{"paper_id":"da6e0012-4ce3-463a-9b38-31cf99539a4e","body_text":"R E S E A R C H Open Access\nGynecologic symptoms and the influence\non reproductive life in 386 women with\nhypermobility type ehlers-danlos\nsyndrome: a cohort study\nJustine Hugon-Rodin 1, Géraldine Lebègue 1, Stéphanie Becourt 1, Claude Hamonet 2 and Anne Gompel 1*\nAbstract\nBackground: Hypermobile Ehlers-Danlos syndrome (hEDS), is probably the most common disease among heritable\nconnective tissue disorders. It affects women more than men and causes symptoms in multiple organs. It is\nassociated with chronic pain, skin fragility and abnormal bleeding. These characteristics may hamper reproductive\nlife. We conducted a study to evaluate the gynecologic and obstetric outcomes in women with hEDS. We also\nexplored a possible hormonal modulation of the hEDS symptoms. The gynecologic and obstetric history of 386\nconsecutive women diagnosed with hEDS was collected by a standardized questionnaire and a medical\nconsultation performed by a senior gynecologist in an expert centre for hEDS between May 2012 and December\n2014.\nResults: We observed a high frequency of gynecologic complaints, specifically: menorrhagia (76 %), dysmenorrhea\n(72 %) and dyspareunia (43 %). Endometriosis was not highly prevalent in this population. The obstetric outcomes\nwere similar to those of the general French population for deliveries by cesarean section (14.6 %) and premature\nbirths (6.2 %) but the incidence of multiple spontaneous abortion (13 %) and spontaneous abortion (28 %) were\nsignificantly higher. A subset of women were sensitive to hormonal fluctuations with more severe symptoms\noccurring during puberty, prior to menstruation, during the postpartum period as well as on oral contraception.\nConclusions: Increased awareness of the gynecological symptomatology in women with hEDS can help\ndiscriminate between endometriosis and thus prevent useless, and potentially dangerous, surgery. This study also\nsuggests that hormonal modulation may be an appropriate treatment for a subset of women with hEDS.\nKeywords: Ehlers-Danlos syndrome, Hypermobility type, Recurrent abortion, Endometriosis, Bleeding disorders,\nPremature delivery\nBackground\nEhlers-Danlos syndromes (EDS) belong to heritable con-\nnective tissue disorders. Geneticists (Villefranche 1997)\nhave categorized six major forms of EDS including the\nclassic type (I, II), hypermobility type (hEDS) (III) and\nvascular type (IV) as being the most frequent clinical\npresentations [1]. However, while the vascular or classical\ntypes of EDS may be associated with genetic variations, the\ndiagnosis of hEDS is based sole ly on clinical criteria. hEDS\nis classically defined on the basis of major criteria: a\nBeighton score of ≥5/9, skin involvement (hyperextensibility\nand/or smooth, velvety skin) an d minor criteria: recurring\njoint dislocations, chronic joint/limb pain and a positive\nfamily history [1]. According to an international group of\nexperts, and because of overlapping symptoms, Join hyper-\nmobile syndrome (JHS) and hEDS could be the same clin-\nical entity [2]. Recent studies suggest that patients with\nhEDS can experience a large range of dysfunction and in\n* Correspondence: anne.gompel@aphp.fr\n1Unité de Gynécologie-Endocrinienne, APHP, Hôpitaux universitaires Paris\nCentre, Université Paris Descartes, Port Royal, 123 Bd de l ’Hôpital, Paris 75014,\nFrance\nFull list of author information is available at the end of the article\n© 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0\nInternational License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and\nreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to\nthe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver\n(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.