Unexpected association between joint hypermobility syndrome/Ehlers–Danlos syndrome hypermobility type and obsessive–compulsive personality disorder

Joint hypermobility syndrome/Ehlers–Danlos syndrome hypermobility type (JHS/EDS-HT) is a largely unrecognized, heritable connective tissue disorder, mainly characterized by joint instability complications, widespread musculoskeletal pain, and minor skin features. In a case–control study, 47 consecutive JHS/EDS-HT patients were investigated for the prevalence of psychiatric disorders and compared to 45 healthy controls in a single center. The psychiatric evaluation consisted of structured clinical interview for DSM-IV criteria by using the SCID-I and the SCID-II. Symptom severity was assessed using the Hamilton Anxiety Rating Scale (HAM-A), the Hamilton Depression Rating Scale (HAM-D), and the Brief Psychiatric Rating Scale (BPRS). The Global Assessment of Functioning Scale (GAF) was used to assess the overall severity of psychological, social, and occupational functions. JHS/EDS-HT patients had significantly higher mean scores for all questionnaires: HAM-A (6.7 vs. 3.8), HAM-D (6.4 vs. 2.7), GAF (75.0 vs. 86.1), and BPRS (27.5 vs. 25.6). The JHS/EDS-HT group had a 4.3 higher risk of being affected by any psychiatric disorder, and in particular, a 5.8 higher risk of having a personality disorder. In particular, 5 JHS/EDS-HT suffered from obsessive–compulsive personality disorder with an observed prevalence rate of 10.6 % (3.6–23.1). Psychiatric assessment of JHS/EDS-HT patients showed an extremely high prevalence of personality disorders (21 %), and of Axis-I disorders (38 %), mostly depressive. This study did not confirm the previously reported increased rate of panic disorders in JHS/EDS-HT.     

Joint position sense and vibratory perception sense in patients with Ehlers–Danlos syndrome type III (hypermobility type)

Neurophysiological deficits could make patients with Ehlers–Danlos syndrome (EDS) type III (hypermobility type) more vulnerable to musculoskeletal problems, particularly to joint instability. The purpose of this study was to investigate whether joint position sense (JPS) and vibratory perception sense (VPS) in EDS type III patients in the knee and shoulder joints are impaired. Thirty-two female EDS type III patients as defined by the Villefranche criteria and 32 individually gender- and age-matched healthy control subjects were included in the study. Range of motion was determined using a goniometer, passive and active JPS were assessed with an isokinetic dynamometer system, and the VPS was measured by a biothesiometer. Daily physical activity was evaluated by the Baecke questionnaire. The EDS type III group showed significantly larger ranges of movement (P < 0.05) and lower levels of sport physical activity (SPA) compared to the control group (P = 0.023). Considering SPA as covariate, the EDS type III group demonstrated a significant impairment in knee joint reposition compared to the control group (P = 0.018). No significant differences were found for shoulder JPS. The VPS was not significantly different in the EDS type III group compared to the control group. In addition, no significant correlation was found between JPS and VPS, neither at the knee nor at the shoulder joint. This is the first study examining proprioception deficits in EDS type III patients as defined by the Villefranche criteria. Further research on the neurophysiological dysfunctions and mechanisms in this pathologic entity is needed.     

Bowel perforation in type IV vascular Ehlers–Danlos syndrome. A systematic review

Spontaneous gastrointestinal (GI) perforation is a well-known complication occurring in patients suffering from Type IV vascular Ehlers–Danlos syndrome (EDS IV). The aim of the present study was to review the current literature on spontaneous GI perforation in EDS IV and illustrate the surgical management and outcome when possible. A systematic review of all the published data on EDS IV patients with spontaneous GI perforation between January 2000 and December 2015 was conducted using three major databases PUBMED, EMBASE, and Cochrane Central Register of Controlled Trails. References of the selected articles were screened to avoid missing main articles. Twenty-seven published case reports and four retrospective studies, including 31 and 527 cases, respectively, matched the search criteria. A case from our institution was added. Mean age was 26 years (range 6–64 years). The most frequent site of perforation was the colon, particularly the sigmoid, followed by small bowel, upper rectum, and finally stomach. The majority of cases were initially managed with Hartmann’s procedure. In recurrent perforations, total colectomy was performed. The reperforation rate was considerably higher in the “partial colectomy with anastomosis” group than in the Hartmann group. Colonic perforation is the most common spontaneous GI perforation in EDS IV patients. An unexpected fragility of the tissues should raise the possibility of a connective tissue disorder and prompt further investigation with eventual management of these high-risk patients with a multidisciplinary team approach in dedicated centres. In the emergency setting, a Hartmann procedure should be performed.     

