Wiskott-Aldrich syndrome: a study of 577 patients defines the genotype as a biomarker for disease severity and survival.

ABSTRACT: Wiskott-Aldrich syndrome (WAS) is a multifaceted monogenic disorder with a broad disease spectrum and variable disease severity and a variety of treatment options including allogeneic hematopoietic stem cell transplantation (HSCT) and gene therapy (GT). No reliable biomarker exists to predict disease course and outcome for individual patients. A total of 577 patients with a WAS variant from 26 countries and a median follow-up of 8.9 years (range, 0.3-71.1), totaling 6118 patient-years, were included in this international retrospective study. Overall survival (OS) of the cohort (censored at HSCT or GT) was 82% (95% confidence interval, 78-87) at age 15 years and 70% (61-80) at 30 years. The type of variant was predictive of outcome: patients with a missense variant in exons 1 or 2 or with the intronic hot spot variant c.559+5G>A (class I variants) had a 15-year OS of 93% (89-98) and a 30-year OS of 91% (86-97), compared with 71% (62-81) and 48% (34-68) in patients with any other variant (class II; P < .0001). The cumulative incidence rates of disease-related complications such as severe bleeding (P = .007), life-threatening infection (P < .0001), and autoimmunity (P = .004) occurred significantly later in patients with a class I variant. The cumulative incidence of malignancy (P = .6) was not different between classes I and II. It confirms the spectrum of disease severity and quantifies the risk for specific disease-related complications. The class of the variant is a biomarker to predict the outcome for patients with WAS.

Primary immune regulatory disorders (PIRD): expanding the mutation spectrum in Turkey and identification of sixteen novel variants.

Human Inborn Errors of Immunity (IEIs) encompass a clinically and genetically heterogeneous group of disorders, ranging from mild cases to severe, life-threatening types. Among these, Primary Immune Regulatory Disorders (PIRDs) constitute a subset of IEIs characterized by diverse clinical phenotypes, prominently featuring severe atopy, autoimmunity, lymphoproliferation, hyperinflammation, autoinflammation, and susceptibility to malignancies. According to the latest report from the International Union of Immunological Societies (IUIS), PIRDs arise from mutations in various genes including LYST, RAB27A, AP3B1, AP3D1, PRF1, UNC13D, STX11, STXBP2, FAAP24, SLC7A7, RASGRP1, CD70, CTPS1, RLTPR, ITK, MAGT1, PRKCD, TNFRSF9, SH2DIA, XIAP, CD27 (TNFRSF7), FAS (TNFRSF6), FASLG (TNFSF6), CASP10, CASP8, FADD, LRBA, STAT3, AIRE, ITCH, ZAP70, TPP2, JAK1, PEPD, FOXP3, IL2RA, CTLA4, BACH2, IL2RB, DEF6, FERMT1, IL10, IL10RA, IL10RB, NFAT5, TGFB1, and RIPK1 genes. We designed a targeted next-generation sequencing (TNGS) workflow using the Ion AmpliSeq™ Primary Immune Deficiency Research Panel to sequence 264 genes associated with IEIs on the Ion S5™ Sequencer. In this study, we report the identification of 38 disease-causing variants, including 16 novel ones, detected in 40 patients across 15 distinct PIRD genes. The application of next-generation sequencing enabled rapid and precise diagnosis of patients with PIRDs.

Facilitated Subcutaneous Immunoglobulin Treatment Increases the Quality of Life and Decreases the Number of Infections and Hospitalizations in Children with Primary Immunodeficiencies.