\nHugon-Rodin et al. Orphanet Journal of Rare Diseases  (2016) 11:124 \nDOI 10.1186/s13023-016-0511-2\n\naddition to mobile, loose joints, chronic pain (musculoskel-\netal pain, headache/migraine) [3] and variable skin involve-\nment, also including dysautonomia, gastrointestinal\nfunctional disorder, fibromyalgia, and chronic fatigue syn-\ndrome among others [4]. Furthermore, not only does the\nclinical spectrum of the disease and its functional conse-\nquences vary widely but there is also a wide inter- and\nintra-familial variability in the severity of symptoms [5–8].\nIts prevalence is classically estimated at 1 in 5000 [1]\nbut may be higher according to recent debate about the\noverlap with JHS reaching 0.75 –2 % [7]. hEDS affects\nwomen more often than men [6,8].\nPrevious studies have found an increase in abnormal\nbleeding, dyspareunia and dysmenorrhea in patients with\nEDS [9–12]. Four studies have reported on the gynaecolo-\ngic and obstetric outcomes in women with both JHS,\nhEDS and other EDS types with some discrepancies on\nthe prevalence of gynecologic complaint, spontaneous\nabortion and obstetrical outcomes [9 –14]. This can be\ndue to pooling different types of EDS in the analysis and\ngetting the information through a self-declaring question-\nnaire. Indeed the last largest study published was based on\nan email questionnaire with no clinical validation [14].\nWe were therefore interested in conducting a study to\nevaluate the prevalence of gynecologic disorders and the\nimpact on obstetric outcome using a standardized ques-\ntionnaire during a medical consultation taking advantage\nof a large cohort of women with hEDS. Because of con-\ntroversial reports on the role of estrogen and progestins\nin hyperlaxity we also thought it would be interesting to\nexplore whether hormonal factors play a role in the\nfluctuating symptoms of hEDS [15] .\nMethods\nThe aim of this cohort study was to describe the\ngynecologic symptoms and the obstetric history of a series\nof women with hEDS. We also explored whether hEDS\nsymptoms were sensitive to the hormonal environment.\n1. Patients\nhEDS is a clinical diagnosis with no confirmatory test\navailable. Hence, all women had been clinically assessed\nat least once by a single national expert in hEDS\nbetween May 2012 and December 2014 then hEDS\nwomen were sent to a consultation in Gynecology and\nincluded. All had been formally diagnosed as having\nhEDS as previously published [16–18]. The diagnosis\nwas based on actual or previous hypermobility, joint\ninstability, chronic pain, skinabnormalities and several\nother criteria as chronic fatigue, proprioceptive\ndisorders, dysautonomia, migraines, digestive disorders.\nAlmost all patients had a family history of hEDS with\nvariability in severity of clinical symptoms among\nrelatives.\n2. Methods\nA standardized original questionnaire was completed\nduring the patient consultation.\nThe questionnaire included questions about:\n– hEDS symptoms, luxation, joint pain, fatigue,\nheadache/migraine and digestive disorders.\n– Gynecologic symptomatology, throughout the\nreproductive life and at the time the\nquestionnaire was administered, including\ndysmenorrhea, metrorrhagia, menorrhagia\n(menstruation > 7 days, or > 5 sanitary napkins/\nday) and dyspareunia.\n– Gestation and parity, pregnancy outcomes and\ndeliveries.\nThe influence of hormones was evaluated by asking\nthe women about changes in the severity of their\npredominant hEDS symptoms (chronic pain and\nfatigue) (worsening, no effect, or improvement)\nduring puberty, while taking hormonal\ncontraceptives, during pregnancy, the postpartum\nperiod, and menopause.