RESUMO
BACKGROUND: Febrile urinary tract infections (UTIs) are among the most severe bacterial infections in infants, in which a subset of patients develops complications. Identifying infants at risk of recurrent infections or kidney damage based on clinical signs is challenging. Previous observations suggest that genetic factors influence UTI outcomes and could serve as predictors of disease severity. In this study, we conducted a nationwide survey of infant genotypes to develop a strategy for infection management based on individual genetic risk. Our aims were to identify genetic susceptibility variants for renal scarring (RS) and genetic host factors predisposing to dilating vesicoureteral reflux (VUR) and recurrent UTIs. METHODS: To assess genetic susceptibility, we collected and analyzed DNA from blood using exome genotyping. Disease-associated genetic variants were identified through bioinformatics analysis, including allelic frequency tests and odds ratio calculations. Kidney involvement was defined using dimercaptosuccinic acid (DMSA) scintigraphy. RESULTS: In this investigation, a cohort comprising 1087 infants presenting with their first episode of febrile UTI was included. Among this cohort, a subset of 137 infants who underwent DMSA scanning was subjected to gene association analysis. Remarkable genetic distinctions were observed between patients with RS and those exhibiting resolved kidney involvement. Notably, the genetic signature indicative of renal scarring prominently featured mitochondrial genes. CONCLUSIONS: In this nationwide study of genetic susceptibility to RS after febrile UTIs in infancy, we identified a profile dominated by mitochondrial polymorphisms. This profile can serve as a predictor of future complications, including RS and recurrent UTIs.
Assuntos
Cicatriz , Febre , Predisposição Genética para Doença , Infecções Urinárias , Refluxo Vesicoureteral , Humanos , Infecções Urinárias/genética , Infecções Urinárias/complicações , Infecções Urinárias/diagnóstico , Masculino , Feminino , Lactente , Cicatriz/genética , Cicatriz/etiologia , Cicatriz/diagnóstico , Refluxo Vesicoureteral/genética , Refluxo Vesicoureteral/complicações , Refluxo Vesicoureteral/diagnóstico , Febre/genética , Rim/patologia , Rim/diagnóstico por imagem , Recidiva , Polimorfismo de Nucleotídeo Único , Genótipo , Nefropatias/genética , Nefropatias/diagnóstico , Nefropatias/etiologiaRESUMO
FIRES and NORSE are clinical presentations of disease processes that, to date, remain unexplained without an established etiology in many cases. Neuroinflammation is thought to have paramount importance in the genesis of these conditions. We hereby report the clinical, EEG, brain MRI, and genetic findings of a nuclear family with recurrent febrile-related encephalopathy with refractory de novo Status Epilepticus. Whole-exome sequencing (WES) revealed a homozygous p.C105W pathogenic variant of FADD gene (FAS-associated protein with death domain, FADD), known to cause ultrarare forms of autosomal recessive immunodeficiency that could be associated with variable degrees of lymphoproliferation, cerebral atrophy, and cardiac abnormalities. The FADD-related conditions disrupt FAS-mediated apoptosis and can cause a clinical picture with the characteristics of FIRES. This observation is important because, on one hand, it increases the number of reported patients with FADD deficiency, showing that this disorder may present variable expressivity, and on the other hand, it demonstrates a genetic cause of FIRES involving a cell-mediated inflammation regulatory pathway. This finding supports early treatment with immunomodulatory therapy and could represent a new avenue of research in the field of new onset refractory status epilepticus and related conditions.
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Proteína de Domínio de Morte Associada a Fas , Humanos , Proteína de Domínio de Morte Associada a Fas/genética , Feminino , Masculino , Convulsões Febris/genética , Estado Epiléptico/genética , Estado Epiléptico/etiologia , Linhagem , Sequenciamento do Exoma , Febre/genética , Febre/complicações , Síndromes Epilépticas/genética , EletroencefalografiaRESUMO
The clinical syndrome caused by cleavage-resistant RIPK1 is known as CRIA (Cleavage-resistant RIPK1-induced autoinflammatory) syndrome. We present a family with three generations affected by CRIA syndrome. Our index patient (P1), a boy born of a non-consanguineous marriage, developed recurrent episodes of fever after 5 months of age, with variable periodicity. His father (P2) and paternal grandmother also had periodic fever. At 23 months of age, P1 was diagnosed with renal biopsy-proven steroid-responsive nephrotic syndrome. His first visit to our center was at 2 years of age. At presentation, he had failure to thrive, microcytic hypochromic anemia, and elevated inflammatory markers and interleukin-6 levels. Amyloid A protein was elevated, serum creatinine was normal, and proteinuria resolved after addition of steroids. Next-generation sequencing showed heterozygous mutation (c.970G>A, p.Asp324His) in RIPK1. This mutation has been reported to cause CRIA syndrome. P2 and P1's asymptomatic younger brother had the same mutation. All the affected members showed variability with respect to frequency and duration of periodic fever as well as the age of onset. Both P1 and P2 had elevated amyloid A, with no evidence of renal dysfunction. P1 and P2 showed improvement in the intensity of fever spikes with colchicine treatment; however, both continue to have periodic fever.
