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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.

© 2022 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.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.

Aim: We aimed to determine the frequency of autoantibody antinuclear (ANA), peripheral anti-neutrophil cytoplasmic antibody (p-ANCA), anti-saccharomyces cerevisiae antibody (ASCA), anti-pancreatic exocrine gland antibody (PAb), goblet cell antibody (GAb) positivities in children with the complaint of chronic diarrhea and inflammatory bowel disease (IBD). We also purposed to explore the role of these autoantibodies in the differential diagnosis of IBD. Materials and Methods: in our study, serum samples of 51 patients with the complaint of chronic diarrhea and 35 healthy controls were analyzed. Clinical and laboratory data at the time of serum sampling were collected and a differential diagnosis was made as the results of performed tests were recorded. For all patients, ANA, p-ANCA, ASCA, GAb, PAb positivities were evaluated by indirect immunofluorescence. the chronic diarrhea group was divided into two groups, namely, the IBD group and non-IBD group. Results: in the chronic diarrhea group, 11 (21.6%) patients had ANA, 3 (5.9%) had p-ANCA, 1 (2%) had PAb, 1 (2%) had Gab and 1 (2%) had ASCA positivity. From the 35 cases of the control group, 8 (22.9%) had ANA, 7 (20%) had ASCA positivity. in the control group, ASCA was found to be high (p=0.007). Six cases were diagnosed as IBD; 1 (16.7%) had ANA, 1 (16.7%) had p-ANCA, 1 (2%) had Gab and 1 (2%) had ASCA positivity. ASCA and GAb positivities were significantly more frequent in the IBD group (p=0.006, p=0.006, respectively). Conclusion: ASCA was determined to be significantly higher in the control group. High positivity in the control group showed that the percentage of nonspecific positivity may be high for this test. ASCA and GAb of those patients with a diagnosis of IBD were found significantly higher. the serologic tests which depend on p-ANCA, ASCA, PAb, GAb can be supportive of diagnoses and differential diagnoses of IBD. Autoantibodies in IBD may be used as a supportive diagnostic tool in selected cases, rather than as the diagnosis of IBD as routine practice.

Background: APACED is a syndrome characterized by autoimmune polyendocrinopathy, candidiasis and ectodermal dystrophy. The most often observed clinical findings are chronic mucucutaneous candidiasis, hypoparatiroidism and autoimmune adrenal insufficiency. Case presentation: A three-year-old male patient admitted with classical signs of juvenile idiopathic arthritis and began to be treated with non-sterodial anti-inflammatory drugs. During follow-up, signs of autoimmunity, candidiasis, nail dystrophy and onychomycosis were observed. The parents were consangineous 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 as APACED syndrome. Conclusion: Inflammatory arthritis is rarely described in APECED cases and is often misdiagnosed as juvenile idiopathic arthritis. In APACED, non-classical symptoms such as arthritis may occur before developing classical symptoms. In patients with arthritis, considering about chronic mucocutaneous candidiasis and signs of autoimmunity will be useful for early diagnosis of APACED before developing complications.

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., Alborz University of Medical Sciences, This work was supported by the vice chancellor for research, Alborz University of Medical Sciences.

Phagocytes including neutrophil granulocytes and macrophages are important cells of the innate immune system whose primary function is to ingest and destroy microorganisms. Neutrophils help their host fight infections by phagocytosis, degranulation, and neutrophil extracellular traps. Neutrophils are the most common type of circulating white blood cells and the principal cell type in acute inflammatory reactions. A total absence of neutrophils or a significant decrease in their number leads to severe immunodeficiency that renders patients vulnerable to recurrent infections by Staphylococcus aureus and Gram-negative bacteria being the most life-threatening. Neutropenia may be classified as mild, moderate or severe in terms of numbers in the peripheral blood, and intermittent, cyclic, or chronic in terms of duration. Besides well-known classic severe congenital neutropenia, chronic neutropenia appears to be associated with an increasing number of primary immunodeficiency diseases (PIDs), including those of myeloid and lymphoid lineage. A comprehensive overview of the diverse clinical presenting symptoms, classification, aetiological and genetic etiologies of chronic isolated and syndromic neutropenia is aimed to be reviewed.

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 symbolscript 6) and non-LRBA deficiency IEI (N symbolscript 13) with overlapping clinical symptoms of immune dys-regulation. Normal values for Breg subpopulations were obtained from patients age-matched healthy cohorts (N symbolscript 48). Furthermore, we investigated the impact of abatacept treatment in LRBA deficient patients receiving biweekly abatacept (N symbolscript 5).Methods: Using a flow cytometric approach with a pre-formulated antibody panel in peripheral blood samples, Breg subsets including plasmablasts symbolscript transitional B cells (CD24hiCD38hi), and B10 cells symbolscript and additionally the CD21low B cells (CD21lowCD38low) were analyzed. Breg function was assessed by the interleukin-10 expression within the symbolscript 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 symbolscript 0.031) and B10 cells (P symbolscript 0.031) as well as a tendency towards higher CD21low B cells (P symbolscript 0.063). Within the non-LRBA deficient cohort, we observe a significant expansion of the plasmablasts (P symbolscript 0.012), and a tendency towards elevated levels of CD21low expressing B cells (P symbolscript 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 symbolscript 0.021). Furthermore, there was a significantly increased level of B cell-activating factor (BAFF; P symbolscript 0.02) and lower IL-12p70 secretion upon stimulation (P symbolscript 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., University Hospital Frankfurt, Germany, This work was funded by the University Hospital Frankfurt, Germany. Authors have no conflict of interest.

