Analysis of Clinical, Immunological and Molecular Features of Leukocyte Adhesion Deficiency Type I in Egyptian Children.

PURPOSE: Leukocyte adhesion deficiency (LAD) represents a rare group of inherited inborn errors of immunity (IEI) characterized by bacterial infections, delayed umbilical stump separation, and autoimmunity. This single-center study aimed at describing the clinical, immunological, and molecular characterizations of 34 LAD-I Egyptian pediatric patients. METHODS: Details of 34 patients' personal medical history, clinical and laboratory findings were recorded; Genetic material from 28 patients was studied. Mutational analysis was done by Sanger sequencing. RESULTS: Omphalitis, skin and soft tissue infections with poorly healing ulcers, delayed falling of the umbilical stump, and recurrent or un-resolving pneumonia were the most common presentations, followed by chronic otitis media, enteropathy, periodontitis; and recurrent oral thrush. Persistent leukocytosis and neutrophilia were reported in all patients, as well as CD18 and CD11b deficiency. CD18 expression was < 2% in around 90% of patients. Sixteen different pathological gene variants were detected in 28 patients who underwent ITGß2 gene sequencing, of those, ten were novel and six were previously reported. Three families received a prenatal diagnosis. Patients were on antimicrobials according to culture's results whenever available, and on prophylactic Trimethoprim-Sulfamethoxazole 5 mg/kg once daily, with regular clinical follow up. Hematopoietic stem cell transplantation (HSCT) was offered for 4 patients. However due to severity of the disease and delay in diagnosis, 58% of the patients passed away in the first 2 years of life. CONCLUSION: This study highlights the importance of early diagnosis and distribution of ITGß2 gene mutation in Egyptian children. Further molecular studies, however, remain a challenging necessity for better disease characterization in the region.

Clinical manifestations and expression of CD18 to guide the diagnosis of leukocyte adhesion deficiency type 1: Mexico experience.

BACKGROUND: Leukocyte adhesion deficiency type 1 (LAD-1) is an inborn error of immunity characterized by a defect in leukocyte trafficking. METHODS: Patients with clinical suspicion of LAD-1 were referred to our institution. Complete blood count and flow cytometric analysis, to identify the expression of CD18, CD11b, and the lymphocyte population phenotyping, were performed, and statistical analysis was completed. RESULTS: We report clinical manifestations and immunological findings of six Mexican patients diagnosed with LAD-1. The diagnosis was based on typical clinical presentation, combined with laboratory demonstration of leukocytosis, and significant reduction or near absence of CD18 and its associated molecules CD11a, CD11b, and CD11c on leukocytes. We found atypical manifestations, not described in other countries, such as early-onset autoimmunity or infections caused by certain microorganisms. CONCLUSIONS: Patients with LAD-1 may present with atypical manifestations, making flow cytometry an indispensable tool to confirm the diagnosis. We present the first report of LAD-1 patients in a Latin American country.

Clinical and immunological characteristics of 69 leukocyte adhesion deficiency-I patients.

BACKGROUND: In order to support the comprehensive classification of Leukocyte Adhesion Deficiency-I (LAD-I) severity by simultaneous screening of CD11a/CD18, this study assessed clinical, laboratory, and genetic findings along with outcomes of 69 LAD-I patients during the last 15 years. METHODS: Sixty-nine patients (40 females and 29 males) with a clinical phenotype suspected of LAD-I were referred to Immunology, Asthma, and Allergy research institute, Tehran, Iran between 2007 and 2022 for further advanced immunological screening and genetic evaluations as well as treatment, were enrolled in this study. RESULTS: The diagnosis median age of the patients was 6 months. Delayed umbilical cord separation was found in 25 patients (36.2%). The median diagnostic delay time was 4 months (min-max: 0-82 months). Forty-six patients (66.7%) were categorized as severe (CD18 and/or CD11a: below 2%); while 23 children (33.3%) were in moderate category (CD18 and/or CD11a: 2%-30%). During the follow-ups, 55.1% of children were alive with a mortality rate of 44.9%. Skin ulcers (75.4%), omphalitis (65.2%), and gingivitis (37.7%) were the most frequent complaints. Genetic analysis of the patients revealed 14 previously reported and three novel pathogenic mutations in the ITGB2 gene. The overall survival of patients with and without hematopoietic stem cell transplantation was 79.3% and 55.6%, respectively. CONCLUSION: Physicians' awareness of LAD-I considering delayed separation of umbilical cord marked neutrophilic leukocytosis, and variability in CD11 and CD18 expression levels, and genetic analysis leads to early diagnosis and defining disease severity. Moreover, the prenatal diagnosis would benefit families with a history of LAD-I.

