History
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Leukocyte adhesion deficiency type I (LAD I) may be diagnosed prior to the onset of infections when delayed umbilical cord separation (normal separation is 3-45 d, with a mean of 10 d) is observed with a persistently high WBC count (>20 X 109/L) in the absence of infection. Patients with leukocyte adhesion deficiency I typically experience from omphalitis, perirectal and labial cellulitis, infections classically seen in patients with neutropenia, otitis media with minimal inflammation, and other indolent necrotic skin infections. Pus is not present, but serosanguineous fluids may be present.
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The most common infectious agents that affect patients with leukocyte adhesion deficiency I include Staphylococcus species, enteric gram-negative bacteria, and fungal organisms, usually Candida albicans. With tooth eruption, gingivitis and periodontitis develop. Wound healing is delayed with poorly formed, thin, and bluish scars. Less frequent, but well-described, complications include aseptic meningitis and croup syndromes of poorly defined etiology. Bacterial typhlitis (inflammation of the cecum commonly found in patients with neutropenia) and intestinal perforation are difficult to diagnose in a timely fashion in patients with leukocyte adhesion deficiency I. Infection is the major cause of death in patients with leukocyte adhesion deficiency I.
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Delayed umbilical cord separation is the classic presentation of leukocyte adhesion deficiency I. However, it is not a reliable finding. In patients with leukocyte adhesion deficiency I, delayed umbilical cord separation is associated with neutrophilia, whereas healthy infants with delayed cord separation lack an elevated WBC count. Omphalitis and perirectal or labial cellulitis associated with extreme neutrophilia (WBC count approximately 45 X 109/L) is highly suggestive of leukocyte adhesion deficiency I.
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Microbicidal activity and oxidative responses against bacteria and Candida species have been shown to be impaired in leukocyte adhesion deficiency I.
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To date, patients described with leukocyte adhesion deficiency II have been of Middle Eastern and Brazilian descent with poor intrauterine or postnatal growth and severe mental retardation recognized shortly after birth. Consanguinity should be sought. Infections in leukocyte adhesion deficiency II are rarely life threatening, but the typical skin and mucosal infections of leukocyte adhesion deficiency I with equally dramatic leukocytosis and absent pus may be observed. Older patients usually manifest fewer infections.
Physical
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For patients with leukocyte adhesion deficiency I, fever is the initial manifestation of infection. Skin and mucosal sites of infection must be rigorously inspected because the inflammatory response is so indolent. Cellulitis, necrosis, and serosanguineous fluid characterize local infection in leukocyte adhesion deficiency I.
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Patients with leukocyte adhesion deficiency II have a characteristic facial appearance, short stature, limb malformations, and severe developmental delay.
Causes
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Leukocyte adhesion deficiency I is an autosomal recessive disorder caused by mutations in the gene that codes for CD18, the ß chain of ß2 integrins, mapped to chromosome arm 21q22.3. In 50% of patients with leukocyte adhesion deficiency I, the gene defects are point mutations of CD18; missense, nonsense, and splice mutations comprise the remainder. Usually, the alleles have 2 distinct mutations. LAD I variants with CD18 that is nonfunctional because of abnormal conformational changes have also been described.
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Leukocyte adhesion deficiency II is caused by mutations in a gene that codes for guanosine 5'-diphosphate (GDP) fucose transporter, which transports GDP fucose to the Golgi complex where glycan, including sialyl Lewis X (the ligand for E and P selectins), are fucosylated. These mutations cause a defect in fucose transport that also results in the nonimmunologic features of severe growth and mental retardation. Thus far, most patients have presented in consanguineous families, consistent with double homozygosity of the alleles.
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Helmus et al identified a genetic defect of leukocyte adhesion deficiency II in a patient whose Golgi GDP-fucose transporter (GFTP) bore a single amino acid exchange that rendered this protein nonfunctional but correctly localized to the Golgi. [5] They also reported a novel dual defect in which a truncated GFTP is unable to localize to the Golgi complex, causing leukocyte adhesion deficiency II in one patient. Furthermore, the missing part of the GFTP can be dissected into 2 regions: one that is needed for Golgi localization, and one that is required for the function of the GFTP. All patients with leukocyte adhesion deficiency II who are genetically analyzed may be subdivided into 2 groups: one in which single amino acid exchanges in the GFTP impair its function but not its subcellular localization, and another group with a dual defect in function and Golgi expression of the GFTP due to the absence of 2 important molecular regions.
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A leukocyte adhesion deficiency II variant with an absence of cell-associated E selectin but with the presence of the soluble E selectin has also been reported.
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Other variants have been reported, creating the potential for confusion and highlighting the need for a common classification. Alon et al have reported a new form of leukocyte adhesion deficiency associated with defective expression of the Rap-1 activator CalDAG-GEF (guanine exchange factor), resulting in impaired signaling via G-protein–coupled receptor (GPCR) at endothelial contacts. [6] Kinashi et al report an inherited activation defect in Rap1, a small guanosine triphosphate (GTP)ase that works as a key regulator of inside-out integrin activation, associated with a pathologic disorder in leukocyte integrin function. [7] Both groups have labeled their finding, leukocyte adhesion deficiency III. These defects also impair platelet aggregation, leading to bleeding disorders. McDowall et al studied the effect of two mutations in the kindlin3 gene on leukocyte function in vitro. [8]
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Impaired leukocyte adhesion can be caused by 2 common drugs (ie, epinephrine and corticosteroids). Both of these drugs demarginate neutrophils from the peripheral vasculature. The mechanism for steroid demargination is not well understood. Epinephrine acts by causing endothelial cells to release cyclic adenosine monophosphate, which, in turn, interrupts adherence.
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A dominant-negative mutation in Rac2 is reported to cause a clinical syndrome indistinguishable from leukocyte adhesion deficiency I. Integrin expression is intact, but actin-associated functions, such as shape change and chemotaxis, and generation of superoxide dependent on nicotinamide adenine dinucleotide phosphate (NADPH) oxidase are defective. Rac2 is a cytosolic GTP–binding protein that acts in a signaling pathway of chemokine receptor-mediated activation of cellular events essential to microbicidal activity.
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Labial ulceration from which Escherichia coli was cultured in an 8-month-old girl with leukocyte adhesion deficiency type 1 (LAD I). Note the thin bluish scar at the superior aspect of the labia from an earlier cellulitis.
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This 3-year-old girl had leukocyte adhesion deficiency type I (LAD I) with complete absence of CD18 expression. Note the typical gingivostomatitis, which was culture-negative for any pathogen.
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This 10-month-old patient with severe leukocyte adhesion deficiency type I (LAD I) developed a cervical adenitis caused by Klebsiella pneumoniae. Following incision and drainage, wound healing took 4 months.
