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Abstract

Visceroptosis is described in several heritable connective tissue disorders, including the hypermobility type of Ehlers-Danlos syndrome (hEDS), a.k.a. joint hypermobility syndrome (JHS). Clinical features of hEDS comprise joint hypermobility, mild skin hyperextensibility, joint instability complications, chronic joint/limb pain, and positive family history. Uterine and rectal prolapse has been reported in nulliparous women. We report on a family with two patients with hEDS. The proposita, a 38-year-old woman, present bilateral kidney prolapse requiring three nephropexies, gastric ptosis treated with gastropexy and Billroth I gastrectomy, and liver prolapse treated with a non-codified hepatopexy procedure. Radiological evaluation also showed ovarian and heart prolapse. To our knowledge this is the first case of multiple visceral ptoses in hEDS. Visceral prolapse may lead to severe morbidity, affecting quality of life and a high rate of relapses after surgical procedures. Further investigations are needed to understand the molecular basis of the disease and retrospective studies on surgical outcomes, presentation of case series can be effective in order to offer a better treatment and prevention for hEDS patients. © 2013 Wiley Periodicals, Inc.

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... In recent years, an increasing number of studies have suggested that functional digestive symptoms, namely irritable bowel syndrome, gastroesophageal reflux disease, and constipation are common complications in patients with EDS-HT (9)(10)(11)(12). Although information concerning the etiology of the abdominal symptoms in EDS-HT is still lacking, several reports have suggested that visceral ptosis is a possible cause (13,14). ...
... Her symptom scores increased markedly after changing to an upright position. it is difficult to currently elucidate whether mobile cecum occurs alone or in connection with EDS-HT, gastrointestinal tract ptosis has been reported as a possible cause of abdominal symptoms in patients with EDS-HT (13,14). We should also pay more attention to mobile cecum as one of the phenotypes of ptosis. ...
... Reinstein et al. described a case of small bowel ptosis and elongated transverse colon ptosis (13). Chiara et al. also reported a case of multiple synchronous visceral ptosis that affected the kidneys, stomach, liver, ovaries and heart, and hy-pothesized that a loose visceral ligament might contribute to the pathophysiology of ptosis (14). In our case, it is clear that the patient's mobile cecum was attributable to the absence of the mesenteric ligament along with right-sided colon. ...
Article
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Ehlers-Danlos syndrome, hypermobility type (EDS-HT) is unexpectedly common and is associated with a high rate of gastrointestinal manifestations. We herein report the first documented case of mobile cecum associated with EDS-HT. A 21-year-old woman with repeated right lower abdominal pain was initially diagnosed with EDS-HT. Abdominal examinations performed in the supine position, such as CT and ultrasonography, showed no gross abnormalities. In contrast, oral barium gastrointestinal transit X-ray images obtained with changes in the patient's body position revealed position-dependent cecal volvulus with mobile cecum. She was finally discharged with a dramatic resolution of her symptoms after laparoscopic cecopexy for mobile cecum.
... Fifteen case reports describe surgical techniques (and their outcomes) for various GI problems in JHS/EDS-HT (Table IV). A definite diagnosis of JHS according to Brighton criteria or EDS-HT according to Villefranche criteria was declared in seven instances [de Weerd et al., 2012;Reinstein et al., 2012;Dordoni et al., 2013;Fogel, 2013;Sardeli et al., 2013;Plackett et al., 2014]. In six patients, the diagnosis of EDS remained unclassified in the original report, but JHS/EDS-HT was considered, retrospectively, the most likely based on the description of extra-GI features [Douglas and Douglas, 1973;Shaikh and Turner, 1988;Leung, 1989;Defuentes et al., 2004;Levine and Adler, 2005;Chen and Jao, 2007]. ...
... In JHS/EDS-HT, surgery appeared repeatedly successful for treating diaphragmatic defects leading to a variety of clinical presentations [Phadke, 1978;Shaikh and Turner, 1988;Leung, 1989;Levine and Adler, 2005]. In turn, surgery was uneffective multiple times for the correction of visceroptosis and pelvic organ prolapse [de Weerd et al., 2012;Dordoni et al., 2013;Pelizzo et al., 2013]. Laparoscopic subtotal colectomy for bowel ptosis had positive results in one instance [Reinstein et al., 2012], as well as the repair of a recto-vaginal fascia with porcine small intestinal submucosa mesh in a woman with pelvic organ discomfort for multiple prolapses [Sardeli et al., 2013]. ...
Article
Gastrointestinal involvement is a well known complication of Ehlers–Danlos syndromes (EDSs), mainly in form of abdominal emergencies due to intestinal/abdominal vessels rupture in vascular EDS. In the last decade, a growing number of works investigated the relationship between a wide spectrum of chronic gastrointestinal complaints and various EDS forms, among which the hypermobility type (a.k.a. joint hypermobility syndrome; JHS/EDS-HT) was the most studied. The emerging findings depict a major role for gastrointestinal involvement in the health status and, consequently, management of JHS/EDS-HT patients. Nevertheless, fragmentation of knowledge limits its impact on practice within the boundaries of highly specialized clinics. In this paper, literature review on gastrointestinal manifestations in JHS/EDS-HT was carried out and identified papers categorized as (i) case-control/cohort studies associating (apparently non-syndromic) joint hypermobility and gastrointestinal involvement, (ii) case-control/cohort studies associating JHS/EDS-HT and gastrointestinal involvement, (iii) case reports/series on various gastrointestinal complications in (presumed) JHS/EDS-HT, and (iv) studies reporting gastrointestinal features in heterogeneous EDS patients' cohorts. Gastrointestinal manifestations of JHS/EDS-HT were organized and discussed in two categories, including structural anomalies (i.e., abdominal/diaphragmatic hernias, internal organ/pelvic prolapses, intestinal intussusceptions) and functional features (i.e., dysphagia, gastro-esophageal reflux, dyspepsia, recurrent abdominal pain, constipation/diarrhea), with emphasis on practice and future implications. In the second part of this paper, a summary of possible nutritional interventions in JHS/EDS-HT was presented. Supplementation strategies were borrowed from data available for general population with minor modifications in the light of recent discoveries in the pathogenesis of selected JHS/EDS-HT features.
... The processes leading to visceral pain in JHS/EDS-HT are not well understood and the relationship between this form of pain and JHS/ EDS-HT still needs appropriate investigations. Fragmented knowledge indicates that visceral and pelvic prolapses are a common, though likely underreported finding in JHS/EDS-HT [Reinstein et al., 2012;Castori et al., 2012a;Dordoni et al., 2013]. Dolichocolon may be an additional common finding in JHS/EDS-HT , but more systematic studies regarding abdominal anatomy are warranted. ...
Article
Joint hypermobility syndrome (JHS) and Ehlers-Danlos syndrome, hypermobility type (EDS-HT) are two clinically overlapping connective tissue disorders characterized by chronic/recurrent pain, joint instability complications, and minor skin changes. Fatigue and headache are also common, although are not yet considered diagnostic criteria. JHS/EDS-HT is a unexpectedly common condition that remains underdiagnosed by most clinicians and pain specialists. This results in interventions limited to symptomatic and non-satisfactory treatments, lacking reasonable pathophysiologic rationale. In this manuscript the fragmented knowledge on pain, fatigue, and headache in JHS/EDS is presented with review of the available published information and a description of the clinical course by symptoms, on the basis of authors' experience. Pathogenic mechanisms are suggested through comparisons with other functional somatic syndromes (e.g., chronic fatigue syndrome, fibromyalgia, and functional gastrointestinal disorders). The re-writing of the natural history of JHS/EDS-HT is aimed to raise awareness among clinical geneticists and specialists treating chronic pain conditions about pain and other complications of JHS/EDS-HT. Symptoms' clustering by disease stage is proposed to investigate both the molecular causes and the symptoms management of JHS/EDS-HT in future studies. © 2013 Wiley Periodicals, Inc.