Pediatric pyoderma gangrenosum associated with leukocyte adhesion deficiency type 1: A case report and review of the literature.

Pyoderma gangrenosum is a rare neutrophilic dermatosis characterized by painful skin ulcers with necrotic, undermined margins. In severe cases, particularly in pediatric patients, work-up for an associated autoimmune, inflammatory, malignant, or genetic disorder should be considered based on the clinical presentation. We report a unique case of pediatric pyoderma gangrenosum with a leukemoid reaction, secondary to an autosomal recessive leukocyte adhesion deficiency type 1.

Clinical and Osteopetrosis-Like Radiological Findings in Patients with Leukocyte Adhesion Deficiency Type III.

BACKGROUND: Leukocyte and platelet integrin function defects are present in leukocyte adhesion deficiency type III (LAD-III) due to mutations in FERMT3. Additionally, osteoclast/osteoblast dysfunction develops in LAD-III. AIM: To discuss the distinguishing clinical, radiological, and laboratory features of LAD-III. METHODS: This study included the clinical, radiological, and laboratory characteristics of twelve LAD-III patients. RESULTS: The male/female ratio was 8/4. The parental consanguinity ratio was 100%. Half of the patients had a family history of patients with similar findings. The median age at presentation and diagnosis was 18 (1-60) days and 6 (1-20) months, respectively. The median leukocyte count on admission was 43,150 (30,900-75,700)/µL. The absolute eosinophil count was tested in 8/12 patients, and eosinophilia was found in 6/8 (75%). All patients had a history of sepsis. Other severe infections were pneumonia (66.6%), omphalitis (25%), osteomyelitis (16.6%), gingivitis/periodontitis (16%), chorioretinitis (8.3%), otitis media (8.3%), diarrhea (8.3%), and palpebral conjunctiva infection (8.3%). Four patients (33.3%) received hematopoietic stem cell transplantation (HSCT) from HLA-matched-related donors, and one deceased after HSCT. At initial presentation, 4 (33.3%) patients were diagnosed with other hematologic disorders, three patients (P5, P7, and P8) with juvenile myelomonocytic leukemia (JMML), and one (P2) with myelodysplastic syndrome (MDS). CONCLUSION: In LAD-III, leukocytosis, eosinophilia, and bone marrow findings may mimic pathologies such as JMML and MDS. In addition to non-purulent infection susceptibility, patients with LAD-III exhibit Glanzmann-type bleeding disorder. In LAD-III, absent integrin activation due to kindlin-3 deficiency disrupts osteoclast actin cytoskeleton organization. This results in defective bone resorption and osteopetrosis-like radiological changes. These are distinctive features compared to other LAD types.

Clinical manifestations and expression of CD18 to guide the diagnosis of leukocyte adhesion deficiency type 1

Background: Leukocyte adhesion deficiency type 1 (LAD-1) is an inborn error of immunity characterized by a defect in leukocyte trafficking. Methods: Patients with clinical suspicion of LAD-1 were referred to our institution. Complete blood count and flow cytometric analysis, to identify the expression of CD18, CD11b, and the lymphocyte population phenotyping, were performed, and statistical analysis was completed. Results: We report clinical manifestations and immunological findings of six Mexican patients diagnosed with LAD-1. The diagnosis was based on typical clinical presentation, combined with laboratory demonstration of leukocytosis, and significant reduction or near absence of CD18 and its associated molecules CD11a, CD11b, and CD11c on leukocytes. We found atypical manifestations, not described in other countries, such as early-onset autoimmunity or infections caused by certain microorganisms. Conclusions: Patients with LAD-1 may present with atypical manifestations, making flow cytometry an indispensable tool to confirm the diagnosis. We present the first report of LAD-1 patients in a Latin American country (AU)

Novel ITGB2 Mutation Is Responsible for a Severe Form of Leucocyte Adhesion Deficiency Type 1.

Leukocyte adhesion deficiency type 1 (LAD1) is a rare autosomal recessive hereditary disorder characterized by recurrent infections, impaired pus formation, delayed wound healing, omphalitis, and delayed separation of the umbilical cord as hallmark features of the disease. It results from mutations in the integrin ß2 subunit gene ITGB2, which encodes the integrin beta chain-2 protein CD18. In this study, we aimed to investigate the case of a five-month-old boy who presented with a clinical phenotype and flow cytometry results suggesting LAD1 disease. Sanger sequencing of all exons and intron boundaries of ITGB2 identified a novel in-frame deletion in exon 7 (ITGB2 c.844_846delAAC, p.Asn282del) in the patient. The p.Asn282del mutation was heterozygous in the child's parents, whereas it was absent in the 96 control individuals from North Africa. This variant was evaluated by two in silico mutation analysis tools, PROVEAN and MutationTaster, which predicted that the mutation was likely to be pathogenic. In addition, molecular modeling with the YASARA View software suggested that this novel mutation may affect the structure of integrin beta-2 and, subsequently, its interaction with integrin alpha-X. In summary, we report a novel pathogenic mutation p.Asn282del associated with LAD1 that expands the mutation diversity of ITGB2 and suggest the combination of flow cytometry and ITGB2 sequencing as a first-line diagnostic approach for LAD disease.

