RESUMEN
AIM: X-linked variants in Filamin A (FLNA) are associated with the Ehlers-Danlos-syndrome-variant form of periventricular heterotopia, and autosomal dominant variants in ubiquitin C-terminal hydrolase L1 (UCHL1) are associated with a late-onset spastic ataxia, peripheral neuropathy and optic atrophy. Here we present a rare case involving both a novel heterozygous whole-gene deletion of UCHL1 and a heterozygous frameshift variant in the FLNA gene resulting in a complex phenotype. METHODS: A 67-year-old female with a confirmed pathogenic variant in the FLNA gene, resulting in an enlarged aorta and joint pains, presented with a 4-year history of severe sensory ataxia, upper motor neuron signs, eye movement abnormalities and severe sensory loss. RESULTS: Neurophysiology including Somatosensory-evoked potentials confirmed the sensory loss as predominantly preganglionic with denervation. Genetic testing revealed a digenic cause of her complex presentation, confirming a pathogenic frameshift variant in the FLNA gene and a heterozygous loss of function deletion in the UCHL1 gene. CONCLUSIONS: To the best of our knowledge, this is the first case with concomitant pathogenic variants in the FLNA and UCHL1 genes which explain the complex phenotype. The severe preganglionic sensory loss is also a rare finding and expands the phenotype of UCHL1 variants.
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Síndrome de Ehlers-Danlos , Humanos , Femenino , Anciano , Filaminas/genética , Mutación , Fenotipo , Síndrome de Ehlers-Danlos/genética , Heterocigoto , Ubiquitina Tiolesterasa/genéticaRESUMEN
The extracellular matrix is a complex network of proteins and other molecules that are essential for the support, integrity, and structure of cells and tissues within the human body. The genes ZNF469 and PRDM5 each produce extracellular-matrix-related proteins that, when mutated, have been shown to result in the development of brittle cornea syndrome. This dysfunction results from aberrant protein function resulting in extracellular matrix disruption. Our group recently identified and published the first known associations between variants in these genes and aortic/arterial aneurysms and dissection diseases. This paper delineates the proposed effects of mutated ZNF469 and PRDM5 on various essential extracellular matrix components, including various collagens, TGF-B, clusterin, thrombospondin, and HAPLN-1, and reviews our recent reports associating single-nucleotide variants to these genes' development of aneurysmal and dissection diseases.
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Matriz Extracelular , Factores de Transcripción , Humanos , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Matriz Extracelular/metabolismo , Matriz Extracelular/genética , Inestabilidad de la Articulación/genética , Inestabilidad de la Articulación/congénito , N-Metiltransferasa de Histona-Lisina/genética , Distrofias Hereditarias de la Córnea/genética , Distrofias Hereditarias de la Córnea/patología , Síndrome de Ehlers-Danlos/genética , Síndrome de Ehlers-Danlos/patología , Aneurisma de la Aorta/genética , Mutación , Proteínas de Unión al ADN/genética , Enfermedades Cutáneas Genéticas/genética , Enfermedades Cutáneas Genéticas/patología , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Anomalías del Ojo , Anomalías CutáneasRESUMEN
Ehlers-Danlos syndromes (EDS) is an umbrella term describing 14 types, of which 13 are rare and monogenic, with overlapping features of joint hypermobility, skin, and vascular fragility, and generalised connective tissue friability. Hypermobile EDS currently has no identified genetic cause. Most of the rare monogenic EDS types can have neurological features, which are often part of major or minor diagnostic criteria for each type. This review aims to highlight the neurological features and other key characteristics of these EDS types. This should improve recognition of these features, enabling more timely consideration and confirmation or exclusion through genetic testing. In practice, many healthcare professionals still refer to patients as having 'EDS'. However, the different EDS types have distinct clinical features as well as different underlying genetic causes and pathogenic mechanisms, and each requires bespoke management and surveillance. Defining the EDS type is therefore crucial, as EDS is not in itself a diagnosis.
