Leukocyte Adhesion Deficiency 1

Mendelian MONDO:0007293 Pathograph 23 Show in embeddings browser Primary Immunodeficiency Leukocyte Adhesion Deficiency

An autosomal recessive inborn error of immunity in which biallelic loss-of-function variants in ITGB2 remove or cripple CD18, the beta subunit shared by every member of the beta-2 integrin family. Because the alpha and beta chains pair intracellularly before reaching the plasma membrane, losing the common beta chain takes all four heterodimers down together - LFA-1, Mac-1, p150,95 and CD11d/CD18 - so a single gene defect removes an entire receptor family rather than one receptor. The consequence is specific and unusually legible. Neutrophils are made and released normally, and they still roll along activated endothelium, because rolling is selectin-mediated and selectins are untouched here. What they cannot do is convert that rolling into firm arrest and then cross the vessel wall. The cell therefore stays in the lumen. That produces the inversion this disease is known for: a marked and persistent blood neutrophilia sitting alongside a tissue compartment that is effectively neutropenic, so infections are severe and necrotic yet form no pus, and wounds do not repair. Delayed separation of the umbilical cord with omphalitis is often the first sign. Severity tracks residual CD18 quantitatively rather than categorically - under 2% of expected neutrophil CD18 expression defines the severe phenotype and 2-30% the moderate one - and the periodontal literature shows attachment loss scaling inversely with whatever CD18 remains. The periodontal arm is curated as its own branch because the mechanism is not the one that was assumed for decades. It is not unchecked infection in a tissue no neutrophil can police; it is an IL-23/IL-17 response that has lost its off switch, because the signal that normally damps it - tissue macrophages clearing transmigrated apoptotic neutrophils - never arrives. That distinction is therapeutic, not semantic: antibiotics and mechanical debridement do not control it, while blocking the axis with ustekinumab did. Allogeneic HSCT is the established curative option for severe disease, and autologous lentiviral ITGB2 gene therapy has now reported a phase 1-2 result. LAD1 is the adhesion arm of the leukocyte adhesion deficiency family; the sibling entry Leukocyte Adhesion Deficiency Type II is a different lesion entirely - an SLC35C1 Golgi GDP-fucose transport failure that removes the selectin ligands and so blocks the rolling step upstream of the one that fails here.

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1
Inheritance
9
Pathophys.
10
Phenotypes
3
Gaps
23
Pathograph
1
Genes
5
Medical Actions
2
Subtypes
1
Trials
13
References
🏷

Classifications

Harrison's Part
IMMUNE RHEUMATOLOGIC GENETICS ENVIRONMENT DISEASE
IUIS Category
phagocyte defect
👪

Inheritance

1
Autosomal recessive HP:0000007
Autosomal recessive. Consanguinity is prominent in the reported series, and family history of LAD-I is one of the diagnostic criteria in the consensus severity algorithm - a presymptomatic newborn with an affected sibling can be classified as severe on laboratory and family-history grounds alone.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:22134107 SUPPORT Other
"Leukocyte adhesion deficiency (LAD) is an autosomal recessive disorder caused by decreased expression or functioning of CD18"
States the inheritance mode directly for CD18 deficiency.
PMID:3555290 SUPPORT Human Clinical
"Leukocyte adhesion deficiency (LAD) is a recently recognized autosomal-recessive trait"
The original clinical genetic characterisation, confirming recessive inheritance.
◆

Subtypes

2
Severe LAD-I (<2% CD18)
Under 2% of expected neutrophil CD18 expression, or at least 2% CD18 with under 2% CD11a and/or CD11b. About two thirds of patients in the largest series. Without definitive therapy the annual risk of life-threatening infection persists or increases year on year, and the consensus is explicit that surviving past two years on supportive care alone is not a marker of milder disease. This is the group for whom allogeneic HSCT or gene therapy is recommended.
Show evidence (2 references)
PMID:42011429 SUPPORT Human Clinical
"Severe LAD-I is defined as <2% of expected PMN CD18 expression, or ≥2% of expected PMN CD18 expression and <2% of expected PMN CD11a and/or CD11b expression."
The consensus definition of this subtype, including the CD11a/CD11b arm that catches patients whose CD18 number alone would misclassify them.
PMID:42011429 SUPPORT Human Clinical
"In patients with severe LAD-I with history of significant morbidity and who receive BSC alone (ie, in absence of definitive therapy), survival beyond 2 years of age is not marker of milder disease."
The prognostic point that distinguishes this subtype from moderate disease - survival is not evidence of a milder phenotype.
Moderate LAD-I (2-30% CD18)
2-30% of expected neutrophil CD18 expression with at least 2% CD11a and/or CD11b. About a third of patients. The clinical course is milder and can be deferred - splice-site variants with delayed symptom onset are described - but it is not static, and the consensus asks for routine reassessment because a moderate patient can progress to meet severe criteria. Residual CD18 does not spare the periodontium proportionally: attachment loss scales inversely with whatever CD18 remains, so moderate patients still develop severe periodontal disease.
Show evidence (2 references)
PMID:42011429 SUPPORT Human Clinical
"Moderate LAD-I is defined as 2-30% of expected PMN CD18 expression."
The consensus definition of this subtype.
PMID:42011429 SUPPORT Human Clinical
"Severity of LAD-I is considered on spectrum and can progress. Hence, patients with moderate LAD-I should be routinely reassessed."
Establishes that the subtype boundary is a point on a spectrum that patients can cross, which is why this is curated as a graded subtype rather than a fixed one.
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Discussions and Knowledge Gaps

3
Is LAD1 periodontitis a failure of neutrophil surveillance against periodontal infection, or an inflammatory response that has lost its neutrophil-dependent brake?
INTERPRETATION OPEN interpretation_periodontitis_is_immunopathology_not_infection
Attached to
pathophysiology#Inflammatory Periodontal Bone Loss pathophysiology#Dysregulated IL-23/IL-17 Axis at Barrier Sites treatments#Antimicrobial Prophylaxis and Aggressive Infection Management
For decades the answer was assumed to be the first, and it is the intuitive reading - neutrophils cannot reach the gingival sulcus, so the bacteria win. Three observations do not fit. Bacterial load inside the diseased gingival tissue is comparable to or lower than in healthy controls. The infiltrate is dense but lymphocytic, with neutrophils visible confined inside vessels. And prophylactic antibiotics from infancy plus dental care did not prevent progression in any patient evaluated. The alternative reading explains all three. Efferocytosis of transmigrated apoptotic neutrophils is the signal that tells tissue macrophages to stop making IL-23. Remove the transmigration and the signal never arrives, so a physiological response to the oral microbiome runs without a brake and IL-17 drives osteoclastic bone loss. On this reading the bacteria are the stimulus rather than the agent, which is why suppressing them incompletely - as antibiotics do at a mucosal surface - changes nothing. The distinction is not academic. It predicts that blocking the axis should work where antimicrobials do not, and blocking it did: anti-IL-17 and anti-IL-23 prevented bone loss in LFA-1-deficient mice, and ustekinumab resolved refractory periodontal inflammation in a patient. It also suggests the same logic may apply at other barrier sites in this disease, and in other conditions where neutrophils fail to reach tissue.
What is the natural history of moderate LAD-I, and which moderate patients will progress to meet severe criteria?
KNOWLEDGE GAP OPEN gap_moderate_lad1_natural_history
Attached to
has_subtypes#Moderate phenotypes#Autoimmune Complications
The severe subtype has a defined prognosis and a definitive treatment recommendation. Moderate LAD-I has neither. The consensus asks for routine reassessment precisely because severity is understood to sit on a spectrum and to be able to progress, but it offers no predictor of who progresses, over what interval, or what should trigger a move to definitive therapy. Two observations make this more than a bookkeeping gap. Residual CD18 does not protect the periodontium proportionally - attachment loss scales inversely with remaining CD18, so moderate patients still lose their dentition. And the autoimmune complications reported in long-term follow-up occurred in patients whose beta-2 integrin expression was partially conserved, which is to say in the moderate range. A subtype defined by a laboratory threshold that does not predict its own major morbidities is a subtype whose boundary needs re-examining. Answering this needs prospective follow-up of a moderate cohort with periodontal, autoimmune and infection endpoints, which no published series provides.
How does autologous lentiviral ITGB2 gene therapy compare with allogeneic HSCT over a horizon long enough to matter, and what level of gene-corrected chimerism is sufficient?
KNOWLEDGE GAP OPEN gap_gene_therapy_versus_allogeneic_hsct
Attached to
treatments#Autologous Lentiviral ITGB2 Gene Therapy (Marnetegragene Autotemcel) treatments#Allogeneic Hematopoietic Stem Cell Transplantation
The phase 1-2 gene therapy result is striking on its own terms - nine children, no graft failure, 100% HSCT-free survival at one year - and it removes the two things that make allogeneic transplantation difficult here, donor availability and alloreactivity. But the comparison that clinicians need has not been made. The allogeneic registry cohort is 84 patients with three-year outcomes; the gene therapy cohort is nine with two years of follow-up, and a cross-study comparison of those two is not a comparison. Two specific questions are open. First, durability: beta-2 integrin expression must be maintained in the myeloid compartment for life, and the threshold fraction of corrected cells needed to hold the phenotype is not established from human data. Second, whether gene therapy addresses the non-infectious arms of the disease - the autoimmune complications seen after allogeneic transplantation, and the periodontal disease - or only the infection burden that both the primary endpoint and the reported outcomes emphasise.
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Pathophysiology