Assuntos
Amiloidose , Febre Familiar do Mediterrâneo , Masculino , Humanos , Colchicina/uso terapêutico , Febre Familiar do Mediterrâneo/diagnóstico , Amiloidose/diagnóstico , Febre/diagnóstico , Febre/tratamento farmacológico , Febre/genética , Mutação , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/uso terapêuticoRESUMO
BACKGROUND: Appropriate treatment and management of children presenting with fever depend on accurate and timely diagnosis, but current diagnostic tests lack sensitivity and specificity and are frequently too slow to inform initial treatment. As an alternative to pathogen detection, host gene expression signatures in blood have shown promise in discriminating several infectious and inflammatory diseases in a dichotomous manner. However, differential diagnosis requires simultaneous consideration of multiple diseases. Here, we show that diverse infectious and inflammatory diseases can be discriminated by the expression levels of a single panel of genes in blood. METHODS: A multi-class supervised machine-learning approach, incorporating clinical consequence of misdiagnosis as a "cost" weighting, was applied to a whole-blood transcriptomic microarray dataset, incorporating 12 publicly available datasets, including 1,212 children with 18 infectious or inflammatory diseases. The transcriptional panel identified was further validated in a new RNA sequencing dataset comprising 411 febrile children. FINDINGS: We identified 161 transcripts that classified patients into 18 disease categories, reflecting individual causative pathogen and specific disease, as well as reliable prediction of broad classes comprising bacterial infection, viral infection, malaria, tuberculosis, or inflammatory disease. The transcriptional panel was validated in an independent cohort and benchmarked against existing dichotomous RNA signatures. CONCLUSIONS: Our data suggest that classification of febrile illness can be achieved with a single blood sample and opens the way for a new approach for clinical diagnosis. FUNDING: European Union's Seventh Framework no. 279185; Horizon2020 no. 668303 PERFORM; Wellcome Trust (206508/Z/17/Z); Medical Research Foundation (MRF-160-0008-ELP-KAFO-C0801); NIHR Imperial BRC.
Assuntos
Benchmarking , Pesquisa Biomédica , Criança , Humanos , Diagnóstico Diferencial , Motivos de Nucleotídeos , Febre/diagnóstico , Febre/genética , RNARESUMO
OBJECTIVES: To describe the clinical phenotype and response to treatment of autoinflammatory disease (AID) patients with the TNFRSF1A-pR92Q variant compared to patients with tumour necrosis factor receptor-associated periodic syndrome (TRAPS) due to pathogenic mutations in the same gene and patients diagnosed with other recurrent fever syndromes including periodic fever with aphthous stomatitis, pharyngitis, and adenitis (PFAPA) and syndrome of undefined recurrent fever (SURF). METHODS: Clinical data from pR92Q variant associated AID, classical TRAPS, PFAPA and SURF patients were obtained from the Eurofever registry, an international, multicentre registry enabling retrospective collection of data on AID patients. RESULTS: In this study, 361 patients were enrolled, including 77 pR92Q variant, 72 classical TRAPS, 152 PFAPA and 60 SURF patients. pR92Q carriers had an older age of disease onset than classical TRAPS and PFAPA patients. Compared to pR92Q variant patients, classical TRAPS patients had more relatives affected and were more likely to have migratory rash and AA-amyloidosis. Despite several differences in disease characteristics and symptoms between pR92Q variant and PFAPA patients, part of the pR92Q variant patients experienced PFAPA-like symptoms. pR92Q variant and SURF patients showed a comparable clinical phenotype. No major differences were observed in response to treatment between the four patient groups. Steroids were most often prescribed and effective in the majority of patients. CONCLUSIONS: Patients with AID carrying the TNFRSF1A-pR92Q variant behave more like SURF patients and differ from patients diagnosed with classical TRAPS and PFAPA in clinical phenotype. Hence, they should no longer be diagnosed as having TRAPS and management should differ accordingly.
