Leukocyte adhesion deficiency type 1
The clinical symptoms of LAD I are the result of two impaired and linked processes: first, the inability for neutrophils to migrate to ingest pathogens in the tissue, which results in an increased susceptibility to infection; and second, the upregulation of the IL-17 / IL-23 axis that results in hyperinflammation. In normal signaling, neutrophils respond to chemotactic signals from inflamed tissues by using integrins to bind to intercellular adhesion molecules (ICAM) on vascular endothelial cells. Once bound to the vascular endothelium, they migrate into the tissue, ingest pathogens, and undergo apoptosis and phagocytosis by macrophages. This leads to downregulation of IL-23 (the cytokine released by macrophages) and downstream downregulation of IL-17 (the cytokine released by T-cells), minimizing inflammation. In LAD I, neutrophils have defective or absent integrins so they are unable to migrate into tissues and downregulate the IL-23 / IL-17 axis. As a result, there is unregulated inflammation. In addition to leukocyte migration, CD18 is also necessary for T-cell function. Thus, mutations in ITGB2 lead to a heterogeneous array of symptoms.
LAD I affects about 1 in 10 million people, with males and females being equally affected. LAD I is characterized by recurrent bacterial infections with the absence of pus formation. The infections are primarily localized to skin and mucosal surfaces and are indolent and necrotic, with high propensity for recurrence. The severity of the infections depends on the extent of CD18 deficiency. In mild / moderate deficiency, patients have 2%-30% of normal CD18 expression and can survive into adulthood. In severe deficiency, patients have less than 2% of normal CD18 expression and may die in infancy if treatment is not provided.
A classic early presentation of LAD I is omphalitis with delayed separation of the umbilical cord stump. As the child grows older, he or she may have recurrent otitis media, perirectal abscesses, and bacterial sepsis. Because of impaired immune response, the infections can necrotize and ulcerate, resembling pyoderma gangrenosum. The most common organisms are Staphylococcus aureus and gram-negative bacilli, although fungal infections can also occur. Patients are not typically predisposed to viral infections.
Patients may also have significant mucosal involvement, including severe gingivitis, oral ulcers, periodontitis, and bone and tooth loss. It is not uncommon for LAD I patients to lose all of their adult teeth by late adolescence. This is thought to be caused by a hyperinflammatory response to oral microbes as a result of IL-23 / IL-17 dysregulation.
One variant of LAD I is the somatic reversion of the ITGB2 mutation, leading to a milder clinical phenotype, most characteristically inflammatory bowel disease. Patients with this variant have reduced neutrophil CD18 expression, but normal CD18 expression in a subset of cytotoxic T-cells.
D72.0 – Genetic anomalies of leukocytes
234582006 – Leukocyte adhesion deficiency - type 1
Differential Diagnosis & Pitfalls
LAD III – Neutrophilia due to defective integrin activation, which affects both neutrophils and platelets. Thus, LAD III patients have increased risk of bleeding.
Delayed umbilical separation (>3 weeks):
- Variant of normal umbilical separation – Cord separation can occur between 3 and 45 days, with the mean being 14 days.
- Urachal cyst – Remnant of a sinus that connects the umbilical cord and bladder; usually asymptomatic unless infected, in which case there will be abdominal pain, fever, and hematuria. Infections occur at an older age.
- Pyoderma gangrenosum – Biopsy reveals large number of neutrophils, unlike in LAD I.