\nA gynecologic examination was performed for each\npatient by a senior gynecologist (A.G). In cases of a\nclinical suspicion of endometriosis (dysmenorrhea,\ndeep dyspareunia, or pelvic nodules found during\nphysical examination) or severe menorrhagia/\ndyspareunia, a pelvic sonogram and, if necessary,\nmagnetic resonance imaging (MRI) were performed\nby an experienced radiologist.\nIn our cohort, hemostatic disorders were\nsystematically ruled out in women presenting with\nmenorrhagia or hemorrhagic disorders.\n3. Statistical analyses\nStatistical analysis used procedures available in SAS\nsoftware (SAS Institute, Inc., Cary, NC). The student\nt-test and the χ2 test were used to assess the\ndifferences in characteristics of women between two\nhEDS groups (not influenced by menstruation and\ninfluenced by menstruation). Data are given as\npercentage, mean and standard deviation (SD).\nA p value of 0.05 was taken to represent statistical\nsignificance.\nResults\nOverall, 386 women were included for analysis. The general\ncharacteristics of the population are described in T able 1.\nThe hEDS symptoms were predominantly luxation in\n86 % of women, joint pain in 96 %, fatigue in 92 % and\ndigestive disorders in 90 %.\nBleeding disorders were the most prominent\ngynecologic symptoms (Table 2). Menorrhagia was\nreported by 76 % of the women with an incidence\nwhich did not vary according to age in premeno-\npausal women ( p =0 . 9 ) .\nHugon-Rodin et al. Orphanet Journal of Rare Diseases  (2016) 11:124 Page 2 of 6\n\nDysmenorrhea was present in 72.8 % of the women\n(Table 2). The frequency of dysmenorrhea did not vary\nsignificantly with age (81 % of the women under 20 years,\n74 % of those between 30 and 40 years and 67 % of\nthose above 40 years; p = 0.1). Among the 369 women\nwho had experienced sexual intercourse, severe dyspar-\neunia was reported by 61 %.\nEndometriosis was diagnosed in 6 % of the women.\nThis percentage includes patients with a history of\nsurgical procedures for suspicion of endometriosis and\nthose for whom a clinical examination and/or a pelvic\nsonogram/MRI was performed.\nObstetric outcomes\nIn the study population, there were 747 pregnancies for\n225 women. The average number of pregnancies per\nwoman was 2.3 ± 2.3, with the average number of deliver-\nies being 1.4 ± 1.4. Of these, 441 deliveries were achieved\nin 196 women. Spontaneous abortions were frequent,\noccurring in 28 % of pregnancies. Forty-five percent of the\nwomen had experienced at least one abortion; recurrent\nabortion (defined as ≥3 abortions with the same partner)\noccurred in 13 % of the women. Recurrent abortions were\nnot consecutive, with live births occurring in most of the\nwomen (87 %). Eighty-five percent of the recurrent abor-\ntions occurred before the age of 40. The mean age for the\nlast abortion was 25.9+/−5.9 years.\nThe majority of the pregnancies followed a favourable\ncourse with severe complications occurring in a limited\nnumber of cases. Twenty-six of the deliveries (6.2 %)\nwere preterm (i.e., before 37 weeks of amenorrhea).\nDespite increased bleeding symptoms in these patients,\nonly 4.8 % of the births were complicated with postpartum\nhaemorrhage. Similarly, despite skin fragility, only 2.4 % of\ndeliveries were complicated with severe vaginal tears.\nCesarean section was performed in 14.6 % of births.\nInfluence of reproductive life on hEDS\nOut of 70.4 % of the women who had experienced symp-\ntoms of hEDS before the onset of puberty, 52 % associ-\nated puberty with a worsening of the symptoms. The\nonset of hEDS symptoms coincided with puberty in\n16.9 % of the cohort. Overall then, 51.5 % of the\npopulation reported that puberty had a deleterious\ninfluence: those for whom puberty was associated with a\nworsening of the symptoms and those for whom puberty\nmarked the onset of symptoms.