RESUMO
The long-term association between mRNA-based coronavirus disease 2019 (COVID-19) vaccination and the development of autoimmune connective tissue diseases (AI-CTDs) remains unclear. In this nationwide, population-based cohort study involving 9,258,803 individuals, we aim to determine whether the incidence of AI-CTDs is associated with mRNA vaccination. The study spans over 1 year of observation and further analyses the risk of AI-CTDs by stratifying demographics and vaccination profiles and treating booster vaccination as time-varying covariate. We report that the risk of developing most AI-CTDs did not increase following mRNA vaccination, except for systemic lupus erythematosus with a 1.16-fold risk in vaccinated individuals relative to controls. Comparable results were reported in the stratified analyses for age, sex, mRNA vaccine type, and prior history of non-mRNA vaccination. However, a booster vaccination was associated with an increased risk of some AI-CTDs including alopecia areata, psoriasis, and rheumatoid arthritis. Overall, we conclude that mRNA-based vaccinations are not associated with an increased risk of most AI-CTDs, although further research is needed regarding its potential association with certain conditions.
Assuntos
Doenças Autoimunes , Vacinas contra COVID-19 , COVID-19 , SARS-CoV-2 , Vacinação , Humanos , Doenças Autoimunes/epidemiologia , Doenças Autoimunes/genética , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , República da Coreia/epidemiologia , COVID-19/prevenção & controle , COVID-19/epidemiologia , Vacinas contra COVID-19/efeitos adversos , Vacinas contra COVID-19/imunologia , Vacinas contra COVID-19/administração & dosagem , Estudos de Coortes , SARS-CoV-2/imunologia , SARS-CoV-2/genética , Idoso , Adulto Jovem , Incidência , Adolescente , Doenças do Tecido Conjuntivo/genética , Doenças do Tecido Conjuntivo/epidemiologia , Vacinas de mRNA , Imunização SecundáriaRESUMO
OBJECTIVE: We employed two-sample Mendelian randomization (MR) to assess the genetic causal relationship between educational attainment (EA) and risk of five common connective tissue diseases (CTDs). METHODS: Educational attainment (self-reported at age ≥30 years) was obtained from a meta-analysis of years of schooling in 766 345 participants of European ancestry from genome-wide association studies (GWAS). A total of 1265 signals associated with EA were identified. Genetic data for five CTDs [rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), polymyositis (PM), and dermatomyositis (DM)] were obtained from the FinnGen consortium. Two-sample MR analyses were performed separately for EA and the five CTDs. RESULTS: We found a negative causal relationship between EA and RA (ORIVW = 0.627, 95% CI = 0.537-0.732, p < .001), and SLE (ORIVW = 0.341, 95% CI = 0.123-0.944, p = .038). There were no genetic causal association between EA and SSc (ORIVW = 0.647, 95% CI = 0.351-1.195, p = .164), PM (ORIVW = 0.938, 95% CI = 0.320-2.746, p = .907), or DM (ORIVW = 0.754, 95% CI = 0.351-1.619, p = .468). None of the analyses revealed any horizontal pleiotropy or heterogeneity. CONCLUSION: Our findings indicated a potential causal association between EA and RA, SLE, emphasizing the need for further investigation and potential integration of EA into clinical practice to enhance treatment strategies.
Assuntos
Doenças do Tecido Conjuntivo , Escolaridade , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Humanos , Fatores de Risco , Doenças do Tecido Conjuntivo/genética , Doenças do Tecido Conjuntivo/epidemiologia , Doenças do Tecido Conjuntivo/diagnóstico , Medição de Risco , Fenótipo , Masculino , Feminino , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/epidemiologia , Lúpus Eritematoso Sistêmico/diagnóstico , Adulto , Pessoa de Meia-IdadeRESUMO
A 6-month-old female infant with megalophthalmos was referred with the suspicion of congenital glaucoma. Refractive measurements obtained with handheld autorefractometry were -7.00 -2.00 × 90° in the right eye and -6.00 -2.00 × 100° in the left eye and ultrasonic axial lengths were 22.50 mm in both eyes. Intraocular pressures and vertical and horizontal corneal diameters of the proband were 11 mm Hg, 11 mm, and 11.50 mm in both eyes, respectively. She was diagnosed as having early-onset high myopia. Her father also had degenerative high myopia (-12.00 diopters) in the right eye, bilateral congenital lens opacities, and retinal detachment in the left eye. Her mother was emmetropic with normal eye examination results. Clinical exome sequencing analysis revealed a novel ENST00000380518.3 c.3528_3530 delins GACCATTAGCA (Chr12:48369813: GCA > TGCTAATGGTC) variant in the collagen type II alpha 1 chain (COL2A1) on chromosome 12q13 (OMIM 108300), consistent with the Stickler syndrome type 1. Subsequent segregation analysis revealed paternal inheritance. Although many pathogenic null variants have been described within the COL2A1 gene, there is currently no documented literature pertaining to this specific variant, making this the inaugural report of its manifestation in scientific discourse. [J Pediatr Ophthalmol Strabismus. 2024;61(3):e23-e27.].
