Transcriptome-wide expression profiling in skin fibroblasts of patients with joint hypermobility syndrome/ehlers-danlos syndrome hypermobility type

Joint hypermobility syndrome/Ehlers-Danlos syndrome hypermobility type (JHS/EDS-HT), is likely the most common systemic heritable connective tissue disorder, and is mostly recognized by generalized joint hypermobility, joint instability complications, minor skin changes and a wide range of satellite features. JHS/EDS-HT is considered an autosomal dominant trait but is still without a defined molecular basis. The absence of (a) causative gene(s) for JHS/EDS-HT is likely attributable to marked genetic heterogeneity and/or interaction of multiple loci. In order to help in deciphering such a complex molecular background, we carried out a comprehensive immunofluorescence analysis and gene expression profiling in cultured skin fibroblasts from five women affected with JHS/EDS-HT. Protein study revealed disarray of several matrix structural components such as fibrillins, tenascins, elastin, collagens, fibronectin, and their integrin receptors. Transcriptome analysis indicated perturbation of different signaling cascades that are required for homeostatic regulation either during development or in adult tissues as well as altered expression of several genes involved in maintenance of extracellular matrix architecture and homeostasis (e.g., SPON2, TGM2, MMP16, GPC4, SULF1), cell-cell adhesion (e.g., CDH2, CHD10, PCDH9, CLDN11, FLG, DSP), immune/inflammatory/pain responses (e.g., CFD, AQP9, COLEC12, KCNQ5, PRLR), and essential for redox balance (e.g., ADH1C, AKR1C2, AKR1C3, MAOB, GSTM5). Our findings provide a picture of the gene expression profile and dysregulated pathways in JHS/EDS-HT skin fibroblasts that correlate well with the systemic phenotype of the patients

Small fiber neuropathy is a common feature of Ehlers-Danlos syndromes

To investigate the involvement of small nerve fibers in Ehlers-Danlos syndrome (EDS). Patients diagnosed with EDS underwent clinical, neurophysiologic, and skin biopsy assessment. We recorded sensory symptoms and signs and evaluated presence and severity of neuropathic pain according to the Douleur Neuropathique 4 (DN4) and ID Pain questionnaires and the Numeric Rating Scale (NRS). Sensory action potential amplitude and conduction velocity of sural nerve was recorded. Skin biopsy was performed at distal leg and intraepidermal nerve fiber density (IENFD) obtained and referred to published sex- and age-adjusted normative reference values. Our cohort included 20 adults with joint hypermobility syndrome/hypermobility EDS, 3 patients with vascular EDS, and 1 patient with classic EDS. All except one patient had neuropathic pain according to DN4 and ID Pain questionnaires and reported 7 or more symptoms at the Small Fiber Neuropathy Symptoms Inventory Questionnaire. Pain intensity was moderate (NRS ≥4 and <7) in 8 patients and severe (NRS ≥7) in 11 patients. Sural nerve conduction study was normal in all patients. All patients showed a decrease of IENFD consistent with the diagnosis of small fiber neuropathy (SFN), regardless of the EDS type. SFN is a common feature in adults with EDS. Skin biopsy could be considered an additional diagnostic tool to investigate pain manifestations in EDS

The use of transverse connectors as reinforcement of multi-leaf walls

The need for new retrofitting techniques is the consequence of an increasing interest in the conservation of historic construction. The global behavior of a stone masonry structure is often governed by the level of connection between masonry wall leaves and the overall quality of the masonry material. This paper presents the results of an investigation carried out on site and in the laboratory on multi-leaf stone masonry panels strengthened using stainless steel rod inserted in a grouted fabric sleeve. The aim is to increase the collaboration between weakly connected masonry leaves. Pull-out tests were conducted on site on full-scale stone masonry wall panels, with the aim of studying the force required to pull out a connector under uniaxial tension. Several wall panels were assembled in the laboratory using solid calcareous stones and weak mortar and the effectiveness of the connectors was tested in shear and compression on both virgin and damaged panels. The experimental tests allowed the analysis of the behavior of the multi-leaf panels. Experimental results show that a substantial improvement of the wall panels' mechanical behavior can be achieved by applying transverse connectors

Recommendations for anesthesia and perioperative management in patients with Ehlers-Danlos syndrome(s)

Ehlers-Danlos syndrome (EDS, ORPHA98249) comprises a group of clinically and genetically heterogeneous heritable connective tissue disorders, chiefly characterized by joint hypermobility and instability, skin texture anomalies, and vascular and soft tissue fragility. As many tissues can be involved, the underlying molecular defect can manifest itself in many organs and with varying degrees of severity, with widespread implications for anesthesia and perioperative management. This review focuses on issues relevant for anesthesia for elective and emergency surgery in EDS. We searched the literature for papers related to all EDS variants; at the moment most of the published data deals with the vascular subtype and, to a lesser extent, classic and hypermobility EDS. Knowledge is fragmented and consists mostly of case reports, small case series and expert opinion. Because EDS patients commonly require surgery, we have summarized some recommendations for general, obstetrical and regional anesthesia, as well as for hemostatic therapy

A Patient with Unilateral Tibial Aplasia and Accessory Scrotum: A Pure Coincidence or Nonfortuitous Association?

