ContentsSynopsisCodesLook ForDiagnostic PearlsDifferential Diagnosis & PitfallsBest TestsManagement PearlsTherapyReferences
Leukocyte adhesion deficiency type 1
Print
Other Resources UpToDate PubMed

Leukocyte adhesion deficiency type 1

Print Images (1)
Contributors: Connie Zhong, Susan Burgin MD
Other Resources UpToDate PubMed

Synopsis

Leukocyte adhesion deficiency type 1 (LAD I) is a rare primary immunodeficiency disorder in which the beta-2 integrin family is defective, resulting in impaired migration of neutrophils from the bloodstream to the tissues. It is autosomal recessive and characterized by a mutation in ITGB2, which encodes the common beta-2 subunit of integrin called CD18. The ITGB2 gene is located on the long arm of chromosome 21, and, depending on the mutation, there can be a complete absence of protein or reduced protein size.

The clinical symptoms of LAD I are the result of two impaired and linked processes: first, the inability for neutrophils to migrate to ingest pathogens in the tissue, which results in an increased susceptibility to infection; and second, the upregulation of the IL-17 / IL-23 axis that results in hyperinflammation. In normal signaling, neutrophils respond to chemotactic signals from inflamed tissues by using integrins to bind to intercellular adhesion molecules (ICAM) on vascular endothelial cells. Once bound to the vascular endothelium, they migrate into the tissue, ingest pathogens, and undergo apoptosis and phagocytosis by macrophages. This leads to downregulation of IL-23 (the cytokine released by macrophages) and downstream downregulation of IL-17 (the cytokine released by T-cells), minimizing inflammation. In LAD I, neutrophils have defective or absent integrins so they are unable to migrate into tissues and downregulate the IL-23 / IL-17 axis. As a result, there is unregulated inflammation. In addition to leukocyte migration, CD18 is also necessary for T-cell function. Thus, mutations in ITGB2 lead to a heterogeneous array of symptoms.

LAD I affects about 1 in 10 million people, with males and females being equally affected. LAD I is characterized by recurrent bacterial infections with the absence of pus formation. The infections are primarily localized to skin and mucosal surfaces and are indolent and necrotic, with high propensity for recurrence. The severity of the infections depends on the extent of CD18 deficiency. In mild / moderate deficiency, patients have 2%-30% of normal CD18 expression and can survive into adulthood. In severe deficiency, patients have less than 2% of normal CD18 expression and may die in infancy if treatment is not provided.

A classic early presentation of LAD I is omphalitis with delayed separation of the umbilical cord stump. As the child grows older, he or she may have recurrent otitis media, perirectal abscesses, and bacterial sepsis. Because of impaired immune response, the infections can necrotize and ulcerate, resembling pyoderma gangrenosum. The most common organisms are Staphylococcus aureus and gram-negative bacilli, although fungal infections can also occur. Patients are not typically predisposed to viral infections.

Patients may also have significant mucosal involvement, including severe gingivitis, oral ulcers, periodontitis, and bone and tooth loss. It is not uncommon for LAD I patients to lose all of their adult teeth by late adolescence. This is thought to be caused by a hyperinflammatory response to oral microbes as a result of IL-23 / IL-17 dysregulation.

One variant of LAD I is the somatic reversion of the ITGB2 mutation, leading to a milder clinical phenotype, most characteristically inflammatory bowel disease. Patients with this variant have reduced neutrophil CD18 expression, but normal CD18 expression in a subset of cytotoxic T-cells.

For more information, see OMIM.

Codes

ICD10CM:
D72.0 – Genetic anomalies of leukocytes

SNOMEDCT:
234582006 – Leukocyte adhesion deficiency - type 1

Look For

Subscription Required

Diagnostic Pearls

Subscription Required

Differential Diagnosis & Pitfalls

LAD II – Presents with neutrophilia and is associated with Bombay (h/h) blood group and intellectual disability.

LAD III – Neutrophilia due to defective integrin activation, which affects both neutrophils and platelets. Thus, LAD III patients have increased risk of bleeding.

Delayed umbilical separation (>3 weeks):
  • Variant of normal umbilical separation – Cord separation can occur between 3 and 45 days, with the mean being 14 days.
  • Urachal cyst – Remnant of a sinus that connects the umbilical cord and bladder; usually asymptomatic unless infected, in which case there will be abdominal pain, fever, and hematuria. Infections occur at an older age. 
Nonhealing ulcers:

Best Tests

Subscription Required

Management Pearls

Subscription Required

Therapy

Subscription Required

References

Subscription Required

Last Reviewed: 05/17/2017
Last Updated: 10/01/2018
Copyright © 2019 VisualDx®. All rights reserved.
Leukocyte adhesion deficiency type 1
Print 1 Images
Leukocyte adhesion deficiency type 1 : Oral ulcers, WBC elevated, Neutrophil count increased, Skin ulcers
Copyright © 2019 VisualDx®. All rights reserved.