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Pediatric Complement Receptor Deficiency Clinical Presentation

  • Author: Alan P Knutsen, MD; Chief Editor: Harumi Jyonouchi, MD  more...
 
Updated: Feb 11, 2013
 

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.[8] 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.[23]

  • 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.
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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.

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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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Contributor Information and Disclosures
Author

Alan P Knutsen, MD Professor of Pediatrics, Director of Pediatric Allergy and Immunology, Director Jeffrey Modell Diagnostic & Research Center for Primary Immuodeficiences (CGCMC), Director of Pediatric Clinical Immunology Laboratory, Department of Pathology, St Louis University Health Sciences Center

Alan P Knutsen, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American College of Allergy, Asthma and Immunology, Clinical Immunology Society

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Chief Editor

Harumi Jyonouchi, MD Faculty, Division of Allergy/Immunology and Infectious Diseases, Department of Pediatrics, Saint Peter's University Hospital

Harumi Jyonouchi, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association of Immunologists, American Medical Association, Clinical Immunology Society, New York Academy of Sciences, Society for Experimental Biology and Medicine, Society for Pediatric Research, Society for Mucosal Immunology

Disclosure: Nothing to disclose.

Acknowledgements

John Wilson Georgitis, MD Consulting Staff, Lafayette Allergy Services

John Wilson Georgitis, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association for the Advancement of Science, American College of Chest Physicians, American Lung Association, American Medical Writers Association, and American Thoracic Society

Disclosure: Nothing to disclose.

References
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Protein defects.
Table 1. Complement Receptors
ReceptorCluster DesignationLigandCell DistributionActivity
CR1CD35C3b/C4bRBC, polymorphonuclear cell, macrophage, B cell, follicular dendritic cellImmune adherence, phagocytosis
CR2CD21C3dg/C3dB cell, follicular dendritic cellCo-receptor for B-cell signaling
CR3CD11b/CD18C3bi, ICAMMyeloidPhagocytosis, immune adherence
CR4CD11c/CD18C3bi, ICAMMyeloidPhagocytosis, immune adherence
C1qRPNoneC1q, MBL, surfactantPolymorphonuclear cell, macrophagePromotes phagocytosis
C3aRNoneC3a, C4aPolymorphonuclear cell, macrophage, epithelial cell, smooth-muscle cellAnaphylatoxin
C4aRNoneC4aPolymorphonuclear cell, macrophage, epithelial cell, smooth-muscle cellAnaphylatoxin
C5aRCD88C5aPolymorphonuclear cell, macrophage, epithelial cell, smooth-muscle cellAnaphylatoxin
ICAM = intercellular adhesion molecule, MBL = mannose-binding lectin
Table 2. Leukocyte Adhesion Defects
DiseaseInheritanceGenetic DefectProtein DefectAffected CellsAffected FunctionManifestations
LAD type 1Autosomal recessiveINTGB2CD18Polymorphonuclear cell, macrophage, lymphocytes, NK cellsTight adherence, chemotaxis, endocytosis, T-cell/NK-cell cytotoxicityDelayed cord separation, skin ulcers, periodontitis, leukocytosis, poor pus formation
LAD type 2Autosomal recessiveFUCT1 encoding for GDP-fucose transporterFucosylated proteins, sialyl-Lewis X (sLeX, CD15s)Polymorphonuclear cell, macrophageRolling, chemotaxis, tetheringSame as LAD type 1 plus hh-blood group, mental retardation
LAD type 3Autosomal recessiveKindlin 3 (FERMT3), involved in activation of integrinKindlin 3Polymorphonuclear cell, macrophage, lymphocytes, NK cellsTight adherenceSame as LAD type 1 plus bleeding tendency
Rac 2 deficiencyPossibly autosomal dominantRAC2Rac2, involved in regulation of actin cytoskeletonPolymorphonuclear cell, decreased TRECsChemotaxis, O2- productionRecurrent infections, poor wound healing, leukocytosis, poor pus formation
E-selectinPossibly autosomal recessiveUnknownE-selectinEndothelial cellsRolling, tetheringRecurrent infections, poor pus formation, mild neutropenia
NK = Natural killer, TRECs = T-cell receptor excision circles
Table 3. Adhesion Molecules
MoleculeCD NumberDistributionLigandFunction
Integrins
LFA-1CD11a/CD18All leukocytesICAM-1, 2, 3Adhesion, migration
CR3CD11b/CD18Polymorphonuclear cell, macrophage, NK cells, eosinophilsICAM-1,2; C3biAdhesion, migration
CR4CD11c/CD18All leukocytesC3bi, ICAM-1, CD23, fibrinogenAdhesion
Alpha4-beta7NoneLymphocytes, NK cells, eosinophilsMadCAM-1, VCAM-1, fibronectinAdhesion, migration, rolling
VLA-4CD49d/CD29Lymphocytes, NK cells, eosinophils, basophilsVCAM-1, fibronectinAdhesion, migration, rolling
Selectins
ECD62EEndothelial cells, plateletsSialylated, fucosylated molecules (sLeX, CD15s) expressed on PSGL-1 and ESL-1Rolling
PCD62PEndothelial cells, plateletsSialylated, fucosylated molecules (sLeX) expressed on PSGL-1No data
LCD62LLeukocytesSialylated, fucosylated molecules (often sulfated) expressed on CD34, MadCAM-1 and other glycoproteins-1Rolling
MadCAM = Mucosal addressin cell adhesion molecule; VCAM = Vascular cell adhesion molecule; VLA = Very late activation antigen
Table 4. Subtypes of Leukocyte Adhesion Deficiency Type 1
SubtypemRNA levelCD18 ExpressionClinical Presentation
1NoneNoneSevere
2LowTraceModerate
3Reference rangeTrace, small protein precursorModerate
4Reference rangeLarge protein precursorSevere
5Reference rangeNormal protein precursorModerate
mRNA = messenger RNA.
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