Autoinflammatory diseases in childhood

Autoinflammatory diseases are defined as recurrent attacks of systemic inflammation that are often unprovoked (or triggered by a minor event) related to a lack of adequate regulation of the innate immune system. Within the past decade, the list of autoinflammatory diseases has included cryopyrin-associated periodic syndromes, familial Mediterranean fever, mevalonate kinase deficiency, tumor necrosis factor receptor-associated periodic syndrome, hereditary pyogenic disorders, pediatric granulomatous autoinflammatory diseases, idiopathic febrile syndromes (systemic-onset juvenile idiopathic arthritis, PFAPA syndrome), complement dysregulation syndromes and Behcet’s disease. The hereditary autoinflammatory diseases are a group of Mendelian disorders characterized by seemingly unprovoked fever and localized inflammation. Autoinflammatory diseases can activate NOD-like receptors and inflammasome products including especially interleukin 1β. In this review, it focuses on how recent advances have impacted hereditary autoinflammatory diseases.

Secondary amyloidosis in autoinflammatory diseases and the role of inflammation in renal damage

The release of proinfammatory cytokines during infam-mation represents an attempt to respond to injury, but it may produce detrimental effects. The infammasome is a large, multiprotein complex that drives proinfammatory cytokine production in response to infection and tissue injury; the best-characterized inflammasome is the nod-like receptor protein-3 （NLRP3）. Once activated, infammasome leads to the active form of caspase-1, the enzyme required for the maturation of interleukin-1beta. Additional mechanisms bringing to renal inflammatory, systemic diseases and fibrotic processes were recently reported, via the activation of the inflammasome that consists of NLRP3, apoptosis associated speck-like protein and caspase-1. Several manuscripts seem to identify NLRP3 infammasome as a possible therapeutic target in the treatment of progressive chronic kidney disease. Serum amyloid A （SAA）, as acute-phase protein with also proinfammatory properties, has been shown to induce the secretion of cathepsin B and infammasome components from human macrophages. SAA is a well recognised potent activator of the NLRP3. Here we will address our description on the involvement of the kidney in autoinflammatory diseases driven mainly by secondary, or reactive, AA amyloidosis with a particular attention on novel therapeutic approach which has to be addressed in suppressing underlying inflammatory disease and reducing the SAA concentration.

Panorama of Autoimmune and Autoinflammatory Diseases in Internal Medicine at the University Hospital Center (UHC) of the Point G

Introduction: Panorama studies of autoimmune and auto-inflammatory diseases are still very little carried out in Africa and particularly in Mali. The objective of this descriptive study with retrospective collection was to describe the epidemiological and clinical profile of all autoimmune and auto-inflammatory diseases in the department of internal medicine at the University Hospital Center of the Point G. Methods: This was a descriptive study with a retrospective survey of the records of patients hospitalized for autoimmune and auto-inflammatory diseases in the department of internal medicine at the CHU of Point G for a study period of 15 years from January 1, 2005 to December 31, 2019. We included in the study all patients hospitalized for autoimmune and auto-inflammatory diseases. Results: During the study period (January 31, 2005 to December 31, 2019), 6383 patients were hospitalized in internal medicine at the University Hospital Center of the Point G, of which 317 patients presented with autoimmune and/or auto-inflammatory disease with an average annual hospital recruitment rate of 21 ± 7.87 cases per year. The female sex accounted for 64.98% with a sex ratio of 0.54. The mean age of patients was 35.27 ± 16.27 years and the extreme ages were 07 and 79 years. Out of the 317 medical records included according to our inclusion criteria, there were 07 cases of association between autoimmune disease and autoinflammatory disease, i.e. 14 cases of autoimmune and autoinflammatory diseases. A total of 331 autoimmune diseases and/or auto-inflammatory diseases were collected, i.e. a frequency of 5.19%, including 291 cases of autoimmune diseases (221 cases of organ-specific autoimmune diseases and 70 cases of systemic autoimmune diseases) and 40 cases of autoinflammatory diseases (no case of monogenic forms, 08 cases of “systemic” polygenic forms and 32 cases of “organ-specific” polygenic forms). Organ-specific autoimmune diseases were dominated by type 1 diabetes (141 cases), Graves’ disease (48 cases) and systemic autoimmune diseases by systemic lupus erythematosus (43 cases), rheumatoid arthritis (16 cases). Among the auto-inflammatory diseases, the “systemic” polygenic forms were dominated by Horton’s disease (02 cases) and the “organ-specific” polygenic forms by gout (16 cases), ulcerative colitis (08 cases). Conclusion: It appears from our study that autoimmune and autoinflammatory diseases are characterized in internal medicine by their frequent occurrence in women and preferably between 25 and 44 years of age with very disparate distribution. We also observed a predominance of organ-specific autoimmune diseases over systemic ones, and “organ-specific” polygenic autoinflammatory diseases over “systemic” ones.