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Síndrome de Ehlers-Danlos , Inestabilidad de la Articulación , Enfermedades Vasculares , Humanos , Síndrome de Ehlers-Danlos/diagnóstico , Síndrome de Ehlers-Danlos/genética , Síndrome de Ehlers-Danlos/patología , Pruebas Genéticas , Inestabilidad de la Articulación/diagnóstico , Inestabilidad de la Articulación/genéticaAsunto(s)
Enfermedades de los Gatos , Colágeno Tipo V , Síndrome de Ehlers-Danlos , Heterocigoto , Síndrome de Ehlers-Danlos/genética , Síndrome de Ehlers-Danlos/veterinaria , Animales , Colágeno Tipo V/genética , Gatos/genética , Enfermedades de los Gatos/genética , Eliminación de Secuencia , MasculinoRESUMEN
BACKGROUND: Ehlers-Danlos syndrome Type IV (aka Vascular Ehlers Danlos, or vEDS) is a dominantly inherited mutation in the Collagen 3A1 gene (COL3A1). The disease is characterized by tissue friability and age-related susceptibility to arterial aneurysm, dissection and rupture as well as uterine and bowl tears. These clinical manifestations result in major surgical intervention and decreased life expectancy. Understanding how mutations in COL3A1 impact the structure and function of the extracellular matrix (ECM) is important to managing the disease and finding treatments. RESULTS: Skin fibroblasts from vEDS subjects heterozygous for the p.G588S pathogenic variant in the COL3A1 gene and a normal individual were cultured and studied. Proteomics analysis identified dozens of upregulated proteins related to extracellular matrix dysregulation that is characteristic of fibrosis. Gene expression libraries from cultured primary fibroblasts were screened for messenger RNA (mRNA) markers of ECM degradation. The proteomics and targeted gene expression array results were largely consistent with dysregulation of the extracellular matrix in vEDS. The data show upregulation of multiple Collagen proteins and genes, other ECM components, and enzymes related to ECM processing and turn-over. vEDS fibroblasts expressed significantly more cross linked C-Telopeptide of Collagen III (CTXIII) than normal fibroblasts, indicative of Collagen III degradation and turn-over. Further, the expression and activity of Lysyl Oxidase (LOX), an enzyme that initiates covalent cross-linking of soluble collagen and elastin into protease resistant fibers, is elevated in vEDS fibroblasts compared to normal fibroblasts. CONCLUSION: Together, these findings suggest dysregulated ECM deposition and processing, reminiscent of a state of fibrosis. Therapeutics that target the dysregulated ECM proteins or help replace damaged tissue may improve clinical outcomes.
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Síndrome de Ehlers-Danlos , Proteína-Lisina 6-Oxidasa , Humanos , Proteína-Lisina 6-Oxidasa/genética , Piel , Matriz Extracelular , Fibrosis , Síndrome de Ehlers-Danlos/genéticaRESUMEN
BACKGROUND: The Ehlers-Danlos syndromes (EDS) are a group of rare hereditary connective tissue disorders. EDS is clinically and genetically heterogeneous and usually involves multiple systems. There are 14 subtypes of EDS with hallmark features including joint hypermobility, skin hyperextensibility, and tissue fragility. The clinical manifestations and their severity differ among the subtypes, encompassing recurrent joint dislocations, scoliosis, arterial aneurysm and dissection, and organ rupture. Challenges in diagnosis and management arise from the complexity of the disease, which is further complicated by its rarity. The development of clinical guidelines and implementation of coordinated multi-disciplinary team (MDT) approaches have emerged as global priorities. MAIN BODY: Chinese Multi-Disciplinary Working Group on the Ehlers-Danlos Syndromes was therefore established. Healthcare professionals were recruited from 25 top hospitals across China. The experts are specialized in 24 fields, including genetics, vascular surgery, dermatology, and orthopedics, as well as nursing care, rehabilitation, psychology, and nutrition. Based on GRADE methodology, the Guidelines were written by the Group supervised by methodologists, following a systemic review of all 4453 articles in PubMed published before August 9, 2023, using the search term "Ehlers Danlos". A coordinated MDT approach for the diagnosis and management of EDS is highly recommended by the Group, along with 29 specific recommendations addressing key clinical questions. In addition to the treatment plan, the Guidelines also emphasize integrating support from nursing care, rehabilitation, psychology, and nutrition. This integration not only facilitates recovery in hospital settings, but most importantly, the transition from an illness-defined life to a more "normalized" life. CONCLUSION: The first guidelines on EDS will shorten the diagnostic odyssey and solve the unmet medical needs of the patients. This article is a synopsis of the full guidelines.
