Publications by authors named "Ayca Kiykim"

55 Publications

Primary antibody deficiencies in Turkey: molecular and clinical aspects.

Immunol Res 2021 Oct 7. Epub 2021 Oct 7.

Istanbul University Graduate School of Health Sciences, Istanbul, Turkey.

Primary antibody deficiencies (PAD) are the most common subtype of primary immunodeficiencies, characterized by increased susceptibility to infections and autoimmunity, allergy, or malignancy predisposition. PAD syndromes comprise of immune system genes highlighted the key role of B cell activation, proliferation, migration, somatic hypermutation, or isotype switching have a wide spectrum from agammaglobulinemia to selective Ig deficiency. In this study, we describe the molecular and the clinical aspects of fifty-two PAD patients. The most common symptoms of our cohort were upper and lower respiratory infections, bronchiectasis, diarrhea, and recurrent fever. Almost all patients (98%) had at least one of the symptoms like autoimmunity, lymphoproliferation, allergy, or gastrointestinal disease. A custom-made next-generation sequencing (NGS) panel, which contains 24 genes, was designed to identify well-known disease-causing variants in our cohort. We identified eight variants (15.4%) among 52 PAD patients. The variants mapped to BTK (n = 4), CD40L (n = 1), ICOS (n = 1), IGHM (n = 1), and TCF3 (n = 1) genes. Three novel variants were described in the BTK (p.G414W), ICOS (p.G60*), and IGHM (p.S19*) genes. We performed Sanger sequencing to validate pathogenic variants and check for allelic segregation in the family. Targeted NGS panel sequencing can be beneficial as a suitable diagnostic modality for diagnosing well-known monogenic PAD diseases (only 2-10% of PADs); however, screening only the coding regions of the genome may not be adequately powered to solve the pathogenesis of PAD in all cases. Deciphering the regulatory regions of the genome and better understanding the epigenetic modifications will elucidate the molecular basis of complex PADs.
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http://dx.doi.org/10.1007/s12026-021-09242-zDOI Listing
October 2021

Functions of NK and iNKT cells in pediatric and adult CVID, ataxia telangiectasia and agammaglobulinemia patients.

Immunol Lett 2021 Sep 30;240:46-55. Epub 2021 Sep 30.

Department of Immunology, Aziz Sancar Institute of Experimental Medicine (Aziz Sancar DETAE), Istanbul University, Istanbul, Turkey. Electronic address:

Primary immune deficiencies (PID) are known to be more than 400 genetic defects caused by the impairment in development and/or functions of the immune system. Common Variable Immunodeficiency (CVID), Ataxia Telangiectasia (AT) and Agammaglobulinemia (AG) are examples of the most common immunodeficiency syndrome. Natural killer (NK) cells are a component of innate immune system and play a major role in the host-rejection of both tumors and virally infected cells. iNKT cells have a role in autoimmune and infectious diseases and controlling of tumor rejection. In this study, NK and iNKT cells and their functions, and intracellular cytokine amount are aimed to determine in patients that suffer CVID, AT and AG. NKp30, NKp46, NKG2D, perforin and granzyme mRNA expression levels were analyzed using RT-PCR. Receptors, cytokine amount of NK cell subset and iNKT were analyzed by flow cytometry. Decreased CD3 T and elevated NK cell subset in pediatric AT were found. Expression of NKp44 was decreased in adult AG, but not in pediatric patients. Low NKp44 expression in CD3CD16CD56 NK cell subset was found in pediatric AT patients. High HLA-DR, perforin and granzyme expression were found in CD3CD16CD56 NK cell subset of pediatric CVID and AT patients. Alteration of the number of NK subsets, NK receptor expression and cytokine production were observed in pediatric patients compared to healthy subjects.
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http://dx.doi.org/10.1016/j.imlet.2021.09.008DOI Listing
September 2021

Food-induced anaphylaxis in early childhood and factors associated with its severity.

Allergy Asthma Proc 2021 Sep;42(5):e135-e144

Pediatric Allergy and Immunology Department, Faculty of Medicine, Sakarya University, Sakarya, Turkey.

Several factors that increase the risk of severe food-induced anaphylaxis have been identified. We aimed to determine the demographic, etiologic, and clinical features of food-induced anaphylaxis in early childhood and also any other factors associated with severe anaphylaxis. We carried out a medical chart review of anaphylaxis cases from 16 pediatric allergy and immunology centers in Turkey. The data of 227 patients with 266 food-induced anaphylaxis episodes were included in the study. The median (interquartile range) age of the first anaphylaxis episode was 9 months (6-18 months); 160 of these patients were boys (70.5%). The anaphylaxis episodes were mild in 75 cases (28.2%), moderate in 154 cases (57.9%), and severe in 37 cases (13.9%). The most frequent food allergens involved were cow's milk (47.4%), nuts (16.7%), and hen's egg (15.8%). Epinephrine was administered in only 98 (36.8%) of these anaphylaxis episodes. A logistic regression analysis revealed two statistically significant factors that were independently associated with severe anaphylaxis: the presence of angioedema and hoarseness during the anaphylactic episode. Urticaria was observed less frequently in patients who developed hypotension. In addition, confusion and syncope were associated with 25.9- and 44.6-fold increases, respectively, in the risk of concomitant hypotension. Cow's milk, nuts, and hen's egg caused the majority of mild and moderate-to-severe anaphylaxis episodes. The presence of angioedema and hoarseness in any patient who presents with a history of food-induced anaphylaxis should alert clinicians that the reaction may be severe. In addition, the presence of confusion, syncope, or stridor probably indicates concomitant hypotension.
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http://dx.doi.org/10.2500/aap.2021.42.210051DOI Listing
September 2021

Adverse COVID-19 outcomes in immune deficiencies: Inequality exists between subclasses.

Allergy 2021 Jul 27. Epub 2021 Jul 27.

