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Background: The only curative therapy for many primary immunodeficiencies is HSCT. aGvHD is a serious and potentially fatal complication of HSCT with an incidence of nearly %50. Furthermore, involvement of the lower gastrointestinal (LGI) tract is associated with a poor prognosis. Unfortunately, there isn’t consensus about second-line therapies for steroid-refractory (SR) aGvHD. Alpha 1 Antitrypsin (AAT) is one of the second-line therapies. There isn’t a study in pediatric population with acute SR-GvHD in the literature. Method: We retrospectively evaluated data of 3 patients that received AAT as second-line therapy for acute SR-GvHD. Results: Each patients’ response to treatment was unique. P1 had a complete response beginning with the third dose of the treatment. P2 showed a partial response to the treatment after the second dose. Despite 8 doses of the treatment, P3 did not achieve remission. Conclusion: AAT may play a promising role in the treatment of severe and refractory aGvHD in children, without causing an additional immune suppression in opposite to agents which were placed in guidelines. Further studies are warranted with AAT for pediatric population.

Severe combined immunodeficiency is an inborn error of immunity characterized by impairments in the numbers and functions of T and B lymphocytes due to various genetic causes, and if it remains untreated, patients succumb to infections during the first 2 years of life. Purpose and Methods: This study reported retrospective data from 72 infants diagnosed with SCID including their major clinical features, HSCT characteristics, and outcomes over a 20-year period (1997–2017). Results: Sixty-one of 72 SCID patients in the study underwent HSCT from 1997 to 2017. Median ages at the time of diagnosis and transplantation were 3.5 months and 5 months, respectively. Consanguinity was present in 68% of the patients, and T − B − NK + phenotype was predominantly identified. The overall survival was 80.3% over a 20-year period. However, the patients transplanted during an active infection had a lower survival rate of 73.9% compared to 100% for patients transplanted infection-free or with a previous infection that had resolved. The survival rate was significantly higher among recipients of HLA-identical transplants (92.9%), compared to recipients of mismatched related transplants (70%). The overall survival increased from 50 (1997–2006) to 85% (2007–2017) during the last 10 years. Conclusions: This is one of the largest single-center studies in Turkey with extensive experience about SCID patients. Early diagnosis of SCID patients before the onset of an infection and early transplantation are shown to be extremely important factors affecting the outcome and increasing the survival regardless of the donor type based on the results of this study. WOS:000659780700002 34114123 Q1

© The Author(s) 2021. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/., Human nude SCID is a rare autosomal recessive inborn error of immunity (IEI) characterized by congenital athymia, alopecia, and nail dystrophy. Few cases have been reported to date. However, the recent introduction of newborn screening for IEIs and high-throughput sequencing has led to the identification of novel and atypical cases. Moreover, immunological alterations have been recently described in patients carrying heterozygous mutations. The aim of this paper is to describe the extended phenotype associated with FOXN1 homozygous, compound heterozygous, or heterozygous mutations. We collected clinical and laboratory information of a cohort of 11 homozygous, 2 compound heterozygous, and 5 heterozygous patients with recurrent severe infections. All, except one heterozygous patient, had signs of CID or SCID. Nail dystrophy and alopecia, that represent the hallmarks of the syndrome, were not always present, while almost 50% of the patients developed Omenn syndrome. One patient with hypomorphic compound heterozygous mutations had a late-onset atypical phenotype. A SCID-like phenotype was observed in 4 heterozygous patients coming from the same family. A spectrum of clinical manifestations may be associated with different mutations. The severity of the clinical phenotype likely depends on the amount of residual activity of the gene product, as previously observed for other SCID-related genes. The severity of the manifestations in this heterozygous family may suggest a mechanism of negative dominance of the specific mutation or the presence of additional mutations in noncoding regions.

