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Background: Ehlers-Danlos syndrome (EDS) is a hereditary disease characterised by joint hypermobility, skin hyperextensibility and tissue fragility. Hypermobile EDS (hEDS is the more frequent subtype. Joint surgery may benefit certain patients after failure of medical treatments, but there is no consensus on the optimal surgical management of patients with hEDS. The aims of this retrospective study were to chart the surgical management of patients with hEDS, to determine the role of arthroscopy and to evaluate the functional results of joint surgery, including the reintervention rates., Results: A total of 69 patients with non-vascular EDS were evaluated (60 female; 87%). Mean (SD) age at first surgery was 25.6 ± 11.1 years. Among the 69 patients, first surgeries were carried out on the knee (n = 50; 39.4%), ankle (n = 28; 22.0%), shoulder (n = 22; 17.3%), wrist (n = 18; 14.2%) and elbow (n = 9; 7.1%). One-fifth of all first operations (20.8%) were carried out by arthroscopy, most often on the knee (36% of knee surgery cases). At the time of primary surgery, the surgeon was alerted to the diagnosis or suspicion of hEDS in only 33.9% of patients. The rate of reoperations (2 to ≥ 5) was 35.7% (10/28) for the ankle, 40.9% (9/22) for the shoulder, 44.4% (4/9) for the elbow, 50% (9/18) for the wrist and 60% (30/50) for the knee. Local or regional anaesthesia was badly tolerated or ineffective in 27.8%, 36.4% and 66.6% of operations on the wrist, shoulder and elbow, respectively. Overall, the majority of patients (> 70%) were satisfied or very satisfied with their surgery, particularly on the non-dominant side. The lowest satisfaction rate was for shoulder surgery on the dominant side (58.3% dissatisfied)., Conclusions: Surgery for joint instability has a greater chance of success when it is carried out in patients with a known diagnosis of EDS before surgery. The majority of patients were satisfied with their surgery and, with the exception of the knee, there was a low rate of reoperations (≤ 50%). Arthroscopic procedures have an important role to play in these patients, particularly when surgery is performed on the knee., (© 2024. The Author(s).)

Purpose: To evaluate the immediate and 4-week effects of compression garments (CG) on balance using a force platform during 8 different visual, static, and dynamic conditions in hypermobile Ehlers-Danlos Syndrome (hEDS) patients., Methods: Thirty-six participants were randomly assigned to a group: physiotherapy alone (PT, n  = 19) or physiotherapy and daily CG wearing for 4 weeks (PT + CG, n  = 17). Both attended 12 physiotherapy sessions (strengthening, proprioception, and balance exercises) for 4 weeks. Primary outcome: sway velocity of the centre of pressure (COP) measured before, immediately with the CG, and at 4 weeks. Secondary outcomes: ellipse area, Romberg quotient, and pain., Results: Sway velocity in dynamic conditions decreased immediately with the CG. After 4 weeks of intervention, sway velocity (95% CI 4.36-39.23, effect size 0.93) and area (95% CI 146-3274, effect size 0.45) on the laterally oscillating platform with eyes-closed improved more in the PT + CG group than the PT group. Romberg quotient on foam cushion improved more in the PT + CG than the PT group. Pain decreased in both groups after 4 weeks with no between-group difference., Conclusion: CG combined with physiotherapy improved dynamic balance measured with COP variables significantly more than physiotherapy alone in people with hEDS., Trial Registration: NCT03359135.

Patients with Ehlers-Danlos Syndrome (EDS) frequently suffer from severe chronic pain. We carried out an observational cohort study to assess the effectiveness of compression garments (CGs) for reducing this pain. Patients with non-vascular EDS were given custom-made Cerecare ® CGs during a visit to a specialist clinic (visit V0). They were followed up over 2 years with visits every 6 months (V1-V4). At each visit, pain was assessed for the joints treated with CGs using a visual analogue scale (VAS; 0-100 mm). Additional measures were obtained to assess neuropathic pain (painDETECT questionnaire), proprioception/balance (Berg Balance Scale), and functional independence, amongst others. Data were analyzed for 67 patients with EDS (hypermobile: 91%; classical: 6%; kyphoscoliotic: 3%). For the most painful joint, the mean VAS rating was 71.5 ± 22.8 mm at V0; this decreased to 53.5 ± 25.5 mm at V1 and 45.7 ± 29 mm at V4 ( t -tests: p < 0.0001). From V0 to V4, improvements were also seen for pain at the other joints, neuropathic pain, functional independence, proprioception/balance, and the incidence of sprains and dislocations/subluxations, although not all comparisons were statistically significant ( p < 0.05 level). These results indicate that CGs may effectively reduce the pain and joint instability in non-vascular EDS patients.