Promotion of vesicular zinc efflux by ZIP13 and its implications for spondylocheiro dysplastic Ehlers–Danlos syndrome

Zinc is essential but potentially toxic, so intracellular zinc levels are tightly controlled. A key strategy used by many organisms to buffer cytosolic zinc is to store it within vesicles and organelles. It is yet unknown whether vesicular or organellar sites perform this function in mammals. Human ZIP13, a member of the Zrt/Irt-like protein (ZIP) metal transporter family, might provide an answer to this question. Mutations in the ZIP13 gene, SLC39A13, previously were found to cause the spondylocheiro dysplastic form of Ehlers–Danlos syndrome (SCD-EDS), a heritable connective tissue disorder. Those previous studies suggested that ZIP13 transports excess zinc out of the early secretory pathway and that zinc overload in the endoplasmic reticulum (ER) occurs in SCD-EDS patients. In contrast, this study indicates that ZIP13’s role is to release labile zinc from vesicular stores for use in the ER and other compartments. We propose that SCD-EDS is the result of vesicular zinc trapping and ER zinc deficiency rather than overload.Zinc is an essential trace element. It serves as a catalytic or structural cofactor and mediates numerous metabolic processes. However, excess zinc is toxic. Therefore, intracellular zinc concentrations must be tightly maintained within a narrow optimal range. Cytosolic labile zinc in mammalian cells has been estimated to be at or below nanomolar concentrations (1, 2). Two metal transporter families, the SLC30A/cation diffusion facilitator (CDF)/zinc transporter (ZnT) family and the SLC39A/Zrt/Irt-like protein (ZIP) family, are primarily responsible for regulating zinc homeostasis in eukaryotes. ZnT proteins export zinc from the cytosol to outside the cell or into intracellular organelles, whereas ZIP transporters import zinc into the cytosol from the extracellular milieu or organellar lumen (3). The human genome encodes 10 ZnTs and 14 ZIPs, and the functions of many of them are still unclear.Zinc is required in the cytosol and organelles, including those of the secretory pathway. Many zinc-dependent proteins reside in the secretory pathway, and others obtain this cofactor as they pass through the secretory system en route to their final destination. Resident zinc-requiring enzymes include the endoplasmic reticulum (ER)-localized chaperones calnexin and calreticulin (4) and GPI-phosphoethanolamine transferases (5, 6). Secreted zinc proteins include matrix metalloproteases (7), alkaline phosphatases (ALPs) (8), and angiotensin-converting enzymes (9). We previously showed that zinc is required for ER function. Both yeast and human cells experience ER stress when zinc deficient (10).Among the ZnT proteins, ZnT5, ZnT6, and ZnT7 reside in the secretory pathway and transport zinc into the Golgi, whereas ZnT8 loads zinc into pancreatic secretory granules for insulin packaging (11, 12). Among ZIP family members, ZIP7 was found in the ER (13), and ZIP9 localizes to the Golgi (14), but their roles are not well understood.ZIP13 is a member of the SLC39A/ZIP family (15). Recessive mutations in the ZIP13 gene, SLC39A13, were found to cause the spondylocheiro dysplastic form of Ehlers–Danlos syndrome (SCD-EDS) (16, 17). EDS is a group of heritable connective tissue disorders characterized by joint hypermobility, skin elasticity, and tissue fragility. Six different types of EDS have been identified, which generally are caused by mutations in collagen genes or genes involved in collagen modification or assembly (18).SCD-EDS clinically resembles EDS type VI caused by mutations in the procollagen-lysine, 2-oxoglutarate 5-dioxygenase (PLOD1) gene encoding lysyl hydroxylase (LH1) (19). LH1 is an ER-resident enzyme responsible for procollagen hydroxylation on lysine residues (18). Lysine hydroxylation is required for cross-linking collagen fibrils for structural integrity. In addition to the overlapping clinical symptoms of SCD-EDS and EDS type VI, SCD-EDS patients show skeletal dysplasia and abnormalities of the hands. Interestingly, SCD-EDS–causing mutations were mapped to SLC39A13 by two independent groups, and two of the authors of this study (C.G. and B.S.) previously had identified a deletion mutation in two family pedigrees (16). Subsequently, Fukada et al. (17) reported an amino acid substitution in ZIP13 from a third family and generated a Slc39a13^−/− knockout mouse that recapitulated the defects observed in the patients, thereby demonstrating that mutations in SLC39A13 cause SCD-EDS. SCD-EDS patients show normal collagen synthesis but decreased levels of collagen lysine and proline hydroxylation (16). Synthesis and posttranslational modifications of the nascent α-chains of collagen occur in the ER. The activities of lysyl and prolyl hydroxylases were not defective when assayed in SCD-EDS cell lysates (16). Because high zinc inhibits these hydroxylases in vitro, we proposed that impaired hydroxylation of lysyl and prolyl residues might be caused by ER zinc overload in SCD-EDS patients. Therefore, it was hypothesized that ZIP13 localized to the early secretory pathway and transported zinc out of the ER (16). This idea was supported by the observation that mouse ZIP13 protein was in the Golgi (17). It is likely that the zinc status of the Golgi and ER are closely linked by vesicular trafficking between those compartments.Here we report our investigations of this hypothesis. We provide evidence that ZIP13 is indeed a zinc transporter. However, we show that, rather than localizing to the Golgi or ER, the endogenous human ZIP13 protein localizes to vesicles. Based on our results, we propose that ZIP13 is critical for zinc homeostasis by releasing labile zinc from vesicular stores for use in the ER and other compartments. Without functional ZIP13, as occurs in SCD-EDS, labile zinc becomes trapped in vesicles where it is unavailable for use elsewhere in the cell. Thus, we propose that the effects of SLC39A13 mutations on collagen modification are the result of zinc deficiency rather than zinc excess in the early secretory pathway.     

