Clinical characteristics.

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

Wiskott-Aldrich syndrome usually presents in infancy. Affected males have thrombocytopenia with intermittent mucosal bleeding, bloody diarrhea, and intermittent or chronic petechiae and purpura; recurrent bacterial, viral, fungal, and/or opportunistic infections; and eczema. Approximately 25%-40% of those who survive the early complications develop one or more autoimmune conditions including hemolytic anemia, immune thrombocytopenic purpura, immune-mediated neutropenia, vasculitis, rheumatoid arthritis, and immune-mediated damage to the kidneys and liver. Individuals with a 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 small platelet volume and thrombocytopenia. Severe disease-related events include severe bleeding episodes (14%), autoimmunity (12%), life-threatening infections (7%), and malignancy (5%).

Males with XLN typically have congenital neutropenia associated with myelodysplasia, hyperactive neutrophils, increased myeloid cell apoptosis, 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; at least one of the following features: eczema, recurrent bacterial, viral, and fungal infections, autoimmune disease(s), malignancy, reduced WASP expression in a fresh blood sample, abnormal antibody response to polysaccharide antigens and/or low isohemagglutinins, or positive maternal family history of a WAS-related disorder; and a hemizygous WAS pathogenic variant identified by molecular genetic testing (necessary to confirm the diagnosis).

The diagnosis of a WAS-related disorder in a female is uncommon. It is usually established by identification of a heterozygous pathogenic variant in WAS by molecular genetic testing in a female with severe skewed X-chromosome inactivation and increased expression of the mutated WAS allele.

Management.

Targeted therapy: The only curative targeted therapy clinically available for Wiskott-Aldrich syndrome is allogeneic hematopoietic stem cell transplantation (HSCT). In those with XLT, decision to treat with HSCT is determined on an individual basis.

Treatment of manifestations: In those with Wiskott-Aldrich syndrome and XLT, treatment is individualized based on disease manifestations and includes management of thrombocytopenia; prevention of infection with immunoglobulin replacement; topical steroids for eczema; antibiotics as needed for chronic skin infections; prophylactic antibiotics for Pneumocystis jirovecii in infants with Wiskott-Aldrich syndrome; intravenous immunoglobulin G; routine non-live immunizations; prompt evaluation and treatment for infection including empiric parenteral antibiotics and exhaustive search for source of infection; and judicious use of immunosuppressants for autoimmune disease prior to definitive treatment.

In those with XLN, treatment includes granulocyte colony-stimulating factor therapy; routine non-live immunizations; prompt evaluation and treatment for infection including empiric parenteral antibiotics and exhaustive search for source of infection; and treatment of myelodysplastic syndrome and acute myelogenous leukemia per hematologist/oncologist.

Surveillance: Complete blood count including platelet count and size and assessment for complications associated with increased bleeding as recommended by hematologist; annual skin examination; assessment by immunologist including for recurrent infections with frequency as recommended by immunologist; annual clinical assessment for autoimmune dysfunction and for manifestations of lymphoma.

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 HSCT.

Evaluation of relatives at risk: Evaluation of at-risk newborn males so that morbidity and mortality can be reduced by early diagnosis and treatment. Evaluation of relatives considering stem cell donation to inform transplant donor decision making.

Genetic counseling.

WAS-related disorders are inherited in an X-linked manner. If the mother of the proband has a WAS pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be symptomatic. Females who inherit the pathogenic variant will be carriers and are typically asymptomatic. Males with a WAS-related disorder transmit the pathogenic variant to all of their daughters and none of their sons. Once the WAS pathogenic variant has been identified in a family member, molecular genetic testing to identify female heterozygotes and prenatal and preimplantation genetic testing are possible.

Suggestive Findings

WAS-related disorders include a phenotypic spectrum ranging from severe to mild. The phenotypes and their diagnostic criteria, modified from the recommendations of the European Society of Immunodeficiencies (ESID), are listed here.

