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Leukocyte-adhesion deficiency

Leukocyte-adhesion deficiency
Author:
Amos Etzioni, MD
Section Editor:
Luigi D Notarangelo, MD
Deputy Editor:
Anna M Feldweg, MD
Literature review current through: May 2024.
This topic last updated: Aug 13, 2023.

INTRODUCTION — Leukocyte trafficking from the bloodstream to tissue is important for the continuous surveillance of foreign antigens, as well as for rapid leukocyte accumulation at sites of inflammatory response or tissue injury. Leukocyte emigration to sites of inflammation is a dynamic process, involving multiple steps in an adhesion cascade. Various adhesion molecules are expressed on both resting and stimulated endothelial cells and leukocytes.

Defects in a number of these adhesion molecules result in recognized clinical syndromes. Three leukocyte-adhesion deficiency (LAD) syndromes have been delineated, and a fourth category of other neutrophil adhesion defects has been proposed [1]:

LAD I, in which the beta-2 integrin family is deficient or defective

LAD II, in which the fucosylated carbohydrate ligands for selectins are absent

LAD III, in which activation of all beta integrins (1, 2, and 3) is defective

Other defects of neutrophil adhesion

The terms "LAD1," "LAD2," and "LAD3" were used in an international classification of inborn errors of immunity (formerly "primary immunodeficiencies"), although the author prefers the more commonly used terms above [2,3]. Issues related to the LAD syndromes will be reviewed here. Other neutrophil disorders and the process of leukocyte-endothelial adhesion during inflammation are discussed separately. (See "Primary disorders of phagocyte number and/or function: An overview" and "Leukocyte-endothelial adhesion in the pathogenesis of inflammation".)

OVERVIEW OF LEUKOCYTE MIGRATION — Inflammation is characterized histologically by the accumulation of leukocytes at the involved site due to the directional migration of circulating leukocytes. Migration out of the vasculature is first initiated by contact between the leukocyte and the inflamed vascular endothelium. Both the vascular endothelium and leukocytes actively mediate this adhesive interaction, which will be reviewed briefly here. A detailed review of the adhesion cascade is found separately. (See "Leukocyte-endothelial adhesion in the pathogenesis of inflammation".)

Adhesion molecules — Both leukocytes and vascular endothelial cells express a variety of surface adhesion molecules that help mediate leukocyte trafficking. Three families of adhesive molecules are responsible for the majority of leukocyte-endothelial interactions (table 1):

Selectins – Selectins are found on both leukocytes and endothelial cells and primarily mediate cellular margination and rolling.

Integrins – Integrins are largely responsible for adhesion of leukocytes to endothelial cells and are composed of heterodimers of covalently associated alpha- and beta-protein chains. Certain members of the beta-1 and beta-2 subclasses of integrins are primarily responsible for the migration of leukocytes into areas of inflammation. Integrins are named and categorized based upon their particular alpha and beta chain.

CD18 is the beta chain common to all members of the beta-2 subclass of integrins, and CD11a, CD11b, and CD11c are the alpha chains associated with lymphocyte function-associated antigen 1 (LFA-1), macrophage antigen 1 (Mac-1), and glycoprotein 150/95 (gp150/95), respectively (figure 1).

Members of the immunoglobulin superfamily of proteins – Immunoglobulin superfamily molecules expressed on endothelial cells interact with integrins on leukocytes and are involved in firm adhesion and transmigration. The molecules of this family that play a role in leukocyte-endothelial adhesion are intercellular adhesion molecule 1 (ICAM-1) and intercellular adhesion molecule 2 (ICAM-2).

Steps of leukocyte migration — The movement of leukocytes from the bloodstream to the tissue occurs in several distinct steps (figure 2). First, under conditions of flow, loose adhesion to the vessel wall causes leukocyte rolling on the endothelium, which primarily occurs in postcapillary venules. This transient and reversible step is a prerequisite for the next stage, the activation of leukocytes. This is followed by firm adhesion (ie, sticking), after which transmigration occurs. Each of these steps involves different adhesion molecules and can be differentially regulated. (See "Leukocyte-endothelial adhesion in the pathogenesis of inflammation", section on 'The adhesion cascade'.)

LAD SYNDROMES — In each of the LAD syndromes, leukocytes (particularly neutrophils) cannot leave the vasculature to migrate normally into tissues under conditions of inflammation or infection.

Three LAD syndromes have been defined:

LAD I, in which the beta-2 integrin family is deficient or defective

LAD II, in which the fucosylated carbohydrate ligands for selectins are absent

LAD III, in which activation of all beta integrins (1, 2, and 3) is defective

There is an additional and growing group of LAD syndromes that results from various defects in the regulation of adhesion proteins, including abnormal endothelial-selectin (E-selectin) expression and deficiency of Ras-related C3 botulinum toxin substrate 2 (Rac-2).