Coexistent tumor necrosis factor receptor–associated periodic fever syndrome and Ehlers–Danlos syndrome

A 32-year-old Caucasian woman had periodic fevers, skin disease, polyarthralgia and hypermobile joints that were consistent with tumor necrosis factor receptor–associated periodic fever syndrome confirmed with a finding of R92Q missense mutation of the TNFRSFA1 gene with Ehlers–Danlos hypermobility type syndrome. They are both autosomal dominant disorders, and their coexistence suggests that they could share some phenotypic features that may require special consideration in management. Conceivably, they could share common gene mutations although no such data are available.     

Ehlers–Danlos syndrome: case report and an electron microscopy study

Ehlers–Danlos syndrome (EDS) type III is a inherited connective tissue disorders characterized by extensibility of the skin, hypermobility of the joints, chronic pain, tissue fragility, easy bruising, and delayed wound healing with result of atrophic scars. The patients report commonly a history of recurrent dislocations of the shoulders and knees after low-impact trauma, chronic joint pain, and early osteoarthritis, which lead to diagnosis. The pathogenesis of this condition is unknown, and the diagnosis is generally made in adult age, based only on clinical criteria. In this report, we describe a case of a 50-year-old woman with a 30-year history of recurrent dislocations and atrophic scars. We performed diagnosis of EDS type III after a complete clinical and instrumental evaluation, comprising of histological and electron microscopic studies, that highlighted collagen abnormalities.     

An unexpected complication. First descriptions of intercostal artery rupture in Ehlers–Danlos syndrome

A case of Ehlers–Danlos syndrome of vascular type with a history of mechanical valve prosthesis was admitted with dyspnea and chest pain. After exclusion of a myocardial infarction, an angio-CT was performed and it revealed a spontaneous rupture of an intercostal artery with subsequent hemothorax and compression atelectasis. The case was complicated by the ongoing anticoagulant therapy for the mechanical valve prosthesis with warfarin. After failure of conservative therapy, the case underwent surgical treatment. As shown in this case, mechanical valve prosthesis with necessary adequate anticoagulation, using long lasting warfarin derivates, could be an unneeded added risk for these patients.     

Response to “Quantitative measures of tissue mechanics to detect hypermobile Ehlers Danlos syndrome and hypermobility syndrome disorders: a systematic review”

Clinical Rheumatology -     

Psychiatric disorders in Ehlers–Danlos syndrome are frequent,diverse and strongly associated with pain

Ehlers–Danlos syndromes (EDS) are a heterogeneous group of hereditary connective tissue disorders characterized by joint hypermobility, widespread musculoskeletal pain and tissue fragility. Psychiatric disorders and psychosocial impairment are common, yet poorly characterized, findings in EDS patients. We investigated the frequency and types of psychiatric disorders and their relationship to systemic manifestations in a cohort of 106 classic and hypermobility type EDS patients. In this retrospective study, extensive medical chart review was performed for patients referred at two genetics clinics who were diagnosed with EDS. Statistical analysis was undertaken to determine the frequency of psychiatric disorders and association with systemic findings. Psychiatric disorders were found in 42.5 % of the EDS cohort, with 22.7 % of patients affected with 2 or more psychiatric diagnoses. Anxiety and depression were most commonly reported, with frequencies of 23.6 and 25.5 %, respectively. A variety of other psychiatric diagnoses were also identified. Abdominal pain [odds ratio (OR) 7.38], neuropathic pain (OR 4.07), migraines (OR 5.21), joint pain (OR 2.85) and fatigue (OR 5.55) were significantly associated with the presence of a psychiatric disorder. The presence of any pain symptom was significantly associated with having a psychiatric disorder (OR 9.68). Muscle pain (OR 2.79), abdominal pain (OR 5.78), neuropathic pain (OR 3.91), migraines (OR 2.63) and fatigue (OR 3.78) were significantly associated with having an anxiety or mood disorder. Joint hypermobility and the classic dermatological features of EDS showed no significant association with having a psychiatric disorder. Our findings demonstrate a high frequency of psychiatric disorders and an association with pain symptoms in EDS.     

