Leukocyte Adhesion Deficiency Research Articles

The sufficiency of genetic diagnosis in managing patients with inborn errors of immunity during prenatal care and childbearing.

Individuals with inborn errors of immunity face challenges in fertility, pregnancy, and genetic disorder transmission. Prenatal genetic counseling is crucial, especially in tribal societies with consanguineous unions. Ten families with confirmed inborn errors of immunity were studied, revealing diverse pregnancy decisions: An architect with autosomal dominant STAT-1 gain of function underwent prenatal diagnosis despite initial plans for preimplantation genetic diagnosis. In a consanguineous family, two children died from leukocyte adhesion deficiency type 1 because the father refused prenatal diagnosis. First cousins opted against terminating the second pregnancy, resulting in two children affected by Bruton disease. Another consanguineous couple, with two children afflicted by ataxia-telangiectasia, chose oocyte donation for their third child, ensuring a healthy birth. Recurrent pregnancy loss was observed in a mother subsequently diagnosed with ZAP70 deficiency. A mother with Wiskott-Aldrich syndrome child opted for in vitro fertilization, leading to a healthy birth post-prenatal diagnosis. A misdiagnosis of anaplastic anemia occurred in a family with multiple instances of Wiskott-Aldrich syndrome. A leukocyte adhesion deficiency type 1 case led to parental dissolution due to the father's refusal to acknowledge the condition. In a non-consanguineous couple, the father's diagnosis of TACI deficiency influenced the mother's decision to discontinue pregnancy post-prenatal diagnosis. Genetic diagnosis alone cannot optimize prenatal care for immune dysregulation disorders. Various factors, including patient education, societal norms, ethics, and economics, impact pregnancy decisions. Clinical immunologists must integrate these elements into guidance strategies to enhance patient outcomes.

Mutations in the SLC35C1 gene, contributing to significant differences in fucosylation patterns, may underlie the diverse phenotypic manifestations observed in leukocyte adhesion deficiency type II patients

Congenital disorders of glycosylation (CDG) are a large family of genetic diseases resulting from defects in the synthesis of glycans and the attachment of glycans to macromolecules. The CDG known as leukocyte adhesion deficiency II (LAD II) is an autosomal, recessive disorder caused by mutations in the SLC35C1 gene, encoding a transmembrane protein of the Golgi apparatus, involved in GDP-fucose transport from the cytosol to the Golgi lumen. In this study, a cell-based model was used as a tool to characterize the molecular background of a therapy based on a fucose-supplemented diet. Such therapies have been successfully introduced in some (but not all) known cases of LAD II. In this study, the effect of external fucose was analyzed in SLC35C1 KO cell lines, expressing 11 mutated SLC35C1 proteins, previously discovered in patients with an LAD II diagnosis. For many of them, the cis-Golgi subcellular localization was affected; however, some proteins were localized properly. Additionally, although mutated SLC35C1 caused different α-1–6 core fucosylation of N-glycans, which explains previously described, more or less severe disorder symptoms, the differences practically disappeared after external fucose supplementation, with fucosylation restored to the level observed in healthy cells. This indicates that additional fucose in the diet should improve the condition of all patients. Thus, for patients diagnosed with LAD II we advocate careful analysis of particular mutations using the SLC35C1-KO cell line-based model, to predict changes in localization and fucosylation rate. We also recommend searching for additional mutations in the human genome of LAD II patients, when fucose supplementation does not influence patients’ state.

Multiplex fluorescent amplification-refractory mutation system PCR method for the detection of 10 genetic defects in Holstein cattle and its comparison with the KASP genotyping assay.