... Patients diagnosed with Ehlers-Danlos syndrome, are characterized by an altered structural integrity of connective tissue [1,2] resulting in frailty [3] and multi-systemic manifestations like orthostatic intolerance, [4] hyper-elastic skin, [5] organ dysfunction [6] and joint instability. [7] The phenotype of EDS-HT is heterogeneous, in which the severity of complaints varies from mild to severe. ...
Article
Purpose: The patients diagnosed with Ehlers-Danlos Syndrome Hypermobility Type (EDS-HT) are characterized by pain, proprioceptive inacuity, muscle weakness, potentially leading to activity limitations. In EDS-HT, a direct relationship between muscle strength, proprioception and activity limitations has never been studied. The objective of the study was to establish the association between muscle strength and activity limitations and the impact of proprioception on this association in EDS-HT patients. Methods: Twenty-four EDS-HT patients were compared with 24 controls. Activity limitations were quantified by Health Assessment Questionnaire (HAQ), Six-Minute Walk test (6MWT) and 30-s chair-rise test (30CRT). Muscle strength was quantified by handheld dynamometry. Proprioception was quantified by movement detection paradigm. In analyses, the association between muscle strength and activity limitations was controlled for proprioception and confounders. Results: Muscle strength was associated with 30CRT (r = 0.67, p = <0.001), 6MWT (r = 0.58, p = <0.001) and HAQ (r = 0.63, p= <0.001). Proprioception was associated with 30CRT (r = 0.55, p < 0.001), 6MWT (r = 0.40, p = <0.05) and HAQ (r = 0.46, p < 0.05). Muscle strength was found to be associated with activity limitations, however, proprioceptive inacuity confounded this association. Conclusions: Muscle strength is associated with activity limitations in EDS-HT patients. Joint proprioception is of influence on this association and should be considered in the development of new treatment strategies for patients with EDS-HT. Implications for rehabilitation Reducing activity limitations by enhancing muscle strength is frequently applied in the treatment of EDS-HT patients. Although evidence regarding treatment efficacy is scarce, the current paper confirms the rationality that muscle strength is an important factor in the occurrence of activity limitations in EDS-HT patients. Although muscle strength is the most dominant factor that is associated with activity limitations, this association is confounded by proprioception. In contrast to common belief proprioception was not directly associated with activity limitations but confounded this association. Controlling muscle strength on the bases of proprioceptive input may be more important for reducing activity limitations than just enhancing sheer muscle strength.
... Recurrent abdominal pain is highly reported in patients with disorders with JH, particularly in JHS/hEDS [18, 19, 43, 44•]. Mechanisms underlying this highly penetrant trait remain elusive although some hypothesis is put forward [45], such as intra-abdominal ligamentous laxity and abdominal visceral prolapses [46,47]. Dysmenorrhea is another leading form of visceral pain in fertile women, and its causes remain undetermined [48,49]. ...
Article
Full-text available
Purpose of review: To summarize current evidence on the links between joint hypermobility (JH) and Ehlers-Danlos syndromes (EDS), with pain and reduced bone mass; to illustrate an updated approach to JH and EDS. Recent findings: In 2017, a novel classification for EDS and JH has been published. Increasing data demonstrate that pain is a major disability determinator in JH and EDS. Recent findings confirm a complex pathogenesis for pain in JH and EDS and suggest a potential role for joint instability, central sensitization and small fiber neuropathy. Some papers present bone mass reduction as an associated feature of JH and EDS. The association is preliminary and reflects heterogeneous mechanisms. Assessment of patients with JH/EDS is now well-structured and based on an integrated approach of clinical evaluations and molecular testing. Pain and reduced bone mass are possibly common satellite manifestations of JH/EDS and need expert consult for appropriate interpretation and management.
... visceral rupture ( i . e . , bowel , lungs , liver , spleen , uterus during pregnancy , heart ) may also occur for internal organs fragility [ Drera et al . , 2011 ; Murray et al . , 2014 ] ; in JHS / EDS - HT internal organs rupture is not reported , whereas visceroptosis due to ligaments hypoplasia and deterioration may be present ( Table II ) [ Dordoni et al . , 2013 ] . The fragility of the capillaries and of the perivascular connective tissues can lead to easy bruising with ecchymosis for minimal traumas both in vEDS and JHS / EDS - HT patients , though these features are more prominent in vEDS [ De Paepe and Malfait , 2004 ] . In fact , in childhood vEDS patients are usually referred to pediatric ...
Article
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Joint hypermobility syndrome/Ehlers-Danlos syndrome hypermobility type (JHS/EDS-HT) is an evolving and protean disorder mostly recognized by generalized joint hypermobility and without a defined molecular basis. JHS/EDS-HT also presents with other connective tissue features affecting a variety of structures and organs, such as skin, eye, bone, and internal organs. However, most of these signs are present in variable combinations and severity in many other heritable connective tissue disorders. Accordingly, JHS/EDS-HT is an "exclusion" diagnosis which needs the absence of any consistent feature indicative of other partially overlapping connective tissue disorders. While both Villefranche and Brighton criteria include such an exclusion as a mandatory item, a systematic approach for reaching a stringent clinical diagnosis of JHS/EDS-HT is still lacking. The absence of a consensus on the diagnostic approach to JHS/EDS-HT concerning its clinical boundaries with similar conditions contribute to limit our actual understanding of the pathologic and molecular bases of this disorder. In this review, we revise the differential diagnosis of JHS/EDS-HT with those heritable connective tissue disorders which show a significant overlap with the former and mostly include EDS classic, vascular and kyphoscoliotic types, osteogenesis imperfecta, Marfan syndrome, Loeys-Dietz syndrome, arterial tortuosity syndrome, and lateral meningocele syndrome. A diagnostic flow chart is also offered with the attempt to support the less experienced clinician in stringently recognizing JHS/EDS-HT and stimulate the debate in the scientific community for both management and research purposes. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
... Although apparently rare, renal, colonic and gastric ptosis may be underestimated in JHS/EDS-HT. Treatment by organopexis is generally unsuccessful [66][67][68] and the link between such an anatomic feature and the presumably associated symptoms remains unclear in JHS/EDS-HT. Colonic reduction by laparoscopy resulted effective once [69]; hiatus hernias and intestinal intussusceptions are likely additional structural manifestations of gastrointestinal involvement in JHS/EDS-HT, but available data are too preliminary to affirm a non-casual relationship; collectively, the rate of functional gastrointestinal symptoms is high, increases with age and ranges from 1/3 to 3/4 of the patients. ...