Assuntos
Artrite , Colágeno Tipo II , Doenças do Tecido Conjuntivo , Perda Auditiva Neurossensorial , Linhagem , Feminino , Humanos , Lactente , Artrite/genética , Artrite/diagnóstico , Colágeno Tipo II/genética , Doenças do Tecido Conjuntivo/genética , Doenças do Tecido Conjuntivo/diagnóstico , DNA/genética , Análise Mutacional de DNA , Sequenciamento do Exoma , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/diagnóstico , Pressão Intraocular/fisiologia , Mutação , Descolamento Retiniano/genética , Descolamento Retiniano/diagnóstico , TurquiaRESUMO
Hereditary connective tissue disorders include more than 200 conditions affecting different organs and tissues, compromising the biological role of the extracellular matrix through interference in the synthesis, development, or secretion of collagen and/or its associated proteins. The clinical phenotype includes multiple signs and symptoms, usually nonspecific but of interest to rheumatologists because of musculoskeletal involvement. The patient´s journey to diagnosis is long, and physicians should include these disorders in their differential diagnoses of diseases with systemic involvement. In this review, insights for the diagnosis and treatment of osteogenesis imperfecta, hypermobility spectrum disorder/Ehlers-Danlos syndrome, Marfan, Loeys-Dietz, and Stickler syndromes are presented.
Assuntos
Doenças do Tecido Conjuntivo , Humanos , Artrite , Colágeno/genética , Doenças do Tecido Conjuntivo/genética , Doenças do Tecido Conjuntivo/terapia , Síndrome de Ehlers-Danlos/genética , Síndrome de Ehlers-Danlos/diagnóstico , Perda Auditiva Neurossensorial , Instabilidade Articular/genética , Síndrome de Loeys-Dietz/genética , Síndrome de Loeys-Dietz/diagnóstico , Síndrome de Marfan/genética , Síndrome de Marfan/diagnóstico , Osteogênese Imperfeita/genética , Descolamento RetinianoRESUMO
BACKGROUND: Stickler syndrome (STL) is a collagenopathy caused by pathogenic variants in collagen-coding genes, mainly COL2A1 or COL11A1 associated with Stickler syndrome type 1 (STL1) or type 2 (STL2), respectively. Affected individuals manifest ocular, auditory, articular, and craniofacial findings in varying degrees. Previous literature and case reports describe high variability in clinical findings for patients with STL. With this case report, we broaden the clinical spectrum of the phenotype. MATERIALS AND METHODS: Case report on two members of a family (mother and son) including clinical examination and genetic testing using targeted trio whole exome sequencing (trio-WES). RESULTS: A boy and his mother presented with microphthalmia, congenital cataract, ptosis, and moderate-to-severe sensorineural hearing loss. Trio-WES found a novel heterozygote missense variant, c.4526A>G; p(Gln1509Arg) in COL11A1 in both affected individuals. CONCLUSIONS: We report a previously undescribed phenotype associated with a COL11A1-variant in a mother and son, expanding the spectrum for phenotype-genotype correlation in STL2, presenting with microphthalmia, congenital cataract, and ptosis not normally associated with Stickler syndrome.