Finally, in 2016, a defect in integrin activation was found in monocytes from patients with cystic fibrosis, which was designated LAD IV [4]. It affects phagocyte function rather than neutrophils and was initially designated as a congenital defect of phagocyte function associated with the syndrome of cystic fibrosis in the 2017 International Union of Immunological Societies phenotypic classification for primary immunodeficiencies [3,5]. (See 'LAD IV' below.)

LAD I — LAD I (OMIM #116920) is an autosomal recessive syndrome resulting from deficiency of and/or defects in CD18, the common beta chain of the beta-2 integrin family. Hundreds of cases have been reported.

Pathogenesis — Early studies found that leukocytes from patients with LAD I were deficient in the expression of the three integrins containing CD18 (figure 1) [6]:

Lymphocyte function-associated antigen 1 (LFA-1, CD11a/CD18)

Macrophage antigen 1 (Mac-1, CD11b/CD18)

Glycoprotein 150/95 (gp 150/95, CD11c/CD18)

In vitro studies demonstrated a marked defect in random migration and chemotaxis. Leukocyte adhesion and transmigration through endothelial cells were also severely impaired. LAD I is an autosomal recessive genetic disease with mutation in the integrin beta-2 gene (ITGB2) encoding the CD18 subunit [6]. Over 80 mutations have been described [7]. Deficient expression of CD18 leads to impaired T cell function as well, which probably contributes to the severity of the immunodeficiency. In contrast to neutrophil and lymphocyte functions, natural killer activity is not affected [8].

Subsequently, the syndrome proved more heterogeneous with the discovery of mutations leading to quantitatively normal but functionally defective CD18. The molecular basis for CD18 deficiency varies, with mutations resulting in aberrant beta messenger ribonucleic acid (mRNA) and/or protein [7,9-11]:

There are a number of reported point mutations, some of which lead to the biosynthesis of defective proteins with single amino acid substitutions.

Other mutations lead to splicing defects, resulting in the production of truncated and unstable proteins. Many of these mutations occur in a highly conserved 240 residue domain, which constitutes the binding site of the beta-2 integrins to their ligands, intercellular adhesion molecule 1 (ICAM-1) and intercellular adhesion molecule 2 (ICAM-2).

Some genetic defects result in the lack or diminished expression of CD18 mRNA. In other cases, there is expression of mRNA or protein precursors of aberrant size, giving rise to both larger and smaller CD18 subunits.

A few mutations lead to a defect in beta-2 integrin adhesive functions, despite normal surface expressions of CD18 [12].

A variant form of the disease was described in three young adults who had somatic reversion mutations [13]. In all three, a T cell subset of predominantly cytotoxic T lymphocytes expressed CD18. Normal CD18 expression was due to a further mutation in one CD18 allele in these T cell subsets. This somatic mosaicism was associated with a milder clinical phenotype. However, all three patients had inflammatory bowel disease, which suggests that altered regulation of this T cell subset is important to the pathogenesis of this disorder.

Dysregulation of IL-23/IL-17 axis — In tissues susceptible to bacterial invasion (eg, oral mucosa, skin, gastrointestinal mucosa), the presence of microbes induces a physiologic interleukin (IL) 23 response under normal conditions. Tissue neutrophils respond by moving into the tissues where they kill microorganisms. Then, they undergo apoptosis, after which they are phagocytosed by macrophages. This process normally results in subsequent downregulation of IL-23, as well as the downstream cytokines IL-17 and granulocyte colony-stimulating factor (G-CSF), turning off the inflammatory signal [14,15]. In the absence of tissue neutrophils in patients with LAD I, inhibition of the IL-23/IL-17 axis is deficient, resulting in an unregulated hyperinflammatory response, which leads to chronic inflammation. In patients with LAD I, this process is particularly important in the gingivae but may also be involved in poorly healing cutaneous wounds that often affect these patients [16]. Evidence for this mechanism includes histochemical and animal studies. A case report described a patient with LAD I who experienced dramatic improvement in periodontitis and healing of a sacral wound with ustekinumab, a monoclonal antibody that binds the p40 subunit shared by IL-12 and IL-23 [16]. (See 'Ustekinumab' below.)

Clinical manifestations — LAD I is characterized clinically by the following (table 2):

Delayed separation of the umbilical cord

Recurrent bacterial infections, primarily localized to skin and mucosal surfaces

Leukocytosis

Absent pus formation

Impaired wound healing

Periodontitis (later in life)

A comprehensive review of 323 LAD cases (17) revealed that the severity of infectious complications appeared to be directly related to the degree of CD18 deficiency. Two phenotypes, designated severe deficiency and moderate deficiency, have been defined [17]:

Severe deficiency – Patients with less than 2 percent of the normal surface expression exhibit a severe form of the disease characterized by earlier, more frequent, and more serious episodes of infection, often leading to death before the age of two years if hematopoietic cell transplantation (HCT) is not undertaken.

