirally transduced hematopoietic stem cells in mice. Blood. 2003;101:2159–66. [PubMed: 12433691]
  • Kolluri R, Tolias KF, Carpenter CL, Rosen FS, Kirchhausen T. Direct interaction of the Wiskott-Aldrich syndrome protein with the GTPase Cdc42. Proc Natl Acad Sci U S A. 1996;93:5615–8. [PMC free article: PMC39296] [PubMed: 8643625]
  • Lemahieu V, Gastier JM, Francke U. Novel mutations in the Wiskott-Aldrich syndrome protein gene and their effects on transcriptional, translational, and clinical phenotypes. Hum Mutat. 1999;14:54–66. [PubMed: 10447259]
  • Lanzi G, Moratto D, Vairo D, Masneri S, Delmonte O, Paganini T, Parolini S, Tabellini G, Mazza C, Savoldi G, Montin D, Martino S, Tovo P, Pessach IM, Massaad MJ, Ramesh N, Porta F, Plebani A, Notarangelo LD, Geha RS, Giliani S. A novel primary human immunodeficiency due to deficiency in the WASP-interacting protein WIP. J Exp Med. 2012;209:29–34. [PMC free article: PMC3260865] [PubMed: 22231303]
  • Liu DW, Zhang ZY, Zhao Q, Jiang LP, Liu W, Tu WW, Song WX, Zhao XD. Wiskott-Aldrich syndrome/X-linked thrombocytopenia in China: Clinical characteristic and genotype-phenotype correlation. Pediatr Blood Cancer. 2015 Sep;62(9):1601–8. [PubMed: 25931402]
  • Lutskiy MI, Rosen FS, Remold-O'Donnell E. Genotype-proteotype linkage in the Wiskott-Aldrich syndrome. J Immunol. 2005;175:1329–36. [PubMed: 16002738]
  • Lutskiy MI, Sasahara Y, Kenney DM, Rosen FS, Remold-O'Donnell E. Wiskott-Aldrich syndrome in a female. Blood. 2002;100:2763–8. [PubMed: 12351383]
  • Mahlaoui N, Pellier I, Mignot C, et al. Characteristics and outcome of early-onset, severe forms of Wiskott-Aldrich syndrome. Blood. 2013;121:1510–6. [PubMed: 23264593]
  • Moratto D, Giliani S, Bonfim C, Mazzolari E, Fischer A, Ochs HD, Cant AJ, Thrasher AJ, Cowan MJ, Albert MH, Small T, Pai SY, Haddad E, Lisa A, Hambleton S, Slatter M, Cavazzana-Calvo M, Mahlaoui N, Picard C, Torgerson TR, Burroughs L, Koliski A, Neto JZ, Porta F, Qasim W, Veys P, Kavanau K, Hönig M, Schulz A, Friedrich W, Notarangelo LD. Long-term outcome and lineage-specific chimerism in 194 patients with Wiskott-Aldrich syndrome treated by hematopoietic cell transplantation in the period 1980-2009: an international collaborative study. Blood. 2011;118:1675–84. [PMC free article: PMC3156052] [PubMed: 21659547]
  • Mullen CA, Anderson KD, Blaese RM. Splenectomy and/or bone marrow transplantation in the management of the Wiskott-Aldrich syndrome: long-term follow-up of 62 cases. Blood. 1993;82:2961–6. [PubMed: 8219187]
  • Notarangelo LD, Ochs HD. Wiskott-Aldrich Syndrome: a model for defective actin reorganization, cell trafficking and synapse formation. Curr Opin Immunol. 2003;15:585–91. [PubMed: 14499269]
  • Orange JS, Ramesh N, Remold-O'Donnell E, Sasahara Y, Koopman L, Byrne M, Bonilla FA, Rosen FS, Geha RS, Strominger JL. Wiskott-Aldrich syndrome protein is required for NK cell cytotoxicity and colocalizes with actin to NK cell-activating immunologic synapses. Proc Natl Acad Sci U S A. 2002;99:11351–6. [PMC free article: PMC123260] [PubMed: 12177428]
  • Ozsahin H, Cavazzana-Calvo M, Notarangelo LD, Schulz A, Thrasher AJ, Mazzolari E, Slatter MA, Le Deist F, Blanche S, Veys P, Fasth A, Bredius R, Sedlacek P, Wulffraat N, Ortega J, Heilmann C, O'Meara A, Wachowiak J, Kalwak K, Matthes-Martin S, Gungor T, Ikinciogullari A, Landais P, Cant AJ, Friedrich W, Fischer A. Long-term outcome following hematopoietic stem-cell transplantation in Wiskott-Aldrich syndrome: collaborative study of the European Society for Immunodeficiencies and European Group for Blood and Marrow Transplantation. Blood. 2008;111:439–45. [PubMed: 17901250]