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Síndrome de Ehlers-Danlos , Síndrome de Ehlers-Danlos/diagnóstico , Síndrome de Ehlers-Danlos/terapia , Síndrome de Ehlers-Danlos/genética , Humanos , China , Guías de Práctica Clínica como AsuntoRESUMEN
Genetic variants in ATP7A are associated with a spectrum of X-linked disorders. In descending order of severity, these are Menkes disease, occipital horn syndrome, and X-linked distal spinal muscular atrophy. After 30 years of diagnostic investigation, we identified a deep intronic ATP7A variant in four males from a family affected to variable degrees by a predominantly skeletal phenotype, featuring bowing of long bones, elbow joints with restricted mobility which dislocate frequently, coarse curly hair, chronic diarrhoea, and motor coordination difficulties. Analysis of whole genome sequencing data from the Genomics England 100,000 Genomes Project following clinical re-evaluation identified a deep intronic ATP7A variant, which was predicted by SpliceAI to have a modest splicing effect. Using a mini-gene splicing assay, we determined that the intronic variant results in aberrant splicing. Sanger sequencing of patient cDNA revealed ATP7A transcripts with exon 5 skipping, or inclusion of a novel intron 4 pseudoexon. In both instances, frameshift leading to premature termination are predicted. Quantification of ATP7A mRNA transcripts using a qPCR assay indicated that the majority of transcripts (86.1 %) have non-canonical splicing, with 68.0 % featuring exon 5 skipping, and 18.1 % featuring the novel pseudoexon. We suggest that the variability of the phenotypes within the affected males results from the stochastic effects of splicing. This deep intronic variant, resulting in aberrant ATP7A splicing, expands the understanding of intronic variation on the ATP7A-related disease spectrum.
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Cutis Laxo , Síndrome de Ehlers-Danlos , Humanos , Masculino , ATPasas Transportadoras de Cobre/genética , Cutis Laxo/genética , Síndrome de Ehlers-Danlos/genética , Mutación , Fragmentos de Péptidos/genética , FenotipoRESUMEN
Recently, an autosomal recessive subtype of connective tissue disorder within the spectrum of Ehlers-Danlos syndrome (EDS), named classical-like EDS type 2 (clEDS2), was identified. clEDS2 is associated with biallelic variants in the adipocyte enhancer binding protein 1 (AEBP1) gene, specifically, affecting its aortic carboxypeptidase-like protein (ACLP) isoform. We described the 15th patient (13th family) diagnosed with clEDS2. This patient presented with notable similarities in phenotype to the documented cases, along with additional characteristics such as significant prematurity and short stature. An EDS sequencing panel-based analysis revealed homozygous AEBP1: NM_001129.5:c.2923del, p.Ala975Profs*22 likely pathogenic variants, and maternally inherited heterozygous COL11A1: NM_001854.4:c.1160A>G, p.Lys387Arg variant of uncertain significance in our patient. Upon comprehensive review of all previously reported clEDS2 patients, our patient exhibited the following overlapping phenotypes, including cutaneous features: hyperextensibility, atrophic scars/delayed wound healing (100%), easy bruising (100%), excessive skin (93%); skeletal features: generalized joint hypermobility (93%), pes planus (93%), dislocation/subluxation (93%); and cardiovascular features (86%). Our patient did not display symptoms of the critical complications reported in a few individuals, including superior mesenteric artery aneurysms and ruptures, aortic root aneurysm/dissection, spontaneous pneumothoraxes, and bowel ruptures. Together, this case expands the genetic and clinical phenotypic spectrum of AEBP1-related clEDS2.