Mild-to-moderate deficiency – Patients with some surface expression of CD18 (variably characterized as 2 to 30 percent of normal) manifest a mild-to-moderate phenotype, with fewer serious infectious episodes and survival into adulthood.

Infections — Infections affecting the skin, respiratory tract, bowel, and perirectal areas are usually apparent from birth onward [18]. A classic presenting infection is omphalitis with delayed separation (ie, later than 30 days) of the umbilical cord stump (picture 1A-B). Otitis media, perirectal abscess, and bacterial sepsis are noted in many patients [19]. Infections can become necrotizing and lead to ulceration [20,21].

Infections are frequently caused by Staphylococcus aureus and gram-negative bacilli. In contrast to their difficulties in defense against bacterial pathogens, patients do not exhibit a marked increase in susceptibility to viral infections. However, there have been reports of deaths due to viral infections in young adults, possibly reflecting poor cell-cell interaction and impaired specific antibody production [17]. More frequent fungal infections are also observed.

Periodontitis — Severe gingivitis and periodontitis are major features among all patients who survive infancy, and complete loss of adult teeth occurs by late adolescence in most patients [22-24]. In the past, periodontitis in LAD I was attributed to lack of neutrophil surveillance of the periodontal tissues. However, dysregulation of the IL-23/IL-17 axis was shown to exacerbate inflammation and bone loss in the susceptible host, indicating that periodontitis results from a hyperinflammatory response to oral microbes [16,25,26]. (See 'Dysregulation of IL-23/IL-17 axis' above.)

Absence of pus formation — The absence of pus formation at the sites of infection is a hallmark of LAD I (picture 2). There is a profound impairment of leukocyte mobilization into extravascular sites of inflammation, and biopsies of infected tissues demonstrate inflammation completely devoid of neutrophils.

Impaired wound healing — Delayed separation of the umbilical cord is one manifestation of impaired wound healing. In addition, scars can acquire a "cigarette paper" appearance (picture 2) [20].

Other disorders — There may be an increased risk of autoimmunity in patients who survive past infancy. In a series of eight patients, four of whom underwent HCT, six had autoantibodies and/or autoimmune disease [7]. One untransplanted patient developed Crohn-like colitis and juvenile idiopathic arthritis. A mouse model of LAD I found an impaired regulatory T cell (Treg)/dendritic cell interaction, contributing to autoimmunity in LAD I [27].

Laboratory abnormalities — A moderate neutrophilia is usually seen in the absence of infection. During infection, a marked peripheral blood leukocytosis (5 to 20 times normal values or up to 100,000/mL) can be observed because of impaired mobilization to extravascular sites of inflammation. Typically, the neutrophilia is accompanied by a mild lymphocytosis, although band forms are uncommon. Biopsies of infected tissues demonstrate inflammatory infiltrates completely devoid of neutrophils.

Evaluation and diagnosis — The diagnosis should be considered in any infant, male, or female with recurrent soft tissue infection and a very high leukocyte count. Criteria for diagnosis were published in 1999. These include clinical features for definitive, possible, and probable diagnosis (table 3).

To confirm the diagnosis, the absence of functional CD18 and the associated alpha subunit molecules CD11a, CD11b, and CD11c on the surface of leukocytes must be demonstrated by flow cytometry using CD11 and CD18 monoclonal antibodies. Because abnormal CD18 is still expressed in some cases of LAD I or low amounts of functional CD18 may be present, CD11a should be demonstrated to be absent in all cases [28]. These tests are commercially available and are highly accurate.

Sequence analysis to define the exact molecular defect in the beta-2 subunit is recommended, especially for prenatal diagnosis in subsequent pregnancies and genetic counseling [6]. Sequence analysis is available in many laboratories working in genetic molecular testing. Preimplantation genetic testing of LAD I was reported [29].

Differential diagnosis — In most cases, the clinical and laboratory findings are very suggestive of LAD I, and the diagnosis is clear.

Neutrophilia — The elevated leukocyte count is a constant feature in LAD I. A variety of other nonmalignant conditions are also associated with more modest increases in neutrophil count. (See "Approach to the patient with neutrophilia", section on 'Causes of neutrophilia'.)

Extremely high leukocyte counts can be observed in the following conditions:

Infections can occasionally cause leukocyte counts in excess of 50,000 cells/microL.