\nIn the whole cohort, 162 women (42 %) had used\ncombined hormonal contraceptives (CHC), for an\naverage duration of 8.8 ± 7.6 years. Progestin-only\ncontraceptives (POP) in the form of a low-dose mini pill\nor antigonadotropic agents at higher doses had been\nprescribed for medical indications (e.g., menorrhagia,\ndysmenorrhea, benign uterine conditions or due to a\ncontraindication to CHC) in 67 women (17 %). An\nimprovement in hEDS symptoms was reported by\n13.6 % of the women using CHC and 25.4 % of those\nusing POP , (p = 0.03) (OR, 0.46 [CI 95 %, 0.23 –0.94]).\nhEDS symptoms worsened for 26 % of the women during\npregnancy and for 37.6 % during the postpartum period.\nOverall, 16.8 % of the women included in the study\nwere postmenopausal. Among these, 22 % reported an\nimprovement in their symptoms after menopause.\nMenopausal hormone therapy (MHT) had been used by\n41.5 % of these patients for a mean duration of 6.8 ±\n5.5 years. Four of these patients observed an improve-\nment in their hEDS symptoms as a result of MHT.\nSub-analysis of the women who experienced cyclic effect\non chronic pain and fatigue\nOver one-third of the women ( n =1 3 3 ) e x p e r i e n c e d a\nworsening of symptoms during each perimenstrual period.\nWe carried out a sub-analysis of these women, to\ndetermine whether they were also affected by puberty,\nCHC or pregnancy compared to those women who\nreported no cyclic influence ( n = 197). There was no\ndifference among the two groups in terms of age at diag-\nnosis, age at onset of symptoms, number of pregnancies\nor CHC duration of use.\nSeventy-eight (59 %) of the women reporting cyclic\nvariations ( p = 0.01) (Table 3) reported that their symp-\ntoms began or worsened at puberty. CHC use was asso-\nciated with a significant worsening of symptoms among\nTable 1 General characteristics of the hEDS population (n =3 8 6 )\nAge at inclusion [mean (SD); in years] 37.8 (14.1)\nAge at diagnosis [mean (SD); in years] 35.3 (14.2)\nAge at first symptoms [mean (SD); in years] 12.5 (11.8)\nAge at puberty [mean (SD); in years] 12.5 (1.7)\nhEDS symptoms\nJoint pain (%) 370 (96)\nFatigue (%) 353 (92)\nLuxation (%) 333 (86)\nDigestive disorders (%) 345 (90.1)\nMigraine and headache (%) 289 (75.5)\nTable 2 Gynecological symptoms and prevalence of\nendometriosis\nSymptoms n (%)\nMenorrhagia 292 (76)\nMetrorrhagia 83 (22)\nDysmenorrhea 278 (72)\nDeep dyspareuniea 118 (38)\nIntromission dyspareuniea 148 (43)\nEndometriosis 20 (6)\nHugon-Rodin et al. Orphanet Journal of Rare Diseases  (2016) 11:124 Page 3 of 6\n\npatients with menstrual aggravation. One-fourth of the\nwomen whose symptoms were influenced by menstru-\nation stated that their symptoms were modified when\ntaking CHC, in contrast with only 5.6 % in the group\nwhose hEDS symptoms were uninfluenced ( p = 0.001)\n(Table 3). Furthermore, women experiencing cyclic mod-\nulations also experienced worsened symptoms during\nthe postpartum period ( p = 0.05).\nDiscussion\nThis study describing the gynaecologic and obstetric\nsymptoms in a large cohort of women with hEDS\nsuggests that most women experience significant gynae-\ncologic symptoms and that few severe complications\noccur during pregnancy. In addition, this is the first\nstudy to describe the impact of reproductive life on\nhEDS clinical outcomes.\nAbnormal bleeding, dysmenorrhea and dyspareunia\nwere the most common gynecologic complaints in our\nhEDS population. Dysmenorrhea was not correlated\nwith age and did not improve after deliveries contrary to\nwhat is observed with idiopathic dysmenorrhea [19]. A\nrecent comprehensive literature review reported that\nsevere dysmenorrhea affected between 2 and 29 % of\nwomen and that dysmenorrhea was negatively associated\nwith women ’s age and parity [20]. Easy bruising and\nbleeding are frequently described in EDS, a result of\nweakness in the capillaries and perivascular connective\ntissue rather than from hemostatic dysfunction [11]. The\nsexual life of these women is also adversely affected by a\nhigh incidence of dyspareunia. Previous studies have also\nfound an increase in abnormal bleeding, dyspareunia\nand dysmenorrhea in patients with EDS [9, 10, 13, 14].