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Purpose: Immunodysregulation, Polyendocrinopathy, Enteropathy, and X-linked syndrome (IPEX), caused by pathogenic FOXP3 variants, is a rare autoimmune disorder with diverse clinical features, including early-onset diabetes, eczema, and enteropathy. Atypical cases show milder symptoms and unique signs, requiring different treatments. Therefore, there are ambiguities in the accurate diagnosis and management of IPEX. We sought to present clinical, genetic, and immunological assessments of 12 IPEX patients with long-term follow-up to facilitate the diagnosis and management of the disease., Methods: Clinical findings and treatment options of the patients were collected over time. Lymphocyte subpopulations, protein expressions, regulatory T (Treg) and circulating T follicular helper (cT FH ) cells, and T-cell proliferation were analyzed., Results: Predominant presentations included autoimmunity (91.6%), failure to thrive (66.7%), and eczema (58.3%). There were four classical and eight atypical IPEX individuals. Allergic manifestations were more common in atypical patients. Notably, chronic diarrhea demonstrated heightened severity compared to other manifestations. Four patients (33.3%) demonstrated eosinophilia, and nine (75%) showed high serum IgE levels. Most patients exhibited normal percentages of Treg cells with reduced CD25, FOXP3, and CTLA-4 expressions, corrected after hematopoietic stem cell transplantation (HSCT). Compared to healthy controls, the T H 2-like skewing accompanied by reduced T H 17-like responses was observed in cT FH and Treg cells of patients. Overall, nine patients (75%) received immunosuppressants (ISs), and six (50%) underwent HSCT, which was the only treatment revealing sustained control. Sirolimus was used in six patients and showed better control than other ISs., Conclusions: The first cohort from Turkey with long-term follow-up results, comparing typical and atypical cases, provides insights into the outcomes of different therapeutic modalities and T- cell subtype changes in IPEX syndrome., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Immunoglobulin G replacement therapy (IgRT), intravenous (IV) and subcutaneous (SC) routes, is pivotal in treatment of primary immunodeficiencies (PID). In recent years, facilitated subcutaneous immunoglobulin (fSCIG), a combination of rHuPH20 and 10% IgG has emerged as a delivery method to combine advantages of both IV and SC., Method: In an observational prospective cohort, we investigated patient experience with fSCIG in PID patients from 5 PID centers for up to 12 months. We assessed the efficacy and safety of this treatment with patient/caregiver- and physician-reported indicators. Additionally, we analyzed patient treatment satisfaction (TSQM-9) and quality of life (QoL)., Results: We enrolled 29 patients (22 pediatric and 7 adults; 14 females and 15 males; (median: 15, min-max: 2-40.9 years) who initiated fSCIG as IgRT-naive (n = 1), switched from conventional rapid-push 10% SCIG (n = 6) or IVIG (n = 22). Among the participants, 19 (65%) exhibited antibody deficiencies, 8 (27%) combined immunodeficiencies, and 2 (7%) immune dysregulations. Remarkably, targeted trough immunoglobulin G levels were achieved under all previous IgRTs as well as fSCIG. No severe systemic adverse drug reactions were documented, despite prevalent local (%86.45) and mild systemic (%26.45) adverse reactions were noted with fSCIG. Due to mild systemic symptoms, 2 patients switched from fSCIG to 10% SCIG. The patient satisfaction survey revealed a notable increase at 2-4th (p = 0.102); 5-8th (p = 0.006) and 9-12th (p < 0.001) months compared to the baseline. No significant trends were observed in QoL surveys., Conclusion: fSCIG demonstrates admissable tolerability and efficacy in managing PIDs in addition to notable increase of patients' drug satisfaction with IgRT. The identified benefits support the continuation of this therapy despite the local reactions., (© 2024. The Author(s).)

