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Leukocyte Adhesion Deficiency

by James Fernandez, MD, PhD

Leukocyte adhesion deficiency results from an adhesion molecule defect that causes granulocyte and lymphocyte dysfunction and recurrent soft-tissue infections.

Inheritance is autosomal recessive.

Leukocyte adhesion deficiency (LAD) is caused by deficiency of adhesive glycoproteins on the surfaces of WBCs; these glycoproteins facilitate cellular interactions, cell attachment to blood vessel walls, cell movement, and interaction with complement fragments. Deficiencies impair the ability of granulocytes (and lymphocytes) to migrate out of the intravascular compartment, to engage in cytotoxic reactions, and to phagocytose bacteria. Severity of disease correlates with degree of deficiency.

Three different types of syndromes have been identified:

  • LAD 1 (deficient or defective β 2 -integrin family)

  • LAD 2 (absent fucosylated carbohydrate ligands for selectins)

  • LAD 3 (defective activation of all β integrins [1, 2, and 3]).

Type 1 results from mutations in the integrin β 2 gene ( ITGB2 ), encoding CD18 of β 2 integrins. Type 2 results from mutations in the glucose diphosphate (GDP)-fucose transporter gene.

Symptoms and Signs

Symptoms usually begin in infancy.

Severely affected infants have recurrent or progressive necrotic soft-tissue infections with staphylococcal and gram-negative bacteria, periodontitis, poor wound healing, no pus formation, leukocytosis, and delayed (> 3 wk) umbilical cord detachment. WBC counts remain high even between infections. Infections become increasingly difficult to control.

Less severely affected infants have few serious infections and mild alterations in blood counts. They can survive until adulthood without intervention.

Developmental delay is common in type 2.

Diagnosis

  • Testing for adhesive glycoproteins on the surface of WBCs

Diagnosis is by detecting absence or severe deficiency of adhesive glycoproteins on the surface of WBCs using monoclonal antibodies (eg, anti-CD11, anti-CD18) and flow cytometry. Leukocytosis on CBC is common but nonspecific. Genetic testing is recommended for siblings.

Treatment

  • Supportive care using prophylactic antibiotics and granulocyte transfusions

  • Bone marrow transplantation

Treatment is with prophylactic antibiotics, often given continuously (usually trimethoprim/sulfamethoxazole). Granulocyte transfusions can also help.

Bone marrow transplantation is the only effective treatment to date and can be curative. Gene therapy, which is under study, appears promising.

For patients with type II, correcting the underlying defect with fucose supplementation should be tried.

Patients with mild or moderate disease can survive into young adulthood. Most patients with severe disease die by age 5 unless treated successfully with bone marrow transplantation.

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