RESUMO
Cholangiocarcinoma (CCA) comprises diverse tumors of the biliary tree and is characterized by late diagnosis, short-term survival, and chemoresistance. CCAs are mainly classified according to their anatomical location and include diverse molecular subclasses harboring inter-tumoral and intratumoral heterogeneity. Besides the tumor cell component, CCA is also characterized by a complex and dynamic tumor microenvironment where tumor cells and stromal cells crosstalk in an intricate network of interactions. Cancer-associated fibroblasts, one of the most abundant cell types in the tumor stroma of CCA, are actively involved in cholangiocarcinogenesis by participating in multiple aspects of the disease including extracellular matrix remodeling, immunomodulation, neo-angiogenesis, and metastasis. Despite their overall tumor-promoting role, recent evidence indicates the presence of transcriptional and functional heterogeneous CAF subtypes with tumor-promoting and tumor-restricting properties. To elucidate the complexity and potentials of cancer-associated fibroblasts as therapeutic targets in CCA, this review will discuss the origin of cancer-associated fibroblasts, their heterogeneity, crosstalk, and role during tumorigenesis, providing an overall picture of the present and future perspectives toward cancer-associated fibroblasts targeting CCA.
Assuntos
Aracnodactilia , Neoplasias dos Ductos Biliares , Sistema Biliar , Fibroblastos Associados a Câncer , Colangiocarcinoma , Contratura , Humanos , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/genética , Neoplasias dos Ductos Biliares/tratamento farmacológico , Ductos Biliares Intra-Hepáticos , Microambiente TumoralRESUMO
Optogenetic actuators have revolutionized the resolution at which biological processes can be controlled. In plants, deployment of optogenetics is challenging due to the need for these light-responsive systems to function in the context of horticultural light environments. Furthermore, many available optogenetic actuators are based on plant photoreceptors that might crosstalk with endogenous signaling processes, while others depend on exogenously supplied cofactors. To overcome such challenges, we have developed Highlighter, a synthetic, light-gated gene expression system tailored for in planta function. Highlighter is based on the photoswitchable CcaS-CcaR system from cyanobacteria and is repurposed for plants as a fully genetically encoded system. Analysis of a re-engineered CcaS in Escherichia coli demonstrated green/red photoswitching with phytochromobilin, a chromophore endogenous to plants, but also revealed a blue light response likely derived from a flavin-binding LOV-like domain. We deployed Highlighter in transiently transformed Nicotiana benthamiana for optogenetic control of fluorescent protein expression. Using light to guide differential fluorescent protein expression in nuclei of neighboring cells, we demonstrate unprecedented spatiotemporal control of target gene expression. We implemented the system to demonstrate optogenetic control over plant immunity and pigment production through modulation of the spectral composition of broadband visible (white) light. Highlighter is a step forward for optogenetics in plants and a technology for high-resolution gene induction that will advance fundamental plant biology and provide new opportunities for crop improvement.
