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Background Wheezing, starting early in life, is a heterogeneous medical condition caused by airway obstruction due to different underlying mechanisms. Primary immunodeficiencies are also among the risk factors that cause wheezing and recurrent bronchiolitis. ADA deficiency is a primary immunodeficiency, also a rare metabolic disease associated with multisystemic clinical findings. Objective This report will be helpful for adressing the importance of thinking primary immunodeficiency in case of wheezing and recurret bronchiolitis. Methods The patient was diagnosed by using a targeted next generation sequencing PID panel. Lymphocyte subsets were measured by flow-cytometry. Results Here we present an infant with ADA deficiency who admitted with wheezing and recurrent bronchiolitis as the first presentation. He was found to have wheezing, relative CD4+ T cell deficiency, and prolonged neutropenia. Conclusion Primary immunodeficiencies including ADA deficiency should be considered in infants with wheezing, recurrent bronchiolitis, lymphopenia and neutropenia.

Dedicator of cytokinesis 8 (

Objective.Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive autoinflammatory disorder associated with ADA2 mutations. We aimed to investigate the characteristics and ADA2 enzyme activities of patients with DADA2 compared to non-DADA2 patients.Methods.This is a descriptive study of 24 patients with DADA2 who were admitted to the Adult and Pediatric Rheumatology, Pediatric Haematology, and Pediatric Immunology Departments of Hacettepe University. All ADA2 exons were screened by Sanger sequencing. Serum ADA2 enzyme activity was measured by modified spectrophotometric method.Results.Twenty-four patients with DADA2 were included: 14 with polyarteritis nodosa (PAN)-like phenotype (Group 1); 9 with Diamond-Blackfan anemia (DBA)-like features, and 1 with immunodeficiency (Group 2). Fourteen PAN-like DADA2 patients did not have the typical thrombocytosis seen in classic PAN. Inflammatory attacks were evident only in Group 1 patients. Serum ADA2 activity was low in all patients with DADA2 except one, who was tested after hematopoietic stem cell transplantation. There was no significant difference in ADA2 activities between PAN-like and DBA-like patients. In DADA2 patients with one ADA2 mutation, serum ADA2 activities were as low as those of patients with homozygote DADA2. ADA2 activities were normal in non-DADA2 patients. ADA2 mutations were affecting the dimerization domain in Group 1 patients and the catalytic domain in Group 2 patients.Conclusion.We suggest assessing ADA2 activity along with genetic analysis because there are patients with one ADA2 mutation and absent enzyme activity. Our data suggest a possible genotype–phenotype correlation in which dimerization domain mutations are associated with PAN-like phenotype, and catalytic domain mutations are associated with hematological manifestations.

V(D)J recombination, during which recognition and repair of broken DNA chains are accomplished by non-homologous end joining pathway, is a critical process in B and T cell development.Null mutations of each enzyme or protein of this pathway result in T- B- NK+ severe combined immunodeficiency whereas hypomorphic mutations result in atypical(leaky)severe combined immunodeficiency forms. We present two siblings with PRKDC (Protein Kinase, DNA-Activated, Catalytic Polypeptide) mutation who presented with granulomatous skin lesions and recurrent lung infections. Primary immune deficiencies may initially present with skin findings. Disruption in central and peripheral B-cell tolerance and impaired intrathymic T-cell maturation,a central player in T-cell tolerance, have been identified as the mechanism of autoimmunity and granuloma seen in patients. The variation in clinical phenotypes of patients with PRKDC mutation suggests that additional factors such as modifying genes, epigenetic and environmental factors may affect the severity and clinical phenotype of the disease. Functional studies during the follow-up and evaluation before and after hematopoeitic stem cell transplantation will hopefully increase our knowledge about the autoimmune and inflammatory process of the disease spectrum.