Purpose: Inborn errors of IFN-γ immunity underlie Mendelian susceptibility to mycobacterial disease (MSMD). Twenty-two genes with products involved in the production of, or response to, IFN-γ and variants of which underlie MSMD have been identified. However, pathogenic variants of IFNG encoding a defective IFN-γ have been described in only two siblings, who both underwent hematopoietic stem cell transplantation (HCST)., Methods: We characterized a new patient with MSMD by genetic, immunological, and clinical means. Therapeutic decisions were taken on the basis of these findings., Results: The patient was born to consanguineous Turkish parents and developed bacillus Calmette-Guérin (BCG) disease following vaccination at birth. Whole-exome sequencing revealed a homozygous private IFNG variant (c.224 T > C, p.F75S). Upon overexpression in recipient cells or constitutive expression in the patient's cells, the mutant IFN-γ was produced within the cells but was not correctly folded or secreted. The patient was treated for 6 months with two or three antimycobacterial drugs only and then for 30 months with subcutaneous recombinant IFN-γ1b plus two antimycobacterial drugs. Treatment with IFN-γ1b finally normalized all biological parameters. The patient presented no recurrence of mycobacterial disease or other related infectious diseases. The treatment was well tolerated, without the production of detectable autoantibodies against IFN-γ., Conclusion: We describe a patient with a new form of autosomal recessive IFN-γ deficiency, with intracellular, but not extracellular IFN-γ. IFN-γ1b treatment appears to have been beneficial in this patient, with no recurrence of mycobacterial infection over a period of more than 30 months. This targeted treatment provides an alternative to HCST in patients with complete IFN-γ deficiency or at least an option to better control mycobacterial infection prior to HCST., (© 2024. The Author(s).)