INTRODUCTION: Immunoglobulin replacement therapy is an effective lifelong treatment modality used in patients with primary immunodeficiency to prevent and/or reduce the incidence of serious infections. Facilitated subcutaneous immunoglobulin (fSCIG) was developed to combine the advantages of intravenous immunoglobulin (IVIG) and subcutaneous immunoglobulin (SCIG) and is the latest method of immunoglobulin G (IgG) administration. In this study, switching to fSCIG administration in primary immunodeficiency patients receiving regular IVIG or SCIG therapy was evaluated, and serum IgG trough levels, frequency of infections, frequency and duration of hospitalizations, duration of absence from school/work, and quality of life were determined. METHODS: In this study, fifteen patients with primary immunodeficiency who were previously receiving IVIG or SCIG treatment, followed by fSCIG, were evaluated retrospectively. Age, diagnosis, current complications, mean IgG value, frequency of infection, frequency of hospitalization, and duration of absenteeism from school and work were recorded during and before fSCIG treatment. At the beginning of fSCIG treatment, at 6th and 12th months, "The Quality of Life Scale" was also evaluated in patients and parents. RESULTS: The most common indications for initiation of fSCIG treatment were the difficulty of access to the hospital and the long transfusion periods. No systemic adverse reactions were reported except for redness, swelling, and mild pain on the injection site. The median IgG values for the last 1 year were 529.6 mg/dL for IVIG (n = 9), 876.2 mg/dL for SCIG (n = 6) and 856.7 mg/dL for fSCIG (n = 15, all patients) treatment. The frequency of infections and the number of hospitalizations decreased significantly in the fSCIG group compared to both previous treatment modalities. There was a significant increase in the quality of life score of the patients and their families when compared with previous treatment modalities. CONCLUSION: fSCIG is an effective treatment method and is well tolerated in patients with immunodeficiency. It provides stable immunoglobulin levels and excellent protection against infections and offers the patients the possibility of home-based therapy.

Current genetic defects in common variable immunodeficiency patients on the geography between Europe and Asia: a single-center experience.

Identification of the causes of monogenetic common variable immunodeficiency (CVID) patients has rapidly increased in the last years by means of worldwide availability of appropriate genetic diagnostic methods. However, up to date, very limited numbers of reports demonstrating the role of geography, ethnicity, and consanguinity have been published. Here, we reported the first study of Turkish CVID patients and compared them with the results of three countries from America, Europe, and Asia. A total of 100 children diagnosed as CVID according to the criteria of European Society for Immunodeficiencies were enrolled, and they were genetically analyzed by using targeted next-generation sequencing and whole-exome sequencing. The median age of our patients was 5.8 years (range, 3.0-16.0 years) at clinical diagnosis and 9.0 years (range, 4.8-21.0 years) at the time of genetic diagnosis. The consanguinity rate was 24%. Disease-causing pathogenic variants were defined in 40% of patients in a total of 17 different genes. Sixteen of 40 identified pathogenic variants were novel (40%). We determined 18 surface molecular defects, 10 cytosolic defects, 9 nuclear defects, and 3 others. In our cohort, the most common gene was TACI (15/40 in pathogenic variant identified cases and 15/100 in all cases) followed by the others such as PLCÒ¯2, LRBA, TCF3, and STAT1. In contrast to our expectations, our results were more similar to American and European population rather than Asians, although we also have high consanguinity rates and live on the geography between Europe and Asia. Genetic investigation is a great challenge, because of the complexity and heterogeneity of the disease, and each country has to know their own current genetic landscape in CVID for a better and successful management of the patients.

Autoimmune Cytopenias Are Highly Associated with Inborn Errors of Immunity and They May Be the Initial Presentations in Cases without Severe Infections.