Assuntos
Artrite , Catarata , Colágeno Tipo XI , Doenças do Tecido Conjuntivo , Perda Auditiva Neurossensorial , Microftalmia , Mutação de Sentido Incorreto , Linhagem , Humanos , Catarata/genética , Catarata/congênito , Catarata/diagnóstico , Microftalmia/genética , Masculino , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/patologia , Doenças do Tecido Conjuntivo/genética , Doenças do Tecido Conjuntivo/diagnóstico , Feminino , Colágeno Tipo XI/genética , Colágeno Tipo XI/deficiência , Artrite/genética , Artrite/diagnóstico , Descolamento Retiniano/genética , Descolamento Retiniano/diagnóstico , Adulto , Fenótipo , Criança , Sequenciamento do Exoma , Descolamento do VítreoRESUMO
Phenotypic features of a hereditary connective tissue disorder, including craniofacial characteristics, hyperextensible skin, joint laxity, kyphoscoliosis, arachnodactyly, inguinal hernia, and diverticulosis associated with biallelic pathogenic variants in EFEMP1 have been previously described in four patients. Genome sequencing on a proband and her mother with comparable phenotypic features revealed that both patients were heterozygous for a stop-gain variant c.1084C>T (p.Arg362*). Complementary RNA-seq on fibroblasts revealed significantly reduced levels of mutant EFEMP1 transcript. Considering the absence of other molecular explanations, we extrapolated that EFEMP1 could be the cause of the patient's phenotypes. Furthermore, nonsense-mediated decay was demonstrated for the mutant allele as the principal mechanism for decreased levels of EFEMP1 mRNA. We provide strong clinical and genetic evidence for the haploinsufficiency of EFEMP1 due to nonsense-medicated decay to cause severe kyphoscoliosis, generalized hypermobility of joints, high and narrow arched palate, and potentially severe diverticulosis. To the best of our knowledge, this is the first report of an autosomal dominant EFEMP1-associated hereditary connective tissue disorder and therefore expands the phenotypic spectrum of EFEMP1 related disorders.
Assuntos
Doenças do Tecido Conjuntivo , Proteínas da Matriz Extracelular , Haploinsuficiência , Síndrome de Marfan , Fenótipo , Humanos , Haploinsuficiência/genética , Feminino , Síndrome de Marfan/genética , Síndrome de Marfan/patologia , Proteínas da Matriz Extracelular/genética , Doenças do Tecido Conjuntivo/genética , Doenças do Tecido Conjuntivo/patologia , Linhagem , Mutação/genética , Degradação do RNAm Mediada por Códon sem Sentido/genética , Masculino , Adulto , Alelos , Predisposição Genética para Doença , CriançaRESUMO
BACKGROUND: Variations in ZNF469 have been associated with Brittle Cornea Syndrome that presents with bluish sclera, loss of vision after trivial trauma, arachnodactyly, and joint laxity. MATERIALS AND METHODS: Detailed medical and family history, physical examination, and molecular analysis. RESULTS: A 21-year-old female presented with bluish discoloration of sclera, diminution of vision following trivial trauma in childhood along with hearing loss and systemic features of arachnodactyly and joint laxity. Clinical diagnosis of brittle cornea syndrome was made which was molecularly proven using next-generation sequencing which identified compound heterozygosity in ZNF469 for pathogenic and likely pathogenic nonsense variants. One variant namely NM_001367624.2:c.5882dup was identified in the exon 3 which was novel and classified as likely pathogenic according to American College of Medical Genetics (ACMG) criteria for variant classification. Another variant NM_001367624.2:c.8992C>T in the exon 2 was classified as pathogenic for Brittle Cornea Syndrome 1. CONCLUSIONS: The report adds to the allelic heterogeneity in ZNF469 causative of Brittle Cornea Syndrome 1 and shall acquaint the physicians about this potentially vision threatening, underdiagnosed, rare syndrome.
Assuntos
Alelos , Instabilidade Articular , Fatores de Transcrição , Humanos , Feminino , Adulto Jovem , Fatores de Transcrição/genética , Instabilidade Articular/genética , Instabilidade Articular/diagnóstico , Instabilidade Articular/congênito , Índia , Anormalidades da Pele/genética , Anormalidades da Pele/diagnóstico , Aracnodactilia/genética , Aracnodactilia/diagnóstico , Doenças do Tecido Conjuntivo/genética , Doenças do Tecido Conjuntivo/diagnóstico , Anormalidades do Olho/genética , Anormalidades do Olho/diagnóstico , Sequenciamento de Nucleotídeos em Larga Escala , Linhagem , Mutação , Éxons/genética , Anormalidades Múltiplas/genética , Síndrome de Ehlers-Danlos/genética , Síndrome de Ehlers-Danlos/diagnóstico , Dermatopatias Genéticas/genética , Dermatopatias Genéticas/diagnóstico , Dermatopatias Genéticas/patologiaRESUMO
Patients with heritable connective tissue disorders (HCTDs), represented by Marfan syndrome, can develop fatal aortic and/or arterial complications before age 50. Therefore, accurate diagnosis, appropriate medical treatment, and early prophylactic surgical treatment of aortic and arterial lesions are essential to improve prognosis. Patients with HCTDs generally present with specific physical features due to connective tissue abnormalities, while some patients with heritable thoracic aortic diseases (HTADs) have few distinctive physical characteristics. The development of genetic testing has made it possible to provide accurate diagnoses for patients with HCTDs/HTADs. This review provides an overview of the diagnosis and treatment of HCTDs/HTADs, including current evidence on cardiovascular interventions for this population.