The common deleterious genetic defects in Holstein cattle include haplotypes 1-6 (HH1-HH6), haplotypes for cholesterol deficiency (HCD), bovine leukocyte adhesion deficiency (BLAD), complex vertebral malformation (CVM) and brachyspina syndrome (BS). Recessive inheritance patterns of these genetic defects permit the carriers to function normally, but homozygous recessive genotypes cause embryo loss or neonatal death. Therefore, rapid detection of the carriers is essential to manage these genetic defects. This study was conducted to develop a single-tube multiplex fluorescent amplification-refractory mutation system (mf-ARMS) PCR method for efficient genotyping of these 10 genetic defects and to compare its efficiency with the kompetitive allele specific PCR (KASP) genotyping assay. The mf-ARMS PCR method introduced 10 sets of tri-primers optimized with additional mismatches in the 3' end of wild and mutant-specific primers, size differentiation between wild and mutant-specific primers, fluorescent labeling of universal primers, adjustment of annealing temperatures and optimization of primer concentrations. The genotyping of 484 Holstein cows resulted in 16.12% carriers with at least one genetic defect, while no homozygous recessive genotype was detected. This study found carrier frequencies ranging from 0.0% (HH6) to 3.72% (HH3) for individual defects. The mf-ARMS PCR method demonstrated improved detection, time and cost efficiency compared with the KASP method for these defects. Therefore, the application of mf-ARMS PCR for genotyping Holstein cattle is anticipated to decrease the frequency of lethal alleles and limit the transmission of these genetic defects.

Analysis of Clinical, Immunological and Molecular Features of Leukocyte Adhesion Deficiency Type I in Egyptian Children

PurposeLeukocyte adhesion deficiency (LAD) represents a rare group of inherited inborn errors of immunity (IEI) characterized by bacterial infections, delayed umbilical stump separation, and autoimmunity. This single-center study aimed at describing the clinical, immunological, and molecular characterizations of 34 LAD-I Egyptian pediatric patients.MethodsDetails of 34 patients’ personal medical history, clinical and laboratory findings were recorded; Genetic material from 28 patients was studied. Mutational analysis was done by Sanger sequencing.ResultsOmphalitis, skin and soft tissue infections with poorly healing ulcers, delayed falling of the umbilical stump, and recurrent or un-resolving pneumonia were the most common presentations, followed by chronic otitis media, enteropathy, periodontitis; and recurrent oral thrush. Persistent leukocytosis and neutrophilia were reported in all patients, as well as CD18 and CD11b deficiency. CD18 expression was < 2% in around 90% of patients. Sixteen different pathological gene variants were detected in 28 patients who underwent ITGß2 gene sequencing, of those, ten were novel and six were previously reported. Three families received a prenatal diagnosis. Patients were on antimicrobials according to culture’s results whenever available, and on prophylactic Trimethoprim-Sulfamethoxazole 5 mg/kg once daily, with regular clinical follow up. Hematopoietic stem cell transplantation (HSCT) was offered for 4 patients. However due to severity of the disease and delay in diagnosis, 58% of the patients passed away in the first 2 years of life.ConclusionThis study highlights the importance of early diagnosis and distribution of ITGß2 gene mutation in Egyptian children. Further molecular studies, however, remain a challenging necessity for better disease characterization in the region.

INTEGRIN BETA2 GENE VARIANT CAUSING LEUKOCYTE ADHESION DEFICIENCY TYPE 1 IN A PAKISTANI FAMILY

Background: Leukocyte adhesion deficiency type 1 (LAD1), an autosomal recessive condition, arises from partial or complete deficiency of CD18 expression. LAD1 patients commonly manifest recurrent skin and respiratory tract infections, delayed umbilical cord separation, and impaired wound healing due to hindered leukocyte migration. This study aims to clinically and molecularly diagnose LAD in a highly consanguineous Pakistani family, investigating a recurrent mutation within the integrin ?2 (ITGB2) gene. Methods: A comprehensive clinical and molecular diagnosis of LAD1 was made in on a patient from a consanguineous Pakistani family. Lymphocyte subset analysis was performed using a flow cytometer, followed by whole exome sequencing and DNA Sanger sequencing to identify the pathogenic mutation within the ITGB2 gene. Further to provide genetic counselling all the healthy siblings were also Sanger sequenced. Results: Flow cytometry indicated CD18 deficiency, while sequencing of the ITGB2 gene unveiled a nonsense mutation, c.186C&gt;A, p. (Cys62*), located in exon four. This mutation segregates in an autosomal recessive pattern within the family. Conclusion: A mutation c.186C&gt;A (Cys62*) in a patient of LAD1 was identified which is potentially pathogenic in nature. Pak J Physiol 2024;20(1):15-8

Functional neutrophil disorders: Chronic granulomatous disease and beyond.

