Leukocyte Adhesion Deficiency Type 1

Leukocyte adhesion deficiency type 1 (LAD1) is an inherited condition in which genetic mutations result in a lack of CD18 expression on neutrophils. These mutations lead to a decrease in the ability of neutrophils to migrate from the blood vessels to the site of injury or infection on recruitment. Patients with this condition will have recurrent infections and delayed wound healing. An elevated neutrophil count may be noted on laboratory evaluation. The diagnosis is confirmed with flow cytometry demonstrating a deficiency in CD18. Hematopoietic stem cell transplantation is the treatment of choice, and it can be curative.

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Epidemiology and Etiology

Epidemiology

  • < 400 cases in the United States
  • All races are affected.
  • Mortality:
    • Most patients with the severe form (< 1% expression of CD18) die within the 1st 2 years of life.
    • Those with 1%–30% expression of CD18 may survive to adulthood.

Etiology

  • Gene: Leukocyte adhesion deficiency type 1 (LAD1) is caused by mutations in the ITGB2 gene. 
  • Mode of inheritance: autosomal recessive 
  • Proteins encoded: CD18, the beta-2 subunit of 3 integrins:
    • Lymphocyte function–associated antigen 1 (LFA-1)
    • Macrophage antigen 1 (Mac-1)
    • Glycoprotein (GP) 150/95

Pathophysiology and Clinical Presentation

Pathophysiology

  • Integrins are important for: 
    • Leukocyte adhesion to endothelial cells during migration
    • Interacting with antigen-presenting cells
    • Cytotoxic killing
  • A deficiency or mutation in these integrins interferes with:
    • Leukocyte adhesion
    • Transmigration
    • Chemotaxis
    • Phagocytosis
    • Respiratory burst 
  • Result: The immune system is unable to properly respond to an infection.
Leukocyte migration leukocyte adhesion deficiency type 1

Steps involved in leukocyte migration:
Leukocyte adhesion deficiency type 1 (LAD1) occurs owing to a mutation in the gene encoding for CD18. This mutation leads to a deficiency of active integrins used in leukocyte adhesion to vascular endothelium, which prevents transmigration to the site of infection.

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Clinical presentation

  • Recurrent bacterial or fungal soft tissue infections
  • Omphalitis (infection of the umbilical cord stump) is common shortly after birth. 
  • Other signs include:
    • Delayed separation of the umbilical cord
    • Periodontal disease
    • Elevated neutrophils
    • Impaired wound healing
    • Fevers

Diagnosis and Management

Diagnosis

  • Involves several preliminary tests of immune function, including basic evaluation of the humoral immune system and the cell-mediated immune system
  • WBC differential will reveal extremely elevated levels of neutrophils.
  • Confirmation with flow cytometry to evaluate for CD18 deficiency

Management

  • Currently, the only curative therapy is hematopoietic stem cell transplantation.
  • Gene therapy is a potential treatment.

Differential Diagnosis

  • Bare lymphocyte syndrome: form of SCID in which MHC molecules are affected. Bare lymphocyte syndrome is notable for having normal levels of B and T cells. The functionality of these cells, not their development, is impaired. Patients can have recurrent bacterial infections, particularly of the respiratory tract. Management includes allogeneic stem cell transplantation.
  • Chronic granulomatous disease: consequence of defective phagocytic cells. Patients will have recurrent infections, abscesses, and granulomatous lesions of multiple organs. The diagnosis is made with neutrophil function testing for superoxide production. Antimicrobial prophylaxis, interferon-gamma, granulocyte transfusion, and hematopoietic stem cell transplantation are potential management options.
  • Chediak-Higashi syndrome (CHS): autosomal recessive disorder caused by mutations affecting a lysosomal trafficking regulator protein. This protein plays a crucial role in the inability of neutrophils to kill phagocytosed microbes. Patients with CHS exhibit recurrent pyogenic infections, easy bleeding and bruising, and neurologic manifestations. This syndrome is also associated with oculocutaneous albinism. The diagnosis is made based on analysis of the patient’s blood or bone marrow smear and genetic testing. The treatment of choice is allogeneic hematopoietic cell transplantation.
  • Hyper-IgE syndrome: hereditary primary immunodeficiency disease characterized by recurrent skin abscesses, pneumonia with pneumatoceles, and eczematous dermatitis. The diagnosis is made with elevated serum IgE levels and can be confirmed with genetic testing. Management includes prophylactic antibiotics and interferon-gamma for severe infections.
  • Severe congenital neutropenia: rare disease resulting from genetic mutations that affect myelopoiesis. Severe congenital neutropenia manifests in infancy with life-threatening bacterial infections. Neutropenia is found on laboratory evaluation, often with an elevated monocyte count. A bone marrow biopsy will also aid in the diagnosis. Management includes granulocyte colony-stimulating factor and hematopoietic stem cell transplantation.
  • Myeloperoxidase deficiency: autosomal recessive disorder that causes impaired microbial killing by phagocytes. The majority of patients with myeloperoxidase deficiency are asymptomatic, while others can have recurrent, severe fungal infections. The diagnosis is made with histochemical staining for myeloperoxidase in neutrophils. There is no specific management for this condition, but patients should be treated for any infections.

References:

  1. Nervi, S.J., Schwartz, R.A., Sidor, M.I. (2019). Leukocyte adhesion deficiency. In Hyonouchi, H. (Ed.), Medscape. Retrieved March 23, 2021, from https://emedicine.medscape.com/article/887236-overview
  2. Etzioni, A. (2020). Leukocyte-adhesion deficiency. In Feldweg, A.M. (Ed.), UpToDate. Retrieved May 3, 2021, from https://www.uptodate.com/contents/leukocyte-adhesion-deficiency

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