Leukocyte Adhesion Deficiency

  • Diagnosis
  • Algorithms
  • Background
  • Lab Tests
  • References
  • Related Content

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

  • Initial screening
    • General immunodeficiency screening
      • CBC with differential
      • Comprehensive metabolic profile
      • Quantitative serum immunoglobulins (IgA, IgG, IgM)
      • Lymphocyte subset analyses – depending on clinical presentation
    • Rule out other diseases associated with immunodeficiency
      • HIV-1,2 testing
      • Plasma cell disorders – monoclonal protein detection, quantitation, and characterization with SPEP, IFE, IgA, IgG, IgM
      • Cystic fibrosis – sweat chloride testing using an accredited cystic fibrosis center
    • Rule out diseases associated with protein losses (eg, protein-losing enteropathy, nephropathy)
  • More specific screening – based on initial screening results
    • Clinical presentation may require multiple immune system investigations (see Immunodeficiency Evaluation algorithms)
    • Definitive diagnosis, prognostication, genetic counseling, and treatment may require genetic testing
    • Complement testing
  • Flow cytometric analysis
    • Assess presence of β2 integrins CD11 and CD18
      • Decreased/absent expression of CD11/CD18 – consistent with leukocyte adhesion deficiency-1 (LAD1)
        • 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 LAD2 is suspected
      • Absent expression of CD15 – consistent with LAD2
  • Other testing 
    • Neutrophil rolling, neutrophil adherence – performed only in specialized laboratories
    • Bombay blood group phenotype testing – for LAD2
    • Platelet aggregation – for LAD3
    • Sequence analysis – to define exact molecular defect

Differential Diagnosis

Leukocyte adhesion deficiency disorders (LAD) are a primary immune deficiency syndromes that affect the leucocyte adhesion process. There are three types of LAD – 1, 2, and 3.  LAD1 is the most common type.

Epidemiology

  • Incidence/prevalence – rare
    • LAD1 – most common type
  • Age – usually identified in infancy or early childhood

Inheritance 

  • At least 3 types identified
    • LAD1
      • Autosomal recessive
      • Mutation of CD18 gene (ITGB2) – defect in expression of common chain (CD18) of β2 integrin family
    • LAD2
      • Autosomal recessive
      • Mutation of FUCT1 gene (GDP-fucose transporter 1) – defect in fucose metabolism leading to absence of sialyl-Lewis X (sLeX) ligand from phagocytes (CD15a)
    • LAD3
      • Autosomal recessive
      • Mutation of KINDLIN-3 gene – defect in inside-out signaling of β1, β2, and β3 integrins on leukocytes and platelets

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

  • LAD1
    • Delayed separation of the umbilical cord
    • Recurrent soft tissue infections/ulcers
    • Chronic periodontitis
    • Marked leukocytosis and neutrophilia
    • Lack of neutrophils and no pus formation at sites of infection
  • LAD2 (very rare)
    • Same features as LAD1 (but no delay in separation of umbilical cord) plus
  • LAD3 (very rare)
    • Same features as LAD1
    • Bleeding tendency

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

CBC with Platelet Count and Automated Differential 0040003
Method: Automated Cell Count/Differential

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

Additional Tests Available

Platelet Aggregation Studies 0030160
Method: Qualitative Aggregation

Guidelines

Al-Herz W, Bousfiha A, Casanova J, Chatila T, Conley M, Cunningham-Rundles C, Etzioni A, Franco J, Gaspar B, Holland S, Klein C, Nonoyama S, Ochs H, Oksenhendler E, Picard C, Puck J, Sullivan K, Tang M. Primary immunodeficiency diseases: an update on the classification from the international union of immunological societies expert committee for primary immunodeficiency. Front Immunol. 2014; 5: 162. PubMed

General References

Etzioni A. Defects in the leukocyte adhesion cascade. Clin Rev Allergy Immunol. 2010; 38(1): 54-60. PubMed

Gazit Y, Mory A, Etzioni A, Frydman M, Scheuerman O, Gershoni-Baruch R, Garty B. Leukocyte adhesion deficiency type II: long-term follow-up and review of the literature. J Clin Immunol. 2010; 30(2): 308-13. PubMed

Harris E, Smith T, Springett G, Weyrich A, Zimmerman G. Leukocyte adhesion deficiency-I variant syndrome (LAD-Iv, LAD-III): molecular characterization of the defect in an index family. Am J Hematol. 2012; 87(3): 311-3. PubMed

Immune Deficiency Foundation. Towson, MD [Accessed: Nov 2015]

Locke B, Dasu T, Verbsky J. Laboratory diagnosis of primary immunodeficiencies. Clin Rev Allergy Immunol. 2014; 46(2): 154-68. PubMed

Notarangelo L, Badolato R. Leukocyte trafficking in primary immunodeficiencies. J Leukoc Biol. 2009; 85(3): 335-43. PubMed

Medical Reviewers

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Last Update: December 2015