Background A20,a protein encoded by the tumor necrosis factor alpha-induced protein 3 gene(TNFAIP3),plays a vital role in the negative regulation of inflammation and immunity.Loss-of-function mutation in TNFAIP3 leads...Background A20,a protein encoded by the tumor necrosis factor alpha-induced protein 3 gene(TNFAIP3),plays a vital role in the negative regulation of inflammation and immunity.Loss-of-function mutation in TNFAIP3 leads to a new described autoinflammatory disease-haploinsufficiency of A20(HA20).Since HA20 was first described in 2016,a number of new cases have been described in this literature,however,the disease and its pathogenesis are poorly understood.This review seeks to improve clinical recognition of this disorder,and promote both earlier diagnosis and initiation of targeted therapies to improve patients’outcomes.Methods We reviewed 26 papers about A20 and HA20,and we summarized genetic variants and clinical manifestations of a total of 61 reported patients from 26 families identified to have a genetic diagnosis of germline pathogenic variants in TNFAIP3/A20.Additionally,we discussed the pathogenesis and treatment of HA20.Results A total of 24 pathogenic variants of A20 had been reported.There was significant clinical heterogeneity,even among those with the same variants in TNFA1P3.Prior to receiving a molecular diagnosis of HA20,patients had been diagnosed with Behcet's disease,rheumatoid arthritis,rheumatic fever,juvenile idiopathic arthritis,systemic lupus erythematosus,and even adult-onset Stills'disease.The patients with HA20 that presented with inflammatory signatures in NF-kB signaling were mostly responsive to treatment.Conclusions HA20 is a monogenic autoinflammatory disease with highly variable clinical manifestations.This extensive heterogeneity makes it difficult to set a clinical diagnostic criteria,and genetic sequencing is necessary for a definitive diagnosis of HA20.展开更多
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 followi...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.展开更多
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 ca...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.展开更多
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 proinfammato...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.展开更多
AIM To describe the frequency and clinical characteristics of patients with undifferentiated periodic fever(UPF) and to investigate whether a clinical classification of UPF based on the PRINTO-Eurofever score can help...AIM To describe the frequency and clinical characteristics of patients with undifferentiated periodic fever(UPF) and to investigate whether a clinical classification of UPF based on the PRINTO-Eurofever score can help predicting the response to treatment and the outcome at follow-up.METHODS Clinical and therapeutic information of patients with recurrent fever who presented at a single pediatric rheumatology center from January 2006 through April 2016 were retrospectively collected. Patients with a clinical suspicion of hereditary periodic fever(HPF) syndrome and patients with clinical picture of periodic fever, aphthae, pharingitis, adenitis(PFAPA) who were refractory to tonsillectomy underwent molecular analysis of five HPF-related genes: MEFV(NM_000243.2), MVK(NM_000431.3), TNFRSF1 A(NM_001065.3), NLRP3(NM_001079821.2), NLRP12(NM_001277126.1). All patients who had a negative genetic result were defined as UPF and further investigated. PRINTO-Eurofever score for clinical diagnosis of HPF was calculated in all cases. RESULTS Of the 221 patients evaluated for periodic fever, twelve subjects with a clinical picture of PFAPA who were refractory to tonsillectomy and 22 subjects with a clinical suspicion of HPF underwent genetic analysis. Twenty-three patients(10.4%) resulted negative and were classified as UPF. The median age at presentation of patients with UPF was 9.5 mo(IQR 4-24). Patients with UPF had a higher frequency of aphthae(52.2% vs 0%, P = 0.0026) and musculoskeletal pain(65.2% vs 18.2%, P = 0.0255) than patients with genetic confirmed HPF. Also, patients with UPF had a higher frequency of aphthous stomatitis(52.2% vs 10.7%, P < 0.0001), musculoskeletal pain(65.2% vs 8,0%, P < 0.0001), and abdominal pain(52.2% vs 4.8%, P < 0.0001) and a lower frequency of pharyngitis(56.6% vs 81.3%, P = 0.0127) compared with typical PFAPA in the same cohort. Twenty-one of 23 patients with UPF(91.3%) received steroids, being effective in 16; 13(56.2%) were given colchicine, which was effective in 6. Symptoms resolution occ展开更多
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 immun...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展开更多