9
Biallelic ITGB2 Loss-of-Function Variants
Both copies of ITGB2 at 21q22.3 carry variants that abolish or cripple CD18. The original molecular study resolved five distinct beta-subunit phenotypes across patients - absent mRNA and precursor, low mRNA and precursor, an aberrantly large precursor, an aberrantly small precursor, and a grossly normal precursor - which is why surface expression ranges from undetectable to near-normal-but-nonfunctional. Most missense variants cluster in the conserved betaI domain encoded by exons 5-9, the ligand-binding face of the receptor.
Genetic context ITGB2 hgnc:6155 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns ITGB2 (hgnc:6155). hgnc:6155 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION
Homozygous or compound heterozygous. Loss of function is established at the protein level rather than inferred from variant class - mutant beta precursors fail to associate with the alpha subunit, which is the defining biochemical result.
Downstream
Failed Beta-2 Integrin Heterodimer Assembly The gene product is the shared beta chain, so a disabling variant removes the assembly partner directly.
Show evidence (2 references)
PMID:3594570 SUPPORT In Vitro
"Here we demonstrate that the primary defect in LAD is in the beta subunit gene."
Assigns the primary lesion to the shared beta subunit gene rather than to any individual alpha chain.
PMID:3594570 SUPPORT In Vitro
"We identified five distinct beta subunit phenotypes in LAD patients: undetectable beta subunit mRNA and protein precursor; low levels of beta subunit mRNA and precursor; an aberrantly large beta subunit precursor, probably due to an extra glycosylation site; an aberrantly small precursor; and a..."
The allelic heterogeneity that underlies the severe-versus-moderate split curated below, including the case where protein is made but does not work.
Failed Beta-2 Integrin Heterodimer Assembly
CD18 is the common beta chain of four heterodimers - LFA-1 (CD11a/CD18), Mac-1 (CD11b/CD18), p150,95 (CD11c/CD18) and CD11d/CD18. The alpha and beta subunits pair inside the cell before trafficking to the surface, so when the beta chain is absent or malformed the alpha chains cannot reach the membrane either. One gene defect therefore removes a whole receptor family, which is why the phenotype is broader than any single-integrin knockout would predict.
alpha/beta integrin subunit pairing GO:0046982 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves alpha/beta integrin subunit pairing, annotated with protein heterodimerization activity (GO:0046982), qualified as loss of function. GO:0046982 is a molecular function from the Gene Ontology. ⇓ LOSS OF FUNCTION
beta-2 integrin complex GO:0008305 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves decreased beta-2 integrin complex, annotated with integrin complex (GO:0008305). GO:0008305 is a cellular component from the Gene Ontology. LFA-1 (CD11a/CD18) GO:0034687 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves decreased LFA-1 (CD11a/CD18), annotated with integrin alphaL-beta2 complex (GO:0034687). GO:0034687 is a cellular component from the Gene Ontology.
Downstream
Absent or Reduced Neutrophil CD18 Expression The flow-cytometry measurement of this node, and the test the diagnosis is made on — surface CD18 is absent or reduced because the heterodimer never assembles.
Defective Neutrophil Firm Adhesion to Endothelium The absent heterodimers are the receptors that mediate firm arrest, so losing them removes the interaction.
Show evidence (3 references)
PMID:35408940 SUPPORT Other
"Since the β and α subunits pair intracellularly, a decreased or mutated β subunit also leads to a decreased expression of the α subunit at the cell surface."
The intracellular-pairing requirement that makes a beta-chain defect take all four alpha chains down with it.
PMID:22134107 SUPPORT Other
"Decreased expression of the common β2 subunit leads to a similar decrease in the expression of all four α subunits on the leukocyte surface."
Confirms the loss spans all four alpha subunits rather than being restricted to LFA-1.
PMID:3555290 SUPPORT Human Clinical
"These include Mac-1 (complement receptor type 3), lymphocyte function-associated antigen-1 (LFA-1), and p150,95."
Names the receptor family lost, from the classic clinical-molecular description of the disease.
Defective Neutrophil Firm Adhesion to Endothelium
Selectin-mediated rolling is intact in LAD1 - the selectins and their ligands are untouched - but the neutrophil cannot convert rolling into integrin-mediated firm arrest on the inflamed vessel wall. LFA-1 binding to endothelial ICAM-1 and ICAM-2 is the step that fails. No other adhesion system substitutes: VLA-4, which lets monocytes and T cells arrest through a beta-1 route, is not expressed on neutrophils, so the neutrophil has no fallback.
neutrophil CL:0000775 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neutrophil (CL:0000775). CL:0000775 is a cell type from the Cell Ontology. vascular endothelial cell CL:0000071 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves vascular endothelial cell, annotated with blood vessel endothelial cell (CL:0000071). CL:0000071 is a cell type from the Cell Ontology.
leukocyte adhesion to vascular endothelial cell GO:0061756 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased leukocyte adhesion to vascular endothelial cell (GO:0061756). GO:0061756 is a biological process from the Gene Ontology. ↓ DECREASED leukocyte cell-cell adhesion GO:0007159 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased leukocyte cell-cell adhesion (GO:0007159). GO:0007159 is a biological process from the Gene Ontology. ↓ DECREASED integrin-mediated signaling pathway GO:0007229 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves integrin-mediated signaling pathway (GO:0007229), qualified as loss of function. GO:0007229 is a biological process from the Gene Ontology. ⇓ LOSS OF FUNCTION
Downstream
Failure of Neutrophil Transmigration into Tissue Transmigration is downstream of firm arrest in the adhesion cascade, so a cell that never arrests never crosses.
Show evidence (2 references)
PMID:22134107 SUPPORT Other
"This deficiency leads to severe impairment of leukocyte adhesion to the vascular wall and leukocyte migration to sites of infection and inflammation."
The adhesion defect at the vessel wall, stated for CD18 deficiency directly.
PMID:35408940 SUPPORT Other
"Since VLA-4 is mainly expressed on monocytes and T cells, but not on neutrophils, it is not able to compensate for the loss of β2 integrins in LAD I"
Explains why the neutrophil has no redundant arrest mechanism, which is why this node is absolute rather than partial in the neutrophil lineage.
Failure of Neutrophil Transmigration into Tissue
Neutrophils remain confined within the vessel lumen and do not cross into infected or inflamed tissue. Histology of LAD1 lesions makes the point plainly - the inflammatory infiltrate is dense but composed of lymphocytes, with neutrophils visible inside vessels and absent from the tissue around them.
neutrophil CL:0000775 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neutrophil (CL:0000775). CL:0000775 is a cell type from the Cell Ontology.
neutrophil extravasation GO:0072672 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased neutrophil extravasation (GO:0072672). GO:0072672 is a biological process from the Gene Ontology. ↓ DECREASED leukocyte migration GO:0050900 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased leukocyte migration (GO:0050900). GO:0050900 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Tissue Neutropenia with Blood Neutrophilia Neutrophils that cannot leave the circulation accumulate in the compartment they are counted in and are missing from the one they are needed in.
Impaired Wound Healing Wound repair requires neutrophil recruitment into the wound bed, which does not occur.
Show evidence (1 reference)
PMID:24670684 SUPPORT Human Clinical
"The infiltrate comprised primarily lymphocytes, whereas neutrophils were confined within vessels."
Direct histological demonstration in patient tissue that neutrophils do not cross the vessel wall, which is the node's claim.
Tissue Neutropenia with Blood Neutrophilia
The signature inversion of this disease. Granulopoiesis is normal and unrestrained, so the circulating neutrophil count is high - markedly so during infection - while the tissue compartment behaves as if the patient were neutropenic. Every downstream consequence of the disease flows from this dissociation, and it is also why the blood count is actively misleading at the bedside: the one number a clinician reaches for moves in the opposite direction to the deficit.
neutrophil CL:0000775 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neutrophil (CL:0000775). CL:0000775 is a cell type from the Cell Ontology.
inflammatory response GO:0006954 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased inflammatory response (GO:0006954). GO:0006954 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Persistent Marked Leukocytosis The blood-count half of that dissociation. Counts are often extreme, and a high count here indicates the disease rather than excluding it.
Pus-Free Necrotic Bacterial and Fungal Infection Pus is accumulated tissue neutrophils; with none arriving, infection proceeds without it.
Dysregulated IL-23/IL-17 Axis at Barrier Sites The absent tissue neutrophils are the input to the efferocytosis feedback loop that normally restrains IL-23 production.
Show evidence (2 references)
PMID:22134107 SUPPORT Other
"Characteristic features are delayed separation of the umbilical cord and strong leukocytosis, especially neutrophilia, during periods of infection."
The blood side of the inversion, described as characteristic of the disease.
PMID:24670684 SUPPORT Human Clinical
"IL-17-induced granulopoiesis factors and chemokines were readily detected in blood plasma of LAD-I patients"
Ties the circulating neutrophilia to sustained granulopoietic drive rather than to a marrow abnormality, which is why the two compartments diverge.
Pus-Free Necrotic Bacterial and Fungal Infection
Recurrent, severe, often life-threatening bacterial and fungal infection of skin and mucosal surfaces, with the diagnostically important feature that lesions do not suppurate. Necrotic skin lesions in LAD1 are frequently labelled pyoderma gangrenosum, which is a misreading - the biopsy characteristically contains no neutrophils at all, which is the opposite of what that diagnosis implies.
inflammatory response GO:0006954 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased inflammatory response (GO:0006954). GO:0006954 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Recurrent Bacterial and Fungal Infections Without Pus The defining infection phenotype: necrosis without the purulence that requires neutrophils to arrive in tissue.
Omphalitis Infection of the umbilical stump, classically the first presentation in the neonatal period.
Show evidence (3 references)
PMID:3555290 SUPPORT Human Clinical
"characterized by recurrent bacterial infections, impaired pus formation and wound healing"
The classic description, which names impaired pus formation alongside the infections rather than as an afterthought.
PMID:42011429 SUPPORT Human Clinical
"Children can also present with severe/recurrent bacterial or fungal infections, recalcitrant periodontitis, and/or necrotic skin wounds/lesions absent pus formation."
Contemporary consensus statement of the same presentation, and the source for including fungal infection rather than bacterial alone.
PMID:28328326 SUPPORT Human Clinical
"Chronic necrotic skin lesions, often incorrectly described as pyoderma gangrenosum (biopsy samples characteristically show no neutrophils), are common in LAD1"
The histological point that the lesions are neutrophil-free, which both supports the node and corrects a common misdiagnosis.
Dysregulated IL-23/IL-17 Axis at Barrier Sites
Tissue macrophages normally down-regulate IL-23 production when they phagocytose transmigrated apoptotic neutrophils. In LAD1 those neutrophils never arrive, so the brake is never applied and an otherwise physiological IL-23 response to the local microbiome runs unchecked, driving T-cell-derived IL-17 to high levels at the gingiva and skin. The elevation is compartmentalised rather than systemic - plasma IL-17 and IL-23 are low or absent - which matters because it means this is a local immunopathology, not a circulating inflammatory syndrome.
gingival CD4+ T cell CL:0000084 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves gingival CD4+ T cell, annotated with T cell (CL:0000084). CL:0000084 is a cell type from the Cell Ontology.
interleukin-17 production GO:0032620 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased interleukin-17 production (GO:0032620). GO:0032620 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Autoimmune Complications Autoimmune and inflammatory complications arising from the dysregulated barrier-site axis rather than from the adhesion defect directly.
Inflammatory Periodontal Bone Loss IL-17 is an osteoclastogenic cytokine, and blocking it or its IL-23 driver prevents the bone loss in the corresponding mouse model.
Show evidence (3 references)
PMID:24670684 SUPPORT Human Clinical
"Defective neutrophil recruitment in LAD-I patients or in LFA-1 (CD11a/CD18)-deficient mice--which exhibit the LAD-I periodontal phenotype--was associated with excessive production of predominantly T cell-derived IL-17 in the periodontal tissue"
The human observation of excess T-cell-derived IL-17 in LAD-I periodontal tissue, and its attribution to the recruitment defect.
PMID:24670684 SUPPORT Human Clinical
"These data reveal that the elevated expression of IL-17 in LAD-I is compartmentalized rather than systemic."
The compartmentalisation, which is why this node is tagged TISSUE and not ORGANISM.
PMID:28328326 SUPPORT Human Clinical
"The phagocytosis of apoptotic neutrophils (efferocytosis) by tissue macrophages acts as a signal to down-regulate the production of interleukin-23 and therefore the downstream cytokines interleukin-17 and granulocyte colony-stimulating factor (G-CSF)."
States the feedback circuit whose input is missing here, which is the mechanism this node asserts.
Inflammatory Periodontal Bone Loss
Early-onset, generalised, severe periodontitis with destruction of tooth-supporting connective tissue and alveolar bone, ending in loss of both primary and permanent dentition. Historically read as unpoliced periodontal infection, but the evidence does not support that: bacterial load within the diseased gingival tissue is comparable to or lower than in healthy controls, and the disease is refractory to antibiotics and to mechanical biofilm removal. The severity scales inversely with residual CD18, tying the dental phenotype quantitatively to the molecular lesion.
osteoclast CL:0000092 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves osteoclast (CL:0000092). CL:0000092 is a cell type from the Cell Ontology.
bone resorption GO:0045453 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased bone resorption (GO:0045453). GO:0045453 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Severe Early-Onset Periodontitis with Tooth Loss The periodontium depends on continuous neutrophil traffic, which is why it fails first and hardest in every adhesion defect.
Premature Loss of Permanent Teeth The endpoint of that bone loss.
Show evidence (3 references)
PMID:24670684 SUPPORT Human Clinical
"Affected individuals display neutrophilia, suffer from recurrent infections, and invariably develop early-onset generalized aggressive periodontitis featuring severe bone loss and premature loss of primary and permanent teeth"
States the periodontal phenotype and its invariability in this disease.
PMID:24670684 SUPPORT Human Clinical
"quantification of bacterial counts in gingival tissue sections from LAD-I patients and healthy controls, using real-time PCR of the 16S rRNA gene, revealed that the bacterial load within the tissue of LAD-I patients was comparable to (if not less than) that of healthy controls"
The measurement that refutes the tissue-invasive-infection reading of this phenotype, and so supports curating it as an immunopathology.
PMID:24670684 SUPPORT Human Clinical
"We observed progressive periodontal disease in all patients evaluated, despite prophylactic antibiotic use since infancy and access to dental care."
The clinical refractoriness to antimicrobial and mechanical management, which is the practical consequence of the mechanism.
Impaired Wound Healing
Wounds fail to repair and skin ulcers persist, because the neutrophil influx that initiates the repair programme does not occur. Clinically this appears as non-healing lesions that progress through repeated antibiotic courses and surgical debridement, and it is one of the features that resolves when the adhesion defect is corrected.
wound healing GO:0042060 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased wound healing (GO:0042060). GO:0042060 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Delayed Umbilical Cord Separation Cord separation depends on neutrophil-mediated tissue remodelling, so delay beyond three weeks is an early and characteristic sign.
Chronic Non-Healing Skin Ulcers The same remodelling failure in skin, producing ulcers that persist rather than close.
Show evidence (2 references)
PMID:3555290 SUPPORT Human Clinical
"characterized by recurrent bacterial infections, impaired pus formation and wound healing"
Names impaired wound healing as a defining feature of the disease.
PMID:22134107 SUPPORT Other
"The patients suffer from recurrent, life-threatening bacterial and fungal infections and from impaired wound healing."
Independent statement of the wound-healing defect alongside the infection phenotype.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Leukocyte Adhesion Deficiency 1 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

10
Blood 1
Persistent Marked Leukocytosis VERY_FREQUENT Increased total leukocyte count HP:0001974 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased total leukocyte count (HP:0001974), qualified as temporality chronic. HP:0001974 is a phenotype from the Human Phenotype Ontology.
Temporal: CHRONIC
Show evidence (2 references)
PMID:22134107 SUPPORT Other
"Characteristic features are delayed separation of the umbilical cord and strong leukocytosis, especially neutrophilia, during periods of infection."
States marked leukocytosis with neutrophilia as a characteristic feature.
PMID:40305711 SUPPORT Human Clinical
"Pretreatment neutrophilia and skin abnormalities related to LAD-I resolved."
The neutrophilia resolving once CD18 is restored, which confirms it is secondary to the adhesion defect rather than an independent marrow phenotype.
Head and Neck 2
Severe Early-Onset Periodontitis with Tooth Loss VERY_FREQUENT HP:0000704 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Periodontitis (HP:0000704), qualified as course progressive; severity severe. HP:0000704 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE Severity: SEVERE
Show evidence (2 references)
PMID:28328326 SUPPORT Human Clinical
"Recurrent oral ulcers cause severe pain and difficulty eating, and severe periodontitis leads to complete loss of adult teeth in almost all patients."
States both the severity and the near-universal outcome, which is the basis for the VERY_FREQUENT band.
PMID:24670684 SUPPORT Human Clinical
"Periodontitis with severe loss of tooth-supporting connective tissue and bone was clinically diagnosed in all patients in our LAD-I cohort"
Every patient in a characterised LAD-I cohort had it, which is the direct cohort support for treating this as near-universal.
Premature Loss of Permanent Teeth FREQUENT HP:0006357 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Premature loss of permanent teeth (HP:0006357). HP:0006357 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24670684 SUPPORT Human Clinical
"invariably develop early-onset generalized aggressive periodontitis featuring severe bone loss and premature loss of primary and permanent teeth"
Names premature loss of permanent teeth as part of the invariable periodontal course.
Immune 2
Recurrent Bacterial and Fungal Infections Without Pus VERY_FREQUENT Recurrent bacterial skin infections HP:0005406 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent bacterial skin infections (HP:0005406), qualified as course progressive. HP:0005406 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (2 references)
PMID:23351991 SUPPORT Human Clinical
"resulting in severe recurrent nonpussing infections and neutrophilia, often preceded by delayed separation of the umbilical cord"
States the non-suppurative character of the infections directly, alongside the neutrophilia and cord sign.
PMID:37492921 SUPPORT Human Clinical
"Skin ulcers (75.4%), omphalitis (65.2%), and gingivitis (37.7%) were the most frequent complaints."
Skin ulceration in 75.4% of the cohort, the most frequent single complaint, supporting the VERY_FREQUENT band.
Autoimmune Complications OCCASIONAL Autoimmunity HP:0002960 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autoimmunity (HP:0002960). HP:0002960 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:29548898 SUPPORT Human Clinical
"In particular, two of them developed renal and intestinal autoimmune diseases, despite the expression of Beta-2 integrin was partially conserved."
Documents autoimmune disease in molecularly confirmed LAD-1 patients, including in those with partial integrin expression.
PMID:29548898 SUPPORT Human Clinical
"suggesting that HSCT is effective for preventing infections in LAD-1, but does not prevent the risk of the autoimmune complications"
The post-transplant persistence, which is the clinically important part of this phenotype and the reason it is curated separately from the infection phenotype.
Integument 2
Chronic Non-Healing Skin Ulcers VERY_FREQUENT HP:0200042 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Skin ulcer (HP:0200042), qualified as temporality chronic. HP:0200042 is a phenotype from the Human Phenotype Ontology.
Temporal: CHRONIC
Show evidence (2 references)
PMID:37492921 SUPPORT Human Clinical
"Skin ulcers (75.4%), omphalitis (65.2%), and gingivitis (37.7%) were the most frequent complaints."
Places skin ulceration at 75.4%, the highest-frequency manifestation in the cohort.
PMID:28328326 SUPPORT Human Clinical
"Chronic necrotic skin lesions, often incorrectly described as pyoderma gangrenosum (biopsy samples characteristically show no neutrophils), are common in LAD1"
Characterises the lesions as common, chronic and neutrophil-free, and flags the recurring misdiagnosis.
Impaired Wound Healing FREQUENT Poor wound healing HP:0001058 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Poor wound healing (HP:0001058). HP:0001058 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:22134107 SUPPORT Other
"The patients suffer from recurrent, life-threatening bacterial and fungal infections and from impaired wound healing."
States impaired wound healing as a feature of the patient population.
PMID:42011429 SUPPORT Human Clinical
"leukocytosis and wounds without pus formation or that do not exhibit tissue repair"
The consensus list of signs that should raise suspicion of LAD-I, which includes wounds that do not repair. The same sentence goes on to name poor wound healing separately; the quote is cut before the inline citation marker that follows.
Prenatal and Birth 2
Delayed Umbilical Cord Separation FREQUENT HP:0032434 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed umbilical cord separation (HP:0032434). HP:0032434 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:37492921 SUPPORT Human Clinical
"Delayed umbilical cord separation was found in 25 patients (36.2%)."
The cohort frequency, which is the basis for the FREQUENT band rather than a higher one.
PMID:42011429 SUPPORT Human Clinical
"Delayed is defined as umbilical cord separation after 21 days of life."
The threshold the consensus criteria use, which is what makes this a recordable diagnostic criterion rather than an impression.
Omphalitis FREQUENT Neonatal omphalitis HP:0032435 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neonatal omphalitis (HP:0032435), qualified as temporality acute. HP:0032435 is a phenotype from the Human Phenotype Ontology.
Temporal: ACUTE
Show evidence (2 references)
PMID:37492921 SUPPORT Human Clinical
"Skin ulcers (75.4%), omphalitis (65.2%), and gingivitis (37.7%) were the most frequent complaints."
Quantifies omphalitis at 65.2% in the largest single-centre LAD-I series, supporting the FREQUENT band.
PMID:42011429 SUPPORT Human Clinical
"Omphalitis was considered the most frequent symptom in patients aged <6 months (87.5%; n = 7/8)"
Expert-consensus ranking of omphalitis as the leading early presentation. Note the percentage is the proportion of panellists agreeing, not a patient frequency.
Cellular 1
Absent or Reduced Neutrophil CD18 Expression VERY_FREQUENT Reduced granulocyte CD18 level HP:0032455 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Reduced granulocyte CD18 level (HP:0032455). HP:0032455 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:42011429 SUPPORT Human Clinical
"LAD-I severity has historically been classified by the percentage of CD18+ polymorphonuclear neutrophils (PMNs) in peripheral blood, with <2% indicating a severe phenotype and ≥2% but <30% indicating a moderate phenotype."
The thresholds themselves, which is what makes this a graded diagnostic measurement rather than a binary one.
PMID:37492921 SUPPORT Human Clinical
"Forty-six patients (66.7%) were categorized as severe (CD18 and/or CD11a: below 2%); while 23 children (33.3%) were in moderate category (CD18 and/or CD11a: 2%-30%)."
The severity distribution observed when the threshold is applied to a real cohort.
🧬

