New Research Roundup [EDS/HSD]
Heritable Connective Tissue Disorders (HCTD) show an overlap in the physical features that can evolve in childhood. It is unclear to what extent children with HCTD experience burden of disease. This study aims to quantify fatigue, pain, disability and general health with standardized validated questionnaires.
Methods. This observational, multicenter study included 107 children, aged 4–18 years, with Marfan syndrome (MFS), 58%; Loeys-Dietz syndrome (LDS), 7%; Ehlers-Danlos syndromes (EDS), 8%; and hypermobile Ehlers-Danlos syndrome (hEDS), 27%. The assessments included PROMIS Fatigue Parent–Proxy and Pediatric self-report, pain and general health Visual-Analogue-Scales (VAS) and a Childhood Health Assessment Questionnaire (CHAQ).
Results. Compared to normative data, the total HCTD-group showed significantly higher parent-rated fatigue T-scores (M = 53 (SD = 12), p = 0.004, d = 0.3), pain VAS scores (M = 2.8 (SD = 3.1), p < 0.001, d = 1.27), general health VAS scores (M = 2.5 (SD = 1.8), p < 0.001, d = 2.04) and CHAQ disability index scores (M = 0.9 (SD = 0.7), p < 0.001, d = 1.23). HCTD-subgroups showed similar results. The most adverse sequels were reported in children with hEDS, whereas the least were reported in those with MFS. Disability showed significant relationships with fatigue (p < 0.001, rs = 0.68), pain (p < 0.001, rs = 0.64) and general health (p < 0.001, rs = 0.59).
Conclusions. Compared to normative data, children and adolescents with HCTD reported increased fatigue, pain, disability and decreased general health, with most differences translating into very large-sized effects. This new knowledge calls for systematic monitoring with standardized validated questionnaires, physical assessments and tailored interventions in clinical care.
Methods. This observational, multicenter study included 107 children, aged 4–18 years, with Marfan syndrome (MFS), 58%; Loeys-Dietz syndrome (LDS), 7%; Ehlers-Danlos syndromes (EDS), 8%; and hypermobile Ehlers-Danlos syndrome (hEDS), 27%. The assessments included PROMIS Fatigue Parent–Proxy and Pediatric self-report, pain and general health Visual-Analogue-Scales (VAS) and a Childhood Health Assessment Questionnaire (CHAQ).
Results. Compared to normative data, the total HCTD-group showed significantly higher parent-rated fatigue T-scores (M = 53 (SD = 12), p = 0.004, d = 0.3), pain VAS scores (M = 2.8 (SD = 3.1), p < 0.001, d = 1.27), general health VAS scores (M = 2.5 (SD = 1.8), p < 0.001, d = 2.04) and CHAQ disability index scores (M = 0.9 (SD = 0.7), p < 0.001, d = 1.23). HCTD-subgroups showed similar results. The most adverse sequels were reported in children with hEDS, whereas the least were reported in those with MFS. Disability showed significant relationships with fatigue (p < 0.001, rs = 0.68), pain (p < 0.001, rs = 0.64) and general health (p < 0.001, rs = 0.59).
Conclusions. Compared to normative data, children and adolescents with HCTD reported increased fatigue, pain, disability and decreased general health, with most differences translating into very large-sized effects. This new knowledge calls for systematic monitoring with standardized validated questionnaires, physical assessments and tailored interventions in clinical care.
OBJECTIVE
The craniocervical junction (CCJ) is anatomically complex and comprises multiple joints that allow for wide head and neck movements. The thecal sac must adjust to such movements. Accordingly, the thecal sac is not rigidly attached to the bony spinal canal but instead tethered by fibrous suspension ligaments, including myodural bridges (MDBs). The authors hypothesized that pathological spinal cord motion is due to the laxity of such suspension bands in patients with connective tissue disorders, e.g., hypermobile Ehlers-Danlos syndrome (EDS).
