Description

• Wiskott-Aldrich syndrome (WAS) is a rare X-linked recessive condition characterized by eczema, recurrent infections, autoimmunity, and malignancies.
• It is seen almost exclusively in males.
• Microthrombocytopenia results in easy bruising and a bleeding diathesis.
• Autoimmune phenomena and eczema are seen.
• Immune dysfunction results in recurrent infections.
• The risk of lymphoma is increased.
• The syndrome has variable expressivity and presents on a continuum of clinical severity. Milder forms may be characterized by thrombocytopenia and mild eczema, whereas autoimmunity and malignancies develop in more severe cases. Disease progression may occur throughout life so severity at diagnosis should not be used to predict disease severity.
• Without hematopoietic stem cell transplantation (HSCT) in WAS, death usually occurs between the ages of 8 and 14 years. The most common causes of death include infection, malignancy, and bleeding.
• System(s) affected: hematologic/lymphatic/immunologic; skin/exocrine
• Synonym(s): Aldrich syndrome; eczema–thrombocytopenia–immunodeficiency syndrome; immunodeficiency 2

Pediatric Considerations

• Onset at birth
• Commonly presents with prolonged bleeding following circumcision
• In the first year of life, patients may be afflicted with pneumonia or meningitis from susceptibility to encapsulated bacteria.
• Later in life, opportunistic organisms and viruses are more likely to cause infections.

Epidemiology

Incidence

• Male predominant (X-linked): >90%
• 1/250,000 live male births in the United States
• Mild thrombocytopenia is occasionally seen in female carriers.
• Onset is at birth, and most diagnoses are made by 24 months of age.

Prevalence

• There are approximately 500 WAS patients in the United States.
• All races are affected, but WAS is less prevalent in blacks and Asians.

Etiology and Pathophysiology

• Defects in WAS protein (WASp) result in abnormal actin polymerization.
• WASp is expressed exclusively in hematopoietic cells and results in pleomorphic effects in many cell lines.
• T-cell lymphopenia is multifactorial, and these cells display abnormal interactions with antigen-presenting cells, immune regulation, migration, and polarization of cytotoxic granules.
• Regulatory T cells fail to suppress T and B cells, which may lead to autoimmunity.
• B-cell lymphopenia, abnormal B cells migration, and autoantibody production result in abnormal immune homeostasis.
• Platelets are intrinsically abnormal, resulting in accelerated destruction and splenic sequestration.
• Natural killer cells, macrophages, monocytes, and neutrophils are also abnormal.
• Associated B-cell and T-cell changes result in:
  • Low IgM, normal IgG (low IgG2), high IgA and IgE
  • Normal CD19 B cells and high CD4 to CD8 ratio
  • Low CD8 counts in 61%
  • Decreased delayed-type hypersensitivity responses, mitogenic responses, natural killer function, and absent isohemagglutinin titers

Genetics

• X-linked recessive trait; gene located at Xp11.22–23. The specific mutation impacts the phenotype. WAS gene encodes the WASp, a 502-amino-acid, proline-rich cytoplasmic protein.
• Complete penetrance and variable expressivity in males
• The small number of cases in women may be explained by nonrandom X inactivation, or phenocopy, owing to mutation in gene-encoding binding partner of WASp; Human Genome Organisation (HUGO) gene symbol WAS (Online Mendelian Inheritance in Man [OMIM] 301000)

Risk Factors

Family history in >60%

General Prevention

• Prenatal genetic counseling is important for patients with a family history of WAS (maternal cousins, uncles, and nephews) to identify carriers.
  • X chromosome analysis can be performed if the familial mutation is unknown.
• Perinatal diagnosis by DNA analysis of fetal blood or chorionic villus sampling (CVS) can be performed if mutation is known.

Commonly Associated Conditions

• Autoimmune disorders: hemolytic anemia, small and large vessel vasculitis, nephritis, rheumatoid arthritis, immune thrombocytopenia, and inflammatory bowel disease. Risk increases with age; up to 40% who survive early complications will develop ≥1 autoimmune conditions.
• Increased susceptibility to herpes virus infection
• Lymphomas
  • Especially in those exposed to Epstein-Barr virus
  • Increased risk in those with autoimmune conditions and with age
  • May occur in usual extranodal locations; brain is primary site in 50% but also lung and GI tract.
• Lymphoreticular tumors
• Atopic dermatitis