Assuntos
Aracnodactilia , Optogenética , Nicotiana/genética , Escherichia coli/genética , Expressão GênicaRESUMO
BACKGROUND: Cholangiocarcinoma (CCA) is still a deadly tumour. Histological and molecular aspects of thioacetamide (TAA)-induced intrahepatic CCA (iCCA) in rats mimic those of human iCCA. Carcinogenic changes and therapeutic vulnerabilities in CCA may be captured by molecular investigations in bile, where we performed bile proteomic and metabolomic analyses that help discovery yet unknown pathways relevant to human iCCA. METHODS: Cholangiocarcinogenesis was induced in rats (TAA) and mice (JnkΔhepa + CCl4 + DEN model). We performed proteomic and metabolomic analyses in bile from control and CCA-bearing rats. Differential expression was validated in rat and human CCAs. Mechanisms were addressed in human CCA cells, including Huh28-KRASG12D cells. Cell signaling, growth, gene regulation and [U-13C]-D-glucose-serine fluxomics analyses were performed. In vivo studies were performed in the clinically-relevant iCCA mouse model. RESULTS: Pathways related to inflammation, oxidative stress and glucose metabolism were identified by proteomic analysis. Oxidative stress and high amounts of the oncogenesis-supporting amino acids serine and glycine were discovered by metabolomic studies. Most relevant hits were confirmed in rat and human CCAs (TCGA). Activation of interleukin-6 (IL6) and epidermal growth factor receptor (EGFR) pathways, and key genes in cancer-related glucose metabolic reprogramming, were validated in TAA-CCAs. In TAA-CCAs, G9a, an epigenetic pro-tumorigenic writer, was also increased. We show that EGFR signaling and mutant KRASG12D can both activate IL6 production in CCA cells. Furthermore, phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in serine-glycine pathway, was upregulated in human iCCA correlating with G9a expression. In a G9a activity-dependent manner, KRASG12D promoted PHGDH expression, glucose flow towards serine synthesis, and increased CCA cell viability. KRASG12D CAA cells were more sensitive to PHGDH and G9a inhibition than controls. In mouse iCCA, G9a pharmacological targeting reduced PHGDH expression. CONCLUSIONS: In CCA, we identified new pro-tumorigenic mechanisms: Activation of EGFR signaling or KRAS mutation drives IL6 expression in tumour cells; Glucose metabolism reprogramming in iCCA includes activation of the serine-glycine pathway; Mutant KRAS drives PHGDH expression in a G9a-dependent manner; PHGDH and G9a emerge as therapeutic targets in iCCA.
Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Animais , Aracnodactilia , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/patologia , Ductos Biliares Intra-Hepáticos/metabolismo , Ductos Biliares Intra-Hepáticos/patologia , Carcinogênese/genética , Colangiocarcinoma/patologia , Contratura , Epigênese Genética , Receptores ErbB/genética , Receptores ErbB/metabolismo , Glucose , Glicina/metabolismo , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Camundongos , Fosfoglicerato Desidrogenase/genética , Proteômica , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Ratos , Serina/metabolismoRESUMO
OBJECTIVE: To identify the pathogenic variants from a patient with suspected congenital contractural arachnodactyly, and to explore the possible molecular genetic pathogenesis, so as to provide evidence for clinical diagnosis. METHODS: Whole exome sequencing was performed for the patient. The splicing site variation of candidate pathogenic genes was verified by Sanger sequencing, and the new transcript sequence was determined by RT-PCR and TA-cloning sequencing. RESULTS: The patient carried a heterozygous c.533-1G>C variant of FBN2 gene, which was not reported. The sequencing of mRNA showed that the variant leaded to the disappearance of the canonical splice acceptor site of FBN2 gene and the activation of a cryptic splice acceptor site at c.533-71, resulting in the insertion of 70 bp sequence in the new transcript. It was speculated that the polypeptide encoded by the new transcript changed from valine (Val) to serine (Ser) at amino acid 179, and prematurely terminated after 26 aminoacids. According to the guidelines of American College of Medical Genetics and Genomics, the variant of FBN2 gene c. 533-1G>C was determined as pathogenic (PVS1+PM2+PP3 ). CONCLUSION: A novel splicing variant of FBN2 gene (c.533-1G>C) was identified, which can lead to congenital contractural arachnodactyly.
Assuntos
Aracnodactilia , Contratura , Aracnodactilia/genética , Contratura/genética , Fibrilina-2/genética , Humanos , Mutação , Sítios de Splice de RNA , Sequenciamento do ExomaRESUMO
Heritable connective tissue disorders are a group of diseases, each rare, characterized by various combinations of skin, joint, musculoskeletal, organ, and vascular involvement. Although kidney abnormalities have been reported in some connective tissue disorders, they are rarely a presenting feature. Here we present three patients with prominent kidney phenotypes who were found by whole exome sequencing to have variants in established connective tissue genes associated with Loeys-Dietz syndrome and congenital contractural arachnodactyly. These cases highlight the importance of considering connective tissue disease in children presenting with structural kidney disease and also serves to expand the phenotype of Loeys-Dietz syndrome and possibly congenital contractural arachnodactyly to include cystic kidney disease and cystic kidney dysplasia, respectively.