Faculty of Medicine, Division of Pediatric Allergy-Immunology, Marmara University, Istanbul, Turkey.

Background: Genetic deficiencies of immune system, referred to as inborn errors of immunity (IEI), serve as a valuable model to study human immune responses. In a multicenter prospective cohort, we evaluated the outcome of SARS-CoV-2 infection among IEI subjects and analyzed genetic and immune characteristics that determine adverse COVID-19 outcomes.

Methods: We studied 34 IEI patients (19M/15F, 12 [min: 0.6-max: 43] years) from six centers. We diagnosed COVID-19 infection by finding a positive SARS-CoV-2 PCR test (n = 25) and/or a lung tomography scoring (CORADS) ≥4 (n = 9). We recorded clinical and laboratory findings prospectively, fitted survival curves, and calculated fatality rates for the entire group and each IEI subclass.

Results: Nineteen patients had combined immune deficiency (CID), six with predominantly antibody deficiency (PAD), six immune dysregulation (ID), two innate immune defects, and one in the autoinflammatory class. Overall, 23.5% of cases died, with disproportionate fatality rates among different IEI categories. PAD group had a relatively favorable outcome at any age, but CIDs and IDs were particularly vulnerable. At admission, presence of dyspnea was an independent risk for COVID-related death (OR: 2.630, 95% CI; 1.198-5.776, p < .001). Concerning predictive roles of laboratory markers at admission, deceased subjects compared to survived had significantly higher CRP, procalcitonin, Troponin-T, ferritin, and total-lung-score (p = .020, p = .003, p = .014, p = .013, p = .020; respectively), and lower absolute lymphocyte count, albumin, and trough IgG (p = .012, p = .022, p = .011; respectively).

Conclusion: Our data disclose a highly vulnerable IEI subgroup particularly disadvantaged for COVID-19 despite their youth. Future studies should address this vulnerability and consider giving priority to these subjects in SARS-Cov-2 therapy trials.
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http://dx.doi.org/10.1111/all.15025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8441734PMC
July 2021

Evolution and long-term outcomes of combined immunodeficiency due to CARMIL2 deficiency.

Allergy 2021 Jul 20. Epub 2021 Jul 20.

Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.

Background: Biallelic loss-of-function mutations in CARMIL2 cause combined immunodeficiency associated with dermatitis, inflammatory bowel disease (IBD), and EBV-related smooth muscle tumors. Clinical and immunological characterizations of the disease with long-term follow-up and treatment options have not been previously reported in large cohorts. We sought to determine the clinical and immunological features of CARMIL2 deficiency and long-term efficacy of treatment in controlling different disease manifestations.

Methods: The presenting phenotypes, long-term outcomes, and treatment responses were evaluated prospectively in 15 CARMIL2-deficient patients, including 13 novel cases. Lymphocyte subpopulations, protein expression, regulatory T (Treg), and circulating T follicular helper (cT ) cells were analyzed. Three-dimensional (3D) migration assay was performed to determine T-cell shape.

Results: Mean age at disease onset was 38 ± 23 months. Main clinical features were skin manifestations (n = 14, 93%), failure to thrive (n = 10, 67%), recurrent infections (n = 10, 67%), allergic symptoms (n = 8, 53%), chronic diarrhea (n = 4, 27%), and EBV-related leiomyoma (n = 2, 13%). Skin manifestations ranged from atopic and seborrheic dermatitis to psoriasiform rash. Patients had reduced proportions of memory CD4 T cells, Treg, and cT cells. Memory B and NK cells were also decreased. CARMIL2-deficient T cells exhibited reduced T-cell proliferation and cytokine production following CD28 co-stimulation and normal morphology when migrating in a high-density 3D collagen gel matrix. IBD was the most severe clinical manifestation, leading to growth retardation, requiring multiple interventional treatments. All patients were alive with a median follow-up of 10.8 years (range: 3-17 years).

Conclusion: This cohort provides clinical and immunological features and long-term follow-up of different manifestations of CARMIL2 deficiency.
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http://dx.doi.org/10.1111/all.15010DOI Listing
July 2021

Impaired respiratory burst contributes to infections in PKCδ-deficient patients.

J Exp Med 2021 Sep 15;218(9). Epub 2021 Jul 15.

Department of Pediatrics, Division of Allergy and Clinical Immunology, Tehran University of Medical Sciences, Tehran, Iran.

Patients with autosomal recessive protein kinase C δ (PKCδ) deficiency suffer from childhood-onset autoimmunity, including systemic lupus erythematosus. They also suffer from recurrent infections that overlap with those seen in patients with chronic granulomatous disease (CGD), a disease caused by defects of the phagocyte NADPH oxidase and a lack of reactive oxygen species (ROS) production. We studied an international cohort of 17 PKCδ-deficient patients and found that their EBV-B cells and monocyte-derived phagocytes produced only small amounts of ROS and did not phosphorylate p40phox normally after PMA or opsonized Staphylococcus aureus stimulation. Moreover, the patients' circulating phagocytes displayed abnormally low levels of ROS production and markedly reduced neutrophil extracellular trap formation, altogether suggesting a role for PKCδ in activation of the NADPH oxidase complex. Our findings thus show that patients with PKCδ deficiency have impaired NADPH oxidase activity in various myeloid subsets, which may contribute to their CGD-like infectious phenotype.
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http://dx.doi.org/10.1084/jem.20210501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8288504PMC
September 2021

Therapeutic options for CTLA-4 insufficiency.

J Allergy Clin Immunol 2021 Jun 7. Epub 2021 Jun 7.

The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania.

Background: Heterozygous germline mutations in cytotoxic T lymphocyte-associated antigen-4 (CTLA4) impair the immunomodulatory function of regulatory T cells. Affected individuals are prone to life-threatening autoimmune and lymphoproliferative complications. A number of therapeutic options are currently being used with variable effectiveness.

Objective: Our aim was to characterize the responsiveness of patients with CTLA-4 insufficiency to specific therapies and provide recommendations for the diagnostic workup and therapy at an organ-specific level.