Mutations in the interleukin-21 receptor (IL-21R) gene are recently defined as primary immunodeficiency diseases. IL-21R defects result in combined immunodeficiency by affecting the functions of innate and adaptive immune system components.A six-year-old girl was admitted to our hospital with complaints of chronic diarrhea that started after the newborn period and generalized rash over the last three months. She had severe respiratory distress due to Cytomegalovirus (CMV) pneumonia requiring mechanical ventilation and was diagnosed as combined immunodeficiency at another hospital at the age of four. Her physical examination on admission revealed erythematous rash on cheeks, extremities, gluteal region, and lymph node enlargements in cervical, axillary, and inguinal regions. CMV DNA and stool

Mutations in the interleukin-21 receptor (IL-21R) gene are recently defined as primary immunodeficiency diseases. IL-21R defects result in combined immunodeficiency by affecting the functions of innate and adaptive immune system components. A six-year-old girl was admitted to our hospital with complaints of chronic diarrhea that started after the newborn period and generalized rash over the last three months. She had severe respiratory distress due to Cytomegalovirus (CMV) pneumonia requiring mechanical ventilation and was diagnosed as combined immunodeficiency at another hospital at the age of four. Her physical examination on admission revealed erythematous rash on cheeks, extremities, gluteal region, and lymph node enlargements in cervical, axillary, and inguinal regions. CMV DNA and stool Cryptosporidium parvum were positive. Marginal zone lymphoma -negative for Epstein-Bar virus- was reported in the lymph node biopsy. Targeted next-generation sequencing Ion AmpliSeq (TM) primary immunodeficiency panel revealed a novel homozygous IL21R c.132delC (p.Ser45fs) mutation. This case is presented to emphasize that IL21R defects should be considered in the differential diagnosis of the patients with recurrent respiratory infections, chronic diarrhea, C. parvum infection, chronic liver disease, sclerosing cholangitis, and malignancy where early hematopoietic stem cell transplantation (HSCT) is life-saving. A total of eight cases with IL21R gene defects have been reported so far. The significance of this case is that it is the first case of malignancy among the published IL-21R deficient patients successfully treated with HSCT.

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), IL12Rβ1 (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.

Systemic capillary leak syndrome (ISCLS) is a rare disease characterized by unexplained reversible capillary hyperpermeability followed by hypoperfusion, hemoconcentration, and either hypoalbuminemia or total hypoproteinemia. An 11-year-old boy was admitted with vomiting, generalized edema, and hyperglycemia, which was preceded by 5 days of coryzal symptoms, lethargy, and oral aft, without fever. On physical examination, he had tachycardia and hypotension, with severe generalized systemic nonitchy edema, and the laboratory tests supported the conclusion that he had severe hemoconcentration with hemoglobin: 184 g/L, hematocrit: 51.3 %, urea: 20 mmol/L, blood glucose: 11.1 mmol/L, and albumin: 19 gr/L, with normal urine analysis. On the fourth day, the patient was diagnosed with ISCLS, by ruling out other causes of shock and hypoalbuminemia. Intravenous immunoglobulin (IVIG) treatment regimen was administered on two consecutive days (day five and day six). His edema decreased on the fifth day, and the patient was deemed clinically well. There was no compartment syndrome, rhabdomyolysis, or pulmonary edema in the recovery period. However, respiratory virus panel PCR was positive for respiratory syncytial virus (RSV) and enterovirus, which were thought to be the triggering cause of ISCLS. For the differential diagnosis of diabetes, his fasting serum glucose was 13.4 mmol/L, simultaneous C-peptide was 0.44 nmol/L, and HbA1c was 64 mmol/mol, and urine ketone was positive. However, antiglutamic acid decarboxylase, anti-insulin antibody, and islet cell antibody were negative. At the last outpatient visit, 22 months after the diagnosis, his insulin dose was still 0.4 IU/kg/day and HbA1c was 40 mmol/mol, and without prophylaxis, there was no ISCLS attack. Conclusion. Early recognition of ISCLS is important for therapeutic awareness, since it is very rare in childhood and occurs usually without any prior provoking factors in healthy children. With the increase in awareness of the disease, knowledge and experiences about pediatric patients may also increase. We think that our case will contribute to the literature since there have been no pediatric diabetic patients with ISCLS reported.

Introduction and objectives: The purpose of this study was to evaluate patients diagnosed with 22q11.2 deletion syndrome and determine the clues directing to diagnosis and evaluation of immunological findings for excellent management of the disease. Material and methods: Thirty-three pediatric patients with 22q11.2 deletion syndrome diag-nosed between 1998 and 2019 at Pediatric Immunology Division of Ege University Faculty of Medicine and SBU Izmir Dr Behcet Uz Children’s Education and Research Hospital were evaluated. Results: This study includes the largest case series reported from Turkey. Congenital car-diac anomalies were the most common pathology associated with the syndrome (90.9%). Hypocalcemic symptoms were observed in 13 patients (40%). Twenty-two of the 33 (66.6%) patients were diagnosed before two years of age. Autoimmune diseases, dysmorphic facial findings, recurrent infections, growth retardation, and speech impairment were other clues for diagnosis in older patients. Clinical spectrum and immunological abnormalities of this syn-drome are quite variable. All T-cell subset counts were less than 5th percentile below median by age in one patient (3%) and 10 patients had normal all T-cell subset counts (30.3%). Overall, 69.6% of the patients had normal IgG, IgA, and IgM levels and two patients had panhypogam-maglobulinemia. Recurrent infections were revealed in 75.7% of the patients during follow-up. Conclusions: Presence of cardiac anomaly is more helpful in the diagnosis, especially under two years of age. Patients with immunologically high or standard risk did not show any differ-ence in terms of numbers and severity of infections and autoimmunity.

