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Yao syndrome, a rare autoinflammatory disorder linked to mutations in the nucleotide-binding oligomerization domain-containing protein-2 (NOD2) gene, manifests through periodic fever, polyarthritis, dermatitis, gastrointestinal disturbances, and sicca-like symptoms. The therapeutic landscape is limited, primarily encompassing glucocorticoids, interleukin-1 (IL-1), and IL-6 inhibitors. This report details the case of a teenager with periodic fevers, arthritis, livedo reticularis, and NOD2 gene mutations R702W and IVS8+158C consistent with Yao syndrome. The individual demonstrated significant improvement with canakinumab therapy. This case report aims to enhance recognition and understanding of Yao syndrome's clinical spectrum and management options.
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A 54-year-old man with a university degree was admitted to our hospital because of a two-year history of progressive dementia. He had familial sensorineural hearing loss and had been treated for epilepsy since his 30s. On admission, he showed severe dementia and parkinsonism without fever or skin rash. Systemic inflammation was evident, and the CSF cell count and IL-6 level were elevated to 53/µl and 307â |pg/ml, respectively. Brain MRI demonstrated diffuse brain atrophy. More detailed anamnesis revealed a history of rheumatoid arthritis in childhood and aseptic meningitis in his 20s. Genetic examination for autoinflammatory diseases demonstrated compound heterozygotic mutations in the NLRP3 gene, causing cryopyrin-associated periodic fever syndrome (CAPS). This case was atypical CAPS presenting as early-onset progressive dementia, without recurrent fever or urticaria-like eruption which are usually seen in this disease.
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Síndromes Periódicas Associadas à Criopirina , Demência , Mutação , Proteína 3 que Contém Domínio de Pirina da Família NLR , Humanos , Síndromes Periódicas Associadas à Criopirina/diagnóstico , Síndromes Periódicas Associadas à Criopirina/complicações , Masculino , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Pessoa de Meia-Idade , Demência/etiologia , Demência/diagnóstico , Exantema/etiologia , Febre/etiologia , Imageamento por Ressonância Magnética , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Diagnóstico Diferencial , Heterozigoto , Biomarcadores/líquido cefalorraquidiano , Biomarcadores/sangue , Progressão da DoençaRESUMO
Cryopyrin-associated periodic syndrome (CAPS) is a genetic disorder and autoinflammatory disease characterized by chronic inflammation throughout the body. The most severe form of CAPS, Chronic Infantile Neurologic Cutaneous, and Articular (CINCA) syndrome, also known as Neonatal Onset Multisystem Inflammatory Disease (NOMID), has three main features: skin rash, CNS involvement, and joint symptoms. Although these symptoms are typically reported shortly after birth, there have been a few reports of prenatal inflammation. Here, we report our experience managing a case of a CAPS infant born in severe neonatal asphyxia due to a ruptured cord associated with severe funisitis. The baby was born at 38 weeks and 6 days of gestation, weighing 2,898â g, through an ultra-emergency Caesarian section prompted by variable deceleration. The Apgar score was 1 point at 1â min and 4 points at 5â min, necessitating intensive care due to hypoxic-ischemic encephalopathy. Upon delivery, it was observed that the umbilical cord had partially ruptured at the site of attachment to the baby, accompanied by arterial hemorrhage. Umbilical cord rupture was considered to be the cause of the sudden decrease in fetal heart rate. Pathological examination also showed that the inflammation of the cord was more severe on the side attached to the fetus and on the arterial side, suggesting that the inflammation had extended from the fetus. The father carried a genetic mutation associated with CINCA syndrome/NOMID (NLRP3 c.2068G>A p.Glu690Lys Hetero), which was also found in the child. Histopathologic examination of the placenta and umbilical cord can provide crucial insights into the intrauterine onset of inflammation, which is the first manifestation of CINCA syndrome/NOMID in newborns. It should be noted that births with a genetic predisposition to CAPS may have complications related to the placenta and umbilical cord.
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Systemic autoinflammatory diseases (SAIDs) are distinct from autoimmune diseases. The former primarily results from abnormal innate immune response and genetic testing is crucial for disease diagnosis. Similar cutaneous involvement is a main feature for both SAID and dermatomyositis (DM), so they can be confused with each other. A literature search of PubMed and MEDLINE was conducted for relevant articles. The similarities and differences between these two types of diseases were analyzed. We found phenotypic similarities between these two types of disorders. Accumulating data supports a major role of the innate immune system and a similar cytokine profile. Molecular testing using an autoinflammatory disease gene panel may help identify SAID patients from the DM population and may offer therapeutic benefit using interleukin-1 (IL-1) inhibitors. A subset of DM, notably amyopathic dermatomyositis in the absence of autoantibodies may be on the spectrum of autoinflammatory disease.