Genetic Associations

1
ITGB2
Gene: ITGB2 hgnc:6155 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ITGB2 (hgnc:6155). hgnc:6155 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (3 references)
PMID:22134107 SUPPORT Other
"In LAD-I, mutations are found in ITGB2, the gene that encodes the β subunit of the β(2) integrins."
The gene-disease assignment from the curated mutation compendium for this disease.
PMID:22134107 SUPPORT Other
"Usually, this leads to the absence or decreased expression of the β2 integrins on the leukocyte surface, but sometimes a normal expression of nonfunctional β2 integrins is found."
The exception that makes CD18 flow cytometry alone insufficient - normal expression of non-functional receptor.
PMID:22134107 SUPPORT Other
"Most of the point mutations are found in a ~240-residue domain that is highly conserved in all β integrin subunits and coded for by exons 5 – 9 of ITGB2"
The variant distribution across the gene, which is what makes exons 5-9 the high-yield region on sequencing.
💊

Medical Actions

5
Allogeneic Hematopoietic Stem Cell Transplantation
Action: allogeneic hematopoietic cell transplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is allogeneic hematopoietic cell transplantation, annotated with Hematopoietic Cell Transplantation (NCIT:C15431). NCIT:C15431 is a clinical intervention from the NCI Thesaurus. Ontology label: Hematopoietic Cell Transplantation NCIT:C15431
Platform: Cell therapy
The established curative treatment for severe LAD-I, replacing the patient's CD18-deficient haematopoiesis with donor cells that express functional beta-2 integrins. The largest outcome series is an EBMT registry cohort of 84 LAD-I and LAD-III patients transplanted between 2007 and 2017, with 3-year overall survival of 83%. The event-free figure is considerably lower and is where the real difficulty lies: 17% graft failure at 3 years and 24% grade II-IV acute GVHD at 100 days, with acute GVHD a significant risk factor for death. Outcomes are better in younger patients, which is why the consensus asks for transplantation as soon as possible after diagnosis and ideally at or before 13 months of age. The registry authors argue that LAD's own inflammatory component contributes to these transplant complications, which is the rationale for anti-inflammatory pretreatment.
Mechanism Target:
Failed Beta-2 Integrin Heterodimer Assembly — Donor-derived leukocytes carry wild-type ITGB2, so the assembly defect is replaced rather than bypassed - which is why the correction is durable and why the entire downstream chain resolves together.
Show evidence (1 reference)
PMID:24670684 SUPPORT Human Clinical
"successful bone marrow transplantation in LAD-I patients reverses the periodontal disease phenotype"
A downstream node of the pathograph reversing after transplantation, which is the clinical demonstration that correcting the molecular lesion corrects the chain.
Show evidence (4 references)
PMID:33570653 SUPPORT Human Clinical
"The curative treatment of LAD-I and LAD-III is allogeneic hematopoietic stem cell transplantation (allo-HSCT)."
States allo-HSCT as the curative treatment for this disease.
PMID:33570653 SUPPORT Human Clinical
"The 3-year overall survival estimate (95% confidence interval [CI]) was 83% (74-92) for the entire cohort: 84% (75-94) and 75% (50-100) for LAD-I and LAD-III, respectively."
The survival outcome from the largest transplant series in this disease.
PMID:33570653 SUPPORT Human Clinical
"We observed cumulative incidences (95% CI) of graft failure (GF) at 3 years of 17% (9%-26%) and grade II to IV acute graft-versus-host disease (aGVHD) at 100 days of 24% (15%-34%)."
The complication rates, which are the reason this is curative but not straightforward and why gene therapy is being developed.
+ 1 more reference
Autologous Lentiviral ITGB2 Gene Therapy (Marnetegragene Autotemcel)
Action: gene therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is gene therapy (NCIT:C15238). NCIT:C15238 is a clinical intervention from the NCI Thesaurus. Ontology label: Gene Therapy NCIT:C15238
Platform: Gene therapy
Autologous CD34+ haematopoietic stem cells transduced ex vivo with a self-inactivating lentiviral vector carrying human ITGB2, given after myeloablative busulfan conditioning. The point of the approach is that it removes the two problems that limit allogeneic transplantation in this disease - donor availability and alloreactivity - and the phase 1-2 result bears that out: nine children with severe LAD-I, no graft failure, no adverse events attributed to the gene therapy itself, and 100% HSCT-free survival at one year. Serious adverse events were attributable to the busulfan conditioning rather than to the product, which is the expected pattern and the remaining cost of the approach.
Mechanism Target:
Biallelic ITGB2 Loss-of-Function Variants — Adds a functional ITGB2 transgene to the patient's own stem cells, correcting the initiating lesion in situ rather than replacing the haematopoietic system.
Show evidence (1 reference)
PMID:40305711 SUPPORT Human Clinical
"a gene therapy of autologous CD34+ hematopoietic stem cells transduced with a self-inactivating lentiviral vector containing human ITGB2"
Describes the product as delivering ITGB2 itself, which is what makes this an intervention on the initiating node.
Show evidence (3 references)
PMID:40305711 SUPPORT Human Clinical
"HSCT-free survival was 100% (95% confidence interval [CI], 66 to 100) at 1 year after infusion (P<0.001)."
The primary efficacy result of the phase 1-2 study.
PMID:40305711 SUPPORT Human Clinical
"Serious adverse events related to myeloablative busulfan conditioning were observed. No adverse events attributed to gene therapy were reported. None of the patients had graft failure."
The safety profile, and the attribution of serious events to conditioning rather than to the product.
PMID:40305711 SUPPORT Human Clinical
"In this study, lentiviral vector-transduced autologous CD34+ HSCT was successful in treating severe LAD-I."
The authors' conclusion. Note the cohort is nine children with 24 months of follow-up, so this establishes feasibility and short-term efficacy rather than equivalence to allogeneic transplantation.
IL-12/IL-23 p40 Blockade with Ustekinumab
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: ustekinumab NCIT:C84237 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses ustekinumab (NCIT:C84237). NCIT:C84237 is a therapeutic agent from the NCI Thesaurus.
Platform: Monoclonal antibody
Ustekinumab binds the p40 subunit shared by IL-12 and IL-23 and so shuts down the IL-23-driven IL-17 response that produces the periodontal and cutaneous immunopathology. This is a mechanism-directed treatment rather than an empirical one - the target was chosen from the observation that LAD1 lesions carry an IL-23/IL-17 signature and that blocking that axis prevents bone loss in the corresponding mouse model. In the index case, psoriasis dosing produced resolution of refractory gingival inflammation and complete healing of a two-year non-healing sacral wound within 10 to 14 months. The 2026 consensus now recommends anti-inflammatory therapy of this kind as part of supportive care, and before transplantation to help engraftment.
Mechanism Target:
Dysregulated IL-23/IL-17 Axis at Barrier Sites — Blocks the shared p40 subunit, removing the IL-23 signal that drives the IL-17 response. It treats the disinhibited inflammatory arm and does nothing for the adhesion defect itself, so it is adjunctive rather than definitive.
Show evidence (1 reference)
PMID:28328326 SUPPORT Human Clinical
"Levels of tissue markers of inflammation, such as interleukin-23 and interleukin-17, went from being very high relative to levels found in volunteers with healthy gingiva and patients with chronic periodontitis"
Shows the drug acting on the node it targets, measured in the tissue rather than inferred from the clinical response.
Show evidence (3 references)
PMID:28328326 SUPPORT Human Clinical
"After 1 year of therapy, our patient had resolution of his inflammatory lesions without serious infections or adverse reactions."
The clinical outcome in the index case, with the safety observation that matters most in an immunodeficient patient.
PMID:28328326 SUPPORT Human Clinical
"By 10 to 14 months, the wound was completely healed with minimal residual scarring"
Healing of a wound that had progressed for two years through antibiotics and repeated debridement, which is the strongest single observation in the report.
PMID:42011429 SUPPORT Human Clinical
"For all patients with LAD-I, anti-inflammatory therapy (eg, ustekinumab) should be prescribed as part of supportive care to treat dysregulated hyperinflammatory component of disease pathology (eg, chronic inflammation)."
Moves this from a single case report to a consensus recommendation, which is why it is curated as a treatment rather than as an experimental observation.
Antimicrobial Prophylaxis and Aggressive Infection Management
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: trimethoprim-sulfamethoxazole CHEBI:3770 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses trimethoprim-sulfamethoxazole, annotated with co-trimoxazole (CHEBI:3770). CHEBI:3770 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Continuous antibacterial and antifungal prophylaxis, with hospital-based aggressive management and often prolonged or repeated courses for intercurrent infection. Trimethoprim-sulfamethoxazole is the prophylactic agent in the published cases. This is the standard of care while awaiting definitive therapy, and its limits are well documented - prophylaxis since infancy did not prevent progressive periodontal disease in any patient in the characterised cohort, because the periodontal arm is inflammatory rather than infective.
Mechanism Target:
Pus-Free Necrotic Bacterial and Fungal Infection — Reduces microbial burden to compensate for the missing neutrophil response. It does not restore neutrophil delivery, so it is compensatory rather than corrective.
Show evidence (3 references)
PMID:42011429 SUPPORT Human Clinical
"All patients with severe LAD-I require prophylactic antimicrobials (ie, antibiotics, antifungals)."
The consensus recommendation for universal antimicrobial prophylaxis in severe disease.
PMID:42011429 SUPPORT Human Clinical
"Infections in patients with severe LAD-I often require prolonged antimicrobial treatment, including multiple courses of antimicrobials."
Characterises the intensity of treatment required, which is part of the burden of illness this entry records.
PMID:24670684 REFUTE Human Clinical
"We observed progressive periodontal disease in all patients evaluated, despite prophylactic antibiotic use since infancy and access to dental care."
Refutes any claim that antimicrobial prophylaxis controls the periodontal arm of the disease. Recorded here rather than omitted because the limit of this treatment is clinically load-bearing - it is what motivates the anti-inflammatory approach.
Genetic Counselling and Prenatal Diagnosis
Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Platform: Behavioral / lifestyle
Autosomal recessive inheritance carries a 25% recurrence risk per pregnancy for carrier couples. Because consanguinity is common in the reported families and ITGB2 sequencing is established, carrier testing and prenatal or preimplantation diagnosis are informative where the family allele is known. Molecular confirmation also has a direct therapeutic consequence here: genetic diagnosis is best practice before allogeneic transplantation and mandatory before gene therapy.
Show evidence (1 reference)
PMID:37492921 SUPPORT Human Clinical
"Moreover, the prenatal diagnosis would benefit families with a history of LAD-I."
The cohort study's own recommendation for prenatal diagnosis in affected families.
🔬