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 ...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.展开更多
Over the centuries the idea of recurrent fevers has mainly been associated with malaria, but many other fevers, such as typhoid and diphtheria were cause for concern. It is only in recent times, with the more severe f...Over the centuries the idea of recurrent fevers has mainly been associated with malaria, but many other fevers, such as typhoid and diphtheria were cause for concern. It is only in recent times, with the more severe forms of fever from infectious origin becoming less frequent or a cause for worry that we started noticing recurrent fevers without any clear infectious cause, being described as having a pathogenesis of autoinflammatory nature. The use of molecular examinations in many cases can allow a diagnosis where the cause is monogenic. In other cases, however the pathogenesis is likely to be multifactorial and the diagnostic-therapeutic approach is strictly clinical. The old fever tree paradigm developed to describe fevers caused by malaria has been revisited here to describe today's periodic fevers from the periodic fever adenitis pharyngitis aphthae syndrome to the more rare autoinflammatory diseases. This model may allow us to place cases that are yet to be identified which are likely to be of multifactorial origin.展开更多
Background: Familial Mediterranean fever (FMF) is an autoinflammatory genetic disorder that associated with different genetic mutations. Frequency of clinical manifestation differs according to age group, geographic r...Background: Familial Mediterranean fever (FMF) is an autoinflammatory genetic disorder that associated with different genetic mutations. Frequency of clinical manifestation differs according to age group, geographic region and ethnic population. Objectives: To study the clinical manifestation of FMF in relation to genotype (M680I, M694V, M694I and V726A). Result: The main presentation of studied group was abdominal pain 65.9% (203), followed by fever 60.4% (186) patients. (Mutation M694V) was the commonest 47.6% (297), followed by (Mutation V726A) in 32.8% (169%), then (Mutation M6802) in 23.4% (121) lastly (Mutation M6941) was in 22.1% (114) patients. Fever was highly associated with mutation (V729A) and it was statistically significant (*p value 0.047). Conclusion: Abdominal pain and fever were the most common manifestation of FMF patients. (Mutation M694V), (Mutation V726A) were the most detected mutation. Third age group;fever was associated with genetic mutation (V726A), abdominal pain with (M6941).展开更多
The purpose of regenerative medicine is to restore or enhance the normal function of human cells, tissues, and organs. From a clinical point of view, the use of stem cells is more advantageous than differentiated cell...The purpose of regenerative medicine is to restore or enhance the normal function of human cells, tissues, and organs. From a clinical point of view, the use of stem cells is more advantageous than differentiated cells because they can be collected more easily and in larger quantities, their proliferation capacity is more pronounced, they are more resistant in cell culture, their aging is delayed, they are able to form a number of cell lines, and they are able to promote vascularization of tissue carriers. The therapeutic use of stem cells for disease modification, immunomodulation, or regenerative purposes are undoubtedly encouraging, but most studies are still in their early stages, and the clinical results reported are not clear with regard to therapeutic efficacy and potential side effects. Uniform regulation of the clinical application of stem cells is also indispensable for this highly customizable, minimally invasive, individualized therapeutic method to become a successful and safe treatment alternative in many different autoimmune and autoinflammatory disorders.展开更多
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 musculo...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.展开更多
<strong>Introduction:</strong> 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 wi...<strong>Introduction:</strong> 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. <strong>Methods:</strong> 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. <strong>Results:</strong> 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>i.e. </i> 14 cases of autoimmune and autoinflammatory diseases. A total of 331 autoimmune diseases and/or auto-inflammatory diseases were collected, <i>i.e. </i> 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 domina展开更多
