Biallelic human SHARPIN loss of function induces autoinflammation and immunodeficiency.

The linear ubiquitin assembly complex (LUBAC) consists of HOIP, HOIL-1 and SHARPIN and is essential for proper immune responses. Individuals with HOIP and HOIL-1 deficiencies present with severe immunodeficiency, autoinflammation and glycogen storage disease. In mice, the loss of Sharpin leads to severe dermatitis due to excessive keratinocyte cell death. Here, we report two individuals with SHARPIN deficiency who manifest autoinflammatory symptoms but unexpectedly no dermatological problems. Fibroblasts and B cells from these individuals showed attenuated canonical NF-κB responses and a propensity for cell death mediated by TNF superfamily members. Both SHARPIN-deficient and HOIP-deficient individuals showed a substantial reduction of secondary lymphoid germinal center B cell development. Treatment of one SHARPIN-deficient individual with anti-TNF therapies led to complete clinical and transcriptomic resolution of autoinflammation. These findings underscore the critical function of the LUBAC as a gatekeeper for cell death-mediated immune dysregulation in humans.

Study of NLRP3 Single Nucleotide Polymorphisms in Juvenile Systemic Lupus Erythematosus (JSLE).

Juvenile systemic lupus erythematosus (JSLE) is a multifaceted multifactorial disorder with an unclear etiopathogenesis. Environmental factors, genetic factors, and dysregulated and defective immune system responses are known to have a role in JSLE etiopathogenesis. NLRP3 inflammasome, as an important contributor to immune-mediated inflammatory responses, is assumed to be involved in JSLE etiopathogenesis. To determine whether the NLRP3 genetic variants are altered in patients with JSLE. Fifty-three patients diagnosed with JSLE and 56 healthy sex-matched controls were studied. NLRP3 (C/G rs10754558, C/T rs3806265, C/T rs4612666, A/C rs35829419) gene polymorphisms were evaluated using a TaqMan single-nucleotide polymorphism assay. C allele at position rs3806265 was detected in higher frequencies in patients than in the control group (37.74% vs 23.21%, P-value = .028). At the genotype level at the same position, CT has a significantly higher frequency in patients than the healthy subjects (75.47% vs 46.43%, P-value = .003). The NLRP3 rs3806265 CT genotype was detected at a higher frequency in patients with JSLE than in the healthy control group.

DNA Methylation of CD70 Promoter in Juvenile Systemic Lupus Erythematosus.

INTRODUCTION: Epigenetic alterations in pathogenesis of systemic lupus erythematosus (SLE) have gained more attention recently in adults. We assessed the methylation of CD70 promoter, a costimulatory molecule on T cells, in juvenile SLE (JSLE), and compared this to that found in controls and the literature of adult SLE patients. METHODS: DNA methylation status was evaluated on peripheral blood from JSLE patients and healthy controls. RESULTS: Twenty-five patients with JSLE and 24 healthy controls were compared. JSLE patients had lower unmethylated CpG islands compared to the control group (mean ± SD; 0.78 ± 0.42 vs 10503.80 ± 39796.95). However, the difference was not significant (P-value; 0.22). CONCLUSION: Despite hypomethylation of CD70 gene promoter in CD4+ T-cells from adult patients with SLE, no statistically significant differences observed in patients with JSLE compared with healthy controls. This may suggest a mechanism different in JSLE patients than in adults.

Phenotypic analysis of pyrin-associated autoinflammation with neutrophilic dermatosis patients during treatment.

OBJECTIVE: In 2016 specific heterozygous gain-of-function mutations in the Mediterranean fever gene MEFV were reported as causal for a distinct autoinflammatory disease coined pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND). We sought to provide an extended report on clinical manifestations in PAAND patients to date and evaluate the efficacy and safety of treatment with the IL-1-blocking agent anakinra. METHODS: We undertook an open-label pilot study with anakinra. Three patients were recruited in a preliminary phase of the study with the intention to expand the treatment cohort in case of a favourable response. Acute-phase reactants and plasma cytokine levels were monitored throughout. Skin biopsies at baseline and at week 12 were stained for relevant cytokines. Available clinical data on treatment responses were retrospectively collected on additional patients. RESULTS: The three patients from the preliminary phase of the study [patients 1-3 (P1-P3)] demonstrated one failed and two partial treatment responses, where one patient opted to continue treatment with anakinra and the other favoured adalimumab. While a partial systemic response was observed, there was no appreciable effect of anakinra on the prominent cutaneous manifestations, reflected in residual local inflammatory cytokine expression in lesional skin. These observations did not warrant further expansion of the treatment cohort. Clinical data was retrospectively collected on an additional eight patients (P4-P11), highlighting both dominant and recessive inheritance with variable penetrance in PAAND and common gastrointestinal involvement that was not previously appreciated. CONCLUSION: In our experience, while anakinra appears safe, it was not superior to biologicals targeting TNF-α in PAAND despite evidence directly implicating dysregulated IL-1ß signalling.

