Leukocyte adhesion deficiency

Leukocyte adhesion deficiency (LAD) is a group of rare primary immunodeficiency disorders characterized by defects in the ability of white blood cells (leukocytes) to migrate from the bloodstream to sites of infection and inflammation. The condition primarily affects the immune system, leaving patients highly susceptible to recurrent, life-threatening bacterial and fungal infections. There are three recognized subtypes: LAD type I (LAD-I), caused by mutations in the ITGB2 gene encoding the CD18 subunit of beta-2 integrins; LAD type II (LAD-II), caused by mutations in the SLC35C1 gene affecting fucose metabolism and selectin ligand formation; and LAD type III (LAD-III), caused by mutations in the FERMT3 gene encoding kindlin-3, which leads to both immune deficiency and a bleeding tendency. The hallmark clinical features of LAD include delayed separation of the umbilical cord (often beyond 3 weeks of life), recurrent severe bacterial infections of the skin, mucous membranes, and gastrointestinal tract, impaired wound healing, and severe periodontitis leading to early tooth loss. A characteristic laboratory finding is persistent marked leukocytosis (elevated white blood cell count) even between infections, because neutrophils cannot leave the bloodstream effectively. Infections often lack pus formation despite the high white cell count, as the neutrophils fail to reach the infected tissue. In LAD-II, patients may also exhibit intellectual disability, short stature, and the rare Bombay blood group phenotype. In LAD-III, patients additionally present with a severe bleeding disorder resembling Glanzmann thrombasthenia. Treatment depends on the subtype and severity. Prophylactic antibiotics are commonly used to prevent infections. For severe LAD-I and LAD-III, hematopoietic stem cell transplantation (HSCT) is the only curative treatment and is recommended early in life for patients with the severe phenotype. LAD-II may partially respond to oral fucose supplementation in some patients. Without transplantation, patients with severe LAD-I often do not survive beyond early childhood. Gene therapy approaches are under investigation as potential future treatments.

Data sourced from FDA regulatory filings and ClinicalTrials.gov. Updated periodically.

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