Methods: Clinical features, laboratory findings, and response to treatment were reviewed retrospectively in an international cohort of 173 carriers of CTLA4 mutation. Patients were followed between 2014 and 2020 for a total of 2624 months from diagnosis. Clinical manifestations were grouped on the basis of organ-specific involvement. Medication use and response were recorded and evaluated.

Results: Among the 173 CTLA4 mutation carriers, 123 (71%) had been treated for immune complications. Abatacept, rituximab, sirolimus, and corticosteroids ameliorated disease severity, especially in cases of cytopenias and lymphocytic organ infiltration of the gut, lungs, and central nervous system. Immunoglobulin replacement was effective in prevention of infection. Only 4 of 16 patients (25%) with cytopenia who underwent splenectomy had a sustained clinical response. Cure was achieved with stem cell transplantation in 13 of 18 patients (72%). As a result of the aforementioned methods, organ-specific treatment pathways were developed.

Conclusion: Systemic immunosuppressants and abatacept may provide partial control but require ongoing administration. Allogeneic hematopoietic stem cell transplantation offers a possible cure for patients with CTLA-4 insufficiency.
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http://dx.doi.org/10.1016/j.jaci.2021.04.039DOI Listing
June 2021

Primary immunodeficiencies: HSCT experiences of a single center in Turkey.

Pediatr Transplant 2021 Nov 6;25(7):e14063. Epub 2021 Jun 6.

Department of Pediatric Hematology-Oncology, Bahcelievler Medical Park Hospital, Altinbas University School of Medicine, Istanbul, Turkey.

Background: Primary immunodeficiency diseases (PID) are characterized by the occurrence of frequent infections and are caused by many genetic defects. Hematopoietic stem cell transplantation (HSCT) is the only curative treatment option for the majority of PID. As a Pediatric Hematology-Oncology-Immunology Transplantation Unit, we wanted to present our HSCT experience regarding treatment of primary immunodeficiency diseases.

Methods: 58 patients were included in the study between January 2014 and June 2019. We searched 9/10 or 10/10 matched-related donor (MRD) firstly, in the absence of fully matched-related donor. We screened matched unrelated donor (MUD) from donor banks. MRD was used in 24 (41.3%) patients, MUD in 20 (34.4%) patients, and haploidentical donors in 14 (24.1%) patients. Demographic data, HSCT characteristics, and outcome were evaluated. While 16 patients had severe combined immunodeficiency (SCID), the remaining was non-SCID.

Results: Of the 58 patients, 38 were male and 20 were female. Median age at transplantation was 12 months (range: 2.5-172 months). Combined immunodeficiencies consisted 67.2% of patients. Mean follow-up time was 27 months (6 months-5 years). Median neutrophil, lymphocyte, and thrombocyte engraftment days were similar in comparison of both donor type and stem cell source. The most common complication was acute GvHD in 15 (25.8%) patients. In total, five patients (31%) belonging to the SCID group and 10 patients (23.8%) belonging to the non-SCID group died. Our total mortality rate was 15 (25.8%) in all patients.

Conclusions: We would like to present our HSCT experiences as a pediatric immunology transplantation center. Existing severe infections before transplantation period, BCGitis, and CMV are important issues of transplantation in Turkey. However, the follow-up time is shorter than some studies, our results regarding complications and survival are similar to previous reports.
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http://dx.doi.org/10.1111/petr.14063DOI Listing
November 2021

Notch4 signaling limits regulatory T-cell-mediated tissue repair and promotes severe lung inflammation in viral infections.

Immunity 2021 06 28;54(6):1186-1199.e7. Epub 2021 Apr 28.

Department of Pediatrics, Harvard Medical School, Boston, MA, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, Massachusetts, USA.

A cardinal feature of COVID-19 is lung inflammation and respiratory failure. In a prospective multi-country cohort of COVID-19 patients, we found that increased Notch4 expression on circulating regulatory T (Treg) cells was associated with disease severity, predicted mortality, and declined upon recovery. Deletion of Notch4 in Treg cells or therapy with anti-Notch4 antibodies in conventional and humanized mice normalized the dysregulated innate immunity and rescued disease morbidity and mortality induced by a synthetic analog of viral RNA or by influenza H1N1 virus. Mechanistically, Notch4 suppressed the induction by interleukin-18 of amphiregulin, a cytokine necessary for tissue repair. Protection by Notch4 inhibition was recapitulated by therapy with Amphiregulin and, reciprocally, abrogated by its antagonism. Amphiregulin declined in COVID-19 subjects as a function of disease severity and Notch4 expression. Thus, Notch4 expression on Treg cells dynamically restrains amphiregulin-dependent tissue repair to promote severe lung inflammation, with therapeutic implications for COVID-19 and related infections.
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http://dx.doi.org/10.1016/j.immuni.2021.04.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080416PMC
June 2021

Reference values for T and B lymphocyte subpopulations in Turkish children and adults

Turk J Med Sci 2021 08 30;51(4):1814-1824. Epub 2021 Aug 30.

Department of Pediatric Allergy-Immunology, Faculty of Medicine, Marmara University, İstanbul, Turkey

Background/aim: Established reference values are critical for the interpretation of immunologic assessments. In particular, the proportion and absolute counts of T- and B- cell subpopulations are subject to change with age and ethnicity. We aimed to establish age- specific reference values for lymphocyte subsets using updated immunophenotyping panels.

Materials And Methods: We studied a total of 297 healthy Turkish subjects aged 0 to 50 years, stratified into major age brackets in a cluster factor of 10 per age-group. The predetermined age intervals contained randomly allocated participants enrolled over a period of 6 months, who were homogenously distributed by sex. We analyzed a complete blood count test and simultaneously with detailed immunophenotyping enumerated the percent and absolute cell counts of lymphocyte subsets.