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[Objective]To summarize the clinical experience of Professor CHEN Jian in treating periodic fever syndrome(PFS)in children from"latent fire".[Methods]Through outpatient follow-up study,collection of medical records and review of relevant literature,this paper summarized the etiology,pathogenesis and Professor CHEN's treatment experience of PFS in children from"latent fire",and a case was presented for verification.[Results]Professor CHEN believes that the core pathogenesis of PFS in children is"latent fire".Phlegm,poison and stasis are not only pathological products,but also important pathogenic factors throughout the course of the disease.Depression is the pathological state of the whole course of the disease.In the treatment,the method of supplementing Qi to remove heat or nourishing Yin to clear heat is used and combined with regulating Qi,and the self-prepared prescription is the effective treatment of PFS in children.The main symptom of the case was periodic fever,which was differentiated as Yin deficiency fever.The treatment of nourishing Yin and clearing heat,promoting Qi movement and relieving depression was applied,and good effect was achieved.[Conclusion]Professor CHEN's treatment of PFS in children from"latent fire"is effective,has certain guiding significance,and is worthy of clinical reference.
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Systemic autoinflammatory diseases (SAIDs) are a group of rare diseases characterized by recurrent or continuous inflammation, typically accompanied by genetic variants. Good responses to anti-TNF therapy were observed in SAIDs patients. However, the mechanisms underlying the disease flare and the response to TNF blocking therapy have not been fully elucidated. Here, single-cell RNA sequencing technology was used to describe the transcriptomic profile of PBMCs and PMNs in two SAID patients both before and after anti-TNF treatment. Interferon responses were involved in the disease flare. After anti-TNF therapy, clinical symptoms were alleviated while TNF and IL-1 were unexpectedly increased, indicating that these inflammatory cytokines are not positively correlated with disease activity. Trajectory analysis showed that inhibition of macrophage differentiation, rather than reduction of the inflammatory cytokines, as the potential mechanism of anti-TNF treatment response in SAIDs.
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Doenças Hereditárias Autoinflamatórias , Síndrome de Imunodeficiência Adquirida dos Símios , Humanos , Animais , Doenças Hereditárias Autoinflamatórias/genética , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Doenças Raras , Exacerbação dos Sintomas , Transcriptoma , Citocinas/genéticaRESUMO
A20 haploinsufficiency (HA20) is an early-onset autoinflammatory disease caused by loss-of-function variants of the TNFAIP3 gene, which encodes the protein A20. HA20 is typically characterized by Behçet's disease-like clinical symptoms, and patients usually present with a family history. Herein, we report a case of HA20 in a pediatric patient, presenting with periodic fever, abdominal pain, and vomiting, with no family history. This patient also harbored a novel heterozygous frameshift variant c.677del (p.Pro226LeufsTer2) of TNFAIP3. We initiated treatment with an anti-tumor necrosis factor-α agent that did not induce symptom resolution; we thus administered combination therapy, including prednisolone. Remission was then successfully achieved. We suggest that HA20 should be considered when an autoinflammatory disease is suspected and periodic fever syndrome is present, even in the absence of a family history of HA20 or Behçet's disease-like symptoms.