Assuntos
Doenças Hereditárias Autoinflamatórias , Linfadenite , Faringite , Estomatite Aftosa , Humanos , Estudos Retrospectivos , Febre/genética , Febre/diagnóstico , Doenças Hereditárias Autoinflamatórias/diagnóstico , Doenças Hereditárias Autoinflamatórias/genética , Doenças Hereditárias Autoinflamatórias/complicações , Faringite/diagnóstico , Linfadenite/diagnóstico , Estomatite Aftosa/diagnóstico , Estomatite Aftosa/genética , Receptores Tipo I de Fatores de Necrose Tumoral/genéticaRESUMO
Periodic fever syndromes include autoinflammatory disorders (AID) that involve innate immunity. These disorders are characterized by recurrent fevers and aberrant multi-organ inflammation, without any involvement of T or B cells or the presence of autoantibodies. A complex genetic architecture has been recognized for many AID. However, this complexity has only been partially uncovered for familial Mediterranean fever and other conditions that have a classical monogenic origin and Mendelian transmission. Several gene panels are currently available for molecular diagnosis in patients suspected of having AID. However, even when an extensive number of genes (up to 50-100) are tested in a cohort of clinically selected patients, the diagnostic yield of AID ranges between 15% and 25%, depending on the clinical criteria used for patient selection. In the remaining 75-85% of cases, it is conceivable that the causative gene or genes responsible for a specific condition are still elusive. In these cases, the disease could be explained by variants, either recessive or dominant, that have a major effect on unknown genes, or by the cumulative impact of different variants in more than one gene, each with minor additive effects. In this study, we focused our attention on five familial cases of AID presenting with classical autosomal dominant transmission. To identify the probable monogenic cause, we performed exome sequencing. Through prioritization, filtering, and segregation analysis, we identified a few variants for each family. Subsequent bioinformatics evaluation and pathway analysis helped to narrow down the best candidate genes for each family to FCRL6, PKN1, STAB1, PTDGR, and VCAM1. Future studies on larger cohorts of familial cases will help confirm the pathogenic role of these genes in the pathogenesis of these complex disorders.
Assuntos
Febre Familiar do Mediterrâneo , Humanos , Sequenciamento do Exoma , Febre Familiar do Mediterrâneo/diagnóstico , Febre Familiar do Mediterrâneo/genética , Inflamação , Síndrome , Febre/genéticaRESUMO
Dravet syndrome (DS) is a debilitating infantile epileptic encephalopathy characterized by seizures induced by high body temperature (hyperthermia), sudden unexpected death in epilepsy (SUDEP), cognitive impairment, and behavioral disturbances. The most common cause of DS is haploinsufficiency of the SCN1A gene, which encodes the voltage-gated sodium channel Nav1.1. In current mouse models of DS, the epileptic phenotype is strictly dependent on the genetic background and most mouse models exhibit drastically higher SUDEP rates than patients. Therefore, we sought to develop an alternative animal model for DS. Here, we report the generation and characterization of a Scn1a halploinsufficiency rat model of DS by disrupting the Scn1a allele. Scn1a+/- rats show reduced Scn1a expression in the cerebral cortex, hippocampus and thalamus. Homozygous null rats die prematurely. Heterozygous animals are highly susceptible to heat-induced seizures, the clinical hallmark of DS, but are otherwise normal in survival, growth, and behavior without seizure induction. Hyperthermia-induced seizures activate distinct sets of neurons in the hippocampus and hypothalamus in Scn1a+/- rats. Electroencephalogram (EEG) recordings in Scn1a+/- rats reveal characteristic ictal EEG with high amplitude bursts with significantly increased delta and theta power. After the initial hyperthermia-induced seizures, non-convulsive, and convulsive seizures occur spontaneously in Scn1a+/- rats. In conclusion, we generate a Scn1a haploinsufficiency rat model with phenotypes closely resembling DS, providing a unique platform for establishing therapies for DS.