Purpose: Immunodeficiency with centromeric instability and facial anomalies (ICF) syndrome is a rare autosomal recessive combined immunodeficiency. The detailed immune responses are not explored widely. We investigated known and novel immune alterations in lymphocyte subpopulations and their association with clinical symptoms in a well-defined ICF cohort., Methods: We recruited the clinical findings from twelve ICF1 and ICF2 patients. We performed detailed immunological evaluation, including lymphocyte subset analyses, upregulation, and proliferation of T cells. We also determined the frequency of circulating T follicular helper (cT FH ) and regulatory T (Treg) cells and their subtypes by flow cytometry., Results: There were ten ICF1 and two ICF2 patients. We identified two novel homozygous missense mutations in the ZBTB24 gene. Respiratory tract infections were the most common recurrent infections among the patients. Gastrointestinal system (GIS) involvements were observed in seven patients. All patients received intravenous immunoglobulin replacement therapy and antibacterial prophylaxis; two died during the follow-up period. Immunologically, CD4 + T-cell counts, percentages of recent thymic emigrant T cells, and naive CD4 + T decreased in two, five, and four patients, respectively. Impaired T-cell proliferation and reduced CD25 upregulation were detected in all patients. These changes were more prominent in CD8 + T cells. GIS involvements negatively correlated with CD3 + T-, CD3 + CD4 + T-, CD16 + CD56 + NK-cell counts, and CD4 + /CD8 + T-cell ratios. Further, we observed expanded cT FH cells and reduced Treg and follicular regulatory T cells with a skewing to a T H 2-like phenotype in all tested subpopulations., Conclusion: The ICF syndrome encompasses various manifestations affecting multiple end organs. Perturbed T-cell responses with increased cT FH and decreased Treg cells may provide further insight into the immune aberrations observed in ICF syndrome., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Purine nucleoside phosphorylase (PNP) deficiency is a rare autosomal recessive combined immunodeficiency. The phenotype is profound T cell deficiency with variable B and NK cell functions and results in recurrent and persistent infections that typically begin in the first year of life. Neurologic findings occur in approximately two-thirds of patients. The mechanism of neurologic abnormalities is unclear. Hematopoietic stem cell transplantation (HSCT) is the only curative treatment for PNP deficiency., Methods: We report here six patients from five unrelated families with PNP deficiency treated in two centers in Turkey. We evaluated the neurological status of patients and compared to post-transplantation period if available. Then, we performed PubMed, Google Scholar, and Researchgate searches using the terms "PNP" and "hematopoietic stem cell transplantation" to find all reported cases of PNP transplantation and compared to our cohort., Results: Six patients were treated in two centers in Turkey. One patient died from post-transplant complications. The other four patients underwent successful HSCT with good immune reconstitution after transplantation (follow-up 21-48 months) and good neurological outcomes. The other patient with a new mutation is still waiting for a matching HLA donor., Discussion: In PNP deficiency, clinical manifestations are variable, and this disease should be considered in the presence of many different clinical findings. Despite the comorbidities that occurred before transplantation, HSCT currently appears to be the only treatment option for this disease. HSCT not only cures immunologic disorders, but probably also improves or at least stabilizes the neurologic status of patients., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Severe combined immunodeficiency (SCID) is one of the most severe forms of inborn errors of immunity characterized by absence or loss of function in T cells. The long-term outcomes of all forms of SCID have been evaluated in a limited number of studies. We aimed to evaluate the pre- and post-transplant manifestations of SCID patients and determine the factors affecting the survival of patients., Methods: We included 54 SCID patients (classical SCID, Omenn syndrome, atypical SCID (AS)) in this study. We evaluated the clinical presentation, infections, and outcome of hematopoietic stem cell transplantation (HSCT). Lymphocyte subsets and T-cell receptor (TCR) repertoire were analyzed by flow cytometry., Results: The median age at diagnosis was 5 (range: 3-24) months and follow-up time was 25 (range: 5-61) months. Symptom onset and diagnostic ages were significantly higher in AS compared to others (p = 0.001; p < 0.001). The most common SCID phenotype was T-B-NK + , and mutations in recombination-activating genes (RAG1/2) were the prominent genetic defect among patients. The overall survival (OS) rate was 83.3% after HSCT, higher than in non-transplanted patients (p = 0.001). Peripheral blood stem cell sources and genotypes other than RAG had a significant favorable impact on CD4 + T cells immune reconstitution after transplantation (p = 0.044, p = 0.035; respectively). Gender matching transplantations from human leukocyte antigen (HLA)-identical and non-identical donors and using peripheral blood stem cell source yielded higher B-cell reconstitution (p = 0.002, p = 0.028; respectively). Furthermore, receiving a conditioning regimen provided better B-cell reconstitution and chimerism (p = 0.003, p = 0.001). Post-transplant TCR diversity was sufficient in the patients and showed an equal distribution pattern as healthy controls. The OS rate was lower in patients who underwent transplant with active infection or received stem cells from mismatched donors (p = 0.030, p = 0.015; respectively)., Conclusion: This study identifies diagnostic and therapeutic approaches predictive of favorable outcomes for patients with SCID., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: MALT1 deficiency is a combined immune deficiency characterized by recurrent infections, eczema, chronic diarrhea, and failure to thrive. Clinical and immunological characterizations of the disease have not been previously reported in large cohorts. We sought to determine the clinical, immunological, genetic features, and the natural history of MALT-1 deficiency., Methods: The clinical findings and treatment outcomes were evaluated in nine new MALT1-deficient patients. Peripheral lymphocyte subset analyses, cytokine secretion, and proliferation assays were performed. We also analyzed ten previously reported patients to comprehensively evaluate genotype/phenotype correlation., Results: The mean age of patients and disease onset were 33 ± 17 and 1.6 ± 0.7 months, respectively. The main clinical findings of the disease were recurrent infections (100%), skin involvement (100%), failure to thrive (100%), oral lesions (67%), chronic diarrhea (56%), and autoimmunity (44%). Eosinophilia and high IgE were observed in six (67%) and two (22%) patients, respectively. The majority of patients had normal T and NK cells, while eight (89%) exhibited reduced B cells. Immunoglobulin replacement and antibiotics prophylaxis were mostly ineffective in reducing the frequency of infections and other complications. One patient received hematopoietic stem cell transplantation (HSCT) and five patients died as a complication of life-threatening infections. Analyzing this cohort with reported patients revealed overall survival in 58% (11/19), which was higher in patients who underwent HSCT (P = 0.03)., Conclusion: This cohort provides the largest analysis for clinical and immunological features of MALT1 deficiency. HSCT should be offered as a curative therapeutic option for all patients at the early stage of life., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

