WISKOTT-ALDRICH SYNDROME
 
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WISKOTT-ALDRICH SYNDROME

 

DEFINITION:

An immunodeficiency disorder of both T- and B-cells characterized by thrombocytopenia, eczema, and recurrent infections.

EPIDEMIOLOGY:

  • incidence: rare
  • age of onset:
    • bleeding and eczema within the first 6 months of life
  • risk factors:
    • familial - x-linked recessive
      • chrom.#: Xp11.3-p11.2
      • gene: ? receptor on active immune cells
      • classic and variant forms may reflect different mutations
    • Males only

PATHOGENESIS:

1. Genetic Defect

  • genetic defect -> ? aberrant receptor on circulating T-lymphocytes and other active immune cells -> combined progressive T and B cell deficiency
    • increased susceptibility to infections
      • viral - CMV, HSV, varicella
      • bacterial - P. carnii
    • altered platelet number, size, and function
      • bleeding tendency

2. Immunodeficiencies

1. T Cell

  • defective T-cell function
    • decreased responsiveness to delayed hypersensitivity skin test antigens
    • T-cells devoid of microvilli by electron microscopy

2. B Cell

  • low IgM but elevated IgA and IgE
  • poor antibody response to:
    • polysaccharide antigens
      • Forssman's antigen
      • lipopolysaccharide VI (E. coli)
      • pneumococcal, Salmonella, streptococcal
    • viral agents
      • HSV, poliomyelitis

3. Types

1. Classic Form

1. Diagnosis

1. Clinical
  • male infant
  • recurrent infections, eczema, bleeding episodes
2. Laboratory
  • thrombocytopenia with small platelets
  • elevated IgA and IgE with decreased IgM
  • absent isohemagglutinins
  • poor antibody responses to polysaccharide antigens

2. Variant Forms

1. Diagnosis

1. Clinical
  • bleeding tendency less severe
  • eczema variably expressed
2. Laboratory
  • immunodeficiency variably expressed

CLINICAL FEATURES:

1. Haematological Manifestations

1. Thrombocytopenia

  • usually first manifestation
  • may occur within first 6 months of life
  • excessive bleeding following circumcision
  • petechiae, purpura, gastrointestinal bleeding (hematemesis, melena),
  • conjunctival, vitreous, and subconjunctival hemorrhages
  • intracranial hemorrhage -> pseudotumor cerebri
  • episodes triggered by severe infections and/or immunizations (polysaccharide vaccines)

2. Lymphopenia

  • recurrent or chronic infections
    • chronic otitis media
    • chronic or recurrent pneumonia
    • persistent rhinorrhea
    • severe varicella
  • cervical lymphadenopathy
  • HSV infections:
    • herpetic skin lesions
    • chronic herpes conjunctivitis -> dendritic keratitis

2. Integument Manifestations

1. Eczema

  • may also occur within the first 6 months of life
  • typical atopic eczematoid rash of increasing severity
  • predilection for antecubital and popliteal fossae
  • tends to become secondarily infected with Staph. -> pruritic

3. Other Manifestations

1. Renal

  • hematuria, nephrotic syndrome, chronic renal failure

2. Gastrointestinal

  • hepatomegaly, splenomegaly

3. Neoplasms

  • occur in those >8 yrs of age with predilection for brain
    • systemic reticuloendotheliosis
    • lymphomas at extranodal sites (brain, gastrointestinal)
    • leukemia

INVESTIGATIONS:

1. Serum

1. CBC

  • anemia, eosinophilia
  • platelets - thrombocytopenia, small, impaired aggregation
  • lymphopenia - with eventual inversion of CD4/CD8 ratio

2. Immunoglobulins

  • extremely high IgA & IgE, with low IgM
  • normal to elevated IgG with normal IgG subclasses
  • absent isohemagglutinins
  • normal complement

2. Diagnosis

  • periodate challenge of T cells for tritiated thymidine turnover of these cells (testing available only at Tufts University and at Mt. Sinai Hospital in Toronto)
  • prenatal
    • DNA marker testing can identify a female carrier with
    • 100% accuracy

3. Imaging Studies

1. Chest X-Ray

  • chronic lung disease

4. Pathology

  • thymus and lymphoid tissue hypoplasia
    • gradual loss of cellular elements
    • poor or nonexistent follicular formation

5. Urine

  • hematuria, proteinuria

MANAGEMENT:

1. Supportive

1. Acute Bleeding Episodes

1. Transfusion

  • with fresh platelets
  • bleeding tends to decrease with age

2. Splenectomy

  • may decrease platelet sequestration but increases risk of infection with encapsulated organisms

2. Infections

  • antiviral agents and antibiotics
  • IgG 100-400 mg/kg IV q monthly
    • prevents pyogenic infections and mandatory after splenectomy

3. Eczema

  • local fluorinated steroids

2. Bone Marrow Transplantation

  • treatment of choice
  • may reestablish lymphocytic and hematopoietic cell lines

3. Prognosis

  • death within first two decades of life of viral or bacterial infections without bone marrow transplantation
  • female carriers phenotypically normal as defective X chromosome is preferentially inactivated in favour of the normal allele

 

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