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Síndrome de Ehlers-Danlos , Mutación del Sistema de Lectura , Homocigoto , Proteínas Represoras , Adolescente , Adulto , Niño , Femenino , Humanos , Masculino , Carboxipeptidasas/genética , Síndrome de Ehlers-Danlos/genética , Síndrome de Ehlers-Danlos/patología , Linaje , Fenotipo , Proteínas Represoras/genéticaRESUMEN
Ehlers-Danlos syndrome (EDS) belongs to a spectrum of rare heritable connective tissue disorders and is characterised by hyperextensibility, joint hypermobility and tissue fragility. Peripheral blood mononuclear cells (PBMCs) from a vascular EDS (vEDS) patient, known as the rarest EDS subtype, carrying a heterozygous nonsense mutation c.430C > T (p.Q105*) in the COL3A1 gene, which is essential for type III collagen synthesis, were reprogrammed into induced pluripotent stem cells (iPSCs). The generated iPSCs exhibit high expression of pluripotency-associated markers, possess trilineage differentiation capacity and reveal a normal karyotype. This novel patient-specific cell line enables in-depth pathophysiological studies of vEDS.
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Síndrome de Ehlers-Danlos Tipo IV , Síndrome de Ehlers-Danlos , Células Madre Pluripotentes Inducidas , Humanos , Codón sin Sentido , Leucocitos Mononucleares , Mutación/genética , Síndrome de Ehlers-Danlos/genética , Colágeno Tipo III/genéticaRESUMEN
Patients with classical Ehlers Danlos syndrome (cEDS) suffer impaired wound healing and from scars formed after injuries that are atrophic and difficult to close surgically. Haploinsufficiency in COL5A1 creates systemic morphological and functional alterations in the entire body. We investigated mechanisms that impair wound healing from corneal lacerations (full thickness injuries) in a mouse model of cEDS (Col5a1+/-). We found that collagen V reexpression in this model is upregulated during corneal tissue repair and that wound healing is delayed, impaired, and results in large atrophic corneal scars. We noted that in a matrix with a 50 % content of collagen V, activation of latent Transforming Growth Factor (TGF) ß is dysregulated. Corneal myofibroblasts with a haploinsufficiency of collagen V failed to mechanically activate latent TGF ß. Second harmonic imaging microscopy showed a disorganized, undulated, and denser collagen matrix in our Col5a1+/- model that suggested alterations in the extracellular matrix structure and function. We hypothesize that a regenerated collagen matrix with only 50 % content of collagen V is not resistant enough mechanically to allow adequate activation of latent TGF ß by fibroblasts and myofibroblasts.
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Lesiones de la Cornea , Síndrome de Ehlers-Danlos , Anomalías Cutáneas , Ratones , Animales , Humanos , Síndrome de Ehlers-Danlos/genética , Síndrome de Ehlers-Danlos/metabolismo , Colágeno/metabolismo , Lesiones de la Cornea/genética , Cicatriz/genética , Factor de Crecimiento Transformador betaRESUMEN
BACKGROUND: Vascular Ehlers-Danlos syndrome (vEDS) is a rare connective tissue disorder with a high risk for arterial, bowel, and uterine rupture, caused by heterozygous pathogenic variants in COL3A1. The aim of this cohort study is to provide further insights into the natural history of vEDS and describe genotype-phenotype correlations in a Dutch multicenter cohort to optimize patient care and increase awareness of the disease. METHODS: Individuals with vEDS throughout the Netherlands were included. The phenotype was charted by retrospective analysis of molecular and clinical data, combined with a one-time physical examination. RESULTS: A total of 142 individuals (50% female) participated the study, including 46 index patients (32%). The overall median age at genetic diagnosis was 41.0 years. More than half of the index patients (54.3%) and relatives (53.1%) had a physical appearance highly suggestive of vEDS. In these individuals, major events were not more frequent (P=0.90), but occurred at a younger age (P=0.01). A major event occurred more often and at a younger age in men compared with women (P<0.001 and P=0.004, respectively). Aortic aneurysms (P=0.003) and pneumothoraces (P=0.029) were more frequent in men. Aortic dissection was more frequent in individuals with a COL3A1 variant in the first quarter of the collagen helical domain (P=0.03). CONCLUSIONS: Male sex, type and location of the COL3A1 variant, and physical appearance highly suggestive of vEDS are risk factors for the occurrence and early age of onset of major events. This national multicenter cohort study of Dutch individuals with vEDS provides a valuable basis for improving guidelines for the diagnosing, follow-up, and treatment of individuals with vEDS.