Since their description by Metchnikoff in 1905, phagocytes have been increasingly recognized to be the entities that traffic to sites of infection and inflammation, engulf and kill infecting organisms, and clear out apoptotic debris all the while making antigens available and accessible to the lymphoid organs for future use. Therefore, phagocytes provide the gateway and the first check in host protection and immune response. Disorders in killing and chemotaxis lead not only to infection susceptibility, but also to autoimmunity. We aim to describe chronic granulomatous disease and the leukocyte adhesion deficiencies as well as myeloperoxidase deficiency and G6PD deficiency as paradigms of critical pathways.

Ustekinumab for pyoderma gangrenosum–like skin ulcerations in late-onset leukocyte adhesion deficiency

BackgroundLeukocyte adhesion deficiency type 1 (LAD-1) is a congenital immunodeficiency leading to impaired trafficking of neutrophils to inflammation sites. Solitary or multiple pyoderma-gangrenosum (PG)-like skin ulcers (PGLU) have been reported previously in 13 children (aged 0.5-19 years) with LAD-1. ObjectiveTo report the case of a 10-year-old boy presenting with PGLU as the first manifestation of LAD-1, treated with ustekinumab. MethodsIn-situ cytokine profiles. ResultsPGLU was triggered by cutaneous ringworm infection (Trichophyton tonsurans). Skin biopsies showed increased intralesional expression of interleukins 17A, 23 and 1β as compared with healthy controls. After an unsuccessful attempt with oral methylprednisolone, ustekinumab induced regression of the ulcerations, associated with complete normalization of the cytokine profile. ConclusionsPG-like skin ulcers, triggered by ringworm infection, can be a late harbinger of LAD-1. Ustekinumab is a safe and effective therapeutic option for LAD-1-patients with PGLU whilst bridging the time until stem-cell transplantation.

Integrins in Health and Disease-Suitable Targets for Treatment?

Integrin receptors are heterodimeric surface receptors that play multiple roles regarding cell-cell communication, signaling, and migration. The four members of the β2 integrin subfamily are composed of an alternative α (CD11a-d) subunit, which determines the specific receptor properties, and a constant β (CD18) subunit. This review aims to present insight into the multiple immunological roles of integrin receptors, with a focus on β2 integrins that are specifically expressed by leukocytes. The pathophysiological role of β2 integrins is confirmed by the drastic phenotype of patients suffering from leukocyte adhesion deficiencies, most often resulting in severe recurrent infections and, at the same time, a predisposition for autoimmune diseases. So far, studies on the role of β2 integrins in vivo employed mice with a constitutive knockout of all β2 integrins or either family member, respectively, which complicated the differentiation between the direct and indirect effects of β2 integrin deficiency for distinct cell types. The recent generation and characterization of transgenic mice with a cell-type-specific knockdown of β2 integrins by our group has enabled the dissection of cell-specific roles of β2 integrins. Further, integrin receptors have been recognized as target receptors for the treatment of inflammatory diseases as well as tumor therapy. However, whereas both agonistic and antagonistic agents yielded beneficial effects in animal models, the success of clinical trials was limited in most cases and was associated with unwanted side effects. This unfavorable outcome is most probably related to the systemic effects of the used compounds on all leukocytes, thereby emphasizing the need to develop formulations that target distinct types of leukocytes to modulate β2 integrin activity for therapeutic applications.

Clinical and functional spectrum of RAC2-related immunodeficiency

AbstractMutations in the small Rho-family guanosine triphosphate hydrolase RAC2, critical for actin cytoskeleton remodeling and intracellular signal transduction, are associated with neonatal severe combined immunodeficiency (SCID), infantile neutrophilic disorder resembling leukocyte adhesion deficiency (LAD), and later-onset combined immune deficiency (CID). We investigated 54 patients (23 previously reported) from 37 families yielding 15 novel RAC2 missense mutations, including one present only in homozygosity. Data were collected from referring physicians and literature reports with updated clinical information. Patients were grouped by presentation: neonatal SCID (n = 5), infantile LAD-like disease (n = 5), or CID (n = 44). Disease correlated to RAC2 activity: constitutively active RAS-like mutations caused neonatal SCID, dominant-negative mutations caused LAD-like disease, whereas dominant-activating mutations caused CID. Significant T- and B-lymphopenia with low immunoglobulins were seen in most patients; myeloid abnormalities included neutropenia, altered oxidative burst, impaired neutrophil migration, and visible neutrophil macropinosomes. Among 42 patients with CID with clinical data, upper and lower respiratory infections and viral infections were common. Twenty-three distinct RAC2 mutations, including 15 novel variants, were identified. Using heterologous expression systems, we assessed downstream effector functions including superoxide production, p21-activated kinase 1 binding, AKT activation, and protein stability. Confocal microscopy showed altered actin assembly evidenced by membrane ruffling and macropinosomes. Altered protein localization and aggregation were observed. All tested RAC2 mutant proteins exhibited aberrant function; no single assay was sufficient to determine functional consequence. Most mutants produced elevated superoxide; mutations unable to support superoxide formation were associated with bacterial infections. RAC2 mutations cause a spectrum of immune dysfunction, ranging from early onset SCID to later-onset combined immunodeficiencies depending on RAC2 activity. This trial was registered at www.clinicaltrials.gov as #NCT00001355 and #NCT00001467.