Assuntos
Dissecção Aórtica , Doenças Cardiovasculares , Doenças do Tecido Conjuntivo , Síndrome de Ehlers-Danlos , Síndrome de Marfan , Humanos , Pessoa de Meia-Idade , Síndrome de Ehlers-Danlos/complicações , Síndrome de Ehlers-Danlos/diagnóstico , Doenças Cardiovasculares/complicações , Doenças do Tecido Conjuntivo/complicações , Doenças do Tecido Conjuntivo/diagnóstico , Doenças do Tecido Conjuntivo/genética , Síndrome de Marfan/complicações , Síndrome de Marfan/diagnóstico , Síndrome de Marfan/genética , Tecido ConjuntivoRESUMO
Czech dysplasia is an autosomal dominant type 2 collagenopathy that is caused by heterozygosity for the recurrent p.(Arg275Cys) COL2A1 variant. Affected individuals usually present with skeletal abnormalities such as metatarsal hypoplasia of the third and fourth toes and early-onset arthropathy, as well as hearing loss. To date, no ophthalmic findings have been reported in patients with Czech dysplasia even though COL2A1 has been implicated in other ocular conditions such as type 1 Stickler syndrome. For the first time, we report the ocular findings in four families with Czech dysplasia, including type 1 vitreous anomaly, hypoplastic vitreous, retinal tears, and significant refractive error. These novel ocular findings expand the phenotype associated with Czech dysplasia and may aid clinicians as an additional diagnostic feature. Patients with congenital abnormalities of vitreous gel architecture have an increased risk of retinal detachment, and as such, patients may benefit from prophylaxis. Considering that many of the patients did not report any ocular symptoms, vitreous phenotyping is of key importance in identifying the need for counseling with regard to prophylaxis.
Assuntos
Artrite , Doenças do Tecido Conjuntivo , Perda Auditiva Neurossensorial , Osteocondrodisplasias , Descolamento Retiniano , Dedos do Pé/anormalidades , Humanos , Doenças do Tecido Conjuntivo/genética , Perda Auditiva Neurossensorial/genética , Descolamento Retiniano/diagnóstico , Descolamento Retiniano/genética , Artrite/genética , Mutação , Colágeno Tipo II/genética , LinhagemRESUMO
AIMS: To synthesize and critically appraise available interventions in the conservative management of hand impairment for children and adolescents with heritable disorders of connective tissue (HDCT). METHODS: A search of peer-reviewed literature and online platforms were included with data regarding hand impairment and function, conservative management and outcome measures extracted and appraised. Levels of evidence were applied to published literature. RESULTS: Ten peer-reviewed papers, eleven webpages and YouTube videos met the inclusion criteria. Reported interventions included: strengthening, orthoses, assistive equipment, education and pacing. Evidence of intervention effectiveness and evidence-based guidance on dosage were absent, with no consistency of outcome measures monitoring intervention effectiveness. Online platforms posted by health professionals predominantly provided advice for families without clinical detail of interventions. CONCLUSIONS: There is a consistent suite of interventions identified in both peer-reviewed literature and online platforms used by clinicians and families to manage hand impairment for children and adolescents with HDCT. Clear dosage parameters and outcome measures are needed in future intervention studies to determine the effectiveness of interventions and guide clinicians in how best to treat hand impairment. Increasing accountability and quality of online resources posted by health professionals for families is warranted to ensure dosage details and precautions are provided.