  • Pai SY, DeMartiis D, Forino C, Cavagnini S, Lanfranchi A, Giliani S, Moratto D, Mazza C, Porta F, Imberti L, Notarangelo LD, Mazzolari E. Stem cell transplantation for the Wiskott-Aldrich syndrome: a single-center experience confirms efficacy of matched unrelated donor transplantation. Bone Marrow Transplant. 2006;38:671–9. [PubMed: 17013426]
  • Parolini O, Ressmann G, Haas OA, Pawlowsky J, Gadner H, Knapp W, Holter W. X-linked Wiskott-Aldrich syndrome in a girl. N Engl J Med. 1998;338:291–5. [PubMed: 9445409]
  • Proust A, Guillet B, Picard C, de Saint Basile G, Pondarré C, Tamary H, Dreyfus M, Tchernia G, Fischer A, Delaunay J. Detection of 28 novel mutations in the Wiskott-Aldrich syndrome and X-linked thrombocytopenia based on multiplex PCR. Blood Cells Mol Dis. 2007;39:102–6. [PubMed: 17400488]
  • Qasim W, Gaspar HB, Thrasher AJ. Progress and prospects: gene therapy for inherited immunodeficiencies. Gene Ther. 2009 Nov;16(11):1285–91. [PubMed: 19776764]
  • Schindelhauer D, Weiss M, Hellebrand H, Golla A, Hergersberg M, Seger R, Belohradsky BH, Meindl A. Wiskott-Aldrich syndrome: no strict genotype-phenotype correlations but clustering of missense mutations in the amino-terminal part of the WASP gene product. Hum Genet. 1996;98:68–76. [PubMed: 8682510]
  • Schurman SH, Candotti F. Autoimmunity in Wiskott-Aldrich syndrome. Curr Opin Rheumatol. 2003;15:446–53. [PubMed: 12819473]
  • Shin CR, Kim MO, Li D, Bleesing JJ, Harris R, Mehta P, Jodele S, Jordan MB, Marsh RA, Davies SM, Filipovich AH. Outcomes following hematopoietic cell transplantation for Wiskott-Aldrich syndrome. Bone Marrow Transplant. 2012;47:1428–35. [PubMed: 22426750]
  • Snapper SB, Meelu P, Nguyen D, Stockton BM, Bozza P, Alt FW, Rosen FS, von Andrian UH, Klein C. WASP deficiency leads to global defects of directed leukocyte migration in vitro and in vivo. J Leukoc Biol. 2005;77:993–8. [PubMed: 15774550]
  • Snapper SB, Rosen FS. The Wiskott-Aldrich syndrome protein (WASP): roles in signaling and cytoskeletal organization. Annu Rev Immunol. 1999;17:905–29. [PubMed: 10358777]
  • Stradal TE, Rottner K, Disanza A, Confalonieri S, Innocenti M, Scita G. Regulation of actin dynamics by WASP and WAVE family proteins. Trends Cell Biol. 2004;14:303–11. [PubMed: 15183187]
  • Sullivan KE, Mullen CA, Blaese RM, Winkelstein JA. A multi-institutional survey of the Wiskott-Aldrich syndrome. J Pediatr. 1994;125:876–85. [PubMed: 7996359]
  • Takimoto T, Takada H, Ishimura M, Kirino M, Hata K, Ohara O, Morio T, Hara T. Wiskott-Aldrich syndrome in a girl caused by heterozygous WASP mutation and extremely skewed X-chromosome inactivation: a novel association with maternal uniparental isodisomy 6. Neonatology. 2015;107:185–90. [PubMed: 25633059]
  • Wada T, Konno A, Schurman SH, Garabedian EK, Anderson SM, Kirby M, Nelson DL, Candotti F. Second-site mutation in the Wiskott-Aldrich syndrome (WAS) protein gene causes somatic mosaicism in two WAS siblings. J Clin Invest. 2003;111:1389–97. [PMC free article: PMC154438] [PubMed: 12727931]
  • Wada T, Schurman SH, Otsu M, Garabedian EK, Ochs HD, Nelson DL, Candotti F. Somatic mosaicism in Wiskott--Aldrich syndrome suggests in vivo reversion by a DNA slippage mechanism. Proc Natl Acad Sci U S A. 2001;98:8697–702. [PMC free article: PMC37498] [PubMed: 11447283]
  • Xie JW, Zhang ZY, Wu JF, Liu DW, Liu W, Zhao Y, Jiang LP, Tang XM, Wang M, Zhao XD. In vivo reversion of an inherited mutation in a Chinese patient with Wiskott-Aldrich syndrome. Hum Immunol. 2015;76:406–13. [PubMed: 25862925]
  • Zhu Q, Watanabe C, Liu T, Hollenbaugh D, Blaese RM, Kanner SB, Aruffo A, Ochs HD. Wiskott-Aldrich syndrome/X-linked thrombocytopenia: WASP gene mutations, protein expression, and phenotype. Blood. 1997;90:2680–9. [PubMed: 9326235]