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Amiloidose , Síndrome de Behçet , Humanos , Criança , Lactente , Síndrome de Behçet/genética , Haploinsuficiência , Fator de Necrose Tumoral alfa/genética , FebreRESUMO
BACKGROUND: Although canakinumab has demonstrated efficacy in multiple trials in patients with periodic fever syndromes (PFS), the evidence on initiation of canakinumab among PFS patients in real world setting is not well understood. We aimed to characterize the reasons for canakinumab initiation among patients with PFS, specifically, cryopyrin-associated periodic syndrome (CAPS), hyperimmunoglobulin D syndrome/mevalonate kinase deficiency (HIDS/MKD), TNF receptor-associated periodic syndrome (TRAPS) and familial Mediterranean fever (FMF). METHODS: Physicians retrospectively reviewed the medical charts of PFS patients prescribed canakinumab between 2016 and 2018. Information collected included patient clinical characteristics, reasons for previous treatment discontinuation and canakinumab initiation. The results were summarized for overall patients, and by children (< 18 years) and adults and by subtype of PFS. RESULTS: Fifty-eight physicians in the US (rheumatologists, 44.8 %; allergists/immunologists, 29.3 %; dermatologists, 25.9 %) abstracted information for 147 patients (children, 46.3 %; males, 57.1 %; CAPS, 36.7 %; TRAPS, 26.5 %; FMF, 26.5 %; HIDS/MKD, 6.8 %; Mixed, 3.4 %). Overall, most patients (90.5 %) received treatment directly preceding canakinumab (NSAIDs, 27.8 % [40.0 % in HIDS/MKD]; anakinra, 24.1 % [32.7 % in CAPS]; colchicine, 21.8 % [35.9 % in FMF]), which were discontinued due to lack of efficacy/effectiveness (39.5 %) and availability of a new treatment (36.1 %). The common reasons for canakinumab initiation were physician perceived efficacy/effectiveness (81.0 %; children, 75.0 %; adults, 86.1 %), lack of response to previous treatment (40.8 %; children, 38.2 %; adults, 43.0 %) and favorable safety profile/tolerability (40.1 %; children, 42.6 %; adults, 38.0 %). Within subtypes, efficacy/effectiveness was the most stated reason for canakinumab initiation in HIDS/MKD (90.9 %), lack of response to previous treatment in FMF (52.4 %) and convenience of administration/dosing in CAPS (27.1 %). CONCLUSIONS: This study provided insights into how canakinumab is initiated in US clinical practice among PFS patients, with physician perceived efficacy/effectiveness of canakinumab, lack of response to previous treatment and favorable safety profile/tolerability of canakinumab being the dominant reasons for canakinumab initiation in all patients and in children and adults and PFS subtypes. Notably, the favorable safety profile/tolerability of canakinumab was more often the reason for initiation among children versus adults.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Síndromes Periódicas Associadas à Criopirina/tratamento farmacológico , Febre Familiar do Mediterrâneo/tratamento farmacológico , Febre/tratamento farmacológico , Doenças Hereditárias Autoinflamatórias/tratamento farmacológico , Deficiência de Mevalonato Quinase/tratamento farmacológico , Adolescente , Adulto , Criança , Pré-Escolar , Prescrições de Medicamentos , Feminino , Humanos , Masculino , Padrões de Prática Médica , Estudos Retrospectivos , Estados Unidos , Adulto JovemRESUMO
Introducción: El síndrome de fiebre periódica, estomatitis aftosa, faringitis y adenitis es un cuadro relativamente frecuente de curso autolimitado y buen pronóstico. Es la más común de las enfermedades autoinflamatorias que presentan fiebre recurrente y su etiología y fisiopatogenia permanecen inciertas. Objetivo: Describir el caso clínico de un niño que consultó por fiebre recurrente y faringitis y se arribó al diagnóstico de síndrome de fiebre periódica, estomatitis aftosa, faringitis y adenitis. Presentación del caso: Se trata de un paciente de 5 años que consultó por un episodio febril acompañado de faringitis y adenitis, con antecedente de múltiples episodios previos. Conclusiones: El síndrome fiebre periódica, estomatitis aftosa, faringitis y adenitis, es una entidad de curso benigno y autolimitado que constituye la causa más común de fiebre recurrente con un gran impacto en la vida de los pacientes. La fisiopatogenia permanece incierta. Es destacable la sospecha clínica para arribar al diagnóstico ya que no existen en la actualidad exámenes complementarios específicos(AU)
Introduction: Periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome is a relatively common picture of self-limiting course and good prognosis. It is the most common of self-inflammatory diseases with recurrent fever and its etiology and physiopathology remain uncertain. Objective: Describe the clinical case of a boy who was checked due recurrent fever and pharyngitis and being diagnosed with Periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome. Case presentation: This is a 5-year-old patient who was consulted due to a febrile episode accompanied by pharyngitis and adenitis, with a history of multiple previous episodes. Conclusions: Periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome is a benign, self-limiting course entity that is the most common cause of recurrent fever with a large impact on patients' lives. Its physiopathology remains uncertain. Clinical suspicion for diagnosis is noteworthy as there are currently no specific complementary test for it(AU)
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Humanos , Masculino , Pré-Escolar , Febre Recorrente , Estomatite Aftosa , Faringite , Febre , LinfadeniteRESUMO
Renal AA amyloidosis is the most serious complication of periodic fever syndrome, which, inadequate suppression, due to persistent inflammation, leads to nephrotic syndrome and renal failure over several years. In most cases, periodic fever syndromes begin to manifest clinically in early childhood. Occurrence in adulthood is considered rare and is associated with a poorer clinical course. Kidney transplantation (KT) is an effective and safe treatment for end-stage chronic kidney disease (CKD) based on AA amyloidosis. In this paper, we present cases of two patients after deceased donor KT, who have been diagnosed with adult periodic fever syndrome. In the first one, diagnosis and treatment began in advanced stage of CKD and therefore underwent KT with compensated disease, while in the second patient, the disease manifested and diagnosed in the post-KT period. Timely initiation of treatment ensured protection of the graft from amyloid deposition.
