NIH
Zebra of the Week: Leukocyte adhesion deficiency type 1 (LAD‑I)
Leukocyte adhesion deficiency type 1 (LAD-I) is a rare, autosomal recessive primary immunodeficiency caused by pathogenic variants in ITGB2, the gene encoding the β2 integrin subunit (CD18). Loss or marked reduction of CD18 impairs leukocyte adhesion and migration across the endothelium, leading to an ineffective innate immune response despite normal or elevated leukocyte counts.
Clinical clues often appear in the newborn period. A classic early sign is delayed separation of the umbilical cord beyond three weeks, frequently complicated by omphalitis. Affected infants and children develop recurrent, severe bacterial and fungal infections, particularly of the skin and mucous membranes. Hallmark features include absence of pus at infection sites, poor wound healing, and marked neutrophilic leukocytosis. As patients age, progressive severe gingivitis and periodontitis can lead to early loss of primary and permanent teeth. Infections may become extensive and necrotic, spreading beyond initial sites.
Diagnosis should be suspected in infants or children with recurrent soft‑tissue infections, delayed cord separation, and minimal inflammatory response. Laboratory evaluation typically shows persistent leukocytosis. Confirmation is achieved by flow cytometry demonstrating reduced or absent CD18 expression on leukocytes, with genetic testing of ITGB2 supporting the diagnosis.
Management focuses on aggressive treatment and prevention of infections. Without definitive therapy, prognosis is poor, with many severely affected patients not surviving infancy or early childhood. Hematopoietic stem cell transplantation remains the only established curative option and should be considered early in severe disease. Early recognition is critical to improving outcomes.
FDA recently approved Kresladi (marnetegragene autotemcel), the first gene therapy for pediatric patients with LAD-1.
Source: Genetic and Rare Diseases Information Center (GARD). Leukocyte adhesion deficiency type 1. National Institutes of Health.