Objective: TCR (T Cell Receptor) which is expressed on T cells is responsible for recognizing antigens presented by HLA molecules of the APCs (Antigen Presenting Cells) and initiation of the immune response. It has been reported that TACI (Transmembrane activator and calcium modulating cyclophilin ligand interactor) mediates the interaction of B cells and dendritic cells which are both responsible for the processing of T cells. Materials and Methods: In this study, 24 TCRVβ clones were analyzed by using multiparametric flow cytometry in seven patients with TACI mutation [two homozygous (c.310T> C) five heterozygous (c.310T> C, c.226G> C, c.260T> A)], four CVID (Common Variable Immunodeficiency) patients who had not TACI defect (non-TACI) and five healthy controls. In this study group, serum Ig levels and infection history, CD4+ and CD8+ cell percentages, and HLA profiles were investigated. Results: Increased TCRVβ13.2 clone was observed in patients with TACI defects unlike control individuals and non-TACI-CVID patients (p=0.02). We found that there was a statistically significant decrease in TCRVβ8 clone (p=0.012) in TACI deficient CVID patients and non-TACI-CVID patients compared to control individuals. TCRVβ20 clones in non-TACI-CVID patients were decreased compared to TACI-CVID patients and control individuals (p=0.009). Decreased TCRVβ8 was also associated with TACI deficient CVID patients. Conclusion: Further studies and large cohorts are needed to understand the relationship between TCRVβ8, TCRVβ13.2, and CVID with TACI mutations.

Backgrounds: Mutations in DNA-binding domains of STAT1 lead to delayed STAT1 dephosphorylation and afterwards gain-of-function. The clinical phenotype is broad and can include chronic mucocutaneous candidiasis and/or combined immunodeficiency. Objectives: We report a case of 7-year old female patient. She had recurrent pneumonia since infancy and she was hospitalized several times. She had persistant lymphopenia with normal immunoglobulin levels and lymphocyte subsets. Findings: STAT1 mutation was defined by next generation Sequencing PID panel. Despite the antifungal therapy, oxygen requirement continued, methylprednisolone and Janus-associated kinase (JAK) inhibitor (ruxolitinib) was started as therapy. Immunodysregulatory features of disease improved after Janus kinase inhibitor treatment. Conclusion: In patients with STAT1 GOF defect, ruxolitinib treatment may be effective for interstitial lung disease if hematopoietic stem cell transplantation can not be performed.

OBJECTIVE: To develop a set of clinical criteria that identifies patients with a potential autoinflammatory IFNopathy. METHODS: Based on a literature review, a set of clinical criteria identifying genetically confirmed monogenic IFNopathies was selected. For validation, the clinical score was assessed in healthy controls (HCs) and 18 disease controls, including 2 known autoimmune IFNopathies, juvenile systemic lupus erythematosus (JSLE, n = 4) and dermatomyositis (JDM, n = 4); adenosine deaminase 2 deficiency (DADA2, n = 4); and oligoarticular juvenile idiopathic arthritis (oJIA, n = 6). We assessed an IFN score (IRG-S) in whole blood by NanoString using a previously published 28-gene-IRG-S and a reduced 6-gene-IRG-S. RESULTS: The 12 patients with a possible IFNopathy had higher clinical scores (3–5) than the patients with sJLE, JDM, DADA2, and oJIA and in HCs. Both the 28-IRG-S and 6-IRG-S were significantly higher in the autoinflammatory IFNopathy patients compared to HCs and oJIA and DADA2 patients but not different from patients with JSLE and JDM. Subsequently, genetic analysis revealed mutations in genes previously reported in genes related to the IFN pathway in 9 of the 12 patients. CONCLUSION: We developed a clinical score to identify patients with possible autoinflammatory IFNopathies. A clinical score was associated with a high IRG-S and may serve to identify patients with an autoinflammatory IFNopathy.

• In the patients with atypical presentations of vasculitis, suspicion of monogenic disorders may avoid delays in diagnosis and treatment.