Although sideroblastic anemias (SAs) may be associated with different etiologies, deterioration of mitochondrial heme biosynthesis in bone marrow erythroid cells is a general abnormality. Congenital SA associated with immunodeficiency, periodic fever, and developmental delay is because of loss-of-function mutations in the TRNT1 gene. We report a patient with a novel homozygous mutation in the TRNT1 gene presenting with anemia with siderocytes, hypogammaglobulinemia, hepatosplenomegaly, and brittle hair but without periodic fever or developmental delay. The patient was presented to emphasize the power of reverse phenotyping in the differential diagnosis of primary immunodeficiency patients with atypical features and to raise awareness for TRNT1 disease in case of coexistent SA and hypogammaglobulinemia.

Background: Recent findings strongly support hematopoietic stem cell transplantation (HSCT) in patients with severe presentation of LPS-responsive beige-like anchor protein (LRBA) deficiency, but long-term follow-up and survival data beyond previous patient reports or meta-reviews are scarce for those patients who do not receive a transplant. Objective: This international retrospective study was conducted to elucidate the longitudinal clinical course of patients with LRBA deficiency who do and do not receive a transplant. Method: We assessed disease burden and treatment responses with a specially developed immune deficiency and dysregulation activity score, reflecting the sum and severity of organ involvement and infections, days of hospitalization, supportive care requirements, and performance indices. Results: of 76 patients with LRBA deficiency from 29 centers (median follow-up, 10 years; range, 1-52), 24 underwent HSCT from 2005 to 2019. the overall survival rate after HSCT (median follow-up, 20 months) was 70.8% (17 of 24 patients); all deaths were due to nonspecific, early, transplant-related mortality. Currently, 82.7% of patients who did not receive a transplant (43 of 52; age range, 3-69 years) are alive. of 17 HSCT survivors, 7 are in complete remission and 5 are in good partial remission without treatment (together, 12 of 17 [70.6%]). in contrast, only 5 of 43 patients who did not receive a transplant (11.6%) are without immunosuppression. Immune deficiency and dysregulation activity scores were significantly lower in patients who survived HSCT than in those receiving conventional treatment (P = .005) or in patients who received abatacept or sirolimus as compared with other therapies, and in patients with residual LRBA expression. Higher disease burden, longer duration before HSCT, and lung involvement were associated with poor outcome. Conclusion: the lifelong disease activity, implying a need for immunosuppression and risk of malignancy, must be weighed against the risks of HSCT., Styrian Children's Cancer Aid Foundation; Slovenian Research AgencySlovenian Research Agency - Slovenia [P3-0343]; Jonas S_oderquist Foundation; Scientific and Technological Research Council of TurkeyTurkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [217S847, 318S202]; Deutsche Forschungsgemeinschaft under Germany's Excellence StrategyGerman Research Foundation (DFG) [390939984, 39087428]; E-Rare program of the European Union by the Deutsche ForschungsgemeinschaftGerman Research Foundation (DFG) [GR1617/14-1/iPAD]; Netzwerke Seltener Erkrankungen of the German Ministry of Education and Research [GAIN_ 01GM1910A]; Finnish Foundation for Pediatric Research and Pediatric Research Center, HUS Helsinki University Hospital; Graduate Research Training Scholarship of the Australian government; Hadassah Australia; ERN-RITA network [739543], M.G. Seidel and the Research Unit for Pediatric Hematology and Immunology are supported in part by the Styrian Children's Cancer Aid Foundation. M. Avbeli Stefanija was supported by the Slovenian Research Agency (grant P3-0343). H. Abolhassani was supported by the Jonas S_oderquist Foundation. S. Baris was supported by the Scientific and Technological Research Council of Turkey for the diagnosis of patients with LRBA deficiency (grants 217S847 and 318S202). B. Grimbacher receives support through the Deutsche Forschungsgemeinschaft under Germany's Excellence Strategy (CIBSS-EXC-2189-Project ID 390939984 and RESIST-EXC 2155-Project ID 39087428); through the E-Rare program of the European Union, managed by the Deutsche Forschungsgemeinschaft (grant GR1617/14-1/iPAD); and through the Netzwerke Seltener Erkrankungen of the German Ministry of Education and Research (grant GAIN_ 01GM1910A). M.R.J. Sepp_anen was supported by the Finnish Foundation for Pediatric Research and Pediatric Research Center, HUS Helsinki University Hospital. I. Meyts is a member of the ERN-RITA network (project identification number 739543). B. Shadur is supported by a Graduate Research Training Scholarship of the Australian government and by Hadassah Australia.