A leukemoid reaction in infants can cause extreme elevations in leukocytes. (See "Approach to the patient with neutrophilia", section on 'Leukemoid reaction/hyperleukocytosis'.)

Rarely, leukemia and other lymphoproliferative disorders may also present with leukocytosis. (See "Acute myeloid leukemia: Clinical manifestations, pathologic features, and diagnosis".)

Severe periodontitis — Severe periodontitis is seen in several other inborn errors of immunity involving neutrophil disorders (figure 3).

Nonhealing ulcers — The nonhealing ulcers of LAD I can be mistaken for pyoderma gangrenosum (PG), although biopsy specimens in LAD I characteristically show an absence of neutrophils, while the infiltrates of PG are densely neutrophilic [30].

Management and prognosis — Management of LAD I depends on the clinical severity. Mild-to-moderate disease usually responds to antibiotic therapy, while severe disease requires bone marrow transplantation or HCT.

Ustekinumab — Ustekinumab, a monoclonal antibody of the p40 subunit common to IL-12 and IL-23, was used successfully to treat refractory periodontitis and a nonhealing sacral ulcer in a case report of a 19-year-old man with mild LAD I [30]. Doses approved for psoriasis were used. Improvement resulted from control of local inflammation since the underlying defect of impaired neutrophil mobility should not be affected. (See 'Dysregulation of IL-23/IL-17 axis' above.)

Although encouraging, the utility of this agent in LAD I requires further studies to determine safety and efficacy, particularly in patients with more severe disease who might experience adverse effects from prolonged additional immune suppression.

Mild-to-moderate phenotype — Infections in patients with the mild-to-moderate LAD I phenotype usually respond to conservative therapy and the prompt use of appropriate antibiotics during acute episodes.

Careful oral hygiene is important to control periodontitis and prevent oral infections. Care should be coordinated between medical and dental providers. (See "Complications, diagnosis, and treatment of odontogenic infections".)

Bacterial infections should be aggressively managed with systemic antibiotics, guided by culture and sensitivity data whenever possible. Prophylactic antibiotics are used in some cases.

Patients with LAD can receive routine vaccinations, including live-virus vaccines. Note that, although the Centers for Disease Control and Prevention (CDC) recommend against live vaccines in patients with LAD [31], this is based on low-level in vitro evidence. The observation that LAD is not associated with an increased incidence of viral infections or severe viral infections also supports the safety of live attenuated viral vaccines [17]. The author suggests that this CDC recommendation should be reexamined.

Granulocyte macrophage colony-stimulating factor (GM-CSF) is not helpful to patients with LAD (I, II, or III), as this agent would increase the neutrophil number, but the cells still cannot emigrate properly.

Prognosis — Patients with the mild-to-moderate phenotype may survive into adulthood. Lifespan has been lengthened by improvements in supportive care and antibiotics. In the early 1990s, approximately one-half of patients lived into their mid-thirties, and survival may have improved further since then.

Severe phenotype — HCT is the only corrective treatment for the severe phenotype, and patients respond well to this intervention. In a 2021 multicenter, retrospective study of data collected from 84 patients with LAD I and III who received allogeneic HCT between 2007 and 2017, the three-year overall survival was 83 percent [32].

Success of transplantation appears related to the degree of matching with the donor [33]. Survival was 50 percent among eight haploidentical transplant recipients versus 82 percent for those patients with matched (family or unrelated) transplants (n = 28). Reduced-intensity conditioning regimens were successful in patients receiving matched, unrelated transplants.

Gene therapy has been studied in preclinical trials, as well as in vivo studies in animals, and has shown promise [34,35]. However, clinical trials have thus far been unsuccessful [36]. A dog model of gene therapy using foamy virus vectors may prove useful in humans [34]. (See "Overview of gene therapy for inborn errors of immunity".)

A general discussion concerning the management of infants with severe immunodeficiency is presented separately. (See "Inborn errors of immunity (primary immunodeficiencies): Overview of management".)

Prognosis — Patients with the severe form of the disease often die in infancy unless HCT is performed. If transplant is accomplished before severe infections have occurred, the prognosis is very good [33,37,38].

LAD II — LAD II is a rare, autosomal recessive syndrome that is due to the absence of fucosylated carbohydrate ligands, resulting in defective rolling of hematopoietic cells (figure 2 and movie 1 and movie 2 and movie 3) [39].

Pathogenesis — The biochemical abnormality in LAD II is a general defect in fucosylation of macromolecules at the stage of specific transport of fucose to the Golgi apparatus (figure 4) [40,41]. Glycans that incorporate fucose, such as sialyl Lewis X (CD15a) and the H antigen (Bombay), are not expressed on myeloid cells.