Wiskott-Aldrich syndrome should be suspected in a male with the following:

• Profound thrombocytopenia (<70,000 platelets/mm³)
• Small platelet size (mean platelet volume >2 standard deviations [SD] below the mean for the laboratory)
• Recurrent bacterial, viral, fungal, and/or other opportunistic infections in infancy or early childhood
• Eczema
• Autoimmune disorder, such as hemolytic anemia, vasculitis, rheumatoid arthritis, or glomerulonephritis
• Increased risk of cancer, particularly lymphoma
• Family history of one or more maternally related males with a WAS-related disorder
• Absent or decreased Wiskott-Aldrich syndrome protein (WASP) in hematopoietic cells 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 antigens (e.g., Pneumovax^®)

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

• 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 neutropenia (XLN) should be suspected in a male with the following:

• 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 (<70,000 platelets/mm³, confirmed with repeat examination)
  • Small platelets (platelet volume <7 fL, or mean platelet volume >2 SD below the mean for the laboratory)
• AND at least ONE of the following:
  • Eczema
  • Recurrent bacterial, viral, and/or fungal 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 a hemizygous WAS pathogenic (or likely pathogenic) variant identified by 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 (or likely pathogenic) variant in WAS by molecular genetic testing (see Table 1) along with clinical features consistent with a WAS-related disorder.

Note: (1) Females heterozygous for a WAS pathogenic variant are typically asymptomatic due to random X-chromosome inactivation that results in sufficient normal WASP expression. Blood cell populations can vary from normal WASP expression to severe skewed X-chromosome inactivation with expression of the mutated WAS allele [Lutskiy et al 2002, Boonyawat et al 2013, Daza-Cajigal et al 2013, Takimoto et al 2015, Hou et al 2021]. (2) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (3) Identification of a hemizygous or heterozygous WAS variant of uncertain significance does not establish or rule out the diagnosis.

Molecular testing approaches can include a combination of gene-targeted testing (single gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Clinical Description

WAS-related disorders comprise a spectrum that includes Wiskott-Aldrich syndrome, X-linked thrombocytopenia (XLT), and X-linked neutropenia (XLN). There is considerable overlap between phenotypes. WAS-related disorders usually present in infancy with low platelet counts, small platelet size, significant risk of bleeding, and, in some individuals, eczema and/or abnormal lymphocyte function with susceptibility to serious bacterial, viral, and fungal infections. Autoimmune disorders and lymphomas are frequent. The clinical phenotype may worsen with age. The clinical complications can vary widely, even in the same kindred. The prognosis for individuals with WAS-related disorders has improved as a result of improved treatment.

The WAS-related disorders clinical score (WAS score) is derived from clinical and laboratory features including thrombocytopenia, eczema, immunodeficiency, autoimmune disorders, and malignancy (see Table 2). 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]. Individuals with a higher WAS score (e.g., 5) at a younger age (e.g., during the first two years of life) may be at increased risk for morbidity and mortality [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]) [Cavannaugh et al 2022].

Genotype-Phenotype Correlations

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

At least 300 different disease-causing variants and six mutational hot spots in WAS have been described. Loss-of-function variants in WAS cause Wiskott-Aldrich syndrome and XLT, whereas gain-of-function variants in the region encoding the conserved GTPase binding domain of Wiskott-Aldrich syndrome protein (WASP) lead to XLN [Stenson et al 2020].

Specific pathogenic variants are not universally associated with a specific clinical phenotype, and disease severity varies considerably within families, even between monozygotic twins [Buchbinder et al 2011], which suggests epigenetic factors, other genetic alterations, and environmental factors (e.g., Epstein-Barr virus [EBV]) could contribute to the phenotypic heterogeneity [Albert et al 2011, Buchbinder et al 2014, Liu et al 2015]. While several reports described missense and certain intronic pathogenic variants in association with XLT or mild disease and nonsense, frameshift, or splice site variants in individuals with severe disease [Jin et al 2004, Liu et al 2015, Vallée et al 2024], other studies failed to find consistent correlation between a particular pathogenic variant type and clinical outcome [Buchbinder et al 2011, Liu et al 2021, Udomkittivorakul et al 2022].

XLN is caused by rare gain-of-function variants in the GTPase binding domain, which cause constitutive activation of WASP in tissues to compensate the reduced myelopoiesis and extremely low number of circulating neutrophil in peripheral blood. Therefore, individuals with XLN are generally not at high risk of infections and do not require permanent granulocyte colony-stimulating factor support. Disease severity varies considerably within families [Keszei et al 2018].