Pyoderma gangrenosum(PG) presents with refractory,sterile,deep ulcers most often on the lower legs.Clinically,PG exhibits four types,i.e.,ulcerative,bullous,pustular,and vegetative types.PG may be triggered by surgica...Pyoderma gangrenosum(PG) presents with refractory,sterile,deep ulcers most often on the lower legs.Clinically,PG exhibits four types,i.e.,ulcerative,bullous,pustular,and vegetative types.PG may be triggered by surgical operation or even by minor iatrogenic procedures such as needle prick or catheter insertion,which is wellknown as pathergy.PG is sometimes seen in association with several systemic diseases including rheumatoid arthritis(RA),inflammatory bowel disease,hematologic malignancy,and Takayasu's arteritis.In particular,various cutaneous manifestations are induced in association with RA by virtue of the activation of inflammatory cells(neutrophils,lymphocytes,macrophages),vasculopathy,vasculitis,drugs,and so on.Clinical appearances of ulcerative PG mimic rheumatoid vasculitis or leg ulcers due to impaired circulation in patients with RA.In addition,patients with PG sometimes develop joint manifestations as well.Therefore,it is necessary for not only dermatologists but also rheumatologists to understand PG.展开更多
Systemic </span><span><span style="font-family:Verdana;">juvenile idiopathic arthritis is classified as an autoimmune entity and a subtype of juvenile idiopathic arthritis, although it has ...Systemic </span><span><span style="font-family:Verdana;">juvenile idiopathic arthritis is classified as an autoimmune entity and a subtype of juvenile idiopathic arthritis, although it has many features of autoinflammatory-type of diseases. This review article will elaborate on the disease’s pathogenesis and its proposed relation to autoinflammatory diseases including defective innate immunity and phagocytosis response leading </span><span style="font-family:Verdana;">excessive</span><span style="font-family:Verdana;"> cytokine release. It also explains the disease’s epidemiology, clinical phenotype, diagnostic challenges, complications </span><span style="font-family:Verdana;">and</span><span style="font-family:Verdana;"> current advancements in the treatment of systemic juvenile idiopathic arthritis, such as IL-1 and IL-6 antagonists </span><span style="font-family:Verdana;">and</span><span style="font-family:Verdana;"> their impact on the disease trajectory. Care of patients with systemic juvenile idiopathic arthritis requires a comprehensive multidisciplinary team to optimize the care and avoid complications of the disease itself such as growth impairment, macrophage activation syndrome </span><span style="font-family:Verdana;">or</span><span style="font-family:Verdana;"> the complications of immunosuppressant and immun</span></span><span style="font-family:Verdana;">omodulatory treatments.展开更多
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 ...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.展开更多
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...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.展开更多
BACKGROUND Patients with paroxysmal nocturnal hemoglobinuria(PNH)have a clonal population of blood cells deficient in glycosylphosphatidylinositol-anchored(GPIanchored)proteins,most of the time resulting from a mutati...BACKGROUND Patients with paroxysmal nocturnal hemoglobinuria(PNH)have a clonal population of blood cells deficient in glycosylphosphatidylinositol-anchored(GPIanchored)proteins,most of the time resulting from a mutation in the X-linked gene PIGA.We report a patient with PNH resulting from a rare biallelic PIGT mutation on chromosome 20.CASE SUMMARY A 47-year-old man was referred to our hospital for febrile pancytopenia.The patient reported a history of recurrent urticaria and arthralgia and he presented during 3 mo recurrent acute dermo-hypodermitis and aseptic meningitidis.Based on clinical cases published with PIGT-PNH,with clinically typical PNH and autoinflammatory symptoms,we treated our patients with repeated infusions of eculizumab to decrease autoinflammatory symptoms and then we performed an allogeneic stem cell transplantation(allo-SCT)with a mismatched unrelated donor.Our patient experienced no acute Graft vs Host disease(GvHD)and a moderate chronic GvHD and is now considered cured at 24 mo after allo-SCT.CONCLUSION This case report suggests that allo-SCT should be considered to cure PIGT-PNH patients.展开更多
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 2...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.展开更多
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 PAP...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.展开更多
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. Withi...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.展开更多
基金This study was supported by Basic Public Welfare Research Project of Zhejiang Province(LGF19H100002).