INTRODUCTION: Inborn errors of immunity (IEIs) are inherited disorders that present with increased susceptibility to infections as well as noninfectious complications. Due to the aberrant immune functions of patients with IEI, autoimmune cytopenia (AIC) may be the initial finding, which makes diagnosis a challenge. We aimed to evaluate the clinical course, laboratory findings, and treatment response of AIC in children with IEI. METHODS: Data of children with autoimmune hemolytic anemia (AIHA) and/or immune thrombocytopenic purpura (ITP) were obtained from a retrospective chart review of IEI patients diagnosed and followed in our center. Demographic and clinical features and therapeutic outcomes were evaluated. Immunologic findings were compared between patients with AIHA, ITP, and Evans syndrome (ES). The patients were also divided into two subgroups based on the presence or absence of immune dysregulation diseases (IDDs), and all data were compared between these two groups. RESULTS: Out of 562 patients with IEI, 6% (n: 34) had AIC which were ITP (23.5%), AIHA (35.5%), and ES (41.2%). AIC was the initial finding in 50% of these 34 patients. Patients with ES had a higher mean percentage of CD8+ T lymphocytes than ITP patients (40.77 ± 20.21% vs. 22.33 ± 12.48%, p = 0.011). Patients with IDDs were more likely to develop ES (p = 0.004), lymphoproliferation (p = 0.005), and resistance to first-line therapy (p = 0.021) than other IEI groups. CONCLUSION: This study shows that AIC may be the initial finding of IEI, particularly when lymphoproliferation and resistance to first-line therapy co-occur. Therefore, detailed investigation should be offered to all patients to avoid diagnostic delay.

Analysis of IL-1ß, TGF-ß, IL-5, ACE, PTPN22 gene polymorphisms, and gene expression levels in Turkish children with IgA vasculitis.

OBJECTIVE: Immunoglobulin-A vasculitis (IgAV) is an inflammatory disease that affects small blood vessels. This study was performed to identify an association between protein tyrosine phosphatase non-receptor type 22 (PTPN22) + 788G > A (rs33996649), transforming growth factor-beta (TGF-ß) -509C > T (rs18004069), interleukin 1-beta (IL-1ß) -511C > T (rs16944), interleukin 5 (IL-5) -746C/T (rs2069812), and angiotensin-converting enzyme (ACE) I/D (rs4646994) gene polymorphisms, susceptibility to IgAV, as well as the mRNA levels of IL-1ß, IL-1ß, and TGF-ß. METHOD: A total of 53 patients with IgAV and 50 healthy controls were enrolled. PTPN22, TGF-ß, IL-1ß, ACE gene polymorphisms, ACE gene I/D polymorphisms, and mRNA expression levels were analyzed using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method, allele-specific PCR, and real-time PCR with TaqMan kits, respectively. RESULTS: PTPN22, TGF-ß, IL-1ß, IL-5, and ACE variants showed no genotype or allele differences between patients with IgAV and controls. Increased levels of IL-1ß and TGF-ß mRNA expressions were observed in patients with IgAV (p < 0.001). Patients with the IL-1ß AG genotype showed significantly increased amounts of arthritis than patients with non-AG (p = 0.004). Age at disease onset was found to be significantly different in patients with IgAV according to the presence of TGF-ß TT genotype (p = 0.047). CONCLUSION: Polymorphisms in PTPN22, TGF-ß, IL-5, IL-1ß, and ACE genes are unlikely to confer susceptibility to IgAV. However, the presence of the AG genotype of IL-1ß is associated with susceptibility to IgAV-related arthritis. This is the first study to report a significant increase in serum mRNA levels of IL-1ß and TGF-ß in IgAV patients, supporting a susceptibility to IgAV in childhood.

Dual Diagnosis of Trichohepatoenteric Syndrome and Lipoid Proteinosis in a Turkish Child.

Introduction: Trichohepatoenteric syndrome (THES) is caused by pathogenic mutations in TTC37 and SKIV2L genes and characterized by intractable diarrhea, facial dysmorphism, hair abnormality, immunodeficiency, and skin abnormalities. Lipoid proteinosis is caused by pathogenic mutations in ECM1 gene and characterized by deposition of hyaline-like material in various tissues resulting in heterogenous clinical findings. Case Presentation: Four years after the diagnosis and management of THES, due to new clinical findings, another reason for underlying features of the patient was considered. WES was performed and a homozygous c.507delT (p.Arg171GlyfsTer7) mutation in the ECM1 gene was detected. Conclusion: This case provides an example of co-existence of multiple genetic defects in a single patient born to consanguineous parents.