Clinical heterogeneity of NLRP12-associated autoinflammatory diseases

Nod-like receptor family pyrin domain-containing protein 12 (NLRP12) is one of the critical pattern recognition receptors which participates in the regulation of multiple inflammatory responses. Mutations in NLRP12 cause exceptionally rare NLRP12-associated autoinflammatory disease (NLRP12-AID). So far, very few patients with NLRP12-AID have been identified worldwide;therefore, data on the clinical phenotype and genetic profile are limited. In this study, we reported 10 patients who presented mainly with periodic fever syndrome or arthritis. Next-generation sequencing (NGS) identified 6 heterozygous mutations of NLRP12, including 2 novel null mutations. Of the patients, some with same mutations showed different clinical features. Compared to healthy controls, the increased levels of cytokines were revealed in the patients' plasmas, as well as in the supernatants of patients’ cells stimulated with lipopolysaccharide (LPS) or tumor necrosis factor-α (TNF-α). The missense mutations did not change the protein expression;but decreased level of NLRP12 protein was shown in the null mutations. And in vitro expression assay demonstrated a truncating protein induced by the frameshift mutation. Further functional studies revealed the deleterious effect of mutations on nuclear factor-kappa B (NF-κB) signaling. Both the null and missense mutations impaired their inhibition of NF-κB activation induced by p65. Collectively, this study reported a relatively large NLRP12-AID case series. Our findings expand the clinical spectrum, and reinforce the diversity of genetic mutations and clinical phenotypes. The NLRP12-associated disorder should be considered when autoinflammatory diseases are encountered in the clinical practice, especially for patients presenting with periodic fever but no other genetic cause identified.

IFIH1 and DDX58 gene variants in pediatric rheumatic diseases

BACKGROUND The IFIH1 gene codes the MDA5 protein and the DDX58 gene codes the RIG-I receptor.Both proteins are parts of the interferon(IFN)I signaling pathway and are responsible for antiviral defense and innate immune response.IFIH1 and DDX58 polymorphisms are associated with a spectrum of autoimmune diseases.Rare gain-of-function IFIH1 mutations have been found in Singleton-Merten and Aicardi-Goutières syndrome,while DDX58 mutation can cause atypical Singleton-Merten syndrome.AIM To characterize children with pediatric rheumatic diseases(PRD)carrying DDX58 or IFIH1 variants.METHODS Clinical exome sequencing was performed on 92 children with different PRD.IFIH1 and DDX58 variants have been detected in 14 children.IFN-I score has been analyzed and the clinical characteristics of patients have been studied.RESULTS A total of seven patients with systemic lupus erythematosus(SLE)(n=2),myelodysplastic syndrome with SLE features at the onset of the disease(n=1),mixed connective tissue disease(MCTD)(n=1),undifferentiated systemic autoinflammatory disease(uSAID)(n=3)have 5 different variants of the DDX58 gene.A common non-pathogenic variant p.D580E has been found in five children.A rare variant of uncertain significance(VUS)p.N354S was found in one patient with uSAID,a rare likely non-pathogenic variant p.E37K in one patient with uSAID,and a rare likely pathogenic variant p.Cys864fs in a patient with SLE.Elevated IFN-I score was detected in 6 of 7 patients with DDX58 variants.Seven patients had six different IFIH1 variants.They were presented with uSAID(n=2),juvenile dermatomyositis(JDM)(n=1),SLElike disease(n=1),Periodic fever with aphthous stomatitis,pharyngitis,and adenitis syndrome(n=1),and systemic onset juvenile idiopathic arthritis(n=1).Three patients have VUS p.E627X,one patient has benign variant p.I923V.Rare VUS p.R595H was detected in the JDM patient.Another rare VUS p.L679Ifs*2 and previously not reported variant p.V599Ffs*5 were detected in the patient with uSAID.One patient with uSAID has rare VUS p.T520A.All patients had elevated IFN-I scores.CONCLUSION Rare compound-heterozygous IFIH1 variant(p.L679Ifs*2 and p.V599Ffs*5),heterozygous IFIH1 variant(p.T520A)and heterozygous DDX58 variant(p.Cys864fs)are probably disease causative for uSAID and SLE.The majority of patients with different DDX58 and IFI1 variants had hyperactivation of the IFN I signaling pathway.

