Clinical Guidance

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 . Specific pathogenic variants are not universally associated with a specific clinical phenotype, and disease severity varies considerably within families, even between monozygotic twins , which suggests epigenetic factors, other genetic alterations, and environmental factors (e.g., Epstein-Barr virus [EBV]) could contribute to the phenotypic heterogeneity .

Source: GeneReviews — "WAS-Related Disorders"

Penetrance

Penetrance is complete in males with a WAS pathogenic variant.

Source: GeneReviews — "WAS-Related Disorders"

Diagnostic Criteria

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:

Source: GeneReviews — "WAS-Related Disorders"

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

Table 3.

Genetic Disorders of Interest in the Differential Diagnosis of Wiskott-Aldrich Syndrome

Gene | Disorder | MOI | Features of Disorder | Comment

Overlapping w/Wiskott-Aldrich syndrome | Distinguishing from Wiskott-Aldrich syndrome

WIPF1

| Wiskott-Aldrich syndrome 2 (OMIM 614493) | AR | • Recurrent infections, eczema, thrombocytopenia

Source: GeneReviews — "WAS-Related Disorders"

Management Guidelines

No clinical practice guidelines for WAS-related disorders have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder.

Evaluations Following Initial Diagnosis

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

Table 4.

WAS-Related Disorders: Recommended Evaluations Following Initial Diagnosis

System/Concern | Evaluation | Comment

Thrombocytopenia

| • Platelet count size

• Assessment for complications assoc w/ bleeding

• Referral to hematologist for periodic CBCs to monitor platelet counts assess for anemia assoc w/bleeding

| Occasionally, mild-to-moderate thrombocytopenia can present later in childhood, mimicking ITP but w/o response to oral steroids.

Eczema

| Skin should be examined for eczema. | Eczema is a variable feature.

Immunodeficiency

| Referral to immunologist for assessment of immunodeficiency: | Recurrent infections are a variable feature.

• T-cell subsets

• Ig levels

• Vaccine titers

• WASP expression

|

Autoimmune disorders

| Clinical assessment for autoimmune dysfunction | Rarely the presenting manifestation but can complicate disease course.

Malignancies

| Clinical assessment for manifestations of lymphoma

Genetic counseling

| By genetics professionals1 | To obtain a pedigree inform affected persons their families re...

Source: GeneReviews — "WAS-Related Disorders"

Clinical Guidance

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.

Source: GeneReviews — "WAS-Related Disorders"

Therapies Under Investigation

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. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "WAS-Related Disorders"

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in are recommended. Table 7. WAS-Related Disorders: Recommended Surveillance

Source: GeneReviews — "WAS-Related Disorders"