Recent studies have shown that people who are immunocompromised may inadvertently play a role in spurring the mutations of the virus that create new variants. This is because some immunocompromised individuals remain at risk of getting COVID-19 despite vaccination, experience more severe disease, are susceptible to being chronically infected and remain contagious for longer if they become infected and considering that immunocompromised individuals represent approximately 2% of the overall population, this aspect should be carefully considered. So far, some autoimmune rheumatic disease (ARD) patients with COVID-19 have been treated with antiviral therapies or anti-SARS-CoV-2 antibody products. However, there is no homogeneous approach to these treatment strategies. This issue was addressed within the European Reference Network (ERN) on Rare and Complex Connective Tissue and Musculoskeletal Diseases (ReCONNET) in a discussion among experts and patient's representatives in the context of the rare and complex connective tissue diseases (rCTDs) covered by the Network. ERN ReCONNET is one of the 24 ERNs launched by the European Commission in 2017 with the aim of tackling low prevalence and rare diseases that require highly specialised treatment and promoting concentration of knowledge and resources through virtual networks involving healthcare providers (HCPs) across the European Union (EU). Considering the urgent need to provide guidance not only to the rCTDs community, but also to the whole ARDs community, a multidisciplinary Task Force, including expert clinicians and European Patient Advocacy Group (ePAG) Advocates, was created in the framework of ERN ReCONNET with the aim of developing overarching principles (OP) and points-to-consider (PtC) on a homogenous approach to treat immunocompromised patients with ARDs (with a particular focus on CTDs) affected by COVID-19 using antiviral therapies and anti-SARS-CoV-2 antibody products. The present work reports the final OP and PtC agreed by the Task Force.

Kyphoscoliotic Ehlers-Danlos syndrome (kEDS) is a rare genetic disorder combining congenital hypotonia, congenital/early onset and progressive kyphoscoliosis, and generalized joint hypermobility. Vascular fragility is another characteristic of the disease rarely described. We report a severe case of kEDS-PLOD1 with several vascular complications leading to difficulties in disease management., Competing Interests: No conflict of interest to disclose., (© 2023 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.)

We described a novel de novo missense variant of the gene encoding Collagen alpha-2(V) chain, associated with the classical Ehlers-Danlos syndrome (cEDS) (OMIM#130010), in a 14-year-old patient who presented with congenital and severe scoliosis, muscle hypotonia, ocular manifestations, and no atrophic scaring. This case expands the phenotypic spectrum of cEDS., Competing Interests: The authors declare that they have no conflict of interest., (© 2022 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.)

Background: FLNA Loss-of-Function (LoF) causes periventricular nodular heterotopia type 1 (PVNH1), an acknowledged cause of seizures of various types. Neurological symptoms are inconstant, and cardiovascular (CV) defects or connective tissue disorders (CTD) have regularly been associated. We aimed at refining the description of CV and CTD features in patients with FLNA LoF and depicting the multisystemic nature of this condition., Methods: We retrospectively evaluated FLNA variants and clinical presentations in FLNA LoF patient with at least one CV or CTD feature, from three cohorts: ten patients from the French Reference Center for Rare Vascular Diseases, 23 patients from the national reference diagnostic lab for filaminopathies-A, and 59 patients from literature review., Results: Half of patients did not present neurological symptoms. Most patients presented a syndromic association combining CV and CTD features. CV anomalies, mostly aortic aneurysm and/or dilation were present in 75% of patients. CTD features were present in 75%. Variants analysis demonstrated an enrichment of coding variants in the CH1 domain of FLNA protein., Conclusion: In FLNA LoF patients, the absence of seizures should not be overlooked. When considering a diagnosis of PVNH1, the assessment for CV and CTD anomalies is of major interest as they represent interlinked features. We recommend systematic study of FLNA within CTD genes panels, regardless of the presence of neurological symptoms., (© 2021. The Author(s).)

