Variable CD18 expression in a 22-year-old female with leukocyte adhesion deficiency I: Clinical case and literature review

Abstract

Key clinical message: Partial leukocyte adhesion deficiency type 1 (LAD-1) deficiency is extremely rare condition with milder infectious manifestation and immune system imbalance leads to increased risks of autoinflammatory complications, such as pyoderma gangrenosum, that can be triggered by trauma or pregnancy. In patients with spice-site ITGB2 variants, partial expression can occur due to different β2 integrin isophorms expression.

Abstract: LAD-1, OMIM ID #116920 is a rare, autosomal recessive disorder that results from mutations in the ITGB2 gene that encodes the CD18 β2 integrin subunit. According to the CD18 expression, LAD-1 is categorized as severe (<2%), moderate (2%-30%), or mild (>30%). Here, we describe a 22-year-old female, who presented with inflammatory skin disease and oral cavity, as well as respiratory tract infections during the first year of life. LAD-1 was diagnosed at the age of 2 years by low expression of CD18 (1%). Whole-exome sequencing identified homozygous c. 59-10C>A variant in the ITGB2 gene. Despite severe phenotype, the patient survived to adulthood without hematopoietic stem cell transplantation and became pregnant at the age of 20 years, with pregnancy complicated by a pyoderma gangrenosum-like lesion. During her life, CD18 expression increased from 1% to 9%; at 22 years of age, 5% of neutrophils and 9% of lymphocytes were CD18⁺. All CD18⁺-lymphocytes were predominantly memory/effector cytotoxic T cells. However, revertant mosaicism was not being established suggesting that CD18 expression variability may be mediated by other mechanisms such as different β2 integrin isophorms expression.

Keywords: CD18 expression; leukocyte adhesion deficiency; pregnancy; pyoderma gangrenosum.

FIGURE 1

Evolution of the skin lesions on the left thigh within pregnancy. (A) Lesion on the left thing (+8 weeks of pregnancy); (B) disease progression, treatment with imipenem/cilastatin, linezolid, levofloxacin, ornidazole and fluconazole is unsuccessful (+8 weeks of pregnancy); (C) large ulcer on the front, medial, and lateral surfaces of the left thigh, covered with necrotic tissues and fibrin, before surgery (+17 weeks of pregnancy); (D–F) wound healing after surgery followed by cyclosporine and prednisolone treatment (+19–39 weeks of pregnancy); (G) scar after complete healing of wound on the left thigh 1 year and 8 months after baby delivery. (H, I) New foci of gangrenous pyoderma (2, 3) on the lower limbs.

FIGURE 2

(A) CD18 expression on lymphocytes and neutrophils in different patient's ages; (B) all CD18⁺ lymphocytes are CD3⁺CD8⁺ positive, about 30% of all CD8⁺ T‐cells were CD18⁺; (C) CD3⁺CD8⁺ CD18⁺ cells phenotype, expression of CD45R0, HLA DR and CD56, back gating and multigating techniques were used to assess coexpression of multiple cell surface markers on CD18⁺ lymphocytes; (D) sequencing of sorted CD18b right and CD18 negative lymphocytes subsets. Both subsets are homozygous for c.59‐10C>A.