Article
Ehlers-Danlos syndrome groups together an increasing number of hereditary connective tissue disorders mainly featuring abnormal skin texture, easy bruising, generalized joint hypermobility, and fragility or dysfunctions of internal organs. Diagnosis may be a hard task due to the phenotypic continuity among the different Ehlers-Danlos syndrome types and a variety of Mendelian and non-Mendelian diseases. The training pathways of most medical professionals do not include a practically oriented knowledge of Ehlers-Danlos syndrome and this further hampers prompt recognition and treatment. The multisystem nature of Ehlers-Danlos syndrome depicts a wide range of combining features mostly involving skin and mucosae, osteoarticular, cardiovascular and gastrointestinal systems, and pelvis. More recent evidence suggests a secondary but potentially disabling involvement of the nervous system. The typical Ehlers-Danlos syndrome patient is affected by chronic symptoms, which are difficultly managed by standard methods and for which a tailored approach is still lacking. In addition, a few patients are affected by Ehlers-Danlos syndrome variants with extreme vascular fragility and are at risk of potentially life-threatening vascular accidents. These individuals need periodic follow-up focused on the cardiovascular system. Comparably with other European countries, also in Italy general awareness on the protean, clinical manifestations of Ehlers-Danlos syndrome is increasing. Diagnostic and management expertise is still scattered in a few centres without a formal national organization and standardization of the cure. However, dissemination of knowledge is improving and many patients are now followed in specialized services coalescing an increasing numbers of specialists with interest in Ehlers-Danlos syndrome.
... When investigated further, gastroparesis, esophageal dysmotility, abnormal small bowel motility, slow transit constipation, rectal defecatory dysfunction, small bowel dilatation, and even celiac disease may be found [3][4][5]. We can find only two full case reports [6][7] and a few brief mentions with illustrative pictures of visceroptosis associated with EDS in the medical literature [5,[8][9]. ...
Article
Full-text available
Abstract: A patient with visceroptosis and the Ehlers-Danlos syndrome, hypermobility type is reported. The literature of this unusual but probably under recognized complication is reviewed. A plea is made to those who might have experience with treating this difficult problem.
... Patients diagnosed with Ehlers-Danlos syndrome, are characterized by an altered structural integrity of connective tissue [1,2] resulting in frailty [3] and multi-systemic manifestations like orthostatic intolerance, [4] hyper-elastic skin, [5] organ dysfunction [6] and joint instability. [7] The phenotype of EDS-HT is heterogeneous, in which the severity of complaints varies from mild to severe. ...
Article
Background Patients with Ehlers Danlos(hypermobility type)(EDS-HT) are characterized by connective tissue laxity which is associated with joint pain and muscle weakness, potentially leading to activity impairment. An important goal during rehabilitation is to reduce activity limitations by increasing muscle strength. However, evidence supporting this rationale is scarce. Muscle strength might be an important determinant of activity limitations; still, the relationship between muscle strength and activity limitations remains unknown. This association might be influenced by other factors, like proprioception. Recent studies have established that proprioception is reduced in patients with EDS-HT, still no studies have investigated its influence on activity impairment as its importance for muscle strength. Objectives To establish the association between muscle strength and activity impairments controlled for proprioception in patients with EDS-HT. Methods 25 patients with EDS-HT, were compared to 25 controls. Activity impairments (dependend variable) were quantified according to the Health Assessment Questionaire(HAQ), Six Minute Walktest(6MWT) and chair rise test(CRT). Muscle strength (Handheld dynamometry) and (knee)proprioception(movement detection) were used as independent variables. Pain(Visual Analog Scale), fatigue(Checklist Individual Strength) and demographics(age, BMI) were inserted as confounders. Inter-variable associations were established by Pearson coefficients. Consecutively multivariate models were constructed, for each dependent variable, by Generalized Equation Estimates(GEE). Results Univariate analysis showed significant associations between all measures of activity impairments and muscle strength (HAQ: r=-.557, p=<.0001, 6MWT: r=.557, p=<.0001, CRT: r=.664 p=<.0001), proprioception (HAQ: r=-.456, p=.001, 6MWT: r=-.400, p=.004, CRT: r=-.552 p=<.0001) and between muscle strength and proprioception (r=-.488, p=<.0001). Multivariate analysis revealed associations between muscle strength and CRT (B:.334(.13), p=.007), 6MWT (B:.366(.03), p=<.0001) and HAQ (B: -.267(.04), p=<.0001). Indicating that muscle weakness is associated with activity impairments. Proprioception was associated with activity impairment but only when quantified by CRT (B: -.381(.14), p=.005). Interaction effects were found between muscle strength and proprioception which contributed independently to activity impairment (CRT: B: -.175(.06), p=.006, HAQ: B:-.144(.05), p=.002). Conclusions Muscle strength is an important factor related to activity impairments in patients with EDS-HT. Activities that require more motor control, such as transfers, are more dependent on proprioceptive information. However, with regard to functional ability, controlling muscle force seems to be dependent on the amount of proprioceptive information available rather than being the product of only muscle power. References Rombaut L, De Paepe A, Malfait F et al. Joint position sense and vibratory perception sense in patients with Ehlers-Danlos syndrome type III. Clin Rheum. 2010;29(3):289-95. Rombaut L, Malfait F, De Wandele I et al. Muscle mass, muscle strength, functional performance, and physical impairment in women with the hypermobility type of Ehlers-Danlos syndrome. Arth Care Res. 2012;64(10):1584-92. Disclosure of Interest None Declared
... In a recent review on this topic, a total of 42 works were identified exploring the relationship between hEDS or GJH with gastrointestinal disorders [Castori et al., 2015a]. Among them, 12 were specifically addressed for better defining the spectrum of gastrointestinal symptoms in syndromic patients [Manning et al., 2003;Castori et al., 2010bCastori et al., , 2011aZarate et al., 2010;Danese et al., 2011;Mastoroudes et al., 2013a;De Wandele et al., 2013, 2014aKovacic et al., 2014;Fikree et al., 2015;Pacey et al., 2015b], and various clinical reports on single complications and/or surgical treatment in EDS [Douglas and Douglas, 1973;Defuentes et al., 2004;Sardeli et al., 2005;Chen and Jao, 2007;Reinstein et al., 2012;Dordoni et al., 2013;Fogel, 2013;Plackett et al., 2014]. ...
Article
The hypermobile type of Ehlers-Danlos syndrome (hEDS) is likely the most common hereditary disorder of connective tissue. It has been described largely in those with musculoskeletal complaints including joint hypermobility, joint subluxations/dislocations, as well as skin and soft tissue manifestations. Many patients report activity-related pain and some go on to have daily pain. Two undifferentiated syndromes have been used to describe these manifestations-joint hypermobility syndrome and hEDS. Both are clinical diagnoses in the absence of other causation. Current medical literature further complicates differentiation and describes multiple associated symptoms and disorders. The current EDS nosology combines these two entities into the hypermobile type of EDS. Herein, we review and summarize the literature as a better clinical description of this type of connective tissue disorder. © 2017 Wiley Periodicals, Inc.
... Dysmotility (usually gastroparesis) is common [22]. Patients often complain of abdominal fullness or bloating after eating a small portion of food, as well as alternating diarrhea and constipation [23]. These patients may need to be kept NPO longer and should be considered full stomach at all times. ...
... We were able to find only two case reports [11,12] and a few brief mentions of visceroptosis and EDS in the main stream medical literature [13][14][15]]. On the Internet there are few mentions. ...