Assuntos
Epilepsias Mioclônicas , Epilepsia , Convulsões Febris , Morte Súbita Inesperada na Epilepsia , Camundongos , Animais , Ratos , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Epilepsias Mioclônicas/genética , Convulsões/genética , Neurônios/metabolismo , Febre/complicações , Febre/genética , Modelos Animais de DoençasRESUMO
BACKGROUND: Haploinsuffiency A20 (HA20) was first described in 2016 and is caused by a mutation in TNFAIP3/A20. Non-related families living on different continents were examined with whole exome sequencing (WES). All had symptoms of Behçet's disease. An autosomal dominant mutation was found. CASE PRESENTATION: When in her early teens, the patient had presented with a painful labial ulcer. She also had recurrent mouth ulcers, sometimes accompanied by fever and elevated CRP, and on occasion by abdominal pain. The ulcers were biopsied, and she was diagnosed with likely Behçet's disease. Some family members were later admitted with similar symptoms, and a genetic cause was suspected. Twenty years later a new genetic test was performed, and a revised diagnosis of HA20 was correctly made. INTERPRETATION: HA20 is a newly identified autoinflammatory disease due to an inherited mutation. This leads to increased production of pro-inflammatory cytokines such as IL-1, IL-6 and TNF α. The disease-causing process in this monogenic, inherited disease is very similar to the immune process in the acquired, multifactorial Behçet's disease. Fever, young age, abdominal involvement and global occurrence are factors that could lead to suspicion of HA20.
Assuntos
Síndrome de Behçet , Feminino , Humanos , Síndrome de Behçet/diagnóstico , Síndrome de Behçet/genética , Febre/genética , Testes Genéticos , Mucosa , Mutação , Úlcera , AdultoRESUMO
PURPOSE: Sideroblastic anemia, immunodeficiency, periodic fevers, and developmental delay (SIFD) is an autosomal recessive syndrome caused by biallelic loss-of-function variant of tRNA nucleotidyl transferase 1 (TRNT1). Efficacious methods to treat SIFD are lacking. We identified two novel mutations in TRNT1 and an efficacious and novel therapy for SIFD. METHODS: We retrospectively summarized the clinical records of two patients with SIFD from different families and reviewed all published cases of SIFD. RESULTS: Both patients had periodic fever, developmental delay, rash, microcytic anemia, and B cell lymphopenia with infections. Whole-exome sequencing of patient 1 identified a previously unreported homozygous mutation of TRNT1 (c.706G > A/p.Glu236Lys). He received intravenous immunoglobulin (IVIG) replacement and antibiotics, but died at 1 year of age. Gene testing in patient 2 revealed compound heterozygous mutations (c.907C > G/p.Gln303Glu and c.88A > G/p.Met30Val) in TRNT1, the former of which is a novel mutation. Periodic fever was controlled in the first month after adalimumab therapy and IVIG replacement, but recurred in the second month. Adalimumab was discontinued and replaced with thalidomide, which controlled the periodic fever and normalized inflammatory markers effectively. A retrospective analysis of reported cases revealed 69 patients with SIFD carrying 46 mutations. The male: female ratio was 1: 1, and the mean age of onset was 3.0 months. The most common clinical manifestations in patients with SIFD were microcytic anemia (82.6%), hypogammaglobulinemia/B cell lymphopenia (75.4%), periodic fever (66.7%), and developmental delay (60.0%). In addition to the typical tetralogy, SIFD features several heterogeneous symptoms involving multiple systems. Corticosteroids, immunosuppressants, and anakinra have low efficacy, whereas etanercept suppressed fever and improved anemia in reports. Bone-marrow transplantation can be used to treat severe SIFD, but carries a high risk. In total, 28.2% (20/71) of reported patients died, mainly because of multi-organ failure. Biallelic mutations located in exon1-intron5 lead to more severe phenotypes and higher mortality. Furthermore, 15.5% (11/71) patients survived to adulthood. The symptoms could be resolved spontaneously in five patients. CONCLUSIONS: Thalidomide can control the inflammation of SIFD and represents a new treatment for SIFD.