\nThe two last publications have selectively reported on\nthe gynaecologic and obstetric outcomes in patients with\nhEDS/JHS. The first involved 82 women in Italy with 93\npregnancies [10] and the second study included about\n770 women with both hypermobility type and other EDS\ntypes as well based on an email questionnaire with no\nclinical validation [9]. Both studies reported similar\nprevalence of dysmenorrhea and dyspareunia in women\nwith hEDS/JHS than in our population. The combin-\nation of these symptoms is highly suggestive of\nendometriosis. The rate of endometriosis we found was\nthe same as that for the general population (3 –6 %) and\nmuch less than in women with chronic pain [21]. While\nit is possible that we underestimated the frequency of\nendometriosis because we did not perform systematic\nlaparoscopy, we suggest that endometriosis may be over-\ndiagnosed in hEDS patients because of reports of\nchronic pain and bleeding. A systematic study would\nnevertheless be interesting to evaluate the prevalence of\nadenomyosis at a young age in women with EDS as it\nmay play a role in the high risk of spontaneous abortion.\nA previous study, which also used a questionnaire, found\na 15 % prevalence of reported endometriosis [9]. A 22 %\nprevalence of endometriosis among women with\nsuspected infertility was reported by women with EDS\nfrom an emailed questionnaire which did not allow to\nvalidate the diagnosis of endometriosis. In our patient\npopulation, the conception rate was close to that for\nwomen in France in general (fertility rate: 1.8 –2.03\nbetween 1980 and 2013 [22]). This finding further\nargues against the hypothesis of an abnormally high\nprevalence of endometriosis in this population. However,\nwhile the rate of conception in our population was similar\nto the normal range, the rate of spontaneous abortions\nwas higher than in the general population (28 % versus\nabout 20 %, respectively). Furthermore, the rate of\nmultiple abortions was much higher in our population\nthan in the French population as a whole (13 % versus\nabout 1 %, respectively) [23]. The cause of the miscar-\nriages is unclear. An increased contractility of the uterus\nor a fragile cervix, related to the connective tissue defect\nand dysautonomic syndrome could be a cause [24]. An-\nother possible explanation could be implantation defects.\nOne novel aspect of our study is the relationship\nbetween hEDS symptoms and reproductive life. It is sig-\nnificant that estradiol receptors are present in many of\nthe body structures and organs including joints, skin,\nand cartilage. Puberty does appear to significantly ex-\nacerbate symptoms. This may result either from the\nrapid growth that is characteristic of this time in life —\nand that significantly affects skin, joints and muscle-\ns—and/or to the rapid increase in estrogen secretion. In\nthe subset of patients who deteriorate during the\nTable 3 The influence of hormones on hEDS symptoms (hEDS symptoms: chronic pain, fatigue)\nhEDS patients not influenced by menstruation\nn = 197 (%)\nhEDS patients influenced by menstruation\nn = 133 (%)\np\nInfluenced by puberty 85/197 (43.2) 79/133 (58.7) 0.01\nImpact of CHC\nWorsened on CHC 5/90 (5.6) 15/58 (25.9) 0.001\nImproved on CHC 12/90 (13.3) 9/58 (15.5)\nUnchanged on CHC 73/90 (81.1) 34/58 (58.6)\nImproved by menopause 6/33 (18.2) 3/17 (17.7) NS\nHugon-Rodin et al. Orphanet Journal of Rare Diseases  (2016) 11:124 Page 4 of 6\n\nperimenstrual