Results: The percentage and absolute counts of lymphocyte subsets show a marked surge across the age-span. T helper, T cytotoxic, and the natural killer cell numbers were increasing from birth until 6 months, followed by a gradual decrease thereafter. B cell numbers were rising until 2 years, followed by a gradual decrease for the upcoming years, accompanied by a steady expansion of unclass-switched- and class-switched- B cells.

Conclusion: We provide updated extensive reference intervals for lymphocyte subpopulations in Turkish people.
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http://dx.doi.org/10.3906/sag-2010-176DOI Listing
August 2021

Proven Food-Induced Acute Urticaria and Predictive Factors for Definitive Diagnosis in Childhood.

Int Arch Allergy Immunol 2021 18;182(7):607-614. Epub 2021 Feb 18.

Pediatric Allergy and Immunology Department, Faculty of Medicine, Istanbul University, Istanbul, Turkey.

Background: Urticaria can be the only sign of a food allergy or can be seen together with other signs and symptoms of a food allergy.

Objective: To determine the demographic, etiologic, and clinical features of food-induced acute urticaria in childhood.

Methods: Patients suspected of food-induced acute urticaria were included in this prospective cross-sectional multicenter study.

Results: Two hundred twenty-nine urticaria cases were included in this study. Seventeen patients who did not meet the inclusion criteria of the study were excluded. Of the 212 included cases, 179 (84.4%) were diagnosed with definitive food-induced acute urticaria. The most common foods causing acute urticaria were cow's milk, hen's eggs, and nuts in 56.4, 35.2, and 19% of cases, respectively. The positive predictive value of a history of milk-induced acute urticaria together with a milk-specific IgE >5 kU/L for cow's milk-induced acute urticaria was 92% (95% CI: 81-96%). A history of cow's milk-induced and/or hen's egg-induced acute urticaria was consistent with a definitive diagnosis of food-induced urticaria (Chen's kappa: 0.664 and 0.627 for milk and eggs, respectively). Urticaria activity scores were higher in patients with food-induced acute urticaria (p = 0.002).

Conclusion: Cow's milk, hen's eggs, and nuts were the most common allergens in the etiology of childhood food-induced acute urticaria. Although the urticaria activity score provides guidance for diagnosis, an oral food challenge is often essential for the definitive diagnosis of a patient with a history of food-induced acute urticaria.
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http://dx.doi.org/10.1159/000513267DOI Listing
September 2021

Two patients with chronic mucocutaneous candidiasis caused by TRAF3IP2 deficiency.

J Allergy Clin Immunol 2021 07 22;148(1):256-261.e2. Epub 2021 Jan 22.

Molecular Development of the Immune System Section, Laboratory of Immune System Biology, and Clinical Genomics Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md. Electronic address:

Background: TRAF3 interacting protein 2 (TRAF3IP2) (Act1) is an adapter protein that interacts with IL-17R via its similar expression to fibroblast growth factor genes and IL-17R domain and coordinates 2 separate proinflammatory pathways following IL-17 cytokine stimulation.

Objective: We sought to elucidate the immunologic consequences of TRAF3IP2 homozygous mutations to improve treatments for immunodeficiency patients with chronic mucocutaneous candidiasis.

Methods: We describe 2 patients presenting with chronic mucocutaneous candidiasis who harbor biallelic nonsense mutations in TRAF3IP2. The cellular and molecular features of this genetic defect were assessed using in vitro cytokine assays and protein analysis.

Results: We show that the homozygous mutation causes complete loss of protein expression. We also show that the absence of TRAF3IP2 was associated with a defective response to combined IL-2/IL-25 (IL-17E) stimulation.

Conclusions: Failure to initiate normal signaling downstream of IL-17R engagement likely contributes to the patients' recurrent fungal infections. These findings add to our molecular understanding of genetic defects affecting this critical pathway of antifungal immunity.
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http://dx.doi.org/10.1016/j.jaci.2020.12.629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8273085PMC
July 2021

A set of clinical and laboratory markers differentiates hyper-IgE syndrome from severe atopic dermatitis.

Clin Immunol 2021 02 7;223:108645. Epub 2020 Dec 7.

Marmara University, Faculty of Medicine, Pediatric Allergy and Immunology, Istanbul, Turkey; Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey; The Isil Berat Barlan Center for Translational Medicine, Pediatric Allergy and Immunology, Istanbul, Turkey. Electronic address:

Hyper-IgE syndrome (HIES) patients may share many features observed in severe atopic dermatitis (SAD), making a diagnostic dilemma for physicians. Determining clinical and laboratory markers that distinguish both disorders could provide early diagnosis and treatment. We analyzed patients (DOCK8 deficiency:14, STAT3-HIES:10, SAD:10) with early-onset SAD. Recurrent upper respiratory tract infection and pneumonia were significantly frequent in HIES than SAD patients. Characteristic facial appearance, retained primary teeth, skin abscess, newborn rash, and pneumatocele were more predictable for STAT3-HIES, while mucocutaneous candidiasis and Herpes infection were common in DOCK8 deficiency, which were unusual in SAD group. DOCK8-deficient patients had lower CD3 and CD4T cells with a senescent phenotype that unique for this form of HIES. Both DOCK8 deficiency and STAT3-HIES patients exhibited reduced switched memory B cells compared to the SAD patients. These clinical and laboratory markers are helpful to differentiate HIES from SAD patients.
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http://dx.doi.org/10.1016/j.clim.2020.108645DOI Listing
February 2021

Telemedicine Applications in a Tertiary Pediatric Hospital in Turkey During COVID-19 Pandemic.

Telemed J E Health 2021 10 9;27(10):1180-1187. Epub 2020 Dec 9.

Division of Pediatric Nephrology, Department of Pediatrics, Cerrahpasa School of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey.

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http://dx.doi.org/10.1089/tmj.2020.0381DOI Listing
October 2021

LRBA deficiency: a rare cause of type 1 diabetes, colitis, and severe immunodeficiency.