Mid-Regional Proadrenomedullin Levels in Primary Immunodeficiencies Complicated with Pulmonary Manifestations.

The development of lower respiratory complications in children with primary immunodeficiencies characterized by recurrent infections significantly contributes to morbidity and mortality. This is clinically more important and specific in the evaluation of prognosis. The inflammatory response that develops throughout the clinical process can cause the release of several biomarkers. This study aimed to evaluate the inflammatory biomarker "mid-regional pro-adrenomedullin (MR-proADM)" levels by distribution of lower respiratory tract complications. Plasma MR-proADM levels were measured in children with (n = 52) and without (n = 103) lower respiratory tract complications. The complicated group was also evaluated as "infective and non-infective" groups. The median MR-proADM levels were higher in the complicated cases (p = 0.175). It was 205.5 (73.4- 562.6) ng/L in the infective group while it was 96.1 (26.1-43.3) ng/L in the non-infective group and the difference between the two groups was statistically significant (p = 0.003). The predictive value of MR-proADM (AUC = 0.749, p = 0.003) was statistically significant compared to CRP (AUC = 0.330, p = 0.040) and SAA (AUC = 0.261, p = 0.004) in the infective group. This study evidences that the MR-proADM levels are higher in PID cases with infective pulmonary complications. Among other markers, MR-proADM appears to be a particularly good predictive inflammation marker for these children. Supplementary Information: The online version contains supplementary material available at 10.1007/s12291-022-01061-9.

Therapeutic modalities and clinical outcomes in a large cohort with LRBA deficiency and CTLA4 insufficiency.

BACKGROUND: LPS-responsive beige-like anchor (LRBA) deficiency (LRBA-/-) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA4) insufficiency (CTLA4+/-) are mechanistically overlapped diseases presenting with recurrent infections and autoimmunity. The effectiveness of different treatment regimens remains unknown. OBJECTIVE: Our aim was to determine the comparative efficacy and long-term outcome of therapy with immunosuppressants, CTLA4-immunoglobulin (abatacept), and hematopoietic stem cell transplantation (HSCT) in a single-country multicenter cohort of 98 patients with a 5-year median follow-up. METHODS: The 98 patients (63 LRBA-/- and 35 CTLA4+/-) were followed and evaluated at baseline and every 6 months for clinical manifestations and response to the respective therapies. RESULTS: The LRBA-/- patients exhibited a more severe disease course than did the CTLA4+/- patients, requiring more immunosuppressants, abatacept, and HSCT to control their symptoms. Among the 58 patients who received abatacept as either a primary or rescue therapy, sustained complete control was achieved in 46 (79.3%) without severe side effects. In contrast, most patients who received immunosuppressants as primary therapy (n = 61) showed either partial or no disease control (72.1%), necessitating additional immunosuppressants, abatacept, or transplantation. Patients with partial or no response to abatacept (n = 12) had longer disease activity before abatacept therapy, with higher organ involvement and poorer disease outcomes than those with a complete response. HSCT was performed in 14 LRBA-/- patients; 9 patients (64.2%) showed complete remission, and 3 (21.3%) continued to receive immunosuppressants after transplantation. HSCT and abatacept therapy gave rise to similar probabilities of survival. CONCLUSIONS: Abatacept is superior to immunosuppressants in controlling disease manifestations over the long term, especially when started early, and it may provide a safe and effective therapeutic alternative to transplantation.

Atypical Localization of Eczema Discriminates DOCK8 or STAT3 Deficiencies from Atopic Dermatitis.