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Amiloidose , Febre Familiar do Mediterrâneo , Nefropatias , Falência Renal Crônica , Transplante de Rim , Síndrome Nefrótica , Adulto , Pré-Escolar , Febre Familiar do Mediterrâneo/complicações , Febre Familiar do Mediterrâneo/tratamento farmacológico , Humanos , Rim , Síndrome Nefrótica/etiologiaRESUMO
Cryopyrin-associated periodic fever syndrome (CAPS) is a highly debilitating disorder, which is characterized by unregulated interleukin-1ß production driven by autosomal dominantly inherited mutations in the NLRP3 gene. Patients with CAPS often present with early-onset episodes of fever and rash. These patients also present with variable systemic signs and symptoms, such as arthritis, sensorineural hearing loss, chronic aseptic meningitis, and skeletal abnormalities, but minimal gastrointestinal symptoms. Recently, effective therapies for CAPS targeted against interleukin-1 have become available. We report a case of a young Japanese woman with CAPS who developed inflammatory bowel disease during canakinumab therapy. The patient had colostomy after intestinal perforation and changed canakinumab to infliximab. To the best of our knowledge, this is the first report of a case of inflammatory bowel disease secondary to CAPS complicated by gastrointestinal symptoms and arthritis which canakinumab could not control. Patients with CAPS who have symptoms that cannot be controlled by canakinumab should be considered for possible co-morbidities.
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Síndromes Periódicas Associadas à Criopirina , Perda Auditiva Neurossensorial , Doenças Inflamatórias Intestinais , Anticorpos Monoclonais Humanizados , Síndromes Periódicas Associadas à Criopirina/complicações , Síndromes Periódicas Associadas à Criopirina/tratamento farmacológico , Síndromes Periódicas Associadas à Criopirina/genética , Feminino , Humanos , Doenças Inflamatórias Intestinais/complicações , Doenças Inflamatórias Intestinais/tratamento farmacológico , Interleucina-1beta , Proteína 3 que Contém Domínio de Pirina da Família NLRRESUMO
INTRODUCTION/OBJECTIVES: The clinicians initially prefer to define patients with the systemic autoinflammatory disease (SAID)'s based on recommended clinical classification criteria; then, they confirm the diagnosis with genetic testing. We aimed to compare the initial phenotypic diagnoses of the patients who were followed up with the preliminary diagnosis of a monogenic SAID, and the genotypic results obtained from the next-generation sequence (NGS) panel. METHOD: Seventy-one patients with the preliminary diagnosis of cryopyrin-associated periodic fever syndrome (CAPS), mevalonate kinase deficiency (MKD), or tumor necrosis factor-alpha receptor-associated periodic fever syndrome (TRAPS) were included in the study. The demographic data, clinical findings, laboratory results, and treatments were recorded. All patients were examined by NGS panel analysis including 16 genes. The genetic results were compared with the initial Federici score to determine whether they were compatible with each other. RESULTS: Thirty patients were initially classified as MKD, 22 as CAPS, and 19 as TRAPS. The frequency of clinical manifestations was urticarial rash 57.7%, diarrhea 49.2%, abdominal pain 47.8%, arthralgia 45%, oral aphthae 43.6%, myalgia 32.3%, tonsillitis 28.1%, and conjunctivitis 25.3%, respectively. After NGS gene panel screening, 13 patients were diagnosed with CAPS, 8 with MKD, 7 with familial Mediterranean fever, 5 with TRAPS, and 2 with NLRP12-associated periodic syndrome. The remaining 36 patients were genetically identified as undefined SAID since they were not classified as one of the defined SAIDs after the result of the NGS panel. CONCLUSIONS: We have demonstrated that clinical diagnostic criteria may not always be sufficient to establish the correct diagnosis. There is still low accordance between clinical diagnoses and molecular analyses. In the case of a patient with a preliminary diagnosis of a monogenic SAID with the negative result of target gene analysis, other autoinflammatory diseases should also be kept in mind in the differential diagnosis. Key Points ⢠Monogenic autoinflammatory diseases can present with different clinical manifestations. ⢠The clinical diagnostic criteria may not always be sufficient to reach the correct diagnosis in autoinflammatory diseases. ⢠In the case of a patient with a preliminary diagnosis of a monogenic SAID with the negative result of target gene analysis, other autoinflammatory diseases should be kept in mind in the differential diagnosis.
