Introduction And Genetics

Wiskott-Aldrich syndrome is an X-linked recessive combined immunodeficiency disorder. It primarily affects males and manifests with a classic clinical triad.

The disease is caused by pathogenic variants in the WASP gene.

Pathophysiology

• The WASP gene encodes the Wiskott-Aldrich syndrome protein.
  • This protein controls the assembly of actin filaments.
  • Actin filaments are required for normal cell migration and cell-cell interactions.
• T cells in affected patients lack the markedly fimbriated surface seen in normal T cells under electron microscopy.
• The primary immunologic defect appears to be the inability of T cells to provide adequate help to B cells.
• This leads to an impaired humoral immune response, especially to polysaccharide antigens.

Clinical Manifestations

Patients present with multi-system involvement early in life.

Bleeding Diathesis

• Bleeding is often the earliest clinical manifestation.
• Infants commonly present with prolonged bleeding from the circumcision site.
• Bloody diarrhea is another frequent presentation during infancy.

Immunodeficiency And Infections

• Recurrent infections typically develop during the first year of life.
• Patients are highly susceptible to encapsulated bacteria.
  • Common pathogens include Streptococcus pneumoniae and Haemophilus influenzae.
  • These organisms cause otitis media, pneumonia, meningitis, and sepsis.
• As the child grows older, infections with opportunistic agents occur.
  • Pneumocystis jirovecii and various herpesviruses become frequent pathogens.

Dermatologic And Autoimmune Features

• Atopic dermatitis usually develops in the first year of life.
• Autoimmunity can occur as the disease progresses.
  • Hemolytic anemia and arthritis are commonly associated autoimmune conditions.

Malignancy Risk

• Patients have a high susceptibility to lymphoreticular malignancies.
• Epstein-Barr virus (EBV) associated malignancies are a major cause of death.

Laboratory Diagnosis

Diagnosis is established by evaluating the hemogram, immunoglobulin levels, and cellular immune function.

Immunoglobulin Profile

The serum immunoglobulin pattern in WAS is distinct and helps in diagnosis.

Management

Management involves aggressive supportive care, infection prophylaxis, and definitive cellular therapies.

Supportive And Medical Care

• Good supportive care includes appropriate nutrition and aggressive management of eczema and cutaneous infections.
• Immunoglobulin replacement therapy is strictly indicated due to profound antibody deficiency.
  • This is required regardless of the patient's serum immunoglobulin levels.
• Only killed vaccines should be administered to these patients.
• Antimicrobial prophylaxis against Pneumocystis jirovecii and herpes simplex virus is often recommended.
• Splenectomy may be necessary for severe and refractory thrombocytopenia.
  • Post-splenectomy patients strictly require lifelong penicillin prophylaxis against encapsulated organisms.

Definitive Therapies