Leukocyte adhesion defect: Clinical correlation with integrin expression and genetics

Abstract

Objectives: Leucocyte adhesion defect 1 (LAD1) is an autosomal recessive defect in integrin expression. In this study we present a case series of 19 children with LAD1. We analysed their clinical and laboratory data and correlated it with integrin expression and underlying genetic defect. Material and Methods: Retrospective case record study of all children diagnosed with LAD1 between 2012 and 2021. Results: Ten females and 9 males were included. Eight cases were born of consanguineous marriage. 78% (15/19) had disease onset within one year of life and 8 of them were neonates. Neonates with LAD1 commonly presented with omphalitis, late-onset sepsis and respiratory infections (RTI). Most common organism isolated from blood was pseudomonas (4/8). CD11/CD18-expression ranged from severely reduced (6/8) to moderately reduced (2/8) but disease was uniformly fatal in the 7/8 patients who could not undergo hematopoietic stem cell transplant (HSCT). Seven children presented between 1month and 1year of age with RTI, bacterial sepsis and soft tissue abscess. Four expired, 1 survived after HSCT and 2 were alive at last follow up. CD11/CD18-expression ranged between 0-1.6% except in 2 cases. One child with 11%-expression is alive without transplant. Another child had 0%-CD11 but 17%-CD18-expression with very low MFI (mean florescence intensity). She succumbed at 20 months of age with perianal abscess, sepsis and RTI but prior to this fatal episode she developed autoimmune cutaneous lesions with lymphocytic infiltration. Four children presented beyond infancy. Median age at onset of symptom was 2 years with skin abscess, oral ulcers, severe periodontitis with tooth loss and pyogenic arthritis. Three of them survived without HSCT, 1 was alive at last follow up. CD11/CD18-expression ranged from 20-32% in these children. Details of cord separation was available in 17 cases and it was delayed (beyond 2 weeks of life) in 9 children. Of the 17 cases with genetic analysis of ITGB2 gene, 16 had a homozygous and 1 had compound heterozygous variant. (nonsense: 2; splice site variants:5; 8: missense variants; 2: deletion). Conclusion: Disease onset less than 1 year age was fatal, irrespective of CD11/CD18 expression. Integrin expression levels beyond 20% and splice site mutation were associated with 100% survival without HSCT but were not event free. Pseudomonas sepsis is the commonest infection in LAD1 neonates. Between 1month to 1year, RTI and gram-negative sepsis dominated and beyond 1st-year skin/perianal abscess was common. Delayed separation of cord was present only in 52% of cases.