文摘Background A20,a protein encoded by the tumor necrosis factor alpha-induced protein 3 gene(TNFAIP3),plays a vital role in the negative regulation of inflammation and immunity.Loss-of-function mutation in TNFAIP3 leads to a new described autoinflammatory disease-haploinsufficiency of A20(HA20).Since HA20 was first described in 2016,a number of new cases have been described in this literature,however,the disease and its pathogenesis are poorly understood.This review seeks to improve clinical recognition of this disorder,and promote both earlier diagnosis and initiation of targeted therapies to improve patients’outcomes.Methods We reviewed 26 papers about A20 and HA20,and we summarized genetic variants and clinical manifestations of a total of 61 reported patients from 26 families identified to have a genetic diagnosis of germline pathogenic variants in TNFAIP3/A20.Additionally,we discussed the pathogenesis and treatment of HA20.Results A total of 24 pathogenic variants of A20 had been reported.There was significant clinical heterogeneity,even among those with the same variants in TNFA1P3.Prior to receiving a molecular diagnosis of HA20,patients had been diagnosed with Behcet's disease,rheumatoid arthritis,rheumatic fever,juvenile idiopathic arthritis,systemic lupus erythematosus,and even adult-onset Stills'disease.The patients with HA20 that presented with inflammatory signatures in NF-kB signaling were mostly responsive to treatment.Conclusions HA20 is a monogenic autoinflammatory disease with highly variable clinical manifestations.This extensive heterogeneity makes it difficult to set a clinical diagnostic criteria,and genetic sequencing is necessary for a definitive diagnosis of HA20.
基金This work was supported by Agency for Science,Technology and Research(A*STAR)of Singapore.
文摘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.
基金supported in part by the National Key Research and Development Program of China(No.2021YFC2702005)National Natural Science Foundation of China(No.81971547)+1 种基金the Research Fund for Outstanding Youth Scholar of Chongqing Talents(No.CQYC201905003)the High-level Medical Reserved Personnel Training Project of Chongqing(No.2019181).
文摘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.
文摘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.
基金Supported by the Institute for Maternal and Child Health IRCCS Burlo Garofolo,No.RC36/11
文摘AIM To describe the frequency and clinical characteristics of patients with undifferentiated periodic fever(UPF) and to investigate whether a clinical classification of UPF based on the PRINTO-Eurofever score can help predicting the response to treatment and the outcome at follow-up.METHODS Clinical and therapeutic information of patients with recurrent fever who presented at a single pediatric rheumatology center from January 2006 through April 2016 were retrospectively collected. Patients with a clinical suspicion of hereditary periodic fever(HPF) syndrome and patients with clinical picture of periodic fever, aphthae, pharingitis, adenitis(PFAPA) who were refractory to tonsillectomy underwent molecular analysis of five HPF-related genes: MEFV(NM_000243.2), MVK(NM_000431.3), TNFRSF1 A(NM_001065.3), NLRP3(NM_001079821.2), NLRP12(NM_001277126.1). All patients who had a negative genetic result were defined as UPF and further investigated. PRINTO-Eurofever score for clinical diagnosis of HPF was calculated in all cases. RESULTS Of the 221 patients evaluated for periodic fever, twelve subjects with a clinical picture of PFAPA who were refractory to tonsillectomy and 22 subjects with a clinical suspicion of HPF underwent genetic analysis. Twenty-three patients(10.4%) resulted negative and were classified as UPF. The median age at presentation of patients with UPF was 9.5 mo(IQR 4-24). Patients with UPF had a higher frequency of aphthae(52.2% vs 0%, P = 0.0026) and musculoskeletal pain(65.2% vs 18.2%, P = 0.0255) than patients with genetic confirmed HPF. Also, patients with UPF had a higher frequency of aphthous stomatitis(52.2% vs 10.7%, P < 0.0001), musculoskeletal pain(65.2% vs 8,0%, P < 0.0001), and abdominal pain(52.2% vs 4.8%, P < 0.0001) and a lower frequency of pharyngitis(56.6% vs 81.3%, P = 0.0127) compared with typical PFAPA in the same cohort. Twenty-one of 23 patients with UPF(91.3%) received steroids, being effective in 16; 13(56.2%) were given colchicine, which was effective in 6. Symptoms resolution occ
文摘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
基金This study was supported by funds from Public Welfare Scientific Research Project of China(201402012)CAMS Central Public Welfare Scientific Research Institute Basal Research Expenses to HW(2016ZX310182-1)+1 种基金CAMS Innovation Fund for Medical Sciences(2016-I2M-1-008)The Capital Health Research and Development of Special(2016-2-40114).