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Colágeno Tipo III , Síndrome de Ehlers-Danlos , Humanos , Síndrome de Ehlers-Danlos/genética , Síndrome de Ehlers-Danlos/epidemiología , Femenino , Masculino , Países Bajos/epidemiología , Adulto , Colágeno Tipo III/genética , Persona de Mediana Edad , Estudios Retrospectivos , Estudios de Cohortes , Fenotipo , Adolescente , Estudios de Asociación Genética , Adulto Joven , Anciano , Síndrome de Ehlers-Danlos Tipo IVRESUMEN
Vascular Ehlers-Danlos Syndrome (vEDS) is an inherited connective tissue disorder caused by COL3A1 gene, mutations that encodes type III collagen, a crucial component of blood vessels. vEDS can be life-threatening as these patients can have severe internal bleeding due to arterial rupture. Here, we generated induced pluripotent stem cell (iPSC) lines from two vEDS patients carrying a missense mutation in the COL3A1 (c.226A > G, p.Asn76Asp) gene. These lines exhibited typical iPSC characteristics including morphology, expression of pluripotency markers, and could differentiate to all three germ layer. These iPSC lines can serve as valuable tools for elucidating the pathophysiology underlying vEDS.
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Colágeno Tipo III , Síndrome de Ehlers-Danlos , Células Madre Pluripotentes Inducidas , Mutación Missense , Síndrome de Ehlers-Danlos/genética , Síndrome de Ehlers-Danlos/patología , Humanos , Colágeno Tipo III/genética , Colágeno Tipo III/metabolismo , Células Madre Pluripotentes Inducidas/metabolismo , Masculino , Femenino , Línea Celular , Adulto , Síndrome de Ehlers-Danlos Tipo IVRESUMEN
Ehlers-Danlos syndromes (EDS) are a group of connective tissue disorders caused by mutations in collagen and collagen-interacting genes. We delineate a novel form of EDS with vascular features through clinical and histopathological phenotyping and genetic studies of a three-generation pedigree, displaying an apparently autosomal dominant phenotype of joint hypermobility and frequent joint dislocations, atrophic scarring, prolonged bleeding time and age-related aortic dilatation and rupture. Coagulation tests as well as platelet counts and function were normal. Reticular dermis displayed highly disorganized collagen fibers and transmission electron microscopy (TEM) revealed abnormally shaped fibroblasts and endothelial cells, with high amount and irregular shape of extracellular matrix (ECM) substance, especially near blood vessels. Genetic analysis unraveled a heterozygous mutation in THBS2 (NM_003247.5:c.2686T>C, p.Cys896Arg). We generated CRISPR/Cas9 knock-in (KI) mice, bearing the heterozygous human mutation in the mouse ortholog. The KI mice demonstrated phenotypic traits correlating with those observed in the human subjects, as evidenced by morphologic, histologic, and TEM analyses, in conjunction with bleeding time assays. Our findings delineate a novel form of human EDS with classical-like elements combined with vascular features, caused by a heterozygous THBS2 missense mutation. We further demonstrate a similar phenotype in heterozygous THBS2Cys896Arg KI mice, in line with previous studies in Thbs2 homozygous null-mutant mice. Notably, THBS2 encodes Thrombospondin-2, a secreted homotrimeric matricellular protein that directly binds the ECM-shaping Matrix Metalloproteinase 2 (MMP2), mediating its clearance. THBS2 loss-of-function attenuates MMP2 clearance, enhancing MMP2-mediated proteoglycan cleavage, causing ECM abnormalities similar to those seen in the human and mouse disease we describe.