... It was speculated that an increased hollow viscera compliance can facilitate visceral sensitivity and hence generate abdominal pain [26]. Intra-abdominal ligamentous laxity and visceral prolapses are occasionally reported in JHS/EDS-HT and may contribute to abdominal pain [92,93]. ...
Article
Introduction: Ehlers-Danlos syndrome (EDS) groups together an increasing number of hereditary soft connective tissue disorders. Among the most common variants, the hypermobility type emerges as the most problematic, due to clinical similarities with the joint hypermobility syndrome, strong association with pain and lack of molecular confirmatory tests. To date, chronic pain and the related physical disability are the most relevant clinical issues in the long-term management of EDS. Areas covered: A literature review was carried out covering all known pain manifestations, i.e. musculoskeletal pain, neuropathic pain, central sensitization, headache and visceral pain, in EDS. The natural history of pain, as well as other critical issues, i.e. heterogeneity, clinical approach and evolving phenotype, of EDS are also addressed. All available data on therapeutic strategies for pain in EDS are extensively reported. Expert opinion: Multidisciplinarity emerges as an undeniable prerequisite for the management of the complex EDS patient reporting pain. All available therapeutic resources, comprising painkillers, physical and psychological therapies, and surgery, show a low evidence of efficacy in the long-term treatment of pain. Education and early diagnosis are primary resources for secondary and tertiary prevention. Novel drug therapies could be developed considering the potential role of a dysfunctional extracellular matrix on pain modulation in EDS.
... Analogous ECM anomalies were reported in other rare EDS types [14,[20][21][22][23], suggesting that defective ECM organization is a common feature of EDS skin fibroblasts, irrespective of the underlining molecular defects. Altered ECM assembly shown in this in vitro model should reproduce both dermal ultrastructural anomalies, such as irregular and loosely packed collagen fibrils identified in diverse EDSs [24,25], and structural impairment of different affected connective tissues in JHS/EDS-HT patients including joints, ligaments, tendon, skin, mucosae, muscle, and bone [17,[26][27][28][29]. ...
Article
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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.
Article
Background Heritable connective tissue disorders (HCTD) present with a wide array of findings, including headache. Because of their unusual substrate, headaches in HCTD can derive from both common and uncommon circumstances.Methods Literature review.ResultsEhlers–Danlos hypermobile type can be recognized by multiple joint findings and its tendency to progress to a multisystem chronic pain syndrome. Ehlers–Danlos classic type also manifests joint laxity and similar pain complaints, but is differentiated by its skin laxity and fragility. Ehlers–Danlos vascular type presents the most severe risk due to blood vessel and hollow organ rupture. Marfan syndrome demonstrates skeletal abnormalities, lens dislocations, and aortic root dilation that can result in dissection.Conclusions In a headache patient, recognizing the presence of an HCTD improves the strategy for diagnosis and management. A brief review of findings related to joints, skin, and arteries may prompt further investigation into the HCTDs.
Article
Background: Hypermobile Ehlers-Danlos Syndrome (hEDS) and the hypermobility spectrum disorders (HSD) can be challenging to diagnose and manage. Gastrointestinal symptoms and disorders of gut-brain interaction are common in this cohort and multifactorial in origin. Aims: The primary aim of this review is to arm the gastroenterologist with a clinically useful understanding of HSD/hEDS, by exploring the association of gastrointestinal disorders with HSD/hEDS, highlighting current pathophysiological understanding and providing a pragmatic approach to managing these patients. Methods: Literature relevant to the gastrointestinal system and hypermobile Ehlers-Danlos Syndrome was systematically searched, critically-appraised and summarized. Results: Diagnosis is based upon clinical criteria and a genetic basis is yet to be defined. The prevalence of many gut symptoms, including abdominal pain (69% vs 27%, p<0.0001), postprandial fullness (34% vs 16%, p=0.01), constipation (73% vs 16%, p<0.001) and diarrhea (47% vs 9%, p<0.001) are significantly higher in HSD/hEDS compared with non-HSD/hEDS individuals. Disorders of gut-brain interaction are also common, particularly functional dyspepsia. The pathophysiology of gut symptoms is poorly understood but may involve effects of connective tissue laxity and its functional consequences, and the influence of autonomic dysfunction, medication and comorbid mental health disorders. Awareness is the key to early diagnosis. Management is limited in evidence-base but ideally should include an integrated multidisciplinary approach. Conclusions: HSD/hEDS is a multisystemic disorder in which gastrointestinal symptoms, particularly related to disorders of gut-brain interaction are common. Deficiencies in knowledge regarding the pathophysiological processes limit evidence-based interventions and remain important areas for future research.
Article
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Chronic pain in the Ehlers-Danlos syndromes (EDS) is common and may be severe. According to one study, nearly 90% of patients report some form of chronic pain. Pain, which is often one of the first symptoms to occur, may be widespread or localized to one region such as an arm or a leg. Studies on treatment modalities are few and insufficient to guide management. The following is a discussion of the evidence regarding the underlying mechanisms of pain in EDS. The causes of pain in this condition are multifactorial and include joint subluxations and dislocations, previous surgery, muscle weakness, proprioceptive disorders, and vertebral instability. Affected persons may also present with generalized body pain, fatigue, headaches, gastrointestinal pain, temporomandibular joint pain, dysmenorrhea, and vulvodynia. Pain management strategies may be focused around treating the cause of the pain (e.g., dislocation of a joint, proprioceptive disorder) and minimizing the sensation of pain. Management strategies for chronic pain in EDS includes physical therapy, medications, as well as durable medical equipment such as cushions, compressive garments, and braces. The different modalities are discussed in this paper. © 2017 Wiley Periodicals, Inc.
Article
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Hypermobile Ehlers-Danlos syndrome (hEDS) is a heritable connective tissue disorder with unknown molecular basis mainly characterized by generalized joint hypermobility, joint instability complications and minor skin changes. The phenotypic spectrum is broad and includes multiple associated symptoms shared with chronic inflammatory systemic diseases. The stricter criteria defined in the 2017 EDS nosology leave without an identity many individuals with symptomatic joint hypermobility and/or features of hEDS; for these patients, the term Hypermobility Spectrum Disorders (HSD) was introduced. We previously reported that in vitro cultured hEDS and HSD patients' skin fibroblasts show a disarray of several extracellular matrix (ECM) components and dysregulated expression of genes involved in connective tissue homeostasis, and inflammatory/pain/immune responses. Herein, we report that hEDS and HSD skin fibroblasts exhibit in vitro a similar myofibroblast-like phenotype characterized by the organization of α-smooth muscle actin cytoskeleton, expression of OB-cadherin/cadherin-11, enhanced migratory capability associated with augmented levels of the ECM-degrading metalloproteinase-9, and altered expression of the inflammation mediators CCN1/CYR61 and CCN2/CTGF. We demonstrate that in hEDS and HSD cells this fibroblast-to-myofibroblast transition is triggered by a signal transduction pathway that involves αvβ3 integrin-ILK complexes, organized in focal adhesions, and the Snail1/Slug transcription factor, thus providing insights into the molecular mechanisms related to the pathophysiology of these protean disorders. The indistinguishable phenotype identified in hEDS and HSD cells resembles an inflammatory-like condition, which correlates well with the systemic phenotype of patients, and suggests that these multisystemic disorders might be part of a phenotypic continuum rather than representing distinct clinical entities.