Assuntos
Anemia Sideroblástica , Síndromes de Imunodeficiência , Linfopenia , Masculino , Humanos , Feminino , Talidomida , Estudos Retrospectivos , Anemia Sideroblástica/diagnóstico , Anemia Sideroblástica/tratamento farmacológico , Anemia Sideroblástica/genética , Adalimumab , Imunoglobulinas Intravenosas/uso terapêutico , Síndromes de Imunodeficiência/genética , Febre/etiologia , Febre/genética , Mutação/genética , Nucleotidiltransferases/genéticaRESUMO
OBJECTIVES: Although most of the autoinfammatory disorders have a confirmed genetic cause, periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome still has an unknown genetic background. However, familial cases of PFAPA syndrome have been reported suggesting a genetic its basis. PFAPA syndrome may also be considered an infammasome disorder as variants in infammasome-associated genes such as CARD8, NLRP3, and MEFV have been reported to contribute to the disease. METHODS: Polymerase chain reaction (PCR)/Sanger sequencing analysis was performed for the detection of the variations in 71 PFAPA patients and 71 healthy controls. NLRP3 concentrations in serum were measured in 71 PFAPA patients and 71 healthy controls. RESULTS: No statistically significant differences were observed in the allele or genotype frequencies of the NLRP3 polymorphisms between the controls and patients (P > 0.05). We found no significant differences for NLRP3 serum levels between PFAPA patients and controls (p > 0.05). Mutations in the MEFV gene were detected in 32.5% of our patients (13/40). CONCLUSIONS: It seems that the synergistic effect of different genes plays a role in the formation of PFAPA syndrome. For this reason, it may be useful to examine the presence of mutations in genes such as NLRP3, MEFV, and CARD8 together while investigating the genetics of PFAPA syndrome. Key points ⢠Familial cases of PFAPA syndrome have been reported suggesting a genetic basis for this syndrome. ⢠Elevated serum or plasma levels of IL-1ß, IL-6, and IL-18 have been demonstrated during PFAPA flares in several studies. ⢠It seems that the synergistic effect of different genes plays a role in the formation of PFAPA syndrome.
Assuntos
Linfadenite , Faringite , Estomatite Aftosa , Humanos , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Estomatite Aftosa/genética , Linfadenite/genética , Faringite/genética , Febre/genética , Febre/complicações , Proteínas de Neoplasias , Proteínas Adaptadoras de Sinalização CARD , Pirina/genéticaRESUMO
Autoinflammatory diseases (AIDs) are defined as disorders of innate immunity. They were initially defined in contrast to autoimmune diseases because of the lack of involvement of the adaptive immune system and circulating autoantibodies. The four monogenic AIDs first described are called the 'historical' AIDs and include FMF (associated with MEFV mutations), cryopyrinopathies (associated with NLRP3 mutations), TNF receptor-associated periodic syndrome (associated with TNFRSF1A mutations) and mevalonate kinase deficiency (MKD; associated with MVK mutations). In the last 10 years, >50 new monogenic AIDs have been discovered due to genetic advances. The most important discovery for adult patients is VEXAS syndrome associated with somatic UBA1 mutations leading to an AID affecting mostly elderly men. Diagnosis of monogenic AIDs is based on personal and family history and detailed analysis of symptoms associated with febrile attacks in the context of elevated peripheral inflammatory markers. This review proposes a practical approach for the diagnosis of the main monogenic AIDs among adult patients.
Assuntos
Síndromes Periódicas Associadas à Criopirina , Febre Familiar do Mediterrâneo , Doenças Hereditárias Autoinflamatórias , Deficiência de Mevalonato Quinase , Masculino , Humanos , Adulto , Idoso , Doenças Hereditárias Autoinflamatórias/diagnóstico , Doenças Hereditárias Autoinflamatórias/genética , Febre/etiologia , Febre/genética , Síndromes Periódicas Associadas à Criopirina/diagnóstico , Síndromes Periódicas Associadas à Criopirina/tratamento farmacológico , Síndromes Periódicas Associadas à Criopirina/genética , Deficiência de Mevalonato Quinase/diagnóstico , Deficiência de Mevalonato Quinase/genética , Febre Familiar do Mediterrâneo/diagnóstico , Febre Familiar do Mediterrâneo/tratamento farmacológico , Febre Familiar do Mediterrâneo/genética , PirinaRESUMO
Fever is an important part of inflammatory response to infection. Although brown adipose tissue (BAT) thermogenesis is known to be potently influenced by systemic inflammation, the role of BAT during infection-induced fever remains largely unknown. Here, we injected mice with a low dose of LPS and found that low-dose LPS can directly induce thermogenesis of brown adipocytes. It is known that miR-143 is highly expressed in the BAT, and miR-143 knockout mice exhibited stronger thermogenesis under cold exposure. Interestingly, miR-143 was negatively correlated with an LPS-induced increase of TNFα and IL-6 mRNA levels, and the IL-6 pathway may mediate the inhibition of miR-143 expression. Moreover, miR-143 is down-regulated by LPS, and overexpression of miR-143 in brown adipocytes by lentivirus could rescue the enhancement of UCP1 protein expression caused by LPS, hinting miR-143 may be an important regulator of the thermogenesis in brown adipocytes. More importantly, the knockout of miR-143 further enhanced the LPS-induced increase of body temperature and BAT thermogenesis, and this result was further confirmed by in vitro experiments by using primary brown adipocytes. Mechanistically, adenylate cyclase 9 (AC9) is a new target gene of miR-143 and LPS increases BAT thermogenesis by a way of inhibiting miR-143 expression, a negative regulator for AC9. Our study considerably improves our collective understanding of the important function of miR-143 in inflammatory BAT thermogenesis.
