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. INTRODUCTION Leukocyte adhesion deficiency type 1 (LAD-1) is the most common form of LAD but is nonetheless extremely rare with about 450 unique cases described in the last half century. Most cases of LAD-1 exhibit life-threatening symptoms. Patients often manifest with delayed separation of the umbilical cord, poor wound healing, leukocytosis, recurrent bacterial and fungal infections, periodontitis, sepsis, and other inflammatory conditions due to impaired polymorphonuclear neutrophils (PMN) migration. Current treatment strategies for LAD-1 are limited. Antibiotic therapy is commonly used to prevent recurrent infections but usually has adverse side effects. Most patients with LAD-1 die in childhood due to recurrent infection and delayed wound healing; few patients survive to adulthood. Mild- and moderate phenotype patients have better survival, though patients not undergoing hematopoietic stem cell transplantation (HSCT) have a high risk of noninfectious complications. Since LAD-1 is a rare disease, and partial deficiency is even more rare, non-infectious complications are mentioned only in few case reports and include malignancies, such as M7 acute myelocytic leukemia, diffuse large B-cell lymphoma,7,8 autoimmune disorders,9–11 and inflammatory complications, the most common of which is pyoderma-like skin lesions. Partial CD18 expression is usually associated with missense or splice site mutations in ITGB2 gene.2,5,20,21 Additionally, somatic revertant mosaicism was described in four unrelated patients, three or them from a single center, suggesting that it may be relatively common event for this disorder. Here, we report on clinical case of adult female with LAD-1 deficiency and variable partial expression of CD18 β2 integrin subunit. Some dermatological aspects and surgical treatment details were published before,24 but in current report, we present the full clinical story since childhood to present days, genetic conformation of LAD I diagnosis and study of CD18 expression in different patient's age. CASE PRESENTATION Clinical history The patient was the second child of the West-Ukrainian family, full-term, and vaginally delivered with a birth weight of 3350 g. Her umbilical cord fell off normally and the umbilical wound healed without features. At 4months, the patient presented with pneumonia and paronychia; at 5months, she manifested atopic dermatitis, complicated by streptoderma, followed by abscess and keloid scars formation; and at 9months, she had an episode of sepsis, stomatitis, mastitis, carditis, and furunculosis. Each of these presentations was accompanied by leukocytosis in the range of 17,000–25,000/mm3 (normal range—5500–12,000/mm3). Her clinical picture prompted an immunologic evaluation, and the absence of adhesion molecules CD18/CD11b on granulocytes was confirmed by flow cytometry at the age of 2 years, establishing the diagnosis of LAD-1. 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 20years, 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.