Periodontal Ehlers-Danlos syndrome (pEDS) is a rare condition caused by pathogenic variants in the C1R and C1S genes, encoding subunits C1r and C1s of the first component of the classical complement pathway. It is characterized by early-onset periodontitis with premature tooth loss, pretibial hyperpigmentation and skin fragility. Rare arterial complications have been reported, but venous insufficiency is rarely described. Here we report 13 novel patients carrying heterozygous pathogenic variants in C1R and C1S including three novel C1S variants (c.962G > C, c.961 T > G and c.961 T > A). In addition to the pEDS phenotype, three patients and one relative displayed widespread venous insufficiency leading to persistent varicose leg ulcers. One patient suffered an intracranial aneurysm with familial vascular complications including thoracic and abdominal aortic aneurysm and dissection and intracranial aneurysm rupture. This work confirms that vascular complications can occur, although they are not frequent, which leads us to propose to carry out a first complete non-invasive vascular evaluation at the time of the diagnosis in pEDS patients. However, larger case series are needed to improve our understanding of the link between complement pathway activation and connective tissue alterations observed in these patients, and to better assess the frequency, type and consequences of the vascular complications., (© 2021 John Wiley & Sons A/S . Published by John Wiley & Sons Ltd.)

COL1 -related overlap disorder is a condition, which is not yet considered as part of the 2017 EDS classification. However, it should be investigated as an alternative diagnosis for any patient with hypermobile EDS. This could allow providing appropriate genetic counseling., Competing Interests: The authors declare that they have no conflict of interests., (© 2021 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.)

Competing Interests: K. Benistan déclare des liens ponctuels avec Cerecare. V. Gisclard déclare n’avoir aucun lien d’intérêts.

Purpose: Pseudoxanthoma elasticum (PXE) is an autosomal recessive disorder caused by variants in the ABCC6 gene. Ectopic mineralization of connective tissues leads to skin, eye, and cardiovascular manifestations with considerable phenotypic variability of unknown cause. We aimed to identify genotype-phenotype correlations in PXE., Methods: A molecular analysis was performed on 458 French PXE probands clinically evaluated using the Phenodex score (PS). Variant topographic analysis and genotype-phenotype correlation analysis were performed according to the number and type of identified variants., Results: Complete molecular analysis of 306 cases allowed the identification of 538 mutational events (88% detection rate) with 142 distinct variants, of which 66 were novel. Missense variant distribution was specific to some regions and residues of ABCC6. For the 220 cases with a complete PS, there was a higher prevalence of eye features in Caucasian patients (P = 0.03) and more severe eye and vascular phenotype in patients with loss-of-function variants (P = 0.02 and 0.05, respectively). Nephrolithiases and strokes, absent from the PS, were prevalent features of the disorder (11 and 10%, respectively)., Conclusion: We propose an updated PS including renal and neurological features and adaptation of follow-up according to the genetic and ethnic status of PXE-affected patients.Genet Med advance online publication 19 January 2017.

Context: Hyperphosphatemic familial tumoral calcinosis (HFTC) and hyperphosphatemia hyperostosis syndrome (HHS) are rare diseases characterized by hyperphosphatemia and ectopic calcifications or recurrent episodes of diaphysitis. In the setting of metabolic or inflammatory diseases, recent data suggest that systemic administration of sodium thiosulfate (STS) could be effective in the treatment of ectopic calcifications but may also be poorly tolerated (digestive symptoms, metabolic acidosis). Our group developed a topical formulation of STS to treat ectopic calcifications locally, therefore limiting patient exposure to the drug and its adverse effects., Objective: We aimed at describing efficacy and tolerance for a topical formulation of STS in treated patients., Design: We performed a retrospective study wherein clinical, radiological, and biological data before and after the application of the topical STS treatment were collected and analyzed., Patients or Other Participants: Three patients admitted to 3 different hospitals with an ectopic calcification secondary to HFTC or HHS were treated with topical STS., Intervention: The topical STS was applied daily by the patients., Results: A significant clinical and radiological decrease of ectopic calcifications was observed after at least 5 months of treatment. The STS treatment was well tolerated and no clinical or biological side effects were observed., Conclusion: Topical STS appears to be a promising treatment for ectopic calcifications secondary to HFTC or HHS.