Multimodality imaging of constrictive pericarditis in H syndrome.

This is the first report of constrictive pericarditis (CP) in a 16-year-old boy with H syndrome with pericardial involvement predominantly over the right ventricle with favorable response to anti-inflammatory treatment. H syndrome, first reported in 2008, is a new auto-inflammatory syndrome with multiorgan involvement due to mutation in the SLC29A3 gene. We described the echocardiographic characteristics of asymmetric pericardial involvement and presented the cardiac computed tomography angiographic and magnetic resonance imaging findings. We reviewed the echocardiographic signs of CP, introduced tricuspid E/A respiratory alternans as a novel echocardiographic sign of right ventricular dominant CP, and explained the underlying mechanism.

Multisystem inflammatory syndrome associated with SARS-CoV-2 infection in 45 children: a first report from Iran.

During the coronavirus disease 2019 (COVID-19) pandemic, a new phenomenon manifesting as a multisystem inflammatory syndrome in children (MIS-C) which has a similar clinical presentation to Kawasaki disease, toxic shock syndrome and severe sepsis has emerged. Although the number of MIS-C reports is increasing, rare reports in Asia is still available. To our knowledge, this study is the largest series of published MIS-C cases in Iran. We performed a retrospective study of all patients with case definition for MIS-C admitted to the three paediatric hospitals in Iran. All of these hospitals are located within the most active COVID-19 pandemic areas (Tehran, Qom and Mazandaran) in Iran. Demographic characteristics, clinical data, laboratory findings, imaging and echocardiographic findings, treatment and outcomes were collected. Between 7 March and 23 June 2020, 45 children were included in the study. The median age of children was 7 years (range between 10 months and 17 years). Common presenting symptoms include fever (91%), abdominal pain (58%), nausea/vomiting (51%), mucocutaneous rash (53%), conjunctivitis (51%) and hands and feet oedema (40%) with median duration of symptoms prior to presentation of 5 (interquartile range (IQR) 3, 7) days. Fifty-three percent of children showed lymphopaenia. Overall, the majority of cases at admission had markedly elevated inflammatory markers erythrocyte sedimentation rate (ESR) (95.5%) and C-reactive protein (CRP) (97%). Ferritin was abnormal in 11 out of 14 tested patients (73%), and it was highly elevated (>500 ng/ml) in 47% of cases. Median fibrinogen level was 210 (IQR 165, 291) mg/dl, D-dimer was 3909 (IQR 848, 4528) ng/ml and troponin was 0.6 (IQR 0.1, 26) ng/ml, respectively. Twenty out of 31 patients (64.5%) had hypoalbuminaemia. In addition, hyponatraemia was found in 64% of cases. Twenty-five patients (56%) presented with cardiac involvement and acute renal failure was observed in 13 cases (29%). Pleural, ascitic, ileitis and pericardial effusions were found in 18%, 11%, 4% and 2% of cases, respectively. In conclusion, this is a first large case series of hospitalised children who met criteria for MIS-C in Iran. There was a wide spectrum of presenting signs and symptoms; evidence of inflammation with abnormal values of CRP, ESR, D-dimer, ferritin and albumin; and multi-organ involvement.

PTPN22 Gene Polymorphisms in Pediatric Systemic Lupus Erythematosus.

Objective: Pediatric systemic lupus erythematosus (PSLE) is a heterogeneous autoimmune disorder of unknown origin. PTPN22 gene polymorphisms have been associated with SLE in different populations. We investigated the associations of the rs2476601, rs1217414, rs33996649, rs1276457, and rs1310182 SNPs in the PTPN22 gene with PSLE. Materials and methods: 55 PSLE patients and 93 healthy controls were recruited. SNPs were genotyped by the real-time PCR allelic discrimination method. Results: We found that the PTPN22 polymorphisms rs1310182 A allele (p = 0.01, OR = 1.92 95% CI = 1.16-3.18), and rs1310182 AA genotype with (p < 0.001) and rs12760457 TT (p = 0.046) were associated with PSLE. No significant associations were found between other SNPs and PSLE. Conclusions: The PTPN22 rs1310182 A allele and rs1310182 AA genotype were associated with PSLE and may be a possible genetic marker for susceptibility to PSLE. However, further investigation would be required to elucidate the mechanistic role of this association.