Tibial aplasia is an uncommon lower limb malformation that can occur isolated or be part of a more complex malformation pattern. We describe a 9-year-old boy born after uneventful pregnancy and delivery. Family history was negative for maternal diabetes and other malformations. The patient presented with left tibial aplasia and homolateral prexial foot polydactyly. He also displayed enamel dysplasia and bifid scotum with cryptorchidism. Literature review failed to identify a significant syndromic association between lower limb defects of the tibial type and the genital anomalies reported here. The combination of tibial aplasia with midline genital malformations further supports the hypothesis that the tibial ray development mirrors the morphogenetic process of the radial structures. Accordingly, the malformation pattern observed in the present patient may be pathogenetically explained by an insult occurring during late blastogenesis

Repairing brickwork panels using titanium rods embedded in the mortar joints

This paper investigates repairing brickwork masonry walls using smooth titanium rods. Firstly, numerical analyses were carried out following a detailed micro-modelling strategy and then an experimental research program was undertaken in the laboratory. Solid clay brick specimens were initially tested, without strengthening, and subsequently re-tested, after repair, using titanium rods. Rods were embedded into the horizontal joints using an epoxy paste or a cement mortar. A double-sided repair was considered. Shear tests were carried out on four brickwork panels, under diagonal loading. The mechanism by which the diagonal shear load was carried was analyzed, varying from the uncracked state, to the final, cracked state, for both control and repaired wall panels. The results demonstrate that it is partially possible to restore the panels’ original in-plane shear capacity by embedding titanium rods into the horizontal bed joints using the epoxy paste. The experimental results were used to evaluate the effectiveness of the titanium repair, and recommendations are made to allow the test data to be used in the design procedure of cracked masonry structures. Unsatisfactory test results were recorded for panels repaired using a cement mortar

Functional Characterization of a Novel TP63 Mutation in a Family With Overlapping Features of Rapp-Hodgkin/AEC/ADULT Syndromes

Heterozygous mutations in TP63 cause a wide spectrum of autosomal dominant developmental disorders variably affecting skin, limbs, and face. TP63 encodes p63, a protein expressed in two main isoforms (Tap63 and ΔNp63) with critical roles in both cell differentiation and development. Some analyses suggest a relationship of the mutation site to the observed clinical picture, although this link is inconsistent. This suggests an appreciable phenotypic continuity within the TP63-related disorders. We report a 3-month-old boy ascertained for congenital scalp erosion and mild features of ectodermal dysplasia. His mother showed full-blown characteristics of Rapp-Hodgkin syndrome plus intense abdominal and popliteal freckling. Molecular investigation identified the novel TP63 mutation c.1697delG. We used a luciferase reporter assay to compare the effects on the p63 transactivation (TA) activity of c.1697delG with that of the p.Arg280Cys and p.Gln634X mutations, associated with ectrodactyly-ectodermal dysplasia-cleft lip/palate syndrome and isolated split hand/foot malformation, respectively. These results demonstrated complex behavior of c.1697delG in the TA of genes involved in epidermal differentiation and development and shed further light in the physiopathology of TP63-related disorders. © 2011 Wiley Periodicals, Inc

Editorial : Neurodevelopmental, neuropsychiatric and psychosocial correlates of joint hypermobility and related disorders

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Genetic testing for Marfan syndrome

Abstract Marfan syndrome (MFS) is an inherited connective tissue disorder caused by heterozygous mutations in the FBN 1 gene. Clinical manifestations of MFS include aortic dilatation and dissection, as well as cardiac valvular, ocular, skeletal and neurological manifestations. Prevalence varies from 6 to 20 per 100,000 individuals. Revised Ghent Nosology (2010) is used to establish a clinically based suspected diagnosis to be confirmed by molecular testing. This Utility Gene Test was prepared on the basis of an analysis of the literature and existing diagnostic protocols. Molecular testing is useful for diagnosis confirmation, as well as differential diagnosis, appropriate genetic counselling and access to clinical trials

Genetic testing for vascular Ehlers-Danlos syndrome and other variants with fragility of the middle arteries

Abstract Ehlers-Danlos syndrome (EDS) is an umbrella term for various inherited connective tissue disorders associated with mutations in genes involved in extracellular matrix formation. "The 2017 International Classification of Ehlers-Danlos Syndromes and related disorders" identifies 13 clinical types with mutations in 19 distinct genes. The present module focuses on forms with major vascular involvement: vascular EDS (vEDS) caused by heterozygous mutations in COL3A1, "vascular-like" EDS (vlEDS) caused by recurrent mutations in COL1A1, classical EDS with vascular fragility associated with heterozygous mutations in COL5A1, and kyphoscoliotic EDS associated with recessive variations in PLOD1 and FKBP14. The overall prevalence of EDS is estimated between 1/10,000 and 1/25,000 and vEDS accounts for about 5 to 10% of all EDS cases. This Utility Gene Test was prepared on the basis of an analysis of the literature and existing diagnostic protocols. Molecular testing is useful for diagnosis confirmation, as well as differential diagnosis, appropriate genetic counselling and access to clinical trials