Leukocyte adhesion deficiency (LAD) disorders are primary immune deficiency syndromes that affect the leukocyte adhesion process. There are three types of LAD: 1, 2, and 3. LAD1 is the most common type.
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 pus and/or 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 serum protein electrophoresis (SPEP), immunofixation electrophoresis (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)
- General immunodeficiency screening
- More specific screening – based on initial screening results
- Clinical presentation may require multiple immune system investigations (refer to the Immunodeficiency Evaluation for Chronic Infections in Adults and Older Children Testing Algorithm and Immunodeficiency Evaluation for Chronic Infections in Infants and Children Testing Algorithm)
- Definitive diagnosis, prognostication, genetic counseling, and treatment may require genetic testing
- Complement testing
- Flow cytometric analysis
- Assess presence of beta 2 (β2) integrins CD11 and CD18
- Decreased/absent expression of CD11/CD18 – consistent with leukocyte adhesion deficiency-1 (LAD1)
- 2-10% expression – moderate deficiency; reasonable survival rate into adulthood
- >10% expression – mild deficiency; may not be recognized until late teen years
- <2% – severe deficiency; majority die in infancy unless bone marrow transplant is performed
- Normal expression of CD11/CD18 – consistent with LAD2 or LAD3
- Decreased/absent expression of CD11/CD18 – consistent with leukocyte adhesion deficiency-1 (LAD1)
- Assess presence of CD15s – indicated if LAD2 is suspected
- Absent expression of CD15s – consistent with LAD2
- Other testing
- Neutrophil rolling, neutrophil adherence, neutrophil motility – performed only in specialized laboratories
- Bombay blood group phenotype testing – present in LAD2
- Platelet aggregation – abnormal in LAD3
- Molecular sequence analysis – defines exact molecular defect
- Assess presence of beta 2 (β2) integrins CD11 and CD18
Differential Diagnosis
- Sepsis
- Neutropenic disorders
- Agranulocytosis
- IRAK-4 deficiency
- Job syndrome
- Chronic granulomatous disease
- Myeloperoxidase deficiency
- Congenital disorders of glycosylation
- Leukemoid reaction in infants
- Other congenital coagulation disorders (particularly in LAD3 due to bleeding tendency)
Background
Epidemiology
- Incidence/prevalence – rare
- LAD1 – most common type
- Age – usually identified in infancy or early childhood
Inheritance
LAD1 | LAD2 | LAD3 | |
---|---|---|---|
Inheritance |
Autosomal recessive |
Autosomal recessive |
Autosomal recessive (very rare) |
Mutation Defect |
Mutation of CD18 gene (ITGB2) – defect in expression of common chain (CD18) of β2 integrin family |
Mutation of FUCT1 gene (GDP-fucose transporter 1) – defect in fucose metabolism leading to absence of sialyl-Lewis X (sLeX) ligand from phagocytes (CD15s) |
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)
- Requires expression of P and E selectins on the endothelial cells with their ligands on leukocytes, which requires the family of integrins be present
- Lack of integrin and selectin expression leads to defective adhesion of neutrophils that in turn leads to increased susceptibility to bacterial and fungal infections
- Other LAD-like syndromes with defects in adhesion/chemotaxis have been identified (eg, RAC-2, which regulates actin cytoskeleton; leukocyte hyperadhesion syndrome)
Clinical Presentation
LAD1 | LAD2 | LAD3 | |
---|---|---|---|
Delayed separation of umbilical cord |
+++ |
– |
+ |
Recurrent soft tissue infections/ulcers |
+++ |
+ |
+ |
Chronic periodontitis later in life |
++ |
++ |
? |
Leukocytosis with neutrophilia |
+ |
+++ |
++ |
Impaired wound healing |
+ |
+ |
+ |
Absence of pus |
+++ |
+ |
+ |
Bleeding tendency |
– |
– |
+++ |
Developmental abnormalities |
– |
+++ |
– |
ARUP Laboratory Tests
Aids in the diagnosis of type I and II leukocyte adhesion deficiency syndromes
Panel measures CD11a, CD11b, CD15s, CD18 on neutrophils
Semi-Quantitative Flow Cytometry
Evaluate patients with suspected inherited qualitative platelet disorders or patients with lifelong platelet-type bleeding
Studies include platelet aggregation studies, ADP; collagen; AA; ristocetin
Qualitative Aggregation
References
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Gazit Y, Mory A, Etzioni A, et al. Leukocyte adhesion deficiency type II: long-term follow-up and review of the literature. J Clin Immunol. 2010;30(2):308-313.
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Harris ES, Smith TL, Springett GM, et al. 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):311-313.
IDF - Leukocyte Adhesion Deficiency
Immune Deficiency Foundation. Towson, MD. [Accessed: Feb 2017]
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Locke BA, Dasu T, Verbsky JW. Laboratory diagnosis of primary immunodeficiencies. Clin Rev Allergy Immunol. 2014;46(2):154-168.
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Notarangelo LD, Badolato R. Leukocyte trafficking in primary immunodeficiencies. J Leukoc Biol. 2009;85(3):335-343.
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Simpson BN, Hogg N, Svensson LM, et al. A new leukocyte hyperadhesion syndrome of delayed cord separation, skin infection, and nephrosis. Pediatrics. 2014;133(1):e257-62.
Medical Experts
Wittwer