Genetic defects in patients with LAD II have been identified in the guanosine diphosphate (GDP) fucose transporter gene (SLC35C1) [41,42]. Mutations in highly conserved transmembrane domains appear to be causative. The patients can be divided genetically into those with normal subcellular expression of the transporter but defective function and those with no expression [43]. LAD II was also designated a congenital disorder of glycosylation (CDG) IIc, since it is a general defect in fucose metabolism [41]. This dual classification has been maintained because patients who live into adulthood mainly demonstrate the metabolic manifestations.

This abnormality in fucosylation in LAD II results in defective rolling of hematopoietic cells, as fucosylated glycoproteins serve as ligands for selectins on endothelial cells. Neutrophils of affected patients fail to bind to purified platelet-derived selectin (P-selectin) and recombinant endothelial-selectin (E-selectin) [6]. Defective rolling and tethering have been observed using intravital microscopy [6]. (See 'Overview of leukocyte migration' above.)

Despite these abnormalities, LAD II neutrophils are able to adhere and transmigrate via beta-2 integrins under conditions of reduced shear forces [6]. This allows some level of neutrophil defense against bacterial infections.

There is evidence for lymphocyte dysfunction in LAD II. Patients can have reduced delayed-type hypersensitivity reactions [44]. This may be due in part to abnormal cytokine release from T helper type 1 cells [45,46].

Clinical manifestations — LAD II has been reported in fewer than 10 patients [47-49]. They were born after uneventful pregnancies and were of normal height and weight at birth. Unlike those with the severe form of LAD I, there was no delay in the separation of the umbilical cord (table 2).

Patients with LAD II have less severe and fewer infections than those with LAD I. Pus formation is impaired, and skin, lung, and periodontal infections are reported but are generally not life threatening [50]. The severity of infections may decrease with time, with adults suffering primarily from periodontitis.

Nonimmune clinical characteristics are an important feature of LAD II. Affected patients have severe intellectual disabilities, are short in stature, and have a distinctive facial appearance (depressed nasal bridge). Microcephaly and cortical atrophy have been described. Children have delays in motor development, including sitting and walking and in speech. Muscular hypotonia and skeletal abnormalities are also seen. Based upon the few patients who have survived to adulthood, it seems that the immune problems dominate clinically in infancy, while, later on in life, the metabolic consequences (CDG-IIc) become more prominent [42]. In a genetic survey of children with short stature and developmental delay, two brothers were found to have a deleterious mutation in SLC35C1, without a leukocyte-adhesion defect [51].

Laboratory findings — As in LAD I, neutrophilia (ranging from 10,000 to 40,000/mm3) is a constant finding, and counts rise further during infection. LAD II is also associated with the rare Bombay (hh) blood phenotype, with red cells lacking A, B, and H antigens. (See "Red blood cell antigens and antibodies".)

Diagnosis — The diagnosis of LAD II should be suspected in the patient with the physical features previously described, mental and growth impairment, recurrent but usually mild infections, marked leukocytosis, and the Bombay blood group. The combination of neutrophilia, Bombay blood group, and severe psychomotor impairment is unique to LAD II.

The absence of sialyl Lewis X expression (CD15a) is demonstrated by flow cytometric analysis of peripheral blood leukocytes treated with a monoclonal antibody directed against sialyl Lewis X, which is available commercially. To confirm the diagnosis, sequence analysis of the gene encoding the GDP-fucose transporter is required. Many commercial laboratories can perform this testing.

Treatment — Among the LAD II patients described so far, infections were common but responded well to antibiotics, although periodontitis is difficult to treat, especially in children with severe intellectual disabilities. (See "Complications, diagnosis, and treatment of odontogenic infections".)

Antibiotic prophylaxis may be necessary in some children with very frequent infections. We typically use trimethoprim-sulfamethoxazole (trimethoprim at a dose of 5 mg/kg once daily). After approximately five years of age, as the adaptive immune response matures, the frequency of infection declines dramatically in many patients.

Fucose supplementation — Because of the proposed defect in fucose metabolism, a trial of fucose supplementation is recommended in all patients diagnosed with LAD II [52]. This would be particularly important in a very young child in whom developmental delay was not yet apparent, as psychomotor function improved in the one successful case [52].

Very few centers have experience with this therapy as it has only been administered to a handful of patients. In the one successful case, the initial dose of fucose was 25 mg/kg body weight per single dose, which was administered five times per day [52]. This was titrated upwards over nine months to a single dose of 492 mg/kg body weight, given five times per day. A young adult male was reported, in whom fucose supplementation led to the disappearance of the chronic skin infections and improvement in behavior and attention span [53].