Article
Background Joint hypermobility is a common, primarily benign finding in the general population. However, in a subset of individuals, joint hypermobility causes a range of clinical problems, mainly affecting the musculoskeletal system and, to a lesser extent, extra-articular disorders. Joint hypermobility often appears as a familial trait and is shared by several inherited connective tissue disorders, including the hypermobility subtype of Ehlers-Danlos syndrome (hEDS) and benign joint hypermobility syndrome (BJHS/JHS). While joint hypermobility has primarily been thought of as a rheumatological disorder, increasing evidence shows significant associations between both hEDS and BJHS with specific extra-articular disorders. To date, the strongest associations of these two conditions are with anxiety disorders, orthostatic tachycardia, various functional gastrointestinal (GI) disorders, and pelvic and bladder dysfunction. This review article focuses on GI disorders associated with both hEDS and BJHS. Purpose The aim of this review is to evaluate existing research and literature regarding associations between JHS (hEDS/BJHS) and GI disorders. Our goal is to raise awareness of BJHS/JHS and hEDS as an explanation for chronic unexplained symptoms and functional GI disorders as well to review the current standard tests available for proper evaluation of GI symptoms in these patients.
Article
Background Joint hypermobility syndrome (JHS) is characterized by excessive connective tissue laxity manifest as joint hypermobility (JH) together with musculoskeletal symptoms. Previous studies have shown an association between JH/JHS and gastrointestinal symptoms, including irritable bowel syndrome (IBS), although its association with specific IBS subtypes is incompletely understood. We aimed to determine the prevalence of JH according to the subtypes of IBS, in particular IBS‐C and IBS‐D. Methods Data of 228 consecutive IBS patients were analyzed. IBS was subtyped into constipation and diarrhea predominant IBS (IBS‐C and IBS‐D), IBS with mixed bowel habits (IBS‐M) and unsubtyped IBS (IBS‐U). JH was defined as a Beighton Score ≥4/9 points and JHS diagnosed according to revised Brighton Criteria. Data of IBS patients were analyzed for psychological comorbidities assessed by Hospital Anxiety and Depression Scale (HADS) and Visceral Sensitivity Index (VSI). Key Results Of 228 IBS patients, 64 (28.1%) suffered from IBS‐C, 89 (39.0%) from IBS‐D, 48 (21.1%) from IBS‐M, and 27 (11.8%) from IBS‐U. JH was diagnosed in 95 patients (41.7%). The prevalence of JH was significantly higher in IBS‐C than IBS‐D (57.8% vs 34.8%, P = .031). There was no significant difference in VSI and HADS according to JH or IBS subtype. Conclusions and Interferences The prevalence of JH was significantly higher in IBS‐C compared to IBS‐D. Abnormalities in the connective tissue biomechanics in those with JH may contribute to a degree of colonic inertia which could result in constipation in JH‐positive IBS patients. Further work is needed to determine the colonic biomechanics in patients with JH.
Article
The Ehlers‐Danlos Syndromes (EDS) and associated hypermobility spectrum disorders (HSD) are a heterogenous group of connective tissue disorders associated with significant morbidity. The urogenital aspects of these disorders are understudied and there is little guidance on the prevalence, types, or outcomes of urogenital complications in EDS/HSD. Our objective was to perform a scoping review to characterize and synthesize the literature reporting urogenital and pelvic complications in EDS/HSD patients. We performed a systematic search of three databases (Medline, CINAHL, Embase) to January 2019. English language, full‐text articles reporting on urogenital or pelvic complications in EDS/HSD were included. A total of 105 studies were included (62 case reports/series, 43 observational) involving patients with hypermobile (23%), vascular (20%), classical (12%) EDS, and HSD (24%). Some studies looked at multiple subtypes (11%) or did not report subtype (33%). Reported complications included urinary (41%), gynecological (36%), obstetrical (25%), renal (9%), and men's health problems (7%), with some studies reporting on multiple areas. Urinary and gynecological complications were most prevalent in patients with HSD, while a broad range of complications were reported in EDS. While further research is required, results suggest a higher index of suspicion for urogenital problems is likely warranted in this population. This article is protected by copyright. All rights reserved.
Article
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Ehlers–Danlos syndrome (EDS)—hypermobility type (HT) is considered to be the most common subtype of EDS and the least severe one; EDS-HT is considered to be identical to the joint hypermobility syndrome and manifests with musculoskeletal complaints, joint instability, and soft tissue overuse injury. Musculoskeletal complaints manifest with joint pain of non-inflammatory origin and/or spinal pain. Joint instability leads to dislocation or subluxation and involves peripheral joints as well as central joints, including the temporomandibular joints, sacroiliac joints, and hip joints. Soft tissue overuse injury may lead to tendonitis and bursitis without joint inflammation in most cases. Ehlers–Danlos syndrome-HT carries a high potential for disability due to recurrent dislocations and subluxations and chronic pain. Throughout the years, extra-articular manifestations have been described, including cardiovascular, autonomic nervous system, gastrointestinal, hematologic, ocular, gynecologic, neurologic, and psychiatric manifestations, emphasizing the multisystemic nature of EDS-HT. Unfortunately, EDS-HT is under-recognized and inadequately managed, leading to neglect of these patients, which may lead to severe disability that almost certainly could have been avoided. In this review article we will describe the known manifestations of the extra-articular systems.
Article
Full-text available
Hypermobility type Ehlers–Danlos syndrome (HT-EDS) is a relatively frequent, although commonly misdiagnosed variant of Ehlers–Danlos syndrome, mainly characterized by marked joint instability and mild cutaneous involvement. Chronic pain, asthenia, and gastrointestinal and pelvic dysfunction are characteristic additional manifestations. We report on 21 HT-EDS patients selected from a group of 40 subjects with suspected mild hereditary connective tissue disorder. General, mucocutaneous, musculoskeletal, cardiovascular, neurologic, gastrointestinal, urogynecological, and ear–nose–throat abnormalities are investigated systematically and tabulated. Six distinct clinical presentations of HT-EDS are outlined, whose tabulation is a mnemonic for the practicing clinical geneticist in an attempt to diagnose this condition accurately. With detailed clinical records and phenotype comparison among patients of different ages, the natural history of the disorder is defined. Three phases (namely, hypermobility, pain, and stiffness) are delineated based on distinguishing manifestations. A constellation of additional, apparently uncommon abnormalities is also identified, including dolichocolon, dysphonia, and Arnold–Chiari type I malformation. Their further investigation may contribute to an understanding of the pathogenesis of the protean manifestations of HT-EDS, and a more effective approach to the evaluation and management of affected individuals. © 2010 Wiley-Liss, Inc.