Assuntos
Adipócitos Marrons , MicroRNAs , Animais , Camundongos , Adipócitos Marrons/metabolismo , Febre/induzido quimicamente , Febre/genética , Febre/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Lipopolissacarídeos/metabolismo , Camundongos Knockout , MicroRNAs/genética , MicroRNAs/metabolismo , Termogênese/genéticaRESUMO
The pathophysiology of hypothermia during sepsis is unclear. Using genomic profiling of blood leukocytes, we aimed to determine if hypothermia is associated with a different gene expression profile compared to fever during sepsis. Patients with sepsis and either hypothermia or fever within 24 hours after ICU admission were included in the study (n = 168). Hypothermia was defined as body temperature below 36 °C. Fever was defined as body temperature equal to or above 38.3°C. We compared blood gene expression (whole-genome transcriptome in leukocytes) in hypothermic septic compared to febrile septic patients in an unmatched analysis and matched for APACHE IV score and the presence of shock. In total, 67 septic patients were hypothermic and 101 patients were febrile. Hypothermia was associated with a distinct gene expression profile in both unmatched and matched analyses. There were significant differences related to the up- and downregulation of canonical signalling pathways. In the matched analysis, the top upregulated gene was cold-inducible mRNA binding protein (CIRBP) which plays a role in cold-induced suppression of cell proliferation. In addition, we found three signalling pathways significantly upregulated in hypothermic patients compared to febrile patients; tryptophan degradation X, phenylalanine degradation IV and putrescine degradation III. In conclusion, there are distinct signalling pathways and genes associated with hypothermia, including tryptophan degradation and CIRBP expression, providing a possible link to the modulation of body temperature and early immunosuppression. Future studies may focus on the canonical signalling pathways presented in this paper to further investigate spontaneous hypothermia in sepsis.
Assuntos
Hipotermia , Sepse , Febre/genética , Humanos , Hipotermia/complicações , Hipotermia/genética , Proteínas de Ligação a RNA/metabolismo , Sepse/complicações , Sepse/genética , Transcriptoma/genética , TriptofanoRESUMO
Crisponi syndrome (CS) is a rare autosomal recessive syndrome, characterized by episodic facial muscle contraction with trismus, abundant salivation along with intermittent hyperthermia, feeding difficulties, characteristic facial dysmorphism, and camptodactyly. Here the authors report two South Indian neonates with confirmed diagnosis of Crisponi syndrome, caused by novel pathogenic variants in cytokine receptor-like factor 1 (CRLF1) gene. The classical clinical findings observed in the present cases were feeding difficulty, facial dysmorphism, tachypnea, contractures, camptodactyly, opisthotonus, hyperthermia, poor growth, and facial muscle contraction resembling probable tetanus. The patients with variants identified in the signal peptide domain had typical spasms from day one of life as compared to the variants in other domains who had later onset at neonatal period. The authors provide a review of the cases described, so far, from India highlighting that no common variants attribute to this rare syndrome. Recognizing this syndrome is crucial to differentiate it from infective conditions and for effective genetic counseling. Though tetanus is almost eradicated in developing countries, genetic causes should be suspected in new cases.