文摘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.
文摘Over the centuries the idea of recurrent fevers has mainly been associated with malaria, but many other fevers, such as typhoid and diphtheria were cause for concern. It is only in recent times, with the more severe forms of fever from infectious origin becoming less frequent or a cause for worry that we started noticing recurrent fevers without any clear infectious cause, being described as having a pathogenesis of autoinflammatory nature. The use of molecular examinations in many cases can allow a diagnosis where the cause is monogenic. In other cases, however the pathogenesis is likely to be multifactorial and the diagnostic-therapeutic approach is strictly clinical. The old fever tree paradigm developed to describe fevers caused by malaria has been revisited here to describe today's periodic fevers from the periodic fever adenitis pharyngitis aphthae syndrome to the more rare autoinflammatory diseases. This model may allow us to place cases that are yet to be identified which are likely to be of multifactorial origin.
文摘Background: Familial Mediterranean fever (FMF) is an autoinflammatory genetic disorder that associated with different genetic mutations. Frequency of clinical manifestation differs according to age group, geographic region and ethnic population. Objectives: To study the clinical manifestation of FMF in relation to genotype (M680I, M694V, M694I and V726A). Result: The main presentation of studied group was abdominal pain 65.9% (203), followed by fever 60.4% (186) patients. (Mutation M694V) was the commonest 47.6% (297), followed by (Mutation V726A) in 32.8% (169%), then (Mutation M6802) in 23.4% (121) lastly (Mutation M6941) was in 22.1% (114) patients. Fever was highly associated with mutation (V729A) and it was statistically significant (*p value 0.047). Conclusion: Abdominal pain and fever were the most common manifestation of FMF patients. (Mutation M694V), (Mutation V726A) were the most detected mutation. Third age group;fever was associated with genetic mutation (V726A), abdominal pain with (M6941).
基金the StartUp Program of Semmelweis University Faculty of Medicine,No.SE10332470
文摘The purpose of regenerative medicine is to restore or enhance the normal function of human cells, tissues, and organs. From a clinical point of view, the use of stem cells is more advantageous than differentiated cells because they can be collected more easily and in larger quantities, their proliferation capacity is more pronounced, they are more resistant in cell culture, their aging is delayed, they are able to form a number of cell lines, and they are able to promote vascularization of tissue carriers. The therapeutic use of stem cells for disease modification, immunomodulation, or regenerative purposes are undoubtedly encouraging, but most studies are still in their early stages, and the clinical results reported are not clear with regard to therapeutic efficacy and potential side effects. Uniform regulation of the clinical application of stem cells is also indispensable for this highly customizable, minimally invasive, individualized therapeutic method to become a successful and safe treatment alternative in many different autoimmune and autoinflammatory disorders.
基金This study was supported by Beijing Association for Golden Bridge Engineering Seed Found of Beijing Association for Science and Technology(JQ17032)the Capital Health Research and Development of Special(2016-2-40114),CAMS Initiative for Innovative Medicine(2016-I2M-1-008),CAMS Central Public Welfare Scientific Research Institute Basal Research Expenses to HW(2016ZX310182-1),and Public Welfare Scientific Research Project of China(201402012).
文摘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.
