Patient Vignette (part 2)
The adhesion marker assay is intended to screen for leukocyte adhesion deficiency type 1 (LAD-1). The laboratory finding in our patient showed a marked decrease in neutrophil CD11b/CD18 integrin expression, as well as a lack of integrin up-regulation, raising a strong concern for LAD-1.
LAD-1 is a rare primary immunodeficiency disorder caused by a defect in CD18. CD18 is the common β chain of β2 integrin family found predominantly on neutrophils. Due to the fact that β2 integrins are expressed on white blood cells in combinations of CD18 (β chain) and CD11 (α chain), abnormal CD18 expression is accompanied by a lack of CD11b expression, as demonstrated by our patient. Integrins are important for the attachment of various cells to other cells and tissues via specific receptors. In the case of the β2 integrins, the major function is to allow neutrophils to adhere to and migrate along endothelial cells and into the neighboring tissues.
Since neutrophils are important in the first line of defense against invading microorganism, the complete absence of β2 integrins causes a severe immunodeficiency by preventing neutrophil movement to sites of infection. The "classic" presentation of LAD-1 is manifested by young infants and is characterized by a delayed separation of the umbilical cord, subsequent recurrent severe skin and mucosal infections with pyogenic microorganisms, and a lack of pus formation at sites of infection. β2 integrins are also relevant for T-cell and antigenpresenting cell function.
Patients display highly elevated blood neutrophil counts (that remain elevated even after infections have been brought under control). In the absence of allogeneic stem cell transplantation, life expectancy is very poor, with most patients not surviving beyond ten years of age.
A less common, moderate, phenotype of LAD-1 has been described in a handful of individuals. In these cases, CD18 is decreased, but not completely absent. Individuals with the moderate phenotype of LAD-1 suffer from recurrent pyoderma gangrenosum-like skin ulcers, delayed wound healing, abnormal scarring, and only intermittently elevated blood neutrophil counts.
Patients usually present in later childhood. Even though infections are not a prominent part of the initial disease course, affected individuals are prone to overwhelming infections. These case descriptions are identical to the clinical description of our patient. In our patient, analysis of the gene encoding CD18 (ITGB2) showed a genotype consistent with LAD-1 (and the observed CD11b/CD18 immunophenotype, as detected by the Adhesion Markers Assay). In summary, our patient best fits the category of "moderate" LAD-1. He presented with a rare manifestation of a rare disease, posing considerable diagnostic and therapeutic challenges. Moderate forms of LAD-1 should be considered in patients with unexplained recurrent skin ulcers. The flow cytometric assay demonstrated in this vignette provides a relatively straightforward diagnostic tool that can quickly screen for LAD-1.