Farber disease: report of three cases with joint involvement mimicking juvenile idiopathic arthritis.

Farber disease is a rare recessive autosomal disorder presented with three main features of joint involvement, subcutaneous nodules and hoarseness. Hereby we describe three new cases of Farber disease. All three cases were first misdiagnosed as juvenile idiopathic arthritis (JIA) due to the presentation of joint swelling. Addition of hoarseness and subcutaneous nodules to the initial joint swelling questioned the diagnosis of JIA and further evaluations led to the diagnosis of Farber disease. The first case was a 4-year old girl in whom a novel genetic mutation in ASAH1 gene was found. The second patient was a 4-year old girl presented with joint swelling at 7 month of age. The third patient was a 9-month boy complicated with severe respiratory distress. All patients were treated with symptomatic and supportive care. Two cases died due to respiratory ailure and infection, but one patient follow up for 2 years after diagnosis. Farber disease should be considered as differential diagnosis in children with early onset of poly articular involvement with subcutaneous nodules and/or hoarseness.

Direct Immunofluorescence Results of the Skin Biopsy and Frequency of Systemic Involvement in Children with Henoch-Schonlein Purpura.

OBJECTIVE: Henoch-Schonlein purpura (HSP) is a common vasculitis in children that can present with multi-organ involvement. The aim of this study is to investigate the correlation between direct immunofluorescence (DIF) results and the systemic involvements of the HSP in pediatric patients. MATERIAL AND METHODS: Those HSP patients with leukocytoclastic vasculitis on their biopsies who also had documented immunoglobulin/complement deposition by DIF were included in our study. Their demographic and laboratory data and clinical manifestations were recorded and analyzed. RESULTS: Medical records of 95 patients (1.5-15 years old) were studied. 26.3% of the patients showed renal, 86.3% articular, and 70.3% gastrointestinal involvement. The risk of renal involvement was significantly higher in those with C3 deposition in their skin DIF. IgM deposition was mostly associated with articular involvement. CONCLUSION: Pediatric HSP patients who had C3 deposition in their skin DIF should be selected for further evaluation regarding HSP nephritis.

The genetic basis of hyaline fibromatosis syndrome in patients from a consanguineous background: a case series.

BACKGROUND: Hyaline fibromatosis syndrome (HFS) is a rare heritable multi-systemic disorder with significant dermatologic manifestations. It is caused by mutations in ANTXR2, which encodes a transmembrane receptor involved in collagen VI regulation in the extracellular matrix. Over 40 mutations in the ANTXR2 gene have been associated with cases of HFS. Variable severity of the disorder in different patients has been proposed to be related to the specific mutations in these patients and their location within the gene. CASE PRESENTATION: In this report, we describe four cases of HFS from consanguineous backgrounds. Genetic analysis identified a novel homozygous frameshift deletion c.969del (p.Ile323Metfs*14) in one case, the previously reported mutation c.134 T > C (p.Leu45Pro) in another case, and the recurrent homozygous frameshift mutation c.1073dup (p.Ala359Cysfs*13) in two cases. The epidemiology of this latter mutation is of particular interest, as it is a candidate for inhibition of nonsense-mediated mRNA decay. Haplotype analysis was performed to determine the origin of this mutation in this consanguineous cohort, which suggested that it may develop sporadically in different populations. CONCLUSIONS: This information provides insights on genotype-phenotype correlations, identifies a previously unreported mutation in ANTXR2, and improves the understanding of a recurrent mutation in HFS.

The Farsi version of the Juvenile Arthritis Multidimensional Assessment Report (JAMAR).

The Juvenile Arthritis Multidimensional Assessment Report (JAMAR) is a new parent/patient reported outcome measure that enables a thorough assessment of the disease status in children with juvenile idiopathic arthritis (JIA). We report the results of the cross-cultural adaptation and validation of the parent and patient versions of the JAMAR in the Farsi language. The reading comprehension of the questionnaire was tested in 10 JIA parents and patients. Each participating centre was asked to collect demographic, clinical data and the JAMAR in 100 consecutive JIA patients or all consecutive patients seen in a 6-month period and to administer the JAMAR to 100 healthy children and their parents. The statistical validation phase explored descriptive statistics and the psychometric issues of the JAMAR: the three Likert assumptions, floor/ceiling effects, internal consistency, Cronbach's alpha, interscale correlations, test-retest reliability, and construct validity (convergent and discriminant validity). A total of 102 JIA patients (14.7% systemic JIA, 67.6% oligoarticular, 15.7% RF negative polyarthritis, 2.0% other categories) and 198 healthy children, were enrolled in three paediatric rheumatology centres. Notably, none of the enrolled JIA patients is affected with enthesitis-related arthritis or undifferentiated arthritis. The JAMAR components discriminated healthy subjects from JIA patients. All JAMAR components revealed satisfactory psychometric performances. In conclusion, the Farsi version of the JAMAR is a valid tool for the assessment of children with JIA and is suitable for use both in routine clinical practice and clinical research.