Hormones (Athens) 2021 Jun 5;20(2):389-394. Epub 2020 Nov 5.

Department of Pediatric Endocrinology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.

The biological role of the lipopolysaccharide-responsive beige-like anchor (LRBA) protein associated with the immune system is not to date well known. However, it is thought to regulate the CTLA4 protein, an inhibitory immunoreceptor. Chronic diarrhea, autoimmune disorders, organomegaly, frequent recurrent infections, hypogammaglobulinemia, chronic lung manifestations, and growth retardation are some features of LRBA deficiency. This rare disease is observed as a result of homozygous mutations in the LRBA gene. An 11.3-year-old male patient presented because of short stature and high blood glucose level. He had a previous history of lymphoproliferative disease, chronic diarrhea, and recurrent infections. His parents were first-degree consanguineous relatives. A diagnosis of type 1 diabetes mellitus (T1DM) was added to the preexisting diagnoses of immunodeficiency, recurrent infection, enteropathy, chronic diarrhea, lymphadenopathy, hepatomegaly, and short stature. Genetic analysis revealed a homozygous mutation in the LRBA gene, c.5047C>T (p.R1683*) (p.Arg1683*). Abatacept treatment was started: the patient's hospital admission frequency decreased, and glucose regulation improved. At follow-up, growth hormone (GH) deficiency was diagnosed, although it was not treated because the underlying disease was not under control. Nevertheless, the patient's height improved with abatacept treatment. LRBA deficiency should be considered in the presence of consanguineous marriage, diabetes, immunodeficiency, and additional autoimmune symptoms. LRBA phenotypes are variable even when the same variants in the LRBA gene are present. Genetic diagnosis is important to determine optimal treatment options. In addition to chronic malnutrition and immunosuppressive therapy, GH deficiency may be one of the causes of short stature in these patients.
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http://dx.doi.org/10.1007/s42000-020-00257-zDOI Listing
June 2021

Immunization practices in children with a history of allergies.

Turk Pediatri Ars 2020 23;55(3):244-250. Epub 2020 Sep 23.

Division of Pediatric Allergy and Immunology, Department of Pediatrics, Marmara University Faculty of Medicine, İstanbul, Turkey.

Aim: In the presence of food allergies, especially egg allergies, primary physicians in Turkey avoid vaccine administration and refer children to a hospital setting. We aimed to evaluate children who had allergies or suspected allergies and were referred to our Well Child Clinic in a university hospital for vaccination.

Material And Methods: Charts of all children referred to our clinic due to concerns for allergies in the last two years, were reviewed. Demographic data, laboratory evaluation and reactions after immunization were recorded.

Results: A total of 122 children with or without a confirmed diagnosis of allergies were referred by primary physicians. In the history, 50 children (43.5%) had reactions with egg, 42 (36.5%) had reactions with multiple foods, nine (7.8%) had reactions with milk and seven (6.1%) had reactions with a previous vaccination. The most common reaction was rash (n=89, 86.4%). Nine children reported anaphylaxis. Skin testing or serum allergen specific IgE measurement revealed that 66 (54.1%) children had sensitization to egg white and 25 (20.5%) had sensitization to egg yolk. Most children (n=87, 71.9%) were referred for all the 12-month vaccines, and 21 children were referred only for the measles-mumps-rubella vaccine (n=21, 17.4%). The median delay time in the administration of the measles-mumps-rubella vaccine was 20.0 (interquartile range: 8.7-41.2) days. No reaction was observed except for one child reporting a slight rash several hours after vaccination.

Conclusion: Egg allergy was the most common barrier of vaccine administration in children referred from family physicians. Given the absence of any reactions, we support the administration of the measles-mumps-rubella vaccine in primary care settings to prevent delays in national vaccine schedule.
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http://dx.doi.org/10.14744/TurkPediatriArs.2020.96636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536451PMC
September 2020

Novel Frameshift Autosomal Recessive Loss-of-Function Mutation in SMARCD2 Encoding a Chromatin Remodeling Factor Mediates Granulopoiesis.

J Clin Immunol 2021 01 6;41(1):59-65. Epub 2020 Oct 6.

Faculty of Medicine, Division of Pediatric Allergy/Immunology, Marmara University, Fevzi Çakmak Mah. No: 41, Pendik, Istanbul, Turkey.

Purpose: Recently, a new form of congenital neutropenia that is caused by germline biallelic loss-of-function mutations in the SMARCD2 gene was described in four patients. Given the rarity of the condition, the clinical spectrum of the disease has remained elusive. We here report a new patient with a novel frameshift mutation and compare our patient with the previously reported SMARCD2-mutant patients, aiming to provide a more comprehensive understanding of the natural course of the disease.

Methods: Clinical and laboratory findings of all reported patients were reviewed. Next-generation sequencing was performed to identify the causative genetic defect. Data on the hematopoietic stem cell transplantation including stem cell sources, conditioning regimen, engraftment, graft-versus-host disease, and infections were also collected.

Results: An 11-year-old female patient had a variety of infections including sepsis, deep tissue abscesses, otitis, pneumonia, gingivitis, and diarrhea since infancy. A novel homozygous mutation in SMARCD2 (c.93delG, p.Ala32Argfs*80) was detected. Bone marrow examination showed hypocellularity and decreased neutrophils with diminished granules and myeloid dysplasia, but no blast excess as in previously reported patients. The neutropenia was non-responsive even to higher doses of granulocyte colony-stimulating factor (G-CSF); therefore, the patient was transplanted at 10 years of age from a HLA-A allele-mismatched unrelated donor using a reduced toxicity conditioning regimen and recovered successfully. Compared with the previous four cases, our patient showed longer survival before transplantation without blastic transformation.

