Immunology · Year 2 · from Immunology
Case 3: Leukocyte Adhesion Deficiency Type 1
Patient Demographics
- Age: 6 weeks old
- Sex: Male
- Ethnicity: Middle Eastern (Saudi Arabian descent)
Chief Complaint
Delayed umbilical cord separation and skin infection
History of Present Illness
A 6-week-old male infant is brought in for evaluation of an infected umbilical stump. The umbilical cord did not separate until 4 weeks of age (normally 1-2 weeks), and since separation, the site has remained red and oozing. He was recently hospitalized for a skin infection on his arm that failed to improve despite IV antibiotics and required extensive debridement. Notably, there was minimal pus despite the severe infection.
Birth History
- Full-term, vaginal delivery
- Birth weight: 3.5 kg
- Uncomplicated pregnancy
- Parents are first cousins
Family History
- Parents are first cousins
- Two older siblings died in infancy from "severe infections"
Physical Examination
- General: Alert infant, appears uncomfortable
- Vital Signs: T 38.8C, HR 170, RR 45
- Umbilicus: Erythematous, indurated, oozing purulent material; extensive surrounding cellulitis
- Skin: Healing wound on left arm from recent debridement; minimal surrounding erythema
- Lungs: Clear
Laboratory Workup
| Test | Result | Reference Range |
|---|---|---|
| WBC | 65,000/uL | 6,000-17,500/uL |
| Neutrophils | 85% (ANC 55,000) | 40-70% |
| Hemoglobin | 10.5 g/dL | 10-14 g/dL |
| Platelets | 450,000/uL | 150,000-400,000/uL |
| Blood culture | Staphylococcus aureus | Negative |
| Wound culture | Staphylococcus aureus | Negative |
| IgG, IgA, IgM | Normal | -- |
| CD18 expression | Absent on neutrophils | Present |
| CD11a, CD11b | Absent | Present |
Clinical Image
Image showing omphalitis (umbilical cord infection), a characteristic presentation of LAD-1. Image source: Wikimedia Commons (https://commons.wikimedia.org/wiki/File:Neonatal_omphalitis.png). Licensed under CC BY-SA 4.0.
Diagnosis
Leukocyte Adhesion Deficiency Type 1 (LAD-1) due to CD18 (beta-2 integrin) deficiency.
Discussion
LAD-1 results from mutations in ITGB2 encoding CD18, the beta-2 integrin chain common to:
- LFA-1 (CD11a/CD18): Binds ICAM-1; essential for leukocyte adhesion to endothelium
- Mac-1 (CD11b/CD18): Binds ICAM-1 and iC3b; important for phagocytosis
- CR4 (CD11c/CD18): Complement receptor
Why can't neutrophils reach infection sites?
- Normal leukocyte recruitment: Rolling (selectins) → Firm adhesion (integrins) → Transmigration
- Without CD18/integrins, neutrophils can roll but cannot firmly adhere
- Neutrophils are trapped in the bloodstream (marked leukocytosis)
- Sites of infection lack neutrophil infiltration (no pus!)
Characteristic clinical features:
- Delayed umbilical cord separation (>3 weeks) - highly characteristic
- Recurrent severe bacterial infections of skin, soft tissue, respiratory tract
- Absence of pus despite high fever and severe infection
- Marked leukocytosis (often >25,000, can exceed 100,000)
- Impaired wound healing
Severity correlates with CD18 expression:
- Severe phenotype (<1% CD18): Often fatal in infancy
- Moderate phenotype (2-10% CD18): Milder disease, may survive to adulthood
Differential: Other LAD types:
- LAD-2: Selectin ligand defect (fucose metabolism); mental retardation, short stature
- LAD-3: Kindlin-3 deficiency; LAD-1-like infections PLUS bleeding (platelet dysfunction)
Treatment
- HSCT: Only curative option; urgently indicated for severe phenotype
- Aggressive antibiotic therapy: Prolonged courses for infections
- Surgical debridement: Often required as neutrophils cannot clear infection
- G-CSF: May help in moderate phenotype by increasing neutrophil numbers
- Prophylactic antibiotics: TMP-SMX
- Gene therapy: Under investigation
- Genetic counseling: Autosomal recessive; family planning discussion
Prognosis: Without HSCT, severe LAD-1 is typically fatal in early childhood.