Abstract
Leukocyte adhesion deficiency (LAD) syndrome is a group of inborn errors of immunity characterized by a defect in the cascade of the activation and adhesion leading to the failure of leukocyte to migrate to the site of tissue injury. Three different types of LAD have been described. The most common subtype is LAD type 1 (LAD1) caused due to defects in the ITGβ2 gene. LAD type 2 (LAD2) is caused by mutations in the SLC35C1 gene leading to a generalized loss of expression of fucosylated glycans on the cell surface and LAD type 3 (LAD3) is caused by mutations in the FERMT3 gene resulting in platelet function defects along with immunodeficiency. There is a paucity of data available from India on LAD syndromes. The present study is a retrospective analysis of patients with LAD collated from 28 different centers across India. For LAD1, the diagnosis was based on clinical features and flow cytometric expression of CD18 on peripheral blood leukocytes and molecular confirmation by Sanger sequencing. For patients with LAD3 diagnosis was largely based on clinical manifestations and identification of the pathogenic mutation in the FERMT3 gene by next-generation Sequencing. Of the total 132 cases diagnosed with LAD, 127 were LAD1 and 5 were LAD3. The majority of our patients (83%) had CD18 expression less than 2% on neutrophils (LAD1°) and presented within the first three months of life with omphalitis, skin and soft tissue infections, delayed umbilical cord detachment, otitis media, and sepsis. The patients with CD18 expression of more than 30% (LAD1+) presented later in life with skin ulcers being the commonest manifestation. Bleeding manifestations were common in patients with LAD3. Persistent neutrophilic leukocytosis was the characteristic finding in all patients. 35 novel mutations were detected in the ITGβ2 gene, and 4 novel mutations were detected in the FERMT3 gene. The study thus presents one of the largest cohorts of patients from India with LAD, focusing on clinical features, immunological characteristics, and molecular spectrum.
Highlights
Leukocyte adhesion deficiency (LAD) is a rare phagocytic disorder characterized by a defect in the trafficking of leukocytes from the blood vessels to the site of tissue injury [1,2,3,4]
It was observed that the absolute neutrophil count (ANC) was higher in LAD type 1 (LAD1)° 40 × 103/ml (11–136× 103/ml) cases as compared to LAD1- 25 × 103/ml (16–74× 103/ml), LAD1+ 27 × 103/ml (10– 91× 103/ml), and LAD type 3 (LAD3) 21 × 103/ml (10–38× 103/ml)
Leukocyte adhesion deficiency is a rare phagocytic disorder associated with defective neutrophil recruitment, rolling, and adhesion [1, 25,26,27]
Summary
Leukocyte adhesion deficiency (LAD) is a rare phagocytic disorder characterized by a defect in the trafficking of leukocytes from the blood vessels to the site of tissue injury [1,2,3,4]. LAD type 2 (LAD2) is caused due to mutations in the SLC35C1 gene leading to defective expression of cell surface fucosylated glycan structures [11, 12] These patients suffer from recurrent bacterial infections, severe mental, and growth retardation characterized by distinct facial characteristics [12]. LAD type 3 (LAD3) is caused by a mutation in the FERMT3 gene that encodes protein kindlin-3 which plays a crucial in integrin activation [14,15,16] These patients have severe recurrent bacterial infections, persistent leukocytosis, and delayed umbilical cord fall with a platelet aggregation defect that results in severe bleeding manifestation [17]. We report a retrospective cohort study of 132 patients LAD patients from 28 different centers of India
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