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Contratura , Tétano , Contratura/genética , Morte Súbita , Fácies , Febre/diagnóstico , Febre/genética , Deformidades Congênitas da Mão , Humanos , Hiperidrose , Recém-Nascido , Mutação , Receptores de Citocinas/genética , Síndrome , Trismo/congênito , Trismo/diagnóstico , Trismo/genéticaRESUMO
Fever is a common symptom of infection in children. Periodic fever syndromes are less common but more complex. One of these Periodic fever syndromes is PFAPA (periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis) syndrome which is known as the most benign syndromes. The cause of this disease is unknown. Various factors, including environmental and genetic factors, are involved in the development of this disease. In this study, the association of rs13075270 and rs13092160 polymorphisms were investigated in CCR1 and CCR3 genes with susceptibility to this syndrome in the Chinese population. In this regard, 38 patients with PFAPA syndrome and 100 healthy individuals were selected. After DNA sampling and extraction, polymorphisms of CCR1 and CCR3 receptor genes were examined by the PCR-RFLP method. Findings were analyzed using SPSS software version 22 with a significant level of P <0.05. The frequency of T/T genotype rs13092160 polymorphism in the patient and control groups was 78.95% and 83%, respectively, C/T genotype was 21.05% and 17% (P = 0.421). The frequency of the C/C genotype was 0 in both groups. Regarding rs13075270 polymorphism, the frequency of T/T genotype in patient and control groups was 15.79% and 81%, C/T genotype was 78.95% and 18% and C/C genotype was 5.26% and 1%, respectively (P<0.05). Thus, in rs13075270 polymorphism, the C/T genotype was associated with the risk of PFAPA syndrome (P<0.05), but rs13092160 polymorphism did not show a significant difference between individuals with PFAPA syndrome and controls.
Assuntos
Febre Familiar do Mediterrâneo/genética , Receptores CCR1/genética , Receptores CCR3/genética , Criança , Febre/complicações , Febre/genética , Humanos , Linfadenite/complicações , Linfadenite/diagnóstico , Linfadenite/genética , Faringite/diagnóstico , Faringite/genética , Estomatite Aftosa/complicações , Estomatite Aftosa/diagnóstico , Estomatite Aftosa/genética , SíndromeRESUMO
OBJECTIVE: To identify the molecular basis of a systemic autoinflammatory disorder (SAID) evocative of TNF receptor-associated periodic syndrome (TRAPS). METHODS: (i) Deep next generation sequencing (NGS) through a SAID gene panel; (ii) variant allele distribution in peripheral blood subpopulations; (iii) in silico analyses of mosaic variants using TNF receptor superfamily 1A (TNFRSF1A) crystal structure; (iv) review of the very rare TNFRSF1A mosaic variants reported previously. RESULTS: In a 36-year-old man suffering from recurrent fever for 12 years, high-depth NGS revealed a TNFRSF1A mosaic variant, c.176G>A p.(Cys59Tyr), which Sanger sequencing failed to detect. This mosaic variant displayed a variant allele fraction of 14% in whole blood; it affects both myeloid and lymphoid lineages. p.(Cys59Tyr), a recurrent germline pathogenic variant, affects a crucial cysteine located in the first cysteine-rich domain (CRD1) and involved in a disulphide bridge. Introduction of a tyrosine at this position is expected to disrupt the CRD1 structure. Review of the three previously reported TNFRSF1A mosaic variants revealed that they are all located in a small region of CRD2 and that germinal cells can be affected. CONCLUSION: This study expands the localization of TNFRSF1A mosaic variants to the CRD1 domain. Noticeably, residues involved in germline TNFRSF1A mutational hot spots can also be involved in post-zygotic mutational events. Including our study, only four patients have been thus far reported with TNFRSF1A mosaicism, highlighting the need for a high-depth NGS-based approach to avoid the misdiagnosis of TRAPS. Genetic counselling has to consider the potential occurrence of TNFRSF1A mosaic variants in germinal cells.