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Síndromes Periódicas Associadas à Criopirina , Febre Familiar do Mediterrâneo , Doenças Hereditárias Autoinflamatórias , Deficiência de Mevalonato Quinase , Síndromes Periódicas Associadas à Criopirina/diagnóstico , Síndromes Periódicas Associadas à Criopirina/genética , Febre/genética , Doenças Hereditárias Autoinflamatórias/diagnóstico , Doenças Hereditárias Autoinflamatórias/genética , Humanos , Deficiência de Mevalonato Quinase/diagnóstico , Deficiência de Mevalonato Quinase/genéticaRESUMO
Recurrent aphthous stomatitis is a chronic inflammatory disease of the oral mucosa. It is characterized by painful mouth ulcers that cannot be explained by an underlying disease. Recurrent oral mucosal ulcers require a proper differential diagnosis to rule out other possible causes before recurrent aphthous stomatitis is diagnosed. The condition is common, with prevalence rates ranging from 5 to 60% in different series. Its pathogenesis is unknown, but multiple factors are considered to play a part. There are no standardized treatments for this condition and none of the treatments are curative. The goal of any treatment should be to alleviate pain, reduce the duration of ulcers, and prevent recurrence.
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Úlceras Orais , Estomatite Aftosa , Humanos , Mucosa Bucal , Dor , Recidiva , Estomatite Aftosa/diagnósticoRESUMO
Immune cells are one of the most complex and diverse systems in the human organism. Such diversity implies an intricate network of different cell types and interactions that are dependently interconnected. The processes by which different cell types differentiate from progenitors, mature, and finally exert their function requires an orchestrated succession of molecular processes that determine cell phenotype and function. The acquisition of these phenotypes is highly dependent on the establishment of unique epigenetic profiles that confer identity and function on the various types of effector cells. These epigenetic mechanisms integrate microenvironmental cues into the genome to establish specific transcriptional programs. Epigenetic modifications bridge environment and genome regulation and play a role in human diseases by their ability to modulate physiological programs through external stimuli. DNA methylation is one of the most ubiquitous, stable, and widely studied epigenetic modifications. Recent technological advances have facilitated the generation of a vast amount of genome-wide DNA methylation data, providing profound insights into the roles of DNA methylation in health and disease. This review considers the relevance of DNA methylation to immune system cellular development and function, as well as the participation of DNA methylation defects in immune-mediated pathologies, illustrated by selected paradigmatic diseases.
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Metilação de DNA/genética , Doença/genética , Sistema Imunitário/metabolismo , DNA/genética , Epigênese Genética/genética , Genoma/genética , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , FenótipoRESUMO
BACKGROUND: Serum phagocyte-derived alarmins S100A8/9 and S100A12 are considered useful for the assessment of inflammatory diseases. Our study evaluated the use of S100 proteins in a pediatric clinical setting for estimating disease activity and supporting diagnosis. METHODS: Patients (n = 136) who had S100 proteins tested as part of clinical care were included in this study and relevant information obtained from the medical record: C-reactive protein (CRP), disease activity status (inactive: = 0 joint; active: > 0 active joint), systemic symptoms in systemic JIA (sJIA), and symptoms of flare of other autoinflammatory and fever syndromes. Patients were categorized as: sJIA, non-systemic JIA (nsJIA), other defined autoinflammatory syndromes (AID) and systemic undifferentiated recurring fever syndromes (SURFS). RESULTS: Patients with sJIA (n = 21) had significantly higher levels of S100A8/9 and S100A12 compared to patients with nsJIA (n = 49), other AIDs (n = 8) or SURFS (n = 14) (all p < 0.0001). Compared to CRP [area under the receiver operating characteristics curve (AUC) = 0.7], S100 proteins were superior in differentiating sJIA from AID and SURFS [AUC = 0.9]. S100A8/9 and S100A12 levels were not associated with disease activity in nsJIA, AID or SURFS. S100A8/9 and S100A12 levels were significantly higher in active sJIA compared to inactive (p = 0.0002 and p = 0.0002 respectively). CONCLUSION: Compared to other autoinflammatory and fever syndromes, sJIA patients have markedly higher levels of S100A8/9 and S100A12 proteins which may assist with diagnosis. S100 levels slightly outperformed CRP in distinguishing sJIA from other diagnoses and in sJIA disease activity. S100 proteins may aid in monitoring disease activity in sJIA patients.
