Leukocyte Adhesion Deficiency

Diagnosis

Indications for Testing

• Child with recurrent infections and in whom more common immunodeficiencies have been ruled out
• Tissue infections with absence of inflammatory cells and high peripheral neutrophil counts

Laboratory Testing

• CBC – reveals leukocytosis with neutrophilia (even in the absence of infection but exaggerated during infection)
• Flow cytometric analysis
  • CD11b and CD18 expression on leukocytes
    • Normal expression – consistent with LAD I or LAD III
    • Decreased expression – consistent with LAD I
      • 1-10% expression – 33% survive to age 40
      • >10% expression – mild deficiency; may not be recognized until late teen years
    • No expression – 75% die in infancy unless transplanted
  • If LAD I suspected – CD15a monoclonal analysis to determine SLe antibody expression
    • Confirm diagnosis with gene sequencing of GDP-fucose transporter
  • CD15
    • Absent or decreased expression – consistent with LAD II
• Other testing – neutrophil rolling, neutrophil adherence, platelet aggregation

Differential Diagnosis

• Sepsis
• Neutropenic disorders
• Agranulocytosis
• IRAK-4 deficiency
• Job syndrome
• Chronic granulomatous disease
• Myeloperoxidase deficiency
• Congenital disorders of glycosylation

Clinical Background

Leukocyte adhesion disorders (LAD) are a primary immune deficiency affecting phagocytic blood cells.

Epidemiology

• Incidence – <1/1,000,000
  • LAD I – most common syndrome
• Age – usually identified in infancy or early childhood

Inheritance 

• Autosomal recessive
• Heterogeneous mutations in the CD18 leukocyte integrin gene
  • At least 3 defects identified
    • LAD I – β2 integrin expression defect
      • Mutation of ITGB2 gene
    • LAD II – selectin defect
      • Mutation of SLC35C1 gene
    • LAD III – combined defect in integrin activation resulting in abnormal functionality of platelets and leukocytes
      • Mutation of RASGRP2 gene

Pathophysiology

• Blood neutrophils are the first line of defense against bacterial and fungal infection
  • β2 integrin interactions aid in initial neutrophil adherence
• LAD involves defects in integrin and selectin expression
  • Defective adhesion of neutrophils that in turn leads to increased susceptibility to bacterial and fungal infections

Clinical Presentation

• LAD I
  • Delayed separation of the umbilical cord
  • Recurrent soft tissue infections
  • Chronic periodontitis
  • Marked leukocytosis
  • Lack of neutrophils in tissue infections
• LAD II
  • Same features as LAD I plus
    • Short stature
    • CNS abnormalities (seizures)
    • Developmental delay
  • No delay in separation of umbilical cord
• LAD III
  • Same features as LAD I with severe bleeding tendency

Treatment

• Early intervention for periodontal disease
• Preventive antibiotics for infection
• Allogeneic bone marrow transplant for severe disease

Indications for Laboratory Testing

• Tests generally appear in the order most useful for common clinical situations
• Click on number for test-specific information in the ARUP Laboratory Test Directory

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
Platelet Aggregation Studies 0030160 Method: Aggregation

Diagnostic Algorithm

  Immunodeficiency Evaluation for Chronic Infections in Adults and Older Children Testing Algorithm

  Immunodeficiency Evaluation for Chronic Infections in Infants and Children Testing Algorithm