Assuntos
Aracnodactilia/genética , Contratura/genética , Fibrilina-2/genética , Síndrome de Loeys-Dietz/genética , Receptor do Fator de Crescimento Transformador beta Tipo I/genética , Proteína Smad2/genética , Adolescente , Aracnodactilia/complicações , Aracnodactilia/diagnóstico por imagem , Aracnodactilia/patologia , Criança , Tecido Conjuntivo/patologia , Doenças do Tecido Conjuntivo/complicações , Doenças do Tecido Conjuntivo/diagnóstico por imagem , Doenças do Tecido Conjuntivo/genética , Doenças do Tecido Conjuntivo/patologia , Contratura/complicações , Contratura/diagnóstico por imagem , Contratura/patologia , Predisposição Genética para Doença , Humanos , Rim/diagnóstico por imagem , Rim/patologia , Doenças Renais Císticas/complicações , Doenças Renais Císticas/genética , Doenças Renais Císticas/patologia , Síndrome de Loeys-Dietz/complicações , Síndrome de Loeys-Dietz/diagnóstico por imagem , Síndrome de Loeys-Dietz/patologia , Masculino , Mutação/genética , Fenótipo , Anormalidades da Pele/complicações , Anormalidades da Pele/genética , Anormalidades da Pele/patologia , Sequenciamento do ExomaRESUMO
Van den Ende-Gupta syndrome (VDEGS) is a rare autosomal recessive condition characterized by distinctive facial and skeletal features, and in most affected persons, by biallelic pathogenic variants in SCARF2. We review the type and frequency of the clinical features in 36 reported individuals with features of VDEGS, 15 (42%) of whom had known pathogenic variants in SCARF2, 6 (16%) with negative SCARF2 testing, and 15 (42%) not tested. We also report three new individuals with pathogenic variants in SCARF2 and clinical features of VDEGS. Of the six persons without known pathogenic variants in SCARF2, three remain unsolved despite extensive genetic testing. Three were found to have pathogenic ABL1 variants using whole exome sequencing (WES) or whole genome sequencing (WGS). Their phenotype was consistent with the congenital heart disease and skeletal malformations syndrome (CHDSKM), which has been associated with ABL1 variants. Of the three unsolved cases, two were brothers who underwent WGS and targeted long-range sequencing of both SCARF2 and ABL1, and the third person who underwent WES and RNA sequencing for SCARF2. Because these affected individuals with classical features of VDEGS lacked a detectable pathogenic SCARF2 variant, genetic heterogeneity is likely. Our study shows the importance of performing genetic testing on individuals with the VDEGS "phenotype," either as a targeted gene analysis (SCARF2, ABL1) or WES/WGS. Additionally, individuals with the combination of arachnodactyly and blepharophimosis should undergo echocardiography while awaiting results of molecular testing due to the overlapping physical features of VDEGS and CHDSKM.
Assuntos
Anormalidades Múltiplas/genética , Aracnodactilia/genética , Blefarofimose/genética , Contratura/genética , Cardiopatias Congênitas/genética , Proteínas Proto-Oncogênicas c-abl/genética , Receptores Depuradores Classe F/genética , Anormalidades Múltiplas/patologia , Adolescente , Adulto , Aracnodactilia/patologia , Blefarofimose/patologia , Criança , Pré-Escolar , Contratura/patologia , Feminino , Genes Recessivos/genética , Heterogeneidade Genética , Predisposição Genética para Doença , Cardiopatias Congênitas/patologia , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Sequenciamento do Exoma , Adulto JovemRESUMO
Shprintzen-Goldberg syndrome (SGS) is a multisystemic connective tissue disorder, with considerable clinical overlap with Marfan and Loeys-Dietz syndromes. These syndromes have commonly been associated with enhanced TGF-ß signaling. In SGS patients, heterozygous point mutations have been mapped to the transcriptional co-repressor SKI, which is a negative regulator of TGF-ß signaling that is rapidly degraded upon ligand stimulation. The molecular consequences of these mutations, however, are not understood. Here we use a combination of structural biology, genome editing, and biochemistry to show that SGS mutations in SKI abolish its binding to phosphorylated SMAD2 and SMAD3. This results in stabilization of SKI and consequently attenuation of TGF-ß responses, both in knockin cells expressing an SGS mutation and in fibroblasts from SGS patients. Thus, we reveal that SGS is associated with an attenuation of TGF-ß-induced transcriptional responses, and not enhancement, which has important implications for other Marfan-related syndromes.
