Search

Background: Signal transducer and activator of transcription 3 (STAT3) gain-of-function (GOF) disease presents with lymphoproliferation, autoimmunity, and failure to thrive. Although Janus kinase inhibitors have alleviated symptoms, their effects on disease pathogenesis remain unclear., Objective: We prospectively investigated the clinical, immunologic, and transcriptomic responses of 4 patients with STAT3 GOF under long-term ruxolitinib treatment., Methods: We conducted clinical and immunologic evaluations at baseline and after ruxolitinib treatment at 3, 8, 12, and more than 12 months. Our assessments included measurement of levels of circulating T follicular helper cells, regulatory T cells, and cytokines, as well as proliferation assays. Furthermore, we investigated the transcriptomic changes with treatment and conducted T-cell receptor sequencing., Results: Ruxolitinib achieved substantial control over the clinical manifestations. Posttreatment evaluations demonstrated a notable increase in naive CD4 + and CD8 + T-cell populations, alongside a significant reduction in effector memory T-cell levels. Additionally, there was a decrease in levels of circulating T follicular helper cells and double-negative T cells. Regulatory T-cell percentages and their canonical markers, which were already reduced before treatment, declined further with ruxolitinib. The treatment did not alter the production of IL-4, IL-17A, IL-10, and IFN-γ cytokines by the CD4 +  T cells. Importantly, ruxolitinib effectively normalized the previously dysregulated transcriptome profile in PBMCs, bringing it closer to that of healthy controls. This normalization was most striking in the downregulation of STAT3-targeted genes, interferon-related genes, myeloid cell activation, and cytotoxic effector CD8 + T-cell genes, with effects persisting for up to 12 months. Self-reactive T-cell indices based on T-cell receptor repertoire analysis revealed potential autoreactive cell clones in the patient samples., Conclusion: Ruxolitinib reversed cellular and transcriptomic signatures, enhancing our understanding of the disease's pathophysiology and highlighting essential immunologic markers for precise monitoring., Competing Interests: Disclosure statement Supported by the Marmara University Scientific Research Project Coordination Unit (grant ADT-2022-10661 [to S.B.]) and the Scientific and Technological Research Council of Türkiye (grant 121S667 [to B.E.]). Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Anhidrotic ectodermal dysplasia (AED) is a rare, mostly X-linked recessive genodermatosis, characterized by congenital defects of ectodermal derivative structures as the central nervous system (CNS) is primarily ectodermal in origin., Purpose: To evaluate CNS variations and abnormalities in AED., Material and Methods: A retrospective analysis was made of the neurological and neuroimaging findings of 17 children (12 boys, 5 girls; median age = 8 years; age range = 2-14 years) diagnosed with AED in our pediatric clinics during 2008-2016. The pattern of CNS variation and abnormalities were evaluated by comparing of these findings with an age- and gender-matched healthy control group with no family history., Results: Of the 17 AED cases identified on the basis of neuroimaging findings, 6 (35.3%) were seen to be normal. Associated CNS variation and abnormalities including cavum septum pellucidum (35.3%), callosal dysgenesis (11.8%), prominent Virchow-Robin spaces (64.7%), cortical sulcal dilation (41.1%), mega cisterna magna (35.3%), focal cortical dysplasia (11.8%), and delayed myelination (58.8%) were observed in 11 (64.7%) children with AED., Conclusion: AED suggests a spectrum of CNS variation and abnormalities, presenting with neurological and neuroimaging findings, demonstrated in the embryonic surface- and neuro-ectoderm derived structures. The results of this study suggest that CNS variation and abnormalities might be associated with AED.

Purpose: Primary immunodeficiency diseases (PIDs) are inherited disorders of the immune system resulting in increased susceptibility to unusual infections and predisposition to autoimmunity and malignancies. The European Society for Immunodeficiencies (ESID) has developed an internet-based database for clinical and research data on patients with PID. This study aimed to provide a minimum estimate of the prevalence of each disorder and to determine the clinical characteristics and outcomes of patients with PID in Turkey., Methods: Clinical features of 1435 patients with primary immunodeficiency disorders are registered in ESID Online Patient Registry by the Pediatric Immunology Departments of the Medical Faculties of Uludag University and Ege University Between 2004 and 2010. These two centers are the major contributors reporting PID patients to ESID database from Turkey., Results: Predominantly antibody immunodeficiency (73.5 %) was the most common category followed by autoinflammatory disorders (13.3 %), other well defined immunodeficiencies (5.5 %), congenital defects of phagocyte number, function or both 3.5 %), combined T and B cell immunodeficiencies (2 %), defects in innate immunity (1 %), and diseases of immune dysregulation (0.7 %). Patients between 0 and 18 years of age constitued 94 % of total and the mean age was 9.2 ± 6 years. The consanguinity rate within the registered patients was 14.3 % (188 of 1130 patients). The prevalance of all PID cases ascertained from the registry was 30.5/100.000. The major cause of the mortality was severe infection which was seen in forty-two of seventy five deceased patients. The highest mortality was observed in patients with severe combined immunodeficiencies and ataxia-telangiectasia., Conclusion: Promoting the awareness of PID among the medical professionals and the general public is required if premature death and serious morbidity occurs due to late diagnosis of the wider spectrum of PID are to be avoided.

Mendelian susceptibility to mycobacterial diseases (MSMD) is a rare syndrome characterized by predisposition to severe, sometimes lethal, disease caused by otherwise poorly virulent mycobacteria. We report here a boy with a recurrent mycobacterial infection from the age of five months. Immunological analyses revealed an inability to respond to IFN-γ, subsequent genetic analyses revealed a novel homozygous mutation, r.679G > A in the IFNGR2 gene, resulting in a G227R substitution, that caused IFN-γR2 deficiency. This is only the 8th mutation in IFN-γR2 known so far. The boy eventually died of hepatic coma due to liver failure at the age of five., (Copyright © 2012 The British Infection Association. Published by Elsevier Ltd. All rights reserved.)