Adult-onset Still's disease: A case report

Rationale: Fever of unknown origin (FUO) is a frequently observed phenomenon in clinical practice. Definite diagnosis of FUO is a great challenge in clinical practice since potential causes for FUO involve more than 200 diseases. Adult-onset Still's disease is a defined clinical entity and a known rare cause of FUO. Patient's concern: A 19-year girl was referred to the clinic with the concern of intermittent fevers and shivering for almost a year despite multiple investigations and consultations. She had undergone intensive serologic, radiologic, laboratory investigations to exclude infectious diseases, connective tissue diseases, and malignancy, and all the investigation showed no conclusive diagnosis. Diagnosis: Adult-onset Stills disease. Intervention: Steroids and supportive treatment. Outcomes:The symptoms were relieved within three days, and the patient became asymptomatic. Lessons: Physicians need to be familiar with the diagnostic criteria of adult-onset Still's disease, or it shall remain a diagnostic dilemma. Besides, all shivers are not infections.

Pyogenic arthritis,pyoderma gangrenosum,and acne syndrome in a Chinese family:A case report and review of literature

BACKGROUND Pyogenic arthritis,pyoderma gangrenosum,and acne(PAPA)syndrome is a rare autosomal dominant genetic disease characterized by severe autoimmune inflammation,caused by mutations in the PSTPIP1 gene.Due to PAPA heterogeneous clinical manifestation,misdiagnosis or delayed diagnoses are difficult to avoid.With the use of whole-exome sequencing,we identified a missense mutation in the PSTPIP1 gene in a Chinese family.To the best of our knowledge,this is the first case of PAPA reported in China.CASE SUMMARY A 9-year-old boy suffered from recurrent aseptic pyogenic arthritis triggered by minor trauma or few obvious predisposing causes for more than 3 years.Pyogenic arthritis occurred every 3-5 mo,affecting his knees,elbows,and ankle joints.Treatments,such as glucocorticoids,antibiotics,even surgeries could alleviate joints pain and swelling to some extent but could not inhibit the recurrence of arthritis.Similar symptoms were present in his younger brother but not in his parents.According to the whole-exome sequencing,a missense mutation in exon 11 of the PSTPIP1 gene(c.748G>C;p.E250Q)was detected in the boy,his young-er brother and his father.Taking into account the similar phenotypic features with PAPA syndrome reported previously,we confirmed a diagnosis of PAPA syndrome for the family.CONCLUSION In this case,a missense mutation(c.748G>C;p.E250Q)in PSTPIP1 gene was identified in a Chinese family with PAPA syndrome.Previous studies emphasize the fact that PAPA syndrome is hard to diagnose just through the clinical manifestations owing to its heterogeneous expression.Genetic testing is an effectual auxiliary diagnostic method,especially in the early stages of pyogenic arthritis.Only if we have a deep understanding and rich experience of this rare disease can we make a prompt diagnosis,develop the best clinical treatment plan,and give good fertility guidance.

The clinical phenotype and genotype of NLRP12-autoinflammatory disease: a Chinese case series with literature review

Background The nucleotide-binding oligomerization domain-like receptor protein 12(NLRP12)-autoinflammatory disorder(NLRP12-AD)is a rare autoinflammatory disease characterized by recurrent fever,rash as well as musculoskeletal symptoms,which is rarely reported in Asian populations.Methods Three cases of NLRP12-AD presented to our hospital were studied after parental consents were obtained.Clinical presentations were recorded on a standardized case report form.Mutations of NLRP12 were detected by primary immunodeficiency disease panels and further examined by Sanger sequencing.PubMed literature search for relevant studies of systemic autoinflammatory disorders,especially NLRP12-AD between January,2000 and January,2019 was carried and the clinical data were summarized.Comparisons were made between groups in terms of onset age and of ethnicity.Results All our patients presented with fever,rash and arthritis/arthralgia,and sensorineural as well as sensorineural deafness(1/3),uveitis(1/3),abdominal pain(1/3),and myalgia(1/3).Two novel mutation variations,p.W581X and p.L558R,are reported here.In addition,we also found that two patients inherited the mutated alleles from their healthy parents,and this may be evidence of haploinsutficiency.Conclusions Although the genotypes are similar,the clinical manifestations between Chinese patients and Western patients vary thus highlighting the possible influence of ethnic and environmental factors.On the other hand,some genetic mutations may lead to specific phenotype,as we have found a high prevalence of sensorineural hearing loss among p.R284X patients.