Background Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive autoinflammatory disorder caused by ADA2 mutations. Objectives We aimed to investigate the characteristics of DADA2 patients along with the ADA2 enzyme levels. Methods 24 DADA2 patients who admitted to the Adult and Pediatric Rheumatology, Pediatric Haematology, and Pediatric Immunology Departments were included. All exons of the ADA2 gene were screened by Sanger sequencing in all DADA2 patients. Serum ADA2 enzyme activity was measured by modified spectrophotometric method. Results 24 DADA2 patients were included; Group 1, 14 DADA2 patients with polyarteritis nodosa (PAN)-like phenotype; Group 2, 9 patients with Diamond-Blackfan anemia (DBA)-like features and one with immune deficiency. 14 PAN-like DADA2 patients did not have the typical thrombocytosis seen in classical PAN. Inflammatory attacks were evident in only Group 1 patients. Serum ADA2 was low in all DADA2 patients except one who was tested after hematopoietic stem cell transplantation. There was no significant difference in ADA2 levels between PAN-like and DBA-like DADA2 patients (Figure 1). ADA2 activities of heterozygote family members were about half the level of the control subjects. However, in heterozygote DADA2 patients, serum ADA2 levels were as low as the ones of homozygote DADA2 patients. ADA2 mutations were affecting the dimerization domain in Group 1 patients and in the catalytic domain in Group 2 patients (Table 1). Conclusion We suggest that enzyme activity of ADA2 should be assessed along with genetic analysis since there are heterozygote patients with absent enzyme activity. Our data confirms a possible genotype phenotype correlation where dimerization domain mutations are associated with a PAN-like phenotype whereas catalytic domain mutations are associated with hematological manifestations. References [1] Navon Elkan P, et al. Mutant ADA2 in a PAN vasculopathy. N Engl J Med 2014;370(10):921-931 [2] Zhou Q, et al. Early-onset stroke and vasculopathy associated with mutations in ADA2. N Engl J Med 2014;370(10):911-920 Acknowledgement This study was supported by Scientific and Technological Research Council of Turkey (TUBITAK) with grant numbers of 315S192. Prof. Nurten Akarsu performed the molecular studies of DBA patients and special thanks to her for great support. Disclosure of Interests Ezgi Deniz Batu: None declared, Ekim Z. Taskiran: None declared, Hatice Asuman Ozkara: None declared, Sule Unal: None declared, Naz Guleray: None declared, Abdulsamet Erden: None declared, Omer Karadag: None declared, Fatma Gumruk: None declared, Mualla Cetin: None declared, Yelda Bilginer: None declared, Hafize Emine Sonmez: None declared, Deniz Cagdas Ayvaz: None declared, Ilhan Tezcan: None declared, Seza Ozen Consultant for: Seza Ozen is receiving consultancy fees from Novartis, Speakers bureau: Roche

Combined immunodeficiencies (CIDs) are heterogeneous group of disorders characterized by abrogated/impaired T cell development and/or functions that resulted from diverse genetic defects. In addition to the susceptibility to infections with various microorganisms, the patients may have lymphoproliferation, autoimmunity, inflammation, allergy and malignancy. Recently, three groups have independently reported patients having mutations in STK4 gene that cause a novel autosomal recessive (AR) CID. We describe here two siblings with a novel STK4 mutation identified during the evaluation of a group of patients with features highly overlapping with those of DOCK-8 deficiency, a form of AR hyperimmunoglobulin E syndrome. The patients' clinical features include autoimmune cytopenias, viral skin (molluscum contagiosum and perioral herpetic infection) and bacterial infections, mild onychomycosis, mild atopic and seborrheic dermatitis, lymphopenia (particularly CD4 lymphopenia), and intermittent mild neutropenia. Determination of the underlying defect and reporting the patients are required for the description of the phenotypic spectrum of each immunodeficiency. Hacettepe Üniversitesi ( 010 01 101 010)