Assuntos
Doenças do Tecido Conjuntivo , Tratamento Conservador , Tecnologia Assistiva , Adolescente , Criança , Humanos , Aparelhos Ortopédicos , Avaliação de Resultados em Cuidados de Saúde , Doenças do Tecido Conjuntivo/genética , Doenças do Tecido Conjuntivo/terapiaRESUMO
Autoimmune connective tissue disorders, including systemic lupus erythematosus, systemic sclerosis (SSc) and dermatomyositis (DM), often manifest with debilitating cutaneous lesions and can result in systemic organ damage that may be life-threatening. Despite recent therapeutic advancements, many patients still experience low rates of sustained remission and significant treatment toxicity. While genetic predisposition plays a role in these connective tissue disorders, the relatively low concordance rates among monozygotic twins (ranging from approximately 4% for SSc to about 11%-50% for SLE) have prompted increased scrutiny of the epigenetic factors contributing to these diseases. In this review, we explore some seminal studies and key findings to provide a comprehensive understanding of how dysregulated epigenetic mechanisms can contribute to the development of SLE, SSc and DM.
Assuntos
Doenças Autoimunes , Doenças do Tecido Conjuntivo , Dermatomiosite , Lúpus Eritematoso Sistêmico , Escleroderma Sistêmico , Humanos , Dermatomiosite/genética , Esclerose , Lúpus Eritematoso Sistêmico/genética , Escleroderma Sistêmico/genética , Escleroderma Sistêmico/tratamento farmacológico , Doenças do Tecido Conjuntivo/genética , Epigênese GenéticaRESUMO
Mixed connective tissue disease (MCTD) is a very rare disorder that belongs in the rare and clinically multifactorial groups of diseases. The pathogenesis of MCTD is still unclear. The best understood epigenetic alteration is DNA methylation whose role is to regulate gene expression. In the literature, there are ever-increasing assumptions that DNA methylation can be one of the possible reasons for the development of Autoimmune Connective Tissue Diseases (ACTDs) such as systemic sclerosis (SSc) and systemic lupus erythematosus (SLE). The aim of this study was to define the global DNA methylation changes between MCTD and other ACTDs patients in whole blood samples. The study included 54 MCTD patients, 43 SSc patients, 45 SLE patients, and 43 healthy donors (HC). The global DNA methylation level was measured by ELISA. Although the global DNA methylation was not significantly different between MCTD and control, we observed that hypomethylation distinguishes the MCTD patients from the SSc and SLE patients. The present analysis revealed a statistically significant difference of global methylation between SLE and MCTD (p < 0.001), SLE and HC (p = 0.008), SSc and MCTD (p ≤ 0.001), and SSc and HC (p < 0.001), but neither between MCTD and HC (p = 0.09) nor SSc and SLE (p = 0.08). The highest % of global methylation (median, IQR) has been observed in the group of patients with SLE [0.73 (0.43, 1.22] and SSc [0,91 (0.59, 1.50)], whereas in the MCTD [0.29 (0.20, 0.54)], patients and healthy subjects [0.51 (0.24, 0.70)] were comparable. In addition, our study provided evidence of different levels of global DNA methylation between the SSc subtypes (p = 0.01). Our study showed that patients with limited SSc had a significantly higher global methylation level when compared to diffuse SSc. Our data has shown that the level of global DNA methylation may not be a good diagnostic marker to distinguish MCTD from other ACTDs. Our research provides the groundwork for a more detailed examination of the significance of global DNA methylation as a distinguishing factor in patients with MCTD compared to other ACTDs patients.
Assuntos
Doenças Autoimunes , Doenças do Tecido Conjuntivo , Lúpus Eritematoso Sistêmico , Doença Mista do Tecido Conjuntivo , Escleroderma Sistêmico , Humanos , Doença Mista do Tecido Conjuntivo/diagnóstico , Doença Mista do Tecido Conjuntivo/genética , Doenças Autoimunes/genética , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/genética , Doenças do Tecido Conjuntivo/diagnóstico , Doenças do Tecido Conjuntivo/genética , Escleroderma Sistêmico/diagnóstico , Escleroderma Sistêmico/genética , Metilação de DNARESUMO
Connective tissue disorders can be caused by pathogenic variants (mutations) in genes encoding extracellular matrix (ECM) proteins. Such disorders typically manifest during development or postnatal growth and result in significant morbidity and mortality. The development of curative treatments for connective tissue disorders is hampered in part by the inability of many mature connective tissues to efficiently regenerate. To be most effective, therapeutic strategies designed to preserve or restore tissue function will likely need to be initiated during phases of significant endogenous connective tissue remodeling and organ sculpting postnatally and directly target the underlying ECM protein mutations. With recent advances in whole exome sequencing, in-vitro and in-vivo disease modeling, and the development of mutation-specific molecular therapeutic modalities, it is now feasible to directly correct disease-causing mutations underlying connective tissue disorders and ameliorate their pathogenic consequences. These technological advances may lead to potentially curative personalized medicine approaches for connective tissue disorders that have previously been considered incurable. In this review, we highlight innovative therapeutic modalities including gene replacement, exon skipping, DNA/mRNA editing, and pharmacological approaches that were used to preserve or restore tissue function in the context of connective tissue disorders. Inherent to a successful application of these approaches is the need to deepen the understanding of mechanisms that regulate ECM formation and homeostasis, and to decipher how individual mutations in ECM proteins compromise ECM and connective tissue development and function.