Role of genetic introgression in introducing mutant alleles in Bos indicus cattle and prevalence of lethal genetic disorders in Bos taurus × Bos indicus and Bos indicus cattle in India.

Fertility is an important trait associated with reproductive performance and animal welfare concern. Lethal alleles affect fertility through early embryonic death, abortions, and stillbirth depending on the genetic expression of the allele. Holstein Friesian and Jersey are two major Bos taurus breeds used widely for increasing milk yield along with purebreds of Bos indicus breeds like Gir, Kankrej, Sahiwal, and Tharparkar. In the present study, prevalence of lethal mutants in crossbred Holstein Friesian (CBHF, n = 2435), crossbred Jersey (CBJY, n = 2874), Gir (n = 3288), Kankrej (n = 593), Sahiwal (n = 965), and Tharparkar (n = 18) were studied. Heterozygous carrier animals were identified for bovine leukocyte adhesion deficiency (BLAD), Citrullinemia, complex vertebral malformation (CVM), Brachyspina, Holstein Haplotype 1 (HH1), Holstein Haplotype 3 (HH3),Holstein Haplotype 4 (HH4) and Jersey Haplotype 1 (JH1). Breed purity analysis confirmed inheritance of Bos taurus genes contributing to the presence of lethal mutant alleles like BLAD, Citrullinemia, HH1, and JH1 in apparently phenotypic Bos indicus animals. Screening and elimination of heterozygous carrier bulls/cows is essential to control fertility loss associated with lethal alleles.

Clinical manifestations and expression of CD18 to guide the diagnosis of leukocyte adhesion deficiency type 1: Mexico experience

Background: Leukocyte adhesion deficiency type 1 (LAD-1) is an inborn error of immunity characterized by a defect in leukocyte trafficking. Methods: Patients with clinical suspicion of LAD-1 were referred to our institution. Complete blood count and flow cytometric analysis, to identify the expression of CD18, CD11b, and the lymphocyte population phenotyping, were performed, and statistical analysis was completed. Results: We report clinical manifestations and immunological findings of six Mexican patients diagnosed with LAD-1. The diagnosis was based on typical clinical presentation, combined with laboratory demonstration of leukocytosis, and significant reduction or near absence of CD18 and its associated molecules CD11a, CD11b, and CD11c on leukocytes. We found atypical manifestations, not described in other countries, such as early-onset autoimmunity or infections caused by certain microorganisms. Conclusions: Patients with LAD-1 may present with atypical manifestations, making flow cytometry an indispensable tool to confirm the diagnosis. We present the first report of LAD-1 patients in a Latin American country.

Clinical manifestations and expression of CD18 to guide the diagnosis of leukocyte adhesion deficiency type 1: Mexico experience.

Leukocyte adhesion deficiency type 1 (LAD-1) is an inborn error of immunity characterized by a defect in leukocyte trafficking. Patients with clinical suspicion of LAD-1 were referred to our institution. Complete blood count and flow cytometric analysis, to identify the expression of CD18, CD11b, and the lymphocyte population phenotyping, were performed, and statistical analysis was completed. We report clinical manifestations and immunological findings of six Mexican patients diagnosed with LAD-1. The diagnosis was based on typical clinical presentation, combined with laboratory demonstration of leukocytosis, and significant reduction or near absence of CD18 and its associated molecules CD11a, CD11b, and CD11c on leukocytes. We found atypical manifestations, not described in other countries, such as early-onset autoimmunity or infections caused by certain microorganisms. Patients with LAD-1 may present with atypical manifestations, making flow cytometry an indispensable tool to confirm the diagnosis. We present the first report of LAD-1 patients in a Latin American country.