Assuntos
Cisteína , Doenças Hereditárias Autoinflamatórias , Masculino , Humanos , Adulto , Cisteína/genética , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Febre/genética , Doenças Hereditárias Autoinflamatórias/genética , Doenças Hereditárias Autoinflamatórias/diagnóstico , MutaçãoRESUMO
OBJECTIVES: Fever has been recently included in the new 2019 EULAR/ACR classification criteria for systemic lupus erythematosus (SLE). Thus, we investigated the possible association of fever with other clinical disease manifestations. Then, we analysed a panel of 30 SNPs to verify their possible contribution to the pathogenesis of this constitutional symptom. METHODS: In this retrospective study we collected clinical/laboratory features in a SLE cohort, including the occurrence of fever (body temperature >37.5°C, excluding infective aetiology). A phenotype-genotype correlation analysis was carried out. RESULTS: We evaluated 167 patients (M/F 12/155, median age at the disease diagnosis 30 years, IQR 17; median disease duration 240 months, IQR 156). Seventy patients (41.9%) reported fever, significantly associated with: serositis and haematological manifestations (p=0.02 and p=0.00001, respectively). A significant association between fever and leukopenia (p=0.003), haemolytic anaemia (p=0.04), and thrombocytopenia (p=0.04) was observed. In addition, significantly higher median SLICC Damage Index (SDI) values were observed in patients with fever in comparison with those without [2 (IQR 3) vs. 1 (IQR 2); p=0.005]. The genotype/phenotype analysis showed an association between fever and the rs13361189 of Immunity Related GTPase M (IRGM) gene (p=0.003; OR 3.89, CI 1.16-13.03), confirmed also in multivariate logistic regression analysis (p=0.028, B=1.39). CONCLUSIONS: The association between IRGM rs13361189 polymorphism and the occurrence of inflammatory fever, could provide new insights into the role of genetic background in the pathogenesis of this SLE-related feature.
Assuntos
Lúpus Eritematoso Sistêmico , Humanos , Estudos Retrospectivos , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/genética , Estudos de Coortes , Polimorfismo Genético , Febre/genéticaRESUMO
Febrile seizures represent the most common type of pathological brain activity in young children and are influenced by genetic, environmental and developmental factors. In a minority of cases, febrile seizures precede later development of epilepsy. We conducted a genome-wide association study of febrile seizures in 7635 cases and 83 966 controls identifying and replicating seven new loci, all with P < 5 × 10-10. Variants at two loci were functionally related to altered expression of the fever response genes PTGER3 and IL10, and four other loci harboured genes (BSN, ERC2, GABRG2, HERC1) influencing neuronal excitability by regulating neurotransmitter release and binding, vesicular transport or membrane trafficking at the synapse. Four previously reported loci (SCN1A, SCN2A, ANO3 and 12q21.33) were all confirmed. Collectively, the seven novel and four previously reported loci explained 2.8% of the variance in liability to febrile seizures, and the single nucleotide polymorphism heritability based on all common autosomal single nucleotide polymorphisms was 10.8%. GABRG2, SCN1A and SCN2A are well-established epilepsy genes and, overall, we found positive genetic correlations with epilepsies (rg = 0.39, P = 1.68 × 10-4). Further, we found that higher polygenic risk scores for febrile seizures were associated with epilepsy and with history of hospital admission for febrile seizures. Finally, we found that polygenic risk of febrile seizures was lower in febrile seizure patients with neuropsychiatric disease compared to febrile seizure patients in a general population sample. In conclusion, this largest genetic investigation of febrile seizures to date implicates central fever response genes as well as genes affecting neuronal excitability, including several known epilepsy genes. Further functional and genetic studies based on these findings will provide important insights into the complex pathophysiological processes of seizures with and without fever.
Assuntos
Epilepsia , Convulsões Febris , Anoctaminas/genética , Criança , Pré-Escolar , Epilepsia/genética , Febre/complicações , Febre/genética , Estudo de Associação Genômica Ampla , Humanos , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Convulsões Febris/genéticaRESUMO
Sideroblastic anemia with immunodeficiency, fevers, and developmental delay (SIFD; MIM #616084) is an autosomal recessive disorder of mitochondrial and cytosolic tRNA processing caused by pathogenic, biallelic variants in TRNT1. Other features of this disorder include central nervous system, renal, cardiac, ophthalmological features, and sensorineural hearing impairment. SIFD was first described in 2013 and to date, it has been reported in 46 patients. Herein, we review the literature and describe two siblings with SIFD and note the novel phenotype of hypoglycemia in the context of growth hormone (GH) deficiency. GH deficiency without hypoglycemia has previously been reported in three patients with SIFD, but GH deficiency had not been firmly ascribed to SIFD. We propose to expand the phenotype to include GH deficiency, hypoglycemia, and previously unreported dysmorphic features. Furthermore, we highlight the intrafamilial variability of the disease by the discordance of our patients' clinical phenotypes and biochemical profiles measured by untargeted metabolomics analysis. Several metabolomic abnormalities were observed in both patients, and these may represent a potential biochemical signature for SIFD.