METHODS
The ultrastructure of MDBs that were intraoperatively harvested from patients with Chiari malformation was investigated with transmission electron microscopy, and 8 patients with EDS were compared with 8 patients without EDS. MRI was used to exclude patients with EDS and craniocervical instability (CCI). Real-time ultrasound was used to compare the spinal cord at C1–2 of 20 patients with EDS with those of 18 healthy control participants.
RESULTS
The ultrastructural damage of the collagen fibrils of the MDBs was distinct in patients with EDS, indicating a pathological mechanical laxity. In patients with EDS, ultrasound revealed increased cardiac pulsatory motion and irregular displacement of the spinal cord during head movements.
CONCLUSIONS
Laxity of spinal cord suspension ligaments and the associated spinal cord motion disorder are possible pathogenic factors for chronic neck pain and headache in patients with EDS but without radiologically proven CCI.
Background: The Ehlers-Danlos Syndromes (EDS) are a group of rare heritable connective tissue disorders caused by various defects in the biosynthesis or secretion of fibrillar collagens. The three main clinical features of EDS are joint hypermobility, skin fragility and general soft tissue fragility. 13 clinical subtypes of EDS are recognized, of which the hypermobile type (hEDS) and classical type (cEDS) are the most prevalent. It has been hypothesized that the (micro-)trauma in the joint due to typical subluxations and dislocations, make EDS patients prone to developing osteoarthritis (OA) in early stage. Conversely, it has been mentioned that joint hypermobility provides a larger joint surface area and prevents OA. Abnormal biomechanical loading has been identified as a risk factor for the development of OA in the wrist and hand. However, no studies have yet been performed in EDS patients.
Objectives: The primary aim was to investigate the presence of any degenerative features for hand OA, and if this differs between cEDS and hEDS patients. The second aim was to evaluate hand function and pain related to OA signs in EDS patients.
Methods: cEDS and hEDS patients between 35 and 50 years old were invited to participate. cEDS diagnosis was genetically confirmed and hEDS diagnosis was performed according the clinical 2017 hEDS criteria. Exclusion criteria were a body mass index ≥35, not being able to stand straight up for five minutes, suffering from an auto-immune disease or rheumatological condition, or pregnancy. Conventional X-rays of both hands were performed and scored independently by three assessors according to Kallman1. Presence of osteophytes (0-3), joint space narrowing (0-3), malalignment (>15°)(0/1), erosions (0/1), subchondral sclerosis (0/1), and subchondral cysts (0/1) were scored in all interphalangeal (distal and proximal), metacarpophalangeal and thumb base joints of both hands1. We defined early hand OA as minimally three features (≥1) were present. Several clinical assessments were made, e.g. tenderness, bony swelling and soft tissue swelling. The Michigan Hand Outcomes Questionnaire (MHOQ) and Australian/Canadian Osteoarthritis Hand Index (AUSCAN) questionnaires were completed.
Results: In total, 31 patients (mean age 41 ± 5.6 years, 13 men and 18 women) diagnosed with EDS participated, of whom 19 with cEDS and with 12 hEDS. In total, 927 joints were assessed. Level of agreement of radiographic assessments was very high (>98%). Early hand OA was found in more than 40% of the EDS patients, with a significant higher frequency in cEDS patients compared to hEDS patients (58% vs. 17%) (p=0.032). Joint space narrowing was most frequently present and significantly more in the cEDS patients compared to hEDS patients (79% vs. 21%) (p=0.003). However, radiographic changes were found in only 10% of all finger joints. Of all fingers, thumb joints were most affected. Regarding the clinical features of hand OA, all patients showed deformity in one or more finger joints, most frequently at the thumb, especially the IP joint (both hyperflexion and hyperextension). Tenderness and bony swelling was present in 36% and 45% of all patients, respectively, whereas soft tissue swelling was less frequently observed (10% of all patients). Here, no significant differences were found between cEDS and hEDS patients. Moderate disability was present (mean (SD) AUSCAN= 45.47 (27.10) and MHQ = 65.97 (14.21). cEDS showed significant less hand pain (p=0.03), a better hand function (p=0.03) and less disability (p=0.026) than hEDS.