Diagnosis

2
Neutrophil Integrin Flow Cytometry (CD18, CD11a, CD11b)
Flow cytometry of peripheral neutrophils for CD18 together with CD11a and CD11b. This is both the diagnostic test and the severity classifier. The expanded panel is not redundancy: a patient can have at least 2% CD18 yet under 2% CD11a or CD11b, and the consensus counts that combination as severe disease - so measuring CD18 alone misclassifies exactly the patients for whom the classification decides whether to transplant.
flow cytometry NCIT:C16585 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:42011429 SUPPORT Human Clinical
"In best clinical practice, PMN CD18, CD11a, and/or CD11b expression should be measured as part of diagnosing and differentiating between moderate and severe LAD-I."
The consensus statement specifying which markers to measure and why.
PMID:42011429 SUPPORT Human Clinical
"Without routine newborn screening for LAD-I, flow cytometry to assess leukocyte integrin expression is typically prompted by presentation of early signs or symptoms"
Establishes flow cytometry as the entry point to diagnosis and notes there is no newborn screening pathway, which is why diagnostic delay is the norm.
ITGB2 Sequencing
Molecular confirmation by sequencing ITGB2. Required rather than optional in two situations - when flow cytometry is equivocal or shows normal expression of non-functional protein, and before gene therapy, where the consensus makes genetic confirmation mandatory. It also enables prenatal and carrier testing in the family.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:42011429 SUPPORT Human Clinical
"Molecular genetic testing in conjunction with flow cytometry is ideal in confirmation of LAD-I diagnosis."
The consensus position on pairing sequencing with flow cytometry.
PMID:37492921 SUPPORT Human Clinical
"Genetic analysis of the patients revealed 14 previously reported and three novel pathogenic mutations in the ITGB2 gene."
Demonstrates ITGB2 sequencing yielding molecular diagnoses in a clinical cohort, including novel variants.
📊

Prevalence

1
Worldwide
Point Prevalence 0.1 per 100,000 <1 in 1,000,000
Roughly 1 per million, as stated by the 2026 international consensus. Read this as an order-of-magnitude figure rather than a measured rate - the same consensus notes only about 300 published cases before 2018, and the literature contains no population-based ascertainment. Reported series are heavily weighted toward consanguineous populations, so the true figure almost certainly varies by an order of magnitude between populations.
Show evidence (1 reference)
PMID:42011429 SUPPORT Human Clinical
"LAD-I affects approximately 1 in 1 million individuals globally."
The consensus statement's own occurrence estimate, which is the basis for the band recorded here.
🔬

Clinical Trials

1
NCT03812263 PHASE_II ACTIVE_NOT_RECRUITING
The phase 1/2 study of RP-L201 (marnetegragene autotemcel), autologous CD34+ cells transduced with the Chim-CD18-WPRE lentiviral vector, in severe LAD-I. Recorded as PHASE_II because the registration lists it as Phase 1/Phase 2 and the schema enum has no combined value. Its results were published in 2025.
Target Phenotypes: Recurrent bacterial skin infections HP:0005406 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Recurrent bacterial skin infections (HP:0005406). HP:0005406 is a phenotype from the Human Phenotype Ontology. Increased total leukocyte count HP:0001974 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Increased total leukocyte count (HP:0001974). HP:0001974 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
clinicaltrials:NCT03812263 SUPPORT Human Clinical
"The primary objectives of the Phase II portion of the study are evaluation of survival, as determined by the proportion of subjects alive at age 2 (24 months) and at least 1-year post-infusion without allogeneic hematopoietic stem cell transplant (HSCT)"
The registration record's statement of the primary endpoint, which is the HSCT-free survival figure reported in the published result.
{ }

Source YAML

click to show 
name: Leukocyte Adhesion Deficiency 1
creation_date: '2026-09-14T02:59:37Z'
category: Mendelian
disease_term:
  preferred_term: leukocyte adhesion deficiency 1
  term:
    id: MONDO:0007293
    label: leukocyte adhesion deficiency 1
synonyms:
- LAD1
- LAD-I
- leukocyte adhesion deficiency type 1
- CD18 deficiency
- LFA-1 immunodeficiency
description: 'An autosomal recessive inborn error of immunity in which biallelic loss-of-function variants in ITGB2 remove or cripple CD18, the beta subunit shared by every member of the beta-2 integrin family. Because the alpha and beta chains pair intracellularly before reaching the plasma membrane, losing the common beta chain takes all four heterodimers down together - LFA-1, Mac-1, p150,95 and CD11d/CD18 - so a single gene defect removes an entire receptor family rather than one receptor.

  The consequence is specific and unusually legible. Neutrophils are made and released normally, and they still roll along activated endothelium, because rolling is selectin-mediated and selectins are untouched here. What they cannot do is convert that rolling into firm arrest and then cross the vessel wall. The cell therefore stays in the lumen. That produces the inversion this disease is known for: a marked and persistent blood neutrophilia sitting alongside a tissue compartment that is effectively neutropenic, so infections are severe and necrotic yet form no pus, and wounds do not repair. Delayed separation of the umbilical cord with omphalitis is often the first sign.

  Severity tracks residual CD18 quantitatively rather than categorically - under 2% of expected neutrophil CD18 expression defines the severe phenotype and 2-30% the moderate one - and the periodontal literature shows attachment loss scaling inversely with whatever CD18 remains. The periodontal arm is curated as its own branch because the mechanism is not the one that was assumed for decades. It is not unchecked infection in a tissue no neutrophil can police; it is an IL-23/IL-17 response that has lost its off switch, because the signal that normally damps it - tissue macrophages clearing transmigrated apoptotic neutrophils - never arrives. That distinction is therapeutic, not semantic: antibiotics and mechanical debridement do not control it, while blocking the axis with ustekinumab did.