Assuntos
Doenças do Tecido Conjuntivo , Medicina de Precisão , Humanos , Doenças do Tecido Conjuntivo/genética , Doenças do Tecido Conjuntivo/terapia , Éxons , Proteínas da Matriz Extracelular , Tecido ConjuntivoRESUMO
BACKGROUND: The risk of developing late radiotoxicity after radiotherapy in patients with high chromosomal radiosensitivity after radiotherapy could potentially be higher compared to the risk in patients with average radiosensitivity. In case of extremely high radiosensitivity, dose reduction may be appropriate. Some rheumatic diseases (RhD), including connective tissue diseases (CTDs) appear to be associated with higher radiosensitivity. The question arises as to whether patients with rheumatoid arthritis (RA) also generally have a higher radiosensitivity and whether certain parameters could indicate clues to high radiosensitivity in RA patients which would then need to be further assessed before radiotherapy. METHODS: Radiosensitivity was determined in 136 oncological patients with RhD, 44 of whom were RA patients, and additionally in 34 non-oncological RA patients by three-colour fluorescence in situ hybridization (FiSH), in which lymphocyte chromosomes isolated from peripheral blood are analysed for their chromosomal aberrations of an unirradiated and an with 2 Gy irradiated blood sample. The chromosomal radiosensitivity was determined by the average number of breaks per metaphase. In addition, correlations between certain RA- or RhD-relevant disease parameters or clinical features such as the disease activity score 28 and radiosensitivity were assessed. RESULTS: Some oncological patients with RhD, especially those with connective tissue diseases have significantly higher radiosensitivity compared with oncology patients without RhD. In contrast, the mean radiosensitivity of the oncological patients with RA and other RhD and the non-oncological RA did not differ. 14 of the 44 examined oncological RA-patients (31.8%) had a high radiosensitivity which is defined as ≥ 0.5 breaks per metaphase. No correlation of laboratory parameters with radiosensitivity could be established. CONCLUSIONS: It would be recommended to perform radiosensitivity testing in patients with connective tissue diseases in general. We did not find a higher radiosensitivity in RA patients. In the group of RA patients with an oncological disease, a higher percentage of patients showed higher radiosensitivity, although the average radiosensitivity was not high.
Assuntos
Artrite Reumatoide , Doenças do Tecido Conjuntivo , Neoplasias , Humanos , Hibridização in Situ Fluorescente , Artrite Reumatoide/genética , Artrite Reumatoide/radioterapia , Doenças do Tecido Conjuntivo/genética , Tolerância a Radiação/genética , Neoplasias/genética , CromossomosRESUMO
The aim of the present study was to investigate the nature and prevalence of nonspecific somatic symptoms, pain and catastrophizing in children with Heritable Connective Tissue Disorders (HCTD), and to determine their association with disability. This observational, multicenter study included 127 children, aged 4-18 years, with Marfan syndrome (MFS) (59%), Loeys-Dietz syndrome (LDS) (8%), Ehlers-Danlos syndromes (EDS) (12%) and hypermobile Ehlers-Danlos syndrome (hEDS) (23%). The assessments included the Children's Somatization Inventory or parent proxy (CSI, PCSI), pain visual-analogue scale (VAS), SUPERKIDZ body diagram, Pain Catastrophizing Scale Child or parent proxy (PCS-C, PCS-P) and Childhood Health Assessment Questionnaire (CHAQ-30). Data from children aged ≥8 years were compared to normative data. In children ≥ 8 years (n = 90), pain was present in 59%, with a median of 4 (IQR = 3-9) pain areas. Compared to normative data, the HCTD group reported significantly higher on the CSI (p ≤ 0.001, d = 0.85), VAS pain intensity (p ≤ 0.001, d = 1.22) and CHAQ-30 (p ≤ 0.001, d = 1.16) and lower on the PCS-C (p = 0.017, d = -0.82) and PCS-P (p ≤ 0.001, d = -0.49). The intensity of nonspecific somatic symptoms and pain explained 45% of the variance in disability (r2 = 0.45 F(2,48) = 19.70, p ≤ 0.001). In children ≤ 7 years (n = 37), pain was present in 35% with a median of 5(IQR = 1-13) pain areas. The mean(SD) VAS scores for pain intensity was 1.5(2.9). Functional disability was moderately correlated to the number of pain areas (r = 0.56, p ≤ 0.001), intensity of nonspecific somatic symptoms (r = 0.63, p ≤ 0.001) and pain (r = 0.83, p ≤ 0.001). In conclusion, this study supports the need for comprehensive assessment of nonspecific somatic symptoms, pain, and disability in children with HCTD to allow tailored treatment.