Clinical manifestations and expression of CD18 to guide the diagnosis of leukocyte adhesion deficiency type 1: Mexico experience

Background: Leukocyte adhesion deficiency type 1 (LAD-1) is an inborn error of immunity characterized by a defect in leukocyte trafficking. Methods: Patients with clinical suspicion of LAD-1 were referred to our institution. Complete blood count and flow cytometric analysis, to identify the expression of CD18, CD11b, and the lymphocyte population phenotyping, were performed, and statistical analysis was completed. Results: We report clinical manifestations and immunological findings of six Mexican patients diagnosed with LAD-1. The diagnosis was based on typical clinical presentation, combined with laboratory demonstration of leukocytosis, and significant reduction or near absence of CD18 and its associated molecules CD11a, CD11b, and CD11c on leukocytes. We found atypical manifestations, not described in other countries, such as early-onset autoimmunity or infections caused by certain microorganisms. Conclusions: Patients with LAD-1 may present with atypical manifestations, making flow cytometry an indispensable tool to confirm the diagnosis. We present the first report of LAD-1 patients in a Latin American country.

A novel leukocyte adhesion deficiency type III mutation manifests functional importance of the compact FERM domain in kindlin-3

BackgroundLeukocyte adhesion deficiency III (LAD-III) is a rare autosomal recessive syndrome characterized by functional deficiencies of platelets and leukocytes that occurs due to mutations in the FERMT3 gene encoding kindlin-3. Kindlin-3 is a FERM domain–containing adaptor protein that is essential in integrin activation. We have previously demonstrated that the FERM domain of kindlin-3 is structurally compact and plays an important role in supporting integrin activation in a mouse model. The impact of destabilizing the compact FERM domain in kindlin-3 on the development of LAD-III in humans remains uncertain. ObjectivesTo use primary cells from a patient with LAD-III to validate the role of the compact FERM domain in kindlin-3 function in platelets and leukocytes. MethodsThe patient is a 4-year-old girl who since infancy has displayed clinical features of LAD-III. Patient platelets and leukocytes were functionally analyzed, and structural analysis of the kindlin-3 variant was conducted. ResultsWe identified a novel homozygous missense mutation in the FERMT3 (c.412G>A, p.E138K) FERM domain. Substantially reduced levels of kindlin-3 were detected in the proband’s platelets and leukocytes. Functional evaluation verified that integrin αIIbβ3-mediated platelet activation, spreading, and aggregation and β2-integrin–mediated neutrophil adhesion and spreading were significantly compromised. Structural analysis revealed that this newly identified E138K substitution in kindlin-3 destabilizes the compacted FERM domain, resulting in poor expression of kindlin-3 in blood cells and subsequent LAD-III. ConclusionWe have identified a novel missense mutation and verified the functional significance of the compact kindlin-3 FERM domain in supporting integrin functions in platelets and leukocytes.

Who's your data? Primary immune deficiency differential diagnosis prediction via machine learning and data mining of the USIDNET registry