A novel ITGB2 variant with long survival in patients with leukocyte adhesion defect type-I.

Leukocyte adhesion deficiency is an autosomal recessive primary immunodeficiency that has been divided into three types: LAD1 (beta-2 integrin (CD18) family deficiency/defect), LAD2 (absence of fucosylated carbonhydrate ligands for selectins) and LAD3 (defective activation of all beta integrins). However, recently LAD4 has been described in cystic fibrosis patients, with a defect in integrin activation reported in monocytes. LAD-I is the most common type and prevalence of 1 in 1,000,000 live births. Clinical features of LAD patients are recurrent bacterial and fungal infections, omphalitis with delayed umbilical stump separation, significant leukocytosis especially neutrophilia during infection periods, impaired pus formation, and delayed traumatic or surgical wound healing. Flow cytometry is considered a useful tool for rapid diagnosis of the disease. The study of CD18 and CD11 (a, b, c) expression patterns in peripheral blood leukocytes helps to distinguish different phenotypes of LAD-I. In general, patients with ≥ 2% CD18 expression tend to have a less severe infection and often survive until adulthood, whereas < 2% CD18 expression often results in death in infancy. In this case report, three siblings, 10, 15, and 17 years old, diagnosed with leukocyte adhesion defect type 1 in adolescence age group, are presented.

Clinical and laboratory findings in patients with leukocyte adhesion deficiency type I: A multicenter study in Turkey.

Leukocyte adhesion deficiency type I is a rare primary immunodeficiency disorder characterized by mutations in the ITGB2 gene encoding CD18. We present clinical and immunological features of 15 patients with leukocyte adhesion deficiency type 1 (LAD-1). Targeted next-generation sequencing was performed with either a primary immunodeficiency gene panel comprising 266 genes or a small LAD-panel consisting of five genes for genetic analysis. To measure the expression level of integrins on the leukocyte surface, flow cytometry analysis was performed. The median age of the patients at diagnosis was 3 (1-48) months. Eleven (73%) of the 15 patients had a LAD-1 diagnosis in their first 6 months and 14 (93%) patients had consanguineous parents. Delayed separation of the umbilical cord was present in 80% (n = 12) of the patients in our cohort, whereas omphalitis was observed in 53% (n = 8) of the patients. Leukocytosis with neutrophil predominance was observed in 73% (n = 11) patients. Nine distinct variants in the ITGB2 gene in 13 of the 15 patients with LAD-1 were characterized, two of which (c.305_306delAA and c.779_786dup) are novel homozygous mutations of ITGB2. Four unrelated patients from Syria had a novel c.305_306delAA mutation that might be a founder effect for patients of Syrian origin. Four (27%) patients underwent hematopoietic stem cell transplantation. Two patients died because of HSCT complications and the other two are alive and well. Early differential diagnosis of the patients is critical in the management of the disease and genetic evaluation provides a basis for family studies and genetic counseling.

Incidental diagnosis of leukocyte adhesion deficiency type II following ABO typing.

Individuals with the Bombay phenotype (Oh) in the ABO blood group system do not express the H, A, and B antigens but have no clinical symptoms. Bombay phenotype with clinical symptoms has been described in leukocyte adhesion deficiency type II (LAD II), a fucosylation disorder caused by mutations in SLC35C1. Only few LAD II patients have been described so far. Here we describe an additional patient, a 22-year old male, born to unrelated parents, presenting with inflammatory skin disease, periodontitis, growth, and mental retardation, admitted to the department of dentistry for treatment under general anesthesia. Pre-operative routine investigations revealed the presence of the Bombay phenotype (Oh). Genomic sequencing identified two novel triplet deletions of the SLC35C1 gene. Functional investigations confirmed the diagnosis of LAD II. Therapy with oral fucose led to the disappearance of the chronic skin infections and improvements in behavior and attention span.

ß2 Integrin Gene (ITGB2) mutation spectra in Pakistani families with leukocyte adhesion deficiency type 1 (LAD1).