period, CHC was also correlated with an\nincrease in symptoms. Our analysis of contraception\nsuggests that, in some women at least, the hEDS symp-\ntoms responsible for increased disability might improve\nwith the use of POP. Our findings suggest that, when\nmenstrual disorders are treated and alleviated either by\nCHC or by POP , EDS symptoms improve and women\nreport less fatigue. In the literature, there is conflicting\ndata as to the effects of hormones on connective tissue,\njoint laxity and tendons. It has been demonstrated that\nestradiol decreases the formation of collagen in tendons\nfollowing exercise [25]. Joint laxity increases during\npregnancy in some women. Another smaller study found\nincreased knee laxity during ovulation compared with the\nluteal phase, but no significant changes during the phases\nof the menstrual cycle [26]. A prospective trial would be\nuseful to determine the precise nature of the role of estro-\ngens and progestins on various symptoms of hEDS.\nThis study also reveals that the prevalence of obstetric\ncomplications is not substantially greater compared to\nthe healthy population and lower [27] in comparison\nwith the previously mentioned large, recently-published\nstudy [14]. This discrepancy may result from the differ-\nent methodologies used in the two studies, or from a\ndifference in the protocols for management of pregnan-\ncies from one country to another. Indeed, the Italian\nstudy fitted more with our results with 10.7 % preterm\ndeliveries; we agree with these authors than caesarean\nsection is not indicated systematically in women with\nhEDs and was performed only in 14 % of our patients.\nStrengths and weaknesses of this study\nStrengths\nThe cohort used in this study is quite large for a rare\ndisease. The standardized questionnaire was filled out\nface to face with the patient; and the medical reports\nwere validated and corroborated by a medical\nexamination performed by a senior gynaecologist\ntrained in the diagnosis of endometriosis. This offers a\nstronger basis for validation of symptoms than the\nstudy carried out by Hurst et al.[ 14] in which\ninformation was gathered via email.\nWeaknesses\nMuch of the data was gathered from patients ’\nrecollection of past events and the information is\ntherefore subject to recall bias. However, the\ngynaecologic symptoms (menorrhagia, dysmenorrhea\nand dyspareunia) persisted at the time of the\nconsultation and could be evaluated more accurately.\nConclusion\nWomen affected by hEDS present significant gynaecolo-\ngic symptoms that are often are disabling, such as\nmenorrhagia, dysmenorrhea, deep and intromission dys-\npareunia. Endometriosis may be incorrectly diagnosed\non the basis of these symptoms, thereby leading to in-\nappropriate treatment. The obstetric outcomes were\nmostly reassuring in this population. Furthermore, hor-\nmones may play a modulatory effect in this syndrome,\nand their influence merits further study.\nAbbreviations\nCHC: Combined hormonal contraception; EDS: Ehlers Danlos syndrome;\nhEDS: Hypermobile type Ehlers Danlos syndrome; JHS: Joint hypermobile\nsyndrome; MHT: Menopausal hormone therapy; MRI: Magnetic resonance\nimaging; POP: Progestin-only contraceptives\nAcknowledgements\nWe thank Isabelle Brock, Margarida Gilger and Felicity Nelson for their\nexcellent help in editing the manuscript.\nFunding\nNone.\nAvailability of data and materials\nIf requested a data base on excel, anonymous can be provided.\nAuthors’ contributions\nGL and SB collected the data and contributed to write the first draft and\nagreed with the last version, JHR interpreted the data, performed the\nstatistical analysis and wrote the manuscript, AG saw all the patients, filled in\nthe questionnaire, was involved in its conception, directed the study and\ncorrected the manuscript, CH selected the patients, established the\ndiagnosis, was involved in the writing of the manuscript. All authors read\nand approved the final manuscript.