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Ιnborn errors of immunity (IEI) represents a heterogenous collection of >480 immune system anomalies, leading to severe infections, autoimmune disorders and malignancies. While these conditions are rare globally, their prevalence is notably higher in the Jordanian population, attributed to elevated rates of consanguinity. The intricate nature of IEI has driven the adoption of genomic technologies for the identification of associated genetic defects. In the present study, whole-exome sequencing was performed on nine Jordanian IEI patient samples, confirming germline single-nucleotide variations (SNVs) in 14 genes through Sanger sequencing. Of note, signal transducer and activator of transcription 1 (STAT1), elastase, neutrophil expressed (ELANE) and interferon induced with helicase c domain 1 (IFIH1) harbored mutations that were previously unreported in the Jordanian IEI population. In addition, mutations in capping protein regulator and myosin 1 linker 2 (c.3683C>T), TNFα-induced protein 3-interacting protein 1 (TNIP1) (c.460C>G) and STAT1 (c.1061T>C) were confirmed, marking their association with Jordanian IEI. For robustness, the genomic databases Ensemble, Genome AD and ClinVar were used to confirm the SNVs' associations with IEI. Kyoto Encyclopedia of Genes and Genomes pathway analysis also showed involvement of the IL-17 signaling pathway (including IL-17 receptor A), T-helper type 17 cell differentiation (including STAT1), the JAK-STAT signaling pathway (including STAT2 and tyrosine kinase 2), neutrophil extracellular trap formation (including ELANE), cocaine addiction [G protein signaling modulator 1 (GPSM1)] and cytokine-cytokine receptor interaction (IL-17 receptor C). In summary, exome sequencing identified a likely causative genetic defect in ELANE (PID-28), STAT1 (PID-30) and IFIH1 (PID-33). The present findings reveal the association of novel STAT1, ELANE mutations with the clinical phenotype of the patients, as well as known mutations in NLRP12, GPSM1 and TNIP1, in addition to novel ELANE, STAT1 and IFIH1 mutations associated in the context of Jordanian IEI. [ABSTRACT FROM AUTHOR]

Purpose of Review: We describe the clinical and genetic findings in four patients from a single family who presented with refractory psoriatic arthritis and were hemizygous in the forkhead box protein 3 (FOXP3) gene (c.1222G>A). Recent Findings: We report four siblings with hemizygous mutation in the FOXP3 gene (c.1222G>A) who presented with type 1 diabetes mellitus and psoriatic arthritis poorly responsive to treatment. Our findings expand the phenotype spectrum of FOXP3 mutations. Summary: Immune dysregulation, polyendocrinopathy, and enteropathy, X-linked (IPEX) syndrome is a rare disorder caused by mutations in FOXP3 gene, which lead to early onset of constellation of autoimmune manifestations. This report highlights the influence of immune dysregulation in juvenile arthritis. [ABSTRACT FROM AUTHOR]

Objective: To report the cumulative articular and extraarticular damage in Arab children with juvenile idiopathic arthritis (JIA) and to identify variables that correlate with disease damage.Methods: We conducted a multicenter, cross-sectional study among 14 pediatric rheumatology centers from 7 Arab countries. JIA patients who met the International League of Associations for Rheumatology classification criteria and had a disease duration of >1 year were enrolled. Disease activity status was assessed using the Juvenile Arthritis Multidimensional Assessment Report. Disease damage was assessed by the Juvenile Arthritis Damage Index, articular (JADI-A) and extraarticular (JADI-E).Results: A total of 702 (471 female) JIA patients with a median age of 11.3 years (interquartile range [IQR] 8.0-14.0 years) were studied. Median age at disease onset was 5 years (IQR 2.0-9.0 years) and the median disease duration was 4 years (IQR 2.0-7.0 years). The most frequent JIA categories were oligoarticular JIA (34.9%), polyarticular JIA (29.5%), and systemic JIA (24.5%). Clinical remission was achieved in 73.9% of patients. At the last clinic visit, 193 patients experienced joint damage, with a mean ± SD JADI-A score of 1.7 ± 4.5, while 156 patients had extraarticular damage, with a mean ± SD JADI-E score of 0.5 ± 1.1. Patients with enthesitis-related arthritis had the highest JADI-A score. JADI-A correlated significantly with the presence of a family history of JIA. JADI-A and JADI-E had a significant correlation with long disease duration.Conclusion: Cumulative damage was common in this Arab JIA cohort, and consanguinity and JIA in a sibling were frequent findings and were associated with a greater cumulative damage. [ABSTRACT FROM AUTHOR]

Chronic granulomatous Disease (CGD) is a rare innate immunodeficiency disorder caused by mutations in one of the six genes (CYBA, CYBB, NCF1, NCF2, NCF4 , and CYBC1 /EROS) encoding the superoxide-producing nicotinamide adenine dinucleotide phosphate (NADPH)—oxidase complex in phagocytes. In the Western population, the most prevalent form of CGD (about two-thirds of all cases) is the X-linked form (X-CGD) caused by mutations in CYBB. The autosomal recessive forms (AR-CGD), due to mutations in the other genes, collectively account for the remaining one-third of CGD cases. We investigated the clinical and molecular features of 22 Jordanian, 7 Libyan, and 2 Iraqi CGD patients from 21 different families. In addition, 11 sibling patients from these families were suspected to have been died from CGD as suggested by their familial and clinical history. All patients except 9 were children of consanguineous parents. Most of the patients suffered from AR-CGD, with mutations in CYBA, NCF1 , and NCF2 , encoding p22 phox , p47 phox , and p67 phox proteins, respectively. AR-CGD was the most frequent form, in Jordan probably because consanguineous marriages are common in this country. Only one patient from non-consanguineous parents suffered from an X910 CGD subtype (0 indicates no protein expression). AR670 CGD and AR220 CGD appeared to be the most frequently found sub-types but also the most severe clinical forms compared to AR470 CGD. As a geographical clustering of 11 patients from eight Jordanian families exhibited the c.1171_1175delAAGCT mutation in NCF2 , segregation analysis with nine polymorphic markers overlapping NCF2 indicates that a common ancestor has arisen ~1,075 years ago. [ABSTRACT FROM AUTHOR]