  Allogeneic HSCT is the established curative option for severe disease, and autologous lentiviral ITGB2 gene therapy has now reported a phase 1-2 result. LAD1 is the adhesion arm of the leukocyte adhesion deficiency family; the sibling entry Leukocyte Adhesion Deficiency Type II is a different lesion entirely - an SLC35C1 Golgi GDP-fucose transport failure that removes the selectin ligands and so blocks the rolling step upstream of the one that fails here.'
parents:
- Primary Immunodeficiency
- Leukocyte Adhesion Deficiency
classifications:
  harrisons_chapter:
  - classification_value: IMMUNE_RHEUMATOLOGIC
    evidence:
    - reference: PMID:24670684
      reference_title: Defective neutrophil recruitment in leukocyte adhesion deficiency type I disease causes local IL-17-driven inflammatory bone loss.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: LAD-I is an autosomal recessive immunodeficiency caused by mutations in the CD18-encoding ITGB2 gene that result in defective neutrophil adhesion and transmigration
      explanation: An immunodeficiency of leukocyte function, which is where Harrison's publishes the primary chapter on the phagocyte-function disorders.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: PMID:22134107
      reference_title: "Hematologically important mutations: leukocyte adhesion deficiency (first update)."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Leukocyte adhesion deficiency (LAD) is an autosomal recessive disorder caused by decreased expression or functioning of CD18
      explanation: A single-gene autosomal recessive disorder, which is the second Part Harrison's covers separately.
  iuis_category:
    classification_value: phagocyte defect
    notes: >-
      IUIS 2022 classification (Tangye et al.), Table 5 "Congenital defects of phagocyte
      number or function", section 2 "Defects of Motility". The LAD1 row gives the genetic
      defect as ITGB2, inheritance AR, OMIM 600065 (the gene entry; the phenotype MIM is
      116920), affected cells N + M + L + NK, affected function adherence/chemotaxis/
      endocytosis/T-NK cytotoxicity, and associated features delayed cord separation, skin
      ulcers, periodontitis and leukocytosis.
    evidence:
    - reference: PMID:35748970
      reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Leukocyte adhesion deficiency type 1 (LAD1) ITGB2 AR 600065
      explanation: The Table 5 row itself. Table 5 is the phagocyte-defect table, so its inclusion of LAD1 is the IUIS category assignment.
    - reference: PMID:35748970
      reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Table 5  Congenit al defects of phagocyte number or function"
      explanation: Names the table that carries the LAD1 row, establishing that the row sits under congenital defects of phagocyte number or function rather than under another IUIS table. Quoted with the PDF-extraction word break intact so the snippet is an exact substring of the cached text.
prevalence:
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: BELOW_1_IN_1000000
  rate_per_100000: 0.1
  notes: >-
    Roughly 1 per million, as stated by the 2026 international consensus. Read this as an
    order-of-magnitude figure rather than a measured rate - the same consensus notes only
    about 300 published cases before 2018, and the literature contains no population-based
    ascertainment. Reported series are heavily weighted toward consanguineous populations,
    so the true figure almost certainly varies by an order of magnitude between populations.
  evidence:
  - reference: PMID:42011429
    reference_title: "International clinical consensus on leukocyte adhesion deficiency-I: Modified Delphi analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: LAD-I affects approximately 1 in 1 million individuals globally.
    explanation: The consensus statement's own occurrence estimate, which is the basis for the band recorded here.
pathophysiology:
- name: Biallelic ITGB2 Loss-of-Function Variants
  role: trigger
  biological_scale: MOLECULAR
  description: >-
    Both copies of ITGB2 at 21q22.3 carry variants that abolish or cripple CD18. The
    original molecular study resolved five distinct beta-subunit phenotypes across patients -
    absent mRNA and precursor, low mRNA and precursor, an aberrantly large precursor, an
    aberrantly small precursor, and a grossly normal precursor - which is why surface
    expression ranges from undetectable to near-normal-but-nonfunctional. Most missense
    variants cluster in the conserved betaI domain encoded by exons 5-9, the ligand-binding
    face of the receptor.
  genetic_context:
    gene:
      preferred_term: ITGB2
      term:
        id: hgnc:6155
        label: ITGB2
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Homozygous or compound heterozygous. Loss of function is established at the protein
      level rather than inferred from variant class - mutant beta precursors fail to
      associate with the alpha subunit, which is the defining biochemical result.
  downstream:
  - target: Failed Beta-2 Integrin Heterodimer Assembly
    causal_link_type: DIRECT
    description: The gene product is the shared beta chain, so a disabling variant removes the assembly partner directly.
    evidence:
    - reference: PMID:3594570
      reference_title: Heterogeneous mutations in the beta subunit common to the LFA-1, Mac-1, and p150,95 glycoproteins cause leukocyte adhesion deficiency.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Mutant beta subunit precursors from LAD patients failed to associate with the LFA-1 alpha subunit.
      explanation: The assembly failure itself, measured on patient-derived precursors - this is the step that connects the genotype to the receptor-family defect.
  evidence:
  - reference: PMID:3594570
    reference_title: Heterogeneous mutations in the beta subunit common to the LFA-1, Mac-1, and p150,95 glycoproteins cause leukocyte adhesion deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Here we demonstrate that the primary defect in LAD is in the beta subunit gene.
    explanation: Assigns the primary lesion to the shared beta subunit gene rather than to any individual alpha chain.
  - reference: PMID:3594570
    reference_title: Heterogeneous mutations in the beta subunit common to the LFA-1, Mac-1, and p150,95 glycoproteins cause leukocyte adhesion deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We identified five distinct beta subunit phenotypes in LAD patients: undetectable beta subunit mRNA and protein precursor; low levels of beta subunit mRNA and precursor; an aberrantly large beta subunit precursor, probably due to an extra glycosylation site; an aberrantly small precursor; and a grossly normal precursor."
    explanation: The allelic heterogeneity that underlies the severe-versus-moderate split curated below, including the case where protein is made but does not work.
- name: Failed Beta-2 Integrin Heterodimer Assembly
  role: central_effector
  biological_scale: MOLECULAR
  description: >-
    CD18 is the common beta chain of four heterodimers - LFA-1 (CD11a/CD18), Mac-1
    (CD11b/CD18), p150,95 (CD11c/CD18) and CD11d/CD18. The alpha and beta subunits pair
    inside the cell before trafficking to the surface, so when the beta chain is absent or
    malformed the alpha chains cannot reach the membrane either. One gene defect therefore
    removes a whole receptor family, which is why the phenotype is broader than any
    single-integrin knockout would predict.
  cellular_components:
  - preferred_term: beta-2 integrin complex
    term:
      id: GO:0008305
      label: integrin complex
    modifier: DECREASED
  - preferred_term: LFA-1 (CD11a/CD18)
    term:
      id: GO:0034687
      label: integrin alphaL-beta2 complex
    modifier: DECREASED
  molecular_functions:
  - preferred_term: alpha/beta integrin subunit pairing
    term:
      id: GO:0046982
      label: protein heterodimerization activity
    modifier: LOSS_OF_FUNCTION
  downstream:
  - target: Absent or Reduced Neutrophil CD18 Expression
    causal_link_type: DIRECT
    description: >-
      The flow-cytometry measurement of this node, and the test the diagnosis is made on — surface CD18 is absent or reduced because the heterodimer never assembles.
  - target: Defective Neutrophil Firm Adhesion to Endothelium
    causal_link_type: DIRECT
    description: The absent heterodimers are the receptors that mediate firm arrest, so losing them removes the interaction.
    evidence:
    - reference: PMID:28328326
      reference_title: Interleukin-12 and Interleukin-23 Blockade in Leukocyte Adhesion Deficiency Type 1.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "the β2 integrins are required for the adhesion of neutrophils to endothelium and the transmigration of neutrophils into tissues"
      explanation: States that the receptors lost at this node are the ones required for the adhesion and transmigration steps below it.
  evidence:
  - reference: PMID:35408940
    reference_title: "Understanding the Role of LFA-1 in Leukocyte Adhesion Deficiency Type I (LAD I): Moving towards Inflammation?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Since the β and α subunits pair intracellularly, a decreased or mutated β subunit also leads to a decreased expression of the α subunit at the cell surface."
    explanation: The intracellular-pairing requirement that makes a beta-chain defect take all four alpha chains down with it.
  - reference: PMID:22134107
    reference_title: "Hematologically important mutations: leukocyte adhesion deficiency (first update)."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Decreased expression of the common β2 subunit leads to a similar decrease in the expression of all four α subunits on the leukocyte surface."
    explanation: Confirms the loss spans all four alpha subunits rather than being restricted to LFA-1.
  - reference: PMID:3555290
    reference_title: "Leukocyte adhesion deficiency: an inherited defect in the Mac-1, LFA-1, and p150,95 glycoproteins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These include Mac-1 (complement receptor type 3), lymphocyte function-associated antigen-1 (LFA-1), and p150,95."
    explanation: Names the receptor family lost, from the classic clinical-molecular description of the disease.
- name: Defective Neutrophil Firm Adhesion to Endothelium
  role: effector
  biological_scale: CELLULAR
  description: >-
    Selectin-mediated rolling is intact in LAD1 - the selectins and their ligands are
    untouched - but the neutrophil cannot convert rolling into integrin-mediated firm arrest
    on the inflamed vessel wall. LFA-1 binding to endothelial ICAM-1 and ICAM-2 is the step
    that fails. No other adhesion system substitutes: VLA-4, which lets monocytes and T cells
    arrest through a beta-1 route, is not expressed on neutrophils, so the neutrophil has no
    fallback.
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  - preferred_term: vascular endothelial cell
    term:
      id: CL:0000071
      label: blood vessel endothelial cell
  biological_processes:
  - preferred_term: leukocyte adhesion to vascular endothelial cell
    term:
      id: GO:0061756
      label: leukocyte adhesion to vascular endothelial cell
    modifier: DECREASED
  - preferred_term: leukocyte cell-cell adhesion
    term:
      id: GO:0007159
      label: leukocyte cell-cell adhesion
    modifier: DECREASED
  - preferred_term: integrin-mediated signaling pathway
    term:
      id: GO:0007229
      label: integrin-mediated signaling pathway
    modifier: LOSS_OF_FUNCTION
  downstream:
  - target: Failure of Neutrophil Transmigration into Tissue
    causal_link_type: DIRECT
    description: Transmigration is downstream of firm arrest in the adhesion cascade, so a cell that never arrests never crosses.
    evidence:
    - reference: PMID:24670684
      reference_title: Defective neutrophil recruitment in leukocyte adhesion deficiency type I disease causes local IL-17-driven inflammatory bone loss.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The LFA-1 integrin (CD11a/CD18) plays a crucial role in firm adhesion, which is essential to the subsequent extravasation of the neutrophils to peripheral tissues
      explanation: States the ordering explicitly - firm adhesion is the prerequisite for extravasation, which is what makes this an edge rather than two parallel defects.
  evidence:
  - reference: PMID:22134107
    reference_title: "Hematologically important mutations: leukocyte adhesion deficiency (first update)."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: This deficiency leads to severe impairment of leukocyte adhesion to the vascular wall and leukocyte migration to sites of infection and inflammation.
    explanation: The adhesion defect at the vessel wall, stated for CD18 deficiency directly.
  - reference: PMID:35408940
    reference_title: "Understanding the Role of LFA-1 in Leukocyte Adhesion Deficiency Type I (LAD I): Moving towards Inflammation?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Since VLA-4 is mainly expressed on monocytes and T cells, but not on neutrophils, it is not able to compensate for the loss of β2 integrins in LAD I"
    explanation: Explains why the neutrophil has no redundant arrest mechanism, which is why this node is absolute rather than partial in the neutrophil lineage.
- name: Failure of Neutrophil Transmigration into Tissue
  role: effector
  biological_scale: TISSUE
  description: >-
    Neutrophils remain confined within the vessel lumen and do not cross into infected or
    inflamed tissue. Histology of LAD1 lesions makes the point plainly - the inflammatory
    infiltrate is dense but composed of lymphocytes, with neutrophils visible inside vessels
    and absent from the tissue around them.
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  biological_processes:
  - preferred_term: neutrophil extravasation
    term:
      id: GO:0072672
      label: neutrophil extravasation
    modifier: DECREASED
  - preferred_term: leukocyte migration
    term:
      id: GO:0050900
      label: leukocyte migration
    modifier: DECREASED
  downstream:
  - target: Tissue Neutropenia with Blood Neutrophilia
    causal_link_type: DIRECT
    description: Neutrophils that cannot leave the circulation accumulate in the compartment they are counted in and are missing from the one they are needed in.
  - target: Impaired Wound Healing
    causal_link_type: DIRECT
    description: Wound repair requires neutrophil recruitment into the wound bed, which does not occur.
  evidence:
  - reference: PMID:24670684
    reference_title: Defective neutrophil recruitment in leukocyte adhesion deficiency type I disease causes local IL-17-driven inflammatory bone loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The infiltrate comprised primarily lymphocytes, whereas neutrophils were confined within vessels.
    explanation: Direct histological demonstration in patient tissue that neutrophils do not cross the vessel wall, which is the node's claim.
- name: Tissue Neutropenia with Blood Neutrophilia
  role: central_effector
  biological_scale: ORGANISM
  description: >-
    The signature inversion of this disease. Granulopoiesis is normal and unrestrained, so
    the circulating neutrophil count is high - markedly so during infection - while the
    tissue compartment behaves as if the patient were neutropenic. Every downstream
    consequence of the disease flows from this dissociation, and it is also why the blood
    count is actively misleading at the bedside: the one number a clinician reaches for moves
    in the opposite direction to the deficit.
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: DECREASED
  downstream:
  - target: Persistent Marked Leukocytosis
    causal_link_type: DIRECT
    description: >-
      The blood-count half of that dissociation. Counts are often extreme, and a high count here indicates the disease rather than excluding it.
  - target: Pus-Free Necrotic Bacterial and Fungal Infection
    causal_link_type: DIRECT
    description: Pus is accumulated tissue neutrophils; with none arriving, infection proceeds without it.
  - target: Dysregulated IL-23/IL-17 Axis at Barrier Sites
    causal_link_type: DIRECT
    description: The absent tissue neutrophils are the input to the efferocytosis feedback loop that normally restrains IL-23 production.
    evidence:
    - reference: PMID:28328326
      reference_title: Interleukin-12 and Interleukin-23 Blockade in Leukocyte Adhesion Deficiency Type 1.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The disruption of this circuit as a result of the paucity of tissue neutrophils in LAD1 leads to exaggerated interleukin-23 and interleukin-17 responses, which appear to account for local LAD1 immunopathologic processes.
      explanation: Names tissue neutrophil paucity as the cause of the cytokine dysregulation, which is exactly this edge.
  evidence:
  - reference: PMID:22134107
    reference_title: "Hematologically important mutations: leukocyte adhesion deficiency (first update)."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Characteristic features are delayed separation of the umbilical cord and strong leukocytosis, especially neutrophilia, during periods of infection."
    explanation: The blood side of the inversion, described as characteristic of the disease.
  - reference: PMID:24670684
    reference_title: Defective neutrophil recruitment in leukocyte adhesion deficiency type I disease causes local IL-17-driven inflammatory bone loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "IL-17-induced granulopoiesis factors and chemokines were readily detected in blood plasma of LAD-I patients"
    explanation: Ties the circulating neutrophilia to sustained granulopoietic drive rather than to a marrow abnormality, which is why the two compartments diverge.
- name: Pus-Free Necrotic Bacterial and Fungal Infection
  role: effector
  biological_scale: ORGANISM
  description: >-
    Recurrent, severe, often life-threatening bacterial and fungal infection of skin and
    mucosal surfaces, with the diagnostically important feature that lesions do not suppurate.
    Necrotic skin lesions in LAD1 are frequently labelled pyoderma gangrenosum, which is a
    misreading - the biopsy characteristically contains no neutrophils at all, which is the
    opposite of what that diagnosis implies.
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: DECREASED
  evidence:
  - reference: PMID:3555290
    reference_title: "Leukocyte adhesion deficiency: an inherited defect in the Mac-1, LFA-1, and p150,95 glycoproteins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "characterized by recurrent bacterial infections, impaired pus formation and wound healing"
    explanation: The classic description, which names impaired pus formation alongside the infections rather than as an afterthought.
  - reference: PMID:42011429
    reference_title: "International clinical consensus on leukocyte adhesion deficiency-I: Modified Delphi analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Children can also present with severe/recurrent bacterial or fungal infections, recalcitrant periodontitis, and/or necrotic skin wounds/lesions absent pus formation."
    explanation: Contemporary consensus statement of the same presentation, and the source for including fungal infection rather than bacterial alone.
  - reference: PMID:28328326
    reference_title: Interleukin-12 and Interleukin-23 Blockade in Leukocyte Adhesion Deficiency Type 1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Chronic necrotic skin lesions, often incorrectly described as pyoderma gangrenosum (biopsy samples characteristically show no neutrophils), are common in LAD1"
    explanation: The histological point that the lesions are neutrophil-free, which both supports the node and corrects a common misdiagnosis.
  downstream:
  - target: Recurrent Bacterial and Fungal Infections Without Pus
    causal_link_type: DIRECT
    description: >-
      The defining infection phenotype: necrosis without the purulence that requires neutrophils to arrive in tissue.
  - target: Omphalitis
    causal_link_type: DIRECT
    description: >-
      Infection of the umbilical stump, classically the first presentation in the neonatal period.
- name: Dysregulated IL-23/IL-17 Axis at Barrier Sites
  role: effector
  biological_scale: TISSUE
  description: >-
    Tissue macrophages normally down-regulate IL-23 production when they phagocytose
    transmigrated apoptotic neutrophils. In LAD1 those neutrophils never arrive, so the
    brake is never applied and an otherwise physiological IL-23 response to the local
    microbiome runs unchecked, driving T-cell-derived IL-17 to high levels at the gingiva
    and skin. The elevation is compartmentalised rather than systemic - plasma IL-17 and
    IL-23 are low or absent - which matters because it means this is a local
    immunopathology, not a circulating inflammatory syndrome.
  cell_types:
  - preferred_term: gingival CD4+ T cell
    term:
      id: CL:0000084
      label: T cell
  biological_processes:
  - preferred_term: interleukin-17 production
    term:
      id: GO:0032620
      label: interleukin-17 production
    modifier: INCREASED
  downstream:
  - target: Autoimmune Complications
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Autoimmune and inflammatory complications arising from the dysregulated barrier-site axis rather than from the adhesion defect directly.
  - target: Inflammatory Periodontal Bone Loss
    causal_link_type: DIRECT
    description: IL-17 is an osteoclastogenic cytokine, and blocking it or its IL-23 driver prevents the bone loss in the corresponding mouse model.
    evidence:
    - reference: PMID:24670684
      reference_title: Defective neutrophil recruitment in leukocyte adhesion deficiency type I disease causes local IL-17-driven inflammatory bone loss.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Local treatment with antibodies to IL-17 or IL-23 in LFA-1-deficient mice not only blocked inflammatory periodontal bone loss but also caused a reduction in the total bacterial burden"
      explanation: An intervention result, which is what establishes the link as causal rather than correlative. Graded MODEL_ORGANISM because the intervention was done in mice - the equivalent experiment has not been run in patients.
  evidence:
  - reference: PMID:24670684
    reference_title: Defective neutrophil recruitment in leukocyte adhesion deficiency type I disease causes local IL-17-driven inflammatory bone loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Defective neutrophil recruitment in LAD-I patients or in LFA-1 (CD11a/CD18)-deficient mice--which exhibit the LAD-I periodontal phenotype--was associated with excessive production of predominantly T cell-derived IL-17 in the periodontal tissue"
    explanation: The human observation of excess T-cell-derived IL-17 in LAD-I periodontal tissue, and its attribution to the recruitment defect.
  - reference: PMID:24670684
    reference_title: Defective neutrophil recruitment in leukocyte adhesion deficiency type I disease causes local IL-17-driven inflammatory bone loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These data reveal that the elevated expression of IL-17 in LAD-I is compartmentalized rather than systemic."
    explanation: The compartmentalisation, which is why this node is tagged TISSUE and not ORGANISM.
  - reference: PMID:28328326
    reference_title: Interleukin-12 and Interleukin-23 Blockade in Leukocyte Adhesion Deficiency Type 1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The phagocytosis of apoptotic neutrophils (efferocytosis) by tissue macrophages acts as a signal to down-regulate the production of interleukin-23 and therefore the downstream cytokines interleukin-17 and granulocyte colony-stimulating factor (G-CSF)."
    explanation: States the feedback circuit whose input is missing here, which is the mechanism this node asserts.
- name: Inflammatory Periodontal Bone Loss
  role: effector
  biological_scale: TISSUE
  description: >-
    Early-onset, generalised, severe periodontitis with destruction of tooth-supporting
    connective tissue and alveolar bone, ending in loss of both primary and permanent
    dentition. Historically read as unpoliced periodontal infection, but the evidence does
    not support that: bacterial load within the diseased gingival tissue is comparable to or
    lower than in healthy controls, and the disease is refractory to antibiotics and to
    mechanical biofilm removal. The severity scales inversely with residual CD18, tying the
    dental phenotype quantitatively to the molecular lesion.
  cell_types:
  - preferred_term: osteoclast
    term:
      id: CL:0000092
      label: osteoclast
  biological_processes:
  - preferred_term: bone resorption
    term:
      id: GO:0045453
      label: bone resorption
    modifier: INCREASED
  evidence:
  - reference: PMID:24670684
    reference_title: Defective neutrophil recruitment in leukocyte adhesion deficiency type I disease causes local IL-17-driven inflammatory bone loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected individuals display neutrophilia, suffer from recurrent infections, and invariably develop early-onset generalized aggressive periodontitis featuring severe bone loss and premature loss of primary and permanent teeth"
    explanation: States the periodontal phenotype and its invariability in this disease.
  - reference: PMID:24670684
    reference_title: Defective neutrophil recruitment in leukocyte adhesion deficiency type I disease causes local IL-17-driven inflammatory bone loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "quantification of bacterial counts in gingival tissue sections from LAD-I patients and healthy controls, using real-time PCR of the 16S rRNA gene, revealed that the bacterial load within the tissue of LAD-I patients was comparable to (if not less than) that of healthy controls"
    explanation: The measurement that refutes the tissue-invasive-infection reading of this phenotype, and so supports curating it as an immunopathology.
  - reference: PMID:24670684
    reference_title: Defective neutrophil recruitment in leukocyte adhesion deficiency type I disease causes local IL-17-driven inflammatory bone loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We observed progressive periodontal disease in all patients evaluated, despite prophylactic antibiotic use since infancy and access to dental care."
    explanation: The clinical refractoriness to antimicrobial and mechanical management, which is the practical consequence of the mechanism.
  downstream:
  - target: Severe Early-Onset Periodontitis with Tooth Loss
    causal_link_type: DIRECT
    description: >-
      The periodontium depends on continuous neutrophil traffic, which is why it fails first and hardest in every adhesion defect.
  - target: Premature Loss of Permanent Teeth
    causal_link_type: DIRECT
    description: >-
      The endpoint of that bone loss.
- name: Impaired Wound Healing
  role: effector
  biological_scale: TISSUE
  description: >-
    Wounds fail to repair and skin ulcers persist, because the neutrophil influx that
    initiates the repair programme does not occur. Clinically this appears as
    non-healing lesions that progress through repeated antibiotic courses and surgical
    debridement, and it is one of the features that resolves when the adhesion defect is
    corrected.
  biological_processes:
  - preferred_term: wound healing
    term:
      id: GO:0042060
      label: wound healing
    modifier: DECREASED
  evidence:
  - reference: PMID:3555290
    reference_title: "Leukocyte adhesion deficiency: an inherited defect in the Mac-1, LFA-1, and p150,95 glycoproteins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "characterized by recurrent bacterial infections, impaired pus formation and wound healing"
    explanation: Names impaired wound healing as a defining feature of the disease.
  - reference: PMID:22134107
    reference_title: "Hematologically important mutations: leukocyte adhesion deficiency (first update)."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The patients suffer from recurrent, life-threatening bacterial and fungal infections and from impaired wound healing."
    explanation: Independent statement of the wound-healing defect alongside the infection phenotype.
  downstream:
  - target: Delayed Umbilical Cord Separation
    causal_link_type: DIRECT
    description: >-
      Cord separation depends on neutrophil-mediated tissue remodelling, so delay beyond three weeks is an early and characteristic sign.
  - target: Chronic Non-Healing Skin Ulcers
    causal_link_type: DIRECT
    description: >-
      The same remodelling failure in skin, producing ulcers that persist rather than close.
phenotypes:
- category: Neonatal
  name: Delayed Umbilical Cord Separation
  frequency: FREQUENT
  diagnostic: true
  description: >-
    Separation of the umbilical cord later than 21 days of life, often with omphalitis. This
    is frequently the first clinical sign and is one of the presenting features that should
    prompt integrin flow cytometry. It is not universal - a 69-patient series recorded it in
    36.2% - so its absence does not exclude the diagnosis, which is the reverse of how the
    sign is often taught.
  phenotype_term:
    preferred_term: Delayed umbilical cord separation
    term:
      id: HP:0032434
      label: Delayed umbilical cord separation
  evidence:
  - reference: PMID:37492921
    reference_title: Clinical and immunological characteristics of 69 leukocyte adhesion deficiency-I patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Delayed umbilical cord separation was found in 25 patients (36.2%).
    explanation: The cohort frequency, which is the basis for the FREQUENT band rather than a higher one.
  - reference: PMID:42011429
    reference_title: "International clinical consensus on leukocyte adhesion deficiency-I: Modified Delphi analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Delayed is defined as umbilical cord separation after 21 days of life.
    explanation: The threshold the consensus criteria use, which is what makes this a recordable diagnostic criterion rather than an impression.
- category: Neonatal
  name: Omphalitis
  frequency: FREQUENT
  description: >-
    Infection of the umbilical stump, rated by the consensus panel as the single most common
    presenting manifestation below six months of age and recorded in 65.2% of a 69-patient
    series.
  phenotype_term:
    preferred_term: Neonatal omphalitis
    term:
      id: HP:0032435
      label: Neonatal omphalitis
    temporality: ACUTE
  evidence:
  - reference: PMID:37492921
    reference_title: Clinical and immunological characteristics of 69 leukocyte adhesion deficiency-I patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Skin ulcers (75.4%), omphalitis (65.2%), and gingivitis (37.7%) were the most frequent complaints."
    explanation: Quantifies omphalitis at 65.2% in the largest single-centre LAD-I series, supporting the FREQUENT band.
  - reference: PMID:42011429
    reference_title: "International clinical consensus on leukocyte adhesion deficiency-I: Modified Delphi analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Omphalitis was considered the most frequent symptom in patients aged <6 months (87.5%; n = 7/8)"
    explanation: Expert-consensus ranking of omphalitis as the leading early presentation. Note the percentage is the proportion of panellists agreeing, not a patient frequency.
- category: Immunologic
  name: Recurrent Bacterial and Fungal Infections Without Pus
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >-
    Recurrent severe infection of skin and mucosal surfaces - and, later, the respiratory and
    gastrointestinal tracts - that is necrotic rather than suppurative. The absence of pus in
    a clinically severe infection is the feature that most reliably distinguishes this
    disease from other phagocyte defects at the bedside, because it is a direct readout of
    the mechanism rather than a downstream complication.
  phenotype_term:
    preferred_term: Recurrent bacterial skin infections
    term:
      id: HP:0005406
      label: Recurrent bacterial skin infections
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:23351991
    reference_title: Leukocyte adhesion deficiencies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "resulting in severe recurrent nonpussing infections and neutrophilia, often preceded by delayed separation of the umbilical cord"
    explanation: States the non-suppurative character of the infections directly, alongside the neutrophilia and cord sign.
  - reference: PMID:37492921
    reference_title: Clinical and immunological characteristics of 69 leukocyte adhesion deficiency-I patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Skin ulcers (75.4%), omphalitis (65.2%), and gingivitis (37.7%) were the most frequent complaints."
    explanation: Skin ulceration in 75.4% of the cohort, the most frequent single complaint, supporting the VERY_FREQUENT band.
- category: Dermatologic
  name: Chronic Non-Healing Skin Ulcers
  frequency: VERY_FREQUENT
  description: >-
    Persistent necrotic skin ulcers that enlarge despite antibiotics and debridement. Often
    labelled pyoderma gangrenosum, but the histology is the opposite of that diagnosis - the
    biopsy characteristically contains no neutrophils.
  phenotype_term:
    preferred_term: Skin ulcer
    term:
      id: HP:0200042
      label: Skin ulcer
    temporality: CHRONIC
  evidence:
  - reference: PMID:37492921
    reference_title: Clinical and immunological characteristics of 69 leukocyte adhesion deficiency-I patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Skin ulcers (75.4%), omphalitis (65.2%), and gingivitis (37.7%) were the most frequent complaints."
    explanation: Places skin ulceration at 75.4%, the highest-frequency manifestation in the cohort.
  - reference: PMID:28328326
    reference_title: Interleukin-12 and Interleukin-23 Blockade in Leukocyte Adhesion Deficiency Type 1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Chronic necrotic skin lesions, often incorrectly described as pyoderma gangrenosum (biopsy samples characteristically show no neutrophils), are common in LAD1"
    explanation: Characterises the lesions as common, chronic and neutrophil-free, and flags the recurring misdiagnosis.
- category: Dental
  name: Severe Early-Onset Periodontitis with Tooth Loss
  frequency: VERY_FREQUENT
  description: >-
    Generalised aggressive periodontitis beginning in childhood, with attachment loss,
    alveolar bone destruction and eventual loss of both primary and permanent teeth. Described
    as invariable in affected individuals, and as leading to complete loss of adult teeth in