Assuntos
Doenças do Tecido Conjuntivo , Síndrome de Ehlers-Danlos , Sintomas Inexplicáveis , Anormalidades da Pele , Humanos , Criança , Doenças do Tecido Conjuntivo/complicações , Doenças do Tecido Conjuntivo/genética , Síndrome de Ehlers-Danlos/complicações , Síndrome de Ehlers-Danlos/genética , Dor/genética , Catastrofização , Tecido ConjuntivoRESUMO
Legg-Calve-Perthes' disease (LCP) is defined as avascular necrosis of the femoral head in a child and may present to a variety of disciplines from general practice to orthopaedics, paediatrics, rheumatology and more. The Stickler syndromes are a group of disorders of type II, IX and XI collagen associated with hip dysplasia, retinal detachment, deafness and cleft palate. The pathogenesis of LCP disease remains an enigma but there have been a small number of cases reporting variants in the gene encoding the α1 chain of type II collagen (COL2A1). Variants in COL2A1 are known to cause type 1 Stickler syndrome (MIM 108300, 609508), which is a connective tissue disorder with a very high risk of childhood blindness, and it is also associated with dysplastic development of the femoral head. It is unclear whether COL2A1 variants make a definitive contribution to both disorders, or whether the two are indistinguishable using current clinical diagnostic techniques. In this paper, we compare the two conditions and present a case series of 19 patients with genetically confirmed type 1 Stickler syndrome presenting with a historic diagnosis of LCP. In contrast to isolated LCP, children with type 1 Stickler syndrome have a very high risk of blindness from giant retinal tear detachment, but this is now largely preventable if a timely diagnosis is made. This paper highlights the potential for avoidable blindness in children presenting to clinicians with features suggestive of LCP disease but with underlying Stickler syndrome and proposes a simple scoring system to assist clinicians.
Assuntos
Artrite , Doenças do Tecido Conjuntivo , Doença de Legg-Calve-Perthes , Humanos , Criança , Doença de Legg-Calve-Perthes/complicações , Doença de Legg-Calve-Perthes/diagnóstico , Doença de Legg-Calve-Perthes/genética , Artrite/complicações , Doenças do Tecido Conjuntivo/complicações , Doenças do Tecido Conjuntivo/diagnóstico , Doenças do Tecido Conjuntivo/genética , Cegueira/genética , Cegueira/prevenção & controleRESUMO
Connective tissue disease-associated interstitial lung disease (CTD-ILD) is a collection of systemic autoimmune disorders resulting in lung interstitial abnormalities or lung fibrosis. CTD-ILD pathogenesis is not well characterized because of disease heterogeneity and lack of pre-clinical models. Some common risk factors are inter-related with idiopathic pulmonary fibrosis, an extensively studied fibrotic lung disease, which includes genetic abnormalities and environmental risk factors. The primary pathogenic mechanism is that these risk factors promote alveolar type II cell dysfunction triggering many downstream profibrotic pathways, including inflammatory cascades, leading to lung fibroblast proliferation and activation, causing abnormal lung remodeling and repairs that result in interstitial pathology and lung fibrosis. In CTD-ILD, dysregulation of regulator pathways in inflammation is a primary culprit. However, confirmatory studies are required. Understanding these pathogenetic mechanisms is necessary for developing and tailoring more targeted therapy and provides newly discovered disease biomarkers for early diagnosis, clinical monitoring, and disease prognostication. This review highlights the central CTD-ILD pathogenesis and biological drivers that facilitate the discovery of disease biomarkers.