Leukocyte adhesion deficiency I (LADI) is an autosomal recessive type of primary immunodeficiency characterized by occurrence of repeated bacterial infections, impaired pus formation and wound healing. Genetic variations in the ß-2 integrin subunit encoding gene ITGB2 have been implicated in causing the disorder. In the present study, we have investigated twelve patients presenting LAD1 features. After collecting clinical and family history, flow cytometry was used to determine levels of CD18 in the patients. Clinical history revealed that umbilical cord separation occurred mostly after 19 days in the patients. Recurrent skin infections were found in seven patients. Eight patients had at least one elder sibling who died due to repeated infections. All patients had marked neutrophilia with only 0.77% of neutrophils expressing CD18. Total 12 patients suffering from LAD1 were Sanger sequenced for ITGB2 gene. Five variants, including a novel p.(Cys286Phe) and four previously reported [p.(Gly273Arg), p.(Asp128Tyr), p.(Cys62*), IVS7 + 1G > A] were identified in 8 cases, while no pathogenic variant was observed in remaining four cases. This study represents the first comprehensive clinical and genetic characterization of LAD1 in Pakistani population. This will facilitate diagnosis and genetic counselling of patients with immunodeficiency disorders in Pakistani population.

Leukocyte Adhesion Deficiency Type 1 Due to Novel ITGB2 Mutation.

Aim Marked neutrophilia and omphalitis in an infant resulted in the diagnosis of the first case of leukocyte adhesion deficiency type 1 (LAD1) in Ireland. Diagnosis LAD1 requires specific molecular diagnostics for its correct identification. Results Early identification of this disorder allowed for rapid referral for haemotopoeitic stem cell transplant which has resulted in an excellent outcome for this patient. Conclusion The identification of a previously unknown ITGB2 mutation resulting in LAD1 in Ireland should alert physicians to the diagnostic possibility of this extremely rare disorder.

Type I leucocyte adhesion deficiency in Yemenian family managed with appropriate treatment: A case series.

Primary immunodeficiencies are rare, inherited diseases, characterized by altered function or absence of immune cells. Among them is leukocyte adhesion deficiency Type I (LAD-I), an autosomal recessive disorder characterized by primary immunodeficiency, caused by mutations in the ITGB2 gene which produces inability of leucocytes to migrate toward the area of inflammation and is associated with recurrent life-threatening bacterial and fungal infections. Pyoderma gangrenosum (PG) is an uncommon noninfectious neutrophilic dermatosis, characterized by recurrent, necrotic ulcers. It is a diagnosis of exclusion and can be challenging and its management is empirical, with local (topical tacrolimus or intralesional triamcinolone) or systemic immunosuppressive therapy (oral or intravenous glucocorticoids, sulfasalazine, especially in cases associated with Crohn's disease, cyclosporine and, recently, anti-tumor necrosis factor drugs such as Infliximab, Etanercept, and Adalimumab). Though skin ulcerations are common, predominant clinical presentation as PG can often mimic other diseases. It is unusual in children even more in LAD-I. Here, we present a Yemenian family with LAD-I from consanguineous relatives. All patients had history of chronic recurrent skin ulcerations without any bleeding tendency, associated with persistent neutrophilia and requiring steroids and antibiotics. There was no history of delayed cord separation and the condition was initially diagnosed as epidermolysis bullosa, but successively as PG. LAD-I should be kept in mind while evaluating patients with PG especially in children with persistent neutrophilia in the absence of other rheumatological disorders. Its diagnosis is extremely important from the management perspective, as treating these patients without adequate antibiotic cover may be fatal, as happened to one of our patient, and these patients often require hematopoietic stem cell transplantation for permanent cure. Therefore, genetic counseling especially in population with high consanguinity is mandatory.

Leucocyte adhesion deficiency-A multicentre national experience.

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 ß2 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.

Leukocyte Adhesion Deficiency Type 1 with Low Expression of CD 11b.

Leukocyte adhesion deficiency type 1 (LAD-1) is a rare autosomal recessive disorder caused by mutations in the gene that codes for CD18, the beta chain of beta-2 integrins, located on the long arm of chromosome 21. This defect results in failure of leukocyte migration to the site of infection due to the absence of surface integrins. Leukocyte adhesion deficiency should be suspected in any patient with recurrent infections, impaired wound healing, history of delayed umbilical cord separation, periodontitis, leukocytosis, recurrent soft tissue and oral infections. Diagnosis is based on the analysis of neutrophils for the surface expression of CD18, CD11a, CD11b and CD11c by flow cytometry. Here, we present a 55-day male infant with umbilical cord separation on the 10th day of life and no history of infection, who was identified with LAD-1 with low expression of CD11b. The purpose of performing LAD flow cytometric analysis in this patient was to screen him for LAD-1 as his elder brother had LAD-1 and one elder sister died undiagnosed with recurrent skin and chest infections at 8 months of age.