Conclusion: This explorative study demonstrates that a high number of EDS patients present with minimal degenerative features of hand OA, but in a minority of joints. Patients with cEDS were significantly more affected, but showed a better function compared to hEDS. Possibly, cEDS patients are more susceptible to develop hand OA.
This report describes an extensive surgical journey for a patient with Ehlers-Danlos syndrome (EDS) who underwent a total temporomandibular joint reconstruction and illustrates an ongoing challenge for oral and maxillofacial surgeons treating patients with connective tissue disorders and managing chronic pain symptoms. The surgical team attempted multiple procedures including 2 failed total temporomandibular joint replacements and a myocutaneous vascularized free flap. This case demonstrates the potential for postoperative complications in patients with EDS.
Background
The Ehlers–Danlos syndrome (EDS) is a group of connective tissue disorders characterized by fragile blood vessels and an increased tendency for bleeding and scarring. Here, we report the outcome of a pars plana vitrectomy for the treatment of rhegmatogenous retinal detachment in a patient with EDS type IV (vascular type).
Case presentation
A 40-year-old Slovenian man with high myopia, unilateral bullous retinal detachment, and vitreous hemorrhage was referred for surgery. The patient had a history of colon perforation, muscle and arterial rupture in both lower limbs, and recurrent shoulder joint luxations. Genetic testing revealed a pathogenic mutation in the COL3A1 gene. The patient underwent a 25-gauge three-port pars plana vitrectomy. The tendency for bleeding during surgery was prevented by endodiathermy applied to the edges of the retinal breaks. Endolaser photocoagulation was performed under air. The surgical procedure was completed with the injection of gas tamponade, followed by the patient remaining for a few days in a face-down position. Mild postoperative vitreous hemorrhage was resorbed in first week after the surgery. Postoperative extensive pigment dispersion on the posterior lens face persisted for several weeks. After the gas tamponade had resorbed, the retina was flat and remained attached during the follow-up period. Eight months after the surgery, visual acuity continued to improve from a preoperative 6/38 to 6/6.6 (Snellen chart) at the last checkup.
Conclusion
A small-gauge pars plana vitrectomy with gas tamponade and laser photocoagulation under air may successfully achieve reattachment of the retina in patients with high myopia with EDS type IV and restore visual acuity.
Introduction: Among protein and fibers in the extracellular matrix (ECM), collagen is the most copious and widely employed in cosmetic, food, pharmaceutical, and biomedical industries due to its extensive biocompatible and versatile properties. In the last years, the knowledge about functions of collagens increased and expanded dramatically. Once considered only crucial for the ECM scaffolding and mechanotransduction, additional functional roles have now been ascribed to the collagen superfamily which are defined by other recently discovered domains, supramolecular assembly and receptors.
Areas covered: Given the importance of each step in the collagen biosynthesis, folding and signaling, medicinal chemists have explored small molecules, peptides, and monoclonal antibodies to modulate enzymes, receptors and interactions with the physiological ligands of collagen. These compounds were also explored toward diseases and pathological conditions. The authors discuss this providing their expert perspectives on the subject area.
Expert opinion: Understanding collagen protein properties and its interactome is beneficial for therapeutic drug design. Nevertheless, compounds targeting collagen-based interactome suffered from the presence of different isoforms for each target and the lack of specific 3D crystal structures able to guide properly drug design.
Collagen is an insoluble fibrous protein that composes the extracellular matrix in animals. Although collagen has been used as a biomaterial since 1881, the properties and the complex structure of collagen are still extensive study subjects worldwide. In this article, several topics of importance for understanding collagen research are reviewed starting from its historical milestones, followed by the description of the collagen superfamily and its complex structures, with a focus on type I collagen. Subsequently, some of the superior properties of collagen-based biomaterials, such as biocompatibility, biodegradability, mechanical properties, and cell activities, are pinpointed. These properties make collagen applicable in biomedicine, such as wound healing, tissue engineering, surface coating of medical devices, and skin supplementation. Moreover, some antimicrobial strategies and the general host tissue responses regarding collagen as a biomaterial are presented. Finally, the current status and clinical application of the three-dimensional (3D) printing techniques for the fabrication of collagen-based scaffolds and the reconstruction of the human heart's constituents, such as capillary structures or even the entire organ, are discussed. Besides, an overall outlook for the future of this unique biomaterial is provided.