Objective: To evaluate the characteristics of the patients who were followed-up with the diagnosis of ataxia telangiectasia (AT) and to assess the relationship between the hyper IgM (HIGM) phenotype and their prognosis. Materials and Methods: From 2007 to 2019, the study included 68 patients aged 3-35 years who were followed-up with the diagnosis of AT. We retrospectively evaluated the clinical and immunological characteristics and follow-up results. Results: There were 36 girls and 32 boys with a median follow-up of 10 years (1-12 years). The most common complaints upon admission were unsteady walk in 87%, infection in 6%, presence of a family history in 6%, and intracranial mass in 1%. The marriage was consanguineous in 85% of the parents. Ataxia was seen in 100% of the patients, telangiectasia in 97%, and immune deficiency in 88%. Bronchiectasis was observed in 23.5% of the patients, chronic diarrhea in 19%, lymphoproliferation in 15%, malignancy in 10%, autoimmunity in 10%, liver failure in 6%, and granulomatous skin lesions in 6%. Thirteen patients (19%) died during follow-up. The HIGM phenotype was identified in 31% of the patients. Recurrent upper and lower respiratory tract infections (p=0.004 and p

Loss-of-function mutations in magnesium transporter 1 (MAGT1) gene cause X-linked magnesium deficiency with Epstein–Barr virus (EBV) infection and neoplasm (X-MEN), a disease with quite diverse clinical and immunological consequences. The phenotypic characteristics of the initially described patients included CD4+ T cell lymphopenia, immune deficiency, EBV viremia, and EBV-related lymphoproliferative disease. To date, a total of 25 patients have been reported. The spectrum of the MAGT1 defect ranges from other viral infections (HSV, VZV, CMV, MCV) and sinopulmonary bacterial infections, autoimmune diseases, non-EBV driven lymphoproliferative disease, Castleman disease, HHV8+ Kaposi's sarcoma, vasculitis (Kawasaki) to glycosylation defects in new patients. Here, we report 2 patients from two different families with novel MAGT1 mutations and different clinical features. The first patient presented with B cell lymphoma and low IgM level without recurrent infections. The second patient presented with recurrent upper respiratory tract infections, Kawasaki-like disease, hypogammaglobulinemia, and T cell lymphopenia. X-MEN disease is the first phenotype identified due to MAGT1 mutation. The identification of new mutations and atypical presentations will clarify whether there is a relationship between the genotype and the phenotype and the characteristics of the disease.

Severe combined immunodeficiency is an inborn error of immunity characterized by impairments in the numbers and functions of T and B lymphocytes due to various genetic causes, and if it remains untreated, patients succumb to infections during the first 2 years of life.This study reported retrospective data from 72 infants diagnosed with SCID including their major clinical features, HSCT characteristics, and outcomes over a 20-year period (1997-2017).Sixty-one of 72 SCID patients in the study underwent HSCT from 1997 to 2017. Median ages at the time of diagnosis and transplantation were 3.5 months and 5 months, respectively. Consanguinity was present in 68% of the patients, and T - B - NK + phenotype was predominantly identified. The overall survival was 80.3% over a 20-year period. However, the patients transplanted during an active infection had a lower survival rate of 73.9% compared to 100% for patients transplanted infection-free or with a previous infection that had resolved. The survival rate was significantly higher among recipients of HLA-identical transplants (92.9%), compared to recipients of mismatched related transplants (70%). The overall survival increased from 50 (1997-2006) to 85% (2007-2017) during the last 10 years.This is one of the largest single-center studies in Turkey with extensive experience about SCID patients. Early diagnosis of SCID patients before the onset of an infection and early transplantation are shown to be extremely important factors affecting the outcome and increasing the survival regardless of the donor type based on the results of this study.