Background: Pathological inflammatory syndromes of unknown etiology are commonly observed in ataxia telangiectasia (AT) and Artemis deficiency. Similar inflammatory manifestations also exist in patients with STING-associated vasculopathy in infancy (SAVI). Objective: We sought to test the hypothesis that the inflammation-associated manifestations observed in patients with AT and Artemis deficiency stem from increased type I IFN signature leading to neutrophil-mediated pathological damage. Methods: Cytokine/protein signatures were determined by ELISA, cytometric bead array, or quantitative PCR. Stat1 phosphorylation levels were determined by flow cytometry. DNA species accumulating in the cytosol of patients' cells were quantified microscopically and flow cytometrically. Propensity of isolated polymorhonuclear granulocytes to form neutrophil extracellular traps (NETs) was determined using fluorescence microscopy and picogreen assay. Neutrophil reactive oxygen species levels and mitochondrial stress were assayed using fluorogenic probes, microscopy, and flow cytometry. Results: Type I and III IFN signatures were elevated in plasma and peripheral blood cells of patients with AT, Artemis deficiency, and SAVI. Chronic IFN production stemmed from the accumulation of DNA in the cytoplasm of AT and Artemis-deficient cells. Neutrophils isolated from patients spontaneously produced NETs and displayed indicators of oxidative and mitochondrial stress, supportive of their NETotic tendencies. A similar phenomenon was also observed in neutrophils from healthy controls exposed to patient plasma samples or exogeneous IFN-α. Conclusions: Type I IFN-mediated neutrophil activation and NET formation may contribute to inflammatory manifestations observed in patients with AT, Artemis deficiency, and SAVI. Thus, neutrophils represent a promising target to manage inflammatory syndromes in diseases with active type I IFN signature. © 2017 American Academy of Allergy, Asthma & Immunology.

Major histocompatibility complex (MHC) class I deficiency syndrome is a rare primary immunodeficiency caused by mutations in the peptide transporter complex associated with antigen presentation (TAP) gene which plays a crucial role in intracellular peptide antigen presentation. A few cases have been reported to date. Recurrent sinopulmonary infections and skin ulcers are the main characteristics of the syndrome. Here we report two siblings diagnosed with TAP1 deficiency syndrome associated only with recurrent sinopulmonary infections with the description of a novel mutation leading to a premature stop codon in TAP1 gene and review of the relevant literature. Both of the siblings had recurrent sinopulmonary infections since childhood, responded to antibiotherapy well, neither of them had hospitalization history because of infections. One had chronic hepatitis B infection which may possibly be related to TAP1 gene defect.

A progressive encephalopathy of unknown etiology has been described in patients with primary immunodeficiency disorders. In this report, we characterize the clinical features of this progressive neurodegenerative dementing disorder in a young man with Bruton agammaglobulinemia, through neuropsychological tests and a video sequence. The clinical course of the encephalopathy seems rather uniform: Cognition, especially frontal lobe function, is affected in the early stages, and some patients develop movement disorders. The syndrome causes severe cognitive and physical disability, and can eventually be fatal. The autoimmunity results from dysregulated immune responses, but the underlying mechanism has not yet been fully explained.

Pattern recognition receptors (PRRs), receptors of the innate immune system, are important in interaction with pathogens. Caspase Recruitment Domain-containing protein 9 (CARD9), a member of PRRs, is an intracellular adaptor protein important in fungal defense. CARD9 deficiency causes a rare primary immunodeficiency (PID) characterized by superficial and deep fungal infections. We report a 17 year-old female with a homozygous nonsense mutation in CARD9, who presented with severe cerebral fungal infection of the central nervous system. She was also found to have an heterozygous NLRP12 mutation, which may have had add-on effect on the severity of the infection.

Dedicator of cytokinesis 8 (DOCK8) deficiency is a rare and recently described immunodeficiency, which is characterized with cutaneous viral and sinopulmonary infections, eczema, and high IgE levels. A DOCK8 deficient patient who had been followed up for severe atopic dermatitis, multiple food allergies, and asthma for several years is reported and clues are given for the diagnosis of DOCK8 deficiency. A 7-year-old girl was referred due to refractory eosinophilia and eczema. She had angioedema of the lips and increase in eczematous lesions during infancy after milk and egg ingestion and during childhood after fish, hazelnut, and wheat-containing food ingestion. She had episodic wheezing attacks since she was 1-year-old, and she had recurrent pneumonia and acute otitis media in the following years. She was hospitalized for pyoderma after a zona zoster infection. Laboratory findings suggested DOCK8 deficiency and mutational analysis verified. She had stem cell transplantation from a matched unrelated donor ...

