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Leukocyte adhesion deficiency
Leukocyte adhesion deficiency (LAD) is a primary immunodeficiency characterized by defects in the leukocyte adhesion process, marked leukocytosis and recurrent infections.
ORPHA:2968Classification level: Disorder
Prevalence is unknown, but less than 350 cases have been reported so far.
Usually the first signs occur in infancy or early childhood. Three distinct defects in the leukocyte adhesion cascade have been defined leading to three distinct entities. LAD-I (see this term) is characterized by life-threatening, recurrent bacterial infections. LAD-II (see this term) presents with leukocytosis, recurrent infections, severe growth delay and intellectual deficit. LAD-III (see this term; also called LAD-I variant) is characterized by both severe bacterial infections and a severe bleeding disorder.
LAD results from an impaired step in the inflammatory process, namely, the migration of leukocytes from the blood vessels to sites of infection, which requires adhesion of leukocytes to the endothelium. LAD-I is caused by mutations in the ITGB2 gene (21q22.3), encoding the beta-2-integrin CD18. LAD-II results from mutations in the SLC35C1 gene (11p11.2), encoding the guanosine 5'-diphosphate (GDP)-fucose transporter. LAD-III is caused by mutations in the FERMT3 gene (11q13.1), encoding kindlin-3 in hematopoietic cells.
Diagnosis is based on the clinical symptoms and on a complete blood count revealing neutrophilia. In LAD-I and LAD-II, flow cytometry should be performed for CD18 and CD15 respectively. In LAD-III, platelet aggregation assays should be performed. In all cases, a genetic analysis confirms the diagnosis.
Differential diagnoses include IRAK-4 deficiency, autosomal dominant hyper IgE syndrome, chronic granulomatous disease (see these terms), neutrophil dysfunction and a leukemoid reaction.
Antenatal diagnosis is feasible by genetic analysis of chorionic villus samples.
In all cases, transmission is autosomal recessive. Genetic counseling should always be offered to the patients and their families.
Management and treatment
Management depends on the type of LAD. Treatment should focus on controlling infections and includes antibiotics and, in many cases, bone marrow transplantation. Without hematopoietic stem cell transplantation, patients with severe LAD-I and LAD-III usually die from infection within the first 2 years of life.
The survival rate in patients with LAD-I who undergo bone marrow transplantation is 75%. Some patients with LAD-II survive to adulthood.