PurposeThere are currently more than 480 primary immune deficiency (PID) diseases and about 7000 rare diseases that together afflict around 1 in every 17 humans. Computational aids based on data mining and machine learning might facilitate the diagnostic task by extracting rules from large datasets and making predictions when faced with new problem cases. In a proof-of-concept data mining study, we aimed to predict PID diagnoses using a supervised machine learning algorithm based on classification tree boosting. MethodsThrough a data query at the USIDNET registry we obtained a database of 2396 patients with common diagnoses of PID, including their clinical and laboratory features. We kept 286 features and all 12 diagnoses to include in the model. We used the XGBoost package with parallel tree boosting for the supervised classification model, and SHAP for variable importance interpretation, on Python v3.7. The patient database was split into training and testing subsets, and after boosting through gradient descent, the predictive model provides measures of diagnostic prediction accuracy and individual feature importance. After a baseline performance test, we used the Class Weighting Hyperparameter, or scale_pos_weight to correct for imbalanced classification. ResultsThe twelve PID diagnoses were CVID (1098 patients), DiGeorge syndrome, Chronic granulomatous disease, Congenital agammaglobulinemia, PID not otherwise classified, Specific antibody deficiency, Complement deficiency, Hyper-IgM, Leukocyte adhesion deficiency, ectodermal dysplasia with immune deficiency, Severe combined immune deficiency, and Wiskott-Aldrich syndrome. For CVID, the model found an accuracy on the train sample of 0.80, with an area under the ROC curve (AUC) of 0.80, and a Gini coefficient of 0.60. In the test subset, accuracy was 0.76, AUC 0.75, and Gini 0.51. The positive feature value to predict CVID was highest for upper respiratory infections, asthma, autoimmunity and hypogammaglobulinemia. Features with the highest negative predictive value were high IgE, growth delay, abscess, lymphopenia, and congenital heart disease. For the rest of the diagnoses, accuracy stayed between 0.75 and 0.99, AUC 0.46–0.87, Gini 0.07–0.75, and LogLoss 0.09–8.55. DiscussionClinicians should remember to consider the negative predictive features together with the positives. We are calling this a proof-of-concept study to continue with our explorations. A good performance is encouraging, and feature importance might aid feature selection for future endeavors. In the meantime, we can learn from the rules derived by the model and build a user-friendly decision tree to generate differential diagnoses.

The impact of Treosulfan-based conditioning for inborn errors of immunity: Is dose monitoring crucial?

In children with inborn errors of immunity (IEI) who will receive a hematopoietic stem cell transplant (HSCT) treosulfan-based conditioning is currently preferred. The aim of this study was to investigate early and late outcomes in pediatric IEI patients receiving pre-HSCT treosulfan and to examine the effect of treosulfan dose monitoring on outcomes. Seventy-three pediatric patients receiving this management between 2015 and 2022 were included. Overall survival rate was 80%, and event-free survival was 67.8%. A larger treosulfan dose AUC after first application increased the rate of early toxicity (p=.034) and slowed lymphocyte engraftment (r=.290; p=.030). Underlying disease, treosulfan AUC, donor type, stem cell type, number of immunosuppressive agents, the dose of anti-thymocyte globulin, and post-transplantation cyclophosphamide did not to increase risk of acute graft-versus-host disease. The risk of mixed chimerism (MC) in patients with autoimmune lymphoproliferative syndrome and leukocyte adhesion deficiency were higher than those with severe combined immunodeficiency (p=.021 and p=.014, respectively). The risk of MC was lower in those receiving peripheral blood stem cells (SC) compared with bone marrow derived SC (OR=.204, p=.022). The AUC of the treosulfan dose was not associated with poorer late outcomes. Treosulfan is an agent that can be used safely in the IEI patient group, level measurement appears essential to identify early toxicities. Prospective studies with more extended follow-up periods are needed.

Defective Treg generation and increased type 3 immune response in leukocyte adhesion deficiency 1

In 15 Turkish LAD-1 patients and controls, we assessed the impact of pathogenic ITGB2 mutations on Th17/Treg differentiation and functions, and innate lymphoid cell (ILC) subsets.The percentage of peripheral blood Treg cells, in vitro-generated induced Tregs differentiated from naive CD4+ T cells were decreased despite the elevated absolute counts of CD4+ cells in LAD-1 patients. Serum IL-23 levels were elevated in LAD-1 patients. Post-curdlan stimulation, LAD-1 patient-derived PBMCs produced more IL-17A. Additionally, the percentages of CD18-deficient Th17 cells expanded from total or naïve CD4+ T cells were higher. The blood ILC3 subset was significantly elevated in LAD-1. Finally, LAD-1 PBMCs showed defects in trans-well migration and proliferation and were more resistant to apoptosis.Defects in de novo generation of Tregs from CD18-deficient naïve T cells and elevated Th17s, and ILC3s in LAD-1 patients' peripheral blood suggest a type 3-skewed immunity and may contribute to LAD-1-associated autoimmune symptoms.

Improved Outcome Following Busulfan-Based Conditioning in Children with Functional Neutrophil Disorders Undergoing Hematopoietic Stem Cell Transplant from HLA-Matched Donors.