Conclusion: Distinctive myeloid features and long-term follow-up including therapy options are presented for the newly described case of SMARCD2 deficiency. This disorder is apparent at infancy and requires early transplantation due to the unrelenting disease course despite conventional therapy.
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http://dx.doi.org/10.1007/s10875-020-00878-4DOI Listing
January 2021

Parents of ataxia-telangiectasia patients display a distinct cellular immune phenotype mimicking ATM-mutated patients.

Pediatr Allergy Immunol 2021 02 19;32(2):349-357. Epub 2020 Oct 19.

Division of Pediatric Allergy-Immunology, Faculty of Medicine, Marmara University, Istanbul, Turkey.

Background: Heterozygous relatives of ataxia-telangiectasia (AT) patients are at an increased risk for certain AT-related manifestations. We also show that there is an increase of infection frequency in parents of AT patients. Thus, we hypothesized that the parents might exhibit immune alterations similar to their affected children.

Methods: Lymphocyte phenotyping to enumerate T- and B-cell subsets was performed. Functional analyses included in vitro quantified γ-H2AX, poly (ADP-ribose) polymerase (PARP) and caspase-9 proteins. Chromosomal instability was determined by comet assay.

Results: We analyzed 20 AT patients (14F/6M), 31 parents (16F/15M), and 35 age-matched healthy controls. The AT patients' parents exhibited low frequency of naive CD4 T- (n = 14, 45%) and recent thymic emigrants (n = 11, 35%) in comparison with the age-matched healthy donors. Interestingly, parents with low naive T cells also demonstrated high rate of recurrent infections (9/14, 64%). In comparison with age-matched controls, parents who had recurrent infections and low naive T cells showed significantly higher baseline γ-H2AX levels and H O -induced DNA damage as well as increased cleaved caspase-9 and PARP proteins.

Conclusion: Parents of AT patients could present with recurrent infections and display cellular defects that mimic AT patients. The observed immunological changes could be associated with increased DNA double-strand breaks.
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http://dx.doi.org/10.1111/pai.13387DOI Listing
February 2021

Diagnostic Modalities Based on Flow Cytometry for Chronic Granulomatous Disease: A Multicenter Study in a Well-Defined Cohort.

J Allergy Clin Immunol Pract 2020 Nov - Dec;8(10):3525-3534.e1. Epub 2020 Jul 28.

Faculty of Medicine, Pediatric Allergy-Immunology, Marmara University, Istanbul, Turkey; Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey. Electronic address:

Background: Chronic granulomatous disease (CGD) is characterized by defective microbial killing due to mutations affecting subunits of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. Definitive genetic identification of disease subtypes may be delayed or not readily available.

Objective: Sought to investigate the role of intracellular staining of NADPH oxidase enzyme subunits in predicting the respective genetic defects in patients with CGD and carriers.

Methods: Thirty-four patients with genetically inherited CGD, including 12 patients with X-linked CGD (gp91 deficiency due to cytochrome b-245, beta polypeptide [CYBB] mutations) and 22 patients with autosomal-recessive CGD (p22, p47, and p67 deficiency due to cytochrome b-245, alpha polypeptide [CYBA], neutrophil cytosolic factor 1 [NCF1] and NCF2 mutations, respectively) were recruited from different immunology centers and followed up prospectively. Dihydrorhodamine testing and NADPH oxidase subunit expression in white blood cells were determined by flow cytometry.

Results: gp91 and p22 defects, which result in simultaneous loss of both proteins due to their complex formation, were differentiated only by comparative analysis of patients' and mothers' intracellular staining. p47 and p67 protein expression was almost undetectable in patients compared with carrier mothers and healthy controls. The expression values of the respective subunits were found to be significantly higher in all controls as compared with carrier mothers, which in turn were higher than those of patients.

Conclusions: Analysis of NADPH oxidase enzyme subunits by flow cytometry in patients and carriers is useful in the rapid prediction of the genetic defect of patients with CGD, thus guiding targeted sequencing and aiding in their early diagnosis.
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http://dx.doi.org/10.1016/j.jaip.2020.07.030DOI Listing
May 2021

Lymphoma Predisposing Gene in an Extended Family: CD70 Signaling Defect.

J Clin Immunol 2020 08 3;40(6):883-892. Epub 2020 Jul 3.

Aziz Sancar Institute of Experimental Medicine, Genetics Department, Istanbul University, Istanbul, Turkey.

Genome-wide sequencing studies in pediatric cancer cohorts indicate that about 10% of patients have germline mutations within cancer predisposition genes. Within this group, primary immune deficiencies take the priority regarding the vulnerability of the patients to infectious agents and the difficulties of cancer management. On the other hand, early recognition of these diseases may offer specific targeted therapies and hematopoietic stem cell transplantation as an option. Besides therapeutic benefits, early diagnosis will provide genetic counseling for the family members. Within this context, an extended family with multiple consanguineous marriages and affected individuals, who presented with combined immune deficiency (CID) and/or Hodgkin lymphoma phenotype, were examined by exome sequencing. A pathogenic homozygous missense CD70 variation was detected (NM_001252.5:c332C>T) in concordance with CD70 phenotype and familial segregation was confirmed. CD70 variations in patients with CID and malignancy have very rarely been reported. This paper reports extended family with multiple affected members with CID and malignancy carrying a missense CD70 variation, and reviews the rare cases reported in the literature. Primary immune deficiencies appear to be a potential cause for pediatric cancers. Better focusing on these inborn disorders to prevent or make an early diagnosis of malignant transformation and reduce mortalities is important.
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http://dx.doi.org/10.1007/s10875-020-00816-4DOI Listing
August 2020

Immediate adverse reactions to intravenous immunoglobulin in primary immune deficiencies: a single center experience.

Turk J Pediatr 2020 ;62(3):379-386

Division of Pediatric Allergy and Immunology, Department of Pediatrics, Marmara University Faculty of Medicine, İstanbul, Turkey.