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Síndrome de Ehlers-Danlos , Heterocigoto , Trombospondinas , Síndrome de Ehlers-Danlos/genética , Síndrome de Ehlers-Danlos/patología , Síndrome de Ehlers-Danlos/metabolismo , Animales , Trombospondinas/genética , Trombospondinas/metabolismo , Humanos , Ratones , Masculino , Femenino , Adulto , Fenotipo , Linaje , Persona de Mediana Edad , Mutación MissenseRESUMEN
This narrative review aims to demonstrate and summarize the complex relationship between Ehlers-Danlos syndromes (EDS) and temporomandibular disorders (TMD) by reviewing the results of observational studies and case reports. EDS are a set of hereditary connective tissue disorders, where generalized joint hypermobility (GJH), especially in the hypermobile subtype (hEDS), is a key symptom. Mutations have been identified in genes that impact the production or assembly of collagen for all subtypes except hEDS. While the correlation between GJH and TMD has been analysed in various studies, fewer studies have examined TMD in patients with EDS, with most showing an increased prevalence of TMD. In case-control studies, an elevated prevalence of myalgia, arthralgia and disc-related disorders was found in individuals with EDS. Various therapeutic interventions have been reported within the literature in the form of case reports and observational studies, but there are no long-term clinical trials with results on the efficacy of different therapeutic approaches to date. This review demonstrates the high prevalence of different TMDs in different subtypes of EDS, but also shows that little is known about the success of treatment thus far. Further clinical research is necessary to provide adequate guidance on targeted treatment.
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Síndrome de Ehlers-Danlos , Inestabilidad de la Articulación , Trastornos de la Articulación Temporomandibular , Humanos , Síndrome de Ehlers-Danlos/complicaciones , Síndrome de Ehlers-Danlos/diagnóstico , Síndrome de Ehlers-Danlos/genética , Inestabilidad de la Articulación/complicaciones , Inestabilidad de la Articulación/epidemiología , Colágeno , Trastornos de la Articulación Temporomandibular/epidemiología , Trastornos de la Articulación Temporomandibular/etiología , Trastornos de la Articulación Temporomandibular/diagnóstico , Estudios de Casos y ControlesRESUMEN
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.
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Enfermedades del Tejido Conjuntivo , Humanos , Artritis , Colágeno/genética , Enfermedades del Tejido Conjuntivo/genética , Enfermedades del Tejido Conjuntivo/terapia , Síndrome de Ehlers-Danlos/genética , Síndrome de Ehlers-Danlos/diagnóstico , Pérdida Auditiva Sensorineural , Inestabilidad de la Articulación/genética , Síndrome de Loeys-Dietz/genética , Síndrome de Loeys-Dietz/diagnóstico , Síndrome de Marfan/genética , Síndrome de Marfan/diagnóstico , Osteogénesis Imperfecta/genética , Desprendimiento de RetinaRESUMEN
Ehlers-Danlos syndromes (EDSs) constitute a heterogeneous group of connective tissue disorders characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. Asymptomatic EDSs, joint hypermobility without associated syndromes, EDSs, and hypermobility spectrum disorders are the commonest phenotypes associated with joint hypermobility. Joint hypermobility syndrome (JHS) is a connective tissue disorder characterized by extreme flexibility of the joints, along with pain and other symptoms. JHS can be a sign of a more serious underlying genetic condition, such as EDS, which affects the cartilage, bone, fat, and blood. The exact cause of JHS could be related to genetic changes in the proteins that add flexibility and strength to the joints, ligaments, and tendons, such as collagen. Membrane proteins are a class of proteins embedded in the cell membrane and play a crucial role in cell signaling, transport, and adhesion. Dysregulated membrane proteins have been implicated in a variety of diseases, including cancer, cardiovascular disease, and neurological disorders; recent studies have suggested that membrane proteins may also play a role in the pathogenesis of JHS. This article presents an exploration of the causative factors contributing to musculoskeletal pain in individuals with hypermobility, based on research findings. It aims to provide an understanding of JHS and its association with membrane proteins, addressing the clinical manifestations, pathogenesis, diagnosis, and management of JHS.