NF-κB essential modulator (NEMO, IKK-γ) deficiency is a rare combined immunodeficiency caused by mutations in the IKBKG gene. Conventionally, patients are afflicted with life threatening recurrent microbial infections. Paradoxically, the spectrum of clinical manifestations includes severe inflammatory disorders. The mechanisms leading to autoinflammation in NEMO deficiency are currently unknown. Herein, we sought to investigate the underlying mechanisms of clinical autoinflammatory manifestations in a 12-years old male NEMO deficiency (EDA-ID, OMIM #300,291) patient by comparing the immune profile of the patient before and after hematopoietic stem cell transplantation (HSCT). Response to NF-kB activators were measured by cytokine ELISA. Neutrophil and low-density granulocyte (LDG) populations were analyzed by flow cytometry. Peripheral blood mononuclear cells (PBMC) transcriptome before and after HSCT and transcriptome of sorted normal-density neutrophils and LDGs were determined using the NanoString nCounter gene expression panels. ISG15 expression and protein ISGylation was based on Immunoblotting. Consistent with the immune deficiency, PBMCs of the patient were unresponsive to toll-like and T cell receptor-activators. Paradoxically, LDGs comprised 35% of patient PBMCs and elevated expression of genes such as MMP9, LTF, and LCN2 in the granulocytic lineage, high levels of IP-10 in the patient's plasma, spontaneous ISG15 expression and protein ISGylation indicative of a spontaneous type I interferon (IFN) signature were observed, all of which normalized after HSCT. Collectively, our results suggest that type I IFN signature observed in the patient, dysregulated LDGs and spontaneously activated neutrophils, potentially contribute to tissue damage in NEMO deficiency., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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.

Purpose: As the population gets older, the elderly and very elderly patients are increasingly been treated in nephrology intensive care units (ICU). In this study we evaluated the characteristics and outcomes of the octogenarians (80-89 years old), nonagenarians (≥ 90 years old) and compared them with elderly (65-79 years old) patients treated in nephrology ICU., Methods: Eighteen nonagenarians, 70 octogenarians and 88 elderly patients were included in the study. Indication for hospitalization, presence of comorbid diseases, and requirement for acute dialysis treatment were investigated. Need for mechanical ventilation, vasopressors, central venous catheterization, urinary catheterization, anticoagulation, and transfusion of blood products were evaluated. Mortality rate and hospital cost were calculated. Data about survival at 1 month after discharge was collected., Results: Causes of hospitalization, need for dialysis treatment, mechanical ventilation, vasopressors, central venous catheterization, urinary catheterization, anticoagulation, and transfusion of blood products were not different between age groups. Diabetes mellitus and malignancy were more frequent in elderly, whereas dementia/Alzheimer's disease was more common in nonagenarians. Although, mortality in ICU was increased as the age increased, it was statistically insignificant. However, 1 month mortality rate after discharge from hospital was increased especially in nonagenarians. In nonagenarians infection, whereas in octogenarians need for dialysis treatment, were related with mortality. Length of intensive care stay and hospital cost did not differ between age groups., Conclusion: Length of nephrology intensive care stay, mortality rate and hospital cost did not differ for very elderly age groups, but mortality risk was higher for nonagenarians after discharge from hospital.

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&#95;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.