\nCompeting interests\nThe authors declare that they have no competing interests.\nConsent for publication\nNot applicable.\nEthics approval and consent to participate\nThis study was approved by the French National Commission for Data\nProtection ( Commission Nationale Informatique et Libertés ). All patients were\nfully informed according to the appropriate French Ethics Law and provided\nwritten consent.\nAuthor details\n1Unité de Gynécologie-Endocrinienne, APHP, Hôpitaux universitaires Paris\nCentre, Université Paris Descartes, Port Royal, 123 Bd de l ’Hôpital, Paris 75014,\nFrance. 2Service de médecine physique et réadaptation, APHP, Hôpitaux\nUniversitaires Paris Centre, Université Paris-Est Créteil, Hôtel Dieu, Place Jean\nXXIII, Paris 75004, France.\nReceived: 15 July 2016 Accepted: 6 September 2016\nReferences\n1. Beighton P, De Paepe A, Steinmann B, Tsipouras P, Wenstrup RJ. Ehlers-\nDanlos syndromes: revised nosology, Villefranche, 1997. Ehlers-Danlos\nNational Foundation (USA) and Ehlers-Danlos Support Group (UK). Am J\nMed Genet. 1998;77(1):31 –7.\n2. Tinkle BT, Bird HA, Grahame R, Lavallee M, Levy HP, Sillence D. The lack of\nclinical distinction between the hypermobility type of Ehlers-Danlos\nsyndrome and the joint hypermobility syndrome (a.k.a. hypermobility\nsyndrome). Am J Med Genet A. 2009;149A(11):2368 –70.\n3. Castori M, Morlino S, Ghibellini G, Celletti C, Camerota F, Grammatico P.\nConnective tissue, Ehlers-Danlos syndrome(s), and head and cervical pain.\nAm J Med Genet C Semin Med Genet. 2015;169C(1):84 –96.\n4. Castori M, Sperduti I, Celletti C, Camerota F, Grammatico P. Symptom and\njoint mobility progression in the joint hypermobility syndrome (Ehlers-\nHugon-Rodin et al. Orphanet Journal of Rare Diseases  (2016) 11:124 Page 5 of 6\n\nDanlos syndrome, hypermobility type). Clin Exp Rheumatol.\n2011;29(6):998–1005.\n5. Hakim et grahame, Nosology and inheritance pattern(s) of joint\nhypermobility syndrome and Ehlers-Danlos syndrome, hypermobility type: a\nstudy of intrafamilial and interfamilial variability in 23 Italian pedigrees.\nCastori M, Dordoni C, Valiante M, Sperduti I, Ritelli M, Morlino S, Chiarelli N,\nCelletti C, Venturini M, Camerota F, Calzavara-Pinton P, Grammatico P,\nColombi M. Am J Med Genet A. 2014 Dec;164A(12):3010 –20.\n6. Castori M, Dordoni C, Valiante M, Sperduti I, Ritelli M, Morlino S, et al.\nNosology and inheritance pattern(s) of joint hypermobility syndrome and\nEhlers-Danlos syndrome, hypermobility type: A study of intrafamilial and\ninterfamilial variability in 23 Italian pedigrees. Am J Med Genet A.\n2014;164(12):3010–20.\n7. Hakim AJ, Sahota A. Joint hypermobility and skin elasticity: the hereditary\ndisorders of connective tissue. Clin Dermatol. 2006;24(6):521 –33.\n8. Malfait F, Hakim AJ, De Paepe A, Grahame R. The genetic basis of the joint\nhypermobility syndromes. Rheumatol Oxf Engl. 2006;45(5):502 –7.\n9. Sorokin Y, Johnson MP, Rogowski N, Richardson DA, Evans MI. Obstetric and\ngynecologic dysfunction in the Ehlers-Danlos syndrome. J Reprod Med.\n1994;39(4):281–4.\n10. Castori M, Morlino S, Dordoni C, Celletti C, Camerota F, Ritelli M, et al.\nGynecologic and obstetric implications of the joint hypermobility syndrome\n(a.k.a. Ehlers-Danlos syndrome hypermobility type) in 82 Italian patients. Am\nJ Med Genet A. 2012;158A(9):2176 –82.\n11. Malfait F, De Paepe A. Bleeding in the heritable connective tissue disorders:\nmechanisms, diagnosis and treatment. Blood Rev. 2009;23(5):191 –7.\n12. Jackson SC, Odiaman L, Card RT, van der Bom JG, Poon M-C. Suspected\ncollagen disorders in the bleeding disorder clinic: a case-control study.