In this child, fucose supplementation caused a dramatic improvement [47,52]. However, this was not observed in two other patients. This variability is probably explained by the existence of different mutations in the GDP-fucose transporter gene. A mutation that altered substrate affinity could be overcome with excess fucose. By comparison, exogenous fucose administration had no effect on a second mutation associated with normal affinity but slower sugar transport. Another report of a child with a mild presentation of LAD II (growth and cognitive impairment with minimal immunologic features) showed improvement in speech and cognition after 27 months of fucose supplementation [54].

Prognosis — It is difficult to generalize about the prognosis of LAD II as so few patients have been reported. Still, most children survive infancy but suffer from chronic periodontitis and severe mental and growth impairment.

LAD III — LAD III (previously referred to as LAD I variant) is a rare, autosomal recessive syndrome characterized by severe infections with marked leukocytosis and accompanied by a life-threatening bleeding disorder. Fewer than 30 patients with LAD III have been reported, many of whom are of Turkish origin [55-60]. The beta-1, beta-2, and beta-3 integrin families are affected, so both leukocytes (which express beta-1 and 2) and platelets (which express beta-3) are defective.

Pathogenesis — In patients with LAD III, integrin expression and structure is intact, but there is a defect in integrin activation by physiologic stimuli. Earlier studies identified defects in the "inside-out" intracellular integrin activation processes [58,61]. Subsequently, a mutation in the gene for diacylglycerol guanine nucleotide exchange factor 1 (CalDAG-GEF1) was found (figure 5). Although defects in CalDAG-GEF1 cause a syndrome resembling LAD III in a mouse model [62], human CalDAG-GEF1 deficiency is characterized with increase bleeding tendency due to defective platelets activation but without any LAD [63].

Following this earlier work, mutations both in the gene for CalDAG-GEF1 and the gene for kindlin 3, FERMT3, were identified [59]. Kindlin 3 is an adaptor protein that binds to the intracellular portions of beta-1, 2, and 3 integrins and is believed to enhance their binding to the protein talin at the cell membrane, leading to increased integrin activation and stronger binding of ligands (ie, immunoglobulin superfamily molecules). In some patients with LAD III, other mechanisms appear to activate integrins in the absence of kindlin 3, potentially leading to reduced clinical severity [64]. (See "Leukocyte-endothelial adhesion in the pathogenesis of inflammation", section on 'Adhesion molecules'.)

Additional patients have been reported with mutations in both CalDAG-GEF1 and kindlin 3 or with mutations only in the kindlin 3 gene [55,60,65]. Complementation studies showed that the functional defect can be restored with transfection of normal kindlin 3, while normal CalDAG-GEF1 did not correct the defect. Thus mutations of kindlin 3 are considered the main molecular defect underlying LAD III [55,60]. Some patients with mutations only in CalDAG-GEF1 were described as having severe bleeding tendency but no LAD [66].

LAD III is characteristic of a group of genetic deficiencies of important adaptor molecules involved in activation of integrins on hematopoietic cells [55,61,67]. Aside from the adhesion defect, natural killer cell activity was also found to be impaired in LAD III [68].

Clinical manifestations — In LAD III, leukocyte dysfunction leads to severe, recurrent bacterial infections, delayed separation of the umbilical cord, and leukocytosis, similar to the clinical presentation of LAD I. Several patients have had osteoporosis-like bone features [69], which were attributed to profound adhesion and spreading defects in bone-resorbing osteoclasts [70].

Dysfunctional platelet aggregation causes bleeding complications, such as cerebral hemorrhage at birth, hematuria, melena, and petechial lesions of the skin and mucosa [55]. The bleeding disorder is similar to that of patients with Glanzmann thrombasthenia. (See "Inherited platelet function disorders (IPFDs)", section on 'Glanzmann thrombasthenia'.)

Evaluation and diagnosis — Evaluation for LAD III should be performed in infants with bleeding complications from birth, severe infections with delayed separation of the umbilical cord, and marked leukocytosis. Diagnosis requires the demonstration of impaired integrin activation, with intact integrin expression. Genetic analysis for mutations in the kindlin 3 gene should be performed in all suspected cases. These studies are available in a few select laboratories.

Treatment and prognosis — Bone marrow transplantation or hematopoietic cell transplantation (HCT) is the only corrective treatment for LAD III. The prognosis is poor unless transplantation is performed in infancy [71]. Only a small number of patients with LAD III have been transplanted [57,72]. However, proceeding to HCT very early may not permit full assessment of disease severity, as significant variability in the phenotypic expression of LAD III has been reported in a review of 34 published cases [73].

Management of bleeding complications — Use of recombinant factor VIIa has been shown to be effective in treating and preventing severe bleeding in a child patient with LAD III [73]. The treatment of the associated bleeding disorder is reviewed elsewhere. (See "Inherited platelet function disorders (IPFDs)", section on 'Recombinant factor VIIa'.)

