Pediatric Complement Receptor Deficiency Clinical Presentation
- Author: Alan P Knutsen, MD; Chief Editor: Harumi Jyonouchi, MD more...
History
The 5 subtypes of leukocyte adhesion deficiency (LAD) 1 depend on the level of messenger RNA (mRNA) CD18 expression, the level of CD18 protein expression, and the clinical severity.[7] In subtypes 1 and 4 of LAD 1, there is absence of CD11/CD18 expression and patients have severe life-threatening infections (see Table 4). In subtypes 2, 3, and 5 of LAD type 1, diminished CD11/CD18 (3-10% of normal) is observed; however, the patients have less severe infections and chronic periodontitis. Initial reports described LAD as delayed separation of the umbilical cord (after 21 d or longer). Delayed separation of the umbilical cord is observed in the severe form of LAD type 1 but may not occur in the milder forms or in LAD type 2.
The hallmark of LAD type 1 is infection without pus and inflammatory response. The immune defect in LAD type 1 results in decreased neutrophil inflammatory responses and decreased cellular cytotoxicity. The types of infections and susceptibility to microorganisms resemble other neutrophil defects. Onset of infections somewhat varies. In the severe form of LAD type 1, infections often have an onset by age 3-4 months. In milder phenotypes of LAD type 1, onset of infections may be delayed. The most common infections in both phenotypes are otitis media, ulcerative stomatitis, gingivitis, periodontitis, and skin subcutaneous abscesses. Periodontitis and gingivitis are the principal infections observed in LAD type 2.
Guidelines for the diagnosis and management of primary immunodeficiencies have been established.[22]
- Patients with LAD have the following types of infections:
- Necrotic cutaneous abscesses and cellulitis
- Mucosal and perirectal abscesses
- Omphalitis
- Periodontitis, leading to gingival hyperplasia and loss of alveolar bone and teeth
- Gingivitis
- Otitis media
- Pneumonia
- Peritonitis
- Necrotizing enterocolitis
- Intestinal ulceration
- Aseptic meningitis
- Patients with LAD are susceptible to a wide spectrum of gram-positive and gram-negative bacteria, most commonly Staphylococcus aureus, Pseudomonas species, enterobacteria, and Candida albicans.
- In LAD type 2, other problems include severe mental retardation, short stature, and distinctive facial features. The facial features include long eyelashes and a broad and depressed nasal bridge.
- In LAD type 3, the clinical manifestations are similar to that seen in LAD type 1, but there is also a bleeding tendency due to abnormal platelet aggregation.
- In E-selectin deficiency, mild neutropenia is observed instead of the marked leukocytosis found in other types of LAD.
Physical
Physical examination findings are those of infections. Infectious sites are typically devoid of inflammatory cells. Signs of inflammation, such as erythema, are absent. In addition, pus is absent in infected drainages. Indolent and necrotic abscesses and cellulitis occur. Gingivitis and periodontitis occur in all the types of LAD. Another hallmark of LAD is poor wound healing. This may lead to the formation of a characteristic paper-thin bluish scar. Lymphoid tissue is normal in size.
Children with LAD type 2 have severe mental retardation, distinctive facies, and short-limbed dwarfism. The facial features include flat face, long eyelashes, broad and depressed nasal bridge, and anteverted nostrils. The palms of the hands are broad, dorsally positioned second toes were reported in one patient, and a simian crease may be present.
Causes
LAD type 1 is an autosomal recessive immunodeficiency disorder affecting the CD11/CD18 complex. Defects in the beta chain result in the absence, insufficient amount, or abnormal function of the common CD18 unit.