Assuntos
Produtos Biológicos , Doenças do Tecido Conjuntivo , Fibrose Pulmonar Idiopática , Doenças Pulmonares Intersticiais , Humanos , Doenças Pulmonares Intersticiais/genética , Doenças Pulmonares Intersticiais/complicações , Doenças do Tecido Conjuntivo/complicações , Doenças do Tecido Conjuntivo/genética , Fibrose Pulmonar Idiopática/diagnóstico , Biomarcadores , Produtos Biológicos/uso terapêuticoRESUMO
Stickler syndrome is a multisystem collagenopathy with affected individuals exhibiting a high rate of ocular complications. Lysyl oxidase-like 3 (LOXL3) is a human disease gene candidate with a critical role in catalyzing collagen crosslinking. A homozygous missense variant of LOXL3 was reported in Stickler syndrome with severe myopia. However, the underlying mechanisms of the LOXL3 missense mutation that causes Stickler syndrome are unknown. In this study, a mouse model of Stickler syndrome induced by LOXL3 mutation (c.2027G â> âA, p.Cys676Try) was obtained using CRISPR/Cas9 gene editing techniques. The Loxl3 mutant mice exhibited perinatal death, spinal deformity, and cleft palate, and Loxl3 mutation also induced skeletal dysplasia and progressive visual degeneration. Furthermore, we observed the damage of the bruch's membrane (BrM) and an increase in the levels of glial fibrillary acidic protein (GFAP) and Rpe65 in the Loxl3 mutant mice. Thus, we provided the critical in vivo evidence that Loxl3 possibly has a pivotal role in maintaining the eye function.
Assuntos
Doenças do Tecido Conjuntivo , Oftalmopatias Hereditárias , Descolamento Retiniano , Feminino , Gravidez , Humanos , Animais , Camundongos , Aminoácido Oxirredutases/genética , Aminoácido Oxirredutases/metabolismo , Descolamento Retiniano/genética , Doenças do Tecido Conjuntivo/genética , Retina/metabolismo , Mutação/genéticaRESUMO
The heritable disorders of connective tissue (HDCTs) are a heterogeneous group of inherited disorders caused by pathogenic variants in genes encoding a wide range of molecules involved in the structure and function of the extracellular matrix. Currently, more than 450 HDCTs are recognized. These include the Ehlers-Danlos syndrome (EDS), Marfan syndrome, Loeys-Dietz syndrome (LDS), Stickler syndrome, and a wide range of skeletal dysplasias. Recent evidence suggests that people with the HDCTs are at an increased risk of Chiari I malformation (CM1).
Assuntos
Artrite , Doenças do Tecido Conjuntivo , Síndrome de Loeys-Dietz , Descolamento Retiniano , Humanos , Tecido Conjuntivo , Doenças do Tecido Conjuntivo/genética , Síndrome de Loeys-Dietz/genéticaRESUMO
PURPOSE: Patients with Stickler syndrome are at high risk of giant retinal tears (GRTs) and detachments. Vitreoretinal interventions can reduce this risk, but there is presently no consensus about the optimal prophylactic approach. The aim of our study was to determine whether 360° laser prophylaxis is a safe and effective procedure to prevent GRT detachments in patients with Stickler syndrome. METHODS: Study subjects were recruited retrospectively through the databases of the vitreoretinal and ophthalmic genetic tertiary services in Manchester, United Kingdom. Clinical data were collected including on prophylactic intervention, the occurrence of retinal detachment, and the presence/type of retinal breaks. RESULTS: One hundred thirteen eyes from 63 patients with Stickler syndrome were studied; 72.6% (82/113) of these eyes received 360° laser prophylaxis. Of these, 9% had a retinal detachment, but no GRTs occurred. Among the 27.4% (31/113) of eyes that had no prophylactic treatment, 23% suffered a retinal detachment and 42.9% of these were associated with a GRT. CONCLUSION: Patients who underwent laser prophylaxis had fewer retinal detachments and no GRTs during an average of 6.1 years of follow-up (median 5 years), suggesting that this is a safe and effective approach for individuals with Stickler syndrome.