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Artrite Juvenil/diagnóstico , Doenças Hereditárias Autoinflamatórias/diagnóstico , Proteínas S100/sangue , Artrite Juvenil/sangue , Biomarcadores/sangue , Calgranulina A/sangue , Calgranulina B/sangue , Estudos Transversais , Doenças Hereditárias Autoinflamatórias/sangue , Humanos , Estudos Retrospectivos , Proteína S100A12/sangue , Sensibilidade e Especificidade , Índice de Gravidade de DoençaRESUMO
Cryopyrin-associated periodic fever syndrome (CAPS) represents an increasingly recognized disease group entity, with varied presentations. CAPS includes 3 clinical entities, namely, familial cold-induced autoinflammatory syndrome (FCAS; MIM #120100), Muckle-Wells syndrome (MWS; MIM #191900) and chronic inflammatory neurologic cutaneous and articular syndrome (CINCA; MIM #607115); which share several overlapping clinical features. These patients often present with early-onset episodes of fever and rash, and variable systemic signs and symptoms, making it a great mimicker of other systemic autoimmune diseases. The episodes are transient and related to exposure to cold temperature and worsen in the winter season. We hereby present a case presenting with recurrent seasonal fever and rash, diagnosed as FCAS/ MWS overlap based on clinical signs and symptoms and positive testing for NLRP3 gene mutation. We also discuss the clinical presentation and complications of CAPS, chiefly FCAS and MWS, along with the previously described pediatric cases of CAPS. We tried to review the complexities of management of such patients, including the genetic diagnosis and the role of biological therapy. Based on the review of the literature, given the evident broad spectrum of symptoms and signs, use of next-generation sequencing can help in prompt diagnosis and early initiation of biological agents, which may play a great role in reducing the complications that these patients may experience in the long run.
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Síndromes Periódicas Associadas à Criopirina/diagnóstico , DNA/análise , Mutação , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Pele/patologia , Biópsia , Criança , Síndromes Periódicas Associadas à Criopirina/genética , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Pele/metabolismoRESUMO
The past two decades have seen an exponential increase in the number of monogenic autoinflammatory disorders described, coinciding with improved genetic sequencing techniques. This group of disorders has evolved to be heterogeneous and certainly more complex than the original four 'periodic fever syndromes' caused by innate immune over-activation. This review aims to provide an update on the classic periodic fever syndromes as well as introducing the broadening spectrum of clinical features seen in more recently described conditions.
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Autoimunidade/imunologia , Doenças Hereditárias Autoinflamatórias/imunologia , Imunidade Inata/imunologia , Síndromes de Imunodeficiência/imunologia , Inflamação/imunologia , Citocinas/imunologia , Febre , Doenças Hereditárias Autoinflamatórias/genética , HumanosRESUMO
BACKGROUND: Acute disseminated encephalomyelitis is generally preceded by an infection, and it is usually self-limiting and non-recurrent. However, when there are multiple attacks of acute disseminated encephalomyelitis followed by optic neuritis, it is defined as acute disseminated encephalomyelitis-optic neuritis. To the best of our knowledge, there are no previous reports of acute disseminated encephalomyelitis and optic neuritis preceded by autoinflammation, triggered by periodic fever syndrome. We report on a case of acute disseminated encephalomyelitis with optic neuritis and periodic fever syndrome in a 12-year-old Ecuadorian Hispanic boy with several relapses over the past 10 years, always preceded by autoinflammatory manifestations and without evidence of infectious processes. Whole exome sequencing was performed, and although the results were not conclusive, we found variants in genes associated with both autoinflammatory (NLRP12) and neurological (POLR3A) phenotypes that could be related to the disease pathogenesis having a polygenic rather than monogenic trait. CONCLUSION: We propose that an autoinflammatory basis should be pursued in patients diagnosed as having acute disseminated encephalomyelitis and no record of infections. Also, we show that our patient had a good response after 1 year of treatment with low doses of intravenous immunoglobulin and colchicine.
