Leukocyte Adhesion Deficiency

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.

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Clinical Overview

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)
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
- Assess presence of CD15 – indicated if LAD2 is suspected
  - Absent expression of CD15 – 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

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

LAD syndromes

LAD Syndromes
	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 (CD15a)	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
- Other LAD-like syndromes with defects in adhesion/chemotaxis have been identified (eg, RAC-2, which regulates actin cytoskeleton; leukocyte hyperadhesion syndrome)

Clinical Presentation

Signs and symptoms based on LAD type

Signs and Symptoms Based on LAD Type
	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 Lab Tests

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.

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

Recommended Use

Use to diagnose type I and II leukocyte adhesion deficiency syndromes

Panel includes CD11b, CD15, CD18

Medical Experts

Wittwer, Carl T., MD, PhD, Medical Director, Immunologic Flow Cytometry at ARUP Laboratories; Professor of Clinical Pathology, University of Utah

References

Guidelines

Al-Herz W, Bousfiha A, Casanova J, Chatila T, Conley ME, Cunningham-Rundles C, Etzioni A, Franco JL, Gaspar B, Holland SM, Klein C, Nonoyama S, Ochs HD, Oksenhendler E, Picard C, Puck JM, Sullivan K, Tang ML. 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 ES, Smith TL, Springett GM, Weyrich AS, Zimmerman GA. 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: Feb 2017]

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

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

Simpson BN, Hogg N, Svensson LM, McDowall A, Daley W, Yarbrough K, Abdul-Rahman OA. A new leukocyte hyperadhesion syndrome of delayed cord separation, skin infection, and nephrosis. Pediatrics. 2014; 133(1): e257-62. PubMed

Testing Algorithms

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

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

Immunodeficiency Evaluation for Chronic Infections in Infants and Children Testing Algorithm

Read more about Immunodeficiency Evaluation for Chronic Infections in Infants and Children Testing Algorithm

Last Update: September 2018