    almost all patients. It is refractory to conventional periodontal care, which is a
    consequence of the mechanism curated above rather than a failure of treatment.
  phenotype_term:
    preferred_term: Periodontitis
    term:
      id: HP:0000704
      label: Periodontitis
    clinical_course: PROGRESSIVE
    severity: SEVERE
  evidence:
  - reference: PMID:28328326
    reference_title: Interleukin-12 and Interleukin-23 Blockade in Leukocyte Adhesion Deficiency Type 1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recurrent oral ulcers cause severe pain and difficulty eating, and severe periodontitis leads to complete loss of adult teeth in almost all patients."
    explanation: States both the severity and the near-universal outcome, which is the basis for the VERY_FREQUENT band.
  - reference: PMID:24670684
    reference_title: Defective neutrophil recruitment in leukocyte adhesion deficiency type I disease causes local IL-17-driven inflammatory bone loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Periodontitis with severe loss of tooth-supporting connective tissue and bone was clinically diagnosed in all patients in our LAD-I cohort"
    explanation: Every patient in a characterised LAD-I cohort had it, which is the direct cohort support for treating this as near-universal.
- category: Dental
  name: Premature Loss of Permanent Teeth
  frequency: FREQUENT
  description: >-
    Loss of the permanent dentition in adolescence or early adulthood, following the
    periodontal bone destruction. Recorded separately from the periodontitis itself because
    it is the endpoint families experience and the outcome that anti-inflammatory therapy is
    aimed at preventing.
  phenotype_term:
    preferred_term: Premature loss of permanent teeth
    term:
      id: HP:0006357
      label: Premature loss of permanent teeth
  evidence:
  - reference: PMID:24670684
    reference_title: Defective neutrophil recruitment in leukocyte adhesion deficiency type I disease causes local IL-17-driven inflammatory bone loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "invariably develop early-onset generalized aggressive periodontitis featuring severe bone loss and premature loss of primary and permanent teeth"
    explanation: Names premature loss of permanent teeth as part of the invariable periodontal course.
- category: Hematologic
  name: Persistent Marked Leukocytosis
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >-
    A persistently high circulating leukocyte and neutrophil count, rising further during
    infection and often reaching values that would suggest leukaemia in another context. It
    is the most counterintuitive finding in the disease and the one most likely to mislead -
    the count is high precisely because the cells cannot get to where they are needed. It
    normalises after successful HSCT or gene therapy, which is the cleanest demonstration
    that it is a consequence of the adhesion defect.
  phenotype_term:
    preferred_term: Increased total leukocyte count
    term:
      id: HP:0001974
      label: Increased total leukocyte count
    temporality: CHRONIC
  evidence:
  - reference: PMID:22134107
    reference_title: "Hematologically important mutations: leukocyte adhesion deficiency (first update)."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Characteristic features are delayed separation of the umbilical cord and strong leukocytosis, especially neutrophilia, during periods of infection."
    explanation: States marked leukocytosis with neutrophilia as a characteristic feature.
  - reference: PMID:40305711
    reference_title: Lentiviral Gene Therapy for Severe Leukocyte Adhesion Deficiency Type 1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Pretreatment neutrophilia and skin abnormalities related to LAD-I resolved.
    explanation: The neutrophilia resolving once CD18 is restored, which confirms it is secondary to the adhesion defect rather than an independent marrow phenotype.
- category: Dermatologic
  name: Impaired Wound Healing
  frequency: FREQUENT
  description: >-
    Poor healing of surgical and traumatic wounds, with dehiscence and persistent granulation
    failure. Listed by the consensus panel among the signs that should raise suspicion of
    LAD-I and prompt integrin flow cytometry.
  phenotype_term:
    preferred_term: Poor wound healing
    term:
      id: HP:0001058
      label: Poor wound healing
  evidence:
  - reference: PMID:22134107
    reference_title: "Hematologically important mutations: leukocyte adhesion deficiency (first update)."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The patients suffer from recurrent, life-threatening bacterial and fungal infections and from impaired wound healing."
    explanation: States impaired wound healing as a feature of the patient population.
  - reference: PMID:42011429
    reference_title: "International clinical consensus on leukocyte adhesion deficiency-I: Modified Delphi analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "leukocytosis and wounds without pus formation or that do not exhibit tissue repair"
    explanation: The consensus list of signs that should raise suspicion of LAD-I, which includes wounds that do not repair. The same sentence goes on to name poor wound healing separately; the quote is cut before the inline citation marker that follows.
- category: Laboratory
  name: Absent or Reduced Neutrophil CD18 Expression
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >-
    Flow cytometry of peripheral neutrophils showing absent or reduced surface CD18, with
    a matching reduction in CD11a and CD11b. This is the defining diagnostic test and also
    the severity metric - below 2% of expected CD18 defines severe disease and 2-30% defines
    moderate disease. In one 69-patient series two thirds were severe by this criterion. The
    measurement is not always sufficient on its own: a patient may express near-normal but
    non-functional protein, which is why the consensus pairs flow cytometry with ITGB2
    sequencing.
  phenotype_term:
    preferred_term: Reduced granulocyte CD18 level
    term:
      id: HP:0032455
      label: Reduced granulocyte CD18 level
  evidence:
  - reference: PMID:42011429
    reference_title: "International clinical consensus on leukocyte adhesion deficiency-I: Modified Delphi analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "LAD-I severity has historically been classified by the percentage of CD18+ polymorphonuclear neutrophils (PMNs) in peripheral blood, with <2% indicating a severe phenotype and ≥2% but <30% indicating a moderate phenotype."
    explanation: The thresholds themselves, which is what makes this a graded diagnostic measurement rather than a binary one.
  - reference: PMID:37492921
    reference_title: Clinical and immunological characteristics of 69 leukocyte adhesion deficiency-I patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Forty-six patients (66.7%) were categorized as severe (CD18 and/or CD11a: below 2%); while 23 children (33.3%) were in moderate category (CD18 and/or CD11a: 2%-30%)."
    explanation: The severity distribution observed when the threshold is applied to a real cohort.
- category: Immunologic
  name: Autoimmune Complications
  frequency: OCCASIONAL
  description: >-
    Autoimmune disease - renal, intestinal, type 1 diabetes, autoimmune cytopenia - reported
    in a long-term follow-up series both in untreated patients and after HSCT. Recorded
    because it is a genuinely under-recognised part of the natural history: it occurred in
    patients whose beta-2 integrin expression was partially preserved, and transplantation
    corrected the infection risk without abolishing it.
  phenotype_term:
    preferred_term: Autoimmunity
    term:
      id: HP:0002960
      label: Autoimmunity
  evidence:
  - reference: PMID:29548898
    reference_title: "Long term outcome of eight patients with type 1 Leukocyte Adhesion Deficiency (LAD-1): Not only infections, but high risk of autoimmune complications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In particular, two of them developed renal and intestinal autoimmune diseases, despite the expression of Beta-2 integrin was partially conserved."
    explanation: Documents autoimmune disease in molecularly confirmed LAD-1 patients, including in those with partial integrin expression.
  - reference: PMID:29548898
    reference_title: "Long term outcome of eight patients with type 1 Leukocyte Adhesion Deficiency (LAD-1): Not only infections, but high risk of autoimmune complications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "suggesting that HSCT is effective for preventing infections in LAD-1, but does not prevent the risk of the autoimmune complications"
    explanation: The post-transplant persistence, which is the clinically important part of this phenotype and the reason it is curated separately from the infection phenotype.
genetic:
- name: ITGB2
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: ITGB2
    term:
      id: hgnc:6155
      label: ITGB2
  notes: >-
    ITGB2 at 21q22.3 encodes CD18, the beta-2 integrin subunit. Two things about the
    allelic spectrum matter clinically. First, the severity gradient is quantitative -
    residual surface CD18 sets the phenotype, and the same gene produces everything from
    neonatal lethal disease to a presentation deferred into adolescence. Second, reduced
    surface expression is the usual but not the only mechanism: a normal amount of
    non-functional protein occurs, which is why the consensus recommends CD11a/CD11b
    measurement and ITGB2 sequencing alongside CD18 flow cytometry rather than relying on
    the CD18 number alone. Most missense variants fall in the conserved betaI domain encoded
    by exons 5-9, which carries the ligand-binding MIDAS motif.
  evidence:
  - reference: PMID:22134107
    reference_title: "Hematologically important mutations: leukocyte adhesion deficiency (first update)."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In LAD-I, mutations are found in ITGB2, the gene that encodes the β subunit of the β(2) integrins."
    explanation: The gene-disease assignment from the curated mutation compendium for this disease.
  - reference: PMID:22134107
    reference_title: "Hematologically important mutations: leukocyte adhesion deficiency (first update)."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Usually, this leads to the absence or decreased expression of the β2 integrins on the leukocyte surface, but sometimes a normal expression of nonfunctional β2 integrins is found."
    explanation: The exception that makes CD18 flow cytometry alone insufficient - normal expression of non-functional receptor.
  - reference: PMID:22134107
    reference_title: "Hematologically important mutations: leukocyte adhesion deficiency (first update)."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Most of the point mutations are found in a ~240-residue domain that is highly conserved in all β integrin subunits and coded for by exons 5 – 9 of ITGB2"
    explanation: The variant distribution across the gene, which is what makes exons 5-9 the high-yield region on sequencing.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Autosomal recessive. Consanguinity is prominent in the reported series, and family
    history of LAD-I is one of the diagnostic criteria in the consensus severity algorithm -
    a presymptomatic newborn with an affected sibling can be classified as severe on
    laboratory and family-history grounds alone.
  evidence:
  - reference: PMID:22134107
    reference_title: "Hematologically important mutations: leukocyte adhesion deficiency (first update)."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Leukocyte adhesion deficiency (LAD) is an autosomal recessive disorder caused by decreased expression or functioning of CD18
    explanation: States the inheritance mode directly for CD18 deficiency.
  - reference: PMID:3555290
    reference_title: "Leukocyte adhesion deficiency: an inherited defect in the Mac-1, LFA-1, and p150,95 glycoproteins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Leukocyte adhesion deficiency (LAD) is a recently recognized autosomal-recessive trait"
    explanation: The original clinical genetic characterisation, confirming recessive inheritance.
has_subtypes:
- name: Severe
  display_name: Severe LAD-I (<2% CD18)
  description: >-
    Under 2% of expected neutrophil CD18 expression, or at least 2% CD18 with under 2% CD11a
    and/or CD11b. About two thirds of patients in the largest series. Without definitive
    therapy the annual risk of life-threatening infection persists or increases year on year,
    and the consensus is explicit that surviving past two years on supportive care alone is
    not a marker of milder disease. This is the group for whom allogeneic HSCT or gene
    therapy is recommended.
  evidence:
  - reference: PMID:42011429
    reference_title: "International clinical consensus on leukocyte adhesion deficiency-I: Modified Delphi analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Severe LAD-I is defined as <2% of expected PMN CD18 expression, or ≥2% of expected PMN CD18 expression and <2% of expected PMN CD11a and/or CD11b expression."
    explanation: The consensus definition of this subtype, including the CD11a/CD11b arm that catches patients whose CD18 number alone would misclassify them.
  - reference: PMID:42011429
    reference_title: "International clinical consensus on leukocyte adhesion deficiency-I: Modified Delphi analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In patients with severe LAD-I with history of significant morbidity and who receive BSC alone (ie, in absence of definitive therapy), survival beyond 2 years of age is not marker of milder disease."
    explanation: The prognostic point that distinguishes this subtype from moderate disease - survival is not evidence of a milder phenotype.
- name: Moderate
  display_name: Moderate LAD-I (2-30% CD18)
  description: >-
    2-30% of expected neutrophil CD18 expression with at least 2% CD11a and/or CD11b. About
    a third of patients. The clinical course is milder and can be deferred - splice-site
    variants with delayed symptom onset are described - but it is not static, and the
    consensus asks for routine reassessment because a moderate patient can progress to meet
    severe criteria. Residual CD18 does not spare the periodontium proportionally: attachment
    loss scales inversely with whatever CD18 remains, so moderate patients still develop
    severe periodontal disease.
  evidence:
  - reference: PMID:42011429
    reference_title: "International clinical consensus on leukocyte adhesion deficiency-I: Modified Delphi analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Moderate LAD-I is defined as 2-30% of expected PMN CD18 expression.
    explanation: The consensus definition of this subtype.
  - reference: PMID:42011429
    reference_title: "International clinical consensus on leukocyte adhesion deficiency-I: Modified Delphi analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Severity of LAD-I is considered on spectrum and can progress. Hence, patients with moderate LAD-I should be routinely reassessed."
    explanation: Establishes that the subtype boundary is a point on a spectrum that patients can cross, which is why this is curated as a graded subtype rather than a fixed one.
treatments:
- name: Allogeneic Hematopoietic Stem Cell Transplantation
  therapeutic_modality: CELL_THERAPY
  description: >-
    The established curative treatment for severe LAD-I, replacing the patient's
    CD18-deficient haematopoiesis with donor cells that express functional beta-2 integrins.
    The largest outcome series is an EBMT registry cohort of 84 LAD-I and LAD-III patients
    transplanted between 2007 and 2017, with 3-year overall survival of 83%. The
    event-free figure is considerably lower and is where the real difficulty lies: 17% graft
    failure at 3 years and 24% grade II-IV acute GVHD at 100 days, with acute GVHD a
    significant risk factor for death. Outcomes are better in younger patients, which is why
    the consensus asks for transplantation as soon as possible after diagnosis and ideally
    at or before 13 months of age. The registry authors argue that LAD's own inflammatory
    component contributes to these transplant complications, which is the rationale for
    anti-inflammatory pretreatment.
  treatment_term:
    preferred_term: allogeneic hematopoietic cell transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  target_mechanisms:
  - target: Failed Beta-2 Integrin Heterodimer Assembly
    description: Donor-derived leukocytes carry wild-type ITGB2, so the assembly defect is replaced rather than bypassed - which is why the correction is durable and why the entire downstream chain resolves together.
    evidence:
    - reference: PMID:24670684
      reference_title: Defective neutrophil recruitment in leukocyte adhesion deficiency type I disease causes local IL-17-driven inflammatory bone loss.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: successful bone marrow transplantation in LAD-I patients reverses the periodontal disease phenotype
      explanation: A downstream node of the pathograph reversing after transplantation, which is the clinical demonstration that correcting the molecular lesion corrects the chain.
  evidence:
  - reference: PMID:33570653
    reference_title: Allogeneic hematopoietic stem cell transplantation in leukocyte adhesion deficiency type I and III.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The curative treatment of LAD-I and LAD-III is allogeneic hematopoietic stem cell transplantation (allo-HSCT).
    explanation: States allo-HSCT as the curative treatment for this disease.
  - reference: PMID:33570653
    reference_title: Allogeneic hematopoietic stem cell transplantation in leukocyte adhesion deficiency type I and III.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The 3-year overall survival estimate (95% confidence interval [CI]) was 83% (74-92) for the entire cohort: 84% (75-94) and 75% (50-100) for LAD-I and LAD-III, respectively."
    explanation: The survival outcome from the largest transplant series in this disease.
  - reference: PMID:33570653
    reference_title: Allogeneic hematopoietic stem cell transplantation in leukocyte adhesion deficiency type I and III.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We observed cumulative incidences (95% CI) of graft failure (GF) at 3 years of 17% (9%-26%) and grade II to IV acute graft-versus-host disease (aGVHD) at 100 days of 24% (15%-34%)."
    explanation: The complication rates, which are the reason this is curative but not straightforward and why gene therapy is being developed.
  - reference: PMID:37492921
    reference_title: Clinical and immunological characteristics of 69 leukocyte adhesion deficiency-I patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The overall survival of patients with and without hematopoietic stem cell transplantation was 79.3% and 55.6%, respectively."
    explanation: A within-cohort comparison of transplanted against non-transplanted patients. Note this is an observational contrast, not a randomised one, so selection effects are not excluded.
- name: Autologous Lentiviral ITGB2 Gene Therapy (Marnetegragene Autotemcel)
  therapeutic_modality: GENE_THERAPY
  description: >-
    Autologous CD34+ haematopoietic stem cells transduced ex vivo with a self-inactivating
    lentiviral vector carrying human ITGB2, given after myeloablative busulfan conditioning.
    The point of the approach is that it removes the two problems that limit allogeneic
    transplantation in this disease - donor availability and alloreactivity - and the phase
    1-2 result bears that out: nine children with severe LAD-I, no graft failure, no adverse
    events attributed to the gene therapy itself, and 100% HSCT-free survival at one year.
    Serious adverse events were attributable to the busulfan conditioning rather than to the
    product, which is the expected pattern and the remaining cost of the approach.
  treatment_term:
    preferred_term: gene therapy
    term:
      id: NCIT:C15238
      label: Gene Therapy
  target_mechanisms:
  - target: Biallelic ITGB2 Loss-of-Function Variants
    description: Adds a functional ITGB2 transgene to the patient's own stem cells, correcting the initiating lesion in situ rather than replacing the haematopoietic system.
    evidence:
    - reference: PMID:40305711
      reference_title: Lentiviral Gene Therapy for Severe Leukocyte Adhesion Deficiency Type 1.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "a gene therapy of autologous CD34+ hematopoietic stem cells transduced with a self-inactivating lentiviral vector containing human ITGB2"
      explanation: Describes the product as delivering ITGB2 itself, which is what makes this an intervention on the initiating node.
  evidence:
  - reference: PMID:40305711
    reference_title: Lentiviral Gene Therapy for Severe Leukocyte Adhesion Deficiency Type 1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HSCT-free survival was 100% (95% confidence interval [CI], 66 to 100) at 1 year after infusion (P<0.001)."
    explanation: The primary efficacy result of the phase 1-2 study.
  - reference: PMID:40305711
    reference_title: Lentiviral Gene Therapy for Severe Leukocyte Adhesion Deficiency Type 1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Serious adverse events related to myeloablative busulfan conditioning were observed. No adverse events attributed to gene therapy were reported. None of the patients had graft failure."
    explanation: The safety profile, and the attribution of serious events to conditioning rather than to the product.
  - reference: PMID:40305711
    reference_title: Lentiviral Gene Therapy for Severe Leukocyte Adhesion Deficiency Type 1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this study, lentiviral vector-transduced autologous CD34+ HSCT was successful in treating severe LAD-I."
    explanation: The authors' conclusion. Note the cohort is nine children with 24 months of follow-up, so this establishes feasibility and short-term efficacy rather than equivalence to allogeneic transplantation.
- name: IL-12/IL-23 p40 Blockade with Ustekinumab
  therapeutic_modality: MONOCLONAL_ANTIBODY
  description: >-
    Ustekinumab binds the p40 subunit shared by IL-12 and IL-23 and so shuts down the
    IL-23-driven IL-17 response that produces the periodontal and cutaneous
    immunopathology. This is a mechanism-directed treatment rather than an empirical one -
    the target was chosen from the observation that LAD1 lesions carry an IL-23/IL-17
    signature and that blocking that axis prevents bone loss in the corresponding mouse
    model. In the index case, psoriasis dosing produced resolution of refractory gingival
    inflammation and complete healing of a two-year non-healing sacral wound within 10 to 14
    months. The 2026 consensus now recommends anti-inflammatory therapy of this kind as part
    of supportive care, and before transplantation to help engraftment.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: ustekinumab
      term:
        id: NCIT:C84237
        label: Ustekinumab
  target_mechanisms:
  - target: Dysregulated IL-23/IL-17 Axis at Barrier Sites
    description: Blocks the shared p40 subunit, removing the IL-23 signal that drives the IL-17 response. It treats the disinhibited inflammatory arm and does nothing for the adhesion defect itself, so it is adjunctive rather than definitive.
    evidence:
    - reference: PMID:28328326
      reference_title: Interleukin-12 and Interleukin-23 Blockade in Leukocyte Adhesion Deficiency Type 1.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Levels of tissue markers of inflammation, such as interleukin-23 and interleukin-17, went from being very high relative to levels found in volunteers with healthy gingiva and patients with chronic periodontitis"
      explanation: Shows the drug acting on the node it targets, measured in the tissue rather than inferred from the clinical response.
  evidence:
  - reference: PMID:28328326
    reference_title: Interleukin-12 and Interleukin-23 Blockade in Leukocyte Adhesion Deficiency Type 1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After 1 year of therapy, our patient had resolution of his inflammatory lesions without serious infections or adverse reactions."
    explanation: The clinical outcome in the index case, with the safety observation that matters most in an immunodeficient patient.
  - reference: PMID:28328326
    reference_title: Interleukin-12 and Interleukin-23 Blockade in Leukocyte Adhesion Deficiency Type 1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By 10 to 14 months, the wound was completely healed with minimal residual scarring"
    explanation: Healing of a wound that had progressed for two years through antibiotics and repeated debridement, which is the strongest single observation in the report.
  - reference: PMID:42011429
    reference_title: "International clinical consensus on leukocyte adhesion deficiency-I: Modified Delphi analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "For all patients with LAD-I, anti-inflammatory therapy (eg, ustekinumab) should be prescribed as part of supportive care to treat dysregulated hyperinflammatory component of disease pathology (eg, chronic inflammation)."
    explanation: Moves this from a single case report to a consensus recommendation, which is why it is curated as a treatment rather than as an experimental observation.
  notes: >-
    The evidence base is one published index case plus expert consensus, not a trial. The
    2017 report itself notes that treatment of additional patients is needed to clarify the
    role of the drug and its long-term safety in patients who are already immunodeficient.
- name: Antimicrobial Prophylaxis and Aggressive Infection Management
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Continuous antibacterial and antifungal prophylaxis, with hospital-based aggressive
    management and often prolonged or repeated courses for intercurrent infection.
    Trimethoprim-sulfamethoxazole is the prophylactic agent in the published cases. This is
    the standard of care while awaiting definitive therapy, and its limits are well
    documented - prophylaxis since infancy did not prevent progressive periodontal disease in
    any patient in the characterised cohort, because the periodontal arm is inflammatory
    rather than infective.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: trimethoprim-sulfamethoxazole
      term:
        id: CHEBI:3770
        label: co-trimoxazole
  target_mechanisms:
  - target: Pus-Free Necrotic Bacterial and Fungal Infection
    description: Reduces microbial burden to compensate for the missing neutrophil response. It does not restore neutrophil delivery, so it is compensatory rather than corrective.
  evidence:
  - reference: PMID:42011429
    reference_title: "International clinical consensus on leukocyte adhesion deficiency-I: Modified Delphi analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients with severe LAD-I require prophylactic antimicrobials (ie, antibiotics, antifungals)."
    explanation: The consensus recommendation for universal antimicrobial prophylaxis in severe disease.
  - reference: PMID:42011429
    reference_title: "International clinical consensus on leukocyte adhesion deficiency-I: Modified Delphi analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Infections in patients with severe LAD-I often require prolonged antimicrobial treatment, including multiple courses of antimicrobials."
    explanation: Characterises the intensity of treatment required, which is part of the burden of illness this entry records.
  - reference: PMID:24670684
    reference_title: Defective neutrophil recruitment in leukocyte adhesion deficiency type I disease causes local IL-17-driven inflammatory bone loss.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "We observed progressive periodontal disease in all patients evaluated, despite prophylactic antibiotic use since infancy and access to dental care."
    explanation: Refutes any claim that antimicrobial prophylaxis controls the periodontal arm of the disease. Recorded here rather than omitted because the limit of this treatment is clinically load-bearing - it is what motivates the anti-inflammatory approach.
- name: Genetic Counselling and Prenatal Diagnosis
  therapeutic_modality: BEHAVIORAL
  description: >-
    Autosomal recessive inheritance carries a 25% recurrence risk per pregnancy for carrier
    couples. Because consanguinity is common in the reported families and ITGB2 sequencing is
    established, carrier testing and prenatal or preimplantation diagnosis are informative
    where the family allele is known. Molecular confirmation also has a direct therapeutic
    consequence here: genetic diagnosis is best practice before allogeneic transplantation
    and mandatory before gene therapy.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:37492921
    reference_title: Clinical and immunological characteristics of 69 leukocyte adhesion deficiency-I patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Moreover, the prenatal diagnosis would benefit families with a history of LAD-I."
    explanation: The cohort study's own recommendation for prenatal diagnosis in affected families.
diagnosis:
- name: Neutrophil Integrin Flow Cytometry (CD18, CD11a, CD11b)
  description: >-
    Flow cytometry of peripheral neutrophils for CD18 together with CD11a and CD11b. This
    is both the diagnostic test and the severity classifier. The expanded panel is not
    redundancy: a patient can have at least 2% CD18 yet under 2% CD11a or CD11b, and the
    consensus counts that combination as severe disease - so measuring CD18 alone
    misclassifies exactly the patients for whom the classification decides whether to
    transplant.
  diagnosis_term:
    preferred_term: flow cytometry
    term:
      id: NCIT:C16585
      label: Flow Cytometry
  evidence:
  - reference: PMID:42011429
    reference_title: "International clinical consensus on leukocyte adhesion deficiency-I: Modified Delphi analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In best clinical practice, PMN CD18, CD11a, and/or CD11b expression should be measured as part of diagnosing and differentiating between moderate and severe LAD-I."
    explanation: The consensus statement specifying which markers to measure and why.
  - reference: PMID:42011429
    reference_title: "International clinical consensus on leukocyte adhesion deficiency-I: Modified Delphi analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Without routine newborn screening for LAD-I, flow cytometry to assess leukocyte integrin expression is typically prompted by presentation of early signs or symptoms"
    explanation: Establishes flow cytometry as the entry point to diagnosis and notes there is no newborn screening pathway, which is why diagnostic delay is the norm.
- name: ITGB2 Sequencing
  description: >-
    Molecular confirmation by sequencing ITGB2. Required rather than optional in two
    situations - when flow cytometry is equivocal or shows normal expression of
    non-functional protein, and before gene therapy, where the consensus makes genetic
    confirmation mandatory. It also enables prenatal and carrier testing in the family.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:42011429
    reference_title: "International clinical consensus on leukocyte adhesion deficiency-I: Modified Delphi analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Molecular genetic testing in conjunction with flow cytometry is ideal in confirmation of LAD-I diagnosis."
    explanation: The consensus position on pairing sequencing with flow cytometry.
  - reference: PMID:37492921
    reference_title: Clinical and immunological characteristics of 69 leukocyte adhesion deficiency-I patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic analysis of the patients revealed 14 previously reported and three novel pathogenic mutations in the ITGB2 gene."
    explanation: Demonstrates ITGB2 sequencing yielding molecular diagnoses in a clinical cohort, including novel variants.
clinical_trials:
- name: NCT03812263
  phase: PHASE_II
  status: ACTIVE_NOT_RECRUITING
  description: >-
    The phase 1/2 study of RP-L201 (marnetegragene autotemcel), autologous CD34+ cells
    transduced with the Chim-CD18-WPRE lentiviral vector, in severe LAD-I. Recorded as
    PHASE_II because the registration lists it as Phase 1/Phase 2 and the schema enum has no
    combined value. Its results were published in 2025.
  target_phenotypes:
  - preferred_term: Recurrent bacterial skin infections
    term:
      id: HP:0005406
      label: Recurrent bacterial skin infections
  - preferred_term: Increased total leukocyte count
    term:
      id: HP:0001974
      label: Increased total leukocyte count
  evidence:
  - reference: clinicaltrials:NCT03812263
    reference_title: "Gene Therapy for Leukocyte Adhesion Deficiency-I (LAD-I): A Phase I/II Clinical Trial to Evaluate the Safety and Efficacy of the Infusion of Autologous Hematopoietic Stem Cells Transduced With a Lentiviral Vector Encoding the ITGB2 Gene"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The primary objectives of the Phase II portion of the study are evaluation of survival, as determined by the proportion of subjects alive at age 2 (24 months) and at least 1-year post-infusion without allogeneic hematopoietic stem cell transplant (HSCT)"
    explanation: The registration record's statement of the primary endpoint, which is the HSCT-free survival figure reported in the published result.
discussions:
- discussion_id: interpretation_periodontitis_is_immunopathology_not_infection
  kind: INTERPRETATION
  status: OPEN
  attaches_to:
  - pathophysiology#Inflammatory Periodontal Bone Loss
  - pathophysiology#Dysregulated IL-23/IL-17 Axis at Barrier Sites
  - treatments#Antimicrobial Prophylaxis and Aggressive Infection Management
  prompt: Is LAD1 periodontitis a failure of neutrophil surveillance against periodontal infection, or an inflammatory response that has lost its neutrophil-dependent brake?
  rationale: >-
    For decades the answer was assumed to be the first, and it is the intuitive reading -
    neutrophils cannot reach the gingival sulcus, so the bacteria win. Three observations
    do not fit. Bacterial load inside the diseased gingival tissue is comparable to or lower
    than in healthy controls. The infiltrate is dense but lymphocytic, with neutrophils
    visible confined inside vessels. And prophylactic antibiotics from infancy plus dental
    care did not prevent progression in any patient evaluated.