Lack of Association between STAT4 Single Nucleotide Polymorphisms and Iranian Juvenile Rheumatoid Arthritis Patients.

Juvenile rheumatoid arthritis (JRA) is a common chronic systemic autoimmune disease in children. Single nucleotide polymorphisms (SNPs) of signal transducer and activator of transcription 4 (STAT4) gene are suspected to have association with the risk of autoimmune diseases. Previous investigations have indicated that the STAT4 rs7574865 T allele was significantly associated with rheumatoid arthritis. In this study, we aimed to evaluate the association of STAT4 SNPs with JRA in Iranian population. T allele of STAT4 rs7574865 SNP was less frequent in patients than in controls, and the difference was not significant (p = 0.19, OR = 0.72, 95% CI: 0.44 -1.17). In addition, G allele of this SNP was frequent but not significant in JRA patients (p = 0.19, OR = 1.38, 95% CI: 0.85-2.25). Neither alleles nor genotypes of rs7601754 SNP of STAT4 gene demonstrated associations with JRA. We recognize that gene variants of STAT4 did not affect JRA susceptibility in Iranian population.

Association of PTPN22 Gene Polymorphisms with Susceptibility to Juvenile Idiopathic Arthritis in Iranian Population.

Juvenile idiopathic arthritis (JIA), the most common cause of chronic arthritis in children, is a complex immune-mediated disease with considerable long-term morbidity and mortality. According to previous studies, PTPN22 gene has been associated with JIA in several populations. In the present study, we attempted to determine the association of PTPN22 single nucleotide polymorphisms (SNPs) with susceptibility to JIA in Iranian population. Using the Real-time PCR allelic discrimination method, samples consisting of 55 unrelated patients and 93 healthy controls were genotyped. Using Fisher exact test or Chi-square test, genotypic and allelic frequencies were estimated. The results of our study indicated a significantly decreased association of rs1310182 (OR = 0.59, 95% CI = 0.36 -0.97, p = 0.037) with JIA. This association may indicate a protective role for rs1310182 SNP against JIA. More research would be needed to elucidate the mechanistic role of this association.

Association Study of MECP2 Gene Single Nucleotide Polymorphisms in Juvenile-Onset Systemic Lupus Erythematosus Patients from Iran.

INTRODUCTION: Juvenile-onset systemic lupus erythematosus is a multigenic autoimmune disorder. Polymorphisms of MECP2 gene have been reported to increase the risk of adult-onset SLE. In this study, we aimed to analyze if MECP2 gene polymorphisms could impress the proneness to JSLE in Iranian population. MATERIAL AND METHODS: Polymorphisms of MECP2 gene were genotyped in 50 Iranian JSLE patients and 426 matched healthy controls employing the real-time PCR allelic discrimination technique. RESULTS: None of the alleles and genotypes of MECP2 gene SNPs had significantly different distribution between patients and controls. The CTAT haplotype was represented more frequently and significantly in JSLE cases than in controls. A strong linkage disequilibrium was observed among the variants. CONCLUSIONS: Although adult-onset SLE had been associated with MECP2 gene variants, this gene is not associated with disease susceptibility in JSLE patients, implying the involvement of different susceptibility genes in the pathogenesis of SLE and JSLE.

Intermittent neutropenia as an early feature of mild mevalonate kinase deficiency.

A 15-month-old boy, born to Iranian consanguineous parents presented with intermittent neutropenia interspersed with episodes of fever and leukocytosis since early infancy. No ELA2 mutations were found and the bone marrow study was normal. At age 4 years he progressed to more typical attacks of periodic attacks of fever, abdominal pain, oral aphthous ulcers, cutaneous rash and leukocytosis. The clinical and laboratory features were compatible with the mild form of mevalonate kinase deficiency, usually named "Hyper-IgD and periodic fever syndrome" (HIDS). Genomic sequencing of the mevalonate kinase (MVK) gene revealed homozygous missense mutation (p.Val377Ile). On demand dexamethasone resulted in a rapid amelioration of febrile episodes. The presentation of intermittent neutropenia has not been reported in HIDS and deserves more attention in large patient cohorts.