Assuntos
Aracnodactilia/genética , Craniossinostoses/genética , Proteínas de Ligação a DNA/genética , Síndrome de Marfan/genética , Mutação , Proteínas Proto-Oncogênicas/genética , Fator de Crescimento Transformador beta/genética , Proteínas de Ligação a DNA/metabolismo , Feminino , Humanos , Masculino , Proteínas Proto-Oncogênicas/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismoRESUMO
Pathogenic heterozygous variants in PIEZO2 typically cause distal arthrogryposis type 5 (DA5) and the closely related Gordon syndrome (GS). Only one case of PIEZO2-related Marden-Walker syndrome (MWS) has been reported to date. We report the phenotypic features of a Saudi female patient with features consistent with MWS in whom we identified a novel de novo likely pathogenic variant in PIEZO2. Our case lends support to the link between PIEZO2 and MWS.
Assuntos
Anormalidades Múltiplas/genética , Aracnodactilia/genética , Blefarofimose/genética , Doenças do Tecido Conjuntivo/genética , Contratura/genética , Canais Iônicos/genética , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/embriologia , Adulto , Agenesia do Corpo Caloso/diagnóstico por imagem , Agenesia do Corpo Caloso/genética , Sequência de Aminoácidos , Substituição de Aminoácidos , Aracnodactilia/diagnóstico por imagem , Aracnodactilia/embriologia , Blefarofimose/diagnóstico por imagem , Blefarofimose/embriologia , Criança , Pé Torto Equinovaro/diagnóstico , Pé Torto Equinovaro/embriologia , Pé Torto Equinovaro/genética , Doenças do Tecido Conjuntivo/diagnóstico por imagem , Doenças do Tecido Conjuntivo/embriologia , Consanguinidade , Contratura/diagnóstico por imagem , Contratura/embriologia , Síndrome de Dandy-Walker/diagnóstico por imagem , Síndrome de Dandy-Walker/embriologia , Síndrome de Dandy-Walker/genética , Feminino , Estudos de Associação Genética , Humanos , Deficiência Intelectual/genética , Canais Iônicos/deficiência , Masculino , Linhagem , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Ultrassonografia Pré-NatalRESUMO
While psychotic symptoms may be the result of a primary psychiatric disorder, they can also be the presenting symptom of an underlying somatic disease. The organic aetiology can vary from benign and transient to severe and enduring disorders. Early diagnosis and treatment can be crucial to the prognosis, though potentially challenging as well, given that several of the organic aetiologies are rare and therefore difficult to identify. This case report describes two pediatric patients with psychiatric manifestations as a result of 22q11.2 deletion syndrome and anti-N-methyl-D-aspartate receptor encephalitis.
Assuntos
Encefalite Antirreceptor de N-Metil-D-Aspartato , Aracnodactilia , Craniossinostoses , Transtornos Psicóticos , Adolescente , Criança , Diagnóstico Precoce , Humanos , Transtornos Psicóticos/diagnóstico , Transtornos Psicóticos/etiologiaRESUMO
Spiders have long been admired for the beauty of their webs. They are celebrated in popular culture as well as in medical eponyms. This contribution provides the historical background for three spider-related eponyms: nevus araneus (spider angioma), arachnodactyly, and the arachnoid mater. Nevus araneus was first named and described by Sir Erasmus Wilson in 1842. Arachnodactyly was described in 1896 by Antoine Marfan using the term pattes d'araignée, which means spider legs. In 1902, Emile Charles Achard proposed the term arachnodactyly for this clinical finding. The arachnoid mater had been named in 1699 by Frederik Ruysch. The clinical management of spider bites from the only two dangerous venomous spiders within the United States, the black widow spider (Latrodectus mactans) and the brown recluse spider (Loxosceles reclusa), is reviewed.