文摘<strong>Introduction:</strong> 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. <strong>Methods:</strong> 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. <strong>Results:</strong> 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>i.e. </i> 14 cases of autoimmune and autoinflammatory diseases. A total of 331 autoimmune diseases and/or auto-inflammatory diseases were collected, <i>i.e. </i> 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 domina
文摘Pyoderma gangrenosum(PG) presents with refractory,sterile,deep ulcers most often on the lower legs.Clinically,PG exhibits four types,i.e.,ulcerative,bullous,pustular,and vegetative types.PG may be triggered by surgical operation or even by minor iatrogenic procedures such as needle prick or catheter insertion,which is wellknown as pathergy.PG is sometimes seen in association with several systemic diseases including rheumatoid arthritis(RA),inflammatory bowel disease,hematologic malignancy,and Takayasu's arteritis.In particular,various cutaneous manifestations are induced in association with RA by virtue of the activation of inflammatory cells(neutrophils,lymphocytes,macrophages),vasculopathy,vasculitis,drugs,and so on.Clinical appearances of ulcerative PG mimic rheumatoid vasculitis or leg ulcers due to impaired circulation in patients with RA.In addition,patients with PG sometimes develop joint manifestations as well.Therefore,it is necessary for not only dermatologists but also rheumatologists to understand PG.
文摘Systemic </span><span><span style="font-family:Verdana;">juvenile idiopathic arthritis is classified as an autoimmune entity and a subtype of juvenile idiopathic arthritis, although it has many features of autoinflammatory-type of diseases. This review article will elaborate on the disease’s pathogenesis and its proposed relation to autoinflammatory diseases including defective innate immunity and phagocytosis response leading </span><span style="font-family:Verdana;">excessive</span><span style="font-family:Verdana;"> cytokine release. It also explains the disease’s epidemiology, clinical phenotype, diagnostic challenges, complications </span><span style="font-family:Verdana;">and</span><span style="font-family:Verdana;"> current advancements in the treatment of systemic juvenile idiopathic arthritis, such as IL-1 and IL-6 antagonists </span><span style="font-family:Verdana;">and</span><span style="font-family:Verdana;"> their impact on the disease trajectory. Care of patients with systemic juvenile idiopathic arthritis requires a comprehensive multidisciplinary team to optimize the care and avoid complications of the disease itself such as growth impairment, macrophage activation syndrome </span><span style="font-family:Verdana;">or</span><span style="font-family:Verdana;"> the complications of immunosuppressant and immun</span></span><span style="font-family:Verdana;">omodulatory treatments.
文摘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.
文摘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.
文摘BACKGROUND Patients with paroxysmal nocturnal hemoglobinuria(PNH)have a clonal population of blood cells deficient in glycosylphosphatidylinositol-anchored(GPIanchored)proteins,most of the time resulting from a mutation in the X-linked gene PIGA.We report a patient with PNH resulting from a rare biallelic PIGT mutation on chromosome 20.CASE SUMMARY A 47-year-old man was referred to our hospital for febrile pancytopenia.The patient reported a history of recurrent urticaria and arthralgia and he presented during 3 mo recurrent acute dermo-hypodermitis and aseptic meningitidis.Based on clinical cases published with PIGT-PNH,with clinically typical PNH and autoinflammatory symptoms,we treated our patients with repeated infusions of eculizumab to decrease autoinflammatory symptoms and then we performed an allogeneic stem cell transplantation(allo-SCT)with a mismatched unrelated donor.Our patient experienced no acute Graft vs Host disease(GvHD)and a moderate chronic GvHD and is now considered cured at 24 mo after allo-SCT.CONCLUSION This case report suggests that allo-SCT should be considered to cure PIGT-PNH patients.
文摘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.
基金Supported by the National Natural Science Foundation of China,No.81770875the Post-Doctor Research Project,West China Hospital,Sichuan University,No.19HXBH053+1 种基金the Health and Family Planning Commission of Sichuan Province,No.19PJ096the 1.3.5 Project for Disciplines of Excellence,West China Hospital,Sichuan University,No.2020HXFH008 and No.ZYJC18003.
文摘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.
文摘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.
