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
- 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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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