Suggested Reading

  • Bosticardo M, Marangoni F, Aiuti A, Villa A, Roncarolo MG. Recent advances in understanding the pathophysiology of Wiskott-Aldrich syndrome. Blood. 2009;113:6288–95. [PubMed: 19351959]
  • French DL, Newman PJ, Poncz M. Inherited disorders of platelets. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). Chap 177. New York, NY: McGraw-Hill.
  • Griffith LM, Cowan MJ, Notarangelo LD, Kohn DB, Puck JM, Pai SY, Ballard B, Bauer SC, Bleesing JJ, Boyle M, Brower A, Buckley RH, van der Burg M, Burroughs LM, Candotti F, Cant AJ, Chatila T, Cunningham-Rundles C, Dinauer MC, Dvorak CC, Filipovich AH, Fleisher TA, Bobby Gaspar H, Gungor T, Haddad E, Hovermale E, Huang F, Hurley A, Hurley M, Iyengar S, Kang EM, Logan BR, Long-Boyle JR, Malech HL, McGhee SA, Modell F, Modell V, Ochs HD, O'Reilly RJ, Parkman R, Rawlings DJ, Routes JM, Shearer WT, Small TN, Smith H, Sullivan KE, Szabolcs P, Thrasher A, Torgerson TR, Veys P, Weinberg K, Zuniga-Pflucker JC. on behalf of the workshop participants. Primary Immune Deficiency Treatment Consortium (PIDTC) report. J Allergy Clin Immunol. 2014;133:335–47. [PMC free article: PMC3960312] [PubMed: 24139498]
  • Gulácsy 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, Tóth B, Erdos M, van der Burg M, Maródi L. J Project Study Group. Genetic characteristics of eighty-seven patients with the Wiskott-Aldrich syndrome. Mol Immunol. 2011 Feb;48(5):788–92. [PubMed: 21185603]
  • Kamani NR, Kumar S, Hassebroek A, Eapen M, LeRademacher J, Casper J, Cowan M, Sánchez de Toledo J, Ferster A, Szabolcs P, Wingard JR, Horwitz E, Filipovich AH. Malignancies after hematopoietic cell transplantation for primary immune deficiencies: a report from the Center for International Blood and Marrow Transplant Research. Biol Blood Marrow Transplant. 2011;17:1783–9. [PMC free article: PMC3370408] [PubMed: 21658461]
  • Massaad MJ, Ramesh N, Geha RS. Wiskott-Aldrich syndrome: a comprehensive review. Ann N Y Acad Sci. 2013;1285:26–43. [PubMed: 23527602]
  • Ochs HD, Filipovich AH, Veys P, Cowan MJ, Kapoor N. Wiskott-Aldrich syndrome: diagnosis, clinical and laboratory manifestations, and treatment. Biol Blood Marrow Transplant. 2009;15:84–90. [PubMed: 19147084]
  • Ochs HD, Thrasher AJ. The Wiskott-Aldrich syndrome. J Allergy Clin Immunol. 2006;117:725–38. [PubMed: 16630926]
  • 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]

Chapter Notes

Author History

Lucas Bronicki, PhD (2016-present)
Sharat Chandra, MD, MRCPCH (2016-present)
Alexandra H Filipovich, MD; Cincinnati Children’s Hospital Medical Center (2004-2016)
Judith Johnson, MS; Cincinnati Children’s Hospital Medical Center (2004-2016)
Chinmayee B Nagaraj, MS (2016-present)
Kejian Zhang, MD, MBA (2004-present)

Revision History

  • 22 September 2016 (sw) Comprehensive update posted live
  • 20 March 2014 (me) Comprehensive update posted live
  • 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
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