Leukocyte adhesion deficiency-I: A comprehensive review of all published cases

Gavrieli

Eur J Clin Investigation

et al. 2019

Leucocyte adhesion deficiency (LAD) is a rare, innate autosomal recessive immunodeficiency with three subtypes. Twenty‐nine patients with LADs were diagnosed and treated in Israeli Medical Centers and in the Palestinian Authority. We discuss the phenotypic, genotypic and biochemical features of LAD‐I, LAD‐II and LAD‐III diagnosed during the neonatal period and early infancy in 18, 6 and 5 patients, respectively. Consanguinity was frequent. Common features were severe infections of variable aetiology, excessive leukocytosis and delayed umbilical cord detachment. In LAD‐I, the integrin CD18 expression varied from negligible to normal. However, CD11a expression was negligible in all tested patients, suggesting both CD11a and CD18 should be used to assess this subtype. LAD‐II patients showed distinctive facial features, physical malformations, short stature and developmental delay. These patients show defective expression of SLeX (CD15a) on cell surface glycoproteins and lack of H antigen on erythroid cell surfaces resulting in Bombay blood group (hh). LAD‐III showed intact but inactive β2 integrins associated with severe infections and significant bleeding disorders caused by defective platelet aggregation and thrombocytopenia. We report four patients with two new unpublished mutations: two LAD‐I patients with c.1099delG in ITGB2 and two LAD‐III patients with c.1069C>T in FERMT3. LAD‐I patients harbouring the c.119_128 deletion in ITGB2 seemed to have better outcomes as compared to other LAD‐I patients. Eight patients with LAD‐I and ‐III underwent successful haematopoietic stem cell transplantation. Cumulative survival was 75%, 50% and 40% for LAD‐I, LAD‐II and LAD‐III, with a median follow‐up of 4 (0.08‐19), 3.25 (1‐32) and 6 (0.08‐8) years, respectively. Prenatal diagnosis is recommended in families with LAD syndromes.

Section: Discussionmentioning

confidence: 97%

“…Each subtype is characterized by specific clinical, biochemical and genetic expressions; although all involve recurrent, life‐threatening infections . LAD‐I has been reported in 323 patients, while only a few patients with LAD‐II and LAD‐III have been reported …”

Section: Introductionmentioning

confidence: 99%

Leucocyte adhesion deficiency—A multicentre national experience

Gavrieli

Eur J Clin Investigation

et al. 2019

“…Severe LAD‐I is generally classified as <2% of CD18‐expressing neutrophils and leads to substantial infant mortality. In fact, mortality for severe LAD‐I was reported as 75% by the age of 2 years in a multicenter retrospective evaluation . On the other hand, most patients with moderate LAD‐I (2%‐30% CD18‐expressing neutrophils) survive childhood, but present with recurrent infections/immunopathology of skin and mucosal surfaces.…”

Section: Defects In Neutrophil Extravasation Into Tissues: Lad‐imentioning

confidence: 99%

“…On the other hand, most patients with moderate LAD‐I (2%‐30% CD18‐expressing neutrophils) survive childhood, but present with recurrent infections/immunopathology of skin and mucosal surfaces. A recent comprehensive review of all published cases of LAD‐I revealed that patients with moderate LAD‐I survive childhood without hematopoietic stem cell transplant (HSCT) treatment; the most frequent manifestation is periodontal disease (>50% of cases), followed by otitis media (36%), sepsis (25%), and perianal skin infections and necrotic ulcers (>10%) . Periodontitis in LAD‐I can be exceptionally severe and start at a very young age, as early as the primary or mixed dentition (termed prepubertal periodontitis) .…”

Section: Defects In Neutrophil Extravasation Into Tissues: Lad‐imentioning

confidence: 99%

Primary immunodeficiencies reveal the essential role of tissue neutrophils in periodontitis

Silva

Brenchley

Moutsopoulos

2018

Immunological Reviews

Summary Periodontitis is a common human inflammatory disease. In this condition, microbiota trigger excessive inflammation in oral mucosal tissues surrounding the dentition, resulting in destruction of tooth‐supporting structures (connective tissue and bone). While susceptibility factors for common forms of periodontitis are not clearly understood, studies in patients with single genetic defects reveal a critical role for tissue neutrophils in disease susceptibility. Indeed, various genetic defects in the development, egress from the bone marrow, chemotaxis, and extravasation are clearly linked to aggressive/severe periodontitis at an early age. Here, we provide an overview of genetic defects in neutrophil biology that are linked to periodontitis. In particular, we focus on the mechanisms underlying Leukocyte Adhesion Deficiency‐I, the prototypic Mendelian defect of impaired neutrophil extravasation and severe periodontitis.

“…Two main phenotypes have been described in LAD‐I. The severe phenotype, with less than 2% CD18 + leukocytes in PB, is associated with life‐threatening infections from the first days of life . Patients with 2% to 30% of CD18 + leukocytes have less severe clinical symptoms, including lower frequency of infections and a longer life expectancy .…”

Section: Gene Therapy In Primary Immunodeficienciesmentioning

confidence: 99%

Advances in the gene therapy of monogenic blood cell diseases

et al. 2019

Self Cite

Hematopoietic gene therapy has markedly progressed during the last 15 years both in terms of safety and efficacy. While a number of serious adverse events (SAE) were initially generated as a consequence of genotoxic insertions of gamma-retroviral vectors in the cell genome, no SAEs and excellent outcomes have been reported in patients infused with autologous hematopoietic stem cells (HSCs) transduced with self-inactivated lentiviral and gammaretroviral vectors. Advances in the field of HSC gene therapy have extended the number of monogenic diseases that can be treated with these approaches. Nowadays, evidence of clinical efficacy has been shown not only in primary immunodeficiencies, but also in other hematopoietic diseases, including beta-thalassemia and sickle cell anemia. In addition to the rapid progression of non-targeted gene therapies in the clinic, new approaches based on gene editing have been developed thanks to the discovery of designed nucleases and improved non-integrative vectors, which have markedly increased the efficacy and specificity of gene targeting to levels compatible with its clinical application. Based on advances achieved in the field of gene therapy, it can be envisaged that these therapies will soon be part of the therapeutic approaches used to treat life-threatening diseases of the hematopoietic system.