Wiskott-Aldrich syndrome (WAS) is an X-linked primary immune deficiency characterized by microthrombocytopenia, eczema, and recurrent infections. We aimed to evaluate the clinical features and outcomes of a WAS cohort.We retrospectively evaluated the clinical courses, immunological features, treatments, and outcomes in a total of 23 WAS patients together with data related to 11 transplanted cases among them between 1982 and 2019.Before admission, 11 patients (48%) were misdiagnosed with immune thrombocytopenia. WAS scores were mostly 4 or 5. Eleven patients were transplanted and they had an overall survival rate of 100% during a median follow-up period of 8.5 years (range: 8 months to 20 years). Five patients who were not transplanted died at a median of 7 years (range: 2-26 years). Nontransplanted patients had high morbidity due to organ damage, mostly caused by autoimmunity, bleeding, and infections. Two novel mutations were also defined.All male babies with microthrombocytopenia should be evaluated for WAS. Hematopoietic stem cell transplantation should be performed at the earliest age with the best possible donors.Wiskott-Aldrich Sendromu (WAS) X’e bağlı geçen mikrotrombositopeni, egzema ve tekrarlayan enfeksiyonlarla karakterize bir primer immün yetmezliktir.1982-2019 yılları arasında izlediğimiz toplam 23 WAS’li hastanın klinik seyirleri, immünolojik özellikleri ve nakil yapılan 11 hastanın nakil ilişkili verileri retrospektif olarak değerlendirildi.Başvurudan önce 11 hasta yanlışlıkla immün trombositopeni tanısı almıştı. WAS skoru çoğunlukla 4 ve 5 puandı. On bir hastaya nakil yapıldı ve ortanca 8,5 yıl (8 ay-20 yıl) izlem süresinde hayatta kalma oranı %100 oldu. Nakil yapılamayan 5 hasta ortanca 7 yılda (2-26 yıl) kaybedildi. Nakil yapılmayan hastalar çoğunlukla otoimmünite, kanama ve enfeksiyonların neden olduğu organ hasarları nedeniyle yüksek morbiditeye sahipti. Ayrıca, iki yeni mutasyon tanımlandı.Mikrotrombositopenisi olan tüm erkek bebekler WAS açısından değerlendirilmelidir. Hematopoetik kök hücre nakli mümkün olan en iyi donörlerle en erken yaşta yapılmalıdır.

Biallelic mutations in the dedicator of cytokinesis 8 gene (DOCK8) cause a progressive combined immunodeficiency (CID) characterized by susceptibility to severe viral skin infections, atopic diseases, recurrent respiratory infections, and malignancy. Hematopoietic stem cell transplantation (HSCT) is only curative treatment for the disease. However, there is limited information about long‐term outcome of HSCT and its effect to protect against cancer development in DOCK8‐deficient patients. In this study, we retrospectively evaluated clinical and immunologic characteristics of 20 DOCK8‐deficient patients and outcome of 11 patients who underwent HSCT. We aimed to report the experience of our center and the result of the largest transplantation series of DOCK8 deficiency in our country. Median follow‐up time is 71 months (min‐max: 16‐172) in all patients and 48 months (min‐max: 5‐84) in transplanted patients. Atopic dermatitis (18/20), recurrent respiratory tract infections (17/20), and food allergy (14/20) were the most frequent clinical manifestations. Failure to thrive (13/20), liver problems (12/20), bronchiectasis (11/20), chronic diarrhea (10/21), and autism spectrum disorders (3/20) were remarkable findings in our series. Elevated IgE level (20/20) and eosinophilia (17/20), low IgM level (15/20), and decreased CD3+ T (10/20) and CD4+ T (11/20) cell count were prominent laboratory findings. HSCT was performed in 11 patients. All patients achieved adequate engraftment and showed improvement in their clinical and immunologic findings. Atopic dermatitis and food allergies improved in all patients, and their dietary restriction was stopped except one patient who was transplanted recently. The frequency of infections was decreased. The overall survival is 91% in HSCT‐received patients and 80% in all. HSCT at the earliest possible period with most suitable donor‐ and patient‐specific appropriate conditioning regimen and GvHD prophylaxis is lifesaving for DOCK8 deficiency cases.