Purpose: The aim of this study was to evaluate the progression of left ventricular hypertrophy in untreated men with Fabry disease and to assess the effects of agalsidase-β (recombinant human α-galactosidase A) on left ventricular hypertrophy., Methods: Longitudinal Fabry Registry data were analyzed from 115 men treated with agalsidase-β (1 mg/kg/2 weeks) and 48 untreated men. Measurements included baseline left-ventricular mass and at least one additional left-ventricular mass assessment over ≥ 2 years. Patients were grouped into quartiles, based on left-ventricular mass slopes. Multivariate logistic regression analyses identified factors associated with left ventricular hypertrophy progression., Results: For men in whom treatment was initiated at the age of 18 to <30 years, mean left ventricular mass slope was -3.6 g/year (n = 31) compared with +9.5 g/year in untreated men of that age (n = 15) (P < 0.0001). Untreated men had a 3.4-fold higher risk of having faster increases in left-ventricular mass compared with treated men (odds ratio: 3.43; 95% confidence interval: 1.05-11.22; P = 0.0415). A baseline age of ≥ 40 years was also associated with left--ventricular hypertrophy progression (odds ratio: 5.03; 95% confidence interval: 1.03-24.49; P = 0.0457) compared with men younger than 30 years., Conclusion: Agalsidase-β treatment for ≥2 years may improve or stabilize left-ventricular mass in men with Fabry disease. Further investigations may determine whether early intervention and stabilization of LVM are correlated with clinical outcomes.

Aims: Fabry disease is a lysosomal storage disorder due to deficient alpha-galactosidase A activity, characterised by glycosphingolipids deposition in tissues. Patients have a common arterial involvement and contract progressive renal and cardiac disease. Although short-term effects of enzyme replacement therapy (ERT) on target organs have been established, no data are available on the long-term outcome., Methods and Results: We studied the effects of ERT (agalsidase beta, 1 mg/kg/14 days) on arterial and cardiac structure and function during a longitudinal study beginning in 1999, with 4.5 ± 0.4 years follow-up (four visits) in 30 patients (age: 33 ± 12 years). In addition, we studied 16 untreated Fabry patients during 2.6 ± 1.6 years (two visits). Aortic stiffness was determined by carotid-femoral pulse wave velocity, central pulse pressure by aplanation tonometry, and carotid and radial intima-media thickness and diameter by high definition echotracking device. Left ventricular mass was determined by MRI. A significant decrease in aortic stiffness (-0.56 ± 0.13 m/s/yr, p = 0.0002) was observed after ERT whereas central pulse pressure did not change. Carotid intima-media thickness (IMT) increased (+18 ± 6 µm/yr; p < 0.005) whereas radial IMT remained stable. Radial artery diameter decreased (-50 ± 20 µm/years, p < 0.05) whereas carotid diameter did not change. Carotid circumferential wall stress was reduced (-1.7 ± 0.6 kPa/yrs, p < 0.01). Left ventricular mass index significantly decreased (-7.8 ± 2.3 g/m(2)/yr, p < 0.005)., Conclusion: A sustained reduction in aortic stiffness and left ventricular hypertrophy, and a limited radial artery wall thickening were observed after long-term enzyme replacement therapy. There was no significant benefit of treatment on carotid hypertrophy.

No reproductive studies have been performed with enzyme replacement therapy (ERT) for Fabry disease (FD, OMIM 301500), a lysosomal storage disorder. Therefore, use during pregnancy is theoretically contraindicated. We report the first case of agalsidase beta treatment throughout pregnancy. High-range proteinuria remained stable and the patient gave birth to a healthy boy after an uncomplicated pregnancy. The decision to administer ERT during pregnancy should be made on an individual basis, considering the FD status and possible risks., (Copyright 2009 Elsevier Masson SAS. All rights reserved.)