A general discussion concerning the management of infants with severe immunodeficiency is presented separately. (See "Inborn errors of immunity (primary immunodeficiencies): Overview of management".)

OTHER SYNDROMES OF DEFECTIVE NEUTROPHIL ADHESION — There are other syndromes of defective leukocyte adhesion that have not been as well characterized or have only been described in one or two patients. These include:

Abnormal endothelium-selectin (E-selectin) expression

Ras-related C3 botulinum toxin substrate 2 (Rac2) deficiency

Leukocyte-hyperadhesion syndrome

Abnormal E-selectin expression — A defect in the selectin system was described in a child with severe recurrent infections and impaired pus formation [74]. In contrast to the other LAD syndromes, only moderate neutropenia was observed. Neutrophil number increased normally during infection. Reported infections included Pseudomonas omphalitis, recurrent ear and urinary tract infections, severe soft tissue infections, and sepsis.

There was markedly reduced expression of E-selectin on blood vessels of inflamed tissue with increased levels of circulating soluble E-selectin. This suggests increased cleavage of surface E-selectin. The underlying defect is unclear as the E-selectin gene sequence was normal in this child.

Rac2 deficiency — Ras-related C3 botulinum toxin substrate 2 (Rac2) is a Rho-GTPase that is essential for several important neutrophil functions. These include rolling via leukocyte-selectin (L-selectin), filamentous (F)-actin assembly, chemotaxis, and superoxide generation in response to some agonists [75,76]. Neutrophils from mice deficient in Rac2 have defects in rolling on endothelium, chemotaxis, and phagocytosis [77].

Rac2 deficiency (also called neutrophil immunodeficiency syndrome; MIM #608203) is a syndrome of global neutrophil dysfunction that was originally described in a male infant with delayed separation of the umbilical cord, poor pus formation, leukocytosis, neutrophilia, and nonhealing perirectal and periumbilical abscesses [78-80]. In contrast to LAD I, wound biopsies showed appropriate numbers of neutrophils. Defects in rolling on endothelium, chemotaxis, and phagocytosis were observed with the child's neutrophils, as well as in a murine model. A de novo, heterozygous dominant-negative Rac2 mutation was identified as the underlying cause of the disease [78].

Infections in this patient healed with granulocyte transfusions. He subsequently underwent successful bone marrow transplantation.

A few other patients with Rac2 deficiency have been reported [81]. Similar to the first patient, the second patient also carried a de novo, dominant-negative mutation. Interestingly, this infant was diagnosed at birth following a positive newborn screening for severe combined immunodeficiency [82]. Clinical manifestations included omphalitis and peritracheal abscess. In addition to neutrophilia and defective chemotaxis, this infant also had CD4+ T cell lymphopenia and hypogammaglobulinemia. Autosomal recessive Rac2 deficiency has been reported in two adult siblings previously diagnosed with common variable immunodeficiency [83]. One of them presented in infancy with recurrent pneumonia and membranous glomerulonephritis and subsequently developed urticaria, autoimmune hypothyroidism, hypogammaglobulinemia, and chronic lung disease. This patient died at 21 years of age of complications after hematopoietic cell transplantation (HCT). Her brother also suffered from recurrent infections, urticaria, autoimmune hypothyroidism, and hypogammaglobulinemia. Both siblings carried a homozygous RAC2 nonsense mutation. There was reduced content of primary and secondary granules in the neutrophils, and chemotaxis was impaired. Naïve T cell lymphopenia was present. Overall, these siblings lacked the typical clinical features suggestive of profound neutrophil defect early in life that is observed in patients with LAD, including the first two patients reported with dominant-negative RAC2 mutation. It is possible that these dominant-negative mutants also compromise Ras-related C3 botulinum toxin substrate 1 (Rac1) function, thereby affecting neutrophil function more profoundly.

Leukocyte-hyperadhesion syndrome — In a single patient with delayed cord separation and recurrent skin infections, no leukocytosis was observed, and adhesion molecule expression and genetic sequencing were normal [84]. Functional studies showed that the patient's lymphocytes were highly adhesive to integrins ligands and displayed decreased migration, suggesting that this hyperadhesiveness may prevent leukocytes from moving to sites of infections.

LAD IV — In patients suffering from cystic fibrosis, a mutation in the gene for cystic fibrosis transmembrane conductance regulator (CFTR) can lead to adhesion deficiency in monocytes but not in lymphocytes or neutrophils [85]. Although integrins are expressed normally, they are not activated. This defect may play an important role in the severe inflammatory process in the lungs in these patients. (See "Cystic fibrosis: Genetics and pathogenesis".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inborn errors of immunity (previously called primary immunodeficiencies)".)