Background There are no data regarding the prevalence of malignancies in patients with primary immunodeficiency (PID) in Turkey. Along with the prevalence of malignancy, we aimed to present the types of malignancy and define the underlying immune deficiency of the patients. Method Between the years 1992 and 2018, from five tertiary immunology clinics, fifty-nine patients with PID who developed malignancy were included. All patients were evaluated for demographics, clinical features, and prognosis. Results The prevalence of malignancy in our cohort was detected as 0.9% (59/6392). The male-to-female ratio was 1.8 (38/21), and the median age of patients was 14 years (range: 1.5-51). The median age at diagnosis of malignancy was 10 years (range: 1.5-51). Ataxia-telangiectasia was the most frequent PID in patients with malignancy (n = 19, 32.2%), and non-Hodgkin lymphoma was the most common malignancy (n = 32, 51.6%). The rate of malignancy in DOCK8 deficiency (n = 7/43, 16.3%) was higher than AT (n = 19/193, 9.8%), Wiskott-Aldrich syndrome (n = 2/22, 9.1%), and common variable immunodeficiency (n = 11/205, 5.4%). EBV quantitative PCR was positive in 16 out of 53 patients (30.2%). Three patients had secondary malignancies. Remission was achieved in 26 patients (44.1%). However, 31 patients (52.5%) died. Two patients (3.4%) are still on chemotherapy. Conclusion This study is the largest cohort investigating the association of malignancy in patients with PID in Turkey. While lymphoid malignancies were the most common malignancy and observed more frequently in AT patients, the risk for malignancy was higher in patients with DOCK8 deficiency compared to AT.

kiykim, ayca/0000-0001-5821-3963; Baris, Safa/0000-0002-4730-9422; AGREBI, Nourhen/0000-0001-5703-9668; Ayaz, Nuray Aktay/0000-0003-3594-7387; Cekic, Sukru/0000-0002-9574-1842; Karaca, Neslihan/0000-0002-2202-7082; Kara, Emine Manolya/0000-0001-6234-7024; /0000-0002-9065-1901; Lo, Bernice/0000-0002-1087-6845, WOS: 000495746100038, PubMed: 31238161, BACKGROUND: LPS-responsive beige-like anchor (LRBA) deficiency presents with susceptibility to infections, autoimmunity, and lymphoproliferation. the long-term efficacy of cytotoxic T-lymphocyte-associated antigen 4-immunoglobulin (abatacept) as targeted therapy for its immune dysregulatory features remains to be established. OBJECTIVE: To determine the clinical and immunologic features of LRBA deficiency and long-term efficacy of abatacept treatment in controlling the different disease manifestations. METHODS: Twenty-two LRBA-deficient patients were recruited from different immunology centers and followed prospectively. Eighteen patients on abatacept were evaluated every 3 months for long-term clinical and immunologic responses. LRBA expression, lymphocyte subpopulations, and circulating T follicular helper cells were determined by flow cytometry. RESULTS: the mean age of the patients was 13.4 +/- 7.9 years, and the follow-up period was 3.4 +/- 2.3 years. Recurrent infections (n = 19 [86.4%]), immune dysregulation (n = 18 [81.8%]), and lymphoproliferation (n = 16 [72.7%]) were common clinical features. the long-term benefits of abatacept in 16 patients were demonstrated by complete control of lymphoproliferation and chronic diarrhea followed by immune dysregulation, most notably autoimmune cytopenias. Weekly or every other week administration of abatacept gave better disease control compared with every 4 weeks. There were no serious side effects related to the abatacept therapy. Circulating T follicular helper cell frequencies were found to be a reliable biomarker of disease activity, which decreased on abatacept therapy in most subjects. However, high circulating T follicular helper cell frequencies persisted in 2 patients who had a more severe disease phenotype that was relatively resistant to abatacept therapy. CONCLUSIONS: Long-term abatacept therapy is effective in most patients with LRBA deficiency. (C) 2019 American Academy of Allergy, Asthma & Immunology, Scientific and Technological Research Council of TurkeyTurkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [217S847]; National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [5R01AI085090]; NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASESUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Allergy & Infectious Diseases (NIAID) [R01AI085090, R01AI085090, R01AI065617, R01AI065617, R01AI085090, R01AI085090, R01AI065617, R01AI065617] Funding Source: NIH RePORTER, This work was supported by grants from the Scientific and Technological Research Council of Turkey (grant no. 217S847 to S.B.) and the National Institutes of Health (grant no. 5R01AI085090 to T.A.C.).

WOS: 000394086700001, PubMed ID: 28168067, Chronic granulomatous disease (CGD) is a primary immune deficiency causing predisposition to infections with specific microorganisms, Aspergillus species and Staphylococcus aureus being the most common ones. A 16-year-old boy with a mutation in CYBB gene coding gp91 phox protein (X-linked disease) developed a liver abscess due to Staphylococcus aureus. In addition to medical therapy, surgical treatment was necessary for the management of the disease. A 30-month-old girl with an autosomal recessive form of chronic granulomatous disease (CYBA genemutation affecting p22(phox) protein) had invasive aspergillosis causing pericarditis, pulmonary abscess, and central nervous system involvement. The devastating course of disease regardless of the mutation emphasizes the importance of early diagnosis and intervention of hematopoietic stem cell transplantation as soon as possible in children with CGD.