Twists and turns of the genetic story of mevalonate kinase-associated diseases:A review

Mevalonate kinase (MK)-associated diseases encompass a broad spectrum of rare auto-inflammatory conditions, all resulting from pathogenic variants in the mevalonate kinase gene (MVK). Their clinical manifestations are highly variable, ranging from more or less serious systemic disorders, such as hereditary recurrent fevers, to purely localized pathologies such as porokeratosis. The oldest condition identified as linked to this gene is a metabolic disease called mevalonic aciduria, and the most recent is disseminated superficial actinic porokeratosis, a disease limited to the skin. The modes of inheritance of MK-associated diseases also diverge among the different subtypes: recessive for the systemic subtypes and dominant with a post-zygotic somatic genetic alteration for MVK-associated porokeratosis. This review quickly retraces the historical steps that led to the description of the various MK-associated disease phenotypes and to a better understanding of their pathophysiology, then summarizes and compares the different genetic mechanisms involved in this group of disorders, and finally discusses the diverse causes that could underlie this phenotypic heterogeneity.

The inflammasomes in health and disease:from genetics to molecular mechanisms of autoinflammation and beyond

Nucleotide-binding oligomerization domain(NOD)-containing protein-like receptors(NLRs)are a recently discovered class of innate immune receptors that play a crucial role in initiating the inflammatory response following pathogen recognition.Some NLRs form the framework for cytosolic platforms called inflammasomes,which orchestrate the early inflammatory process via IL-1b activation.Mutations and polymorphisms in NLR-coding genes or in genetic loci encoding inflammasome-related proteins correlate with a variety of autoinflammatory diseases.Moreover,the activity of certain inflammasomes is associated with susceptibility to infections as well as autoimmunity and tumorigenesis.In this review,we will discuss how identifying the genetic characteristics of inflammasomes is assisting our understanding of both autoinflammatory diseases as well as other immune system-driven disorders.

Toward a better understanding of typeⅠinterferonopathies:a brief summary,update and beyond

Backgrounds TypeⅠinterferonopathy is a group of autoinflammatory disorders associated with prominent enhanced typeⅠinterferon signaling.The mechanisms are complex,and the clinical phenotypes are diverse.This review briefly summarized the recent progresses of typeⅠinterferonopathy focusing on the clinical and molecular features,pathogeneses,diagnoses and potential therapies.Data sources Original research articles and literature reviews published in PubMed-indexed journals.Results TypeⅠinterferonopathies include Aicardi-Goutières syndrome,spondyloenchondro-dysplasia with immune dysregulation,stimulator of interferon genes-associated vasculopathy with onset in infancy,X-linked reticulate pigmentary disorder,ubiquitin-specific peptidase 18 deficiency,chronic atypical neutrophilic dermatitis with lipodystrophy,and Singleton-Merten syndrome originally.Other disorders including interferon-stimulated gene 15 deficiency and DNAseⅡdeficiency are believed to be interferonopathies as well.Intracranial calcification,skin vasculopathy,interstitial lung disease,failure to thrive,skeletal development problems and autoimmune features are common.Abnormal responses to nucleic acid stimuli and defective regulation of protein degradation are main mechanisms in disease pathogenesis.First generation Janus kinase inhibitors including baricitinib,tofacitinib and ruxolitinib are useful for disease control.Reverse transcriptase inhibitors seem to be another option for Aicardi-Goutières syndrome.Conclusions Tremendous progress has been made for the discovery of typeⅠinterferonopathies and responsible genes.Janus kinase inhibitors and other agents have potential therapeutic roles.Future basic,translational and clinical studies towards disease monitoring and powerful therapies are warranted.

A novel plasminogen mutation in a child with hereditary periodic syndrome: A case report

Introduction:Plasminogen(PLG)deficiency is an ultrarare disease.The reported manifestations in literature were linked to pseudomembrane formation and mucosal surfaces inflammation.Recently,PLG,its activa-tors and its receptors have gained more attention in inflammation regulatory processes,including the release of proinflammatory signaling molecules,and thus its role is believed to have clinical implications beyond what has been known.Case Report:We present a child with recurrent fever who,although managed initially as familial Mediterranean fever,later on,developed a constellation of findings that were not explained by a classified autoinflammatory disease.Genetic testing revealed a novel homozygous PLG mutation(PLG:c.466G>A:p.D156N)and a likely benign heterozygous MEFV gene variant.We propose that the PLG mutation is responsible for the clinical manifestations,which may or may not be exacerbated by the coexistence of the MEFV variant.A relationship between the PLG pathway,inflammation,and FMF severity has been addressed recently in several studies.Conclusion:This report highlights the recently recognized role of the PLG pathway in inflammatory diseases and describes a potentially new presenta-tion of PLG pathogenesis.Further studies are needed to confirm this finding and allow for a more definitive conclusion.