We describe seven Turkish children with DOCK8 deficiency who have not been previously reported. Three patients presented with typical features of recurrent or severe cutaneous viral infections, atopic dermatitis, and recurrent respiratory or gastrointestinal tract infections. However, four patients presented with other features. Patient 1-1 featured sclerosing cholangitis and colitis; patient 2-1, granulomatous soft tissue lesion and central nervous system involvement, with primary central nervous system lymphoma found on follow-up; patient 3-1, a fatal metastatic leiomyosarcoma; and patient 4-2 showed no other symptoms initially besides atopic dermatitis. Similar to other previously reported Turkish patients, but in contrast to patients of non-Turkish ethnicity, the patients' lymphopenia was primarily restricted to CD4(+) T cells. Patients had homozygous mutations in DOCK8 that altered splicing, introduced premature terminations, destabilized protein, or involved large deletions within the gene. Genotyping of remaining family members showed that DOCK8 deficiency is a fully penetrant, autosomal recessive disease. In our patients, bone marrow transplantation resulted in rapid improvement followed by disappearance of viral skin lesions, including lesions resembling epidermodysplasia verruciformis, atopic dermatitis, and recurrent infections. Particularly for patients who feature unusual clinical manifestations, immunological testing, in conjunction with genetic testing, can prove invaluable in diagnosing DOCK8 deficiency and providing potentially curative treatment.

Sarcoidosis, a multisystem disorder of unknown etiology that involves multiple organs, is rare in children. The true incidence and prevalence of childhood sarcoidosis is unknown. As in adults, many children with sarcoidosis may be asymptomatic; the disease may remain undiagnosed. A complete and systematic evaluation of the patient is essential for the sarcoidosis diagnosis in children. Here, we describe a case of 12-year-old female who presented with 2 years history of uveitis and hepatosplenomegaly. A chest computerized tomography revealed scattered peripheral pulmonary nodules and bilateral hiliar lymphadenopathy. Bone marrow aspiration and liver biopsy were not diagnostic. A lung biopsy showed non-necrotizing epithelioid cell granulomas. She was diagnosed with sarcoidosis according to demonstration of granulomatous

Myasthenia gravis is among the rare complications after allogeneic hematopoietic stem cell transplantation and is usually associated with chronic GVHD. Herein, we report a 2-year and 10 months of age female with Griscelli syndrome, who developed severe myasthenia gravis at post-transplant +22nd month and required respiratory support with mechanical ventilation. She was unresponsive to cyclosporine A, methylprednisolone, intravenous immunoglobulin, and mycophenolate mofetil and the symptoms could only be controlled after plasma exchange and subsequent use of rituximab, in addition to cyclosporine A and mycophenolate mofetil maintenance. She is currently asymptomatic on the 6th month of follow-up. Pediatr Blood Cancer 2014;61:928–930. © 2013 Wiley Periodicals, Inc.

Common variable immunodeficiency (CVID) is a frequent primary immune deficiency (PID), which consists of a heterogeneous group of disorders and can present with recurrent infections, chronic diarrhea, autoimmunity, chronic pulmonary and gastrointestinal diseases, and malignancy. Secondary amyloidosis is an uncommon complication of CVID. We report an unusual case of a 27-year-old male patient who presented with recurrent sinopulmonary infections, chronic diarrhea, and hypogammaglobulinemia and was diagnosed with CVID. The patient was treated with intravenous immunoglobulin (IVIg) therapy once every 21 days and daily trimethoprim-sulfamethoxazole for prophylaxis. Two years after initial diagnosis, the patient was found to have progressive decline in IgG levels (as low as 200–300 mg/dL) despite regular Ig infusions. The laboratory tests revealed massive proteinuria and his kidney biopsy showed accumulation of AA type amyloid. We believe that the delay in the diagnosis of CVID and initiation of Ig replacement therapy caused chronic inflammation due to recurrent infections in our patient and this led to an uncommon and life-threatening complication, amyloidosis. Patients with CVID require regular follow-up for the control of infections and assessment of adequacy of Ig replacement therapy. Amyloidosis should be kept in the differential diagnosis when managing patients with CVID.