Purpose: Human signal transducer and activator of transcription 1 (STAT1) gain-of-function (GOF) mutations present with a broad range of manifestations ranging from chronic mucocutaneous candidiasis and autoimmunity to combined immunodeficiency (CID). So far, there is very limited experience with hematopoietic stem cell transplantation (HSCT) as a therapeutic modality in this disorder. Here, we describe two patients with heterozygous STAT1 GOF mutations mimicking CID who were treated with HSCT., Methods: Data on the HSC sources, conditioning regimen, graft-versus-host disease (GvHD) and antimicrobial prophylaxis, and the post-transplant course including engraftment, GvHD, transplant-related complications, infections, chimerism, and survival were evaluated. Pre- and post-transplant immunological studies included enumeration of circulating interferon gamma (IFN-γ)- and interleukin 17 (IL-17)-expressing CD4 + T cells and analysis of IFN-β-induced STAT1 phosphorylation in patient 1 (P1)'s T cells., Results: P1 was transplanted with cord blood from an HLA-identical sibling, and P2 with bone marrow from a fully matched unrelated donor using a reduced toxicity conditioning regimen. While P1 completely recovered from her disease, P2 suffered from systemic CMV disease and secondary graft failure and died due to severe pulmonary involvement and hemorrhage. The dysregulated IFN-γ production, suppressed IL-17 response, and enhanced STAT1 phosphorylation previously found in the CD4 + T cells of P1 were normalized following transplantation., Conclusion: HSCT could be an alternative and curative therapeutic option for selected STAT1 GOF mutant patients with progressive life-threatening disease unresponsive to conventional therapy. Morbidity and mortality-causing complications included secondary graft failure, infections, and bleeding.

Purpose: Chronic kidney disease (CKD) is a progressive condition characterized by irreversible loss of functional nephron mass due to variety of causes; an inevitable complication of CKD is metabolic bone disease, and this pathology is called as renal osteodystrophy (ROD). In this study, we aimed to determine the levels of serum sRANKL and intracellular NF-κB levels in peripheral blood osteoclast precursor cells in patients with stage 3 CKD., Materials and Methods: Forty-one male patients aged 35-60 with CKD identified as stage 3 according to GFR calculated on the basis of creatinine values and 27 healthy male subjects with age ranging from 40 to 60 as control group were included in this study. Levels of biochemical parameters, vitamin D3, parathyroid hormone, bone mineral density, sRANKL and NF-κB were determined by using photometric, electrochemiluminescence, HPLC, ELISA and flow cytometric methods in control and patient groups, respectively., Results: When stage 3 CKD patients were compared with controls, patients with stage 3 CKD had statistically significantly higher iPTH levels, but they had statistically significantly lower vitamin D3 levels. However, the other biochemical parameters, bone mineral density, sRANKL and NF-κB levels did not reveal any significance., Conclusion: In conclusion, vitamin D3 and iPTH levels seem to be important parameters for evaluating the early stages of ROD. The lack of statistically significant differences in the levels of sRANKL and NF-κB suggests that these parameters are not sufficient in the evaluation of bone metabolism in the early stages of renal failure.