WOS: 000406926000003, Aim: Severe congenital neutropenia is a rare immunodeficiency disease characterized by lack of mature neutrophils. We evaluated the association between the molecular, clinical and laboratory findings together with genotype-phenotype relationship in 10 patients with neutropenia. Materials and Methods: The clinical and laboratory findings of ten patients with severe congenital neutropenia were obtained and the diagnosis was confirmed by mutation analysis. Results: The mutation analysis by DNA sequencing revealed HAX-1 mutation in 3 patients from the same family and ELANE/ELA-2 mutation in 1 patient. We compared the patients who had normalization in neutrophil counts and clinical findings spontaneously by age with the patients with HAX1 and ELANE/ELA2 defects and observed that patients with known genetic defects had higher monocyte and immunoglobulin levels on admission. Conclusion: The risk of persistence of neutropenia and the chance to reach a genetic diagnosis is higher in neutropenic patients who have accompanying eosinophilia, monocytosis and hypergammaglobulinemia at the time of initial investigation.

Incidence of inflammatroy bowel disease (IBD) is growing among adults and children all over the world. Approximately 20% of patients with IBD are diagnosed before the age of 16 years

Hepatic abscess is a well-known complication in chronic granulomatous disease (CGD), occuring in approximately 40–50% of patients

Karaca N, Azarsiz E, Akarcan SE, Aksu G, Kutukculer N. Thymic output changes in children with clinical findings signaling a probable primary immunodeficiency. Turk J Pediatr 2019; 61: 885-894. Thymic maturation evaluation is inevitable for patients with clinical and laboratory findings for a primary immunodeficiency, as the T cellimmunodeficiencies are the most severe type. In this study, we aimed to show the usage of T cell surface molecule `CD31` for the evaluation of thymic output in patients (n: 66) with a large spectrum of findings signing a probable primary immunodeficiency. Besides the classical clinical and laboratory approach for these patients, T cell subpopulations as naive, memory, recent thymic emigrant cells were also investigated. The humoral immunodeficiency (34.8%), combined immunodeficiency (34.8%) and cardiopathy (7.6%) were the most frequent diagnosis groups. CD4+CD45RA+ naive T-cells percentages (p: 0.011) and absolute counts (p: 0.004) and absolute CD4+CD45RA+CD31+ RTE (recent thymic emigrant) cell counts (p: 0.007) were significantly lower in combined immunodeficiency group. Naive T-cells (p: 0.037) and RTE cells (p: 0.032) were also lower in patients who had cardiac surgery in the past. In conclusion, flow cytometric CD31+thymic naive RTE cell evaluation may provide rapid clinical information especially on T-cell immune dysfunction and CD4+CD45RA+CD31+ RTE cells may be used as an alternative to TRECs in the diagnosis of combined immunodeficiencies.

Staphylococcus aureus, Burkholderia cepacia, Serratia marcescens, Nocardia spp., and Aspergillus spp. are the most common organisms which cause infections in chronic granulomatous disease (CGD) patients

2-s2.0-85033440113, Anti-beta-2-glycoprotein I antibodies (anti-?2GPI) which are the main antiphospholipid antibodies that characterize the autoimmune “antiphospholipid syndrome” are pathogenic and are contributing to thrombosis. We aimed to evaluate the presence and the diagnostic importance of these antibodies in children with different rheumatologic diseases with or without thrombosis risk. A total of 100 children with different rheumatologic diseases evaluated retrospectively. The mean anti-?2GPI IgG (p = 0.108), IgA (p = 0.547), and IgM (p = 0.807) levels showed no statistically significant difference between different diagnosis groups. But anti-?2GPI IgA and IgM levels were higher in SLE patient group. The mean anti-?2GPI IgG (p = 0.375), IgA (p = 0.811), and IgM (p = 0.276) levels were not also showed difference between disease groups with/without predisposition to thrombosis even though concentrations were higher in thrombosis group. In children with rheumatological complaints, anti-?2GPI antibody measurements should not be the first diagnostic criteria if vasculitis is not thought as the primary defect underlying the clinical symptoms. © 2017, Association of Clinical Biochemists of India.

Purine nucleoside phosphorylase deficiency is one of the severe combined immunodeficiencies, which often clinically manifests with recurrent infections, neurologic symptoms and autoimmune diseases, and leads to thymocyte development and peripheral T cell activation defects. It is an immunologic emergency for childhood. In this case series, four cases with purine nucleoside phosphorylase deficiency were evaluated. Recurrent febrile infections and neuromotor developmental retardation were among the presenting symptoms in all cases. Absolute lymphocyte counts and serum uric acid levels were very low, and serum immunoglobulin levels were normal or slightly lower in all cases. The genetic molecular analysis of four patients revealed three predefined mutations in the purine nucleoside phosphorylase gene. Three of the four patients were lost due to sepsis during follow-up, and one patient was lost due to veno-occlusive disease in the post-hematopoietic stem cell transplantation period. We presented these cases to emphasize that purine nucleoside phosphorylase deficiency should always be considered in patients with frequent recurrent infections, neurologic findings, low serum uric acid levels, and lymphopenia.