Mutations in DOCK8 result in autosomal recessive Hyper-IgE syndrome with combined immunodeficiency (CID). However, the natural course of disease, long-term prognosis, and optimal therapeutic management have not yet been clearly defined. In an international retrospective survey of patients with DOCK8 mutations, focused on clinical presentation and therapeutic measures, a total of 136 patients with a median follow-up of 11.3 years (1.3-47.7) spanning 1693 patient years, were enrolled. Eczema, recurrent respiratory tract infections, allergies, abscesses, viral infections and mucocutaneous candidiasis were the most frequent clinical manifestations. Overall survival probability in this cohort [censored for hematopoietic stem cell transplantation (HSCT)] was 87 % at 10, 47 % at 20, and 33 % at 30 years of age, respectively. Event free survival was 44, 18 and 4 % at the same time points if events were defined as death, life-threatening infections, malignancy or cerebral complications such as CNS vasculitis or stroke. Malignancy was diagnosed in 23/136 (17 %) patients (11 hematological and 9 epithelial cancers, 5 other malignancies) at a median age of 12 years. Eight of these patients died from cancer. Severe, life-threatening infections were observed in 79/136 (58 %); severe non-infectious cerebral events occurred in 14/136 (10 %). Therapeutic measures included antiviral and antibacterial prophylaxis, immunoglobulin replacement and HSCT. This study provides a comprehensive evaluation of the clinical phenotype of DOCK8 deficiency in the largest cohort reported so far and demonstrates the severity of the disease with relatively poor prognosis. Early HSCT should be strongly considered as a potential curative measure.

nterleukin-10 (IL-10) and IL-10 receptor (IL-10R) deficiencies, which are caused by loss of function mutations in the related genes, are primary immunodeficiencies that result in severe dysregulation of the immune system.1, 2 Patients usually present early in life with an inflammatory bowel disease-like phenotype accompanied with severe perianal disease. Other clinical features of the disease are chronic folliculitis, recurrent respiratory diseases and arthritis

GS2 is a rare autosomal recessive disease characterized by hypopigmentation, variable immunodeficiency with HLH. HSCT is the only curative treatment for GS2. We analyzed the outcome of 10 children with GS2 who underwent HSCT at our center between October 1997 and September 2013. The median age of the patients at transplant was 13.5 months (range, 6-58 months). All of the patients developed HLH before HSCT and received HLH 94 or HLH 2004 protocols. Donors were HLA-identical relatives in 8 patients, HLA-mismatched relatives in 2 patients. Engraftment was achieved in all except one patient. None of the patients developed acute GVHD. Chronic GVHD occurred in one and veno-occlusive disease occurred in four patients. Eight of the patients are under remission without any neurologic sequelae-median time of disease-free survival is 92.4 months. The present study shows successful transplant outcome without long-term neurologic sequelae in patients with GS2 who underwent HSCT from HLA-related donors.

Background Coronin-1A (CORO1A) is a regulator of actin dynamics important for T-cell homeostasis. CORO1A deficiency causes T − B + natural killer–positive severe combined immunodeficiency or T-cell lymphopenia with severe viral infections. However, because all known human mutations in CORO1A abrogate protein expression, the role of the protein's functional domains in host immunity is unknown. Objective We sought to identify the cause of the primary immunodeficiency in 2 young adult siblings with a history of disseminated varicella, cutaneous warts, and CD4 + T-cell lymphopenia. Methods We performed immunologic, genetic, and biochemical studies in the patients, family members, and healthy control subjects. Results Both patients had CD4 + T-cell lymphopenia and decreased lymphocyte proliferation to mitogens. IgG, IgM, IgA, and specific antibody responses were normal. Whole-genome sequencing identified a homozygous frameshift mutation in CORO1A disrupting the last 2 C-terminal domains by replacing 61 amino acids with a novel 91-amino-acid sequence. The CORO1A S401fs mutant was expressed in the patients' lymphocytes at a level comparable with that of wild-type CORO1A in normal lymphocytes but did not oligomerize and had impaired cytoskeletal association. CORO1A S401fs was associated with increased filamentous actin accumulation in T cells, severely defective thymic output, and impaired T-cell survival but normal calcium flux and cytotoxicity, demonstrating the importance of CORO1A oligomerization and subcellular localization in T-cell homeostasis. Conclusions We describe a truncating mutation in CORO1A that permits protein expression and survival into young adulthood. Our studies demonstrate the importance of intact CORO1A C-terminal domains in thymic egress and T-cell survival, as well as in defense against viral pathogens.