PURPOSE: Autosomal recessive dedicator of cytokinesis 8 (DOCK8-/-) and autosomal dominant signal transducer and activator of transcription 3 (STAT3-/+) deficiencies are inborn errors of immunity (IEI) disorders present with the classic features of eczema and create a dilemma during differentiation from atopic dermatitis (AD). Therefore, an appropriate approach is required for eczema to diagnose DOCK8-/- and STAT3-/+ early. Here, we described a set of clinical and immunological variables, including atypical AD localizations and lymphocyte subsets, to differentiate DOCK8-/- or STAT3-/+ from AD. METHODS: This multicenter study involved 100 patients with DOCK8-/- and STAT3-/+ and moderate/severe AD. We recruited disease manifestations, including detailed localizations of eczema, infections, and allergy. Principle component analysis (PCA) was used to discriminate DOCK8-/- or STAT3-/+ from AD. RESULTS: There were 43 patients with DOCK8-/-, 23 with STAT3-/+, and 34 with AD. Pneumonia, severe infections, mucocutaneous candidiasis, and skin abscesses were commonly observed in DOCK8 and STAT3 deficiencies. Atypical skin involvement with neonatal rash, retro auricular, axillary, sacral, and genital eczema discriminate DOCK8-/- and STAT3-/+ from AD with high specificity ranges between 73.5 and 94.1% and positive predictive index ranges between 55 and 93.1%. Together with using absolute numbers of CD3+, CD4+, and CD8+ T cells, the combined clinical and laboratory features showed perfect differentiation between DOCK8-/- or STAT3-/+ and AD via PCA. CONCLUSIONS: The described features can be easily implemented by physicians providing early diagnosis of DOCK8 and STAT3 deficiencies.

An Extraordinary Case of Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED) Syndrome Misdiagnosed as Juvenile Idiopathic Arthritis on Admission.

Background: APECED is a syndrome characterized by autoimmune polyendocrinopathy, candidiasis, and ectodermal dystrophy. The most observed clinical findings are chronic mucocutaneous candidiasis, hypoparathyroidism, and autoimmune adrenal insufficiency. Case Presentation. A three-year-old male patient was admitted with classical signs of juvenile idiopathic arthritis and treated with nonsteroidal anti-inflammatory drugs. During follow-up, signs of autoimmunity, candidiasis, nail dystrophy, and onychomycosis were observed. The parents were consanguineous, and targeted next-generation sequencing was performed. A homozygous mutation in the AIRE gene SAND domain (c.769C > T, p.Arg257Ter) was detected, and the patient was diagnosed with APECED syndrome. Conclusion: Inflammatory arthritis is rarely described in association with APECED and is often misdiagnosed as juvenile idiopathic arthritis. In APECED cases, nonclassical symptoms such as arthritis may occur before developing classical symptoms and considering the diagnosis of APECED in patients with CMC and arthritis is useful for early diagnosis before development of complications and management of disease.

Eight years of follow-up experience in children with mendelian susceptibility to mycobacterial disease and review of the literature.

BACKGROUND: Mendelian susceptibility to mycobacterial disease (MSMD) is a rare primary immunodeficiency, caused by non-tuberculous mycobacteria or Bacillus Calmette-Guerin (BCG) vaccine and characterized by severe diseases in childhood. OBJECTIVE: In this study, we examined eight years followed-up 12 Turkish children with genetically proven MSMD and we tried to evaluate the survival rate with succesfull disease management, rate of consanguinity, molecular, cellular and clinical features of patients. In addition, we wanted to emphasize the importance of early diagnosis before administration of BCG vaccine in countries where this vaccine is routinely used. METHODS: Twelve patients diagnosed with molecular studies [IFNγR1 complete (n = 1), IFNγR2 partial (n = 3), IL12Rß1 (n = 6), NEMO (n = 1), STAT1 mutation (n = 1)] were included. RESULTS: Ten patients (83%) were born from consanguineous parents and frequency of family history for the primary immunodeficiency was 58% (n = 7). All the cases had been immunized with BCG vaccine (Mycobacterium bovis) due to lack of early diagnosis. Two patients had BCG-itis and four patients had "BCG-osis". Survival rate was 75% after successful disease management with antibiotics, anti-tuberculous agents and recombinant IFN-γ. CONCLUSIONS: It was concluded that MSMD must be differentiated from different forms of primary immunodeficiencies, so clinicians should be aware of MSMD especially in patients with BCG vaccine complications and non-tuberculous mycobacterial infection.