Mycobacterial infections, particularly with low-virulence mycobacteria, may point toward a defect in the type 1 cytokine pathway or the IL-12:IFN-γ loop Patients with NEMO defect may present without ectodermal dysplasia NEMO mutations should be considered in all males with disseminated mycobacterial infection High ferritin levels, which is a marker of systemic inflammation, may accompany active mycobacterial disease

Introduction. LPS-responsive beige-like anchor (LRBA) protein deficiency is a disease of immune dysregulation with autoimmunity affecting various systems. Case Presentation. Two male siblings with a novel LRBA mutation had different primary findings at admission: the younger sibling had chronic early-onset diarrhoea and the elder one had autoimmune haemolytic anaemia. During long-term follow-up for IPEX phenotype, both developed hypogammaglobulinaemia, enteropathy and lung involvement. The patients partially responded to immunosuppressive therapies. A homozygous c.2496C>A, p.Cys832Ter (p.C832*) mutation in the LRBA gene causing a premature stop codon was detected. After molecular diagnosis, abatacept, as a target-specific molecule, was used with promising results. Conclusion. LRBA deficiency is a recently defined defect, with variable presentations in different patients; a single, definitive treatment option is thus not yet available.

WOS: 000448707400001, PubMed ID: 30405923, When caring for patients with life-limiting diseases, improving survival and optimizing quality of life are the primary goals. For patients with X-linked hyper-IgM syndrome (XHIGM), the treatment modality has to be decided for a particular patient regarding hematopoietic stem cell transplantation or intravenous immunoglobulin replacement therapy with P jiroveci prophylaxis. A seven-year-old male patient was admitted with recurrent upper and lower respiratory tract infections and recurrent otitis media. His initial immunologic evaluation revealed low IgG and normal IgA and IgM levels with normal lymphocyte phenotyping and inadequate specific antibody responses. He was diagnosed as common variable immunodeficiency and began to receive intravenous immunoglobulin (WIG) (0.5 gm/kg) with four-week intervals. During follow-up for 23 years under IVIG therapy, he was extremely well and never had severe infections. In 2017, targeted next generation sequencing was performed in order to understand his molecular pathology. A previously described hemizygous c.31C>T(p.ArgllTer) mutation was found in CD4OLG gene. The mother was heterozygous carrier for this mutation and his sister did not have any mutation. Flow cytometric analysis for CD40LG expression on activated T cells showed highly decreased, but not absent, CD40LG expression. In conclusion, diagnostic delay is a clinical problem for patients with CD40LG deficiency, because of low or normal IgM levels, showing that all the hypogammaglobulinemic patients, not only with high serum IgM levels, but also with normal to low IgM levels, have to be examined for CD40LG expression on activated T lymphocytes. Secondly, type of CD40LG mutations leads to enormous interpatient variations regarding serwn IgM levels, CD40LG levels on activated 'F cells, age at diagnosis, severity of clinical findings, and follow-up therapies with or without hematopoietic stem cell therapy.

WOS: 000438116300013, PubMed ID: 29978731, Common variable immunodeficiency (CVID) and immunoglobulin A deficiency (IgAD) are the most prevalent primary immunodeficiency disorders. High rates of familial inheritance have been described in CVID and IgAD, but it is unknown in different ethnic populations. We aimed to determine the prevalence of familial cases and whether they showed more severe clinical characteristics than sporadic ones in Turkish patients. A total of 40 CVID and 70 IgAD patients and their 251 first-degree relatives (FDRs) were evaluated. Demographic, clinical, and laboratory data were reviewed. A familial case was defined as a patient with at least one affected FDR (A-FDR). The rate of parental consanguinity was 19.1%. There were 37 familial cases (37/110) (33.6%) with at least one A-FDR. There were 48 A-FDRs who had immunoglobulins lower than age-related normals (48/251) (19.1%). Pulmonary infections were significantly higher in familial cases. To our knowledge, this study includes the highest number of CVID/IgAD patients and their FDRs in literature. Familial cases are at least 30% of the IgAD and CVID patients, and they have more frequent lower respiratory tract infections than sporadic ones, so these patients have to be evaluated depending on their being familial or sporadic for better management. The risk of carrying any immunologic alterations in relatives of patients with IgAD and CVID is approximately 20%. Although most A-FDRs are asymptomatic, considering the risk of progression to CVID by age, we highly recommend routine screening for FDRs.

Background: Severe combined immunodeficiency (SCID) syndromes are a heterogenous group of diseases characterized by impairment in both cellular and humoral immunity with a range of genetic disorders. Complete recombinase activating gene (RAG) deficiency is associated with classical T - B - NK + SCID which is the most common phenotype of Turkish SCID patients. There is a broad spectrum of hypomorfic RAG mutations including Omenn syndrome, leaky or atypical SCID with expansion of γδ T cells, autoimmunity and cytomegalovirus (CMV) infections. Methods: Twenty-one (44%) patients had RAG1 deficiency of all 44 SCID patients followed up by pediatric immunology department. A retrospective analysis was conducted on the medical records of all SCID patients with RAG1 deficiency. Results: Eight patients were classified as T - B - NK + SCID, five patients as T + B - NK + SCID (three of these were Omenn phenotype), and eight patients as T + B + NK + SCID phenotype. Mean age of the whole study group, mean age at onset of symptoms and mean age at diagnosis were 87.7 ± 73.8 (12 - 256), 4.4 ± 8.2 (1 - 36) and 29.1 ± 56.8 (1 - 244) months, respectively. Consanguinity was present in 11 (52%) of 21 patients. Autoimmunity was found in six patients (28%). Ten patients (47%) had CMV infection, four (19%) had Epstein-Barr virus (EBV) infections and three (14%) had Bacillus Calmette-Guerin (BCG) infections. Seven patients who had refractory cytopenia (two pancytopenia and five bicytopenia) underwent bone marrow biopsy, three of whom had bone marrow fibrosis. Future evaluations must be considered about bone marrow fibrosis in RAG1 deficiency patients. Eosinophilia was observed in 10 patients, seven of whom did not have Omenn phenotype. Conclusion: Non-Omenn phenotype RAG1 deficiencies can also present with eosinophilia. This report is presented to emphasize that RAG1 mutations may lead to diverse clinical phenotypes. J Clin Med Res. 2016;8(5):379-384 doi: http://dx.doi.org/10.14740/jocmr2316w