Article
Full-text available
Joint hypermobility syndrome (JHS), or Ehlers-Danlos syndrome (EDS) hypermobility type (EDS-HT), is a underdiagnosed heritable connective tissue disorder characterized by generalized joint hypermobility and a wide range of visceral, pelvic, neurologic, and cognitive dysfunctions. Deterioration of quality of life is mainly associated with pain and fatigue. Except for the recognized effectiveness of physiotherapy for some musculoskeletal features, there are no standardized guidelines for the assessment and treatment of pain and fatigue. In this work, a practical classification of pain presentations and factors contributing in generating painful sensations in JHS/EDS-HT is proposed. Pain can be topographically classified in articular limb (acute/subacute and chronic), muscular limb (myofascial and fibromyalgia), neuropathic limb, back/neck, abdominal and pelvic pain, and headache. For selected forms of pain, specific predisposing characteristics are outlined. Fatigue appears as the result of multiple factors, including muscle weakness, respiratory insufficiency, unrefreshing sleep, dysautonomia, intestinal malabsorption, reactive depression/anxiety, and excessive use of analgesics. A set of lifestyle recommendations to instruct patients as well as specific investigations aimed at characterizing pain and fatigue are identified. Available treatment options are discussed in the set of a structured multidisciplinary approach based on reliable outcome tools.
Chapter
Full-text available
Ehlers-Danlos syndrome (EDS), classic type is a connective tissue disorder characterized by skin hyperextensibility, abnormal wound healing, and joint hypermobility. It includes two previously designated subtypes (EDS type I and EDS type II) that are now recognized to form a continuum of clinical findings. The skin is smooth, velvety to the touch, and hyperelastic; i.e., it extends easily and snaps back after release (unlike lax, redundant skin, as in cutis laxa). The skin is fragile, as manifested by splitting of the dermis following relatively minor trauma, especially over pressure points (knees, elbows) and areas prone to trauma (shins, forehead, chin). Wound healing is delayed, and stretching of scars after apparently successful primary wound healing is characteristic. Complications of joint hypermobility, such as dislocations of the shoulder, patella, digits, hip, radius, and clavicle, usually resolve spontaneously or are easily managed by the affected individual. Other features include hypotonia with delayed motor development, fatigue and muscle cramps, and easy bruising. Less common findings include mitral and tricuspid valve prolapse, aortic root dilatation, and spontaneous rupture of large arteries. The diagnosis of EDS, classic type is established by family history and clinical examination. Quantitative and qualitative studies of type V collagen chains are usually not useful in confirming a diagnosis. At least 50% of individuals with classic EDS have an identifiable mutation in COL5A1 or COL5A2, the genes encoding type V collagen; however, this number may be an underestimate, since no prospective molecular studies of COL5A1 and COL5A2 have been performed in a clinically well-defined group. Molecular genetic testing for these two genes is available on a clinical basis. Treatment of manifestations: Children with hypotonia and delayed motor development benefit from physiotherapy. Non-weight-bearing exercise promotes muscle strength and coordination. Anti-inflammatory drugs may alleviate joint pain. Those with hypotonia, joint instability, and chronic pain may need to adapt lifestyles accordingly. Dermal wounds are closed without tension, preferably in two layers. For other wounds, deep stitches are applied generously; cutaneous stitches are left in place twice as long as usual; and the borders of adjacent skin are carefully taped to prevent stretching of the scar. Cardiovascular problems are treated in a standard manner. Prevention of primary manifestations: Young children with skin fragility can wear pads or bandages over the forehead, knees, and shins to avoid skin tears. Older children can wear soccer pads or ski stockings with shin padding during activities. Ascorbic acid (vitamin C) may reduce bruising. Surveillance: Yearly echocardiogram when aortic dilatation and/or mitral valve prolapse are present. Agents/circumstances to avoid: Acetylsalicylate; sports that strain joints. EDS, classic type is inherited in an autosomal dominant manner. It is estimated that approximately 50% of affected individuals have inherited the disease-causing mutation from an affected parent, and approximately 50% of affected individuals have a de novo disease-causing mutation. Each child of an affected individual has a 50% chance of inheriting the mutation. Prenatal testing for pregnancies at increased risk may be possible for families in which the disease-causing mutation has been identified in an affected family member.
Article
Full-text available
Categorization of the Ehlers-Danlos syndromes began in the late 1960s and was formalized in the Berlin nosology. Over time, it became apparent that the diagnostic criteria established and published in 1988 did not discriminate adequately between the different types of Ehlers-Danlos syndromes or between Ehlers-Danlos syndromes and other phenotypically related conditions. In addition, elucidation of the molecular basis of several Ehlers-Danlos syndromes has added a new dimension to the characterization of this group of disorders. We propose a revision of the classification of the Ehlers-Danlos syndromes based primarily on the cause of each type. Major and minor diagnostic criteria have been defined for each type and complemented whenever possible with laboratory findings. This simplified classification will facilitate an accurate diagnosis of the Ehlers-Danlos syndromes and contribute to the delineation of phenotypically related disorders.
Article
Categorization of the Ehlers-Danlos syndromes began in the late 1960s and was formalized in the Berlin nosology. Over time, it became apparent that the diagnostic criteria established and published in 1988 did not discriminate adequately between the different types of Ehlers-Danlos syndromes or between Ehlers-Danlos syndromes and other phenotypically related conditions. In addition, elucidation of the molecular basis of several Ehlers-Danlos syndromes has added a new dimension to the characterization of this group of disorders. We propose a revision of the classification of the Ehlers-Danlos syndromes based primarily on the cause of each type. Major and minor diagnostic criteria have been defined for each type and complemented whenever possible with laboratory findings. This simplified classification will facilitate an accurate diagnosis of the Ehlers-Danlos syndromes and contribute to the delineation of phenotypically related disorders. Am. J. Med. Genet. 77:31–37, 1998. © 1998 Wiley-Liss, Inc.
Article
The pathophysiology of pelvic floor disorders still remains not well understood. Increasing age as well as vaginal multiparity are the main commonly accepted factors. The hypothesis of a defect of connective tissues of the pelvic floor with aging due to collagen deficiency and/or elastic fiber degradation is often highlighted. The issue of a potential protective role of HRT is also discussed although the recent results from the WHI would suggest a negative impact of HRT on urinary incontinence, especially when HRT is initiated in elderly women, far from the menopause. Nevertheless, environmental factors cannot explain the full pathogenesis of pelvic organ prolapse (POP) and the contribution of genetic factors to the development of pelvic floor disorders is widely recognized. Support for a genetic influence on POP derives from reports suggesting that heritability is a strong contributing factor and a familial history of POP is considered as a classical risk factor. However, the characterization of the underlying molecular mechanisms remains limited, since POP may be considered the end result of a multifactorial process leading to destruction of vaginal wall connective tissue. Experimental studies in mice with null mutations in the genes encoding different putative factors involved in elastic fibers remodeling and homeostasis are crucial in the understanding of the pathogenesis of POP. Mice with null mutation in the gene encoding lysyl oxidase-like 1 (LOXL1) or fibulin-5, demonstrate signs of elastinopathy including the development of a POP in the postpartum. Likewise, homeobox genes such as HOXA11, which are essential in the embryonic development of the urogenital tract might also be involved in the pathogenesis of POP. The better understanding of the underlying determinants of pelvic floor disorders with a special focus on genetic factors may offer new therapeutic strategies, in addition to or replacement of surgical procedures.