Gaucher disease (GD, OMIM #230800, 230900, 231000) is a lysosomal surcharge disorder caused by a deficiency in glucocerebrosidase, a lysosomal enzyme also referred to as acid beta-glucosidase or, in rare cases, by a deficiency in the activator protein saposin C. Partial deficiency of acid beta-glucosidase is associated with the presence of glucosylceramide, also known as glucocerebroside (Gb1), deposits in the reticuloendothelial cells of the liver, spleen and bone marrow, in non-neuronopathic type 1, GD. Profound deficiency of acid beta-glucosidase caused by disabling mutations is additionally associated with neurological manifestations in the less common type 2 and type 3 Gaucher diseases. Type 2 GD culminates in early death as a result of devastating neurological disease. Congenital ichtyosis with a collodion baby phenotype is also part of the spectrum of clinical presentations of type 2 GD. Recombinant glucocerebrosidase (imiglucerase) is an effective mean of treating type 1 GD and should be initiated early on in life. Although imiglucerase has recently been approved for the treatment of type 3 GD, enzyme replacement therapy cannot reverse the neurological manifestations in type 2 or type 3 GD. Following genetic counseling and informed consent, direct enzymatic assay of acid beta-glucosidase and molecular testing of the GBA mutations on chorionic villi samples (CVS) can be offered to families in which type 2 or type 3 GD has been diagnosed. Improvement in substrate deprivation therapy or gene therapy may provide a cure for patients with these disorders in the future.

Progressive decline in kidney function is a cardinal manifestation of Fbry disease. Proteinuria is usually the earliest biological marker of renal involvement. Renoprotection should associate both effective Enzyme Replocement Therapy (ERT) and non-specific anti-proteinuric therapy as recommended for all chronic kidney diseases. ERT has demonstrated high efficiency in the early clearing of globotriaosylceromide deposits, however the functional protecting effect on GFR decrease remains to be validated, especially in patients with CKD stage 3 or higher Estimation of GFR should be very cautious using creatinine based formulas, leading to measure GFR whenever possible in order to characterize the progression of CKD in Fabry patients.

Preclinical and phase I/II studies gave the proof of principle of enzyme replacement therapy (ERT) with recombinant alpha-galactosidase A through the demonstration of the clearance of the accumulated subtrate from plasma and tissues. In a multicenter, randomized, placebo-controlled, double-blind phase Ill study, the biological efficacy of recombinant alpha-galactosidose A (agalsidase beta 1 mg/kg/714 days) was demonstrated on the basis of complete clearance of accumulated globotriaosylceramide from the endothelia of the kidney, heart and skin. The phase III extension study data gives additional results: kidney function appears to be stabilized after 54 to 60 months of treatment with agolsidase beta in most patients. Intent-to-treat analysis of a double-blind, randomized, placebo-controlled, phase IV study, showed that, adjusted for on imbalance in baseline proteinuria, agalsidase beta significantly reduces by 53% the risk of a first clinical event (renal, cardiac and cerebrovascular), compared with placebo. Clinical benefits of ERT depend on patients' clinical status at baseline, therefore prompting for onset of ERT before irreversible damage occur and underlying the need to stratify patients' populations to better understand the outcome of ERT.

Fabry disease (FD) is an X-linked inborn error of metabolism resulting from the deficient activity of alpha-galactosidase A which leads to the widespread deposition of glycosphingolipids in lysosomes, and to ischemic complications involving kidneys, heart and brain. Among neurological symptoms, strokes and transient ischemic attacks (TIA) have been reported. A 30-year-old male patient, with FD, was referred to us for evaluation of a sudden episode of dizziness, with disequilibrium, and diplopia, in agreement with the diagnosis of a TIA. Head magnetic resonance imaging (MRI) showed no cerebrovascular involvement but revealed the presence of Chiari type I malformation (CMI). We subsequently performed head MRI in a cohort of 44 consecutive hemizygous male patients and seven heterozygous females affected with FD, and identified three additional cases (two males and one female) of CMI. Whether the association is coincidental or not will need further studies but our data suggest that CMI should be ruled out in all Fabry patients.