WOS: 000350167200008, PubMed ID: 25703555, Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb) and a few related mycobacteria, is a devastating disease, killing more than a million individuals per year worldwide. However, its pathogenesis remains largely elusive, as only a small proportion of infected individuals develop clinical disease either during primary infection or during reactivation from latency or secondary infection. Subacute, hematogenous, and extrapulmonary disease tends to be more frequent in infants, children, and teenagers than in adults. Life-threatening primary TB of childhood can result from known acquired or inherited immunodeficiencies, although the vast majority of cases remain unexplained. We review here the conditions conferring a predisposition to childhood clinical diseases caused by mycobacteria, including not only M.tb but also weakly virulent mycobacteria, such as BCG vaccines and environmental mycobacteria. Infections with weakly virulent mycobacteria are much rarer than TB, but the inherited and acquired immunodeficiencies underlying these infections are much better known. Their study has also provided genetic and immunological insights into childhood TB, as illustrated by the discovery of single-gene inborn errors of IFN- immunity underlying severe cases of TB. Novel findings are expected from ongoing and future human genetic studies of childhood TB in countries that combine a high proportion of consanguineous marriages, a high incidence of TB, and an excellent clinical care, such as Iran, Morocco, and Turkey., European Research CouncilEuropean Research Council (ERC) [ERC-2010-AdG-268777]; French National Research Agency (ANR)French National Research Agency (ANR) [ANR-10-IAHU-01, ANR-08-MIEN-014-02]; Institut National de la Sante et de la Recherche Medicale, Universite Paris DescartesInstitut National de la Sante et de la Recherche Medicale (Inserm); St. Giles Foundation; Rockefeller University from the National Center for Research Resources [8ULTR000043]; National Center for Advancing Sciences (NCATS) of the National Institute of Health; Rockefeller University; National Institute of Allergy and Infectious DiseasesUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Allergy & Infectious Diseases (NIAID) [U01AI088685, R01AI089970, R37AI095983], We thank all clinicians from many countries around the world for their help and contribution in the investigation of TB patients. Special thanks to A. Strickler and J. F. Emile for providing the pictures. We also thank all members of the Necker and Rockefeller branches of the Laboratory of Human Genetics of Infectious Diseases. This work was supported by grants from the European Research Council (ERC-2010-AdG-268777), the French National Research Agency (ANR) under "the Investments for the Future" grant number ANR-10-IAHU-01, ANR-08-MIEN-014-02, Institut National de la Sante et de la Recherche Medicale, Universite Paris Descartes, the St. Giles Foundation, the Rockefeller University grant number 8ULTR000043 from the National Center for Research Resources and the National Center for Advancing Sciences (NCATS) of the National Institute of Health, the Rockefeller University, the National Institute of Allergy and Infectious Diseases grant number U01AI088685, R01AI089970, and R37AI095983. The authors have no financial or commercial conflict of interest to declare.

PubMed ID: 30155784, [No abstract available]

"Çalışmada 57 yazar bulunmaktadır. Bu yazarlardan sadece Bursa Uludağ Üniversitesi mensuplarının girişleri yapılmıştır.” Background: In contrast to adult-onset inflammatory bowel disease (IBD), where many genetic loci have been shown to be involved in complex disease etiology, early-onset IBD (eoIBD) and associated syndromes can sometimes present as monogenic conditions. As a result, the clinical phenotype and ideal disease management in these patients often differ from those in adult-onset IBD. However, due to high costs and the complexity of data analysis, high-throughput screening for genetic causes has not yet become a standard part of the diagnostic work-up of eoIBD patients. Methods: We selected 28 genes of interest associated with monogenic IBD and performed targeted panel sequencing in 71 patients diagnosed with eoIBD or early-onset chronic diarrhea to detect causative variants. We compared these results to whole-exome sequencing (WES) data available for 25 of these patients. Results: Target coverage was significantly higher in the targeted gene panel approach compared with WES, whereas the cost of the panel was considerably lower (approximately 25% of WES). Disease-causing variants affecting protein function were identified in 5 patients (7%), located in genes of the IL10 signaling pathway (3), WAS (1), and DKC1 (1). The functional effects of 8 candidate variants in 5 additional patients (7%) are under further investigation. WES did not identify additional causative mutations in 25 patients. Conclusions: Targeted gene panel sequencing is a fast and effective screening method for monogenic causes of eoIBD that should be routinely established in national referral centers. Federal Ministry of Education & Research (BMBF) - IFB/CCI: 01EO1303 - E:med/SysInflame: 012X1306F - DZIF: 8000805-3 German Research Foundation (DFG) - FR 2821/6-1