Alterations in B and NK cells highly correlate with disease severity in children with COVID-19.

Background/aim: Children with coronavirus disease 2019 (COVID-19) present milder symptoms than adults and are at lower risk of hospitalization and life-threatening complications. However, the kinetics of lymphocyte subsets and serum immunoglobulins in the peripheral blood during COVID-19 infection remains unclear. In this study, it was aimed to determine the changes in hematological and immunological parameters, especially in the lymphocyte subsets, in the peripheral blood of children with different COVID-19 disease severity. Materials and methods: The study was planned as a prospective cohort and included 68 children aged 0-18 years who were admitted to Ege University Faculty of Medicine Department of Pediatrics and diagnosed with COVID-19 infection between May 2020 and December 2021. In addition to demographic characteristics, clinical findings, and severity criteria, hematological, biochemical, and immunological laboratory (T/B lymphocyte subgroups, serum immunoglobulins) results were noted and examined if there were some correlations between disease severity and the laboratory values. Results: In the study group, while 60.6% (n = 40) of the patients received treatment in the hospital, 10.6% (n = 7) needed intensive care treatment. Lymphopenia (35.3%) was more common than neutropenia (14.7%) in the COVID-19-infected children. CD19+ B cells were low in a very high percentage of patients (26.5%), and 16.2% had low levels of NK cells. Significant correlation between disease severity and CD19+lymphocytes, CD19+CD38+IgMlow lymphocytes, CD19+CD38+CD27highIgMhigh lymphocytes, CD19+CD81+ lymphocytes (p = 0.001, p = 0.008, p = 0.014, p = 0.025, and rs = 0.394, rs = 0.326, rs = 0.303, rs = 0.280, respectively), significant inverse correlation between disease severity and absolute lymphocytes counts and CD3-CD16+CD56+ lymphocytes (p = 0.004, 0.014, and rs = -0.353, rs = -0.304, respectively) were observed. The percentage of hospitalized patients with low CD3 levels (15%) was significantly higher than that of the outpatients with low CD3 levels. Conclusion: As the severity of the disease increased, the CD19+, CD19+CD38+IgMlow, CD19+CD38+CD27highIgMhigh, and CD19+CD81+ lymphocytes percentages increased, while the lymphocyte count and NK cell percentage decreased. Therefore, detecting these prognostic immunobiomarkers related to the severity of the disease may contribute considerably to management of the illness.

Clinical, immunological, molecular and therapeutic findings in monogenic immune dysregulation diseases: Middle East and North Africa registry.

Monogenic immune dysregulation diseases (MIDD) are caused by defective immunotolerance. This study was designed to increase knowledge on the prevalence and spectrum of MIDDs, genetic patterns, and outcomes in Middle East and North Africa (MENA). MIDD patients from 11 MENA countries (Iran, Turkey, Kuwait, Oman, Algeria, Egypt, United Arab Emirates, Tunisia, Jordan, Qatar, and Azerbaijan) were retrospectively evaluated. 343 MIDD patients (58% males and 42% female) at a median (IQR) age of 101 (42-192) months were enrolled. The most common defective genes were LRBA (23.9%), LYST (8.2%), and RAB27A (7.9%). The most prevalent initial and overall manifestations were infections (32.2% and 75.1%), autoimmunity (18.6% and 41%), and organomegaly (13.3% and 53.8%), respectively. Treatments included immunoglobulin replacement therapy (53%), hematopoietic stem cell transplantation (HSCT) (14.3%), immunosuppressives (36.7%), and surgery (3.5%). Twenty-nine (59.2%) patients survived HSCT. Along with infectious complications, autoimmunity and organomegaly may be the initial or predominant manifestations of MIDD.