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:

• The phenotype of affected males in the same kindred can vary widely [Keszei et al 2018].
• Splice site variants may allow production of multiple gene products, including normally spliced WASP [Jin et al 2004].
• Reversion of an inherited pathogenic variant to a benign variant in a subpopulation of cells with improvement of clinical symptoms has been reported [Xie et al 2015].
• It is likely that the clinical phenotype in WAS-related disorders is modified by a somatic WAS pathogenic variant involving the second allele [Du et al 2006, Boztug et al 2008], pathogenic variants in other genes (e.g., those modifying atopy), epigenetic [Buchbinder et al 2011] and environmental factors, and/or encounters with ubiquitous or rare pathogens.

Some studies have focused on WASP expression as a better predictor of clinical severity of a WAS-related disorder than the pathogenic variant alone [Lemahieu et al 1999].

• In one study, 74.2% of individuals who produced WASP had XLT, while 86.5% of individuals who produced no WASP had Wiskott-Aldrich syndrome [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 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 in 1,000,000 live male births. About 1.2% of all individuals in the United States with primary immune deficiency have Wiskott-Aldrich syndrome [Buchbinder et al 2014, Quinn et al 2022].

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.

Genetic disorders of interest in the differential diagnosis Wiskott-Aldrich syndrome include those listed in Table 3.

Human immunodeficiency virus (HIV) infection can also be considered in males who initially present with Pneumocystis carinii pneumonia. HIV infection results in gradual destruction of the immune system. Individuals infected with HIV are at risk for illness and death from opportunistic infections and neoplasms; however, persistent thrombocytopenia is rarely, if ever, seen in individuals with HIV infection.

X-Linked Thrombocytopenia (XLT)

The differential diagnosis for XLT includes GATA1-related X-linked cytopenia, which is characterized by thrombocytopenia and/or anemia ranging from mild to severe and one or more of the following: platelet dysfunction, mild beta-thalassemia, neutropenia, and congenital erythropoietic porphyria in males. Thrombocytopenia typically presents in infancy as a bleeding disorder with easy bruising and mucosal bleeding, such as epistaxis. Anemia ranges from minimal (mild dyserythropoiesis) to severe (hydrops fetalis requiring in utero transfusion). At the extreme end of the GATA1-related clinical spectrum, severe hemorrhage and/or erythrocyte transfusion dependence are lifelong; at the milder end, anemia and the risk for bleeding decrease spontaneously with age.

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 detailed reviews of congenital neutropenia, see Furutani et al [2019] and Spoor et al [2019].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with a WAS-related disorder, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Treatment options vary based on the predicted disease burden in a particular individual. See Buchbinder et al [2014] for a review of treatment options for Wiscott-Aldrich syndrome.

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 6 are recommended.

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 HSCT.

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of at-risk male relatives of an affected individual so that morbidity and mortality can be reduced by early diagnosis and treatment. Of note, evaluation of newborn at-risk males is recommended before any elective procedure such as circumcision.

Rapid screening of at-risk males may be accomplished by WASP staining using flow cytometry. Definitive testing requires molecular genetic testing for the familial WAS pathogenic variant.

For hematopoietic stem cell donation. Any relative considering stem cell donation should undergo WASP flow cytometry-based testing for WASP expression and, if needed, WAS molecular genetic testing to clarify their genetic status so that informed risk-vs-benefit discussions for both recipient and donor can be incorporated into transplant donor-option decision making.

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

Therapies Under Investigation

Gene therapy. Lentiviral-mediated gene therapy for Wiskott-Aldrich syndrome is feasible and can result in significant benefit for treated individuals. However, long-term observation is warranted to confirm the superior safety of lentiviral gene transfer as an alternative treatment option for Wiskott-Aldrich syndrome.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

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

Risk to Family Members

Parents of a male proband

• The father of an affected male will not have a WAS-related disorder nor will he be hemizygous for a WAS pathogenic variant; therefore, he does not require further evaluation/testing.
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the WAS pathogenic variant cannot be detected in her leukocyte DNA, she most likely has gonadal mosaicism. Note: Females who are heterozygous for a WAS pathogenic variant rarely have significant clinical symptoms.
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier), the affected male may have a de novo WAS pathogenic variant (in which case the mother is not a carrier), or the mother may have somatic/gonadal mosaicism [Arveiler et al 1990]. About one third of affected males with no previous family history of the disorder have a de novo pathogenic variant.
• Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.
  Note: Testing of maternal leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.