BACKGROUND Primary immunodeficiency disorder (PID), being a chronic disorder, may increase the prevalence of psychopathologies, but there are few studies on the effect of disease-related factors on psychopathology in this population. The aim of this study was therefore to assess and compare three groups: children with PID who receive i.v. immunoglobulin treatment; children with juvenile idiopathic arthritis (JIA); and healthy controls with respect to their mental health status. METHODS Forty-four children with PID, 32 children with JIA and 30 healthy controls, underwent psychiatric evaluation. The Childhood Depression Inventory and the screen for child anxiety-related emotional disorders questionnaire were completed by the participants. The child behavior checklist was completed by the mothers of the participants. In addition, disease-related factors were identified. RESULTS The frequency of mood disorders between the three groups differed. There was no difference between the PID and JIA groups with respect to the prevalence of mood disorders and other psychopathologies. The disease-related factors were associated with the frequency of mood disorder in PID patients. CONCLUSION The rate of psychopathology was similar in patients with PID and JIA and higher than the controls. Some of the disease-related factors were associated with the frequency of mood disorders in the PID patients.

Ataxia-telangiectasia (AT) is a rare multisystem, neurodegenerative genetic disorder that is characterised by progressive neurological abnormalities, oculocutaneous telangiectasias and immunodeficiency. Delay in diagnosis or misdiagnosis is probable due to its wide clinical heterogeneity in infancy. Recurrent sinopulmonary infections are often the only presenting symptom and usually patients have decreased immunoglobulins. A total 10% of patients who present with decreased serum immunoglobulin G and A and with normal or elevated immunoglobulin M levels are often misdiagnosed as hyperimmunoglobulin M syndrome. Definitive diagnosis is made if a patient with progressive cerebellar ataxia has a disease causing mutation on the ATM gene. Ataxia-telangiectasia guideline of the European Society for Immunodeficiencies defines the probable diagnosis criteria. We evaluated twenty ataxia-telangiectasia patients (mean age 13.8±4.1 years) retrospectively who were followed-up for a mean of 38.6±27.0 months. Twelve patients had a family history of consanguinity. A total of 80% patients suffered from various infections. Neoplasms occurred in three of them. Patients showed immunological abnormalities as low IgG (45%), low IgA (65%) and elevated IgM (60%) levels. CD3+CD4+ T lymphocyte frequency was low in 45% patients. The mean AFP concentration at the diagnosis was 191.9±140.1 ng/ mL and the raised IgM values did not show any statistically significant relationship with high AFP concentrations. Frequency of the elevated IgM concentrations in (60%) patients raises the concerns about thinking this finding has to be accepted as a probable diagnosis criterium.

Susceptibility to mycobacterial diseases is observed in some primary immunodeficiency diseases. In this study, we aimed to evaluate mycobacterial infections in primary immunodeficiency diseases.Patients under follow-up by Ege University Pediatric Immunology Department for severe combined and combined immunodeficiencies, interleukin 12/ interferon gamma receptor deficiency, nuclear factor kappa-beta essential modulator deficiency and chronic granulomatosis disease were evaluated retrospectively in terms of the frequency and characteristics of mycobacterial infections using a questionnaire form for demographic properties, clinical features and laboratory tests.A diagnosis of mycobacterial infection was made clinically in a total of 25 patients including five (11.3%) of 45 patients who had severe combined immune deficiency, 12 (52.3%) of 21 patients who had chronic granulomatous disease, four patients (100%) who had interferon gamma receptor 2 partical deficiency, two patients (100%) who had interleukin 12 receptor beta 1 deficiency and one patient (100%) who had nuclear factor kapa-beta essential modulator deficiency. Mycobacterium strain could be typed in 14 (33%) of these 25 patients includingNon-tuberculosis mycobacteria including mainly

WOS: 000413141200005, PubMed ID: 29062247, Aim: Susceptibility to mycobacterial diseases is observed in some primary immunodeficiency diseases. In this study, we aimed to evaluate mycobacterial infections in primary immunodeficiency diseases. Material and Methods: Patients under follow-up by Ege University Pediatric Immunology Department for severe combined and combined immunodeficiencies, interleukin 12/interferon gamma receptor deficiency, nuclear factor kappa-beta essential modulator deficiency and chronic granulomatosis disease were evaluated retrospectively in terms of the frequency and characteristics of mycobacterial infections using a questionnaire form for demographic properties, clinical features and laboratory tests. Results: A diagnosis of mycobacterial infection was made clinically in a total of 25 patients including five (11.3%) of 45 patients who had severe combined immune deficiency, 12 (52.3%) of 21 patients who had chronic granulomatous disease, four patients (100%) who had interferon gamma receptor 2 partical deficiency, two patients (100%) who had interleukin 12 receptor beta 1 deficiency and one patient (100%) who had nuclear factor kapa-beta essential modulator deficiency. Mycobacterium strain could be typed in 14 (33%) of these 25 patients including Mycobacterium bovis, Mycobacterium chelonea, Mycobacterium elephantis, Mycobacterium fortuitum, and Mycobacterium tuberculosis. All patients were treated with anti-tuberculosis therapy. Thirty-six percent of these 25 patients underwent hematopoietic stem cell transplantation. Eight patients (five before, three after transplantation) died. Conclusions: Non-tuberculosis mycobacteria including mainly Mycobacterium bovis were observed with a higher rate compared to Mycobacterium tuberculosis in primary immunodeficiencies, especially in those affecting the interleukin 12/interferon gamma pathway. Early diagnosis of primary immunodeficiencies with neonatal screening program and preventing administration of the Bacille Calmette-Guerin vaccine in these patients is important.