Vascular Manifestations of Type IV Ehlers–Danlos Syndrome

Ehlers–Danlos syndrome (EDS) is a hereditary disorder of the connective tissue. Ten different types of EDS have been described, most of which are associated with skin hyperflexibility and joint hypermobility. The type most frequently encountered by surgeons is the arterial ecchymotic type, or type IV. The phenotypical variance that characterizes EDS can make recognition difficult. The diagnosis is often made after vascular or gastrointestinal complications have occurred. We are describing a young pregnant patient with EDS type IV who developed a carotico-cavernous fistula, a crural artery pseudoaneurysm and died due to spontaneous intestinal rupture.     

11β-Hydroxysteroid dehydrogenase type 1: relevance of its modulation in the pathophysiology of obesity, the metabolic syndrome and type 2 diabetes mellitus

Recent evidence strongly argues for a pathogenic role of glucocorticoids and 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in obesity and the metabolic syndrome, a cluster of risk factors for atherosclerotic cardiovascular disease and type 2 diabetes mellitus (T2DM) that includes insulin resistance (IR), dyslipidaemia, hypertension and visceral obesity. This has been partially prompted not only by the striking clinical resemblances between the metabolic syndrome and Cushing's syndrome (a state characterized by hypercortisolism that associates with metabolic syndrome components) but also from monogenic rodent models for the metabolic syndrome (e.g. the leptin-deficient ob/ob mouse or the leptin-resistant Zucker rat) that display overall increased secretion of glucocorticoids. However, systemic circulating glucocorticoids are not elevated in obese patients and/or patients with metabolic syndrome. The study of the role of 11β-HSD system shed light on this conundrum, showing that local glucocorticoids are finely regulated in a tissue-specific manner at the pre-receptor level. The system comprises two microsomal enzymes that either activate cortisone to cortisol (11β-HSD1) or inactivate cortisol to cortisone (11β-HSD2). Transgenic rodent models, knockout (KO) for HSD11B1 or with HSD11B1 or HSD11B2 overexpression, specifically targeted to the liver or adipose tissue, have been developed and helped unravel the currently undisputable role of the enzymes in metabolic syndrome pathophysiology, in each of its isolated components and in their prevention. In the transgenic HSD11B1 overexpressing models, different features of the metabolic syndrome and obesity are replicated. HSD11B1 gene deficiency or HSD11B2 gene overexpression associates with improvements in the metabolic profile. In face of these demonstrations, research efforts are now being turned both into the inhibition of 11β-HSD1 as a possible pharmacological target and into the role of dietary habits on the establishment or the prevention of the metabolic syndrome, obesity and T2DM through 11β-HSD1 modulation. We intend to review and discuss 11β-HSD1 and obesity, the metabolic syndrome and T2DM and to highlight the potential of its inhibition for therapeutic or prophylactic approaches in those metabolic diseases.     

Assessment of bleeding disorders in Sheehan's syndrome: are bleeding disorders the underlying cause of Sheehan's syndrome?

Sheehan's syndrome (SS) is an adenopituitary insufficiency caused by hypovolemia secondary to excessive blood loss during or after childbirth. However, the mechanism of postpartum hemorrhage and ischemia is not clear. We aimed to evaluate the bleeding disorders among patients with SS, in comparison with healthy controls. In addition, we investigated underlying causes in postpartum hemorrhage that begin the event. The present study was conducted at the Dicle University School of Medicine. Forty-eight patients with SS and 50 age-matched female healthy controls were included. Biochemical and hormonal variables were measured, as was platelet function by means of closure times (PFA-100 testing using collagen plus epinephrine and collagen plus ADP), von Willebrand factor (vWF) level, prothrombin time (PT), activated partial thromboplastin time (aPTT), international normalized ratio (INR), and coagulation factors. Although PT and INR were significantly higher in patients with SS (both P<0.01), aPTT and levels of fibrinogen, vWF, and factors II, V, VII, VIII, IX, X, XI, and XII did not differ significantly. Closure times with collagen/epinephrine and collagen/ADP also did not differ significantly between patients with SS and control patients. The nonspecific etiology and presence of excessive postpartum hemorrhage in patients with SS suggest that coagulation disorders may play a role in their predisposition to bleeding. The increased PT and INR noted might implicate bleeding diathesis as the underlying etiology, although no significant decreases were noted in factor levels. Further studies are needed to elucidate this complex mechanism of this disorder.