    The alternative reading explains all three. Efferocytosis of transmigrated apoptotic
    neutrophils is the signal that tells tissue macrophages to stop making IL-23. Remove the
    transmigration and the signal never arrives, so a physiological response to the oral
    microbiome runs without a brake and IL-17 drives osteoclastic bone loss. On this reading
    the bacteria are the stimulus rather than the agent, which is why suppressing them
    incompletely - as antibiotics do at a mucosal surface - changes nothing.

    The distinction is not academic. It predicts that blocking the axis should work where
    antimicrobials do not, and blocking it did: anti-IL-17 and anti-IL-23 prevented bone loss
    in LFA-1-deficient mice, and ustekinumab resolved refractory periodontal inflammation in
    a patient. It also suggests the same logic may apply at other barrier sites in this
    disease, and in other conditions where neutrophils fail to reach tissue.
- discussion_id: gap_moderate_lad1_natural_history
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - has_subtypes#Moderate
  - phenotypes#Autoimmune Complications
  prompt: What is the natural history of moderate LAD-I, and which moderate patients will progress to meet severe criteria?
  rationale: >-
    The severe subtype has a defined prognosis and a definitive treatment recommendation.
    Moderate LAD-I has neither. The consensus asks for routine reassessment precisely because
    severity is understood to sit on a spectrum and to be able to progress, but it offers no
    predictor of who progresses, over what interval, or what should trigger a move to
    definitive therapy.

