Leukocyte Adhesion Deficiency (LAD) Syndrome

Inherited disorder affecting leukocytes resulting in localized bacterial infections rapidly progressing to an extensive life-threatening level.

Lymphocyte Function-Associated Antigen-1 Immunodeficiency; LFA-1 Deficiency.

Immunologic disorder affects phagocytic properties of leukocytes as a consequence of lack of expression of β2 integrin CD18 (LAD I) or of its selective ligand (LAD II).

Fewer than 200 cases of LAD I and 10 cases of LAD II have been reported in the literature. No racial predominance for LAD I; LAD II has been reported only in people of Middle Eastern descent.

Both forms are autosomal recessive (equal number of males and females). LAD I is caused by mutations in the gene for CD18 (β chain of β2 integrins). Gene map locus is 21q22.3. LAD II is caused by mutations in a gene that fucosylates sialyl Lewis X (ligand for E selectin), resulting in a defect in fucose metabolism.

β Integrins are transmembrane glycoproteins that transmit signals from the extracellular surface to cytoskeletal proteins, thus playing a critical role in phagocytic functions. The β2 integrin CD18 is expressed on leukocytes, and its ligands are expressed on endothelial cells. Binding of CD18 to ligands also mediates cytokine production, cytotoxicity, apoptosis, and proliferation. LAD I is a result of a mutation in CD18 gene, the expression of which is severely diminished (<1% in 75% of affected patients).

Sialylated Lewis X (SleX or CD15) is the major selectin ligand; both the sialic acid and the fucose moieties of SleX are needed for binding to selectins. This ligand is missing in LAD II; affected patients also have a defect in fucose metabolism.

Neutrophilia (>20 × 109 WBC/l) in the absence of infection; impaired microbicidal activity and oxidative responses against bacteria and Candida (in LAD I); flow cytometry shows a considerable decrease in β2 integrin CD18 on leukocytes (LAD I). In LAD II, Bombay blood group phenotype is detected and biochemical activity of GMD is decreased.

Patients with LAD I present with delayed umbilical cord separation followed by various types of localized infection caused by Staphylococcus bacteria (plus fungal organisms, usually Candida albicans) without pus (omphalitis, perirectal and labial cellulitis, classic infections in neutropenic patients, otitis media with minimal inflammation, and other indolent necrotic skin infections) prone to generalization. In less severely affected patients, periodontitis accompanying tooth eruption and oral ulcerations may be the presenting symptoms. Patients with severe LAD I die before age 1 year as a consequence of severe bacterial or, less frequently, life-threatening viral infections. Patients with LAD II do not have delayed umbilical cord separation and usually do not die of infection. They have severe mental retardation, neurologic impairment, and short stature.

Blood examination: white blood cells and platelet count must be obtained. Consider fucose supplementation in patients with LAD II.

None specific. Administer broad-spectrum IV antibiotic therapy.

Epinephrine and corticosteroids are responsible for adhesion defects by demarginating neutrophils from the peripheral vasculature. These agents must be avoided in LAD patients.

Glanzmann Thromboasthenia: An autosomal recessive bleeding disorder characterized by failure of platelet aggregation and absent or diminished clot retraction. It has been classified clinically into types I and II. In type I, platelets show absence of the glycoprotein IIb/IIIa (GPIIb-IIIa) complexes at their surface and lack fibrinogen and clot retraction capability. In type II, the platelets express the GPIIb-IIIa complex at reduced levels (5-20% controls), have detectable amounts of fibrinogen, and have low or moderate clot retraction capability. The disorder is manifest soon after birth with episodic mucocutaneous bleeding and unprovoked bruising. Epistaxis frequently occurs. Women experience copious menstrual hemorrhage. Intracranial bleeding may occur. Bleeding time is prolonged, with normal platelet count, platelet morphology, and coagulation times. Platelets fail to aggregate, either spontaneously or in response to agonists, such as ADP, thrombin, or epinephrine, although there may be a transient response to ristocetin.