Purpose: Although various studies have improved our knowledge about the clinical features and outcomes of acute kidney injury developing in the hospital (AKI-DI) in elderly subjects, data about acute kidney injury developing outside the hospital (AKI-DO) in elderly patients (age ≥ 65 years) are still extremely limited. This study was performed to investigate prevalence, clinical outcomes, hospital cost and related factors of AKI-DO in elderly and very elderly patients., Methods: We conducted a prospective, observational study in patients (aged ≥ 65 years) who were admitted to our center between May 01, 2012, and May 01, 2013. Subjects with AKI-DO were divided into two groups as "elderly" (group 1, 65-75 years old) and "very elderly" (group 2, >75 years old). Control group (group 3) consisted of the hospitalized patients aged 65 years and older with normal serum creatinine level. In-hospital outcomes and 6-month outcomes were recorded. Rehospitalization rate within 6 months of discharge was noted. Hospital costs and mortality rates of each group were investigated. Risk factors for AKI-DO were determined., Results: The incidence of AKI-DO that required hospitalization in elderly and very elderly patients was 5.8 % (136/2324) and 11 % (100/905), respectively (p < 0.001), with an overall incidence of 7.3 % (236/3229). Chronic kidney disease (CKD) was developed in 43.4 % of group 1 and 67 % of group 2 within the 6 months of discharge (p < 0.001). Progression to CKD was significantly lower in the control group than in groups 1 and 2 (p < 0.001). Mortality rates for groups 1, 2 and 3 were 23.5 % (n = 32), 31 % (n = 31) and 4.2 % (n = 8), respectively (p < 0.05). Rehospitalization rate within the 6 months of discharge for the groups with AKI-DO was higher than for the control group (p < 0.001). Hospital cost of groups 1 and 2 was significantly higher than that of the control group (p < 0.001). Nonsteroidal anti-inflammatory drugs (NSAIDs) (OR: 6.839, 95 % CI = 4.392-10.648), angiotensin-converting enzyme inhibitors (ACEI) (OR: 7.846, 95 % CI = 5.161-11.928), angiotensin receptor blockers (ARB) (OR: 6.466, 95 % CI = 4.813-8.917), radiocontrast agents (OR: 8.850, 95 % CI = 5.857-13.372), hypertension (OR: 4.244, 95 % CI = 2.729-6.600), diabetes mellitus (OR: 2.303, 95 % CI = 1.411-3.761), heart failure (OR: 3.647, 95 % CI = 2.276-5.844) and presence of infection (OR: 3.149, 95 % CI = 1.696-5.845) were found as the risk factors for AKI-DO in elderly patients (p < 0.001 for all). Patients with AKI-DO had higher 6-month mortality rate (HR 1.721, 95 % CI: 1.451-2.043, p < 0.001). Mortality risk increased 0.519 times at 20th day., Conclusions: The incidence of AKI-DO requiring hospitalization is higher in very elderly patients than elderly ones, especially in male gender. Use of ACEI, ARB, NSAID and radiocontrast agents is the main risk factors for the development of AKI-DO in the elderly.

Purpose: Loss and gain-of-function (GOF) mutations in human signal transducer and activator of transcription 1 (STAT1) lead to distinct phenotypes. Although recurrent infections are common to both types of STAT1 mutations, GOF mutations are distinguished by chronic mucocutaneous candidiasis and autoimmunity. However, the clinical spectra of STAT1 GOF mutations continue to expand. We here describe two patients with STAT1 GOF mutations presenting early in life with combined immunodeficiency (CID)., Methods: Clinical data and laboratory findings including immunophenotyping, level of interferon (IFN)-γ/IL-17(+) T cells, interferon-induced STAT1 phosphorylation, and JAK inhibitor assays were evaluated. Sequencing of STAT1 gene was performed by Sanger sequencer., Results: Patient 1 (P1) had persistent oral candidiasis and cytomegalovirus (CMV) infection since 2 months of age and later developed cavitary lung lesions due to Mycobacterium tuberculosis. Patient 2 (P2) presented with oral candidiasis and recurrent pneumonia at 4 months of age and subsequently developed CMV pneumonitis. Both patients suffered heterozygous missense mutations in STAT1, leading to deleterious amino acid substitutions in the DNA binding domain (P1: c.1154C > T; p.T385M; P2. c.971G > T; p.C324F). Circulating CD4(+) T cells of both patients exhibited increased interferon-γ and decreased IL-17 expression as compared to controls. They also exhibited increased IFN-β and -γ-induced STAT1 phosphorylation that was reversed upon treatment with the JAK kinase inhibitor ruxolitinib., Conclusion: STAT1 GOF mutations may present early in life with CID, consistent with the clinical heterogeneity of the disease. JAK kinase inhibitors may potentially be useful in some patients as adjunct therapy pending definitive treatment with bone marrow transplantation.

