WAS-Related Disorders

Excerpt

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.