\nHaemoph Off J World Fed Hemoph. 2013;19(2):246 –50.\n13. Mcintosh LJ, Mallett VT, Frahm JD, Richardson DA, Evans MI. Gynecologic\ndisorders in women with Ehlers-Danlos syndrome. J Soc Gynecol Investig.\n1995;2(3):559–64.\n14. Hurst BS, Lange SS, Kullstam SM, Usadi RS, Matthews ML, Marshburn PB, et\nal. Obstetric and gynecologic challenges in women with Ehlers-Danlos\nsyndrome. Obstet Gynecol. 2014;123(3):506 –13.\n15. Heitz NA, Eisenman PA, Beck CL, Walker JA. Hormonal changes throughout\nthe menstrual cycle and increased anterior cruciate ligament laxity in\nfemales. J Athl Train. 1999;34(2):144 –9.\n16. Zeitoun J-D, Lefèvre JH, de Parades V, Séjourné C, Sobhani I, Coffin B, et al.\nFunctional digestive symptoms and quality of life in patients with Ehlers-\nDanlos syndromes: results of a national cohort study on 134 patients. PLoS\nOne. 2013;8(11):e80321.\n17. Guilleminault C, Primeau M, Chiu H-Y, Yuen KM, Leger D, Metlaine A. Sleep-\ndisordered breathing in Ehlers-Danlos syndrome: a genetic model of OSA.\nChest. 2013;144(5):1503–11.\n18. Hamonet C, Frédy D, Lefèvre JH, Bourgeois-Gironde S, Zeitoun J-D. Brain\ninjury unmasking Ehlers-Danlos syndromes after trauma: the fiber print.\nOrphanet J Rare Dis. 2016;11:45.\n19. Sundell G, Milsom I, Andersch B. Factors influencing the prevalence and\nseverity of dysmenorrhoea in young women. Br J Obstet Gynaecol.\n1990;97(7):588–94.\n20. Ju H, Jones M, Mishra G. The prevalence and risk factors of dysmenorrhea.\nEpidemiol Rev. 2014;36:104 –13.\n21. Janssen EB, Rijkers ACM, Hoppenbrouwers K, Meuleman C, D ’Hooghe TM.\nPrevalence of endometriosis diagnosed by laparoscopy in adolescents with\ndysmenorrhea or chronic pelvic pain: a systematic review. Hum Reprod\nUpdate. 2013;19(5):570 –82.\n22. Indicateur conjoncturel de fécondité [Internet]. Ined - Institut national\nd’études démographiques. 2016 [cited 2016 Jan 6]. Available from: https://\nwww.ined.fr/fr/tout-savoir-population/chiffres/europe-pays-developpes/\nindicateurs-fecondite/\n23. Berkane N, Fiori O, Uzan S. Bilan à réaliser devant des fausses couches à\nrépétition du premier trimestre. In: mises à jour en gynécologie et\nobstétrique. 2006. p. 127 –42. http://www.cngof.asso.fr/d_livres/2006_GO_\n127_berkane.pdf.\n24. De Wandele I, Calders P, Peersman W, Rimbaut S, De Backer T, Malfait F, et al.\nAutonomic symptom burden in the hypermobility type of Ehlers-Danlos\nsyndrome: a comparative study with two other EDS types, fibromyalgia, and\nhealthy controls. Semin Arthritis Rheum. 2014;44(3):353–61.\n25. Hansen M, Kongsgaard M, Holm L, Skovgaard D, Magnusson SP, Qvortrup K,\net al. Effect of estrogen on tendon collagen synthesis, tendon structural\ncharacteristics, and biomechanical properties in postmenopausal women. J\nAppl Physiol Bethesda Md 1985. 2009;106(4):1385 –93.\n26. Park S-K, Stefanyshyn DJ, Loitz-Ramage B, Hart DA, Ronsky JL. Changing\nhormone levels during the menstrual cycle affect knee laxity and stiffness in\nhealthy female subjects. Am J Sports Med. 2009;37(3):588 –98.\n27. HAS, http://www.has-sante.fr/portail/upload/docs/application/pdf/2010-10/\nmesure_de_la_longueur_du_col_de_luterus_par_echographie_\nendovaginale_-_document_davis.pdf.\n•  We accept pre-submission inquiries \n  Our selector tool helps you to find the most relevant journal\n  We provide round the clock customer support \n  Convenient online submission\n  Thorough peer review\n  Inclusion in PubMed and all major indexing services \n  Maximum visibility for your research\nSubmit your manuscript at\nwww.biomedcentral.com/submit\nSubmit your next manuscript to BioMed Central \nand we will help you at every step:\nHugon-Rodin et al. Orphanet Journal of Rare Diseases  (2016) 11:124 Page 6 of 6","source_license":"CC0","license_restricted":false}