Background And Objective: Adverse reactions related to intravenous immunoglobulin (IVIG) infusions vary from 1 to 81%, with an average of 20%. They may be classified as immediate; occurring during the infusion itself or delayed; occurring after the infusion has been ceased. In the present study, we aimed to evaluate the frequency of immediate adverse reactions due to IVIG infusions in primary immune deficiency (PID) patients.

Methods: The study population was composed of 109 patients. A total of 763 infusions were recorded for demographic data and adverse reactions.

Results: The participants included 32 girls (29%) and 77 boys (71%). The mean age was 11.8 ± 5.7 years (0.6- 33.5 years). Early adverse events (AE) were recorded in 34 (4.5%) among 763 IVIG infusions including 30 mild (88.2%), 3 moderate (8.8%) and 1 severe (2.9%). The most common immediate adverse reactions were fever (29.4%) and headache (29.4%). The risk of AE was higher among primary antibody deficiency (PAD), compared to combined immunodeficiency (OR 2.61, 95%CI 1.061-6.475; p = 0.037).

Conclusions: Use of various intravenous immunoglobulin treatments should be considered with regard to side effect profiles observed. In our cohort, PID patient experienced mostly mild AE; PAD was associated with an increased risk of AE.
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http://dx.doi.org/10.24953/turkjped.2020.03.004DOI Listing
August 2021

Genetic Characteristics, Infectious, and Noninfectious Manifestations of 32 Patients with Chronic Granulomatous Disease.

Int Arch Allergy Immunol 2020 8;181(7):540-550. Epub 2020 Jun 8.

Department of Pediatric Infectious Disease, Istanbul University-Cerrahpasa, Cerrahpasa Medical School, Istanbul, Turkey.

Background: Chronic granulomatous disease (CGD) is a rare genetic disorder characterized by failure of phagocytic leukocytes to destroy certain microbes. We present a study on CGD patients enrolled at a single medical center concerning the infectious and noninfectious complications and genetic properties of the disease.

Methods: Icotinamide adenine dinucleotide phosphate oxidase activity and the expression of flavocytochrome b558 were measured by flow cytometry, and clinical outcomes of the patients were listed in relation to the genetic results.

Results: The clinical and genetic findings of 32 pediatric cases with CGD from 23 families were enrolled. Pneumonia and anemia were the most common infectious and noninfectious symptoms. Genetic analysis showed that 10 families (43.5%) carried CYBB variants and 13 families (56.5%) have autosomal recessive (AR) CGD, in which 6 families (26%) carried NCF1 variants, 4 (17.4%) carried CYBA variants, and 3 (13%) carried NCF2 variants. The median age of clinical onset was 3.3 and 48 months for patients with X-linked CGD (X-CGD) and AR-CGD, respectively. The onset of symptoms before age 1 year was 94% in X-CGD, 28.5% in AR-CGD, and 12.5% in patients with oxidase residual activity. Moreover, a de novo germline mutation at c.1415delG in CYBB (OMIM#300481) and a novel c.251_263del13bp in CYBA (OMIM#608508) were also investigated.

Conclusions: Ihydrorhodamine-1,2,3 assay could not detect carrier mother in de novo case with CYBB variant. Most X-CGD patients have the onset of symptoms before age 1 year. Additionally, residual oxidase activity in AR-CGD causes a delay in onset, diagnosis, and prophylaxis. The protective role of residual activity is limited while the infection is ongoing and becoming serious.
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http://dx.doi.org/10.1159/000507366DOI Listing
November 2020

Mutational landscape of severe combined immunodeficiency patients from Turkey.

Int J Immunogenet 2020 Dec 22;47(6):529-538. Epub 2020 May 22.

Department of Genetics, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey.

Severe combined immunodeficiency (SCID) has a diverse genetic aetiology, where a clinical phenotype, caused by single and/or multiple gene variants, can give rise to multiple presentations. The advent of next-generation sequencing (NGS) has recently enabled rapid identification of the molecular aetiology of SCID, which is crucial for prognosis and treatment strategies. We sought to identify the genetic aetiology of various phenotypes of SCIDs and assessed both clinical and immunologic characteristics associated with gene variants. An amplicon-based targeted NGS panel, which contained 18 most common SCID-related genes, was contumely made to screen the patients (n = 38) with typical SCID, atypical SCID or OMENN syndrome. Allelic segregations were confirmed for the detected gene variants within the families. In total, 24 disease-causing variants (17 known and 7 novel) were identified in 23 patients in 9 different SCID genes: RAG1 (n = 5), RAG2 (n = 2), ADA (n = 3), DCLRE1C (n = 2), NHEJ1 (n = 2), CD3E (n = 2), IL2RG (n = 3), JAK3 (n = 4) and IL7R (n = 1). The overall success rate of our custom-made NGS panel was 60% (39.3% for NK+ SCID and 100% for NK- SCID). Incidence of autosomal-recessive inherited genes is more frequently found in our cohort than the previously reported populations probably due to the high consanguineous marriages in Turkey. In conclusion, the custom-made sequencing panel was able to identify and confirm the previously known and novel disease-causing variants with high accuracy.
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http://dx.doi.org/10.1111/iji.12496DOI Listing
December 2020

The evaluation of malignancies in Turkish primary immunodeficiency patients; a multicenter study.

Pediatr Allergy Immunol 2020 07 9;31(5):528-536. Epub 2020 Mar 9.

Division of Pediatric Allergy and Clinical Immunology, Uludag University Faculty of Medicine, Bursa, Turkey.

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.
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http://dx.doi.org/10.1111/pai.13231DOI Listing
July 2020

Management of Systemic Hypersensitivity Reactions to Gonadotropin-Releasing Hormone Analogues during Treatment of Central Precocious Puberty.

Horm Res Paediatr 2020 23;93(1):66-72. Epub 2020 Jan 23.

Department of Paediatric Endocrinology, Marmara University School of Medicine, Istanbul, Turkey.

Background: Besides local reactions, systemic hypersensitivity reactions such as urticaria, anaphylaxis, serum sickness and Henoch-Schönlein purpura (HSP) have been reported during gonadotropin-releasing hormone (GnRH) analogue treatment.