Protein kinase C delta (PRKCD) has essential functions in controlling B-cell proliferation and apoptosis, development of B-cell tolerance and NK-cell cytolitic activity. Human PRKCD deficiency was recently identified to be causative for an autoimmune lymphoproliferative syndrome like disorder with significant B-cell proliferation particularly of immature B cells. Here we report a child with a novel mutation in PRKCD gene who presented with CMV infection and an early onset SLE-like disorder which was successfully treated with hydroxychloroquine.

Recently autosomal recessively inherited mutations in the gene encoding Jagunal homolog 1 (JAGN1) was described as a novel disease-causing gene of severe congenital neutropenia (SCN) JAGN1-mutant neutrophils were characterized by abnormality in endoplasmic reticulum structure, absence of granules, abnormal N-glycosylation of proteins and susceptibility to apoptosis. These findings imply the role of JAGN1 in neutrophil survival. Here, we report two siblings with a homozygous mutation in JAGN1 gene, exhibiting multisystemic involvement.

Purpose: Hyponatremia is a common electrolyte disorder in hospitalized patients. Clinical features, outcome and cost of hyponatremia-associated admission and hospitalization in elderly and very elderly patients are not well known., Methods: Elderly (>64 years) patients admitted to the emergency department (ED) and hospitalized between January 1, 2010, and December 31, 2010, were evaluated. Hyponatremia was defined as serum sodium level below 135 mmol/L. Hyponatremic patients were divided into two groups: group 1 (n = 150, 65-74 years old) and group 2 (n = 103, >74 years old)., Results: A total of 4,960 patients above 65 years of age admitted to ED and hospitalized were included. Prevalence of ED in group 1 and group 2 was 4.1 % (150/3,651) and 7.8 % (103/1,309), respectively (p < 0.001). Vomiting and diarrhea were the most important complaints. A total of 111 (43.8 %) patients were being treated with renin-angiotensin system (RAS) blockers. Mortality, morbidity and hospital cost increased in parallel to decrease in serum Na(+) level and increase in age. Group 2 subjects had not only higher intensive care need (p < 0.01) and mortality rates (p < 0.01), but also higher hospital cost burden (p < 0.05) compared to group 1. Alzheimer's disease was one of the most common co-morbidity in patients, particularly in group 2 (5.3 % vs. 21.3 %, p < 0.001)., Conclusion: Hyponatremia-associated hospitalization is an important and potentially lethal condition in elderly and very elderly patients. Clinicians should be careful when prescribing RAS blockers and diuretics in elderly patients.

Aim: We aimed to evaluate the metabolic parameters and diabetes complications which would probably affect the serum retinol-binding protein 4 (RBP4) levels in Type 2 diabetic individuals. In addition to serum RBP4 concentration, the levels of its ligands, serum retinol and transthyretin (TTR) were also considered in this evaluation., Subjects and Methods: Serum RBP4, retinol, and TTR levels were measured in 53 Type 2 diabetic subjects and 30 body mass index (BMI)- matched controls. The molar ratios of RBP4 to retinol and RBP4 to TTR were compared., Results: While the RBP4 values were similar to those in the control group in Type 2 diabetic patients, the molar ratio of RBP4 to TTR was found to be higher than that of the control group. The serum RBP4 levels in patients who had retinopathy and macrovascular disease were similar to those in patients who did not. However, the RBP4 levels, molar ratios of RBP4 to retinol and RBP4 to TTR in micro- macroalbuminuric patients were found to be significantly higher than in normoalbuminuric subjects and controls. There was no correlation between the RBP4 levels and the patients' age, BMI, duration of diabetes, LDL, triglyceride, serum creatinine, and glycated hemoglobin values. Micro-macroalbuminuria and estimated glomerular filtration rate were independent determinants for increased serum RBP4 levels., Conclusion: According to the data obtained from this study, diabetic retinopathy and cardiovascular complications do not affect the serum RBP4 level in Type 2 diabetes. Renal functions rather than the metabolic factors of diabetes determine the RBP4 level and its relation with its ligands.