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

• If the mother of the proband has a WAS pathogenic variant, the chance of transmitting it in each pregnancy is 50%.
  • Males who inherit the pathogenic variant will be symptomatic. The clinical presentation of males with a WAS pathogenic variant can vary widely even within the same family. In some families, males in their seventh decade may have mild manifestations such as chronic thrombocytopenia, whereas other male relatives with the condition may have severe symptoms in early infancy or childhood. Long-term prognosis varies based on the disease burden in a particular individual [Beel & Vandenberghe 2009, Albert et al 2011, Buchbinder et al 2011].
  • Females who inherit the pathogenic variant will be carriers and are typically asymptomatic due to random X-chromosome inactivation that results in sufficient normal Wiskott-Aldrich syndrome protein (WASP) expression. Mild thrombocytopenia is noted in a small proportion. Heterozygous females rarely present with typical features of Wiskott-Aldrich syndrome such as severe thrombocytopenia and/or immunologic dysfunction due to severe skewed X-chromosome inactivation with expression of the mutated WAS allele [Lutskiy et al 2002, Boonyawat et al 2013, Daza-Cajigal et al 2013, Takimoto et al 2015, Hou et al 2021].
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the WAS pathogenic variant cannot be detected in the leukocyte DNA of the mother, sibs remain at increased risk because of the possibility of maternal gonadal mosaicism [Arveiler et al 1990].

Offspring of a male proband. Males with a WAS-related disorder transmit the WAS pathogenic variant to:

• All of their daughters, who will be carriers (see Clinical Description, Heterozygous Females); and
• None of their sons.

Other family members. The maternal aunts and maternal cousins of a male proband may be at risk of having a WAS pathogenic variant.

Note: Molecular genetic testing may be able to identify the family member in whom a de novo pathogenic variant arose, information that could help determine genetic risk status of the extended family.

Carrier Detection

Molecular genetic testing. Identification of female heterozygotes requires prior identification of the WAS pathogenic variant in the family.

Note: (1) Females who are heterozygous (carriers) for this X-linked disorder are typically asymptomatic (see Clinical Description, Heterozygous Females).

Flow cytometry. In female carriers, flow cytometry has been shown to detect lower levels of WASP in monocytes but not lymphocytes (except in females with WAS pathogenic variants in distal exons); however, molecular genetic testing remains the gold standard for carrier detection [Yamada et al 2000, Basu et al 2024].

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 and discussion of the availability of prenatal/preimplantation genetic 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.

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

Prenatal Testing and Preimplantation Genetic Testing

Once the WAS pathogenic variant has been identified in a family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

WAS encodes actin nucleation-promoting factor WAS (also called Wiskott-Aldrich syndrome protein, or WASP), which is expressed exclusively in hematopoietic cells and has a role in signal transduction [Cory et al 1996, Snapper & Rosen 1999] and actin cytoskeleton organization in response to external stimuli in white blood cells [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 natural killer (NK) cells, WASP is expressed and localized to the activating immunologic synapse with filamentous actin, which presumably plays an important role in NK cell cytolytic function [Orange et al 2002].

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].

Mechanism of disease causation. Wiskott-Aldrich syndrome and XLT are caused by loss-of-function variants. XLN is caused by gain-of-function variants in the GTPase binding domain.

Author Notes

Miao Sun, PhD. Dr Sun's clinical work mainly focuses on exome and genome sequencing for rare germline-related conditions. Dr Sun is interested in immunodeficiency, metabolic disorders, and neurodevelopmental disease. Email: ude.csu.alhc@nusoaim

Author History

Lucas Bronicki, PhD; University of Cincinnati College of Medicine (2016-2024)
Sharat Chandra, MD (2016-present)
Shanmuganathan Chandrakasan, MD (2024-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)
Miao Sun, PhD (2024-present)
Kejian Zhang, MD, MBA (2004-present)

Revision History

• 15 August 2024 (sw) Comprehensive update posted live
• 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 live
• 30 September 2004 (me) Review posted live
• 1 October 2003 (jj) Original submission

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