Aim: To present the clinical presentation of 9 cases with systemic hypersensitivity reactions to GnRH analogues and discuss the management of such reactions based on our experience.

Patients And Methods: Nine of 232 (3.8%) patients with central precocious puberty receiving GnRH analogue treatment had systemic hypersensitivity reactions in 4 years' period. Six patients had a type 1 hypersensitivity reaction (generalized hives, pruritus, and/or edema) to triptorelin acetate (TA), 2 patients to leuprolide acetate (LA), and 1 patient to both medications who also developed anaphylaxis to LA during intradermal test (IDT). Another patient on TA had skin lesions suggestive of HSP. GnRH analogue treatment was discontinued in 2 patients after discussion with the parents. Treatment was changed to another GnRH analogue preparation in 6 patients and was maintained with the same medication with antihistamines and corticosteroid premedication in 1 patient. None of the patients developed new reactions after these precautions.

Conclusion: Systemic hypersensitivity reactions should be carefully evaluated and cross-reaction to the other GnRH analogues should be kept in mind. Discontinuation of GnRH analogue is always an option. However, if continuation of GnRH analogue is elected, we recommend switching to an alternative GnRH analogue, which should be considered only after a skin prick test (SPT) and IDT. In the lack of the possibility to perform SPT and IDT, injections may be administered under strict medical supervision in a well-equipped facility to manage anaphylaxis. We discuss additional options in situations where alternative GnRH analogues are unavailable, which enabled us to continue treatment in most cases without further problems.
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http://dx.doi.org/10.1159/000505329DOI Listing
April 2021

Lymphocyte Subset Abnormalities in Pediatric-Onset Common Variable Immunodeficiency.

Int Arch Allergy Immunol 2020 3;181(3):228-237. Epub 2020 Jan 3.

Division of Pediatric Allergy-Immunology, Faculty of Medicine, Marmara University, Istanbul, Turkey,

Introduction: Common variable immunodeficiency (CVID) is characterized by recurrent infections, autoimmunity, lymphoproliferation, hypogammaglobulinemia, and defective antibody production. In CVID, B-cell abnormalities were described to predict end organ involvement and prognosis. Pediatric-onset CVID is much rarer than adult CVID, and lymphocyte subset abnormalities have not been thoroughly evaluated.

Objective: We sought to determine lymphocyte subset abnormalities and their association with end organ involvement in pediatric-onset CVID patients.

Methods: The clinical manifestations and laboratory findings including absolute numbers and percentages of B-, T-, and NK cell populations were assessed in pediatric-onset CVID patients and compared to age-matched healthy controls. The patients were divided into 2 groups according to age at assessment (pediatric CVID patients: 10-16 years, n = 9; and adult CVID patients: >16 years, n = 13). The comparisons between lymphocyte subsets and organ involvement were also evaluated.

Results: Mean age at symptom onset was 18 (3-204) months. All CVID patients with pediatric onset had decreased levels of total and memory B cells, CD4+ T cells, CD4+CD45RA+ naive T cells, and recent thymic emigrant (RTE) cells. On the other hand, they had increases in CD8+CD45RO+ memory T cells. Interestingly, adult CVID patients demonstrated high frequencies of activated and double-negative T cells, which were unique only for this group of patients. Specific cellular abnormalities associated with the reduction in B and NK cells and increase in CD8+ T cells were found in patients with bronchiectasis. Moreover, in pediatric CVID patients, low serum IgA levels and decreased numbers of naive T and RTE cells were determined as risk factors for chronic diarrhea.

Conclusions: Specific abnormalities in B- and T-lymphocyte compartments were identified in pediatric-onset CVID patients and appear to be associated with end organ manifestations.
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http://dx.doi.org/10.1159/000504598DOI Listing
May 2020

Malignancy and lymphoid proliferation in primary immune deficiencies; hard to define, hard to treat.

Pediatr Blood Cancer 2020 02 17;67(2):e28091. Epub 2019 Nov 17.

Department of Pediatrics, Division of Pediatric Allergy and Immunology, School of Medical, Marmara University, Istanbul, Turkey.

Background: Regarding the difficulties in recognition and management of the malignancies in primary immune deficiencies (PIDs), we aimed to present the types, risk factors, treatment options, and prognosis of the cancers in this specific group.

Methods: Seventeen patients with PID who developed malignancies or malignant-like diseases were evaluated for demographics, clinical features, treatment, toxicity, and prognosis.

Results: The median age of malignancy was 12.2 years (range, 2.2-26). Lymphoma was the most frequent malignancy (n = 7), followed by adenocarcinoma (n = 3), squamous cell carcinoma (n = 2), cholangiocarcinoma (n = 1), Wilms tumor (n = 1), and acute myeloid leukemia (n = 1). Nonneoplastic lymphoproliferation mimicking lymphoma was observed in five patients. The total overall survival (OS) was 62.5% ± 12.1%. The OS for lymphoma was 62.2% ± 17.1% and found to be inferior to non-PID patients with lymphoma (P = 0.001).

Conclusion: In patients with PIDs, malignancy may occur and negatively affect the OS. The diagnosis can be challenging in the presence of nonneoplastic lymphoproliferative disease or bone marrow abnormalities. Awareness of susceptibility to malignant transformation and early diagnosis with multidisciplinary approach can save the patients' lives.
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http://dx.doi.org/10.1002/pbc.28091DOI Listing
February 2020

Autosomal recessive agammaglobulinemic patient with a novel large deletion in IGHM presenting with mild clinical phenotype.

Clin Immunol 2020 01 1;210:108295. Epub 2019 Nov 1.

Division of Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkey; Istanbul Jeffrey Modell Center for Primary Immunodeficiencies, Turkey. Electronic address:

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http://dx.doi.org/10.1016/j.clim.2019.108295DOI Listing
January 2020
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