To define the spectrum and phenotypic characteristics of systemic autoinflammatory diseases (SAIDs) other than familial Mediterranean fever (FMF) in Arab children and to delineate diagnostic evaluation. Data retrospectively collected on patients with clinical and/or genetically proven SAIDs other than FMF at 10 tertiary Arab pediatric rheumatology clinics from 1990 to 2018. The collected data comprised the clinical findings and diagnostic evaluation including genetic testing, the provided treatment and the accrual damage related to SAIDs. A total of 144 patients (93 female) with a median age at onset of 2.5 (range 0.1–12) years were enrolled. The initial diagnosis was inaccurate in 49.3%. Consanguinity rate among parents was 74.6%. The median time-to-diagnosis for all SAIDs was 2.5 (range 0.1–10) years. There were 104 patients (72.2%) with a confirmed diagnosis and 40 patients with suspected SAIDs. Seventy-two had monogenic and 66 patients with multifactorial SAIDs while six patients had undifferentiated SAIDs. The most frequent monogenic SAIDs were LACC1 mediated monogenic disorders (n = 23) followed by CAPS (12), TRAPS (12), HIDS (12), and Majeed's syndrome (6). The most frequent multifactorial SAIDs was CRMO (34), followed by PFAPA (18), and early onset sarcoidosis (EOS) (14). Genetic analysis was performed in 69 patients; 50 patients had genetically confirmed disease. Corticosteroid used for 93 patients while biologic agents for 96 patients. Overall, growth failure was the most frequent accrual damage (36%), followed by cognitive impairment (13%). There were three deaths because of infection. This study shows a heterogenous spectrum of SAIDs with a high number of genetically confirmed monogenic diseases; notably, LACC1 associated diseases. Hopefully, this work will be the first step for a prospective registry for SAIDs in Arab countries. [ABSTRACT FROM AUTHOR]

Background: Atopic dermatitis (AD) is a common chronic inflammatory skin disorder that affects up to 3% of adults and 15%-20% of children across the world. Although the mainstay of treatment is topical corticosteroids and/or calcineurin inhibitors, a majority of patients will not achieve a control of their condition and will need systemic treatment with steroids and immunosuppressants (1). Omalizumab is a humanized anti-IgE antibody licensed by the European Medical Agency for treatment of severe allergic asthma and spontaneous chronic urticaria in children older than 6 and 12 years, respectively; and a promising efficacy of omalizumab in the treatment of severe refractory AD has been shown by the ADAPT randomized clinical trial (2). Case report: A 6-year-old male patient being treated and followed at a pediatric dermatology clinic for a diagnosis of AD since the age of 3 years, showed unresponsive disease to different topical treatment options and non-pharmacological measures. The patient was referred to our clinic for systemic treatment when his SCORAD index was 70/103. At our immunology clinic, we did an extensive workup to unveil a comorbid or underlying disease. His labs showed high IgE levels at 2500 IU/mL, hypereosinophilia, and normal IgA, IgM, and lymphocyte subsets. We started him on different lines of immunosuppressants, including cyclosporine, prednisolone, tacrolimus, and intensive topical treatment; however, the patient did not show any noticeable response for 2 years. We then started him on omalizumab 300 mg twice weekly, and the SCORAD index dropped to 57 at 12 weeks and 55 at 18 weeks. The drug is still well tolerated, and we were able to stop systemic steroids at 15 weeks of treatment. Conclusion: Off-label use of omalizumab in a 6-year-old child with refractory severe AD was effective and safe in controlling the disease even though conventional systemic immunosuppressants proved ineffective. [ABSTRACT FROM AUTHOR]

To evaluate giant aneurysms (GiAn) prevalence in Arab countries and examine contributing factors; and to review Kawasaki disease (KD) publication trends and collaborations among Arab nations. A scoping literature review was conducted to analyze the publications across the Arab world, spanning 16 countries from 1978 to 2023. The collected articles were a combination of database search with a call on Kawasaki Disease Arab Initiative (Kawarabi) members to share non-PubMed publications. Over 45 years, 50 articles originated from the Arab Countries with a 30% average annual growth rate in KD research output. Publications were evenly split between case reports (42%) and institutional series (52%). Research productivity lagged in developing nations with UAE, KSA and Egypt, contributed to 64% of total publications. Among 26 institutional series, 256 coronary artery aneurysms (CAA) from a total of 1264 KD cases were reported. Of those, 25 CAA were GiAn (prevalence 1.43% [range 0–12.5%]). The initial KD misdiagnosis rate was 4%, and incomplete KD (iKD) averaged 10.6%. Series (38.5%) that did not report iKD correlated with a higher prevalence of CAA, but not of GiAn. Longer fever duration emerged as a pivotal factor for GiAn (OR 5.06, 95%CI 1.51–17). This review unveils the research landscape of KD in the Arab world over 45 years. Initial misdiagnosis, untreated cases, delayed diagnosis and underreporting of iKD are contributing factors for an underestimated epidemiology, explaining the higher GiAn prevalence. This calls for strategic interventions to enhance KD research in these countries, aligning with Kawarabi’s mission. [ABSTRACT FROM AUTHOR]