Sensitivity and specificity of adenosine deaminase in diagnosis of juvenile idiopathic arthritis.

BACKGROUND: Juvenile Idiopathic Arthritis (JIA) is one of the most common chronic rheumatic diseases inchildren with unknown etiology and pathogenesis. It also has no diagnostic test and its clinical diagnosis ismade through ruling out other types of arthritis. The aim of this study was to evaluate the level of ADA (AdenosineDeaminase) in the serum of JIA patients and to compare it with that of patients with Reactive Arthritis(RA). Evaluation of sensitivity and specificity of serum ADA level in JIA was another objective. METHODS: The study included 120 children with JIA (mean age= 7.6 ± 4.3 years) and 40 children with RA(mean age= 5.5 ± 3.1 years). The ADA was measured in the active phase of both diseases. RESULTS: The mean ADA serum level was obtained as 15.8 ± 11.8 U/l in JIA patients and 14.3 ± 7.5 U/l in RApatients. The difference was statistically insignificant (p= 0.4). Another finding of this study was the significantspecificity (77.5%) of this laboratory parameter for JIA in comparison with its low sensitivity (36.7%). Positivepredictive value was 83% and negative predictive value 29%. CONCLUSION: Determination of ADA serum levels is a noninvasive reliable and easy biomarker for diagnosis ofJIA and it can be used as alternative parameters representing disease activity.

Exploring the association between serum Vitamin D levels and the development of coronary artery lesions in Kawasaki disease - a systematic review.

BACKGROUND: Kawasaki Disease (KD) involves arterial inflammation, primarily affecting the coronary arteries and leading to coronary artery lesions. Recent advancements in understanding the immunomodulatory roles of vitamin D have prompted investigations into the potential correlation between serum vitamin D levels and the risk of coronary artery lesions (CAL) in KD. This review aims to explore this association. METHODS: A systematic search utilizing relevant keywords related to Kawasaki disease and coronary artery lesions was conducted across four databases (PubMed, Embase, Scopus, and Web of Science). The quality of the incorporated studies was assessed utilizing the Newcastle-Ottawa Scale. The study protocol is registered in PROSPERO under the registry code CRD42024493204. RESULTS: In a review of five studies involving 442 KD patients and 594 healthy controls, KD patients generally had lower serum vitamin D levels compared to controls, with mixed findings on the association with coronary artery lesions and IVIG resistance. While three studies supported lower vitamin D in KD, one showed no significant difference. Regarding CAL, one study found lower vitamin D, another found higher levels associated with CAL, and two found no significant difference. CONCLUSIONS: Overall, the evidence is inconclusive, but there's a trend suggesting potential benefits of sufficient vitamin D levels in Kawasaki disease rather than evidence refuting any association with clinical outcomes.

Acute Abdomen as a Clinical Presentation of COVID-19-Associated Multisystem Inflammatory Syndrome in Children.

Background: On December 2019, a novel coronavirus disease (COVID-19) spread worldwide and became a pandemic. Multisystem inflammatory syndrome in children (MIS-C) due to cytokine release syndrome following COVID-19 presents with various manifestations. We hypothesize that one of the rare manifestations is acute abdomen. Case Presentation. In this case series, eight cases (five girls and three boys) of gastrointestinal (GI) involvement and acute abdomen were reported to be associated with the cytokine storm due to COVID-19 infection. All patients were of Iranian nationality (Caucasian ethnicity), with a mean age of 8.9 years (range 3.5-14). They all presented with fever and acute abdominal pain. Additionally, maculopapular rash and edema of the extremities were common presentations. Free fluid on abdominal ultrasound or computerized tomography (CT) scan was observed in all patients. All cases tested positive for COVID-19. In six cases, laparotomy or abdominal surgery was performed for a diagnosis of acute abdomen, but appendicitis was confirmed in only one case. None of the cases presented with phlegmon. Elevated serum lipase and amylase levels were noted in two cases. Seven patients received corticosteroid pulse therapy. Clinical symptoms improved after one or two doses, and all patients were discharged after 4 weeks of follow-up with no mortality or morbidity. Conclusion: Patients experiencing unexplained acute abdominal pain along with fever, skin rash, and peripheral edema, who had a history of COVID-19 infection prior to or during the episode of acute abdomen symptoms, should be considered to have MIS-C. Furthermore, methylprednisolone pulse therapy could be a safe treatment option, reducing hospitalization duration in this patient population.