SUMMARY AND RECOMMENDATIONS

Types of LAD – In patients with a leukocyte-adhesion deficiency (LAD) syndrome, leukocytes (particularly neutrophils) cannot leave the vasculature to migrate normally into tissues under conditions of inflammation or infection.

Three LAD syndromes have been delineated (figure 2 and table 2):

LAD I, in which the beta-2 integrin family is deficient or defective

LAD II, in which the fucosylated carbohydrate ligands for selectins are absent

LAD III, in which activation of all beta integrins (1, 2, and 3) is defective

An additional group of LAD syndromes is emerging that is composed of various defects in adhesion proteins or their regulation. These include abnormal endothelial-selectin (E-selectin) expression and Ras-related C3 botulinum toxin substrate 2 (Rac-2) deficiency. (See 'Other syndromes of defective neutrophil adhesion' above.)

LAD I – LAD I is characterized clinically by recurrent bacterial infections, a persistent neutrophilia that increases markedly during infection, absent pus formation (a hallmark finding), and impaired wound healing (picture 2). A classic presenting infection is omphalitis, with delayed separation of the umbilical cord (picture 1A-B). (See 'LAD I' above.)

LAD I should be considered in any infant with recurrent soft tissue infection and a very high leukocyte count. The diagnosis is made by demonstrating the absence of both CD18 and the associated alpha subunit molecules (CD11a, CD11b, and CD11c) by flow cytometry using CD11 and CD18 monoclonal antibodies. Severe and moderate phenotypes are delineated based upon the degree of leukocyte CD18 expression. (See 'Evaluation and diagnosis' above.)

Patients with moderate LAD I require meticulous oral and dental care to control periodontitis and oral infections and prompt and complete treatment of other bacterial infections as they arise. (See 'Management and prognosis' above.)

Patients with severe LAD I and acceptably matched donors are candidates for hematopoietic cell transplantation (HCT). Gene therapy may be available in the future. (See 'Severe phenotype' above.)

LAD II – LAD II results from the absence of fucosylated carbohydrate ligands on hematopoietic cells. Because these glycoproteins serve as ligands for selectins, this abnormality results in defective rolling of leukocytes. (See 'LAD II' above.)

Patients with LAD II have less severe and fewer infections than those with LAD I. Skin, lung, and periodontal infections are common, although generally not life threatening. However, nonimmunologic sequelae are prominent as affected patients have severe intellectual disabilities, short stature, and a distinctive facial appearance (depressed nasal bridge). Children have delays in motor development and speech (table 2). (See 'LAD II' above.)

The diagnosis should be suspected in children with neutrophilia and psychomotor impairment. The presence of the Bombay blood group in such a child strongly suggests the diagnosis. Flow cytometry demonstrates the absence of sialyl Lewis X expression (CD15a), and the diagnosis is confirmed with sequence analysis of the gene encoding the guanosine diphosphate (GDP)-fucose transporter. (See 'Diagnosis' above.)

Patients with LAD II require careful oral and dental care to control periodontitis and oral infections and prompt and complete treatment of other bacterial infections as they arise. (See 'Treatment' above.)

For young children with frequent and/or severe infections despite the above measures, we suggest prophylactic administration of trimethoprim-sulfamethoxazole (Grade 2C). We administer a dose of 5 mg per kg once daily. Antibiotic prophylaxis is not usually needed once the child exceeds approximately five years of age. (See 'Treatment' above.)

We suggest a trial of fucose supplementation in all patients with LAD II (Grade 2C). This is most likely to be successful in patients diagnosed early in life. The initial dose of fucose is 25 mg/kg body weight (per dose), administered five times daily. (See 'Fucose supplementation' above.)

LAD III – LAD III is a rare, autosomal recessive syndrome that results from defective integrin activation by physiologic stimuli. Both leukocytes and platelets are affected, resulting in severe bacterial infections, similar to those seen in LAD I, as well as bleeding complications due to defective platelet function (table 2). (See 'LAD III' above.)

The diagnosis requires a demonstration of impaired integrin activation with intact integrin expression and mutations in the kindlin 3 gene. These studies are performed in a few select laboratories. (See 'Evaluation and diagnosis' above.)

For patients with severe LAD III and acceptably matched donors, HCT may correct the presumed hematopoietic defect. (See 'Treatment and prognosis' above.)

LAD IV – There is an addition disorder named LAD IV, which is a phagocyte disorder. (See 'LAD IV' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges E Richard Stiehm, MD, who contributed as a Section Editor to earlier versions of this topic review.

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Topic 3918 Version 30.0

References

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