Hematopoietic stem-cell transplantation (HSCT) is the only curative treatment for chronic granulomatous disease (CGD) and leukocyte-adhesion deficiency (LAD), but both diseases have high rates of graft failure in transplant and patients with these diseases are often referred to HSCT with significant comorbidity. The intensity of the conditioning regimen should be balanced between the need to ensure durable engraftment and to minimize toxicity when transplanting young children with infections and organ damage. We report on 26 children transplanted at our institution with CGD and LAD over 24years. We found a higher incidence of graft failure in patients receiving treosulfan based conditioning for their first transplant. There was no effect of conditioning regimen on overall survival, as all 8 patients that proceeded to a second busulfan-based HSCT were salvaged. We recommend giving patients with CGD and LAD fully myeloablative conditioning with either a busulfan-based regimen or the combination of treosulfan, fludarabine, and thiotepa.

Rare and heterogeneous manifestations of leucocyte adhesion deficiency type 1: report of two cases with diagnostic dilemmas and novel ITGB2 mutation

BackgroundPrimary immunodeficiency disorders (PID) are rare disorders with heterogeneous manifestations, overlapping with other diseases such as autoimmunity, malignancy, and infections. This makes the diagnosis very challenging and delays management. Leucocyte adhesion defects (LAD) are a group of PIDs in which patients lack adhesion molecules on leukocytes needed for their emigration through blood vessels to the site of infection. Patients with LAD can present with diverse clinical features including severe and life-threatening infections, early in life, and the absence of pus formation around infection or inflammation. There is often delayed umbilical cord separation, omphalitis, late wound healing, and a high white blood cell count. If not recognized and managed early, can lead to life-threatening complications and death.Case PresentationLAD 1 is characterized by homozygous pathogenic variants in the integrin subunit beta 2 (ITGB2) gene. We report two cases of LAD1 with unusual presentations (post-circumcision excessive bleeding and chronic inflammation of the right eye) which were confirmed by flow cytometric analysis and genetic testing. We found two disease-causing ITGB2 pathogenic variants in both cases.ConclusionsThese cases highlight the importance of a multidisciplinary approach to recognizing clues in patients with uncommon manifestations of a rare disease. This approach initiates a proper diagnostic workup of primary immunodeficiency disorder leading to a better understanding of the disease, and appropriate patient counseling, and helps clinicians to be better equipped to deal with complications.

Clinical and Osteopetrosis-Like Radiological Findings in Patients with Leukocyte Adhesion Deficiency Type III.

Leukocyte and platelet integrin function defects are present in leukocyte adhesion deficiency type III (LAD-III) due to mutations in FERMT3. Additionally, osteoclast/osteoblast dysfunction develops in LAD-III. To discuss the distinguishing clinical, radiological, and laboratory features of LAD-III. This study included the clinical, radiological, and laboratory characteristics of twelve LAD-III patients. The male/female ratio was 8/4. The parental consanguinity ratio was 100%. Half of the patients had a family history of patients with similar findings. The median age at presentation and diagnosis was 18 (1-60) days and 6 (1-20) months, respectively. The median leukocyte count on admission was 43,150 (30,900-75,700)/μL. The absolute eosinophil count was tested in 8/12 patients, and eosinophilia was found in 6/8 (75%). All patients had a history of sepsis. Other severe infections were pneumonia (66.6%), omphalitis (25%), osteomyelitis (16.6%), gingivitis/periodontitis (16%), chorioretinitis (8.3%), otitis media (8.3%), diarrhea (8.3%), and palpebral conjunctiva infection (8.3%). Four patients (33.3%) received hematopoietic stem cell transplantation (HSCT) from HLA-matched-related donors, and one deceased after HSCT. At initial presentation, 4 (33.3%) patients were diagnosed with other hematologic disorders, three patients (P5, P7, and P8) with juvenile myelomonocytic leukemia (JMML), and one (P2) with myelodysplastic syndrome (MDS). In LAD-III, leukocytosis, eosinophilia, and bone marrow findings may mimic pathologies such as JMML and MDS. In addition to non-purulent infection susceptibility, patients with LAD-III exhibit Glanzmann-type bleeding disorder. In LAD-III, absent integrin activation due to kindlin-3 deficiency disrupts osteoclast actin cytoskeleton organization. This results in defective bone resorption and osteopetrosis-like radiological changes. These are distinctive features compared to other LAD types.