Definition/General
Introduction:
Leukocyte adhesion deficiency (LAD) is a group of rare primary immunodeficiency disorders characterized by defective neutrophil adhesion and migration to sites of infection
Three types are recognized: LAD-I (CD18 deficiency), LAD-II (fucose deficiency), and LAD-III (kindlin-3 deficiency)
Results in recurrent severe infections despite high neutrophil counts.
Origin:
Results from defects in neutrophil adhesion molecules
LAD-I: ITGB2 mutations (CD18/β2 integrin deficiency)
LAD-II: SLC35C1 mutations (GDP-fucose transporter deficiency)
LAD-III: FERMT3 mutations (kindlin-3 deficiency)
Leads to impaired neutrophil extravasation and tissue migration.
Classification:
Classified into three types: LAD-I (CD18 deficiency, most common)
LAD-II (fucosylation defect, rare)
LAD-III (kindlin-3 deficiency, bleeding + infections)
Severe vs moderate based on CD18 expression (<2% vs 2-30%).
Epidemiology:
Very rare disorder with less than 300 cases reported worldwide
LAD-I most common (>90% cases)
Autosomal recessive inheritance
Consanguinity common
Higher prevalence in certain populations.
Clinical Features
Presentation:
Recurrent severe bacterial infections
Delayed umbilical cord separation (>3 weeks)
Persistent leukocytosis (neutrophilia)
Poor wound healing
Absent pus formation
Necrotizing infections.
Symptoms:
Severe skin and soft tissue infections
Necrotizing gingivitis and periodontitis
Recurrent pneumonia
Perianal abscesses
Osteomyelitis
Bleeding tendency (LAD-III)
Growth retardation.
Risk Factors:
Consanguineous parents
Family history of recurrent infections
Delayed cord separation
Persistent neutrophilia
Geographic clustering in some populations.
Screening:
CD18 expression (flow cytometry)
Neutrophil adhesion assays
Complete blood count (leukocytosis)
Chemotaxis studies
Genetic testing
Family screening.
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Gross Description
Appearance:
Bone marrow aspirate shows normal to increased cellularity
Increased neutrophils and precursors
Morphologically normal neutrophils
Normal other lineages
Reactive left shift.
Characteristics:
Hypercellular bone marrow
Granulocytic hyperplasia
Normal neutrophil morphology
Functional defect not morphologically apparent
Increased myeloid-to-erythroid ratio.
Size Location:
Normal bone marrow distribution
Lymph nodes enlarged (reactive)
No organomegaly typically
Infection sites lack neutrophilic infiltration
Poor abscess formation.
Multifocality:
Systemic neutrophil dysfunction
Preserved bone marrow production
Functional migration defect
Compensatory hyperplasia
Persistent peripheral neutrophilia.
Microscopic Description
Histological Features:
Hypercellular bone marrow (60-90% cellularity)
Granulocytic hyperplasia with left shift
Morphologically normal neutrophils
Normal maturation sequence
Increased myeloid precursors.
Cellular Characteristics:
Normal neutrophil morphology
Normal nuclear segmentation
Normal cytoplasmic granules
Functional adhesion defect (not morphological)
Increased band forms.
Architectural Patterns:
Preserved bone marrow architecture
Expanded granulocytic areas
Normal sinusoidal pattern
Reactive hyperplasia
No inflammatory infiltrates.
Grading Criteria:
Severity by CD18 expression: Severe (<2% normal)
Moderate (2-30% normal)
Neutrophil count persistently >15,000/μL
Infection severity
Functional assays abnormal.
Immunohistochemistry
Positive Markers:
MPO highlights increased neutrophils
Elastase marks neutrophil granules
CD15 identifies neutrophils
Glycophorin A shows normal erythropoiesis
CD34 shows stem cells.
Negative Markers:
CD18 (β2 integrins) reduced/absent
CD11a, CD11b, CD11c reduced (LAD-I)
Sialyl-Lewis X absent (LAD-II)
Abnormal cell surface markers.
Diagnostic Utility:
Demonstrates CD18 deficiency
Shows normal neutrophil morphology
Confirms granulocytic hyperplasia
Identifies adhesion molecule defects
Distinguishes from other neutrophil disorders
Guides genetic testing.
Molecular Subtypes:
LAD-I (CD18 deficiency)
LAD-II (fucosylation defect)
LAD-III (kindlin-3 deficiency)
Severe vs moderate expression levels
Different clinical presentations.
Molecular/Genetic
Genetic Mutations:
ITGB2 mutations (LAD-I, chromosome 21q22.3)
SLC35C1 mutations (LAD-II, GDP-fucose transporter)
FERMT3 mutations (LAD-III, kindlin-3)
Autosomal recessive inheritance
Different mutation spectra worldwide.
Molecular Markers:
Absent/reduced CD18 expression (LAD-I)
Defective fucosylation (LAD-II)
Impaired integrin activation (LAD-III)
Normal neutrophil count and morphology
Defective chemotaxis.
Prognostic Significance:
Severe LAD-I poor prognosis
Moderate LAD-I better outcomes
LAD-II milder infections
LAD-III bleeding complications
BMT curative
Gene therapy promising.
Therapeutic Targets:
Bone marrow transplantation (curative)
Antimicrobial prophylaxis
Aggressive infection treatment
G-CSF (limited benefit)
Gene therapy (experimental)
Supportive care.
Differential Diagnosis
Similar Entities:
Chronic granulomatous disease
Severe congenital neutropenia
Neutrophil-specific granule deficiency
Myeloperoxidase deficiency
Hyper-IgE syndrome
Secondary neutrophilia.
Distinguishing Features:
LAD: High neutrophil counts
LAD: Absent pus formation
LAD: CD18 deficiency
CGD: Normal neutrophil counts
CGD: Granuloma formation
SCN: Low neutrophil counts
HIES: Elevated IgE
HIES: Eosinophilia.
Diagnostic Challenges:
Confirming adhesion defects
Distinguishing LAD subtypes
CD18 expression testing
Functional assays
Genetic testing
Treatment timing.
Rare Variants:
Atypical LAD presentations
Compound heterozygous mutations
Late-onset forms
Partial phenotypes
Geographic variants.
Sample Pathology Report
Template Format
Sample Pathology Report
Complete Report: This is an example of how the final pathology report should be structured for this condition.
Specimen Information
Bone marrow aspirate and biopsy from [site], adequate for evaluation
Diagnosis
Leukocyte Adhesion Deficiency (Suspected)
Classification
Classification: Primary immunodeficiency with neutrophil adhesion defect
Bone Marrow Cellularity
Cellularity: [X]% for age (hypercellular), with granulocytic hyperplasia
Lineage Assessment
Granulopoiesis: markedly increased with normal morphology. Erythropoiesis: normal. Megakaryopoiesis: normal
Morphological Features
Shows granulocytic hyperplasia with morphologically normal neutrophils
Special Studies
CD18 expression: recommend flow cytometry analysis
Functional studies: recommend adhesion and chemotaxis assays
Genetic testing: recommend LAD gene panel
Clinical Correlation
Reactive granulocytic hyperplasia. Clinical features suggest leukocyte adhesion deficiency
Final Diagnosis
Bone marrow showing reactive granulocytic hyperplasia. Clinical suspicion of leukocyte adhesion deficiency requires functional confirmation