Data
Type V collagen mutations are associated with classic Ehlers–Danlos Syndrome (EDS), but it is unknown for which proportion they account and to what extent other genes are involved. We analyzed COL5A1 and COL5A2 in 126 patients with a diagnosis or suspicion of classic EDS. In 93 patients, a type V collagen defect was found, of which 73 were COL5A1 mutations, 13 were COL5A2 mutations and seven were COL5A1 null‐alleles with mutation unknown. The majority of the 73 COL5A1 mutations generated a COL5A1 null‐allele, whereas one‐third were structural mutations, scattered throughout COL5A1. All COL5A2 mutations were structural mutations. Reduced availability of type V collagen appeared to be the major disease‐causing mechanism, besides other intra‐ and extracellular contributing factors. All type V collagen defects were identified within a group of 102 patients fulfilling all major clinical Villefranche criteria, that is, skin hyperextensibility, dystrophic scarring and joint hypermobility. No COL5A1/COL5A2 mutation was detected in 24 patients who displayed skin and joint hyperextensibility but lacked dystrophic scarring. Overall, over 90% of patients fulfilling all major Villefranche criteria for classic EDS were shown to harbor a type V collagen defect, which indicates that this is the major—if not only—cause of classic EDS. Hum Mutat 33:1485–1493, 2012. © 2012 Wiley Periodicals, Inc.
Article
Joint hypermobility syndrome (JHS) emerges as likely the most common clinical form of Ehlers-Danlos syndrome. Given the striking predominance of affected women, practitioners often face gynecologic and obstetric issues. However, their decisions are still based on personal experience rather than literature due to the lack of a consistent body of evidence. We collected a set of gynecologic and obstetric features in 82 post-puberal women with JHS attending two Italian centers. Common gynecologic findings were dysmenorrhea (82.9%), meno/metrorrhagias (53.7%), irregular menses (46.3%), and dispareunia/vulvodinia (31.7%). Forty women were nulliparous and 42 had one or more pregnancy for a total of 93 diagnosed conceptions. Of them, 16.1% were spontaneous abortions, 6.5% voluntary interruptions, 10.7% preterm deliveries, and 66.7% deliveries at term. Overall outcome of proceeding pregnancies was good with no stillbirth and fetal/neonatal hypoxic/ischemic event. Non-operative vaginal delivery was registered in 72.2%, forceps/vacuum use in 5.5% and cesarean in 22.3%. Local/total anesthesia was successfully performed in 17 pregnancies without any problem. Major post-partum complications included abnormal scar formation after cesarean or episiotomy (46.1%), hemorrhage (19.4%), pelvic prolapses (15.3%), deep venous thrombosis (4.2%), and coccyx dislocation (1.4%). Prolapses were the most clinically relevant complication and associated with episiotomy. Gathered data were discussed for practically oriented considerations.
Chapter
Prolidase deficiency is a rare, autosomal recessively inherited disorder in which deficient activity of prolidase results in a massive urinary excretion of X-Pro and X-Hyp dipeptides derived from generalized protein breakdown. The chapter includes discussions on the clinical features of the disorder, inheritance and prevalence, diagnosis, prognosis and management.
Article
Gastrointestinal complications are common in patients with Ehlers-Danlos syndrome, affecting up to 50% of individuals depending on the subtype. The spectrum of gastrointestinal manifestations is broad and ranges from life threatening spontaneous perforation of the visceral organs to a more benign functional symptoms. Here we describe the clinical and radiographic manifestations of visceroptosis of the bowel, a rare complication of Ehlers-Danlos syndrome that is characterized by prolapse of abdominal organs below their natural position. We further review the literature on gastrointestinal complications in the different forms of Ehlers-Danlos syndrome.
Article
Type V collagen mutations are associated with classic Ehlers-Danlos Syndrome (EDS), but it is unknown for which proportion they account and to what extent other genes are involved. We analyzed COL5A1 and COL5A2 in 126 patients with a diagnosis or suspicion of classic EDS. In 93 patients, a type V collagen defect was found, of which 73 were COL5A1 mutations, 13 were COL5A2 mutations and seven were COL5A1 null-alleles with mutation unknown. The majority of the 73 COL5A1 mutations generated a COL5A1 null-allele, whereas one-third were structural mutations, scattered throughout COL5A1. All COL5A2 mutations were structural mutations. Reduced availability of type V collagen appeared to be the major disease-causing mechanism, besides other intra- and extracellular contributing factors. All type V collagen defects were identified within a group of 102 patients fulfilling all major clinical Villefranche criteria, that is, skin hyperextensibility, dystrophic scarring and joint hypermobility. No COL5A1/COL5A2 mutation was detected in 24 patients who displayed skin and joint hyperextensibility but lacked dystrophic scarring. Overall, over 90% of patients fulfilling all major Villefranche criteria for classic EDS were shown to harbor a type V collagen defect, which indicates that this is the major-if not only-cause of classic EDS. Hum Mutat 33:1485-1493, 2012. © 2012 Wiley Periodicals, Inc.
Chapter
Ehlers-Danlos syndrome (EDS), hypermobility type is generally considered the least severe type of EDS, although significant complications, primarily musculoskeletal, can and do occur. The skin is often soft or velvety and may be mildly hyperextensible. Subluxations and dislocations are common; they may occur spontaneously or with minimal trauma and can be acutely painful. Degenerative joint disease is common. Chronic pain, distinct from that associated with acute dislocations, is a serious complication of the condition and can be both physically and psychologically disabling. Easy bruising is common. Functional bowel disorders are likely underrecognized. Autonomic dysfunction, such as orthostatic intolerance, may also be seen. Aortic root dilation is typically of a mild degree with no increased risk of dissection in the absence of significant dilation. Psychological dysfunction, psychosocial impairment, and emotional problems are common. The diagnosis of EDS, hypermobility type is based entirely on clinical evaluation and family history. In most individuals with EDS, hypermobility type, the gene in which mutation is causative is unknown and unmapped. Haploinsufficiency of tenascin-X (encoded by TNXB) has been associated with EDS, hypermobility type in a small subset of affected individuals. Testing for TNXB mutations is available on a limited clinical basis. Treatment of manifestations: Physical therapy tailored to the individual; assistive devices (braces to improve joint stability; wheelchair or scooter to offload stress on lower-extremity joints; suitable mattress to improve sleep quality); pain medication tailored to symptoms; appropriate therapy for gastritis/reflux /delayed gastric emptying/irritable bowel syndrome; possible beta-blockade for progressive aortic enlargement; psychological and/or pain-oriented counseling. Prevention of primary manifestations: Low-resistance exercise to increase both core and extremity muscle tone for improved joint stability; appropriate writing utensils to reduce finger and hand strain. Prevention of secondary complications: Calcium, vitamin D, low-impact weight-bearing exercise to maximize bone density. Surveillance: DEXA every other year if bone loss is confirmed. Pregnancy management: Labor and delivery may progress very rapidly, even in primigravid women. There is no clear advantage to vaginal vs cesarean delivery. Pregnant women with known aortic root dilation should have an echocardiogram in each trimester. Agents/circumstances to avoid: Joint hyperextension; resistance/isometric exercise can exacerbate joint instability and pain; high-impact activity increases the risk of acute subluxation/dislocation, chronic pain, and osteoarthritis; crutches, canes, and walkers, which put increased stress on the upper extremities, should be used with caution. EDS, hypermobility type is inherited in an autosomal dominant manner. Most individuals diagnosed with the syndrome have an affected parent. The proportion of cases caused by de novo mutations is unknown. Each child of an individual with EDS, hypermobility type has a 50% chance of inheriting the disorder. Prenatal testing is available on a limited basis if the disease-causing mutation has been identified in the family.
