Leukocyte adhesion deficiency (LAD) is a primary immunodeficiency inherited disorder characterized by defects in the integrin receptors of white blood cells that lead to impaired adhesion and chemotaxis. Clinically LAD is characterized by recurrent life-threatening infections of the skin, mouth, and respiratory tract, delayed umbilical cord separation, impaired pus formation, poor wound healing, persistent leukocytosis, and periodontitis. Usually the first signs occur in infancy or early childhood. Skin infections may evolve into large ulcers. Severe periodontitis is often present later in life and leads to early tooth loss. A lack of swelling, redness, heat, or pus is observed in the area of infection. These clinical features are due to defective leukocyte adhesion to endothelial cells, absence of transmigration into inflamed tissues as well as deficient phagocytosis and chemotaxis.
Management of leukocyte adhesion deficiency is focused on controlling infections and includes antibiotics. Hematopoietic cell transplantation represents the only cure for LAD, but gene therapy may be available in the future. Prognosis depends on the severity of the disease. Without hematopoietic stem cell transplantation, death in patients with severe LAD occurs from infection within the first two years of life, whereas patients with a moderate form of the disease have a better chance of surviving into adulthood. Survival rate after bone marrow transplantation is 75%.
LAD is caused by mutations in the ITGB2 gene on chromosome 21q22.3. This gene encodes the beta-2-integrin, CD18. It is essential for the migration of leukocytes from the blood vessels to sites of infection, which requires firm adhesion of leukocytes to the endothelium. Defects in the function of the protein, secondary to mutations in this gene, lead to an impaired step in the inflammatory process. As a result, patients show increased susceptibility to infection. Severity of the disease correlates with the degree of CD18 deficiency.
Al-Wahadneh et al. (2004) reported the case of a 4 month-old female infant with leukocyte adhesion deficiency type I. A successful matched HLA- related allogeneic bone marrow transplantation was performed and engraftment was demonstrated on the 12th day. The patient developed Grade III grafts versus host disease (GVHD), veno-occlusive disease of the liver, and late onset hemorrhagic cystitis. She recovered with appropriate immune reconstitution.
Dababneh et al. (2008) reported the case of generalized advanced periodontal destruction of the permanent and deciduous dentition in a young Jordanian girl with a severe phenotype of leukocyte adhesion deficiency type I. Flow cytometry findings demonstrated total absence of CD18, CD11b, and CD11c. Periodontal findings included the early onset of the disease, which affected the primary teeth and permanent dentitions, the intense redness and inflammation of the gingiva, and the rapid periodontal destruction that seems refractory to conventional non-surgical periodontal therapy.
Monies et al. (2017) outlined the genomic landscape of Saudi Arabia based on the findings of 1000 diagnostic panels and exomes. One female patient suffered from inflammatory bowel disease. She was earlier misdiagnosed with Crohn’s disease and treated with anti-inflammatory agents for several years. Using a multigene panel for immune-system disorders, a homozygous mutation (c.1756C>T, p.R586W) was identified in exon 13 of the patient’s ITGB2 gene, associated with LADI. This led to a drastically different management and helped illustrate the importance of molecular testing to confirm diagnoses. Further, the atypical presentation of the patient helped expand the phenotype of this disorder.
Fathallah et al. (2001) carried out a molecular study on four unrelated Tunisian families with five children affected by LAD1, to determine the spectrum of the mutations in the ITGB2 gene causing LAD in these families. All those children (one male and four female) were born from related healthy parents. Three of the four families are consanguineous. The four female patients had the severe form, while the male patient had the moderate form of the disease. They all had delayed umbilical cord separation and suffered recurrent infections. Fathallah et al. (2001) identified four different mutations in the families studied. Two were novel single-bp deletions (1497delG and 1920delG) leading to the severe form of the disease. The two others were missense mutations (G284S and R593C) and they were already reported in patients of different ethnic origin except that the R593C substitution seems to have occurred de novo in one of the patients.
To contribute with your findings to the content of this record, please fill the CTGA Database Information Submission Form and email it, along with supportive documents, to firstname.lastname@example.org.