Introduction LPS-responsive beige-like anchor protein (LRBA) deficiency is a primary immunodeficiency categorized as common variable immunodeficiency associated with autoimmune manifestations and inflammatory bowel diseases; however, the clinical spectrum has been extended. Here, we present our cohort of Turkish LRBA-deficient patients from a single center, demonstrating a diversity of clinical manifestations. Method Seven affected individuals from five families were assessed retrospectively in this study. Results Of the seven patients with LRBA deficiency, four had homozygous, and two had compound heterozygous mutations. One patient remained disease free until the last follow-up (age 17 years). The most common clinical manifestations of the six symptomatic patients were organomegaly (6/6), autoimmunity (6/6), and chronic diarrhea (5/6). Recurrent infectious episodes were observed in three patients. None of the patients had hypogammaglobulinemia at presentation. B cell subpopulation analysis revealed low numbers of switched-memory B cell numbers in two of the four tested patients. During the disease course, three of the patients died, two of them underwent successful hematopoietic stem cell transplantation (HSCT) from matched sibling donors, and one is under abatacept therapy. Conclusion LRBA defects should always be kept in mind as a differential diagnosis for patients with autoimmune disease affecting multiple organs, chronic diarrhea, and organomegalies. In our experience, early HSCT is a life-saving therapeutic strategy.

Introduction HSCT is the curative therapeutic option in PIDs. Due to the increase in survival rates, reduced-toxicity conditioning regimens with treosulfan have become another alternative. The purpose of this retrospective study was to analyze the outcome of treosulfan-based conditioning before HSCT for patients with PID. Method A total of 15 patients that received a treosulfan-based conditioning regimen for HSCT were recruited. Type of diagnosis, donor and stem cell source, pretransplant organ damage, infections, engraftment, chimerism, and transplant-related toxicities were analyzed. Results At a median follow-up time of 32 months, the overall survival was 86.7%. Following HSCT, 14 of 15 patients had engraftment, with 86.7% of the cohort having full-donor chimerism. The most common toxicity was seen on the skin (53.3%). Acute GVHD and chronic GVHD were documented in 53% and 20% of the study population, respectively. Although the cohort consisted of patients with pretransplant liver damage, SOS manifestations were documented in 20%. Conclusion Treosulfan-based conditioning regimens before HSCT are associated with lower toxicity compared to myeloablative regimens, are safe, and have high engraftment rates with full-donor chimerism in patients having PID, regardless of the specified genetic diagnosis and donor type.

Biallelic mutations in the genes encoding CD27 or its ligand CD70 underlie inborn errors of immunity (IEIs) characterized predominantly by Epstein-Barr virus (EBV)-associated immune dysregulation, such as chronic viremia, severe infectious mononucleosis, hemophagocytic lymphohistiocytosis (HLH), lymphoproliferation, and malignancy. A comprehensive understanding of the natural history, immune characteristics, and transplant outcomes has remained elusive. Here, in a multi-institutional global collaboration, we collected the clinical information of 49 patients from 29 families (CD27, n = 33; CD70, n = 16), including 24 previously unreported individuals and identified a total of 16 distinct mutations in CD27, and 8 in CD70, respectively. The majority of patients (90%) were EBV+ at diagnosis, but only ∼30% presented with infectious mononucleosis. Lymphoproliferation and lymphoma were the main clinical manifestations (70% and 43%, respectively), and 9 of the CD27-deficient patients developed HLH. Twenty-one patients (43%) developed autoinflammatory features including uveitis, arthritis, and periodic fever. Detailed immunological characterization revealed aberrant generation of memory B and T cells, including a paucity of EBV-specific T cells, and impaired effector function of CD8+ T cells, thereby providing mechanistic insight into cellular defects underpinning the clinical features of disrupted CD27/CD70 signaling. Nineteen patients underwent allogeneic hematopoietic stem cell transplantation (HSCT) prior to adulthood predominantly because of lymphoma, with 95% survival without disease recurrence. Our data highlight the marked predisposition to lymphoma of both CD27- and CD70-deficient patients. The excellent outcome after HSCT supports the timely implementation of this treatment modality particularly in patients presenting with malignant transformation to lymphoma.