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Síndrome de Ehlers-Danlos , Inestabilidad de la Articulación , Proteínas de la Membrana , Humanos , Síndrome de Ehlers-Danlos/metabolismo , Síndrome de Ehlers-Danlos/genética , Inestabilidad de la Articulación/metabolismo , Inestabilidad de la Articulación/genética , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismoRESUMEN
Ehlers-Danlos syndromes (EDS) represent a group of rare genetic disorders affecting connective tissues. Globally, approximately 1.5 million individuals suffer from EDS, with 10,000 reported cases in Canada alone. Understanding the histological properties of collagen in EDS has been challenging, but advanced techniques like atomic force microscopy (AFM) have opened up new possibilities for label-free skin imaging. This approach, which explores Type I collagen fibrils at the nanoscale, could potentially enhance EDS diagnosis and our knowledge of collagen type I-related connective tissue disorders. In the current study, we have employed AFM to examine ex-vivo skin biopsies from four individuals: one with classical EDS (cEDS), one with hypermobile EDS (hEDS), one with hEDS and Scleroderma (hEDS-Scleroderma), and one healthy control. Picrosirius red (PS) staining was used to highlight collagen differences in the samples. For each case, 14 images and 1400 force curves were obtained, with seven images and 700 force curves representing healthy collagen (PS-induced red staining) and the rest showcasing disrupted collagen (yellow staining). The results showed that PS staining was uniform throughout the control section, while cEDS and hEDS displayed localized areas of yellow staining. In the case of hEDS-Scleroderma, the yellow staining was widespread throughout the section. AFM images revealed irregular collagen fibrils in the disrupted, yellow-stained areas, contrasting with aligned and well-registered collagen fibrils in healthy, red-stained regions. Additionally, the study assessed the ability of non-AFM specialists to differentiate between healthy and disrupted collagen in AFM images, yielding substantial agreement among raters according to Fleiss's and Cohen's kappa scores (0.96 and 0.79±0.1, respectively). Biomechanical analysis revealed that normal healthy collagen exhibited a predominant population at 2.5 GPa. In contrast, EDS-affected collagen displayed subpopulations with lower compressive elastic modulus, indicating weaker collagen fibrils in EDS patients. Although these findings pertain to a limited number of cases, they offer valuable insights into the nanoscale collagen structure and biomechanics in individuals with EDS. Over time, these insights could be developed into specific biomarkers for the condition, improving diagnosis and treatment for EDS and related connective tissue disorders.
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Síndrome de Ehlers-Danlos , Microscopía de Fuerza Atómica , Síndrome de Ehlers-Danlos/patología , Síndrome de Ehlers-Danlos/metabolismo , Síndrome de Ehlers-Danlos/genética , Humanos , Piel/patología , Piel/metabolismo , Nanoestructuras/química , Femenino , Masculino , Colágeno/metabolismo , Adulto , Colágeno Tipo I/metabolismo , Persona de Mediana EdadRESUMEN
We describe the case of a young 33-year-old woman that was referred to our clinic for evidence of migrant cavitary nodules at CT scan, dyspnea, and blood sputum. Her physical examination showed translucent and thin skin, evident venous vascular pattern, vermilion of the lip thin, micrognathia, thin nose, and occasional Raynaud phenomenon. We prescribed another CT scan that showed multiple pulmonary nodules in both lungs, some of which had evidence of cavitation. Because bronchoscopy was not diagnostic, we decided to perform surgical lung biopsy. At histologic examination, we found the presence of irregularly shaped, but mainly not dendritic, foci of ossification that often contained bone marrow and were embedded or surrounded by tendinous-like fibrous tissue. After incorporating data from the histologic examination, we decided to perform genetic counseling and genetic testing with the use of whole-exome sequencing. The genetic test revealed a heterozygous de novo missense mutation of COL3A1 gene, which encodes for type III collagen synthesis, and could cause vascular Ehlers-Danlos syndrome.
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Colágeno Tipo III , Hemoptisis , Tomografía Computarizada por Rayos X , Humanos , Femenino , Adulto , Hemoptisis/etiología , Hemoptisis/diagnóstico , Colágeno Tipo III/genética , Síndrome de Ehlers-Danlos/diagnóstico , Síndrome de Ehlers-Danlos/complicaciones , Síndrome de Ehlers-Danlos/genética , Diagnóstico Diferencial , Mutación Missense , Nódulos Pulmonares Múltiples/diagnóstico , Nódulos Pulmonares Múltiples/diagnóstico por imagen , Pulmón/diagnóstico por imagen , Pulmón/patologíaRESUMEN
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.