Leukocyte Adhesion Deficiency

Diagnosis

Indications for Testing

  • Child with delayed separation of the umbilical cord/or recurrent infections 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
    • Assess presence of β2 integrins CD11 and CD18
      • Decreased/absent expression of CD11/CD18 – consistent with leukocyte adhesion deficiency I (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 bone marrow transplant is performed
    • Access presence of CD15 – indicated if LAD II is suspected
      • Absent expression of CD15 – consistent with LAD II
  • Other testing 
    • Neutrophil rolling, neutrophil adherence – performed only in specialized laboratories
    • Bombay blood group phenotype testing – for LAD II
    • Platelet aggregation – for LAD III
    • Sequence analysis – to define exact molecular defect

Differential Diagnosis

Clinical Background

Leukocyte adhesion deficiency disorders (LAD) are a primary immune deficiency syndromes that affect the leucocyte adhesion process. There are three types of LAD – I, II, and III.  LAD I is the most common type.

Epidemiology

  • Incidence/prevalence – rare
    • LAD I – most common type
  • Age – usually identified in infancy or early childhood

Inheritance 

  • LAD I and II – autosomal recessive
  • At least 3 types identified
    • LAD I – defect in expression of common chain (CD18) of β2 integrin family
      • Mutation of CD18 gene (ITGB2)
    • LAD II – defect in fucose metabolism leading to absence of sialyl-Lewis X (sLeX) ligand from phagocytes (CD15a)
      • Mutation of SLC35C1 gene (GDP-fucose transporter 1)
    • LAD III – defect in inside-out signaling of β1, β2, and β3 integrins on leukocytes and platelets
      • Mutation of FERMT3 (KINDLIN-3) or RASGRP2 gene
      • Mode of inheritance is unclear

Pathophysiology

  • LAD involves defects in integrin and selectin expression 
    • Blood neutrophils – the first line of defense against bacterial and fungal infection
    • Blood leukocytes migrate into the site of inflammation
      • Requires expression of P and E selectins on the endothelial cells with their ligands on leukocytes, which requires the family of integrins be present
        • CD18 – essential component of the β2 integrins (CD11a/CD18, CD11b/CD18, and CD11c/CD18)
    • Lack of integrin and selectin expression leads to 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 and neutrophilia
    • Lack of neutrophils and no pus formation at sites of infection
  • LAD II (very rare)
    • Same features as LAD I (but no delay in separation of umbilical cord) plus
  • LAD III (very rare)
    • Same features as LAD I due to the functional defect in β2 integrin
    • Bleeding tendency due to defect in β3 integrin

Treatment

  • Early intervention for periodontal disease
  • Preventive antibiotics for infection
  • Interferon-gamma and leukocyte transfusions
  • Allogeneic bone marrow transplant for severe disease
  • Gene therapy with insertion of the CD18 subunit (under investigation)
  • Fucose replacement (variable effectiveness for LAD II)
  • Blood transfusion for bleeding episodes in LAD III

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
Test Name and Number Recommended Use Limitations Follow Up
CBC with Platelet Count and Automated Differential 0040003
Method: Automated Cell Count/Differential

Initial testing to identify abnormalities in neutrophils

   
Leukocyte Adhesion Deficiency Panel 2004359
Method: Semi-Quantitative Flow Cytometry

Diagnose LAD I by assessing the presence of β2 integrins (CD11/CD18)

Diagnose LAD II by assessing the presence of CD15

Measures CD11b, CD15, CD18

   
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
Platelet Aggregation Studies 0030160
Method: Aggregation