Regulatory B cells in patients suffering from inborn errors of immunity with severe immune dysregulation.

BACKGROUND: Immune dysregulation as a result of an inborn error of immunity (IEI) leads to the complicated symptoms of refractory multi-organ immune dysregulation. B lymphocytes with immune regulatory capacity (Breg) are activated by environmental triggers and act as regulators of the immune response as observed in several autoimmune diseases. OBJECTIVE: We sought to investigate the Breg profile and the CD21low expressing B cells of patients with LRBA deficiency (N = 6) and non-LRBA deficiency IEI (N = 13) with overlapping clinical symptoms of immune dysregulation. Normal values for Breg subpopulations were obtained from patients age-matched healthy cohorts (N = 48). Furthermore, we investigated the impact of abatacept treatment in LRBA deficient patients receiving biweekly abatacept (N = 5). METHODS: Using a flow cytometric approach with a pre-formulated antibody panel in peripheral blood samples, Breg subsets including plasmablasts (CD27+CD38hi), transitional B cells (CD24hiCD38hi), and B10 cells (CD24hiCD27+), and additionally the CD21low B cells (CD21lowCD38low) were analyzed. Breg function was assessed by the interleukin-10 expression within the CD19+ population. Additionally, B cell cytokines were measured in cell culture supernatants. RESULTS: We observe significant alterations of B cell/Breg subpopulations in the LRBA deficient cohort including a severe lack of memory B cells (P = 0.031) and B10 cells (P = 0.031) as well as a tendency towards higher CD21low B cells (P = 0.063). Within the non-LRBA deficient cohort, we observe a significant expansion of the plasmablasts (P = 0.012), and a tendency towards elevated levels of CD21low expressing B cells (P = 0.063). The treatment with abatacept ameliorated disease symptoms in the LRBA deficient cohort and led to an effective decrease in CD21low B cells over time (P = 0.021). Furthermore, there was a significantly increased level of B cell-activating factor (BAFF; P = 0.02) and lower IL-12p70 secretion upon stimulation (P = 0.020) in the LRBA cohort. CONCLUSION: Aberrant maturation of Breg subsets and the pathological expansion of CD21low B cells in patients with IEI may have therapeutic implications. Patients suffering from LRBA deficiency show a lack of memory B cells, insufficient expansion of B10 cells, increased BAFF levels as well as an increase in circulating CD21low B cells. Abatacept treatment results in a steady decrease in CD21low B cells.

A Novel BLNK Gene Mutation in a Four-Year-Old Child Who Presented with Late Onset of Severe Infections and High IgM Levels and Diagnosed and Followed as X-Linked Agammaglobulinemia for Two Years.

Agammaglobulinemia is a rare inherited immunodeficiency disorder. Mutations in the BLNK gene cause low levels of mature B lymphocytes in the peripheral blood leading to recurrent infections. We present a four-year-old Turkish boy who had recurrent respiratory tract infections in the last six months. He had very low IgG (81 mg/dl) and IgA levels (<5 mg/dl) with high IgM (258 mg/dl). Flow cytometric analysis of lymphocyte subsets showed low CD19+ B cells (0.05%). Homozygous c.790C > T (p.Gln264Ter) mutation was detected in the BLNK gene with Targeted Next Generation Sequencing (TNGS) gene analysis. Agammaglobulinemia may be due to different genetic etiologies together with complex genetic events. Although the first diagnosis to be considered in male patients is Bruton's agammaglobulinemia, patients with normal BTK sequence and/or expression should be investigated with a large genetic study such as TNGS in the early period to reach a definitive diagnosis. This male case of agammaglobulinemia highlights the necessity of considering BLNK mutations in children with B cell deficiency, even though they are known to be rare causes of agammaglobulinemia. Our case is also remarkable with high IgM levels before intravenous immunoglobulin replacement therapy and with late-onset severe infections.