Article
The Ehlers-Danlos syndromes (EDSs) comprise a heterogeneous group of diseases, characterized by fragility of the soft connective tissues and widespread manifestations in skin, ligaments, joints, blood vessels and internal organs. The clinical spectrum varies from mild skin and joint hyperlaxity to severe physical disability and life-threatening vascular complications. The current Villefranche classification recognizes six subtypes, most of which are linked to mutations in genes encoding fibrillar collagens or enzymes involved in post-translational modification of these proteins. Mutations in type V and type III collagen cause classic or vascular EDS respectively, while mutations involving the processing of type I collagen are involved in the kyphoscoliosis, arthrochalasis and dermatosparaxis type of EDS. Establishing the correct EDS subtype has important implications for genetic counseling and management and is supported by specific biochemical and molecular investigations. Over the last years, several new EDS variants have been characterized which call for a refinement of the Villefranche classification. Moreover, the study of these diseases has brought new insights into the molecular pathogenesis of EDS by implicating genetic defects in the biosynthesis of other extracellular matrix (ECM) molecules, such as proteoglycans and tenascin-X, or genetic defects in molecules involved in intracellular trafficking, secretion and assembly of ECM proteins.
Article
The pathophysiology of pelvic floor disorders still remains not well understood. Increasing age as well as vaginal multiparity are the main commonly accepted factors. The hypothesis of a defect of connective tissues of the pelvic floor with aging due to collagen deficiency and/or elastic fiber degradation is often highlighted. The issue of a potential protective role of HRT is also discussed although the recent results from the WHI would suggest a negative impact of HRT on urinary incontinence, especially when HRT is initiated in elderly women, far from the menopause. Nevertheless, environmental factors cannot explain the full pathogenesis of pelvic organ prolapse (POP) and the contribution of genetic factors to the development of pelvic floor disorders is widely recognized. Support for a genetic influence on POP derives from reports suggesting that heritability is a strong contributing factor and a familial history of POP is considered as a classical risk factor. However, the characterization of the underlying molecular mechanisms remains limited, since POP may be considered the end result of a multifactorial process leading to destruction of vaginal wall connective tissue. Experimental studies in mice with null mutations in the genes encoding different putative factors involved in elastic fibers remodeling and homeostasis are crucial in the understanding of the pathogenesis of POP. Mice with null mutation in the gene encoding lysyl oxidase-like 1 (LOXL1) or fibulin-5, demonstrate signs of elastinopathy including the development of a POP in the postpartum. Likewise, homeobox genes such as HOXA11, which are essential in the embryonic development of the urogenital tract might also be involved in the pathogenesis of POP. The better understanding of the underlying determinants of pelvic floor disorders with a special focus on genetic factors may offer new therapeutic strategies, in addition to or replacement of surgical procedures.
Article
Hypermobility type Ehlers-Danlos syndrome (HT-EDS) is a relatively frequent, although commonly misdiagnosed variant of Ehlers-Danlos syndrome, mainly characterized by marked joint instability and mild cutaneous involvement. Chronic pain, asthenia, and gastrointestinal and pelvic dysfunction are characteristic additional manifestations. We report on 21 HT-EDS patients selected from a group of 40 subjects with suspected mild hereditary connective tissue disorder. General, mucocutaneous, musculoskeletal, cardiovascular, neurologic, gastrointestinal, urogynecological, and ear-nose-throat abnormalities are investigated systematically and tabulated. Six distinct clinical presentations of HT-EDS are outlined, whose tabulation is a mnemonic for the practicing clinical geneticist in an attempt to diagnose this condition accurately. With detailed clinical records and phenotype comparison among patients of different ages, the natural history of the disorder is defined. Three phases (namely, hypermobility, pain, and stiffness) are delineated based on distinguishing manifestations. A constellation of additional, apparently uncommon abnormalities is also identified, including dolichocolon, dysphonia, and Arnold-Chiari type I malformation. Their further investigation may contribute to an understanding of the pathogenesis of the protean manifestations of HT-EDS, and a more effective approach to the evaluation and management of affected individuals.
Article
Gastrointestinal manifestations of collagen diseases are very rare. The authors report on a patient who has features of Marfan syndrome with mobile liver caused by the absence of its suspensory ligaments. This patient presented with an acute intestinal obstruction secondary to a congenital band across the distal transverse colon. Recurrent intestinal obstruction after resection of the band necessitated the performance of partial colectomy with ileotransverse anastomosis. The patient's phenotypic features are suggestive but not diagnostic of Marfan syndrome. Nevertheless, isolated skeletal manifestations of Marfan syndrome with documented FBN1 gene mutation have been reported, suggesting the existence of milder forms of the syndrome not exhibiting the classic diagnostic criteria. The authors postulate that the absence of suspensory ligaments of the liver in this patient could be attributed to the defective connective tissue of Marfan syndrome.
Article
This study was undertaken to determine the prevalence of urinary incontinence and pelvic organ prolapse in a cohort of women with either Marfan syndrome or Ehlers-Danlos syndrome. Study Design: Female patients with either Marfan syndrome or Ehlers-Danlos syndrome were identified through a medical records search at two urban hospitals. Each patient's medical record was reviewed, and the history of pelvic organ prolapse and urinary incontinence was obtained through telephone interview. Twelve women with Marfan syndrome were identified. Among these women 5 (42%) reported a history of urinary incontinence and 4 (33%) reported a history of pelvic organ prolapse. Eight women with Ehlers-Danlos syndrome were identified. Among these women 4 (50%) reported a history of urinary incontinence and 6 (75%) reported a history of pelvic organ prolapse. Women with Marfan or Ehlers-Danlos syndrome have high rates of urinary incontinence and pelvic organ prolapse. This finding supports the hypothesized etiologic role of connective tissue disorders as a factor in the pathogenesis of these conditions.
Article
A 38-year-old man with Ehlers-Danlos syndrome was examined for abdominal pain and fever. An In-111 leukocyte scan performed to detect the possible source of occult sepsis revealed intense activity above the liver. The presence of the intrathoracic spleen was confirmed on a Tc-99m sulfur colloid scan. Computed tomography showed herniation of the stomach, colon, and spleen through a large diaphragmatic defect into the chest. The mechanism of a wandering spleen in this patient is most likely ligamentous laxity caused by Ehlers-Danlos syndrome, which also accounts for the hiatus hernia.
Connective tissue and its heritable disorders: Molecular genetics and medicals aspects Comprehensive molecular analysis dem-onstrates type V collagen mutations in over 90% of patients with classic EDS and allows to refine diagnostic criteria
  • Royce Pm Steinmann
  • D Syx
  • F Malfait
  • De B Callewaert
  • J Backer
  • O Vanakker
  • De P Coucke
  • Paepe
Royce PM, Steinmann B. 2002. Connective tissue and its heritable disorders: Molecular genetics and medicals aspects. New York: Wiley–Liss. p. 1201. Symoens S, Syx D, Malfait F, Callewaert B, De Backer J, Vanakker O, Coucke P, De Paepe A. 2012. Comprehensive molecular analysis dem-onstrates type V collagen mutations in over 90% of patients with classic EDS and allows to refine diagnostic criteria. Hum Mutat 33:1485–1493.
The revised (Brighton 1998) criteria for the diagnosis of benign joint hypermobility syndrome (BJHS)
  • Grahme
Ehlers-Danlos syndromes: Revised nosology, Villefranche
  • Beighton
  • Royce