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| Receptor | Cluster Designation | Ligand | Cell Distribution | Activity |
| CR1 | CD35 | C3b/C4b | RBC, polymorphonuclear cell, macrophage, B cell, follicular dendritic cell | Immune adherence, phagocytosis |
| CR2 | CD21 | C3dg/C3d | B cell, follicular dendritic cell | Co-receptor for B-cell signaling |
| CR3 | CD11b/CD18 | C3bi, ICAM | Myeloid | Phagocytosis, immune adherence |
| CR4 | CD11c/CD18 | C3bi, ICAM | Myeloid | Phagocytosis, immune adherence |
| C1qRP | None | C1q, MBL, surfactant | Polymorphonuclear cell, macrophage | Promotes phagocytosis |
| C3aR | None | C3a, C4a | Polymorphonuclear cell, macrophage, epithelial cell, smooth-muscle cell | Anaphylatoxin |
| C4aR | None | C4a | Polymorphonuclear cell, macrophage, epithelial cell, smooth-muscle cell | Anaphylatoxin |
| C5aR | CD88 | C5a | Polymorphonuclear cell, macrophage, epithelial cell, smooth-muscle cell | Anaphylatoxin |
| ICAM = intercellular adhesion molecule, MBL = mannose-binding lectin | ||||
| Disease | Inheritance | Genetic Defect | Protein Defect | Affected Cells | Affected Function | Manifestations |
| LAD type 1 | Autosomal recessive | INTGB2 | CD18 | Polymorphonuclear cell, macrophage, lymphocytes, NK cells | Tight adherence, chemotaxis, endocytosis, T-cell/NK-cell cytotoxicity | Delayed cord separation, skin ulcers, periodontitis, leukocytosis, poor pus formation |
| LAD type 2 | Autosomal recessive | FUCT1 encoding for GDP-fucose transporter | Fucosylated proteins, sialyl-Lewis X (sLeX, CD15s) | Polymorphonuclear cell, macrophage | Rolling, chemotaxis, tethering | Same as LAD type 1 plus hh-blood group, mental retardation |
| LAD type 3 | Autosomal recessive | Kindlin 3 (FERMT3), involved in activation of integrin | Kindlin 3 | Polymorphonuclear cell, macrophage, lymphocytes, NK cells | Tight adherence | Same as LAD type 1 plus bleeding tendency |
| Rac 2 deficiency | Possibly autosomal dominant | RAC2 | Rac2, involved in regulation of actin cytoskeleton | Polymorphonuclear cell, decreased TRECs | Chemotaxis, O2- production | Recurrent infections, poor wound healing, leukocytosis, poor pus formation |
| E-selectin | Possibly autosomal recessive | Unknown | E-selectin | Endothelial cells | Rolling, tethering | Recurrent infections, poor pus formation, mild neutropenia |
| NK = Natural killer, TRECs = T-cell receptor excision circles | ||||||
| Molecule | CD Number | Distribution | Ligand | Function |
| Integrins | ||||
| LFA-1 | CD11a/CD18 | All leukocytes | ICAM-1, 2, 3 | Adhesion, migration |
| CR3 | CD11b/CD18 | Polymorphonuclear cell, macrophage, NK cells, eosinophils | ICAM-1,2; C3bi | Adhesion, migration |
| CR4 | CD11c/CD18 | All leukocytes | C3bi, ICAM-1, CD23, fibrinogen | Adhesion |
| Alpha4-beta7 | None | Lymphocytes, NK cells, eosinophils | MadCAM-1, VCAM-1, fibronectin | Adhesion, migration, rolling |
| VLA-4 | CD49d/CD29 | Lymphocytes, NK cells, eosinophils, basophils | VCAM-1, fibronectin | Adhesion, migration, rolling |
| Selectins | ||||
| E | CD62E | Endothelial cells, platelets | Sialylated, fucosylated molecules (sLeX, CD15s) expressed on PSGL-1 and ESL-1 | Rolling |
| P | CD62P | Endothelial cells, platelets | Sialylated, fucosylated molecules (sLeX) expressed on PSGL-1 | No data |
| L | CD62L | Leukocytes | Sialylated, fucosylated molecules (often sulfated) expressed on CD34, MadCAM-1 and other glycoproteins-1 | Rolling |
| MadCAM = Mucosal addressin cell adhesion molecule; VCAM = Vascular cell adhesion molecule; VLA = Very late activation antigen | ||||
| Subtype | mRNA level | CD18 Expression | Clinical Presentation |
| 1 | None | None | Severe |
| 2 | Low | Trace | Moderate |
| 3 | Reference range | Trace, small protein precursor | Moderate |
| 4 | Reference range | Large protein precursor | Severe |
| 5 | Reference range | Normal protein precursor | Moderate |
| mRNA = messenger RNA. | |||
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