Comparing the levels of CTLA-4-dependent biological defects in patients with LRBA deficiency and CTLA-4 insufficiency.

BACKGROUND: Lipopolysaccharide-responsive beige-like anchor protein (LRBA) deficiency and cytotoxic T-lymphocyte protein-4 (CTLA-4) insufficiency are recently described disorders that present with susceptibility to infections, autoimmunity, and lymphoproliferation. Clinical and immunological comparisons of the diseases with long-term follow-up have not been previously reported. We sought to compare the clinical and laboratory manifestations of both diseases and investigate the role of flow cytometry in predicting the genetic defect in patients with LRBA deficiency and CTLA-4 insufficiency. METHODS: Patients were evaluated clinically with laboratory assessments for lymphocyte subsets, T follicular helper cells (TFH ), LRBA expression, and expression of CD25, FOXP3, and CTLA4 in regulatory T cells (Tregs) at baseline and 16 h post-stimulation. RESULTS: LRBA-deficient patients (n = 29) showed significantly early age of symptom onset, higher rates of pneumonia, autoimmunity, chronic diarrhea, and failure to thrive compared to CTLA-4 insufficiency (n = 12). In total, 29 patients received abatacept with favorable responses and the overall survival probability was not different between transplanted versus non-transplanted patients in LRBA deficiency. Meanwhile, higher probability of survival was observed in CTLA-4-insufficient patients (p = 0.04). The T-cell subsets showed more deviation to memory cells in CTLA-4-insufficiency, accompanied by low percentages of Treg and dysregulated cTFH cells response in both diseases. Cumulative numbers of autoimmunities positively correlated with cTFH frequencies. Baseline CTLA-4 expression was significantly diminished in LRBA deficiency and CTLA-4 insufficiency, but significant induction in CTLA-4 was observed after short-term T-cell stimulation in LRBA deficiency and controls, while this elevation was less in CTLA-4 insufficiency, allowing to differentiate this disease from LRBA deficiency with high sensitivity (87.5%) and specificity (90%). CONCLUSION: This cohort provided detailed clinical and laboratory comparisons for LRBA deficiency and CTLA-4 insufficiency. The flow cytometric approach is useful in predicting the defective gene; thus, targeted sequencing can be conducted to provide rapid diagnosis and treatment for these diseases impacting the CTLA-4 pathway.

Severe combined immunodeficiencies: Expanding the mutation spectrum in Turkey and identification of 12 novel variants.

Human Inborn Errors of Immunity (IEIs) are clinically and genetically heterogeneous group of diseases, with relatively mild clinical course or severe types that can be life-threatening. Severe combined immunodeficiency (SCID) is the most severe form of IEIs, which is caused by monogenic defects that impair the proliferation and function of T, B, and NK cells. According to the most recent report by the International Union of Immunological Societies (IUIS), SCID is caused by mutations in IL2RG, JAK3, FOXN1, CORO1A, PTPRC, CD3D, CD3E, CD247, ADA, AK2, NHEJ1, LIG4, PRKDC, DCLRE1C, RAG1 and RAG2 genes. The targeted next-generation sequencing (TNGS) workflow based on Ion AmpliSeq™ Primary Immune Deficiency Research Panel was designed for sequencing 264 IEI-related genes on Ion S5™ Sequencer. Herein, we present 21 disease-causing variants (12 novel) which were identified in 22 patients in eight different SCID genes. Next-generation sequencing allowed a rapid and an accurate diagnosis SCID patients.

Erratum: X-linked agammaglobulinemia: investigation of clinical and laboratory findings, novel gene mutations and prevention of infective complications in long-term follow-up.

[This corrects the article on p. 37 in vol. 10, PMID: 33815962.].