Assuntos
Aracnodactilia , Aracnoide-Máter , Epônimos , Nevo , Aranhas , Animais , Aracnodactilia/patologia , Viúva Negra , Aranha Marrom Reclusa , Humanos , Nevo/patologia , Picada de Aranha/patologiaRESUMO
Fibrillins constitute a family of large extracellular glycoproteins which multimerize to form microfibrils, an important structure in the extracellular matrix. It has long been assumed that fibrillin-2 was barely present during postnatal life, but it is now clear that fibrillin-2 molecules form the structural core of microfibrils, and are masked by an outer layer of fibrillin-1. Mutations in fibrillins give rise to heritable connective tissue disorders, including Marfan syndrome and congenital contractural arachnodactyly. Fibrillins also play an important role in matrix sequestering of members of the transforming growth factor-ß family, and in context of Marfan syndrome excessive TGF-ß activation has been observed. TGF-ß activation is highly dependent on integrin binding, including integrin αvß8 and αvß6, which are upregulated upon TGF-ß exposure. TGF-ß is also involved in tumor progression, metastasis, epithelial-to-mesenchymal transition and tumor angiogenesis. In several highly vascularized types of cancer such as hepatocellular carcinoma, a positive correlation was found between increased TGF-ß plasma concentrations and tumor vascularity. Interestingly, fibrillin-1 has a higher affinity to TGF-ß and, therefore, has a higher capacity to sequester TGF-ß compared to fibrillin-2. The previously reported downregulation of fibrillin-1 in tumor endothelium affects the fibrillin-1/fibrillin-2 ratio in the microfibrils, exposing the normally hidden fibrillin-2. We postulate that fibrillin-2 exposure in the tumor endothelium directly stimulates tumor angiogenesis by influencing TGF-ß sequestering by microfibrils, leading to a locally higher active TGF-ß concentration in the tumor microenvironment. From a therapeutic perspective, fibrillin-2 might serve as a potential target for future anti-cancer therapies.
Assuntos
Aracnodactilia/genética , Contratura/genética , Fibrilina-2/genética , Síndrome de Marfan/genética , Neoplasias/genética , Neovascularização Patológica/genética , Animais , Aracnodactilia/patologia , Tecido Conjuntivo/patologia , Contratura/patologia , Modelos Animais de Doenças , Endotélio Vascular/patologia , Fibrilina-2/metabolismo , Humanos , Síndrome de Marfan/patologia , Mutação , Neoplasias/irrigação sanguínea , Neoplasias/patologia , Neovascularização Patológica/patologia , Fator de Crescimento Transformador beta/metabolismo , Microambiente Tumoral/genéticaRESUMO
SKI pathogenic variations are associated with Shprintzen-Goldberg Syndrome (SGS), a rare systemic connective tissue disorder characterized by craniofacial, skeletal and cardiovascular features. So far, the clinical description, including intellectual disability, has been relatively homogeneous, and the known pathogenic variations were located in two different hotspots of the SKI gene. In the course of diagnosing Marfan syndrome and related disorders, we identified nine sporadic probands (aged 2-47 years) carrying three different likely pathogenic or pathogenic variants in the SKI gene affecting the same amino acid (Thr180). Seven of these molecular events were confirmed de novo. All probands displayed a milder morphological phenotype with a marfanoid habitus that did not initially lead to a clinical diagnosis of SGS. Only three of them had learning disorders, and none had intellectual disability. Six out of nine presented thoracic aortic aneurysm, which led to preventive surgery in the oldest case. This report extends the phenotypic spectrum of variants identified in the SKI gene. We describe a new mutational hotspot associated with a marfanoid syndrome with no intellectual disability. Cardiovascular involvement was confirmed in a significant number of cases, highlighting the importance of accurately diagnosing SGS and ensuring appropriate medical treatment and follow-up.