CHAPTERS:
The Collagen Superfamily: Everything You Always Wanted to Know
Mélanie Salamito, Pauline Nauroy, Florence Ruggiero
Procollagen Trafficking and its Implications in Osteogenesis Imperfecta
Shakib Omari, Elena Makareeva, Sergey Leikin
Collagens in the Physiopathology of the Ehlers–Danlos Syndromes
Fransiska Malfait, Robin Vroman, Marlies Colman, Delfien Syx
Cartilage Collagens and Associated Disorders
Uwe Hansen
Collagen IV-Related Diseases and Therapies
Afshan Dean, Tom Van Agtmael
Collagens and Muscle Diseases: A Focus on Collagen VI
Valentina Tonelotto, Silvia Castagnaro, Matilde Cescon, Paolo Bonaldo
Skin Blistering and Collagens: From Bench to Therapies
Alexander Nyström, Dimitra Kiritsi, Leena Bruckner-Tuderman
Collagens as New Players in Nervous System Diseases
Anne Heikkinen, Michael A. Fox, Taina Pihlajaniemi
Background: Patients with hypermobile Ehlers-Danlos syndrome (hEDS) often report symptoms of cutaneous flushing, pruritis, vomiting, diarrhea and anaphylactoid responses to environmental, food, and mechanical stimuli. There is a growing body of literature investigating the possible link between disorders of mast cell regulation including mast cell activation syndrome (MCAS) and connective tissue disorders including hEDS. The evidence for such a relationship, however, remains limited.1
Objectives: We aimed to evaluate the association between hEDS and MCAS among hospitalized patients using a nationally representative cohort.
Methods: Hospitalized patients with a diagnosis of hEDS or MCAS were identified in the 2016-2018 National Inpatient Sample (NIS) using the International Classification of Diseases 10 system (ICD-10). The NIS is an all-payer inpatient database that estimates over 37 million annual U.S. hospitalizations and is maintained by the Healthcare Cost and Utilization Project. The primary outcomes were prevalence of EDS and MCAS among hospitalized patients. Secondary outcomes included cause of admission, mortality, length of stay, and cost of care. Multivariate hierarchical regression analysis was using adjusting for demographics, hospital factors, and comorbid conditions.
Results: Among 37,665 patients identified in this study, 35,115 (95.9%) patients had hEDS and 3,630 (9.6%) patients had MCAS. 1080 patients had concomitant diagnosis of hEDS (3.1%) and MCAS (29.8%), of whom 555 (51.4%) were diagnosed in 2018 compared with 100 (9.3%) patients in 2016 (P<0.001). The mean age of patients with both conditions was significantly lower than those diagnosed with hEDS (29.5 vs 36.6 years, P<0.001) or MCAS (29.5 vs 39.8 years, P<0.001) alone. Those with comorbid hEDS and MCAS were more likely female (95.8% vs 84.5%, P<0.001), had private insurance (67.6% vs 52.4%, P<0.001) and were among the highest income quartile (47.4% vs 31.9%, P<0.001). There were no significant differences in mortality or overall comorbidity burden. Patients with hEDS and MCAS had higher adjusted hospitalization charges ($64,445 vs $54,782, β=0.15, P<0.05) and longer adjusted lengths of stay (6.4 vs 4.9 days, IRR 1.35, P<0.001).
Conclusion: Nearly 1 in 3 patients diagnosed with MCAS have comorbid diagnosis of hEDS. This association appeared to increase over time with the increasing diagnosis of MCAS. Social determinants of disease such as health insurance status and income appeared to be associated with the identification of the overlap syndrome. These findings merit further investigation into the co-occurrence of these disease entities and development of consistent clinical diagnostic criteria.