    Two observations make this more than a bookkeeping gap. Residual CD18 does not protect
    the periodontium proportionally - attachment loss scales inversely with remaining CD18,
    so moderate patients still lose their dentition. And the autoimmune complications
    reported in long-term follow-up occurred in patients whose beta-2 integrin expression was
    partially conserved, which is to say in the moderate range. A subtype defined by a
    laboratory threshold that does not predict its own major morbidities is a subtype whose
    boundary needs re-examining.

    Answering this needs prospective follow-up of a moderate cohort with periodontal,
    autoimmune and infection endpoints, which no published series provides.
- discussion_id: gap_gene_therapy_versus_allogeneic_hsct
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - treatments#Autologous Lentiviral ITGB2 Gene Therapy (Marnetegragene Autotemcel)
  - treatments#Allogeneic Hematopoietic Stem Cell Transplantation
  prompt: How does autologous lentiviral ITGB2 gene therapy compare with allogeneic HSCT over a horizon long enough to matter, and what level of gene-corrected chimerism is sufficient?
  rationale: >-
    The phase 1-2 gene therapy result is striking on its own terms - nine children, no graft
    failure, 100% HSCT-free survival at one year - and it removes the two things that make
    allogeneic transplantation difficult here, donor availability and alloreactivity. But the
    comparison that clinicians need has not been made. The allogeneic registry cohort is 84
    patients with three-year outcomes; the gene therapy cohort is nine with two years of
    follow-up, and a cross-study comparison of those two is not a comparison.

    Two specific questions are open. First, durability: beta-2 integrin expression must be
    maintained in the myeloid compartment for life, and the threshold fraction of corrected
    cells needed to hold the phenotype is not established from human data. Second, whether
    gene therapy addresses the non-infectious arms of the disease - the autoimmune
    complications seen after allogeneic transplantation, and the periodontal disease - or
    only the infection burden that both the primary endpoint and the reported outcomes
    emphasise.
notes: >-
  GeneReviews. A PubMed search for a GeneReviews chapter on leukocyte adhesion deficiency or
  ITGB2 returns no hits, so the GeneReviews phenotype baseline does not apply to this entry.
  The 2026 international Delphi consensus (PMID:42011429) is used as the equivalent
  expert-curated clinical baseline, since it supplies diagnostic criteria, a severity
  algorithm, and standard-of-care recommendations in the form a GeneReviews chapter would.

  Orphanet. No ORPHA reference is cited. The Orphadata bulk XML is not present in this
  checkout (data/orphadata/ holds only MANIFEST.yaml), so no ORPHA cache file could be
  generated or quoted, and fabricating an ORPHA code from memory is exactly the failure the
  reference policy forbids. The prevalence record is therefore anchored to the consensus
  statement instead.

  OMIM numbering. The IUIS Table 5 row gives OMIM 600065 for LAD1. That is the ITGB2 gene
  entry; the phenotype MIM number for the disease is 116920. Both are correct in their own
  right and the IUIS table uses the gene number throughout its OMIM column, so the row is not
  in error - but the two should not be conflated when reading the classification evidence.

  Relationship to LAD2 and LAD3. This entry covers the adhesion arm of the family only.
  Leukocyte Adhesion Deficiency Type II (SLC35C1) fails one step earlier in the same cascade
  - absent fucosylated selectin ligands abolish rolling - and carries the Bombay blood
  phenotype and neurodevelopmental features that LAD1 does not. LAD3 (FERMT3) leaves the
  integrins present but unable to be conformationally activated, and adds a bleeding
  tendency from the same defect in platelets.
references:
- reference: PMID:3555290
  title: "Leukocyte adhesion deficiency: an inherited defect in the Mac-1, LFA-1, and p150,95 glycoproteins."
- reference: PMID:3594570
  title: Heterogeneous mutations in the beta subunit common to the LFA-1, Mac-1, and p150,95 glycoproteins cause leukocyte adhesion deficiency.
- reference: PMID:22134107
  title: "Hematologically important mutations: leukocyte adhesion deficiency (first update)."
- reference: PMID:23351991
  title: Leukocyte adhesion deficiencies.
- reference: PMID:24670684
  title: Defective neutrophil recruitment in leukocyte adhesion deficiency type I disease causes local IL-17-driven inflammatory bone loss.
- reference: PMID:28328326
  title: Interleukin-12 and Interleukin-23 Blockade in Leukocyte Adhesion Deficiency Type 1.
- reference: PMID:29548898
  title: "Long term outcome of eight patients with type 1 Leukocyte Adhesion Deficiency (LAD-1): Not only infections, but high risk of autoimmune complications."
- reference: PMID:33570653
  title: Allogeneic hematopoietic stem cell transplantation in leukocyte adhesion deficiency type I and III.
- reference: PMID:35408940
  title: "Understanding the Role of LFA-1 in Leukocyte Adhesion Deficiency Type I (LAD I): Moving towards Inflammation?"
- reference: PMID:35748970
  title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
- reference: PMID:37492921
  title: Clinical and immunological characteristics of 69 leukocyte adhesion deficiency-I patients.
- reference: PMID:40305711
  title: Lentiviral Gene Therapy for Severe Leukocyte Adhesion Deficiency Type 1.
- reference: PMID:42011429
  title: "International clinical consensus on leukocyte adhesion deficiency-I: Modified Delphi analysis."
📚

References & Deep Research

References

13
PMID:3555290
Leukocyte adhesion deficiency: an inherited defect in the Mac-1, LFA-1, and p150,95 glycoproteins.
No top-level findings curated for this source.
PMID:3594570
Heterogeneous mutations in the beta subunit common to the LFA-1, Mac-1, and p150,95 glycoproteins cause leukocyte adhesion deficiency.
No top-level findings curated for this source.
PMID:22134107
Hematologically important mutations: leukocyte adhesion deficiency (first update).
No top-level findings curated for this source.
PMID:23351991
Leukocyte adhesion deficiencies.
No top-level findings curated for this source.
PMID:24670684
Defective neutrophil recruitment in leukocyte adhesion deficiency type I disease causes local IL-17-driven inflammatory bone loss.
No top-level findings curated for this source.
PMID:28328326
Interleukin-12 and Interleukin-23 Blockade in Leukocyte Adhesion Deficiency Type 1.
No top-level findings curated for this source.
PMID:29548898
Long term outcome of eight patients with type 1 Leukocyte Adhesion Deficiency (LAD-1): Not only infections, but high risk of autoimmune complications.
No top-level findings curated for this source.
PMID:33570653
Allogeneic hematopoietic stem cell transplantation in leukocyte adhesion deficiency type I and III.
No top-level findings curated for this source.
PMID:35408940
Understanding the Role of LFA-1 in Leukocyte Adhesion Deficiency Type I (LAD I): Moving towards Inflammation?
No top-level findings curated for this source.
PMID:35748970
Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee.
No top-level findings curated for this source.
PMID:37492921
Clinical and immunological characteristics of 69 leukocyte adhesion deficiency-I patients.
No top-level findings curated for this source.
PMID:40305711
Lentiviral Gene Therapy for Severe Leukocyte Adhesion Deficiency Type 1.
No top-level findings curated for this source.
PMID:42011429
International clinical consensus on leukocyte adhesion deficiency-I: Modified Delphi analysis.
No top-level findings curated for this source.