Assuntos
Aracnodactilia , Craniossinostoses , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Síndrome de Marfan , Mutação , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Adolescente , Adulto , Aracnodactilia/diagnóstico , Aracnodactilia/genética , Aracnodactilia/metabolismo , Criança , Pré-Escolar , Craniossinostoses/diagnóstico , Craniossinostoses/genética , Craniossinostoses/metabolismo , Feminino , Humanos , Masculino , Síndrome de Marfan/diagnóstico , Síndrome de Marfan/genética , Síndrome de Marfan/metabolismo , Pessoa de Meia-Idade , Patologia MolecularRESUMO
22q11.2 deletion syndrome (22q11.DS) is a neurogenetic disorder caused by a microdeletion in chromosome 22. Its phenotype includes high rates of psychiatric disorders, immune system abnormalities, and cognitive impairments. We assessed the quality of sleep in 22q11.2DS and its potential link to inflammatory markers and cognitive deficits. Thirty-three 22q11.2DS individuals and 24 healthy controls were studied. Sleep parameters were assessed by the Pittsburgh sleep quality index (PSQI) questionnaire and correlated with serum cytokine levels and cognitive functioning, measured using the Penn computerized neurocognitive battery (CNB). The 22q11.2DS individuals had significantly worse sleep quality scores than the controls, unrelated to the psychiatric or physical comorbidities common to 22q11.2DS. Interleukin 6 levels were correlated with the overall score of the PSQI questionnaire for nonpsychotic 22q11.2DS participants only. Several domains of the CNB were associated with poorer sleep quality, suggesting that cognitive impairments in 22q11.2DS may be at least partially explained by poor sleep quality. Our findings confirm sleep impairments in individuals with 22q11.2DS, which might negatively affect their cognitive functioning, and corroborate a potential role of immunological pathways in the 22q11.2DS neuro-phenotype.
Assuntos
Disfunção Cognitiva/genética , Síndrome de DiGeorge/genética , Predisposição Genética para Doença , Transtornos do Sono-Vigília/genética , Adolescente , Adulto , Aracnodactilia/sangue , Aracnodactilia/genética , Aracnodactilia/fisiopatologia , Criança , Cromossomos Humanos Par 22/genética , Disfunção Cognitiva/fisiopatologia , Craniossinostoses/sangue , Craniossinostoses/genética , Craniossinostoses/fisiopatologia , Citocinas/sangue , Síndrome de DiGeorge/sangue , Síndrome de DiGeorge/fisiopatologia , Feminino , Estudos de Associação Genética , Humanos , Interleucina-6/sangue , Masculino , Síndrome de Marfan/sangue , Síndrome de Marfan/genética , Síndrome de Marfan/fisiopatologia , Pessoa de Meia-Idade , Transtornos do Sono-Vigília/fisiopatologia , Inquéritos e Questionários , Adulto JovemRESUMO
BACKGROUND Shprintzen-Goldberg syndrome (SGS) is an extremely rare collagenopathy, most often caused by autosomal-dominant mutations in the SKI proto-oncogene, which is a component of the transforming growth factor beta (TGF-ß) signaling pathway. Approximately 50-60 cases of SGS have been recorded in the literature worldwide since its discovery in 1982. This collagen disorder affects bone and vascular development throughout the body, resulting in craniosynostosis, scoliosis, chest deformities, and aortic root dilation. Patients may have problems in the central nervous system, including Chiari 1 malformation, hydrocephalus, and dilation of the lateral ventricles. Unfortunately, the symptoms of SGS closely parallel those of related collagenopathies involving mutations in the TGF-ß signaling pathway, which makes accurate diagnosis difficult without genetic testing, especially in cases with complex presentation. CASE REPORT In this report we present the unique and complex disease manifestations in a 9-year-old girl with SGS. The patient had severe cervical spinal instability that resolved after surgical occipital-C4 fusion with an autograft from the rib. Midface distraction surgery was used to treat the patient's craniosynostosis and related facial deformities. This surgery was complicated by loss of 750 mL of blood due to insufficient dura and prominent vasculature. CONCLUSIONS Connective tissue symptoms associated with SGS can involve dural and vascular problems, as seen in this case report. Thus, the risk of extreme blood loss should be anticipated any time midface distraction surgery is performed on an SGS patient. Continued research is needed to define how this case relates to the SGS patient population.