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Encefalomielite Aguda Disseminada/fisiopatologia , Febre/imunologia , Imageamento por Ressonância Magnética , Neurite Óptica/fisiopatologia , Administração Oral , Criança , Colchicina/uso terapêutico , Encefalomielite Aguda Disseminada/diagnóstico por imagem , Encefalomielite Aguda Disseminada/tratamento farmacológico , Encefalomielite Aguda Disseminada/imunologia , Febre/tratamento farmacológico , Supressores da Gota/uso terapêutico , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Masculino , Neurite Óptica/diagnóstico por imagem , Neurite Óptica/tratamento farmacológico , Neurite Óptica/imunologia , Recidiva , Resultado do Tratamento , Sequenciamento do ExomaRESUMO
BACKGROUND: Despite recent advances in the diagnosis and understanding of many autoinflammatory diseases, there are still a great number of patients with phenotypes that do not fit any clinically- and/or genetically-defined disorders. CASE PRESENTATION: We describe a fourteen-year-old boy who presented at two and a half years of age with recurrent febrile episodes. Over the course of the disease, the episodes increased in frequency and severity, with new signs and symptoms continuing to appear. Most importantly, these included skin changes, splenomegaly and transaminitis. Only partial control of the disease was achieved with anti-IL-1 therapy. Extensive investigation showed generalized inflammation without immune deficiency, with increased levels of serum amyloid A and several pro-inflammatory cytokines including interferon-γ, as well as an increased type I interferon score. Exome sequence analysis identified P369S and R408Q variants in the MEFV innate immunity regulator, pyrin (MEFV) gene and T260 M and T320 M variants in the NLR family pyrin domain containing 12 (NLRP12) gene. CONCLUSION: Patients with unclassified and/or unexplained autoinflammatory syndromes present diagnostic and therapeutic challenges and collectively form a substantial part of every cohort of patients with autoinflammatory diseases. Therefore, it is important to acquire their full genomic profile through whole exome and/or genome sequencing and present their cases to a broader audience, to facilitate characterization of similar patients. A critical mass of well-characterized cases will lead to improved diagnosis and informed treatment.
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Doenças Hereditárias Autoinflamatórias/genética , Adolescente , Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Colágeno Tipo VI/genética , Citocinas/sangue , Citocinas/líquido cefalorraquidiano , Febre/etiologia , Variação Genética/genética , Doenças Hereditárias Autoinflamatórias/diagnóstico , Doenças Hereditárias Autoinflamatórias/patologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Cariotipagem , Masculino , Proteínas dos Microtúbulos/genética , Receptores Imunológicos/genética , Sequenciamento Completo do GenomaRESUMO
BACKGROUND: This case follows a 14-month-old female, who despite multiple presentations to several physicians, continued to have recurrent febrile episodes with gross motor delay. Her case revealed an often missed diagnosis of Mevalonate Kinase Deficiency, that now has an FDA approved treatment that both reduces recurrence and produces remission. CASE PRESENTATION: A 14-month-old female with a history of gross motor delay, frequent Upper Respiratory Tract infections, and otitis media presented to an urgent care for inconsolability and refusal to bear weight on her right leg. She had recently been treated with amoxicillin for acute otitis media and had developed a diffuse maculopapular rash, without any associated respiratory or gastrointestinal distress that persisted beyond cessation of the antibiotics. The patient presented multiple times to an urgent care over the subsequent week for fussiness, fever, anorexia, lymphadenopathy, with labs concerning for worsening anemia and elevated inflammatory markers. Subsequently, the patient was admitted to the hospital for suspected osteomyelitis versus oncologic process. X-Ray imaging of the patient's lower extremities showed osseous abnormalities inconsistent with infection. A metabolic work-up showed elevated urine mevalonic acid, and follow-up genetic testing was positive for mutations in both copies of her mevalonate kinase gene. This led to the diagnosis of MKD. CONCLUSIONS: Often, episodic presentations require multiple perspectives to reveal the underlying cause. This case illustrates how apparent simple febrile episodes has the potential for more complexity upon further evaluation.