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WAS-Related Disorders.

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GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019.
2004 Sep 30 [updated 2016 Sep 22].

Author information

1
Assistant Professor, Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio
2
Assistant Professor of Clinical Pediatrics, Division of Human Genetics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio
3
Genetic Counselor, Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
4
Associate Professor of Clinical Pediatrics, Division of Human Genetics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio

Excerpt

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.

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