Assuntos
Aracnodactilia/cirurgia , Perda Sanguínea Cirúrgica , Craniossinostoses/cirurgia , Dura-Máter/anormalidades , Síndrome de Marfan/cirurgia , Osteotomia de Le Fort/efeitos adversos , Criança , Feminino , Humanos , Proto-Oncogene MasRESUMO
The term linkeropathies (LKs) refers to a group of rare heritable connective tissue disorders, characterized by a variable degree of short stature, skeletal dysplasia, joint laxity, cutaneous anomalies, dysmorphism, heart malformation, and developmental delay. The LK genes encode for enzymes that add glycosaminoglycan chains onto proteoglycans via a common tetrasaccharide linker region. Biallelic variants in XYLT1 and XYLT2, encoding xylosyltransferases, are associated with Desbuquois dysplasia type 2 and spondylo-ocular syndrome, respectively. Defects in B4GALT7 and B3GALT6, encoding galactosyltransferases, lead to spondylodysplastic Ehlers-Danlos syndrome (spEDS). Mutations in B3GAT3, encoding a glucuronyltransferase, were described in 25 patients from 12 families with variable phenotypes resembling Larsen, Antley-Bixler, Shprintzen-Goldberg, and Geroderma osteodysplastica syndromes. Herein, we report on a 13-year-old girl with a clinical presentation suggestive of spEDS, according to the 2017 EDS nosology, in whom compound heterozygosity for two B3GAT3 likely pathogenic variants was identified. We review the spectrum of B3GAT3-related disorders and provide a comparison of all LK patients reported up to now, highlighting that LKs are a phenotypic continuum bridging EDS and skeletal disorders, hence offering future nosologic perspectives.
Assuntos
Fenótipo de Síndrome de Antley-Bixler/genética , Aracnodactilia/genética , Doenças Ósseas/congênito , Craniossinostoses/genética , Nanismo/genética , Glucuronosiltransferase/genética , Síndrome de Marfan/genética , Mutação , Osteocondrodisplasias/genética , Fenótipo , Dermatopatias Genéticas/genética , Adolescente , Fenótipo de Síndrome de Antley-Bixler/patologia , Aracnodactilia/patologia , Doenças Ósseas/genética , Doenças Ósseas/patologia , Craniossinostoses/patologia , Nanismo/patologia , Feminino , Humanos , Síndrome de Marfan/patologia , Osteocondrodisplasias/patologia , Dermatopatias Genéticas/patologiaRESUMO
The Shprintzen-Goldberg syndrome (SGS) or velo-cardio-facial syndrome (VCFS) is an extremely rare disorder of connective tissue with a characteristic facial dysmorphism, marfanoid features, craniosynostosis, dolichocephaly, cardiovascular anomalies and mild to moderate mental retardation. It may be a de novo gene mutation or inherited as an autosomal dominant disorder having SKI gene and Fibrillin-1 gene (FBN1) mutations, located on chromosome 15q21.1. We report a case of a 3-month, developmentally delayed male infant admitted to the hospital with syndromic facies, craniosynostosis, joint laxity and on echocardiography, aortic root dilatation. A probable diagnosis of SGS was made on the clinical grounds. We did not have the facility for genetic chromosomal analysis. He was discharged with family counselling and follow-up for future developmental rehabilitation.
Assuntos
Anormalidades Múltiplas/genética , Aracnodactilia/diagnóstico , Craniossinostoses/diagnóstico , Síndrome de DiGeorge/diagnóstico , Síndrome de Marfan/diagnóstico , Anorexia , Caquexia , Consanguinidade , Ecocardiografia , Anormalidades do Olho , Fácies , Tórax em Funil , Humanos , Lactente , Instabilidade Articular , Masculino , Hipotonia Muscular , Doenças Raras , DermatopatiasRESUMO
Shprintzen-Goldberg syndrome (SGS) is a rare systemic connective tissue disorder characterized by craniofacial, skeletal, and cardiovascular manifestations. It is associated with a significant risk of intellectual disability, a feature which distinguishes it from Marfan and Loeys-Dietz syndromes. SGS is mainly caused by mutations in the SKI gene, a repressor of TGF-ß activity. Most SKI mutations are found in exon 1 of the gene and are located in the R-SMAD domain, a proposed hotspot for de novo mutations. Here, we report on a de novo SKI mutation located in the DHD domain of SKI. By adding our finding to previously reported de novo SKI mutations, a new mutational hotspot in the DHD domain is proposed. Our patient presented with a lipomeningomyelocele, tethered cord, and spina bifida but with no SGS-related clinical findings apart from a marfanoid habitus and long slender fingers. Specifically, she did not have an intellectual disability, craniofacial, or cardiovascular abnormalities. By comparing the clinical findings on patients with mutations in the R-SMAD and DHD domains of SKI, we propose that mutations in those domains have different effects on TGF-ß activity during embryonic development with resulting phenotypic differences.
Assuntos
Proteínas de Ligação a DNA/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Mutação , Domínios Proteicos/genética , Proteínas Proto-Oncogênicas/genética , Disrafismo Espinal/diagnóstico , Disrafismo Espinal/genética , Aracnodactilia/diagnóstico , Aracnodactilia/genética , Criança , Anormalidades Craniofaciais/genética , Craniossinostoses/diagnóstico , Craniossinostoses/genética , Análise Mutacional de DNA , Diagnóstico Diferencial , Estudos de Associação Genética/métodos , Humanos , Deficiência Intelectual/genética , Síndrome de Marfan/diagnóstico , Síndrome de Marfan/genética , Linhagem , Fenótipo , RadiografiaRESUMO
A 10-year-old male with history of Beals syndrome presented with hearing loss and was found to have middle and inner ear dysplasia and left temporal encephalocele on imaging. Beals syndrome is a rare autosomal dominant connective tissue disorder caused by a mutation in the fibrillin-2 gene. Skeletal manifestations of Beals have been reported, including anomalies of the long bones, calvarium, and spine. External ear abnormalities with "crumpled ear" deformity are seen in the majority of patients. This is the first case to report imaging findings of the middle and inner ear in a patient with Beals.
Assuntos
Aracnodactilia/complicações , Contratura/complicações , Orelha Interna/patologia , Orelha Média/patologia , Encefalocele/diagnóstico por imagem , Osso Esfenoide/diagnóstico por imagem , Osso Temporal/diagnóstico por imagem , Criança , Encefalocele/etiologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Osso Esfenoide/anormalidades , Osso Temporal/anormalidades , Tomografia Computadorizada por Raios XRESUMO
CASE: Congenital vertical talus (CVT) is a rare rigid flatfoot disorder with a rocker-bottom flatfoot appearance. It is characterized by hindfoot valgus and equinus, with associated midfoot dorsiflexion and forefoot abduction. We describe a patient who was born with dysmorphic features and subsequently was diagnosed with Beals contractural arachnodactyly. After the diagnosis of bilateral CVT was made, it was treated with a single-stage open reduction. There was a unilateral recurrence, which was treated with revision surgery. The patient had an excellent functional outcome. CONCLUSION: CVT often requires surgical management and may recur. To our knowledge, this is the first reported case of CVT associated with Beals contractural arachnodactyly.